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id="_NBK577084_"><span itemprop="name">Evidence review for spasticity</span></h1><div class="subtitle">Cannabis-based medicinal products</div><p><b>Evidence review C</b></p><p><i>NICE Guideline, No. 144</i></p><div class="half_rhythm">London: <a href="https://www.nice.org.uk" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=publisher"><span itemprop="publisher">National Institute for Health and Care Excellence (NICE)</span></a>; <span itemprop="datePublished">2019 Nov</span>.<div class="small">ISBN-13: <span itemprop="isbn">978-1-4731-3578-9</span></div></div><div><a href="/books/about/copyright/">Copyright</a> © NICE 2019.</div></div><div class="bkr_clear"></div></div><div id="ch3.s1"><h2 id="_ch3_s1_">Effectiveness of cannabis-based medicinal products for the treatment of spasticity</h2><div id="ch3.s1.1"><h3>Introduction</h3><p>Spasticity is a specific form of increased muscle tone (hypertonia) associated with a number of neurological disorders. The prevalence of lower limb spasticity reported in a <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905098/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">systematic review</a> was 28–37% in people with stroke, 41–69% in people with multiple sclerosis, 13% in people with traumatic brain injury and 75% moderate-severe spasticity in people with cerebral palsy. The impact of spasticity and co-existing disorders on the individual varies. Common problems include motor developmental delay (in children), pain from muscle spasms, impaired motor function affecting the person’s ability to participate in society, and difficulties with daily care due to the onset of secondary complications of spasticity. Management should be tailored to meet the problems faced by the individual and achieve their goals.</p><p>The NICE guidelines on <a href="https://www.nice.org.uk/guidance/cg145" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Spasticity in under 19s</a>, <a href="https://www.nice.org.uk/guidance/cg186" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Multiple sclerosis</a>, <a href="https://www.nice.org.uk/guidance/ng119" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Cerebral palsy in adults</a>, <a href="https://www.nice.org.uk/guidance/ng119" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Cerebral palsy in under 25s</a> and <a href="https://www.nice.org.uk/guidance/ng42" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Motor neurone disease</a>, include recommendations on how to manage spasticity in these conditions.</p><p>The aim of this review is to examine the effectiveness of cannabis-based medicinal products (CBMP) for people with spasticity. This review also aims to identify adverse events, complications and contraindications associated with the use of CBMP. Additionally, this review will examine individual patient requirements, treatment durations, reviewing and stopping criteria with the use of CBMP.</p><div id="ch3.s1.1.1"><h4>Review question</h4><p>What is the clinical and cost effectiveness of cannabis-based medicinal products for people with spasticity?</p><p>What are the adverse effects or complications of cannabis-based medicinal products for people with spasticity?</p><p>What are the contraindications, potential interactions and risks and cautions for use of cannabis-based medicinal products for people with spasticity?</p><p>What are the individual patient monitoring requirements, treatment durations, reviewing and stopping criteria, including how should treatment be withdrawn or stopped, for use of cannabis-based medicinal products for people with spasticity?</p><p>The review protocol for this review question is in <a href="#ch3.appa">Appendix A</a>. The PICO table below formed part of the search strategy to identify studies associated with spasticity.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3tab1"><a href="/books/NBK577084/table/ch3.tab1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figch3tab1" rid-ob="figobch3tab1"><img class="small-thumb" src="/books/NBK577084/table/ch3.tab1/?report=thumb" src-large="/books/NBK577084/table/ch3.tab1/?report=previmg" alt="Table 1. PICO table." /></a><div class="icnblk_cntnt"><h4 id="ch3.tab1"><a href="/books/NBK577084/table/ch3.tab1/?report=objectonly" target="object" rid-ob="figobch3tab1">Table 1</a></h4><p class="float-caption no_bottom_margin">PICO table. </p></div></div></div></div><div id="ch3.s1.2"><h3>Methods and process</h3><p>This evidence review was developed using the methods and process described in <a href="https://www.nice.org.uk/process/pmg20/chapter/introduction-and-overview" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Developing NICE guidelines: the manual</a>
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<u>(2018)</u>. A review protocol was developed to encompass the 4 review questions around effectiveness, adverse events, contraindications and monitoring requirements. This review protocol can be found in <a href="#ch3.appa">Appendix A</a>. Methods specific to the review questions are described in the review protocol in <a href="#ch3.appb">Appendix B</a>.</p><p>Declarations of interest were recorded according to <a href="https://www.nice.org.uk/Media/Default/About/Who-we-are/Policies-and-procedures/declaration-of-interests-policy.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NICE’s 2018 conflicts of interest policy</a>.</p><p>A broad search strategy was used to identify all studies that examined the effectiveness of cannabis-based medicinal products (CBMP) in the treatment of intractable nausea and vomiting, chronic pain, spasticity and severe treatment-resistant epilepsy. Review protocol highlighted in <a class="figpopup" href="/books/NBK577084/table/ch3.tab1/?report=objectonly" target="object" rid-figpopup="figch3tab1" rid-ob="figobch3tab1">Table 1</a> and <a href="#ch3.appa">Appendix A</a> was used to identify studies associated with spasticity.</p><p>For the adult population, randomised controlled trials (RCTs) and systematic review of RCTs were considered. The committee noted that a minimum of 5 RCTs were required to provide adequate evidence. If fewer than 5 RCTs were identified, prospective cohort studies would also be considered for inclusion.</p><p>For children, RCTs and systematic reviews of RCTs were considered. The review protocol also specified that in the event of fewer than 5 RCTs being identified, prospective and retrospective cohort studies would also be considered for inclusion.</p><p>Additional information on safety concerns and contraindications will be obtained from the Summary of Product Characteristics and other relevant sources, such as the U.S Food and Drugs Administration.</p><p>Studies were also excluded if they examined the use of:
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<ul id="ch3.l5"><li id="ch3.lt19" class="half_rhythm"><div>Synthetic cannabinoids in schedule 1 of the 2001 regulations,</div></li><li id="ch3.lt20" class="half_rhythm"><div>Smoked cannabis-based products</div></li></ul></p><p>The review protocol also specifies that where possible, subgroup analyses would be conducted to explore the effectiveness of cannabis-based medicinal products in young people, children and babies, pregnant women and women who are breastfeeding, people with existing substance abuse and people with hepatic and renal failure.</p><p>For THC:CBD spray (THC:CBD spray), some studies used a dose greater than the maximum 12 sprays per day recommended in the product SPC. As the higher doses could have a different level of effectiveness or number of adverse events, the results for THC:CBD spray were split into subgroups: those within the recommended dose and those above the recommended dose. Two of the studies that used a dose within that recommended by the SPC were enriched enrolment trials. This design split the trials into two phases: Phase A where all participants were given THC: CBD spray and Phase B (RCT phase) where only those participants who responded to the treatment were included. This study design may result in more favourable outcomes for the intervention and fewer cases of adverse events. As a result, the studies that used an enriched enrolment design were highlighted in the forest plots and brought to the attention of the committee while they were discussing the evidence. There was not a large evidence base for any of the CBMP for spasticity and so it was decided not to group the results by length of follow-up period.</p><p>Some results were presented as the least squares mean. These results were included in the meta-analysis and a sensitivity analysis was used to assess their impact on the outcomes. Sensitivity analysis revealed that none of the least squares means changed the outcomes of the meta-analyses and so the results were included. Any results that were presented as least squares means have been identified in the footnotes of relevant forest plots.</p></div><div id="ch3.s1.3"><h3>Clinical evidence</h3><p>The overall search for evidence of effectiveness of cannabis-based medicinal products for spasticity, nausea and vomiting, severe treatment resistant epilepsy and chronic pain returned a total of 19,491 results. After removing duplicates, 9,341 references were screened on their titles and abstracts. 75 studies were obtained for treatment of spasticity and reviewed against the inclusion criteria as described in the review protocol for spasticity (<a href="#ch3.appa">Appendix A</a>). Overall, 15 RCTs (12 parallel and 3 crossover) were included (see <a href="#ch3.appe">Appendix E</a> for evidence tables). The effectiveness and safety of CBMP was investigated for people with spasticity related to multiple sclerosis (13 studies), motor neurone disease (2 studies) and spinal cord injury (1 study). All studies investigated spasticity in adults (see <a class="figpopup" href="/books/NBK577084/table/ch3.tab2/?report=objectonly" target="object" rid-figpopup="figch3tab2" rid-ob="figobch3tab2">Table 2</a>). No studies were identified for any of the subgroup analyses. Observational studies were also incorporated into the literature search and no paediatric studies were identified.</p><p>See <a href="#ch3.appe">Appendix E</a> for evidence tables and <a href="#ch3.appn">Appendix N</a> for excluded studies.</p><div id="ch3.s1.3.1"><h4>Quality assessment of clinical studies included in the evidence review</h4><p>In this review, parallel RCTs and crossover RCTs were identified. The quality of the evidence was initially graded as high. Most of the evidence identified was for the use of CBMP for people with multiple sclerosis. For crossover studies, the committee identified 1 week as an adequate washout period.</p><p>See <a href="#ch3.apph">Appendix H</a> for full GRADE tables and <a href="#ch3.appf">Appendix F</a> for forest plots in situations where data have been meta-analysed.</p></div><div id="ch3.s1.3.2"><h4>Interventions</h4><p>Of the 15 studies included, 12 studies looked at management of spasticity in multiple sclerosis, 2 studies looked at spasticity in motor neurone disease and 1 investigated spasticity resulting from spinal cord injury. The included studies looked at the following interventions:
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<ul id="ch3.l6"><li id="ch3.lt21" class="half_rhythm"><div>Tetrahydrocannabinol: Cannabidiol (THC: CBD) spray</div></li><li id="ch3.lt22" class="half_rhythm"><div>THC capsules (synthetic THC)</div></li><li id="ch3.lt23" class="half_rhythm"><div>THC capsules (cannabis extract)</div></li><li id="ch3.lt24" class="half_rhythm"><div>Nabilone</div></li></ul></p><p>At the time of writing this evidence review, with the exception of THC:CBD spray (Sativex), most CBMP such as tetrahydrocannabinol (a schedule 2 controlled drug) did not have a UK marketing authorisation for treating spasticity. Although Sativex has UK authorisation for the treatment of spasticity it does not currently have UK marketing authorisation for either motor neurone disease or spinal cord injury.</p></div><div id="ch3.s1.3.3"><h4>Summary of clinical studies included in the evidence review</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3tab2"><a href="/books/NBK577084/table/ch3.tab2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figch3tab2" rid-ob="figobch3tab2"><img class="small-thumb" src="/books/NBK577084/table/ch3.tab2/?report=thumb" src-large="/books/NBK577084/table/ch3.tab2/?report=previmg" alt="Table 2. summary of included adult studies." /></a><div class="icnblk_cntnt"><h4 id="ch3.tab2"><a href="/books/NBK577084/table/ch3.tab2/?report=objectonly" target="object" rid-ob="figobch3tab2">Table 2</a></h4><p class="float-caption no_bottom_margin">summary of included adult studies. </p></div></div><p>See <a href="#ch3.appe">Appendix E</a> for evidence tables and <a href="#ch3.appi">Appendix I</a> for further information on adverse events.</p><p>As part of this evidence review, in addition to reviewing efficacy and safety data, studies were reviewed for information about patient monitoring and reviewing and stopping criteria when cannabis-based medicinal products were prescribed.</p><p>The interventions, doses, monitoring and stopping criteria are summarised in <a class="figpopup" href="/books/NBK577084/table/ch3.tab3/?report=objectonly" target="object" rid-figpopup="figch3tab3" rid-ob="figobch3tab3">tables 4</a> and <a class="figpopup" href="/books/NBK577084/table/ch3.appm.tab4/?report=objectonly" target="object" rid-figpopup="figch3appmtab4" rid-ob="figobch3appmtab4">5</a> below:</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3tab3"><a href="/books/NBK577084/table/ch3.tab3/?report=objectonly" target="object" title="Table 4" class="img_link icnblk_img figpopup" rid-figpopup="figch3tab3" rid-ob="figobch3tab3"><img class="small-thumb" src="/books/NBK577084/table/ch3.tab3/?report=thumb" src-large="/books/NBK577084/table/ch3.tab3/?report=previmg" alt="Table 4. summary of interventions and doses in the included studies with adult population." /></a><div class="icnblk_cntnt"><h4 id="ch3.tab3"><a href="/books/NBK577084/table/ch3.tab3/?report=objectonly" target="object" rid-ob="figobch3tab3">Table 4</a></h4><p class="float-caption no_bottom_margin">summary of interventions and doses in the included studies with adult population. </p></div></div><p>See <a href="#ch3.appe">Appendix E</a> for evidence tables.</p></div></div><div id="ch3.s1.4"><h3>Economic evidence</h3><div id="ch3.s1.4.1"><h4>Included studies</h4><p>A systematic review of the economic literature was conducted. 1,863 studies were retrieved by the search. Following review of titles and abstracts, 9 full-text studies were retrieved for detailed consideration. Two relevant cost–utility analyses were identified and included in this review.</p><p>The included studies were critically appraised using the economic evaluation checklist from NICE guideline manual 2018 <a href="#ch3.apph">Appendix H</a>.</p><div id="ch3.s1.4.1.1"><h5>THC: CBD spray plus standard of care vs. standard of care alone for the treatment of spasticity in multiple sclerosis</h5><div id="ch3.s1.4.1.1.1"><h5>
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<a class="bibr" href="#ch3.appm.ref18" rid="ch3.appm.ref18">Gras et al. 2016</a>
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</h5><p><a class="bibr" href="#ch3.appm.ref18" rid="ch3.appm.ref18">Gras et al. (2016)</a> conducted a cost-utility analysis in the UK, from the perspective of the NHS in Wales and Personal Social Services. This study was funded by the manufacturer of THC: CBD spray. The model was a Markov model comparing THC: CBD spray plus standard of care (SoC) with SoC alone for the treatment of moderate to severe spasticity in multiple sclerosis (NRS score ≥ 4, measured using the spasticity 0–10 NRS). Patients had not responded adequately to other anti-spasticity medication.</p><p>Treatment effects were taken from the pivotal trial (<a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna et al. 2011</a>), an enriched design randomised controlled trial. (n=572 at the enrichment phase, n=241 RCT phase). Patients were only included in the RCT phase of the trial if they showed a minimum 20% improvement in spasticity during the single-blind enrichment phase of the trial. The utility was measured using the EQ-5D data from the same trial.</p><p>Resource use was based on a published clinical expert survey (<a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson et al. 2015</a>), including community-based visits, outpatient clinic visits, A&E visits, hospital admissions, home care visits, equipment costs (such as wheelchairs, walking aids). The model assumed all resource use from <a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson et al. 2015</a> were attributed to spasticity alone while some of the costs might overlap with the management costs of MS patients.</p><p>Costs were taken from the Department of Health (DoH) NHS reference costs 2012–2013 and Unit costs of health and social care (PSSRU 2013).</p><p>Base care results showed that compared to SoC alone, THC: CBD spray plus SoC was £3,836 more expensive and produced 0.35 more QALYs over a 30-year time horizon. Probabilistic sensitivity analysis showed a 100% probability that THC: CBD spray plus SoC was a cost-effective strategy compared to SoC alone at the £20,000–£30,000 per QALY threshold.</p><p>Parameter uncertainty was explored on the unit cost, resource utilisation rates, resource quantities, utility values, and discount rate. The uncertainty of the transition probabilities or the discontinuations remained unclear as the model did not explore these in the sensitivity analysis.</p><p>This study was judged as directly applicable but with very serious limitations (see <a href="#ch3.appl">Appendix L</a>).</p></div><div id="ch3.s1.4.1.1.2"><h5>
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<a class="bibr" href="#ch3.appm.ref23" rid="ch3.appm.ref23">Lu et al. 2012</a>
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</h5><p><a class="bibr" href="#ch3.appm.ref23" rid="ch3.appm.ref23">Lu et al. (2012)</a> conducted a cost-utility analysis in the UK, from the UK NHS perspective. The model was a Markov model comparing Sativex (THC: CBD spray) plus standard treatment with standard treatment alone for patients with spasticity due to MS and not responding adequately to oral anti-spasticity medication.</p><p>Treatment withdrawal rates were taken from the pivotal trial (<a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna et al. 2011</a>. The utility was measured using the EQ-5D data from a conference presentation (<a class="bibr" href="#ch3.appm.ref30" rid="ch3.appm.ref30">Montalban et al. 2009</a> based on the RCT by <a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna et al. 2011</a>). The utility of response and no response were 0.57 and 048, respectively.</p><p>Resource use was based on expert opinions and only consisted of clinical visits. Costs were taken from the NHS reference costs 2009. The model assumed no other resource use associated with spasticity due to MS. Costs were taken from the NHS reference costs 2009.</p><p>Base care results showed that compared to standard treatment alone, THC: CBD spray plus standard treatment was £7,627 more expensive and produced 0.1548 more QALYs over a 5-year time horizon. Probabilistic sensitivity analysis showed a 10.2% probability that THC: CBD spray plus standard treatment was a cost-effective strategy compared to standard treatment alone at £30,000 per QALY threshold.</p><p>Parameter uncertainty was explored on the transition probabilities, utilities, THC: CBD average daily sprays, cost of clinic visits. Several scenario analyses (e.g. time horizon) were also conducted.</p><p>This study was judged as directly applicable but with potentially serious limitations (see <a href="#ch3.appl">Appendix L</a>).</p></div></div></div><div id="ch3.s1.4.2"><h4>Excluded studies</h4><p>Seven studies were excluded following the full-text review. The list of excluded studies can be found in <a href="#ch3.appj">Appendix J</a>.</p></div><div id="ch3.s1.4.3"><h4>Economic model</h4><p>A de-novo cost-utility analysis was developed for this guideline (see <a href="#ch3.appm">Appendix M</a> for full details). The analysis was a Markov model comparing the standard of care (SoC) plus cannabis to the standard of care alone over the 5-year time horizon. The target population are patients with spasticity who had not responded adequately to any standard spasticity treatment. The standard of care is defined as any interventions that would usually be used in this patient group, including licensed oral anti-spasticity medications if appropriate.</p><p>Cohorts of patients were followed from the initiation of the treatment. In the cannabis strategy, patients who did not achieve a response may discontinue cannabis. Responders remained on treatment but were subject to treatment discontinuation, after which they transitioned to the non-responder state. In the SoC strategy, the model assumed that a proportion of responders would lose the treatment benefit and become non-responders. This was modelled as discontinuation of the treatment benefit. The model assumed that all patients would always receive SoC in the background.</p><p>The treatment effects of THC: CBD spray, derived from the meta-analysis of four relevant RCTs of THC: CBD spray in patients with MS spasticity (see <a href="#ch3.appf">Appendix F</a> for details), were presented as odds ratios (ORs) compared to the placebo from the RCTs (<a class="bibr" href="#ch3.appm.ref9" rid="ch3.appm.ref9">Collin et al., 2007</a>, <a class="bibr" href="#ch3.appm.ref10" rid="ch3.appm.ref10">2010</a>; <a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna et al., 2011</a>; <a class="bibr" href="#ch3.appm.ref27" rid="ch3.appm.ref27">Markova et al., 2019</a>). The treatment response for the THC: CBD spray strategy]) was based on a large observational study (<a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina et al. 2017</a>).</p><p>Baseline characteristics of the model cohort and discontinuation in patients achieving a treatment response are based on the same observational study (N=1,597) of THC: CBD spray in multiple sclerosis spasticity. Treatment response was defined as a reduction of ≥30% on the numerical rating scale (NRS) for spasticity.</p><p>Health state utilities in the model were based on a published utility regression model of EQ-5D, spasticity NRS and EDSS (<a class="bibr" href="#ch3.appm.ref41" rid="ch3.appm.ref41">Svensson, Borg and Nilsson, 2014</a>). The committee agreed that medicinal cannabis was unlikely to have an impact on EDSS scores, but that mean EDSS should be reflected, based on their experience and published evidence. We simulated 10,000 hypothetical patients with NRS and EDSS scores based on the baseline NRS (mean 7.5; SD 1.45) and mean EDSS (mean 6.4; SD 1.2) data from <a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina et al. (2017)</a>. We used data on the patients who had improved by at least 30% from the <a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina et al. (2017)</a> dataset and estimated the proportion of patients achieving greater levels of response (for example, 45–49% response). The weighted average utility of response and no response were 0.44 and 0.288, respectively. The utility difference between response and no response was much greater compared with the ones applied in <a class="bibr" href="#ch3.appm.ref23" rid="ch3.appm.ref23">Lu et al. 2012</a> (response and no response utility were 057 and 0.48, respectively), which were based on data observed in the underpinning trial.</p><p>Drug acquisition costs were estimated using pack/vial costs and the number of doses required per 4-week model cycle. The model applied the Sativex (THC: CBD spray) discount: NHS Pay for Responder scheme that first 3 × 10ml vial (90 doses per vial) for free and pay for responder only. The background management costs associated with spasticity were taken from a published UK study (<a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson, Gras, Bardos, & Broughton, 2015</a>), which reported spasticity management costs by NRS categories. Some of the reported resource use from <a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson et al. (2015)</a> might not be spasticity specific, such as wheelchair use. The model assumed that 50% of the resource use costs from <a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson et al. (2015)</a> were attributed to spasticity alone and therefore could be influenced by the treatment effect, based on a suggestion from the committee.</p><p>The model incorporated adverse events (AEs), based on the estimated incidence rate of serious and non-serious AEs for cannabinoid and control (placebo) (<a class="bibr" href="#ch3.appm.ref44" rid="ch3.appm.ref44">Wang et al., 2008</a>). Costs and disutility associated with AEs were incorporated into the model.</p><p>Base-case results showed that, compared with standard of care alone, THC: CBD spray plus SoC was £1,580 more expensive and produced 0.081 more QALYs over a 5-year time horizon. The ICER was £19,512 per QALY gained. Probabilistic sensitivity analysis showed a 47.7% probability that, compared with standard treatment alone, THC: CBD spray plus SoC is associated with an ICER of £20,000/QALY or better and a 66.0% probability of an ICER of £30,000/QALY or better.</p><p>Parameter uncertainty was explored on the baseline characteristics, treatment effects, adverse events, discontinuation, mortality, utilities, THC: CBD average daily sprays, cost of spasticity management. Several scenario analyses, particularly on the assumptions on discontinuation, treatment response and utility estimation, were also conducted. The model was most sensitive to treatment effects. When varied over their plausible ranges, a large number of the examined parameters had the potential to change model outputs to one side or the other of a £20,000 / QALY threshold. However, the model was relatively robust if QALYs are valued at £30,000 each: only the main effectiveness parameter (relative likelihood of response to THC:CBD spray), the probability of adverse events, and the proportion of costs that are attributable to spasticity had sufficient impact that the ICER could exceed £30,000/QALY.</p></div></div><div id="ch3.s1.5"><h3>Summary of evidence</h3><p>The summary of evidence in this section reflects the evidence on effectiveness of cannabis-based medicinal products. Evidence statements are stratified by population and reflect evidence that was statistically significant. Further information on adverse events is also provided. The format of the evidence summary table is explained in the methods in <a href="#ch3.appb">Appendix B</a>. Further information on adverse events is provided in <a href="#ch3.appi">Appendix I</a>.</p><div id="ch3.s1.5.1"><h4>Clinical evidence</h4><div id="ch3.s1.5.1.1"><h5>THC: CBD spray (dose higher than recommended) versus placebo</h5><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3tab4"><a href="/books/NBK577084/table/ch3.tab4/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3tab4" rid-ob="figobch3tab4"><img class="small-thumb" src="/books/NBK577084/table/ch3.tab4/?report=thumb" src-large="/books/NBK577084/table/ch3.tab4/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.tab4"><a href="/books/NBK577084/table/ch3.tab4/?report=objectonly" target="object" rid-ob="figobch3tab4">Table</a></h4><p class="float-caption no_bottom_margin">MD −0.76 (−1.50, −0.01)</p></div></div><div id="ch3.s1.5.1.1.1"><h5>Commonly reported adverse events</h5><ul id="ch3.l8"><li id="ch3.lt27" class="half_rhythm"><div>Commonly reported adverse events in studies included dizziness, somnolence, fatigue, nausea, dry mouth and asthenia</div></li></ul></div></div><div id="ch3.s1.5.1.2"><h5>THC: CBD spray (within recommended dose) versus placebo</h5><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3tab5"><a href="/books/NBK577084/table/ch3.tab5/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3tab5" rid-ob="figobch3tab5"><img class="small-thumb" src="/books/NBK577084/table/ch3.tab5/?report=thumb" src-large="/books/NBK577084/table/ch3.tab5/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.tab5"><a href="/books/NBK577084/table/ch3.tab5/?report=objectonly" target="object" rid-ob="figobch3tab5">Table</a></h4><p class="float-caption no_bottom_margin">3 Parallel RCTs 1 cross-over RCT</p></div></div><div id="ch3.s1.5.1.2.1"><h5>Commonly reported adverse events</h5><ul id="ch3.l9"><li id="ch3.lt28" class="half_rhythm"><div>Commonly reported adverse events in studies included dizziness, somnolence, nausea, vertigo and fatigue</div></li></ul></div></div><div id="ch3.s1.5.1.3"><h5>THC capsules (synthetic THC) versus placebo</h5><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3tab6"><a href="/books/NBK577084/table/ch3.tab6/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3tab6" rid-ob="figobch3tab6"><img class="small-thumb" src="/books/NBK577084/table/ch3.tab6/?report=thumb" src-large="/books/NBK577084/table/ch3.tab6/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.tab6"><a href="/books/NBK577084/table/ch3.tab6/?report=objectonly" target="object" rid-ob="figobch3tab6">Table</a></h4><p class="float-caption no_bottom_margin">MD −1.38 (−2.47, −0.29)</p></div></div><div id="ch3.s1.5.1.3.1"><h5>Commonly reported adverse events</h5><ul id="ch3.l10"><li id="ch3.lt29" class="half_rhythm"><div>Commonly reported adverse events in studies included dizziness, sleep problems, balance problems, dissociative or perception disorders and somnolence.</div></li></ul></div></div><div id="ch3.s1.5.1.4"><h5>THC capsules (purified THC from cannabis extract) versus placebo</h5><p>No significant results were found for purified THC capsules v placebo</p><div id="ch3.s1.5.1.4.1"><h5>Commonly reported adverse events</h5><ul id="ch3.l11"><li id="ch3.lt30" class="half_rhythm"><div>Commonly reported adverse events in studies included dizziness, muscular weakness, headache, euphoric mood and dry mouth.</div></li></ul></div></div><div id="ch3.s1.5.1.5"><h5>THC: CBD cannabis extract capsules versus placebo</h5><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3tab7"><a href="/books/NBK577084/table/ch3.tab7/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3tab7" rid-ob="figobch3tab7"><img class="small-thumb" src="/books/NBK577084/table/ch3.tab7/?report=thumb" src-large="/books/NBK577084/table/ch3.tab7/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.tab7"><a href="/books/NBK577084/table/ch3.tab7/?report=objectonly" target="object" rid-ob="figobch3tab7">Table</a></h4><p class="float-caption no_bottom_margin">MD 3.70 (1.77, 5.63)</p></div></div><div id="ch3.s1.5.1.5.1"><h5>Commonly reported adverse events</h5><ul id="ch3.l12"><li id="ch3.lt31" class="half_rhythm"><div>Commonly reported adverse events in studies included dizziness, sleep problems, gastrointestinal problems, bladder problems and fatigue</div></li></ul></div></div></div><div id="ch3.s1.5.2"><h4>Motor neurone disease</h4><div id="ch3.s1.5.2.1"><h5>THC: CBD spray versus placebo</h5><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3tab8"><a href="/books/NBK577084/table/ch3.tab8/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3tab8" rid-ob="figobch3tab8"><img class="small-thumb" src="/books/NBK577084/table/ch3.tab8/?report=thumb" src-large="/books/NBK577084/table/ch3.tab8/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.tab8"><a href="/books/NBK577084/table/ch3.tab8/?report=objectonly" target="object" rid-ob="figobch3tab8">Table</a></h4><p class="float-caption no_bottom_margin">MD −0.27 (−0.51, −0.03)</p></div></div><div id="ch3.s1.5.2.1.1"><h5>Commonly reported adverse events</h5><ul id="ch3.l13"><li id="ch3.lt32" class="half_rhythm"><div>Commonly reported adverse events in studies included asthenia, somnolence, vertigo, nausea and syncope.</div></li></ul></div></div><div id="ch3.s1.5.2.2"><h5>THC capsules (purified THC from cannabis extract) versus placebo</h5><p>No significant results were found for purified THC capsules v placebo</p><div id="ch3.s1.5.2.2.1"><h5>Commonly reported adverse events</h5><ul id="ch3.l14"><li id="ch3.lt33" class="half_rhythm"><div>Commonly reported adverse events in studies included drowsiness and slight weakness in lower limbs.</div></li></ul></div></div></div><div id="ch3.s1.5.3"><h4>Spinal cord injury</h4><div id="ch3.s1.5.3.1"><h5>THC capsules (purified THC from cannabis extract) versus placebo</h5><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3tab9"><a href="/books/NBK577084/table/ch3.tab9/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3tab9" rid-ob="figobch3tab9"><img class="small-thumb" src="/books/NBK577084/table/ch3.tab9/?report=thumb" src-large="/books/NBK577084/table/ch3.tab9/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.tab9"><a href="/books/NBK577084/table/ch3.tab9/?report=objectonly" target="object" rid-ob="figobch3tab9">Table</a></h4><p class="float-caption no_bottom_margin">MD −2.55 (−3.84, −1.26)</p></div></div><div id="ch3.s1.5.3.1.1"><h5>Commonly reported adverse events</h5><ul id="ch3.l15"><li id="ch3.lt34" class="half_rhythm"><div>Commonly reported adverse events in studies included drowsiness, dry mouth and asthenia, mild vertigo, mild ataxia, and headache and lack of motivation.</div></li></ul></div></div></div><div id="ch3.s1.5.4"><h4>Health economics evidence statements</h4><p>Two published, directly applicable, UK-based cost–utility analyses compared oromucosal THC: CBD spray plus standard of care with standard of care alone for the treatment of spasticity in multiple sclerosis. An independently produced study with potentially serious limitations found that THC: CBD spray is associated with an ICER of £49,300 per QALY, with 10.2% probability that the ICER is £30,000 per QALY or better. The other, a manufacturer-sponsored analysis with very serious limitations, found that THC: CBD spray is associated with an ICER of £11,000 per QALY, with 100% probability that the ICER is £30,000 per QALY or better.</p><p>One directly applicable UK cost–utility analysis with minor limitations conducted for this guideline compared THC: CBD spray plus standard treatment with standard treatment alone for the treatment of spasticity. THC: CBD spray plus standard treatment compared to standard treatment alone was £1,580 more expensive and produced 0.081 more QALYs over five years (ICER = £19,512/QALY). Probabilistic sensitivity analysis showed a 47.7% probability that that the ICER is £20,000 per QALY or better.</p></div></div><div id="ch3.s1.6"><h3>The committee’s discussion of the evidence</h3><div id="ch3.s1.6.1"><h4>Interpreting the evidence</h4><div id="ch3.s1.6.1.1"><h5>The outcomes that matter most</h5><p>The committee decided that outcomes including reduction in spasticity from baseline and the proportion of patients achieving 30% or greater improvement in spasticity were key outcomes for assessing effectiveness. The number of adverse events was also considered important to evaluate the safety of cannabis-based medicinal products. Other outcomes considered by the committee included the dose, treatment duration, contraindications, monitoring requirements and stopping criteria.</p></div><div id="ch3.s1.6.1.2"><h5>The quality of the evidence</h5><p>Most of the evidence examined the use of THC:CBD spray for people with multiple sclerosis. However, the outcomes for these were low quality and had short follow up periods. Only 2 studies examined the use of cannabis-based medicinal products for people with motor neurone disease and 1 evaluated their use for people with spinal cord injury. The committee therefore agreed that they only had sufficient evidence to assess the effectiveness and adverse events for the use of THC:CBD spray for people with spasticity due to multiple sclerosis. Additionally, no paediatric studies were identified. Seven studies examined the use of THC:CBD spray for spasticity in people with multiple sclerosis. All were directly applicable, but some were downgraded for risk of bias, most commonly because of an enriched enrolment design or limited information on randomisation, allocation concealment and blinding. Three of these studies used maximum doses of between 24–48 sprays per day, higher than the maximum dose of 12 sprays per day recommended in the SPC, although the mean dose in two of these was similar to that in the dose-capped studies. The effectiveness and adverse events associated with allowing higher doses could differ to those which would be experienced when in the maximum dose is restricted, as in current clinical practice. Consequently, we conducted subgroup analysis on the studies that did and did not have their maximum daily dose restricted to 12 doses per day.</p><p>Two of the studies that used THC:CBD spray within the recommended dose used an enriched-enrolment study design (Markova 2018, <a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna 2011</a>). This design split the trials into two phases: Phase A where all participants were given THC:CBD spray and Phase B (RCT phase) where only those participants who responded to the treatment were included. Both studies classified responders as people who showed a 20% reduction in spasticity during Phase A. The Markova trial also specified that patients who experienced a 20% improvement had to show an 80% reduction in that improvement during a 4-week washout period before the RCT began. The committee discussed the risk of bias of these studies, with some stating that, in comparison to a standard RCT, this study design is more similar to the process that would be followed in clinical practice. However, others highlighted that this design may favour responders and result in more positive outcomes and fewer adverse events once the RCT phase is reached. Given these potential effects on the outcomes, the studies were downgraded for risk of bias but were evaluated as directly applicable.</p><p>The committee highlighted potential issues with the sensitivity of some of the outcomes used to assess spasticity. Clinician-measured spasticity was assessed using the 5-point Ashworth or 6-point Modified Ashworth scale and although these are commonly used to measure spasticity in research they are not often used in clinical practice and can be insensitive to change that would be considered meaningful to individual patients. As a result, improvements in spasticity may not register on the Ashworth or Modified Ashworth scales but this change may still be considered an improvement by the patient. A bigger treatment effect may therefore be seen in other outcomes, such as patient-reported change in spasticity, which is often scored using a 10-point numerical rating scale or 100-point visual analogue score.</p><p>Although there were limitations to some of the studies, most of the evidence for THC:CBD spray was from recent studies. The committee were therefore satisfied that the treatments used in the trials before the addition of cannabis-based medicinal products reflected current practice.</p></div><div id="ch3.s1.6.1.3"><h5>Benefits and harms</h5><p>The committee agreed that there were benefits for the use of THC:CBD spray for the treatment of spasticity in multiple sclerosis. The clinical evidence showed improvements in patient-reported spasticity and could not differentiate between adverse events for THC:CBD spray and placebo. Also, economic modelling showed that THC:CBD spray would offer sufficient QALY gains if reduction in spasticity led to a halving of management costs and acquisition cost of THC:CBD spray (Sativex) was also reduced (in addition to the existing pay-for-responders scheme). Therefore, the committee agreed that under these conditions Sativex could be recommended to treat moderate to severe spasticity in adults with multiple sclerosis if other pharmacological treatments had not been effective.</p><p>There was limited evidence for the use of other cannabis-based medicinal products for the treatment of spasticity in other conditions. As a result, the committee could not confidently assess either the benefits or harms associated with these treatments and could not recommend them for use. The committee therefore made a research recommendation designed to help improve the understanding of the effects of cannabis-based medicinal products other than Sativex. The committee also highlighted that it is important to understand the effects of these products for people with conditions other than multiple sclerosis. People with cerebral palsy are a group that could particularly benefit from treatments that may help to reduce spasticity and so were included as a consideration for subgroup analysis.</p><p>Although one of the main concerns over the use of cannabis-based medicinal products is the potential for adverse events, the evidence could not differentiate between THC:CBD spray and placebo for the majority of the adverse event-related outcomes. However, it was suggested that the number of adverse events in the meta-analysis may have been reduced due to the studies which used enriched enrolment designs. The committee decided that despite the potential effect of the enriched enrolment studies, adverse events may not be a major concern. This decision was based on reports from some of the studies that many of the adverse events occurred near the beginning of treatment and could often be resolved during the dose titration phase. This was supported by the clinical experience of the committee, suggesting that the longer-term benefits of THC:CBD spray may outweigh the potential harms.</p></div></div><div id="ch3.s1.6.2"><h4>Cost effectiveness and resource use</h4><p>The committee considered the evidence from two published economic evaluations that had been included in the clinical review. One manufacturer funded study (<a class="bibr" href="#ch3.appm.ref18" rid="ch3.appm.ref18">Gras 2016</a>) found that THC: CBD spray was associated with an incremental cost-effectiveness ratio (ICER) of around £10,000/QALY gained over standard care (SoC) in the MS population. This study found that THC: CBD spray was associated with a QALY gain of 0.35 over 30 years and an incremental cost of £3,836 which was derived from £98,501 costs in the SoC arm and £102,337 in the THC: CBD spray arm. The relatively small incremental (and high absolute) costs arise in this model because it uses estimates of resource use associated with different spasticity NRS scores that reflect the totality of background MS management costs and then makes the assumption that use of these resources is entirely related to NRS. Because of the wide variety of reasons that a patient might receive more or less intense management, the committee found this assumption highly implausible and so considered this study had overestimated the resource savings associated with reducing spasticity and therefore had serious limitations for decision-making. The other study included in the review was <a class="bibr" href="#ch3.appm.ref23" rid="ch3.appm.ref23">Lu 2012</a>. This study was funded by the National Institute for Health Research and concluded that THC: CBD spray was associated with an additional 0.15 QALYS over 5 years at an additional £7,627, leading to an ICER of £49,257/QALY gained. This was the economic evaluation that underpinned the 2014 MS guideline committee’s decision not to recommend THC: CBD spray on the grounds of cost-ineffectiveness. This study’s clinical evidence is based solely on the <a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna 2011</a> RCT and had a number of other potential limitations including the sources of utility and cost data, not considering costs associated with adverse events and a different threshold for treatment response. Overall the committee considered this study relevant but with potentially serious limitations for decision-making.</p><p>A <i>de novo</i> economic model was produced for this review question which aimed to improve upon the published analyses by including evidence from all the relevant RCTs in the area along with recently published longer term patient registry data, adverse event data and the flexibility to conduct sensitivity and scenario analyses.</p><p>The committee noted that despite THC: CBD spray being found to be clinically effective at reducing spasticity, no studies found any significant differences in health-related quality of life (HRQoL) measures whether using the EQ-5D, SF-36 or VAS 0–100 instruments. Additionally, differences in point estimates between the two arms of all trials collecting HRQoL measures were very small. They considered that this might be because HRQoL measures have some level of insensitivity to changes in spasticity NRS and are therefore not capturing the benefits of the treatment appropriately. Another contributory factor could be condition severity in the population in the trials, as patients with advanced MS typically have many other important symptoms that can influence their HRQoL and reducing spasticity might not change their self-reported scores by much. The economic model estimated a fairly large difference in HRQoL between responders and non-responders of 0.15, which may therefore have been an overestimate. This difference was 0.09 in data that Lu et al report was observed in the Novotna trial, but using a lower response cut-off, which might also explain the discrepancy.</p><p>The economic model was mostly based on short term data from the RCTs and single arm discontinuation data from a registry of advanced MS patients treated with THC: CBD spray. The short-term response data was extrapolated over a 5 year time horizon, making use of the discontinuation data as well as estimated spasticity management costs and adverse event data. The committee discussed these limitations and requested a series of scenario analyses that examined discontinuation from response in both arms of the model over time.</p><p>The model only included data on >30% responders but the committee felt that THC:CBD spray might be prescribed on an ongoing basis for >20% responders in clinical practice, who would receive all of the treatment cost but less of the benefit. It’s results may therefore be biased in favour of THC:CBD spray.</p><p>Over 5 years, the model produced costs of £30,630 in the SoC arm and £32,210 in the SoC + cannabis arm with incremental QALYs of 0.081, leading to an ICER of £19,512/QALY gained. A large number of sensitivity and scenario analyses were conducted on the model and, in most of the plausible analyses, the ICER remained in the range normally considered cost-effective by NICE’s advisory committees. The committee discussed the use of the SoC + THC: CBD spray and SoC + placebo arms of the RCTs to model the THC: CBD spray and SoC arms of the economic analysis. While this method is standard for Health Technology Assessment, they noted that the response levels were reasonably high in both arms of the RCTs although the economic model, which combined the RCT with patient registry data predicted this value at ~13%. Some element of this response would be attributable to regression to the mean and some to the placebo effect, the latter of which they suspected would wane over time. They noted that without longer term data on differential response rates it was difficult to be confident that the extrapolations used in the model represented clinical reality. Nevertheless, most plausible variations in parameters and assumptions led to ICERs that were within or below the normal range of cost-effectiveness of £20–30,000/QALY gained, following a change of the list price of THC: CBD spray from £375 to £300. The model’s most important limitations were likely to overestimate the cost-effectiveness rather than underestimate it. A scenario analysis using 20% instead of 30% as the cut-off for treatment response and continuation produced an ICER of £24,992/QALY.</p><p>There was little direct evidence and no cost-effectiveness data on the quality of life improvements and resource savings associated with using other CBMPs in spasticity in general so the committee decided to make a recommendation against using them outside the context of a clinical trial.</p></div><div id="ch3.s1.6.3"><h4>Other factors the committee took into account</h4><p>It was highlighted that one of the difficulties faced when trying to determine the effects of a treatment in multiple sclerosis is that it is a progressive disease. Most studies appeared to control for this by stating that patients must have had stable treatment for a specified period before the beginning of the trial. This may have helped to identify treatment effects rather than changes due to disease progression. However, it was suggested that this criterion may have meant that the people included in these trials had less severe spasticity than some of those who might be prescribed cannabis-based medicinal products. Many studies also specified that people should have an Ashworth or Modified Ashworth score of 2 or above. This suggests that many participants had less severe spasticity than those who may be prescribed cannabis-based medicinal products, who often have more severe spasticity categorised by an Ashworth score or 3 or 4. Taking this limitation into consideration along with the clinical and cost effectiveness evidence, the committee agreed that there was scope for THC: CBD spray to be offered as part of a 4-week trial to treat moderate to severe spasticity in adults with multiple sclerosis if other pharmacological treatments are not effective and the company provides THC:CBD (Sativex) according to its pay-for-responders scheme.</p><p>The committee noted that there was a lack of evidence for the use of cannabis-based medicinal products for children with spasticity. Additionally, THC: CBD spray (Sativex) is not currently licensed in children. Due to this, the committee were unable to make recommendations for the use of THC: CBD spray (Sativex) in children. However, the committee did identify this as an area where further research was needed. Therefore, the committee drafted a research recommendation to explore the clinical and cost effectiveness of cannabis-based medicinal products other than Sativex for people with spasticity which includes children as a subgroup.</p><p>The committee also discussed the need for improved tools to assess outcomes for people with spasticity. This was particularly important for quality of life, where a reduction in spasticity is not always accompanied by improvements in quality of life scores. Although there are a number of questionnaires available to assess quality of life, such as the EQ-5D, none of these are specifically designed for people with spasticity. The committee thought that this was an important factor to consider when assessing treatment effectiveness and so this was included as part of the research recommendation.</p><div id="ch3.box2" class="box boxed-text-box whole_rhythm hide-overflow"><p>This evidence review supports <a href="/books/n/niceng144/?report=reader" class="toc-item">recommendations 1.3.1</a> and <a href="/books/n/niceng144/?report=reader" class="toc-item">1.3.2</a> and the research recommendation on spasticity.</p></div></div></div></div><div id="ch3.s2"><h2 id="_ch3_s2_">Glossary</h2><div id="ch3.s2.1"><h3>Cannabis-based medicinal products</h3><p>In this guideline cannabis-based medicinal products include:
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<ul id="ch3.l16"><li id="ch3.lt35" class="half_rhythm"><div>cannabis-based products for medicinal use as set out by the UK Government in the <a href="http://www.legislation.gov.uk/uksi/2018/1055/made" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">2018 Regulations</a></div></li><li id="ch3.lt36" class="half_rhythm"><div>the licensed products delta-9-tetrahydrocannibinol combined with cannabidiol (Sativex) and nabilone</div></li><li id="ch3.lt37" class="half_rhythm"><div>plant-derived cannabinoids such as pure cannabidiol (CBD)</div></li><li id="ch3.lt38" class="half_rhythm"><div>synthetic compounds which are identical in structure to naturally occurring cannabinoids such as delta-tetrahydrocannabinol (THC), for example, dronabinol.</div></li></ul></p></div></div><div id="ch3.appa"><h2 id="_ch3_appa_">Appendix A. Review protocols</h2><p>Review protocol for clinical effectiveness, cost effectiveness, contraindications, potential interactions, individual patient monitoring requirements, treatment durations, reviewing and stopping criteria for cannabis based medicinal products</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3appatab1"><a href="/books/NBK577084/table/ch3.appa.tab1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3appatab1" rid-ob="figobch3appatab1"><img class="small-thumb" src="/books/NBK577084/table/ch3.appa.tab1/?report=thumb" src-large="/books/NBK577084/table/ch3.appa.tab1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.appa.tab1"><a href="/books/NBK577084/table/ch3.appa.tab1/?report=objectonly" target="object" rid-ob="figobch3appatab1">Table</a></h4><p class="float-caption no_bottom_margin">What is the clinical and cost effectiveness of cannabis-based medicinal products for people with spasticity? What are the adverse effects or complications of cannabis-based medicinal products for people with spasticity?</p></div></div></div><div id="ch3.appb"><h2 id="_ch3_appb_">Appendix B. Methods</h2><div id="ch3.appb.s1"><h3>Priority screening</h3><p>The reviews undertaken for this guideline all made use of the priority screening functionality with the EPPI-reviewer systematic reviewing software. This uses a machine learning algorithm (specifically, an SGD classifier) to take information on features (1, 2 and 3 word blocks) in the titles and abstract of papers marked as being ‘includes’ or ‘excludes’ during the title and abstract screening process, and re-orders the remaining records from most likely to least likely to be an include, based on that algorithm. This re-ordering of the remaining records occurs every time 25 additional records have been screened.</p><p>As an additional check to ensure this approach did not miss relevant studies, the included studies lists of included systematic reviews were searched to identify any papers not identified through the primary search.</p></div><div id="ch3.appb.s2"><h3>Evidence synthesis and meta-analyses</h3><p>Where possible, meta-analyses were conducted to combine the results of quantitative studies for each outcome. For continuous outcomes analysed as mean differences, where change from baseline data were reported in the trials and were accompanied by a measure of spread (for example standard deviation), these were extracted and used in the meta-analysis. Where measures of spread for change from baseline values were not reported, the corresponding values at study end were used and were combined with change from baseline values to produce summary estimates of effect. These studies were assessed to ensure that baseline values were balanced across the treatment groups; if there were significant differences at baseline these studies were not included in any meta-analysis and were reported separately. For continuous outcomes analysed as standardised mean differences, where only baseline and final time point values were available, change from baseline standard deviations were estimated, assuming a correlation coefficient of 0.5.</p></div><div id="ch3.appb.s3"><h3>Evidence of effectiveness of interventions</h3><div id="ch3.appb.s3.1"><h4>Quality assessment</h4><p>Parallel RCTs and crossover RCTs were quality assessed using the Cochrane Risk of Bias Tool 2.0.</p><p>Each individual study was classified into one of the following three groups:
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<ul id="ch3.l19"><li id="ch3.lt45" class="half_rhythm"><div>Low risk of bias – The true effect size for the study is likely to be close to the estimated effect size.</div></li><li id="ch3.lt46" class="half_rhythm"><div>Some concern around risk of bias – There is a possibility the true effect size for the study is substantially different to the estimated effect size.</div></li><li id="ch3.lt47" class="half_rhythm"><div>High risk of bias – It is likely the true effect size for the study is substantially different to the estimated effect size.</div></li></ul></p><p>Each individual study was also classified into one of three groups for directness, based on if there were concerns about the population, intervention, comparator and/or outcomes in the study and how directly these variables could address the specified review question. Studies were rated as follows:
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<ul id="ch3.l20"><li id="ch3.lt48" class="half_rhythm"><div>Direct – No important deviations from the protocol in population, intervention, comparator and/or outcomes.</div></li><li id="ch3.lt49" class="half_rhythm"><div>Partially indirect – Important deviations from the protocol in one of the population, intervention, comparator and/or outcomes.</div></li><li id="ch3.lt50" class="half_rhythm"><div>Indirect – Important deviations from the protocol in at least two of the following areas: population, intervention, comparator and/or outcomes.</div></li></ul></p></div><div id="ch3.appb.s3.2"><h4>Methods for combining intervention evidence</h4><p>Meta-analyses of interventional data were conducted with reference to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins et al. 2011).</p><p>A pooled relative risk was calculated for dichotomous outcomes (using the Mantel–Haenszel method) reporting numbers of people having an event. Both relative and absolute risks were presented, with absolute risks calculated by applying the relative risk to the pooled risk in the comparator arm of the meta-analysis (all pooled trials).</p><p>Fixed- and random-effects models (der Simonian and Laird) were fitted for all syntheses, with the presented analysis dependent on the degree of heterogeneity in the assembled evidence. Fixed-effects models were the preferred choice to report, but in situations where the assumption of a shared mean for fixed-effects model were clearly not met, even after appropriate pre-specified subgroup analyses were conducted, random-effects results are presented. Fixed-effects models were deemed to be inappropriate if one or both of the following conditions was met:
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<ul id="ch3.l21"><li id="ch3.lt51" class="half_rhythm"><div>Significant between study heterogeneity in methodology, population, intervention or comparator was identified by the reviewer in advance of data analysis. This decision was made and recorded before any data analysis was undertaken.</div></li><li id="ch3.lt52" class="half_rhythm"><div>The presence of significant statistical heterogeneity in the meta-analysis, defined as I<sup>2</sup>≥50%.</div></li></ul></p><p>Meta-analyses were performed in Cochrane Review Manager V5.3</p></div><div id="ch3.appb.s3.3"><h4>Minimal clinically important differences (MIDs)</h4><p>The Core Outcome Measures in Effectiveness Trials (COMET) database was searched to identify published minimal clinically important difference thresholds relevant to this guideline. Identified MIDs were assessed to ensure they had been developed and validated in a methodologically rigorous way, and were applicable to the populations, interventions and outcomes specified in this guideline. In addition, the Guideline Committee were asked to prospectively specify any outcomes where they felt a consensus MID could be defined from their experience. In particular, any questions looking to evaluate non-inferiority (that one treatment is not meaningfully worse than another) required an MID to be defined to act as a non-inferiority margin.</p><p>One study [<a class="bibr" href="#ch3.appn.ref1" rid="ch3.appn.ref1">Farrar 2008</a>] determined the clinical importance of change on a 0–10 numerical rating scale (NRS). The study estimated the level of change from baseline on the 0–10 NRS spasticity scale that constituted a minimal clinically important difference as anchored to the patient’s global impression of change (PGIC). The findings showed that ‘minimally improved’ or better on the PGIC produced cut-off point of −0.9 for the raw score change. Therefore, −0.9 was used as a MID for the NRS scale.</p><p>No MIDs were identified for other outcomes. Therefore, line of no effect was used to assess imprecision.</p><p>When decisions were made in situations where MIDs were not available, the ‘Evidence to Recommendations’ section of that review should make explicit the committee’s view of the expected clinical importance and relevance of the findings. In particular, this includes consideration of whether the whole effect of a treatment (which may be felt across multiple independent outcome domains) would be likely to be clinically meaningful, rather than simply whether each individual sub outcome might be meaningful in isolation.</p></div><div id="ch3.appb.s3.4"><h4>GRADE for pairwise meta-analyses of interventional evidence</h4><p>GRADE was used to assess the quality of evidence for the selected outcomes as specified in ‘Developing NICE guidelines: the manual (2018)’. Data from all study designs was initially rated as high quality and the quality of the evidence for each outcome was downgraded or not from this initial point, based on the criteria given in <a class="figpopup" href="/books/NBK577084/table/ch3.tab1/?report=objectonly" target="object" rid-figpopup="figch3tab1" rid-ob="figobch3tab1">Table 1</a></p><p id="ch3.appb.tab1"><a href="/books/NBK577084/table/ch3.appb.tab1/?report=objectonly" target="object" rid-ob="figobch3appbtab1" class="figpopup">Table 1. Rationale for downgrading quality of evidence for intervention studies</a></p><p>The quality of evidence for each outcome was upgraded if any of the following three conditions were met:
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<ul id="ch3.l22"><li id="ch3.lt53" class="half_rhythm"><div>Data from non-randomised studies showing an effect size sufficiently large that it cannot be explained by confounding alone.</div></li><li id="ch3.lt54" class="half_rhythm"><div>Data showing a dose-response gradient.</div></li><li id="ch3.lt55" class="half_rhythm"><div>Data where all plausible residual confounding is likely to increase our confidence in the effect estimate.</div></li></ul></p></div><div id="ch3.appb.s3.5"><h4>Summary of the evidence</h4><p>The evidence is presented in the form of a table because the committee agreed in advance that effect sizes would be an important consideration. Summary of evidence is stratified by comparison and reflects evidence that was statistically significant.</p><p>Where the data are only consistent, at a 95% confidence level, with an effect in one direction (i.e. one that is ‘statistically significant’), and the magnitude of that effect is most likely to meet or exceed the MID (i.e. the point estimate is not in the zone of equivalence). In such cases, we state that the evidence showed that there is an effect. In all other cases, we state that the evidence could not differentiate between the comparators.</p></div><div id="ch3.appb.s3.6"><h4>Quality assessment</h4><p>Single arm studies were also included in this review. These studies were quality assessed using the Institute of Health Economics (IHE) Quality Appraisal Checklist. Studies were assessed on the methods of participant recruitment, retention and outcome measurement (as appropriate), with each individual study classified into one of the following three groups:
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<ul id="ch3.l23"><li id="ch3.lt56" class="half_rhythm"><div>Low risk of bias – The true result for the study is likely to be close to the estimated result</div></li><li id="ch3.lt57" class="half_rhythm"><div>Moderate risk of bias – There is a possibility the true result for the study is substantially different to the estimated result.</div></li><li id="ch3.lt58" class="half_rhythm"><div>High risk of bias – It is likely the true result for the study is substantially different to the estimated result.</div></li></ul></p><p>Each individual study was also classified into one of three groups for directness, based on if there were concerns about the population or outcomes in the study and how directly these variables could address the specified review question. Studies were rated as follows:
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<ul id="ch3.l24"><li id="ch3.lt59" class="half_rhythm"><div>Direct – No important deviations from the protocol in population, intervention, comparator and/or outcomes.</div></li><li id="ch3.lt60" class="half_rhythm"><div>Partially indirect – Important deviations from the protocol in one of the population, intervention, comparator and/or outcomes.</div></li><li id="ch3.lt61" class="half_rhythm"><div>Indirect – Important deviations from the protocol in at least two of the population, intervention, comparator and/or outcomes.</div></li></ul></p></div></div></div><div id="ch3.appc"><h2 id="_ch3_appc_">Appendix C. Literature search strategies</h2><p>A single systematic search was conducted for all of the questions within this evidence review between 19<sup>th</sup> December 2018 and 21st January 2019. The following databases were searched MEDLINE, MEDLINE in Process, MEDLINE e pub Ahead of print, Embase, (all via the Ovid platform), Cochrane Database of Systematic Reviews CENTRAL (all via the Wiley platform), and the HTA and DARE databases (both via the CRD platform). NICE inhouse RCT, systematic review, and observational filters were attached where appropriate.</p><p>The MEDLINE strategy is presented below. This was translated for other databases
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<ol id="ch3.l25"><li id="ch3.lt62" class="half_rhythm"><div>Medical Marijuana/</div></li><li id="ch3.lt63" class="half_rhythm"><div>cannabinoids/ or cannabidiol/ or cannabinol/ or cannabis/</div></li><li id="ch3.lt64" class="half_rhythm"><div>((cannabi* or hemp or marijuana or marihuana) adj4 (medicine* or medicinal or medical or oil or oils or product* or extract* or therap* or CBD or vap* or spray* or inhal* or compound* or resin* or derivative*)).tw.</div></li><li id="ch3.lt65" class="half_rhythm"><div>(epidiolex* or cannabidiol* or cannabinoid*).tw.</div></li><li id="ch3.lt66" class="half_rhythm"><div>(sativex or nabiximols or tetrabinex or nabidiolex).tw.</div></li><li id="ch3.lt67" class="half_rhythm"><div>(nabilone or cesamet).tw.</div></li><li id="ch3.lt68" class="half_rhythm"><div>(tilray* or bedrocan* or bedrobinol* or bedica* or bediol* or bedrolite*).tw.</div></li><li id="ch3.lt69" class="half_rhythm"><div>Dronabinol/</div></li><li id="ch3.lt70" class="half_rhythm"><div>(dronabinol* or marinol* or syndros*).tw.</div></li><li id="ch3.lt71" class="half_rhythm"><div>(9-ene-tetrahydrocannabinol* or 9enetetrahydrocannabinol*).tw.</div></li><li id="ch3.lt72" class="half_rhythm"><div>(THC or tetrahydrocannabinol*).tw.</div></li><li id="ch3.lt73" class="half_rhythm"><div>(“delta(1)-thc*” or “delta(1)-tetrahydrocannabinol*” or “delta(9)-thc*” or “delta(9)-tetrahydrocannabinol*”).tw.</div></li><li id="ch3.lt74" class="half_rhythm"><div>(9-delta-tetra-hydrocannabinol* or “9-delta-THC*” or “9 delta tetra hydrocannabinol*” or “9 delta THC*”).tw.</div></li><li id="ch3.lt75" class="half_rhythm"><div>(1-delta-tetra-hydrocannabinol* or “1-delta-THC*” or “1 delta tetra hydrocannabinol” or “1 delta thc*”).tw.</div></li><li id="ch3.lt76" class="half_rhythm"><div>THCa.tw.</div></li><li id="ch3.lt77" class="half_rhythm"><div>CBDa.tw.</div></li><li id="ch3.lt78" class="half_rhythm"><div>cannabinol*.tw.</div></li><li id="ch3.lt79" class="half_rhythm"><div>cannabigerol*.tw.</div></li><li id="ch3.lt80" class="half_rhythm"><div>cannabichromene*.tw.</div></li><li id="ch3.lt81" class="half_rhythm"><div>(tetrahydrocannabivarin* or THCV).tw.</div></li><li id="ch3.lt82" class="half_rhythm"><div>(cannabidivarin* or CBDV).tw.</div></li><li id="ch3.lt83" class="half_rhythm"><div>or/1–21</div></li><li id="ch3.lt84" class="half_rhythm"><div>animals/ not humans/</div></li><li id="ch3.lt85" class="half_rhythm"><div>22 not 23</div></li><li id="ch3.lt86" class="half_rhythm"><div>limit 24 to english language</div></li><li id="ch3.lt87" class="half_rhythm"><div>Randomized Controlled Trial.pt.</div></li><li id="ch3.lt88" class="half_rhythm"><div>Controlled Clinical Trial.pt.</div></li><li id="ch3.lt89" class="half_rhythm"><div>Clinical Trial.pt.</div></li><li id="ch3.lt90" class="half_rhythm"><div>exp Clinical Trials as Topic/</div></li><li id="ch3.lt91" class="half_rhythm"><div>Placebos/</div></li><li id="ch3.lt92" class="half_rhythm"><div>Random Allocation/</div></li><li id="ch3.lt93" class="half_rhythm"><div>Double-Blind Method/</div></li><li id="ch3.lt94" class="half_rhythm"><div>Single-Blind Method/</div></li><li id="ch3.lt95" class="half_rhythm"><div>Cross-Over Studies/</div></li><li id="ch3.lt96" class="half_rhythm"><div>((random$ or control$ or clinical$) adj3 (trial$ or stud$)).tw.</div></li><li id="ch3.lt97" class="half_rhythm"><div>(random$ adj3 allocat$).tw.</div></li><li id="ch3.lt98" class="half_rhythm"><div>placebo$.tw.</div></li><li id="ch3.lt99" class="half_rhythm"><div>((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).tw.</div></li><li id="ch3.lt100" class="half_rhythm"><div>(crossover$ or (cross adj over$)).tw.</div></li><li id="ch3.lt101" class="half_rhythm"><div>or/20–33</div></li><li id="ch3.lt102" class="half_rhythm"><div>Meta-Analysis.pt.</div></li><li id="ch3.lt103" class="half_rhythm"><div>Network Meta-Analysis/</div></li><li id="ch3.lt104" class="half_rhythm"><div>Meta-Analysis as Topic/</div></li><li id="ch3.lt105" class="half_rhythm"><div>Review.pt.</div></li><li id="ch3.lt106" class="half_rhythm"><div>exp Review Literature as Topic/</div></li><li id="ch3.lt107" class="half_rhythm"><div>(metaanaly$ or metanaly$ or (meta adj3 analy$)).tw.</div></li><li id="ch3.lt108" class="half_rhythm"><div>(review$ or overview$).ti.</div></li><li id="ch3.lt109" class="half_rhythm"><div>(systematic$ adj5 (review$ or overview$)).tw.</div></li><li id="ch3.lt110" class="half_rhythm"><div>((quantitative$ or qualitative$) adj5 (review$ or overview$)).tw.</div></li><li id="ch3.lt111" class="half_rhythm"><div>((studies or trial$) adj2 (review$ or overview$)).tw.</div></li><li id="ch3.lt112" class="half_rhythm"><div>(integrat$ adj3 (research or review$ or literature)).tw.</div></li><li id="ch3.lt113" class="half_rhythm"><div>(pool$ adj2 (analy$ or data)).tw.</div></li><li id="ch3.lt114" class="half_rhythm"><div>(handsearch$ or (hand adj3 search$)).tw.</div></li><li id="ch3.lt115" class="half_rhythm"><div>(manual$ adj3 search$).tw.</div></li><li id="ch3.lt116" class="half_rhythm"><div>or/35–48</div></li><li id="ch3.lt117" class="half_rhythm"><div>34 or 49</div></li><li id="ch3.lt118" class="half_rhythm"><div>19 and 50</div></li><li id="ch3.lt119" class="half_rhythm"><div>Observational Studies as Topic/</div></li><li id="ch3.lt120" class="half_rhythm"><div>Observational Study/</div></li><li id="ch3.lt121" class="half_rhythm"><div>Epidemiologic Studies/</div></li><li id="ch3.lt122" class="half_rhythm"><div>exp Case-Control Studies/</div></li><li id="ch3.lt123" class="half_rhythm"><div>exp Cohort Studies/</div></li><li id="ch3.lt124" class="half_rhythm"><div>Cross-Sectional Studies/</div></li><li id="ch3.lt125" class="half_rhythm"><div>Controlled Before-After Studies/</div></li><li id="ch3.lt126" class="half_rhythm"><div>Historically Controlled Study/</div></li><li id="ch3.lt127" class="half_rhythm"><div>Interrupted Time Series Analysis/</div></li><li id="ch3.lt128" class="half_rhythm"><div>Comparative Study.pt.</div></li><li id="ch3.lt129" class="half_rhythm"><div>case control$.tw.</div></li><li id="ch3.lt130" class="half_rhythm"><div>case series.tw.</div></li><li id="ch3.lt131" class="half_rhythm"><div>(cohort adj (study or studies)).tw.</div></li><li id="ch3.lt132" class="half_rhythm"><div>cohort analy$.tw.</div></li><li id="ch3.lt133" class="half_rhythm"><div>(follow up adj (study or studies)).tw.</div></li><li id="ch3.lt134" class="half_rhythm"><div>(observational adj (study or studies)).tw.</div></li><li id="ch3.lt135" class="half_rhythm"><div>longitudinal.tw.</div></li><li id="ch3.lt136" class="half_rhythm"><div>prospective.tw.</div></li><li id="ch3.lt137" class="half_rhythm"><div>retrospective.tw.</div></li><li id="ch3.lt138" class="half_rhythm"><div>cross sectional.tw.</div></li><li id="ch3.lt139" class="half_rhythm"><div>or/26–45</div></li><li id="ch3.lt140" class="half_rhythm"><div>25 and 46</div></li><li id="ch3.lt141" class="half_rhythm"><div>57 or 79</div></li></ol></p><p>Searches to identify economic evidence were run on 20<sup>th</sup> December 2018 in MEDLINE, MEDLINE in Process, MEDLINE e pub Ahead of print, Econlit and Embase (all va the Ovid platform), NHS EED and the Health Technology Assessment Database (via the CRD platform). NICE inhouse economic evaluation and Quality of Life filters were attached to lines 1 to 25 of the core strategy (lines 1 to 25 of the MEDLINE version shown above) in the MEDLINE and Embase databases. The MEDLINE version of the filters is displayed below.</p><p>Economic evaluations</p><p>Economics/</p><ul id="ch3.l26" class="simple-list"><li id="ch3.lt142" class="half_rhythm"><div>exp “Costs and Cost Analysis”/</div></li><li id="ch3.lt143" class="half_rhythm"><div>Economics, Dental/</div></li><li id="ch3.lt144" class="half_rhythm"><div>exp Economics, Hospital/</div></li><li id="ch3.lt145" class="half_rhythm"><div>exp Economics, Medical/</div></li><li id="ch3.lt146" class="half_rhythm"><div>Economics, Nursing/</div></li><li id="ch3.lt147" class="half_rhythm"><div>Economics, Pharmaceutical/</div></li><li id="ch3.lt148" class="half_rhythm"><div>Budgets/</div></li><li id="ch3.lt149" class="half_rhythm"><div>exp Models, Economic/</div></li><li id="ch3.lt150" class="half_rhythm"><div>Markov Chains/</div></li><li id="ch3.lt151" class="half_rhythm"><div>Monte Carlo Method/</div></li><li id="ch3.lt152" class="half_rhythm"><div>Decision Trees/</div></li><li id="ch3.lt153" class="half_rhythm"><div>econom$.tw.</div></li><li id="ch3.lt154" class="half_rhythm"><div>cba.tw.</div></li><li id="ch3.lt155" class="half_rhythm"><div>cea.tw.</div></li><li id="ch3.lt156" class="half_rhythm"><div>cua.tw.</div></li><li id="ch3.lt157" class="half_rhythm"><div>markov$.tw.</div></li><li id="ch3.lt158" class="half_rhythm"><div>(monte adj carlo).tw.</div></li><li id="ch3.lt159" class="half_rhythm"><div>(decision adj3 (tree$ or analys$)).tw.</div></li><li id="ch3.lt160" class="half_rhythm"><div>(cost or costs or costing$ or costly or costed).tw.</div></li><li id="ch3.lt161" class="half_rhythm"><div>(price$ or pricing$).tw.</div></li><li id="ch3.lt162" class="half_rhythm"><div>budget$.tw.</div></li></ul><p>expenditure$.tw.</p><p>(value adj3 (money or monetary)).tw.</p><p>(pharmacoeconomic$ or (pharmaco adj economic$)).tw.</p><p>or/1–25</p><p>Quality of Life</p><ul id="ch3.l27" class="simple-list"><li id="ch3.lt163" class="half_rhythm"><div>“Quality of Life”/</div></li><li id="ch3.lt164" class="half_rhythm"><div>quality of life.tw.</div></li><li id="ch3.lt165" class="half_rhythm"><div>“Value of Life”/</div></li><li id="ch3.lt166" class="half_rhythm"><div>Quality-Adjusted Life Years/</div></li><li id="ch3.lt167" class="half_rhythm"><div>quality adjusted life.tw.</div></li><li id="ch3.lt168" class="half_rhythm"><div>(qaly$ or qald$ or qale$ or qtime$).tw.</div></li><li id="ch3.lt169" class="half_rhythm"><div>disability adjusted life.tw.</div></li><li id="ch3.lt170" class="half_rhythm"><div>daly$.tw.</div></li><li id="ch3.lt171" class="half_rhythm"><div>Health Status Indicators/</div></li><li id="ch3.lt172" class="half_rhythm"><div>(sf36 or sf 36 or short form 36 or shortform 36 or sf thirtysix or sf thirty six or shortform thirtysix or shortform thirty six or short form thirtysix or short form thirty six).tw.</div></li><li id="ch3.lt173" class="half_rhythm"><div>(sf6 or sf 6 or short form 6 or shortform 6 or sf six or sfsix or shortform six or short form six).tw.</div></li><li id="ch3.lt174" class="half_rhythm"><div>(sf12 or sf 12 or short form 12 or shortform 12 or sf twelve or sftwelve or shortform twelve or short form twelve).tw.</div></li><li id="ch3.lt175" class="half_rhythm"><div>(sf16 or sf 16 or short form 16 or shortform 16 or sf sixteen or sfsixteen or shortform sixteen or short form sixteen).tw.</div></li><li id="ch3.lt176" class="half_rhythm"><div>(sf20 or sf 20 or short form 20 or shortform 20 or sf twenty or sftwenty or shortform twenty or short form twenty).tw.</div></li><li id="ch3.lt177" class="half_rhythm"><div>(euroqol or euro qol or eq5d or eq 5d).tw.</div></li><li id="ch3.lt178" class="half_rhythm"><div>(qol or hql or hqol or hrqol).tw.</div></li><li id="ch3.lt179" class="half_rhythm"><div>(hye or hyes).tw.</div></li><li id="ch3.lt180" class="half_rhythm"><div>health$ year$ equivalent$.tw.</div></li><li id="ch3.lt181" class="half_rhythm"><div>utilit$.tw.</div></li><li id="ch3.lt182" class="half_rhythm"><div>(hui or hui1 or hui2 or hui3).tw.</div></li><li id="ch3.lt183" class="half_rhythm"><div>disutili$.tw.</div></li><li id="ch3.lt184" class="half_rhythm"><div>rosser.tw.</div></li><li id="ch3.lt185" class="half_rhythm"><div>quality of wellbeing.tw.</div></li><li id="ch3.lt186" class="half_rhythm"><div>quality of well-being.tw.</div></li><li id="ch3.lt187" class="half_rhythm"><div>qwb.tw.</div></li><li id="ch3.lt188" class="half_rhythm"><div>willingness to pay.tw.</div></li><li id="ch3.lt189" class="half_rhythm"><div>standard gamble$.tw.</div></li><li id="ch3.lt190" class="half_rhythm"><div>time trade off.tw.</div></li><li id="ch3.lt191" class="half_rhythm"><div>time tradeoff.tw.</div></li><li id="ch3.lt192" class="half_rhythm"><div>tto.tw.</div></li><li id="ch3.lt193" class="half_rhythm"><div>or/1–30</div></li></ul><p>A search of the MHRA was undertaken on the 24<sup>th</sup> January 2019 to look for safety updates, alerts and recalls. The search terms are displayed below.</p><ul id="ch3.l28" class="simple-list"><li id="ch3.lt194" class="half_rhythm"><div>Sativex</div></li><li id="ch3.lt195" class="half_rhythm"><div>Dronabinol</div></li><li id="ch3.lt196" class="half_rhythm"><div>Epidiolex</div></li><li id="ch3.lt197" class="half_rhythm"><div>Nabiximols</div></li><li id="ch3.lt198" class="half_rhythm"><div>Abalone</div></li><li id="ch3.lt199" class="half_rhythm"><div>Tetrabinex</div></li><li id="ch3.lt200" class="half_rhythm"><div>Nabidiolex</div></li><li id="ch3.lt201" class="half_rhythm"><div>Cesamet</div></li><li id="ch3.lt202" class="half_rhythm"><div>Tilray</div></li><li id="ch3.lt203" class="half_rhythm"><div>Bedrocan</div></li><li id="ch3.lt204" class="half_rhythm"><div>Bedrobinol</div></li><li id="ch3.lt205" class="half_rhythm"><div>Bedica</div></li><li id="ch3.lt206" class="half_rhythm"><div>Bediol</div></li><li id="ch3.lt207" class="half_rhythm"><div>Bedrolite</div></li><li id="ch3.lt208" class="half_rhythm"><div>Marinol</div></li><li id="ch3.lt209" class="half_rhythm"><div>Syndros</div></li><li id="ch3.lt210" class="half_rhythm"><div>THC</div></li><li id="ch3.lt211" class="half_rhythm"><div>Tetrahydrocannabinol</div></li><li id="ch3.lt212" class="half_rhythm"><div>Cannabinol</div></li><li id="ch3.lt213" class="half_rhythm"><div>Cannibigerol</div></li><li id="ch3.lt214" class="half_rhythm"><div>Cannabichromene</div></li><li id="ch3.lt215" class="half_rhythm"><div>Tetrahydrocannabivarin</div></li><li id="ch3.lt216" class="half_rhythm"><div>Cannabidivarin</div></li></ul></div><div id="ch3.appd"><h2 id="_ch3_appd_">Appendix D. Clinical evidence study selection</h2><div id="ch3.appd.s1"><h3>RCTs and systematic reviews of RCTs search</h3><div id="ch3.appd.fig1" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appdf1&p=BOOKS&id=577084_ch3appdf1.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appdf1.jpg" alt="Image ch3appdf1" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch3.appd.s2"><h3>Health economics search</h3><div id="ch3.appd.fig2" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appdf2&p=BOOKS&id=577084_ch3appdf2.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appdf2.jpg" alt="Image ch3appdf2" class="tileshop" title="Click on image to zoom" /></a></div></div></div></div><div id="ch3.appe"><h2 id="_ch3_appe_">Appendix E. Clinical evidence tables</h2><div id="ch3.appe.s1"><h3>Parallel RCTs</h3><p id="ch3.appe.et1"><a href="/books/NBK577084/bin/ch3-appe-et1.pdf" class="bk_dwnld_icn bk_dwnld_pdf">Download PDF</a><span class="small"> (1.6M)</span></p></div><div id="ch3.appe.s2"><h3>Cross-over RCTs</h3><p id="ch3.appe.et2"><a href="/books/NBK577084/bin/ch3-appe-et2.pdf" class="bk_dwnld_icn bk_dwnld_pdf">Download PDF</a><span class="small"> (1.4M)</span></p></div></div><div id="ch3.appf"><h2 id="_ch3_appf_">Appendix F. Forest plots</h2><div id="ch3.appf.s1"><h3>Multiple sclerosis</h3><div id="ch3.appf.s1.1"><h4>THC: CBD oromucosal spray versus placebo</h4><div id="ch3.appf.s1.1.1"><h5>Spasticity: Modified Ashworth Scale – change from baseline</h5><div id="ch3.appf.fig1" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff1&p=BOOKS&id=577084_ch3appff1.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff1.jpg" alt="Image ch3appff1" class="tileshop" title="Click on image to zoom" /></a></div></div><div id="ch3.appf.s1.1.1.1"><h5>Pooled estimates</h5><div id="ch3.appf.fig2" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff2&p=BOOKS&id=577084_ch3appff2.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff2.jpg" alt="Image ch3appff2" class="tileshop" title="Click on image to zoom" /></a></div></div></div></div><div id="ch3.appf.s1.1.2"><h5>Spasticity: Numerical rating Scale- change from baseline</h5><div id="ch3.appf.fig3" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff3&p=BOOKS&id=577084_ch3appff3.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff3.jpg" alt="Image ch3appff3" class="tileshop" title="Click on image to zoom" /></a></div></div><div id="ch3.appf.s1.1.2.1"><h5>Pooled estimates</h5><div id="ch3.appf.fig4" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff4&p=BOOKS&id=577084_ch3appff4.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff4.jpg" alt="Image ch3appff4" class="tileshop" title="Click on image to zoom" /></a></div></div></div></div><div id="ch3.appf.s1.1.3"><h5>Spasticity: Numerical rating scale responder (>30% improvement in spasticity)</h5><div id="ch3.appf.fig5" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff5&p=BOOKS&id=577084_ch3appff5.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff5.jpg" alt="Image ch3appff5" class="tileshop" title="Click on image to zoom" /></a></div></div><div id="ch3.appf.s1.1.3.1"><h5>Pooled estimates</h5><div id="ch3.appf.fig6" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff6&p=BOOKS&id=577084_ch3appff6.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff6.jpg" alt="Image ch3appff6" class="tileshop" title="Click on image to zoom" /></a></div></div></div></div><div id="ch3.appf.s1.1.4"><h5>Total adverse events</h5><div id="ch3.appf.fig7" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff7&p=BOOKS&id=577084_ch3appff7.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff7.jpg" alt="Image ch3appff7" class="tileshop" title="Click on image to zoom" /></a></div></div><div id="ch3.appf.s1.1.4.1"><h5>Pooled estimates</h5><div id="ch3.appf.fig8" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff8&p=BOOKS&id=577084_ch3appff8.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff8.jpg" alt="Image ch3appff8" class="tileshop" title="Click on image to zoom" /></a></div></div></div></div><div id="ch3.appf.s1.1.5"><h5>Treatment-related adverse events</h5><div id="ch3.appf.fig9" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff9&p=BOOKS&id=577084_ch3appff9.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff9.jpg" alt="Image ch3appff9" class="tileshop" title="Click on image to zoom" /></a></div></div><div id="ch3.appf.s1.1.5.1"><h5>Pooled estimates</h5><div id="ch3.appf.fig10" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff10&p=BOOKS&id=577084_ch3appff10.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff10.jpg" alt="Image ch3appff10" class="tileshop" title="Click on image to zoom" /></a></div></div></div></div><div id="ch3.appf.s1.1.6"><h5>Total serious adverse events</h5><div id="ch3.appf.fig11" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff11&p=BOOKS&id=577084_ch3appff11.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff11.jpg" alt="Image ch3appff11" class="tileshop" title="Click on image to zoom" /></a></div></div><div id="ch3.appf.s1.1.6.1"><h5>Pooled estimates</h5><div id="ch3.appf.fig12" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff12&p=BOOKS&id=577084_ch3appff12.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff12.jpg" alt="Image ch3appff12" class="tileshop" title="Click on image to zoom" /></a></div></div></div></div><div id="ch3.appf.s1.1.7"><h5>Withdrawal due to adverse events</h5><div id="ch3.appf.fig13" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff13&p=BOOKS&id=577084_ch3appff13.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff13.jpg" alt="Image ch3appff13" class="tileshop" title="Click on image to zoom" /></a></div></div><div id="ch3.appf.s1.1.7.1"><h5>Pooled estimates</h5><div id="ch3.appf.fig14" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff14&p=BOOKS&id=577084_ch3appff14.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff14.jpg" alt="Image ch3appff14" class="tileshop" title="Click on image to zoom" /></a></div></div></div></div></div><div id="ch3.appf.s1.2"><h4>THC capsules (synthetic THC)</h4><div id="ch3.appf.s1.2.1"><h5>Spasticity: Ashworth Scale – change from baseline (total score)</h5><div id="ch3.appf.fig15" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff15&p=BOOKS&id=577084_ch3appff15.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff15.jpg" alt="Image ch3appff15" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch3.appf.s1.2.2"><h5>Total adverse events</h5><div id="ch3.appf.fig16" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff16&p=BOOKS&id=577084_ch3appff16.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff16.jpg" alt="Image ch3appff16" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch3.appf.s1.2.3"><h5>Total serious adverse events</h5><div id="ch3.appf.fig17" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff17&p=BOOKS&id=577084_ch3appff17.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff17.jpg" alt="Image ch3appff17" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch3.appf.s1.2.4"><h5>Withdrawals due to adverse events</h5><div id="ch3.appf.fig18" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff18&p=BOOKS&id=577084_ch3appff18.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff18.jpg" alt="Image ch3appff18" class="tileshop" title="Click on image to zoom" /></a></div></div></div></div><div id="ch3.appf.s1.3"><h4>THC:CBD cannabis extract capsules</h4><div id="ch3.appf.s1.3.1"><h5>Spasticity: Ashworth Scale – change from baseline (total score)</h5><div id="ch3.appf.fig19" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff19&p=BOOKS&id=577084_ch3appff19.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff19.jpg" alt="Image ch3appff19" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch3.appf.s1.3.2"><h5>Effects of spasticity: MSSS-88 – change from baseline (subscales)</h5><div id="ch3.appf.fig20" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff20&p=BOOKS&id=577084_ch3appff20.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff20.jpg" alt="Image ch3appff20" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch3.appf.s1.3.3"><h5>Total adverse events</h5><div id="ch3.appf.fig21" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff21&p=BOOKS&id=577084_ch3appff21.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff21.jpg" alt="Image ch3appff21" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch3.appf.s1.3.4"><h5>Total serious adverse events</h5><div id="ch3.appf.fig22" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff22&p=BOOKS&id=577084_ch3appff22.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff22.jpg" alt="Image ch3appff22" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch3.appf.s1.3.5"><h5>Withdrawals due to adverse events</h5><div id="ch3.appf.fig23" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff23&p=BOOKS&id=577084_ch3appff23.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK577084/bin/ch3appff23.jpg" alt="Image ch3appff23" class="tileshop" title="Click on image to zoom" /></a></div></div></div></div></div></div><div id="ch3.apph"><h2 id="_ch3_apph_">Appendix H. GRADE tables</h2><div id="ch3.apph.s1"><h3>Multiple sclerosis</h3><div id="ch3.apph.s1.1"><h4>THC:CBD spray</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3apphtab1"><a href="/books/NBK577084/table/ch3.apph.tab1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3apphtab1" rid-ob="figobch3apphtab1"><img class="small-thumb" src="/books/NBK577084/table/ch3.apph.tab1/?report=thumb" src-large="/books/NBK577084/table/ch3.apph.tab1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.apph.tab1"><a href="/books/NBK577084/table/ch3.apph.tab1/?report=objectonly" target="object" rid-ob="figobch3apphtab1">Table</a></h4><p class="float-caption no_bottom_margin">MD 0.16 (−0.50, 0.83)</p></div></div></div><div id="ch3.apph.s1.2"><h4>THC capsules (synthetic THC)</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3apphtab2"><a href="/books/NBK577084/table/ch3.apph.tab2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3apphtab2" rid-ob="figobch3apphtab2"><img class="small-thumb" src="/books/NBK577084/table/ch3.apph.tab2/?report=thumb" src-large="/books/NBK577084/table/ch3.apph.tab2/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.apph.tab2"><a href="/books/NBK577084/table/ch3.apph.tab2/?report=objectonly" target="object" rid-ob="figobch3apphtab2">Table</a></h4><p class="float-caption no_bottom_margin">MD −1.38 (−2.47, −0.29)</p></div></div></div><div id="ch3.apph.s1.3"><h4>THC capsules (purified THC from cannabis extract)</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3apphtab3"><a href="/books/NBK577084/table/ch3.apph.tab3/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3apphtab3" rid-ob="figobch3apphtab3"><img class="small-thumb" src="/books/NBK577084/table/ch3.apph.tab3/?report=thumb" src-large="/books/NBK577084/table/ch3.apph.tab3/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.apph.tab3"><a href="/books/NBK577084/table/ch3.apph.tab3/?report=objectonly" target="object" rid-ob="figobch3apphtab3">Table</a></h4><p class="float-caption no_bottom_margin">MD −0.38 (−1.30, 0.54)</p></div></div></div><div id="ch3.apph.s1.4"><h4>THC:CBD cannabis extract capsules</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3apphtab4"><a href="/books/NBK577084/table/ch3.apph.tab4/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3apphtab4" rid-ob="figobch3apphtab4"><img class="small-thumb" src="/books/NBK577084/table/ch3.apph.tab4/?report=thumb" src-large="/books/NBK577084/table/ch3.apph.tab4/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.apph.tab4"><a href="/books/NBK577084/table/ch3.apph.tab4/?report=objectonly" target="object" rid-ob="figobch3apphtab4">Table</a></h4><p class="float-caption no_bottom_margin">MD −0.32 (−1.31, 0.66)</p></div></div></div></div><div id="ch3.apph.s2"><h3>Motor neurone disease</h3><div id="ch3.apph.s2.1"><h4>THC:CBD spray</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3apphtab5"><a href="/books/NBK577084/table/ch3.apph.tab5/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3apphtab5" rid-ob="figobch3apphtab5"><img class="small-thumb" src="/books/NBK577084/table/ch3.apph.tab5/?report=thumb" src-large="/books/NBK577084/table/ch3.apph.tab5/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.apph.tab5"><a href="/books/NBK577084/table/ch3.apph.tab5/?report=objectonly" target="object" rid-ob="figobch3apphtab5">Table</a></h4><p class="float-caption no_bottom_margin">MD −0.27 (−0.51, −0.03)</p></div></div></div><div id="ch3.apph.s2.2"><h4>THC capsules (synthetic THC)</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3apphtab6"><a href="/books/NBK577084/table/ch3.apph.tab6/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3apphtab6" rid-ob="figobch3apphtab6"><img class="small-thumb" src="/books/NBK577084/table/ch3.apph.tab6/?report=thumb" src-large="/books/NBK577084/table/ch3.apph.tab6/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.apph.tab6"><a href="/books/NBK577084/table/ch3.apph.tab6/?report=objectonly" target="object" rid-ob="figobch3apphtab6">Table</a></h4><p class="float-caption no_bottom_margin">MD −0.35 (−1.14, 0.45)</p></div></div></div></div><div id="ch3.apph.s3"><h3>Spinal cord injury</h3><div id="ch3.apph.s3.1"><h4>THC capsules (synthetic THC)</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3apphtab7"><a href="/books/NBK577084/table/ch3.apph.tab7/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3apphtab7" rid-ob="figobch3apphtab7"><img class="small-thumb" src="/books/NBK577084/table/ch3.apph.tab7/?report=thumb" src-large="/books/NBK577084/table/ch3.apph.tab7/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.apph.tab7"><a href="/books/NBK577084/table/ch3.apph.tab7/?report=objectonly" target="object" rid-ob="figobch3apphtab7">Table</a></h4><p class="float-caption no_bottom_margin">MD −2.55 (−3.84, −1.26)</p></div></div></div></div></div><div id="ch3.appi"><h2 id="_ch3_appi_">Appendix I. Adverse events</h2><div id="ch3.appi.s1"><h3>Multiple sclerosis</h3><div id="ch3.appi.s1.1"><h4>THC:CBD oromucosal spray</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3appitab1"><a href="/books/NBK577084/table/ch3.appi.tab1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3appitab1" rid-ob="figobch3appitab1"><img class="small-thumb" src="/books/NBK577084/table/ch3.appi.tab1/?report=thumb" src-large="/books/NBK577084/table/ch3.appi.tab1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.appi.tab1"><a href="/books/NBK577084/table/ch3.appi.tab1/?report=objectonly" target="object" rid-ob="figobch3appitab1">Table</a></h4><p class="float-caption no_bottom_margin">Treatment-related adverse events experienced by more than 4 participants THC: CBD spray: Dizziness 32%; Fatigue 11%; Urinary tract infection 11%; Dry mouth 9%; Balance impaired 7%; Nausea 7%; Headache 7%; Diarrhoea 6%; Oral pain 5%; Somnolence 5%; Confusion <a href="/books/NBK577084/table/ch3.appi.tab1/?report=objectonly" target="object" rid-ob="figobch3appitab1">(more...)</a></p></div></div></div><div id="ch3.appi.s1.2"><h4>THC capsules (synthetic THC)</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3appitab2"><a href="/books/NBK577084/table/ch3.appi.tab2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3appitab2" rid-ob="figobch3appitab2"><img class="small-thumb" src="/books/NBK577084/table/ch3.appi.tab2/?report=thumb" src-large="/books/NBK577084/table/ch3.appi.tab2/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.appi.tab2"><a href="/books/NBK577084/table/ch3.appi.tab2/?report=objectonly" target="object" rid-ob="figobch3appitab2">Table</a></h4><p class="float-caption no_bottom_margin">Adverse events experienced by ≥10% participants THC: Falls and injuries 31%; Mobility, balance and co-ordination problems 33%; Infections (excluding urinary tract) 29%; Fatigue and tiredness 25%; Dizziness and light-headedness 32%; Muscle disorders <a href="/books/NBK577084/table/ch3.appi.tab2/?report=objectonly" target="object" rid-ob="figobch3appitab2">(more...)</a></p></div></div></div><div id="ch3.appi.s1.3"><h4>THC capsules (purified THC from cannabis extract)</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3appitab3"><a href="/books/NBK577084/table/ch3.appi.tab3/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3appitab3" rid-ob="figobch3appitab3"><img class="small-thumb" src="/books/NBK577084/table/ch3.appi.tab3/?report=thumb" src-large="/books/NBK577084/table/ch3.appi.tab3/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.appi.tab3"><a href="/books/NBK577084/table/ch3.appi.tab3/?report=objectonly" target="object" rid-ob="figobch3appitab3">Table</a></h4><p class="float-caption no_bottom_margin">Adverse events reported more than once THC: Nervous system (Dizziness 58%; Headache 50%; Somnolence 25%; Muscular weakness 33%; Spasticity 25%; Paresthesia 17%; Tremor 17%; Tinnitus 17%); Psychiatric/mood (Euphoric mood 33%; Insomnia 8%); General disorders <a href="/books/NBK577084/table/ch3.appi.tab3/?report=objectonly" target="object" rid-ob="figobch3appitab3">(more...)</a></p></div></div></div><div id="ch3.appi.s1.4"><h4>THC:CBD cannabis extract capsules</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3appitab4"><a href="/books/NBK577084/table/ch3.appi.tab4/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3appitab4" rid-ob="figobch3appitab4"><img class="small-thumb" src="/books/NBK577084/table/ch3.appi.tab4/?report=thumb" src-large="/books/NBK577084/table/ch3.appi.tab4/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.appi.tab4"><a href="/books/NBK577084/table/ch3.appi.tab4/?report=objectonly" target="object" rid-ob="figobch3appitab4">Table</a></h4><p class="float-caption no_bottom_margin">Adverse events Cannabis extract: Bladder 26%; Gastrointestinal 37%; Pain 24%; Depression or anxiety 9%; Vision 8%; Infection 16%; Dizzy or lightheadedness 50%; Dry mouth 20%; Weakness or reduced mobility 23%; Sleep 40%; Spasms or stiffness 33%; Tremor <a href="/books/NBK577084/table/ch3.appi.tab4/?report=objectonly" target="object" rid-ob="figobch3appitab4">(more...)</a></p></div></div></div></div><div id="ch3.appi.s2"><h3>Motor neurone disease</h3><div id="ch3.appi.s2.1"><h4>THC:CBD oromucosal spray</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3appitab5"><a href="/books/NBK577084/table/ch3.appi.tab5/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3appitab5" rid-ob="figobch3appitab5"><img class="small-thumb" src="/books/NBK577084/table/ch3.appi.tab5/?report=thumb" src-large="/books/NBK577084/table/ch3.appi.tab5/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.appi.tab5"><a href="/books/NBK577084/table/ch3.appi.tab5/?report=objectonly" target="object" rid-ob="figobch3appitab5">Table</a></h4><p class="float-caption no_bottom_margin">Most common adverse events THC: CBD spray: General disorders (Asthenia 24%; Malaise 3%); Nervous system disorders (Dizziness 7%; Balance disorder 3%; Memory impairment 3%; Somnolence 17%; Syncope 7%; Tremors 3%; Spasticity 3%); Psychiatric disorders (Anxiety <a href="/books/NBK577084/table/ch3.appi.tab5/?report=objectonly" target="object" rid-ob="figobch3appitab5">(more...)</a></p></div></div></div><div id="ch3.appi.s2.2"><h4>THC capsules (synthetic THC)</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3appitab6"><a href="/books/NBK577084/table/ch3.appi.tab6/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3appitab6" rid-ob="figobch3appitab6"><img class="small-thumb" src="/books/NBK577084/table/ch3.appi.tab6/?report=thumb" src-large="/books/NBK577084/table/ch3.appi.tab6/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.appi.tab6"><a href="/books/NBK577084/table/ch3.appi.tab6/?report=objectonly" target="object" rid-ob="figobch3appitab6">Table</a></h4><p class="float-caption no_bottom_margin">Adverse events THC: Drowsiness (15%); Slight weakness in lower limbs</p></div></div></div></div><div id="ch3.appi.s3"><h3>Spinal cord injury</h3><div id="ch3.appi.s3.1"><h4>Nabilone</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3appitab7"><a href="/books/NBK577084/table/ch3.appi.tab7/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3appitab7" rid-ob="figobch3appitab7"><img class="small-thumb" src="/books/NBK577084/table/ch3.appi.tab7/?report=thumb" src-large="/books/NBK577084/table/ch3.appi.tab7/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.appi.tab7"><a href="/books/NBK577084/table/ch3.appi.tab7/?report=objectonly" target="object" rid-ob="figobch3appitab7">Table</a></h4><p class="float-caption no_bottom_margin">THC: Drowsiness 27%; Dry mouth and asthenia 18%; Mild vertigo 18%; Mild ataxia, headache and lack of motivation 9% Adverse events not reported for placebo</p></div></div></div></div></div><div id="ch3.appj"><h2 id="_ch3_appj_">Appendix J. Excluded studies</h2><div id="ch3.appj.s1"><h3>Clinical studies</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3appjtab1"><a href="/books/NBK577084/table/ch3.appj.tab1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3appjtab1" rid-ob="figobch3appjtab1"><img class="small-thumb" src="/books/NBK577084/table/ch3.appj.tab1/?report=thumb" src-large="/books/NBK577084/table/ch3.appj.tab1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.appj.tab1"><a href="/books/NBK577084/table/ch3.appj.tab1/?report=objectonly" target="object" rid-ob="figobch3appjtab1">Table</a></h4><p class="float-caption no_bottom_margin">Sacca, F., Pane, C., Carotenuto, A. et al. (2016) The use of medical-grade Cannabis (Bedrocan) in patients non-responders to nabiximols (sativex). Multiple sclerosis (Houndmills, Basingstoke, England) conference32ndcongressoftheeuropeancommitteefortreatmentandresearchinmultiplescl <a href="/books/NBK577084/table/ch3.appj.tab1/?report=objectonly" target="object" rid-ob="figobch3appjtab1">(more...)</a></p></div></div></div><div id="ch3.appj.s2"><h3>Economic studies</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3appjtab2"><a href="/books/NBK577084/table/ch3.appj.tab2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3appjtab2" rid-ob="figobch3appjtab2"><img class="small-thumb" src="/books/NBK577084/table/ch3.appj.tab2/?report=thumb" src-large="/books/NBK577084/table/ch3.appj.tab2/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.appj.tab2"><a href="/books/NBK577084/table/ch3.appj.tab2/?report=objectonly" target="object" rid-ob="figobch3appjtab2">Table</a></h4></div></div></div></div><div id="ch3.appk"><h2 id="_ch3_appk_">Appendix K. Research recommendations</h2><dl id="ch3.l29" class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd id="ch3.lt217"><p class="no_top_margin">
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<b>What is the clinical and cost effectiveness of cannabis based medicinal products other than Sativex for people with spasticity? In particular, what is the impact of spasticity on improvements in quality of life?</b>
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</p></dd></dl></dl><p>Sixteen studies were identified which examined the clinical effectiveness of cannabis-based medicinal products. These studies identified the effectiveness of interventions such as THC:CBD oromucosal spray for treating spasticity in people with multiple sclerosis. However, there was limited evidence for other cannabis-based medicinal products and for conditions other than multiple sclerosis. In particular, there was limited evidence on the effects of a change in spasticity on quality of life.</p><p>Further research is needed using a robust study design such as a parallel RCT to explore the clinical and cost effectiveness of cannabis-based medicinal products other than Sativex as an adjunct to optimal therapy in children and adults with spasticity. This should include the development of a quality of life questionnaire validated specifically for people with spasticity. Studies should be UK based. Research in this area is essential to inform future updates of key recommendations in this guidance which in turn can help improve patient outcomes.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3appktab1"><a href="/books/NBK577084/table/ch3.appk.tab1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3appktab1" rid-ob="figobch3appktab1"><img class="small-thumb" src="/books/NBK577084/table/ch3.appk.tab1/?report=thumb" src-large="/books/NBK577084/table/ch3.appk.tab1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.appk.tab1"><a href="/books/NBK577084/table/ch3.appk.tab1/?report=objectonly" target="object" rid-ob="figobch3appktab1">Table</a></h4><p class="float-caption no_bottom_margin"><i>Population:</i> Adults and children with spasticity who haven’t fully responded to optimal treatment Specific subgroups:
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People with cerebral palsy </p></div></div></div><div id="ch3.appl"><h2 id="_ch3_appl_">Appendix L. Health economics evidence tables</h2><p id="ch3.appl.et1"><a href="/books/NBK577084/bin/ch3-appl-et1.pdf" class="bk_dwnld_icn bk_dwnld_pdf">Download PDF</a><span class="small"> (1.3M)</span></p></div><div id="ch3.appm"><h2 id="_ch3_appm_">Appendix M. Economic model</h2><div id="ch3.appm.s1"><h3>Background</h3><p>Following the legislation changes and the Home Office announcement in October 2018, doctors on the Specialist Register of the General Medical Council will be able to prescribe cannabis-based medicinal products.</p><p>NICE has never produced an economic analysis to determine the cost-effectiveness of medicinal cannabis in spasticity, albeit THC: CBD spray (Sativex) has been licensed by the MHRA as a treatment for spasticity in multiple sclerosis (MS) under Schedule 4 of the 2001 Regulations.</p><p>NICE has previously considered a published cost-effectiveness analysis of THC: CBD spray in MS spasticity within the guideline of multiple sclerosis in adults (CG186) and the advisory committee did not recommend its use because they concluded it was not a cost-effective treatment.</p><p>Given the recent legislation changes and more recent data became available, the committee was interested in developing a de novo economic model to examine the cost-effectiveness of medicinal cannabis in patients with spasticity who had not responded adequately to any standard oral anti-spasticity medications.</p></div><div id="ch3.appm.s2"><h3>Methods</h3><div id="ch3.appm.s2.1"><h4>Population, interventions/comparators and outcomes</h4><p>The objective of this analysis is to develop a de novo economic model to estimate the cost-effectiveness of the cannabis-derived medicinal products as a treatment option for spasticity. The target population in the model are patients with spasticity who had not responded adequately to any standard spasticity treatment, before undergoing invasive interventions or surgery.</p><p>The model compared the costs and effectiveness of the standard of care (SoC) plus cannabis to the standard of care alone. The standard of care is defined as any interventions that would usually be used in this patient group, including licensed oral anti-spasticity medications if appropriate (although our group are, by definition, non-responders to these). It is assumed that all patients in the cannabis strategy received a cannabis-derived medicinal product as an add-on treatment to the standard of care. The committee agree that this is consistent with the existing clinical practice.</p><p>Outcomes were measured in quality-adjusted life years (QALYs). The incremental cost-effectiveness ratio (ICER) is expressed as a cost per QALY.</p><p>The analysis was conducted from the perspective of NHS and Personal Social Services (PSS) in the UK and considered only the costs and outcomes which were relevant to this guideline. Productivity loss and carer’s QALYs were not considered.</p></div><div id="ch3.appm.s2.2"><h4>Model structure</h4><p>This section is intended to give a structural overview of the model and its underpinning assumptions. Derivation of parameters is discussed in the <a href="#ch3.appm.s2.3">Model Parameters</a> section.</p><p>A Markov model was constructed in Excel. The model adopted a 4-week cycle length. All transition probabilities were adjusted accordingly using a standard methodology (<a class="bibr" href="#ch3.appm.ref29" rid="ch3.appm.ref29">Miller and Homan, 1994</a>). The time horizon for the base case analysis was 5 years. The committee agreed that there is no evidence to suggest that medicinal cannabis would impact the mortality of patients with spasticity and that most of the available evidence is short term in nature. A short time horizon is therefore appropriate. A longer time horizons of 10, 20 and 30 years were considered in the sensitivity analysis.</p><p>We considered structuring our model in a similar way to the chronic pain model produced for this guideline, which tied NRS scores to costs and HRQoL but this structure would have required treatment effects to be assigned specific probability distributions. We tested the assumption that spasticity NRS treatment effects were normally distributed in two ways. Firstly we calculated change from baseline in a publicly available dataset that included >1,500 MS patients treated with CBD:THC oromucosal spray (<a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina et al. 2017</a>) and examined the histogram on percentage improvement (<a class="figpopup" href="/books/NBK577084/figure/ch3.appm.fig1/?report=objectonly" target="object" rid-figpopup="figch3appmfig1" rid-ob="figobch3appmfig1">Figure 1</a>).</p><p id="ch3.appm.fig1"><a href="/books/NBK577084/figure/ch3.appm.fig1/?report=objectonly" target="object" rid-ob="figobch3appmfig1" class="figpopup">Figure 1. Histogram of response in patients treated with CBD:THC</a></p><p>We also used the baseline and change from baseline NRS data from the RCTs to simulate 60,000 theoretical patients assuming bounded normal distributions, which enabled us to calculate the proportion who improved by >30% and >50% and compare the resulting relative risks with those observed in the RCTs. The results are in <a class="figpopup" href="/books/NBK577084/table/ch3.tab2/?report=objectonly" target="object" rid-figpopup="figch3tab2" rid-ob="figobch3tab2">Table 2</a>: Comparison of Relative Risks derived from Simulations and RCTs <a class="figpopup" href="/books/NBK577084/table/ch3.tab2/?report=objectonly" target="object" rid-figpopup="figch3tab2" rid-ob="figobch3tab2">Table 2</a> and show reasonable agreement at the 30% level but poor agreement at the 50% level.</p><p id="ch3.appm.tab1"><a href="/books/NBK577084/table/ch3.appm.tab1/?report=objectonly" target="object" rid-ob="figobch3appmtab1" class="figpopup">Table 2. Comparison of Relative Risks derived from Simulations and RCTs</a></p><p>Based on these data we concluded that the continuous data were not appropriate to use and we would adopt a categorical model structure.</p><p>The model structure (see <a class="figpopup" href="/books/NBK577084/figure/ch3.appm.fig2/?report=objectonly" target="object" rid-figpopup="figch3appmfig2" rid-ob="figobch3appmfig2">Figure 2</a>) is designed to reflect the clinical evidence from RCTs (<a class="bibr" href="#ch3.appm.ref9" rid="ch3.appm.ref9">Collin et al., 2007</a>, <a class="bibr" href="#ch3.appm.ref10" rid="ch3.appm.ref10">2010</a>; <a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna et al., 2011</a>; <a class="bibr" href="#ch3.appm.ref27" rid="ch3.appm.ref27">Markova et al., 2019</a>). The model structure is similar to a published cost-effectiveness model funded by the National Institute for Health Research (NIHR) (<a class="bibr" href="#ch3.appm.ref23" rid="ch3.appm.ref23">Lu et al., 2012</a>).</p><ul id="ch3.l34"><li id="ch3.lt236" class="half_rhythm"><div>The model focused on spasticity caused by MS as good clinical evidence was only available in this population.</div></li><li id="ch3.lt237" class="half_rhythm"><div>Cohorts of patients were followed from the initiation of the treatment. Patients received either cannabis plus SoC or SoC alone</div></li><li id="ch3.lt238" class="half_rhythm"><div>Treatment response was defined as a reduction of ≥30% on the numerical rating scale (NRS) for spasticity</div></li><li id="ch3.lt239" class="half_rhythm"><div>In the cannabis strategy, patients who did not achieve a response may discontinue cannabis and receive SoC alone
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<ul id="ch3.l35" class="circle"><li id="ch3.lt240" class="half_rhythm"><div>No patients who were not >30% responders continued treatment in the base case analysis. This is an important limitation as the committee felt that treatment might be offered on an ongoing basis to some >20% responders in clinical practice.</div></li><li id="ch3.lt241" class="half_rhythm"><div>Responders remained on treatment but were subject to treatment discontinuation, after which they transitioned to the non-responder state</div></li></ul></div></li><li id="ch3.lt242" class="half_rhythm"><div>In the SoC strategy, the model assumed that a proportion of responders would lose the treatment benefit and become non-responders. This was modelled as discontinuation of the treatment benefit.
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<ul id="ch3.l36" class="circle"><li id="ch3.lt243" class="half_rhythm"><div>The model assumed that all patients would always receive SoC in the background.</div></li></ul></div></li><li id="ch3.lt244" class="half_rhythm"><div>The half-cycle correction was incorporated to take into account that the transitions happened continuously throughout each cycle, not just at the end of at the beginning of each cycle (<a class="bibr" href="#ch3.appm.ref39" rid="ch3.appm.ref39">Sonnenberg and Beck, 1993</a>; <a class="bibr" href="#ch3.appm.ref31" rid="ch3.appm.ref31">Naimark, Kabboul and Krahn, 2013</a>).</div></li><li id="ch3.lt245" class="half_rhythm"><div>Costs and outcomes were discounted at 3.5% in line with the latest NICE reference case (<a class="bibr" href="#ch3.appm.ref32" rid="ch3.appm.ref32">NICE, 2013</a>).</div></li></ul><p id="ch3.appm.fig2"><a href="/books/NBK577084/figure/ch3.appm.fig2/?report=objectonly" target="object" rid-ob="figobch3appmfig2" class="figpopup">Figure 2. Model structure</a></p></div><div id="ch3.appm.s2.3"><h4>Model parameters</h4><div id="ch3.appm.s2.3.1"><h5>Baseline characteristics</h5><p>Baseline characteristics of the model cohort are based on a large observational study (N=1,597) of THC: CBD spray (Sativex) in multiple sclerosis spasticity (<a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina et al., 2017</a>). The model assumed the mean age of the cohort at the start of the model was 51, and 47.3% are male. The model also assumed that patients had a spasticity NRS of 7.5 and MS expanding disability status scale (EDSS) of 6.4 at baseline. The mean NRS and EDSS were based on the average of the supplementary patient-level data from (<a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina et al., 2017</a>).</p><p>In the base case analysis, the model assumed a natural progression of NRS over time that NRS increased 0.227 per year, based on an increase of 1 unit in NRS took 1,609 days reported in an observational study (<a class="bibr" href="#ch3.appm.ref5" rid="ch3.appm.ref5">Arroyo et al. 2011</a>, <a class="bibr" href="#ch3.appm.ref18" rid="ch3.appm.ref18">Gras et al. 2016</a>).</p></div><div id="ch3.appm.s2.3.2"><h5>Treatment effects</h5><p>Treatment response was defined as a reduction of ≥30% on the spasticity NRS. The clinical review identified four relevant RCTs of THC: CBD spray in patients with MS spasticity. No evidence was available for other types of medicinal cannabis or for other indications.</p><p>Two of the 4 included RCTs allowed patients exceeding the maximum licenced daily dose (12 sprays) (<a class="bibr" href="#ch3.appm.ref9" rid="ch3.appm.ref9">Collin et al., 2007</a>, <a class="bibr" href="#ch3.appm.ref10" rid="ch3.appm.ref10">2010</a>) and the mean THC: CBD spray doses were 9.4 and 8.5 sprays per day respectively. The other two RCTs only allowed patients receiving the within the licenced daily dose of THC: CBD spray (<a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna et al., 2011</a>; <a class="bibr" href="#ch3.appm.ref27" rid="ch3.appm.ref27">Markova et al., 2019</a>) and the mean THC: CBD spray dose were 8.3 and 7.3 sprays per day respectively. The two within-dose RCTs had an enrichment design that all patients received and responded to THC: CBD spray for 4 weeks prior to the placebo-controlled phase.</p><p>The treatment effects of THC: CBD spray, derived from the meta-analysis in the clinical review (see <a href="#ch3.appf">Appendix F</a> for details), were presented as odds ratios (ORs) compared to the placebo from the RCTs. The OR results are summarised in <a class="figpopup" href="/books/NBK577084/table/ch3.appm.tab2/?report=objectonly" target="object" rid-figpopup="figch3appmtab2" rid-ob="figobch3appmtab2">Table 3</a>. The committee agreed that the model applied ORs from all four RCTs in the base case as the mean daily dose from all these trials are less than the maximum licenced dose of 12 THC: CBD sprays per day. The OR for THC: CBD spray within dose was tested in a sensitivity analysis.</p><p id="ch3.appm.tab2"><a href="/books/NBK577084/table/ch3.appm.tab2/?report=objectonly" target="object" rid-ob="figobch3appmtab2" class="figpopup">Table 3. Treatment effects in ORs</a></p><p>The OR results should be interpreted as follows:
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<ul id="ch3.l37"><li id="ch3.lt246" class="half_rhythm"><div>An OR of 1 indicates that there was no difference in the odds of an event between the active and placebo arms</div></li><li id="ch3.lt247" class="half_rhythm"><div>An OR <1 indicates that there are lower odds of an event in the treatment arm compared with the placebo (favours placebo)</div></li><li id="ch3.lt248" class="half_rhythm"><div>An OR >1 indicates that the odds of an event are higher in the treatment arm compared with the placebo (favours treatment)</div></li></ul></p><p>We combined the reciprocal of these odds ratios with THC:CBD response data to obtain response in the SoC arm of the model.</p><p>We had a number of options with regard to THC:CBD response. In line with methods outlined in NICE DSU Technical Support Document 13 we preferred data from the Messina registry over data from the RCTs in the base case. We also performed random effect (because i2 >50%) meta-analyses of response in the <a class="bibr" href="#ch3.appm.ref9" rid="ch3.appm.ref9">Collin 2007</a> and <a class="bibr" href="#ch3.appm.ref10" rid="ch3.appm.ref10">2010</a> RCTs and of all 4 RCTs combined. For this final analysis we had to account for the enrichment design and did this by multiplying the proportion of 30% responders in the cannabis arm of the second phase by the total number of 20% responders in the initial phase. The resulting number was divided by the total N to calculate the proportion of people who would have achieved a 30% response following treatment with THC:CBD. This produced data for <a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Navotna 2011</a> and Markova 2018 of 33% and 43% respectively, which were similar to the 31% and 40% observed in the standard-design Collin RCTs. Standard errors for input into the meta-analyses were calculated using the standard error of a proportion approach.</p><p id="ch3.appm.tab3"><a href="/books/NBK577084/table/ch3.appm.tab3/?report=objectonly" target="object" rid-ob="figobch3appmtab3" class="figpopup">Table 4. Response in Cannabis and SoC arms of the model</a></p><p>The model allowed comparison of other types of medicinal cannabis plus SoC compared to SoC alone. However, due to lack of evidence, the model assumed all other medicinal cannabis has the same treatment effects as THC: CBD spray. This is highly uncertain as there is no good quality evidence on whether other types of medicinal cannabis influence MS spasticity.</p></div><div id="ch3.appm.s2.3.3"><h5>Treatment discontinuation</h5></div><div id="ch3.appm.s2.3.4"><h5>Discontinuation following cannabis treatment initiation</h5><p>As described in the model structure section, the model assumed that majority of patients who did not respond to THC: CBD spray would discontinue the treatment and switch to receive SoC only and no longer accrued costs associated with THC: CBD spray.</p></div><div id="ch3.appm.s2.3.5"><h5>Discontinuation in patients achieving a treatment response</h5><p>Following the initial treatment response, the model assumed that the treatment responders might discontinue THC: CBD spray, either due to loss of efficacy or adverse events. Patients who discontinued the treatment would lose the treatment benefit and become a non-responder. This was based on the observational study (<a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina et al., 2017</a>), which followed up the patients on THC: CBD spray for 2 years. These patients were treated for a period of 1 month with responders remaining on treatment and non-responders discontinuing. We selected only the responders, subtracted 28 days from the total time on treatment, converted the time on treatment from days to years and performed survival analysis on these patients where discontinuations were classed as events. The model contains multiple options for discontinuation. Option 1 was to fit a parametric curve to the data. Based on AIC/BIC statistics we selected a gompertz parametric curve to use within our economic model (<a class="figpopup" href="/books/NBK577084/table/ch3.appm.tab4/?report=objectonly" target="object" rid-figpopup="figch3appmtab4" rid-ob="figobch3appmtab4">Table 5</a>).</p><p id="ch3.appm.tab4"><a href="/books/NBK577084/table/ch3.appm.tab4/?report=objectonly" target="object" rid-ob="figobch3appmtab4" class="figpopup">Table 5. Model fit statistics for discontinuation survival curve</a></p><p>The committee agreed that patients in the SoC alone strategy would also experience loss of treatment response over time. Option 1 assumed loss of response would be equal in the SoC arm and the CBMP arm. For Option 2 we fitted a competing risks model to the Messina data, coding adverse events alone as a separate, competing risk to other discontinuations. We followed the methodology in section 6.3 of the CRAN-R documentation on the flexsurv package<sup><a href="#ch3.fn1">a</a></sup> but used a gompertz model instead of the Weibull example given (because the original gompertz model provided the best fit to the data [<a class="figpopup" href="/books/NBK577084/table/ch3.appm.tab4/?report=objectonly" target="object" rid-figpopup="figch3appmtab4" rid-ob="figobch3appmtab4">Table 5</a>]). The survival curve for the CBMP arm took account of both competing risks whereas the survival curve for the SoC arm included only non-adverse event related discontinuations. Option 3 was to fit an exponential curve and assume various levels of arbitrary discontinuation and hazard ratios to see how these might affect the results.</p><p>There were no deaths recorded in the dataset although there were a number of censoring events with no reason recorded and it is possible that some of these were in fact deaths. By handling deaths separately from discontinuation it is possible that there is a small amount of double counting in the economic model. Given the relatively low average age in the dataset and therefore low mortality rate, and the fact that this issue would apply to both model arms, we assessed this limitation as minor.</p><p>Clearly there are limitations with all these approaches but in the absence of long-term data on changes in response in either the active treatment or standard of care arm the committee acknowledged that they were the best available, noted them as limitations and explored them in sensitivity analysis. Overall, Option 2 (the competing risks model with differential discontinuation) was preferred in the base case.</p><p id="ch3.appm.fig3"><a href="/books/NBK577084/figure/ch3.appm.fig3/?report=objectonly" target="object" rid-ob="figobch3appmfig3" class="figpopup">Figure 3. Cumulative Hazard Curves from Competing Risks Model</a></p><p><a class="figpopup" href="/books/NBK577084/figure/ch3.appm.fig4/?report=objectonly" target="object" rid-figpopup="figch3appmfig4" rid-ob="figobch3appmfig4">Figure 4</a> shows the estimated proportion of patients remaining as responders during the 5-year time horizon. The model assumed progression in NRS of 0.23 points per year (<a class="bibr" href="#ch3.appm.ref18" rid="ch3.appm.ref18">Gras et al 2016</a>) in both groups in the base case so costs rise and QALYs decrease somewhat in both groups over time.</p><p id="ch3.appm.fig4"><a href="/books/NBK577084/figure/ch3.appm.fig4/?report=objectonly" target="object" rid-ob="figobch3appmfig4" class="figpopup">Figure 4. Proportion of patients remained as responders over time</a></p></div><div id="ch3.appm.s2.3.6"><h5>Mortality</h5><p>The model assumed that patients with MS have a higher mortality risk compared to the general population. Published standardised mortality ratios (SMRs) (<a class="bibr" href="#ch3.appm.ref26" rid="ch3.appm.ref26">Manouchehrinia et al., 2016</a>) were applied to the UK life table (<a class="bibr" href="#ch3.appm.ref36" rid="ch3.appm.ref36">ONS, 2018</a>) to estimate the mortality risk of patients with MS-related spasticity in the model.</p><p>The committee agreed that there is no evidence that medicinal cannabis has additional survival benefit compared to the SoC only strategy, so the model assumed the same mortality risk for both cannabis + SoC and SoC alone strategies.</p></div><div id="ch3.appm.s2.3.7"><h5>Adverse events</h5><p>A systematic review of adverse effects of medical cannabinoids (<a class="bibr" href="#ch3.appm.ref44" rid="ch3.appm.ref44">Wang et al., 2008</a>) estimated the incidence rate of non-serious adverse events (AEs) for cannabinoid and control (placebo) were 10.37 and 6.87 events per person-year, respectively. For serious adverse events in cannabinoid and control were 0.37 and 0.25 events per person-year, respectively. The event rates per person-year were converted to per cycle event rate in the model.</p><p>For simplicity, we assumed non-serious adverse events were split between the important/common AEs selected by the committee: dizziness, dry mouth, fatigue, headache, nausea. The frequency of non-serious AEs is based on data reported by <a class="bibr" href="#ch3.appm.ref44" rid="ch3.appm.ref44">Wang et al., 2008</a> and, because a very wide variety of events were reported, rescaled to include only those events listed above so the total added up to 100% (see <a class="figpopup" href="/books/NBK577084/table/ch3.appm.tab5/?report=objectonly" target="object" rid-figpopup="figch3appmtab5" rid-ob="figobch3appmtab5">Table 6</a> for details).</p><p id="ch3.appm.tab5"><a href="/books/NBK577084/table/ch3.appm.tab5/?report=objectonly" target="object" rid-ob="figobch3appmtab5" class="figpopup">Table 6. Frequency of most important non-serious AEs (for determining proportions)</a></p><p>The consequent event rates per cycle and per year in the model were summarised in <a class="figpopup" href="/books/NBK577084/table/ch3.appm.tab6/?report=objectonly" target="object" rid-figpopup="figch3appmtab6" rid-ob="figobch3appmtab6">Table 7</a>.</p><p id="ch3.appm.tab6"><a href="/books/NBK577084/table/ch3.appm.tab6/?report=objectonly" target="object" rid-ob="figobch3appmtab6" class="figpopup">Table 7. Adverse event rates per cycle</a></p></div><div id="ch3.appm.s2.3.8"><h5>Utility</h5><p>Due to lack of relevant health utility data in the UK, health state utilities in the model were based on a published utility regression model of EQ-5D, spasticity NRS and EDSS of 98 patients in Sweden (<a class="bibr" href="#ch3.appm.ref41" rid="ch3.appm.ref41">Svensson, Borg and Nilsson, 2014</a>). The R-squared for the regression model was 0.6545. The regression coefficients are summarised in <a class="figpopup" href="/books/NBK577084/table/ch3.appm.tab7/?report=objectonly" target="object" rid-figpopup="figch3appmtab7" rid-ob="figobch3appmtab7">Table 8</a>.</p><p id="ch3.appm.tab7"><a href="/books/NBK577084/table/ch3.appm.tab7/?report=objectonly" target="object" rid-ob="figobch3appmtab7" class="figpopup">Table 8. Utility regression model</a></p><p>We used simulations to produce a range of options for utility values associated with NRS scores 1–10.</p><p>We simulated 10,000 hypothetical patients with NRS and EDSS scores based on the baseline NRS (mean 7.5; SD 1.45) and mean EDSS (mean 6.4; SD 1.2) data from (<a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina et al., 2017</a>) along with the correlation coefficient (=0.34) between these two variables, assuming a multivariate normal distribution For each option the average utility value for each NRS score would be the input used in the economic mode. The options we considered were:-
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<ol id="ch3.l38"><li id="ch3.lt249" class="half_rhythm"><div>Full regression model for each theoretical patient</div></li><li id="ch3.lt250" class="half_rhythm"><div>Full regression model but simulations use a weaker (0.17) correlation coefficient</div></li><li id="ch3.lt251" class="half_rhythm"><div>Use the results of the full regression model to refit a coefficient for NRS alone</div></li><li id="ch3.lt252" class="half_rhythm"><div>Use the reported NRS coefficient only</div></li><li id="ch3.lt253" class="half_rhythm"><div>Use the reported NRS coefficient along with the coefficient for the mean level of EDSS of 6.5</div></li></ol></p><p id="ch3.appm.tab8"><a href="/books/NBK577084/table/ch3.appm.tab8/?report=objectonly" target="object" rid-ob="figobch3appmtab8" class="figpopup">Table 9. Options for utility values at each spasticity NRS level</a></p><p>Based on their experience and there being reported difference in the EDSS outcome from the clinical review committee agreed that medicinal cannabis was unlikely to have an impact on EDSS scores but that mean EDSS should be reflected. They therefore agreed that option 5 was the most appropriate.</p><p>Next we needed to convert the utility estimates for NRS to dichotomous utility values for responders and non-responders. For non-responders we assumed they would have the baseline level NRS and so used the data from the Messina dataset to calculate an initial beta-distribution (chosen because NRS is bounded by 0 and 10) of NRS to calculate a weighted average. We used the method of moments method to convert mean and SD of NRS into the necessary alpha and beta parameters.</p><p id="ch3.appm.fig5"><a href="/books/NBK577084/figure/ch3.appm.fig5/?report=objectonly" target="object" rid-ob="figobch3appmfig5" class="figpopup">Figure 5. Beta distribution of baseline NRS score for calculating costs and utilities</a></p><p>For responders the method was somewhat more complex. Each of these patients must have improved by at least 30% but some would have improved a great deal more than that. To calculate the level of improvement at each 5% increment above 30% we used data on the patients who had improved by at least 29% (to account for rounding error) from the Messina dataset and fit a ‘survival curve’ to greater levels of response (see <a class="figpopup" href="/books/NBK577084/figure/ch3.appm.fig6/?report=objectonly" target="object" rid-figpopup="figch3appmfig6" rid-ob="figobch3appmfig6">Figure 6</a>). The ‘survival’ data that underpinned this were the proportional response data (change in NRS divided by baseline NRS) minus 0.29. Every observation was counted as an ‘event’ for the purposes of fitting the curve. Based on AIC/BIC statistics we selected a generalised gamma curve for use in our economic model (<a class="figpopup" href="/books/NBK577084/table/ch3.appm.tab9/?report=objectonly" target="object" rid-figpopup="figch3appmtab9" rid-ob="figobch3appmtab9">Table 10</a>).</p><p id="ch3.appm.tab9"><a href="/books/NBK577084/table/ch3.appm.tab9/?report=objectonly" target="object" rid-ob="figobch3appmtab9" class="figpopup">Table 10. Model fit data for >30% responders survival curve</a></p><p>We included options in the model for this curve to be conditional on 25% and 28% response (using the same methodology as above but using data on patients who had improved by at least 25% or 28% instead of 29%) as there are some limitations with converting changes in a 1–10 categorical scale to percentage cut-offs but neither of these produced a significantly different survival curve (see <a class="figpopup" href="/books/NBK577084/table/ch3.appm.tab10/?report=objectonly" target="object" rid-figpopup="figch3appmtab10" rid-ob="figobch3appmtab10">Table 11</a>).</p><p id="ch3.appm.fig6"><a href="/books/NBK577084/figure/ch3.appm.fig6/?report=objectonly" target="object" rid-ob="figobch3appmfig6" class="figpopup">Figure 6. % of patients had NRS improvement by at least 30%</a></p><p id="ch3.appm.tab10"><a href="/books/NBK577084/table/ch3.appm.tab10/?report=objectonly" target="object" rid-ob="figobch3appmtab10" class="figpopup">Table 11. Options for “response among responders” curve</a></p><p>We multiplied this data on the proportion of patients achieving each level of 30%+improvement, calculated using 5% segments of the cumulative probability distribution from the fitted curve, along with the initial beta distribution of pain and the utility value at each NRS score to calculate a weighted average utility among the responder cohort.</p><p>The weighted average utility of response and no response were 0.44 and 0.288, respectively. Compared with the average QALY weight in the Swedish general population (50–59 years old) of 0.82 (<a class="bibr" href="#ch3.appm.ref7" rid="ch3.appm.ref7">Burström, Johannesson and Diderichsen, 2001</a>; <a class="bibr" href="#ch3.appm.ref41" rid="ch3.appm.ref41">Svensson, Borg and Nilsson, 2014</a>), patients with spasticity had substantially lower utility regardless of treatment response. These values were applied as the health states utilities in the model.</p><p>The magnitude of utility difference between responder’s and nonresponses in our analysis was much greater than observations from published studies. Compared with the response and no response utilities in a published UK cost-effectiveness model (<a class="bibr" href="#ch3.appm.ref23" rid="ch3.appm.ref23">Lu et al., 2012</a>), the authors assumed 0.57 utility for responders and 0.48 for non-responders.</p><p>EQ-5D data from the RCTs showed a limited difference in quality of life between THC: CBD spray and placebo arms (<a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna et al., 2011</a>) but reported a significant difference between THC: CBD spray and placebo in spasticity treatment response. However, the study only observed mean EQ-5D difference of 0.02 between THC: CBD spray and placebo. Similar results were reported in another RCT (<a class="bibr" href="#ch3.appm.ref10" rid="ch3.appm.ref10">Collin et al., 2010</a>) that the difference in EQ-5D was 0.02 between THC: CBD spray and placebo. Neither observation was statistically significant. These studies also reported very small differences between the arms on the 0–100 Visual Analogue Scale despite the large treatment effect on spasticity. Two studies (<a class="bibr" href="#ch3.appm.ref22" rid="ch3.appm.ref22">Langford et al., 2013</a>; <a class="bibr" href="#ch3.appm.ref27" rid="ch3.appm.ref27">Markova et al., 2019</a>) reported no significant difference in SF-36. Overall, there was limited evidence that reduction in spasticity would lead to meaningful improvements in HRQoL, as measured by conventional instruments. The contribution of the severity of the condition, the ‘true’ relationship between spasticity and HRQoL and the insensitivity of the measures are unknown. It is possible, given the other observed data, that our model overestimates the utility gain associated with response to treatment.</p><p>AE utility decrements were taken from the literature (<a class="bibr" href="#ch3.appm.ref2" rid="ch3.appm.ref2">Ara and Brazier, 2011</a>; <a class="bibr" href="#ch3.appm.ref19" rid="ch3.appm.ref19">Hagiwara et al., 2018</a>) as shown in <a class="figpopup" href="/books/NBK577084/table/ch3.appm.tab11/?report=objectonly" target="object" rid-figpopup="figch3appmtab11" rid-ob="figobch3appmtab11">Table 12</a>. The model assumed that all adverse events lasted for a short duration (3–7 days).</p><p id="ch3.appm.tab11"><a href="/books/NBK577084/table/ch3.appm.tab11/?report=objectonly" target="object" rid-ob="figobch3appmtab11" class="figpopup">Table 12. AE disutility and duration of the events</a></p><p>The synthesis of utilities in the model follows a validated multiplicative approach (<a class="bibr" href="#ch3.appm.ref3" rid="ch3.appm.ref3">Ara and Wailoo, 2012</a>):</p><p>Evidence shows that using the baseline utility of perfect health (utility=1) ignores the natural decline in mental/physical functions due to age and co-morbidities which also affect QoL. This also assumes the detriment on QoL associated with a health condition is constant irrespective of age (<a class="bibr" href="#ch3.appm.ref1" rid="ch3.appm.ref1">Ara and Brazier, 2010</a>). To avoid these limitations, the baseline utility that was applied in the economic model is based on age-adjusted EQ-5D data for UK general population (<a class="bibr" href="#ch3.appm.ref21" rid="ch3.appm.ref21">Kind, Hardman and Macran, 1999</a>).</p><p>To derive the condition-specific utility values for the model health states and adverse events, a multiplier (M<sub>A</sub>) is estimated based on the proportional difference between the health condition utility (U<sub>A</sub>) and the utility of people without the condition (U<sub>nA</sub>):
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<div class="pmc_disp_formula whole_rhythm clearfix" id="ch3.deq1"><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow twelve_col"><math id="ch3.eq1" display="block"><mrow><msub><mtext>M</mtext><mtext>A</mtext></msub><mtext> = </mtext><msub><mtext>U</mtext><mtext>A</mtext></msub><mtext>/ </mtext><msub><mtext>U</mtext><mrow><mtext>nA</mtext></mrow></msub></mrow></math></div><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow last bk_equ_label "><div><span class="nowrap"></span></div></div></div></p><p>Utility multipliers were calculated according to the health states (response and no response) and adverse events.</p><p>Multiplicative approach, as described by <a class="bibr" href="#ch3.appm.ref3" rid="ch3.appm.ref3">Ara and Wailoo, 2012</a>, is applied to combine the health state utility multiplier (M<sub>A</sub>) and AE utility multiplier (M<sub>B</sub>):
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<div class="pmc_disp_formula whole_rhythm clearfix" id="ch3.deq2"><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow twelve_col"><math id="ch3.eq2" display="block"><mrow><msub><mtext>M</mtext><mrow><mtext>A.B</mtext></mrow></msub><mtext> = </mtext><msub><mtext>M</mtext><mtext>A</mtext></msub><mtext> </mtext><mo>×</mo><mtext> </mtext><msub><mtext>M</mtext><mtext>B</mtext></msub></mrow></math></div><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow last bk_equ_label "><div><span class="nowrap"></span></div></div></div></p><p>The combined multipliers were applied to the UK general population utility to estimate the utility of patients in the model. All utilities were adjusted by the cycle length (4 weeks).</p><p>Following the utility synthesis methods described above, the health state utility multipliers for response and no response were 0.537 and 0.352, respectively.</p><p>The AE disutility was estimated as a utility decrement and was applied using the additive approach (<a class="bibr" href="#ch3.appm.ref3" rid="ch3.appm.ref3">Ara and Wailoo, 2012</a>). Each of the AE multipliers was summarised in <a class="figpopup" href="/books/NBK577084/table/ch3.appm.tab12/?report=objectonly" target="object" rid-figpopup="figch3appmtab12" rid-ob="figobch3appmtab12">Table 13</a>:</p><p id="ch3.appm.tab12"><a href="/books/NBK577084/table/ch3.appm.tab12/?report=objectonly" target="object" rid-ob="figobch3appmtab12" class="figpopup">Table 13. AE disutility per event</a></p><p>To estimate the treatment specific AE utility decrement, the AE disutility were aggregated with the AE probabilities (dizziness for example):</p><p>The utility decrement for dizziness = dizziness disutility * % of patients with dizziness * number of days having dizziness</p><p>The weighted average AE utility decrement per year for cannabis + SoC and SoC alone strategies are 0.00329 and 0.00218, respectively.</p><p>As shown above, adverse events have almost no influence on utility. This is primarily because they only last for a few days each.</p></div><div id="ch3.appm.s2.3.9"><h5>Costs</h5></div><div id="ch3.appm.s2.3.10"><h5>Treatment costs</h5><p>Drug acquisition costs were estimated using pack/vial costs, the number of doses required per 4-week cycle. Pack/vial costs, and the associated dose strengths and pack sizes, were sourced from NHS Drug Tariff or other publicly available sources, with the doses per cycle and packs per cycle sourced from the product monographs for each therapy or published literature. The summary of drug acquisition costs was summarised in <a class="figpopup" href="/books/NBK577084/table/ch3.appm.tab13/?report=objectonly" target="object" rid-figpopup="figch3appmtab13" rid-ob="figobch3appmtab13">Table 14</a>. For medicinal cannabis, which is unavailable in the UK, such as Bedrocan products and dronabinol, the costs do not include any other costs (e.g. importation costs).</p><p>The model focused on THC: CBD spray (Sativex) as most of the evidence was on THC: CBD spray. THC: CBD spray costs £300 per 270 doses (note that the consultation version of this guideline was based on a previous list price of £375, but this was subsequently reduced by the manufacturer). The licensed dose of THC: CBD spray is a maximum of 12 sprays per day. The model applied the THC: CBD spray discount: NHS Pay for Responder scheme that first 3 × 10ml vial (90 doses per vial) for free and pay for responder only.</p><p>The model assumed a mean THC: CBD spray initial dose of 8.55 sprays per day based on the weighted average dose from the included RCTs (<a class="bibr" href="#ch3.appm.ref9" rid="ch3.appm.ref9">Collin et al., 2007</a>, <a class="bibr" href="#ch3.appm.ref10" rid="ch3.appm.ref10">2010</a>; <a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna et al., 2011</a>; <a class="bibr" href="#ch3.appm.ref27" rid="ch3.appm.ref27">Markova et al., 2019</a>). The model assumed the mean dose decreased to 6.5 per day by 12 weeks and to 6.3 by 24 weeks and remained constant. This was tested in the sensitivity analysis.</p><p>Based on the clinical expert opinions, the committee believes that the initial dose would decrease over time and stabilise around 6 months. The committee also agreed that the mean initial dose from a dataset of Sativex use at a large UK tertiary centre (<a class="bibr" href="#ch3.appm.ref13" rid="ch3.appm.ref13">De Trane et al. 2016</a>, <a class="bibr" href="#ch3.appm.ref14" rid="ch3.appm.ref14">2017</a> and personal communications with author) is similar to the mean dose from RCTs. The doses among responders decreased over time, similar to the ones reported in the Italian registry by <a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina et al. 2017</a>. Therefore, the committee agreed that it is appropriate to use the mean dose data from <a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina et al. 2017</a> and assume doses decrease over time. The committee decided that it is more appropriate to take the doses from the same reference (<a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina et al. 2017</a>) for other model parameters such as treatment response and discontinuation.</p><p>The committee reviewed the post-marketing study by <a class="bibr" href="#ch3.appm.ref17" rid="ch3.appm.ref17">Etges et al. 2016</a>. They had concerns that reported mean dose is based on a combination of patients with MS spasticity and other indications from the UK, Germany and Switzerland. It does not report the mean dose for UK patients with spasticity. They also had concerns that this study does not report the efficacy data or reported doses decreasing over time, as observed in the Sativex patient registries. Therefore, they concluded that it is not appropriate to use the mean dose from <a class="bibr" href="#ch3.appm.ref17" rid="ch3.appm.ref17">Etges et al. 2016</a>.</p><p>For dronabinol, the model applied an average acquisition cost of £1.63 per capsule (converted from US price) and assumed that patients received 6.3 capsules per day observed in an RCT (<a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek et al., 2003</a>).</p><p>As patients in both cannabis + SoC and SoC alone strategy received SoC, the model assumed £0 drug treatment cost for the SoC.</p><p id="ch3.appm.tab13"><a href="/books/NBK577084/table/ch3.appm.tab13/?report=objectonly" target="object" rid-ob="figobch3appmtab13" class="figpopup">Table 14. Medicinal cannabis costs</a></p></div><div id="ch3.appm.s2.3.11"><h5>Background management costs</h5><p>The background resource uses associated with various levels of spasticity were taken from a published UK study (<a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson et al. 2015</a>), which reported spasticity management costs by NRS categories: NRS 0–2, 2–4, 4–6, 6–8 and 8–10. The costs associated with each type of resource use were inflated from 2013 price to 2017/18 price using PSSRU 2018 HCHS inflation index (PSSRU 2018). The estimations were based on a survey of health care professionals. Advanced spasticity is highly associated with advanced disease more generally and as such, moving an average patient who is experiencing NRS 8–10 to NRS 6–8 would be unlikely to reduce resource use by the total difference between the two categories. This is because some of the reported resource use might not be spasticity specific, such as wheelchair use. The resource use costs were summarised in <a class="figpopup" href="/books/NBK577084/table/ch3.appm.tab14/?report=objectonly" target="object" rid-figpopup="figch3appmtab14" rid-ob="figobch3appmtab14">Table 15</a>:</p><p id="ch3.appm.tab14"><a href="/books/NBK577084/table/ch3.appm.tab14/?report=objectonly" target="object" rid-ob="figobch3appmtab14" class="figpopup">Table 15. spasticity management costs by NRS (based on Stevenson et al. 2015)</a></p><p>Based on the committee consensus and topic expert opinion, the committee does not think that the resource use reported in <a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson et al. 2015</a> is 100% attributable to spasticity alone. The committee felt that the vignette from the health care professional survey could be misleading as it implied the disability described in the health states were caused by spasticity only. They felt that some of the physical disability specified in the vignette, particularly in the most severe health state, were most likely related to the underlying MS. Based on published evidence and the committee clinical opinions, they do not think treating spasticity would improve the underlying disability associated with MS (measured by EDSS). Therefore, the committee believes that <a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson et al. 2015</a> overestimated spasticity-related resource use.</p><p>The committee estimated that 50% of the resource use costs from <a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson et al. (2015)</a> could be attributed to spasticity alone and therefore could be influenced by the treatment effect. However, this estimation was highly uncertain, and it was tested in the sensitivity analysis.</p><p>Not all the costs of social care come under the NHS/PSS perspective. The model assumed that the home care visits were funded by various bodies, as shown in <a class="figpopup" href="/books/NBK577084/table/ch3.appm.tab15/?report=objectonly" target="object" rid-figpopup="figch3appmtab15" rid-ob="figobch3appmtab15">Table 16</a>, based on data from Parkinson’s disease guideline (NG71). The model also assumed that 50% of part self-part NHS/PSS-funded home care visits were paid by the patients. The model did not include the costs of self-funded home care visits.</p><p id="ch3.appm.tab15"><a href="/books/NBK577084/table/ch3.appm.tab15/?report=objectonly" target="object" rid-ob="figobch3appmtab15" class="figpopup">Table 16. Proportion of funding bodies for home care visits</a></p><p>The weighted average spasticity management costs for responders and non-responders were derived in the same way as the estimates for utility. The average spasticity management costs of response and no response of the 10,000 simulations were £138.72 and £473.09 per cycle, respectively.</p></div><div id="ch3.appm.s2.3.12"><h5>Adverse event costs</h5><p>For non-serious AEs, we assumed that 50% of patients would visit their GP and accrued a GP visit cost.</p><p>For the serious adverse events, the model assumed these events required an A&E visit and a proportion of patients required an ambulance (25%) or an inpatient stay (25%).</p><p>The unit costs of the resource use were summarised in <a class="figpopup" href="/books/NBK577084/table/ch3.appm.tab16/?report=objectonly" target="object" rid-figpopup="figch3appmtab16" rid-ob="figobch3appmtab16">Table 17</a>.</p><p id="ch3.appm.tab16"><a href="/books/NBK577084/table/ch3.appm.tab16/?report=objectonly" target="object" rid-ob="figobch3appmtab16" class="figpopup">Table 17. resource use of AE management</a></p><p>The costs per event applied in the model were summarised in <a class="figpopup" href="/books/NBK577084/table/ch3.appm.tab17/?report=objectonly" target="object" rid-figpopup="figch3appmtab17" rid-ob="figobch3appmtab17">Table 18</a>:</p><p id="ch3.appm.tab17"><a href="/books/NBK577084/table/ch3.appm.tab17/?report=objectonly" target="object" rid-ob="figobch3appmtab17" class="figpopup">Table 18. Resource use costs per AE</a></p></div><div id="ch3.appm.s2.3.13"><h5>Scenario analysis: 20% response cut-off</h5><p>We undertook a special scenario analysis where we tried to approximate the use of THC:CBD in clinical practice, where patients are likely to continue with treatment if they achieve at least a 20% response. In order to do this we had to calculate several new parameters; the probability of response on cannabis, the odds ratio of response and the distribution of response among responders. All other parameters within the model remained the same except those that depend on the values taken by the above (such as utility among responders).</p><p>The baseline probability of achieving a 20% response was taken from the <a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina 2017</a> data, where 1009 out of 1432 patients with complete response data achieved this level of response.</p><p>The odds ratio of treatment response was taken from studies that reported these data and pooled in fixed effects (i2=0%) meta-analysis.</p><p id="ch3.appm.tab18"><a href="/books/NBK577084/table/ch3.appm.tab18/?report=objectonly" target="object" rid-ob="figobch3appmtab18" class="figpopup">Table 19. OR of response at 20% cut-off</a></p><p>As with the primary analysis, levels of response beyond 20% were dictated by fitting a survival curve to the percentage response data, this time subtracting 0.19 from each value. AIC/BIC statistic again showed a gamma curve provided the best fit to these data. The resulting data are in <a class="figpopup" href="/books/NBK577084/table/ch3.appm.tab19/?report=objectonly" target="object" rid-figpopup="figch3appmtab19" rid-ob="figobch3appmtab19">Table 20</a>.</p><p id="ch3.appm.tab19"><a href="/books/NBK577084/table/ch3.appm.tab19/?report=objectonly" target="object" rid-ob="figobch3appmtab19" class="figpopup">Table 20. Proportion of responders in each response category (>=20%)</a></p><p>The response proportions are used to dictate the utility and resource use among responders. In this scenario analysis the overall NRS among responders is slightly higher because patients do not need to have improved by as much to continue treatment. The model calculates a utility among >=20% responders as 0.4 (down from 0.44) and a mean resource use per cycle of £104 (up from £69). The utility and resource use among non-responders remains the same as these patients were assumed to drop back to baseline in the model.</p><p>In this analysis substantially more patients respond to both Cannabis (70% vs 29%) and the SoC (38% vs 13%). These data are both somewhat lower than those reported in the clinical trials because they are anchored to the real-world response observed in Messina, which was lower than in the RCTs.</p><p>In this scenario analysis we removed the assumption that 10% of non-responders continue treatment.</p></div><div id="ch3.appm.s2.3.14"><h5>Parametrisation in the probabilistic sensitivity analysis</h5><p><a class="figpopup" href="/books/NBK577084/table/ch3.appm.tab20/?report=objectonly" target="object" rid-figpopup="figch3appmtab20" rid-ob="figobch3appmtab20">Table 21</a> summarised all the parameters included in the probabilistic sensitivity analysis (PSA).</p><p id="ch3.appm.tab20"><a href="/books/NBK577084/table/ch3.appm.tab20/?report=objectonly" target="object" rid-ob="figobch3appmtab20" class="figpopup">Table 21. parameters in the probabilistic sensitivity analysis</a></p></div></div></div><div id="ch3.appm.s3"><h3>Results</h3><p>In the base case, THC: CBD spray + SoC was compared to SoC alone strategy. The total QALYs gained, and total costs, as well as the breakdown of the total costs, are outlined in <a class="figpopup" href="/books/NBK577084/table/ch3.appm.tab21/?report=objectonly" target="object" rid-figpopup="figch3appmtab21" rid-ob="figobch3appmtab21">Table 22</a>. Over the 5-year time horizon, THC: CBD spray + SoC strategy accrued higher treatment costs and AE costs but had a cost saving of £2,460 from reducing the resource use of the spasticity management. Compared to SoC alone, THC: CBD spray + SoC accrued £1,580 more costs and generated 0.081 more QALYs. The ICER was £19,512 per QALY gained.</p><p id="ch3.appm.tab21"><a href="/books/NBK577084/table/ch3.appm.tab21/?report=objectonly" target="object" rid-ob="figobch3appmtab21" class="figpopup">Table 22. Base case results</a></p><p>The PSA results were based on the mean of 5,000 iterations and the graphical presentation all PSA iterations was shown in <a class="figpopup" href="/books/NBK577084/figure/ch3.appm.fig7/?report=objectonly" target="object" rid-figpopup="figch3appmfig7" rid-ob="figobch3appmfig7">Figure 7</a>. The mean ICER from PSA was £21,167 per QALY, and THC: CBD spray + SoC generated £1,654 more costs and 0.078 more QALYs, similar to the ICER in the base case. At the £20,000/QALY threshold, there is a 47.7% probability that THC: CBD spray + SoC will be cost-effective, compared with a 66.0% probability of being cost-effective at the £30,000/QALY threshold(<a class="figpopup" href="/books/NBK577084/figure/ch3.appm.fig8/?report=objectonly" target="object" rid-figpopup="figch3appmfig8" rid-ob="figobch3appmfig8">Figure 8</a>).</p><p id="ch3.appm.fig7"><a href="/books/NBK577084/figure/ch3.appm.fig7/?report=objectonly" target="object" rid-ob="figobch3appmfig7" class="figpopup">Figure 7. PSA scatterplot</a></p><p id="ch3.appm.fig8"><a href="/books/NBK577084/figure/ch3.appm.fig8/?report=objectonly" target="object" rid-ob="figobch3appmfig8" class="figpopup">Figure 8. Cost-effectiveness acceptability curve</a></p><p><a class="figpopup" href="/books/NBK577084/table/ch3.appm.tab22/?report=objectonly" target="object" rid-figpopup="figch3appmtab22" rid-ob="figobch3appmtab22">Table 23</a> showed the scenario analyses using different model assumptions. The model was sensitive to the assumptions related to treatment effects (odds ratios), the dosing of THC: CBD spray and the QoL assumptions.</p><p id="ch3.appm.tab22"><a href="/books/NBK577084/table/ch3.appm.tab22/?report=objectonly" target="object" rid-ob="figobch3appmtab22" class="figpopup">Table 23. scenario analyses</a></p><p><a class="figpopup" href="/books/NBK577084/figure/ch3.appm.fig9/?report=objectonly" target="object" rid-figpopup="figch3appmfig9" rid-ob="figobch3appmfig9">Figure 9</a> and <a class="figpopup" href="/books/NBK577084/figure/ch3.appm.fig10/?report=objectonly" target="object" rid-figpopup="figch3appmfig10" rid-ob="figobch3appmfig10">Figure 10</a> showed results of ten of the most sensitive parameters in a tornado diagram.</p><p id="ch3.appm.fig9"><a href="/books/NBK577084/figure/ch3.appm.fig9/?report=objectonly" target="object" rid-ob="figobch3appmfig9" class="figpopup">Figure 9. Tornado diagram of one-way sensitivity analysis at the £20,000/QALY threshold</a></p><p id="ch3.appm.fig10"><a href="/books/NBK577084/figure/ch3.appm.fig10/?report=objectonly" target="object" rid-ob="figobch3appmfig10" class="figpopup">Figure 10. Tornado diagram of one-way sensitivity analysis at the £30,000/QALY threshold</a></p><p>Two-way sensitivity analyses were conducted some of the most important parameters; probability of response and utility values associated with the two health states. The green areas in <a class="figpopup" href="/books/NBK577084/figure/ch3.appm.fig11all/?report=objectonly" target="object" rid-figpopup="figch3appmfig11all" rid-ob="figobch3appmfig11all">Figure 11</a> show the combinations of values that lead to THC:CBD spray being cost-effective when QALYs are valued at either £20,000 or £30,000 each and the default values are indicated by orange highlights. The values within each cell represent incremental net monetary benefit.</p><div id="ch3.appm.fig11all" class="figure bk_fig"><h3><span class="label">Figure 11</span><span class="title">Results of Two-way sensitivity analyses</span></h3><p id="ch3.appm.fig11"><a href="/books/NBK577084/figure/ch3.appm.fig11/?report=objectonly" target="object" rid-ob="figobch3appmfig11" class="figpopup">Treatment response of cannabis vs. standard of care at £20,000 threshold</a></p><p id="ch3.appm.fig12"><a href="/books/NBK577084/figure/ch3.appm.fig12/?report=objectonly" target="object" rid-ob="figobch3appmfig12" class="figpopup">Treatment response of cannabis vs. standard of care at £30,000 threshold</a></p><p id="ch3.appm.fig13"><a href="/books/NBK577084/figure/ch3.appm.fig13/?report=objectonly" target="object" rid-ob="figobch3appmfig13" class="figpopup">Utility of responder vs. non-responder at £20,000 threshold</a></p><p id="ch3.appm.fig14"><a href="/books/NBK577084/figure/ch3.appm.fig14/?report=objectonly" target="object" rid-ob="figobch3appmfig14" class="figpopup">Utility of responder vs. non-responder at £30,000 threshold</a></p><p id="ch3.appm.fig15"><a href="/books/NBK577084/figure/ch3.appm.fig15/?report=objectonly" target="object" rid-ob="figobch3appmfig15" class="figpopup">THC:CBD spray (Sativex) dose per day vs. % of resource use attributable to spasticity at £20,000 threshold</a></p><p id="ch3.appm.fig16"><a href="/books/NBK577084/figure/ch3.appm.fig16/?report=objectonly" target="object" rid-ob="figobch3appmfig16" class="figpopup">THC:CBD spray (Sativex) dose per day vs. % of resource use attributable to spasticity at £30,000 threshold</a></p></div><p>A number of threshold analyses were conducted on the response, ORs of THC: CBD spray + SoC vs SoC, cost per pack for THC: CBD spray, proportion of management costs that are spasticity related, as shown in <a class="figpopup" href="/books/NBK577084/figure/ch3.appm.fig17/?report=objectonly" target="object" rid-figpopup="figch3appmfig17" rid-ob="figobch3appmfig17">Figure 12</a> to <a class="figpopup" href="/books/NBK577084/figure/ch3.appm.fig21/?report=objectonly" target="object" rid-figpopup="figch3appmfig21" rid-ob="figobch3appmfig21">Figure 16</a>.</p><p id="ch3.appm.fig17"><a href="/books/NBK577084/figure/ch3.appm.fig17/?report=objectonly" target="object" rid-ob="figobch3appmfig17" class="figpopup">Figure 12. Threshold analysis on placebo response (fixed value for cannabis response)</a></p><p id="ch3.appm.fig18"><a href="/books/NBK577084/figure/ch3.appm.fig18/?report=objectonly" target="object" rid-ob="figobch3appmfig18" class="figpopup">Figure 13. Threshold analysis on cannabis response (fixed value for placebo response)</a></p><p id="ch3.appm.fig19"><a href="/books/NBK577084/figure/ch3.appm.fig19/?report=objectonly" target="object" rid-ob="figobch3appmfig19" class="figpopup">Figure 14. Threshold analysis on OR vs placebo</a></p><p id="ch3.appm.fig20"><a href="/books/NBK577084/figure/ch3.appm.fig20/?report=objectonly" target="object" rid-ob="figobch3appmfig20" class="figpopup">Figure 15. Threshold analysis on THC: CBD spray pack cost</a></p><p id="ch3.appm.fig21"><a href="/books/NBK577084/figure/ch3.appm.fig21/?report=objectonly" target="object" rid-ob="figobch3appmfig21" class="figpopup">Figure 16. Threshold analysis on proportion of management costs that are spasticity related</a></p></div><div id="ch3.appm.s4"><h3>Discussion</h3><p>The base-case analysis showed that compared to SoC alone, at the new list price of £300 per pack, THC: CBD spray + SoC was associated with an ICER of £19,512 per QALY gained over a 5-year time horizon. The ICER results were lower than another UK cost-effectiveness model by <a class="bibr" href="#ch3.appm.ref23" rid="ch3.appm.ref23">Lu et al., 2012</a>, which reported an ICER of £49,257, which is probably due to the more favourable utility estimates we used in our model. Using the Lu et al utility estimates, the model produces an ICER of £42,344/QALY. This difference may be due to a number of input parameters, particularly the use of all 4 RCTs and a patient registry within our model rather than the results of a single RCT.</p><p>The clinical evidence showed THC: CBD spray + SoC improved the spasticity NRS compared to SoC alone and accrued cost saving in the resource use related to spasticity management. The clinical evidence also showed that THC: CBD spray had little impact on the disability scale (EDSS) (Ball et al. 2015, Kilestein et al. 2012, <a class="bibr" href="#ch3.appm.ref27" rid="ch3.appm.ref27">Markova et al. 2019</a>, van Amerongen et al. 2018, Zajicek et al. 2012) which importantly influences patients’ quality of life. This was reflected in the minimal EQ-5D difference observed in the THC: CBD spray trials (<a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna et al., 2011</a>, <a class="bibr" href="#ch3.appm.ref10" rid="ch3.appm.ref10">Collin et al., 2010</a>). Nevertheless, using a published regression analysis, our model estimated utility values of 0.29 and 0.44 for responders and non-responders. This 50% gain in HRQoL for treatment response may be an overestimate, given the lack of empirical data in support of this finding. In the committee’s experience, observable differences in quality of life are common in patients who achieve a spasticity response following treatment with THC: CBD spray, however.</p><p>The model was most sensitive to the cost of treatment, number of sprays per day, the treatment effects and treatment response parameters, which was expected. However, the THC: CBD spray strategy had much lower ICERs in the scenarios where we assumed medicinal cannabis had a strong impact on patients’ disability scale (EDSS), which the committee decided were not credible.</p><p>It is worth noting that the model was highly sensitive to the assumptions related to resource use. Doubling background management cost, effectively assuming that 100% of MS management was related specifically to spasticity, the cannabis strategy became dominant. A published study estimated that worse spasticity NRS was associated with higher resource use for spasticity management in MS (<a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson et al. 2015</a>). It was unclear how much of the reported resource use from <a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson et al. (2015)</a> attributed to spasticity only as there appeared to be large overlaps between the resource used managing spasticity and that used managing patients’ underlying disease. The manufacturer’s published model assumed that all reported resource use from <a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson et al. (2015)</a> were attributed to spasticity (<a class="bibr" href="#ch3.appm.ref18" rid="ch3.appm.ref18">Gras et al. 2016</a>), which may have led to an overestimate of cost-saving from THC: CBD spray and therefore a very low ICER of £10,891 per QALY.</p><p>The model produces somewhat different total costs and QALYs to the published cost-effectiveness analyses. On the cost side, this is principally due to the omission of social care costs in Lu and the inclusion of probable non-spasticity social care costs in Gras as well as the much longer time horizon in the case of the latter. Our model produced the lowest overall QALYs because its baseline utility values were the lowest but it also included the most optimistic QoL differential for treatment effect. The manufacturer funded Gras study only produced 0.35 incremental QALYs over a 30 year time horizon.</p><p>In the base case, the model assumed patients in the SoC alone strategy would have a response similar to the placebo response observed in the RCTs. Due to lack of long-term data, the model assumed that the treatment effect (the relative difference between THC: CBD spray + SOC and SoC alone) remain constant throughout the 5-year time horizon. As the long-term observational study of THC: CBD spray indicated that the treatment response was sustained over at least 2 years, the model assumed the response in the SoC alone strategy sustained as well. This preserved the regression to the mean and placebo effect components of the changes from baseline observed in the trials, which should be the same in both arms. To discontinue more patients from response in the SoC arm than in the cannabis arm would either imply a differential placebo effect or a strengthening treatment effect and we did not have any evidence of either. This might be a limitation as the committee thought that the placebo response from the RCTs would diminish after 6 months or so, however. We experimented with different shaped discontinuation curves: assuming that there is a 10% year-on-year discontinuation in both arms, for example, resulted in a lower ICER of £14,958/QALY.</p><p>The model included the current publicly available discount scheme offered by the only manufacturer of THC: CBD to the NHS, in which that treatment is provided for free during the first cycle but that the NHS pays for responders thereafter. Because the indication for responders is 20% improvement rather than the 30% cutoff used in the clinical trials it is likely that THC: CBD, as it is used in practice, will be offered to patients who have seen between a 20% and 30% improvement. The primary analysis attempts to adjust for this by assuming that 10% of people in the treatment arm would continue treatment even if they didn’t achieve a 30% response. Without this adjustment, the model produces an ICER of £8,759/QALY, which would be an overestimate of the cost-effectiveness of THC:CBD spray as if people with less than a 30% response would continue treatment as they would gain fewer QALYs and management savings and incur the same treatment costs as their full-responder counterparts. It is unclear whether the 10% adjustment produces an under or over-estimate of the true cost-effectiveness of this intervention. We then conducted a specific scenario analysis adjusting multiple parameters to model 20% responders receiving ongoing treatment and the model produced an ICER of £24,992/QALY. This was principally because there was an expected lower utility differential between responders and non-responders, fewer resource savings between the two groups and greater response in the SoC arm. Overall, this is an important limitation of the analysis but the explorations we have conducted on the model do not indicate that plausible adjustments lead to ICERs that are qualitatively different from those produced by the primary analysis.</p><p>When varied over their plausible ranges, a large number of the examined parameters had the potential to change model outputs to one side or the other of a £20,000 / QALY threshold. However, the model was relatively robust if QALYs are valued at £30,000 each: only the main effectiveness parameter (relative likelihood of response to THC:CBD spray), the probability of adverse events, and the proportion of costs that are attributable to spasticity had sufficient impact that the ICER could exceed £30,000/QALY.</p><p>The model did not compare different medicinal cannabis products against each other. Due to a lack of clinical evidence, the model could not accurately determine the cost-effectiveness of any other medicinal cannabis except THC: CBD spray. It is worth noting that THC: CBD spray had one of the lowest daily costs compared to most of the other medicinal cannabis products. Hence, if assuming all medicinal cannabis had the same treatment effects, THC: CBD spray would potentially dominate all the other cannabis products for treating patients with spasticity.</p></div><div id="ch3.appm.rl.r1"><h3>References</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="ch3.appm.ref1">Ara, R. & Brazier, J. E., 2010. Populating an economic model with health state utility values: moving toward better practice. Value in health: the journal of the International Society for Pharmacoeconomics and Outcomes Research, 8, 13(5), pp. 509–518. [<a href="https://pubmed.ncbi.nlm.nih.gov/20230546" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20230546</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch3.appm.ref2">Ara, R. & Brazier, J. E., 2011. Using health state utility values from the general population to approximate baselines in decision analytic models when condition-specific data are not available. Value in health: the journal of the International Society for Pharmacoeconomics and Outcomes Research, 14(4), pp. 539–545. [<a href="https://pubmed.ncbi.nlm.nih.gov/21669378" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21669378</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch3.appm.ref3">Ara, R. & Wailoo, A., 2012. Using health state utility values in models exploring the cost-effectiveness of health technologies. Value in health: the journal of the International Society for Pharmacoeconomics and Outcomes Research, 15(6), pp. 971–974. [<a href="https://pubmed.ncbi.nlm.nih.gov/22999149" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22999149</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch3.appm.ref4">Arroyo, R., Massana, M. & Vila, C., 2013. Correlation between spasticity and quality of life in patients with multiple sclerosis: the CANDLE study. The International journal of neuroscience, 12, 123(12), pp. 850–858. [<a href="https://pubmed.ncbi.nlm.nih.gov/23819835" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23819835</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch3.appm.ref5">Arroyo, R., Vila, C. & Clissold, S., 2011. Retrospective observational study of the management of multiple sclerosis patients with resistant spasticity in Spain: the ‘5E’ study. Expert review of pharmacoeconomics & outcomes research, 4, 11(2), pp. 205–213. 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et al., 2006. Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England), 10, 12(5), pp. 639–645. [<a href="https://pubmed.ncbi.nlm.nih.gov/17086911" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17086911</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch3.appm.ref44">Wang, T., Collet, J.-P., Shapiro, S. & Ware, M. A., 2008. Adverse effects of medical cannabinoids: a systematic review. CMAJ: Canadian Medical Association journal = journal de l’Association medicale canadienne, 6, 178(13), pp. 1669–1678. [<a href="/pmc/articles/PMC2413308/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2413308</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18559804" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18559804</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch3.appm.ref45">Zajicek, J.
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et al., 2003. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): Multicentre randomised placebo-controlled trial. Lancet. [<a href="https://pubmed.ncbi.nlm.nih.gov/14615106" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14615106</span></a>]</div></p></li></ul></div></div><div id="ch3.appn"><h2 id="_ch3_appn_">Appendix N. Included studies</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch3appntab1"><a href="/books/NBK577084/table/ch3.appn.tab1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch3appntab1" rid-ob="figobch3appntab1"><img class="small-thumb" src="/books/NBK577084/table/ch3.appn.tab1/?report=thumb" src-large="/books/NBK577084/table/ch3.appn.tab1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch3.appn.tab1"><a href="/books/NBK577084/table/ch3.appn.tab1/?report=objectonly" target="object" rid-ob="figobch3appntab1">Table</a></h4></div></div><div id="ch3.appn.rl.r1"><h3>Other references</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="ch3.appn.ref1">Farrar, J., Troxel, A., Stott, C., Duncombe, P. and Jensen, M. (2008). Validity, reliability, and clinical importance of change in a 0—10 numeric rating scale measure of spasticity: a post hoc analysis of a randomized, double-blind, placebo-controlled trial. Clinical Therapeutics, 30(5), pp.974–985. [<a href="https://pubmed.ncbi.nlm.nih.gov/18555944" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18555944</span></a>]</div></p></li></ul></div></div><div><h2 id="NBK577084_footnotes">Footnotes</h2><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ch3.fn1"><p class="no_top_margin"><a href="https://cran.r-project.org/web/packages/flexsurv/vignettes/flexsurv.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://cran<wbr style="display:inline-block"></wbr>​.r-project<wbr style="display:inline-block"></wbr>​.org/web/packages/flexsurv<wbr style="display:inline-block"></wbr>​/vignettes/flexsurv.pdf</a></p></div></dd></dl></dl></div><div style="display:none"><div style="display:none" id="figch3appmfig1"><img alt="Image ch3appmf1" src-large="/books/NBK577084/bin/ch3appmf1.jpg" /></div><div style="display:none" id="figch3appmfig2"><img alt="Image ch3appmf2" src-large="/books/NBK577084/bin/ch3appmf2.jpg" /></div><div style="display:none" id="figch3appmfig4"><img alt="Image ch3appmf4" src-large="/books/NBK577084/bin/ch3appmf4.jpg" /></div><div style="display:none" id="figch3appmfig6"><img alt="Image ch3appmf6" src-large="/books/NBK577084/bin/ch3appmf6.jpg" /></div><div style="display:none" id="figch3appmfig7"><img alt="Image ch3appmf7" src-large="/books/NBK577084/bin/ch3appmf7.jpg" /></div><div style="display:none" id="figch3appmfig8"><img alt="Image ch3appmf8" src-large="/books/NBK577084/bin/ch3appmf8.jpg" /></div><div style="display:none" id="figch3appmfig9"><img alt="Image ch3appmf9" src-large="/books/NBK577084/bin/ch3appmf9.jpg" /></div><div style="display:none" id="figch3appmfig10"><img alt="Image ch3appmf10" src-large="/books/NBK577084/bin/ch3appmf10.jpg" /></div><div style="display:none" id="figch3appmfig17"><img alt="Image ch3appmf17" src-large="/books/NBK577084/bin/ch3appmf17.jpg" /></div><div style="display:none" id="figch3appmfig21"><img alt="Image ch3appmf21" src-large="/books/NBK577084/bin/ch3appmf21.jpg" /></div><div style="display:none" id="figch3appmfig11"><img alt="Image ch3appmf11" src-large="/books/NBK577084/bin/ch3appmf11.jpg" /></div><div style="display:none" id="figch3appmfig12"><img alt="Image ch3appmf12" src-large="/books/NBK577084/bin/ch3appmf12.jpg" /></div><div style="display:none" id="figch3appmfig13"><img alt="Image ch3appmf13" src-large="/books/NBK577084/bin/ch3appmf13.jpg" /></div><div style="display:none" id="figch3appmfig14"><img alt="Image ch3appmf14" src-large="/books/NBK577084/bin/ch3appmf14.jpg" /></div><div style="display:none" id="figch3appmfig15"><img alt="Image ch3appmf15" src-large="/books/NBK577084/bin/ch3appmf15.jpg" /></div><div style="display:none" id="figch3appmfig16"><img alt="Image ch3appmf16" src-large="/books/NBK577084/bin/ch3appmf16.jpg" /></div></div></div><div class="fm-sec"><div><p>Final</p></div><div><p>Evidence review underpinning recommendations 1.3.1 and 1.3.2 in the NICE guideline</p><p>These evidence reviews were developed by NICE Guideline Updates Team</p></div><div><p><b>Disclaimer</b>: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.</p><p>Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.</p><p>NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the <a href="http://wales.gov.uk/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Welsh Government</a>, <a href="http://www.scotland.gov.uk/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Scottish Government</a>, and <a href="http://www.northernireland.gov.uk/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Northern Ireland Executive</a>. All NICE guidance is subject to regular review and may be updated or withdrawn.</p></div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © NICE 2019.</div><div class="small"><span class="label">Bookshelf ID: NBK577084</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/35107908" title="PubMed record of this title" ref="pagearea=meta&targetsite=entrez&targetcat=link&targettype=pubmed">35107908</a></span></div></div><div class="small-screen-prev"></div><div class="small-screen-next"></div></article><article data-type="table-wrap" id="figobch3tab1"><div id="ch3.tab1" class="table"><h3><span class="label">Table 1</span><span class="title">PICO table</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.tab1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.tab1_lrgtbl__"><table><tbody><tr><th id="hd_b_ch3.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Population</th><td headers="hd_b_ch3.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><p>Adults, young people, children and babies with spasticity.</p>
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<p>Specific considerations will be given to:
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<ul id="ch3.l1"><li id="ch3.lt1" class="half_rhythm"><div>Young people, children and babies</div></li><li id="ch3.lt2" class="half_rhythm"><div>Pregnant women and women who are breastfeeding</div></li><li id="ch3.lt3" class="half_rhythm"><div>People with existing substance abuse</div></li><li id="ch3.lt4" class="half_rhythm"><div>People with hepatic and renal failure</div></li></ul></p></td></tr><tr><th id="hd_b_ch3.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Comparator</th><td headers="hd_b_ch3.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<ul id="ch3.l2"><li id="ch3.lt5" class="half_rhythm"><div>Placebo</div></li><li id="ch3.lt6" class="half_rhythm"><div>Any relevant treatment (including physiotherapy, botulinum toxin, other management of symptoms)</div></li><li id="ch3.lt7" class="half_rhythm"><div>Combination of treatments</div></li><li id="ch3.lt8" class="half_rhythm"><div>Usual or standard care.</div></li></ul></td></tr><tr><th id="hd_b_ch3.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Outcomes</th><td headers="hd_b_ch3.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<ul id="ch3.l3"><li id="ch3.lt9" class="half_rhythm"><div>30% or greater improvement in spasticity</div></li><li id="ch3.lt10" class="half_rhythm"><div>Change in spasticity using any validated scale which measures spasticity</div></li><li id="ch3.lt11" class="half_rhythm"><div>Serious adverse events</div></li><li id="ch3.lt12" class="half_rhythm"><div>Adverse events including but not limited to sleep problems, fatigue, road traffic accidents, psychological distress, dizziness, headache, confusion state, paranoia, psychosis, substance dependence, diarrhoea at the start of treatment</div></li><li id="ch3.lt13" class="half_rhythm"><div>Withdrawals due to adverse events</div></li><li id="ch3.lt14" class="half_rhythm"><div>Substance abuse due to the use of cannabis-based medicinal product</div></li><li id="ch3.lt15" class="half_rhythm"><div>Misuse/diversion</div></li><li id="ch3.lt16" class="half_rhythm"><div>Hepatic and renal failure</div></li></ul>
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Outcomes requiring a narrative synthesis:
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<ul id="ch3.l4"><li id="ch3.lt17" class="half_rhythm"><div>Contraindications as listed in exclusion criteria</div></li><li id="ch3.lt18" class="half_rhythm"><div>Monitoring requirements, treatment durations, reviewing and stopping criteria, including how treatment should be withdrawn and stopped in the methods of included studies</div></li></ul></td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3tab2"><div id="ch3.tab2" class="table"><h3><span class="label">Table 2</span><span class="title">summary of included adult studies</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.tab2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.tab2_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference</th><th id="hd_h_ch3.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Population</th><th id="hd_h_ch3.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Intervention/ comparator</th><th id="hd_h_ch3.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Outcomes</th><th id="hd_h_ch3.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Limitations</th></tr></thead><tbody><tr><th headers="hd_h_ch3.tab2_1_1_1_1 hd_h_ch3.tab2_1_1_1_2 hd_h_ch3.tab2_1_1_1_3 hd_h_ch3.tab2_1_1_1_4 hd_h_ch3.tab2_1_1_1_5" id="hd_b_ch3.tab2_1_1_1_1" colspan="5" rowspan="1" style="text-align:left;vertical-align:middle;">Multiple sclerosis: THC: CBD spray versus placebo</th></tr><tr><td headers="hd_h_ch3.tab2_1_1_1_1 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>
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<a class="bibr" href="#ch3.appm.ref9" rid="ch3.appm.ref9">Collin 2007</a>
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</p>
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<p>(UK, Romania)</p>
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<p>Parallel RCT</p>
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</td><td headers="hd_h_ch3.tab2_1_1_1_2 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Patients with spasticity due to MS in at least 2 muscle groups with an Ashworth score of 2 or more whose current therapy failed to provide adequate relief. Patients had stable disease for at least 3 months before the study.</p>
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<p>Follow-up: 2 and 6 weeks after beginning treatment</p>
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</td><td headers="hd_h_ch3.tab2_1_1_1_3 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>THC: CBD spray (Sativex: 2.7 mg: 2.5 mg) vs placebo</p>
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<p>(n=189)</p>
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<p>During a 2-week titration phase the initial dose (1 spray) was increased to a maximum 48 sprays per day. The maintenance dose was sustained for 4 weeks.</p>
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</td><td headers="hd_h_ch3.tab2_1_1_1_4 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Change in spasticity from baseline (Ashworth)</p>
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<p>Change in spasticity from baseline (NRS)</p>
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<p>NRS responder (30% reduction in spasticity score)</p>
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</td><td headers="hd_h_ch3.tab2_1_1_1_5 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Maximum dose was above the recommended maximum in the SPC for Sativex of 12 sprays per day</td></tr><tr><td headers="hd_h_ch3.tab2_1_1_1_1 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>
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<a class="bibr" href="#ch3.appm.ref10" rid="ch3.appm.ref10">Collin 2010</a>
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</p>
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<p>(UK, Czech Republic)</p>
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<p>Parallel RCT</p>
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</td><td headers="hd_h_ch3.tab2_1_1_1_2 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Patients who have had spasticity due to MS for at least 3 months and had a mean daily NRS spasticity score of at least 24 during the 6-day baseline period. Patients had to have stable treatment for at least 30 days before study entry.</p>
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<p>Follow-up: 14 weeks</p>
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</td><td headers="hd_h_ch3.tab2_1_1_1_3 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>THC: CBD spray (Sativex: 2.7 mg: 2.5 mg) vs placebo</p>
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<p>(n=337)</p>
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<p>During the titration phase patients self-titrated to their optimal dose with a maximum of 24 sprays per day. No information on length of the titration phase</p>
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</td><td headers="hd_h_ch3.tab2_1_1_1_4 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Change in spasticity from baseline (NRS)</p>
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<p>NRS responder (30% reduction in spasticity score)</p>
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<p>Adverse events</p>
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<p>Serious adverse events</p>
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</td><td headers="hd_h_ch3.tab2_1_1_1_5 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Maximum dose was above the recommended maximum in the SPC for Sativex of 12 sprays per day</td></tr><tr><td headers="hd_h_ch3.tab2_1_1_1_1 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>
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<a class="bibr" href="#ch3.appm.ref22" rid="ch3.appm.ref22">Langford 2013</a>
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</p>
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<p>(UK, Czech Republic, Canada, Spain, France)</p>
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<p>Parallel RCT</p>
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</td><td headers="hd_h_ch3.tab2_1_1_1_2 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Patients with central neuropathic pain due to MS for at least 3 months and a score of at least 24 on pain NRS in the 6 days before study entry.</p>
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<p>Follow up: 14 weeks</p>
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</td><td headers="hd_h_ch3.tab2_1_1_1_3 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>THC: CBD spray (Sativex: 2.7 mg: 2.5 mg) vs placebo</p>
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<p>(n=141)</p>
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<p>During the 1-week titration period patients self-titrated to their optimal dose using a pre-defined escalation scheme. The maximum dose was 12 sprays per day.</p>
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</td><td headers="hd_h_ch3.tab2_1_1_1_4 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Change in spasticity from baseline (NRS)</p>
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<p>Treatment-related adverse events</p>
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<p>Treatment-related serious adverse events</p>
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<p>Withdrawal due to adverse events</p>
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</td><td headers="hd_h_ch3.tab2_1_1_1_5 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.tab2_1_1_1_1 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Leocani 2015</p>
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<p>(Italy)</p>
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<p>Cross-over RCT</p>
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</td><td headers="hd_h_ch3.tab2_1_1_1_2 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Patients with progressive primary or secondary MS for at least 12 months with moderate to severe spasticity as defined by a Modified Ashworth Scale score of at least 1+ in 1 limb. Patients were 18 years or older with an EDSS score of 3.0–6.5.</p>
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<p>Follow up: 2 weeks per study arm</p>
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</td><td headers="hd_h_ch3.tab2_1_1_1_3 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>THC: CBD spray (Sativex: 2.7 mg: 2.5 mg) vs placebo</p>
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<p>(n=34)</p>
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<p>During the 2-week titration phase the initial dose was increased by 1 spray per day until symptom relief was obtained with the minimum number of adverse events. The maximum does was 12 sprays per day.</p>
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</td><td headers="hd_h_ch3.tab2_1_1_1_4 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Change in spasticity from baseline (Ashworth)</p>
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<p>Total adverse events</p>
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<p>Withdrawal due to adverse events</p>
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</td><td headers="hd_h_ch3.tab2_1_1_1_5 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.tab2_1_1_1_1 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Markova 2018</p>
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<p>(Czech Republic, Austria)</p>
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<p>Parallel RCT</p>
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</td><td headers="hd_h_ch3.tab2_1_1_1_2 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Patients with MS-related spasticity symptoms for at least 12 months with moderate to severe spasticity defined as an NRS score greater than 4. Patients were 18 years or older, had at least a 20% reduction in spasticity during Phase A. During the wash-out period from Phase A, at least 80% of this reduction had to be lost (i.e. an increase in spasticity once treatment was stopped).</p>
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<p>Follow up: 12 weeks</p>
|
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</td><td headers="hd_h_ch3.tab2_1_1_1_3 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>THC: CBD spray (Sativex: 2.7 mg: 2.5 mg) vs placebo</p>
|
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<p>(n=106)</p>
|
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<p>Dose was titrated up during the single-blind 4-week trial period (Phase A) to a maximum of 12 sprays per day.</p>
|
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</td><td headers="hd_h_ch3.tab2_1_1_1_4 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Change in spasticity from baseline (Modified Ashworth)</p>
|
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<p>Change in spasticity from baseline (NRS)</p>
|
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<p>NRS responder (30% reduction in spasticity score)</p>
|
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<p>Total adverse events</p>
|
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<p>Serious adverse events</p>
|
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<p>Withdrawal due to adverse events</p>
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</td><td headers="hd_h_ch3.tab2_1_1_1_5 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Enriched enrolment study. Patients were only included in the RCT phase of the trial if they showed a minimum 20% improvement in spasticity during the single-blind phase (Phase A) of the trial. This may increase efficacy and reduce the incidence of adverse events.</td></tr><tr><td headers="hd_h_ch3.tab2_1_1_1_1 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>
|
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<a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna 2011</a>
|
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</p>
|
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<p>(UK, Spain, Poland, Czech Republic, Italy)</p>
|
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<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_2 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>Patients with a diagnosis of MS for at least 6 months and moderate to severe spasticity due to MS (defined by an NRS score of 4 or higher) for at least 3 months. Patients had to have at least a 20% reduction in spasticity during phase A.</p>
|
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<p>Follow up: 12 weeks</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_3 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>THC: CBD spray (Sativex: 2.7 mg: 2.5 mg) vs placebo</p>
|
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<p>(n=241)</p>
|
|
<p>During the 10-day titration period patients self-titrated using a pre-defined escalation scheme to a maximum 12 sprays per day.</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_4 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Change in spasticity from baseline (NRS)</p>
|
|
<p>NRS responder (30% reduction in spasticity score)</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_5 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Enriched enrolment study. Patients were only included in the RCT phase of the trial if they showed a minimum 20% improvement in spasticity during the single-blind phase (Phase A) of the trial. This may increase efficacy and reduce the incidence of adverse events.</p>
|
|
<p>There was no evidence of a wash-out period between Phase A and Phase B.</p>
|
|
</td></tr><tr><td headers="hd_h_ch3.tab2_1_1_1_1 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Wade 2004</p>
|
|
<p>(UK)</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_2 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Patients with a diagnosis of MS and 1 of 5 target symptoms at a sufficient level of severity (spasticity, spasms, bladder problems, tremor, pain other than musculoskeletal).</p>
|
|
<p>Follow up: 6 weeks</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_3 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>THC: CBD spray (Sativex: 2.7 mg: 2.5 mg) vs placebo</p>
|
|
<p>(n=160)</p>
|
|
<p>Patients were instructed to slowly self-titrate, aiming for an optimal balance of symptom relief and adverse events. Maximum dose was 120 mg THC and 120 mg CBD (approximately 44 sprays per day)</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_4 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Change in spasticity from baseline (VAS)</p>
|
|
<p>Change in spasticity from baseline (Modified Ashworth Scale)</p>
|
|
<p>Withdrawal due to adverse events</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_5 hd_b_ch3.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Maximum dose was above the recommended maximum in the SPC for Sativex of 12 sprays per day</td></tr><tr><th headers="hd_h_ch3.tab2_1_1_1_1 hd_h_ch3.tab2_1_1_1_2 hd_h_ch3.tab2_1_1_1_3 hd_h_ch3.tab2_1_1_1_4 hd_h_ch3.tab2_1_1_1_5" id="hd_b_ch3.tab2_1_1_9_1" colspan="5" rowspan="1" style="text-align:left;vertical-align:middle;">Multiple sclerosis: THC capsules versus placebo (synthetic THC)</th></tr><tr><td headers="hd_h_ch3.tab2_1_1_1_1 hd_b_ch3.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Ball 2015</p>
|
|
<p>(UK)</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_2 hd_b_ch3.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Patients with a diagnosis of primary or secondary MS with evidence of disease progression in the year before study enrolment. Patients were aged 18–65 with an EDSS score of 4.0–6.5</td><td headers="hd_h_ch3.tab2_1_1_1_3 hd_b_ch3.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Delta9-THC 3.5 mg capsules (synthetic THC - dronabinol) vs placebo</p>
|
|
<p>(n=498)</p>
|
|
<p>During the 4-week titration phase patients could increase the initial dose by 1 capsule twice daily until the maximum weight-related dose was achieved or adverse events developed</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_4 hd_b_ch3.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MSSS-88 score</p>
|
|
<p>Adverse events</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_5 hd_b_ch3.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.tab2_1_1_1_1 hd_b_ch3.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>
|
|
<a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a>
|
|
</p>
|
|
<p>(UK)</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_2 hd_b_ch3.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Patients who had a diagnosis of MS which was stable for 6 months before study entry and an Ashworth score of 2 or higher in 2 or more lower limb muscles. Patients were aged 18–64 years.</p>
|
|
<p>Follow up: 15 weeks</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_3 hd_b_ch3.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 intervention arms v placebo:
|
|
<ol id="ch3.l7"><li id="ch3.lt25" class="half_rhythm"><div>Delta9-THC 2.5 mg capsules (synthetic THC - dronabinol)</div></li><li id="ch3.lt26" class="half_rhythm"><div>THC: CBD capsules (2.5 mg:1.25 mg) (cannabis extract)</div></li></ol>
|
|
<p>(n=657)</p><p>During the 5-week titration phase patients could increase the initial dose each week by 1 capsule twice per day. Maximum dose was based on body weight</p></td><td headers="hd_h_ch3.tab2_1_1_1_4 hd_b_ch3.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Change in spasticity from baseline (Ashworth Scale)</p>
|
|
<p>Adverse events</p>
|
|
<p>Serious adverse events</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_5 hd_b_ch3.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.tab2_1_1_1_1 hd_b_ch3.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Zajicek 2005</p>
|
|
<p>(UK)</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_2 hd_b_ch3.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Long-term follow-up from <a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a></p>
|
|
<p>Follow up: 52 weeks</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_3 hd_b_ch3.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>See <a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a></p>
|
|
<p>n=383</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_4 hd_b_ch3.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">See <a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a></td><td headers="hd_h_ch3.tab2_1_1_1_5 hd_b_ch3.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><th headers="hd_h_ch3.tab2_1_1_1_1 hd_h_ch3.tab2_1_1_1_2 hd_h_ch3.tab2_1_1_1_3 hd_h_ch3.tab2_1_1_1_4 hd_h_ch3.tab2_1_1_1_5" id="hd_b_ch3.tab2_1_1_13_1" colspan="5" rowspan="1" style="text-align:left;vertical-align:middle;">Multiple sclerosis: THC capsules versus placebo (purified THC from cannabis extract)</th></tr><tr><td headers="hd_h_ch3.tab2_1_1_1_1 hd_b_ch3.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Van Amerongen 2018</p>
|
|
<p>(Netherlands)</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_2 hd_b_ch3.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Patients with progressive primary or secondary MS according to revised McDonald criteria for more than 1 year. Patients had moderate spasticity defined by an Ashworth score of 2 or higher, stable treatment for at least 30 days before study enrolment and an EDSS score of 4.5–7.5</p>
|
|
<p>Follow up: 4 weeks</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_3 hd_b_ch3.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Delta9-THC capsules (Namisol - purified THC from cannabis extract) at doses of 3, 5 and 8 mg vs placebo</p>
|
|
<p>The optimal dose was found during 2 clinic visits with a cross-over of 3, 5 and 8 mg THC and 100-minute interval between doses. No information on the timing of the clinic visits</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_4 hd_b_ch3.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Change in spasticity from baseline (Ashworth Scale)</p>
|
|
<p>Change in spasticity from baseline (NRS)</p>
|
|
<p>Adverse events</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_5 hd_b_ch3.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><th headers="hd_h_ch3.tab2_1_1_1_1 hd_h_ch3.tab2_1_1_1_2 hd_h_ch3.tab2_1_1_1_3 hd_h_ch3.tab2_1_1_1_4 hd_h_ch3.tab2_1_1_1_5" id="hd_b_ch3.tab2_1_1_15_1" colspan="5" rowspan="1" style="text-align:left;vertical-align:middle;">Multiple sclerosis: THC:CBD cannabis extract capsules versus placebo (purified THC from cannabis extract)</th></tr><tr><td headers="hd_h_ch3.tab2_1_1_1_1 hd_b_ch3.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>
|
|
<a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a>
|
|
</p>
|
|
<p>(UK)</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_2 hd_b_ch3.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">See <a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a> (THC capsules)</td><td headers="hd_h_ch3.tab2_1_1_1_3 hd_b_ch3.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">See <a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a> (THC capsules)</td><td headers="hd_h_ch3.tab2_1_1_1_4 hd_b_ch3.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">See <a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a> (THC capsules)</td><td headers="hd_h_ch3.tab2_1_1_1_5 hd_b_ch3.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.tab2_1_1_1_1 hd_b_ch3.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Zajicek 2005</p>
|
|
<p>(UK)</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_2 hd_b_ch3.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">See <a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a> (THC capsules)</td><td headers="hd_h_ch3.tab2_1_1_1_3 hd_b_ch3.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">See <a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a> (THC capsules)</td><td headers="hd_h_ch3.tab2_1_1_1_4 hd_b_ch3.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">See <a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a> (THC capsules)</td><td headers="hd_h_ch3.tab2_1_1_1_5 hd_b_ch3.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.tab2_1_1_1_1 hd_b_ch3.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Zajicek 2012</p>
|
|
<p>(UK)</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_2 hd_b_ch3.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Patients aged 18–64 years with a diagnosis of MS according to the McDonald criteria and stable symptoms for 6 months prior to study entry</p>
|
|
<p>Follow up: 12 weeks</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_3 hd_b_ch3.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Delta9-THC capsules (extract from cannabis sativa L, standardised on cannabidiol (range 0.8–1.8 mg) and containing 2.5 mg Δ9- THC:1.25 mg CBD as the main cannabinoid vs placebo</p>
|
|
<p>(n=279)</p>
|
|
<p>During the 2-week titration phase the initial dose was increased by 5 mg per day every 3 days for up to 12 days to a maximum dose of 25 mg per day</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_4 hd_b_ch3.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MSSS-88 score (by category not overall score)</p>
|
|
<p>Treatment-related adverse events</p>
|
|
<p>Total serious adverse events</p>
|
|
<p>Withdrawals due to adverse events</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_5 hd_b_ch3.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><th headers="hd_h_ch3.tab2_1_1_1_1 hd_h_ch3.tab2_1_1_1_2 hd_h_ch3.tab2_1_1_1_3 hd_h_ch3.tab2_1_1_1_4 hd_h_ch3.tab2_1_1_1_5" id="hd_b_ch3.tab2_1_1_19_1" colspan="5" rowspan="1" style="text-align:left;vertical-align:middle;">Motor neurone disease: THC: CBD spray versus placebo</th></tr><tr><td headers="hd_h_ch3.tab2_1_1_1_1 hd_b_ch3.tab2_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Riva 2018</p>
|
|
<p>(Italy)</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_2 hd_b_ch3.tab2_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Patients aged 18–80 with amyotrophic lateral sclerosis as defined by the revised El Escorial criteria or primary lateral sclerosis according to Pringle’s criteria. Patients had a spasticity score of at least 1 on the Modified Ashworth scale in 2 or more muscle groups and had stable treatment for 30 days before study enrolment</p>
|
|
<p>Follow up: 4 weeks</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_3 hd_b_ch3.tab2_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>THC: CBD spray (2.7 mg: 2.5 mg) vs placebo</p>
|
|
<p>(n=60)</p>
|
|
<p>During the 2-week titration phase the initial dose was increased up to a maximum dose of 12 sprays per day. No information provided on how the dose was titrated</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_4 hd_b_ch3.tab2_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Change in spasticity from baseline (NRS)</p>
|
|
<p>Change in spasticity from baseline (Ashworth)</p>
|
|
<p>Total adverse events</p>
|
|
<p>Treatment-related adverse events</p>
|
|
<p>Total serious adverse events</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_5 hd_b_ch3.tab2_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><th headers="hd_h_ch3.tab2_1_1_1_1 hd_h_ch3.tab2_1_1_1_2 hd_h_ch3.tab2_1_1_1_3 hd_h_ch3.tab2_1_1_1_4 hd_h_ch3.tab2_1_1_1_5" id="hd_b_ch3.tab2_1_1_21_1" colspan="5" rowspan="1" style="text-align:left;vertical-align:middle;">Motor neurone disease: Nabilone versus placebo</th></tr><tr><td headers="hd_h_ch3.tab2_1_1_1_1 hd_b_ch3.tab2_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Wissel 2006</p>
|
|
<p>(Austra, Germany, Switzerland)</p>
|
|
<p>Cross-over RCT</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_2 hd_b_ch3.tab2_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Patients with chronic upper motor neurone syndrome and disabling spasticity-related pain. Passive stretch of the spastic muscles had to result in increased pain perception in the stimulated muscles</td><td headers="hd_h_ch3.tab2_1_1_1_3 hd_b_ch3.tab2_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Delta9-THC capsules (nabilone – 0.5 mg) vs placebo</p>
|
|
<p>(n=13)</p>
|
|
<p>During the 1-week titration phase the initial dose (0.5 mg) could be increased to 1 mg per day</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_4 hd_b_ch3.tab2_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Change in spasticity from baseline (Ashworth)</td><td headers="hd_h_ch3.tab2_1_1_1_5 hd_b_ch3.tab2_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><th headers="hd_h_ch3.tab2_1_1_1_1 hd_h_ch3.tab2_1_1_1_2 hd_h_ch3.tab2_1_1_1_3 hd_h_ch3.tab2_1_1_1_4 hd_h_ch3.tab2_1_1_1_5" id="hd_b_ch3.tab2_1_1_23_1" colspan="5" rowspan="1" style="text-align:left;vertical-align:middle;">Spinal cord injury: Nabilone versus placebo</th></tr><tr><td headers="hd_h_ch3.tab2_1_1_1_1 hd_b_ch3.tab2_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Pooyania 2010</p>
|
|
<p>(Canada)</p>
|
|
<p>Cross-over RCT</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_2 hd_b_ch3.tab2_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Patients aged 18–65 with spinal cord injury which occurred within the previous year at level C5 (ASIA grade A-D) or below. Patients had moderate spasticity with an Ashworth score of 3 or above, no change in ASIA neurologic level in the last 6 months and stable treatment for 30 days before study entry</p>
|
|
<p>Follow up: 4 weeks per trial arm</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_3 hd_b_ch3.tab2_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Delta9-THC capsules (nabilone – 0.5 mg) vs placebo</p>
|
|
<p>(n=12)</p>
|
|
<p>During weeks 3 and 4 the initial dose (0.5 mg) could be increased to 0.5 mg twice per day depending on adverse events</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_4 hd_b_ch3.tab2_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Change in spasticity from baseline (Ashworth)</p>
|
|
<p>Change in spasticity from baseline (VAS)</p>
|
|
<p>Total serious adverse events</p>
|
|
</td><td headers="hd_h_ch3.tab2_1_1_1_5 hd_b_ch3.tab2_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3tab3"><div id="ch3.tab3" class="table"><h3><span class="label">Table 4</span><span class="title">summary of interventions and doses in the included studies with adult population</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.tab3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.tab3_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Intervention (number of studies, n)</th><th id="hd_h_ch3.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Indication</th><th id="hd_h_ch3.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Dose and duration</th><th id="hd_h_ch3.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Patient monitoring</th><th id="hd_h_ch3.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Stopping criteria</th></tr></thead><tbody><tr><td headers="hd_h_ch3.tab3_1_1_1_1" rowspan="2" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>THC: CBD spray</p>
|
|
<p>(n= 7)</p>
|
|
</td><td headers="hd_h_ch3.tab3_1_1_1_2" rowspan="2" colspan="1" style="text-align:left;vertical-align:top;">Multiple sclerosis</td><td headers="hd_h_ch3.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>
|
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<u>Higher dose than recommended</u>
|
|
</p>
|
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<p>Maximum 24 - 48 sprays per day (1 spray = 2.7 mg THC:2.5 mg CBD)</p>
|
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<p>One study reported a titration phase of 2 weeks</p>
|
|
<p>No information on timing of doses</p>
|
|
</td><td headers="hd_h_ch3.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Two RCTs included monitoring visits 2 weeks after the beginning of treatment. One study also included an additional follow-up at 6 weeks.</p>
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<p>Monitoring visits included a review of the doses used, use of concomitant medication, spasticity and adverse events.</p>
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</td><td headers="hd_h_ch3.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>One RCT reported that the development of adverse events could lead to medication being stopped.</p>
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|
<p>No information was provided on how the dose was reduced.</p>
|
|
</td></tr><tr><td headers="hd_h_ch3.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>
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<u>Within recommended dose</u>
|
|
</p>
|
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<p>Maximum 12 sprays per day (1 spray = 2.7 mg THC:2.5 mg CBD)</p>
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<p>Titration phases were between 1 - 4 weeks. One study reported that the dose was increased by 1 spray per day until symptom relief was achieved with minimum adverse events</p>
|
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<p>No information on timing of doses</p>
|
|
</td><td headers="hd_h_ch3.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Two RCTs reported the timing of monitoring visits. One study included a visit 2 weeks after the start of treatment and the other reported visits at baseline followed by 4, 6 and 10 weeks after beginning medication.</p>
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<p>Monitoring included a review of adverse events, spasticity and routine blood and urine analysis including a review of THC levels.</p>
|
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</td><td headers="hd_h_ch3.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>One RCT reported that patients were monitored for adverse events and, if necessary, the dose was reduced until adverse events were resolved.</p>
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|
<p>No information was provided on how the dose was reduced.</p>
|
|
</td></tr><tr><td headers="hd_h_ch3.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>THC capsules</p>
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|
<p>(synthetic THC)</p>
|
|
<p>(n=3)</p>
|
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</td><td headers="hd_h_ch3.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Multiple sclerosis</td><td headers="hd_h_ch3.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Maximum dose was based on body weight</p>
|
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<p>Titration phases were between 4 – 5 weeks during which time the dose could be increased each week by 1 capsule twice daily. Dose could be increased until maximum age-related dose was reached, or adverse events developed</p>
|
|
<p>No information on timing of doses</p>
|
|
</td><td headers="hd_h_ch3.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>One RCT included initial monitoring visits at 2 and 4 weeks after the beginning of treatment to allow for dose adjustment and monitoring of adverse events. Later follow-up visits were at 3 and 6 months and every 6 months from then on. Another RCT included monitoring visits at 2, 4, 8 and 12 weeks.</p>
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|
<p>Monitoring visits included a review of adverse events, spasticity, muscle spasms, walking ability, haematology, liver function and a general health questionnaire.</p>
|
|
</td><td headers="hd_h_ch3.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>One RCT reported that patients were monitored for adverse events. If adverse events were considered intolerable then the dose was reduced.</p>
|
|
<p>If necessary, medication was reduced by 1 capsule twice daily until the patient was off medication.</p>
|
|
</td></tr><tr><td headers="hd_h_ch3.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>THC capsules</p>
|
|
<p>(cannabis extract)</p>
|
|
<p>(n=1)</p>
|
|
</td><td headers="hd_h_ch3.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Multiple sclerosis</td><td headers="hd_h_ch3.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Maximum dose 16 mg per day (initial dose of 3, 5 and 8 mg)</p>
|
|
<p>Titration phase took place during 2 clinic visits</p>
|
|
<p>No information on timing of doses</p>
|
|
</td><td headers="hd_h_ch3.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>One RCT included a monitoring visit at 2 weeks.</p>
|
|
<p>No information was provided for the timing of further follow up visits or what was reviewed during these visits.</p>
|
|
</td><td headers="hd_h_ch3.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>One RCT reported that adverse events were monitored, and patients were returned to their initial dose if adverse events were intolerable.</p>
|
|
<p>No information was provided on how the dose was reduced.</p>
|
|
</td></tr><tr><td headers="hd_h_ch3.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>THC: CBD capsules</p>
|
|
<p>(cannabis extract)</p>
|
|
<p>(n=3)</p>
|
|
</td><td headers="hd_h_ch3.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Multiple sclerosis</td><td headers="hd_h_ch3.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Maximum dose was based on body weight for 1 study and was 25 mg THC for another (Initial dose was 1 capsule – 2.5 mg THC:1.25 mg CBD)</p>
|
|
<p>Titration phase for 1 study was 5 weeks during which time the dose was increased each week by 1 capsule twice daily. Another study had a titration phase of 12 days during which the dose could be increased by 5 mg THC every 3 days</p>
|
|
<p>No information on the timing of doses</p>
|
|
</td><td headers="hd_h_ch3.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>One RCT included monitoring visits every 2 weeks for the first 6 weeks after the start of medication followed by visits every 2–4 weeks from week 7 onwards. Another study included monitoring visits at 2, 4, 8 and 12 weeks.</p>
|
|
<p>Monitoring visits included a review of adverse events, spasticity, muscle spasms, walking ability and a general health questionnaire.</p>
|
|
</td><td headers="hd_h_ch3.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not reported</td></tr><tr><td headers="hd_h_ch3.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>THC: CBD spray</p>
|
|
<p>(n=1)</p>
|
|
</td><td headers="hd_h_ch3.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Motor neurone disease</td><td headers="hd_h_ch3.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Maximum 12 sprays per day (1 spray = 2.7 mg THC:2.5 mg CBD)</p>
|
|
<p>Titration phase of 2 weeks but no information on how dose was titrated</p>
|
|
<p>No information on the timing of doses</p>
|
|
</td><td headers="hd_h_ch3.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>One RCT included monitoring visits at baseline and 4 weeks after the beginning of medication in addition to a follow up phone call at 3 weeks.</p>
|
|
<p>Monitoring included a review of adverse events, spasticity, pain, spasm frequency and sleep quality.</p>
|
|
</td><td headers="hd_h_ch3.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Medication was stopped if there was no improvement in symptoms. If patients experienced intolerable adverse events, they were advised not to increase the dose. Medication was temporarily stopped if nausea and anxiety were reported.</p>
|
|
<p>No information was provided on how the dose was reduced.</p>
|
|
</td></tr><tr><td headers="hd_h_ch3.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>THC capsules</p>
|
|
<p>(synthetic THC)</p>
|
|
<p>(n=1)</p>
|
|
</td><td headers="hd_h_ch3.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Motor neurone disease</td><td headers="hd_h_ch3.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Maximum 1 mg per day (initial dose 0.5 mg per day)</p>
|
|
<p>During the 3<sup>rd</sup> week the dose could be increased to the maximum dose</p>
|
|
<p>No information provided on the timing of doses</p>
|
|
</td><td headers="hd_h_ch3.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
|
|
<p>No information was provided on the timing of monitoring visits.</p>
|
|
<p>Monitoring included a review of spasticity, motor performance, use of concomitant medication and adverse events.</p>
|
|
</td><td headers="hd_h_ch3.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not reported</td></tr><tr><td headers="hd_h_ch3.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>THC capsules</p>
|
|
<p>(synthetic THC)</p>
|
|
<p>(n=1)</p>
|
|
</td><td headers="hd_h_ch3.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Spinal cord injury</td><td headers="hd_h_ch3.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Maximum 0.5 mg twice per day initial dose 0.5 mg once per day) depending on adverse events</p>
|
|
<p>No information provided on the timing of doses</p>
|
|
</td><td headers="hd_h_ch3.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>No information was provided on the timing of monitoring visits.</p>
|
|
<p>Monitoring included a review of side effects, vital signs and adverse events.</p>
|
|
</td><td headers="hd_h_ch3.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
|
|
<p>Patients were monitored for adverse events. If considered necessary, they could return to the initial dose at any time during treatment.</p>
|
|
<p>No information was provided on how the dose was reduced.</p>
|
|
</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3tab4"><div id="ch3.tab4" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.tab4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.tab4_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch3.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch3.tab4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch3.tab4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Effect size (95% CI)</th><th id="hd_h_ch3.tab4_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th><th id="hd_h_ch3.tab4_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Interpretation of effect</th></tr></thead><tbody><tr><th headers="hd_h_ch3.tab4_1_1_1_1 hd_h_ch3.tab4_1_1_1_2 hd_h_ch3.tab4_1_1_1_3 hd_h_ch3.tab4_1_1_1_4 hd_h_ch3.tab4_1_1_1_5 hd_h_ch3.tab4_1_1_1_6" id="hd_b_ch3.tab4_1_1_1_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Reduction in patient-reported spasticity from baseline (Numerical rating scale)</th></tr><tr><td headers="hd_h_ch3.tab4_1_1_1_1 hd_b_ch3.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3 (<a class="bibr" href="#ch3.appm.ref9" rid="ch3.appm.ref9">Collin 2007</a>, <a class="bibr" href="#ch3.appm.ref10" rid="ch3.appm.ref10">Collin 2010</a>, Wade 2004)</td><td headers="hd_h_ch3.tab4_1_1_1_2 hd_b_ch3.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.tab4_1_1_1_3 hd_b_ch3.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">558</td><td headers="hd_h_ch3.tab4_1_1_1_4 hd_b_ch3.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD −0.76</p>
|
|
<p>(−1.50, −0.01)</p>
|
|
</td><td headers="hd_h_ch3.tab4_1_1_1_5 hd_b_ch3.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td><td headers="hd_h_ch3.tab4_1_1_1_6 hd_b_ch3.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours THC:CBD spray</td></tr><tr><th headers="hd_h_ch3.tab4_1_1_1_1 hd_h_ch3.tab4_1_1_1_2 hd_h_ch3.tab4_1_1_1_3 hd_h_ch3.tab4_1_1_1_4 hd_h_ch3.tab4_1_1_1_5 hd_h_ch3.tab4_1_1_1_6" id="hd_b_ch3.tab4_1_1_3_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Number of people reporting 30% or greater reduction in spasticity (Numerical rating scale)</th></tr><tr><td headers="hd_h_ch3.tab4_1_1_1_1 hd_b_ch3.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 (<a class="bibr" href="#ch3.appm.ref9" rid="ch3.appm.ref9">Collin 2007</a>, <a class="bibr" href="#ch3.appm.ref10" rid="ch3.appm.ref10">Collin 2010</a>)</td><td headers="hd_h_ch3.tab4_1_1_1_2 hd_b_ch3.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.tab4_1_1_1_3 hd_b_ch3.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">521</td><td headers="hd_h_ch3.tab4_1_1_1_4 hd_b_ch3.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 0.71</p>
|
|
<p>(0.53, 0.94)</p>
|
|
</td><td headers="hd_h_ch3.tab4_1_1_1_5 hd_b_ch3.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td><td headers="hd_h_ch3.tab4_1_1_1_6 hd_b_ch3.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours THC:CBD spray</td></tr><tr><th headers="hd_h_ch3.tab4_1_1_1_1 hd_h_ch3.tab4_1_1_1_2 hd_h_ch3.tab4_1_1_1_3 hd_h_ch3.tab4_1_1_1_4 hd_h_ch3.tab4_1_1_1_5 hd_h_ch3.tab4_1_1_1_6" id="hd_b_ch3.tab4_1_1_5_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Total adverse events</th></tr><tr><td headers="hd_h_ch3.tab4_1_1_1_1 hd_b_ch3.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch3.appm.ref10" rid="ch3.appm.ref10">Collin 2010</a>)</td><td headers="hd_h_ch3.tab4_1_1_1_2 hd_b_ch3.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.tab4_1_1_1_3 hd_b_ch3.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">288</td><td headers="hd_h_ch3.tab4_1_1_1_4 hd_b_ch3.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 1.20</p>
|
|
<p>(1.10, 1.32)</p>
|
|
</td><td headers="hd_h_ch3.tab4_1_1_1_5 hd_b_ch3.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td><td headers="hd_h_ch3.tab4_1_1_1_6 hd_b_ch3.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours placebo</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3tab5"><div id="ch3.tab5" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.tab5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.tab5_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch3.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch3.tab5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch3.tab5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Effect size (95% CI)</th><th id="hd_h_ch3.tab5_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th><th id="hd_h_ch3.tab5_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Interpretation of effect</th></tr></thead><tbody><tr><th headers="hd_h_ch3.tab5_1_1_1_1 hd_h_ch3.tab5_1_1_1_2 hd_h_ch3.tab5_1_1_1_3 hd_h_ch3.tab5_1_1_1_4 hd_h_ch3.tab5_1_1_1_5 hd_h_ch3.tab5_1_1_1_6" id="hd_b_ch3.tab5_1_1_1_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Reduction in patient-reported spasticity from baseline (Numerical rating scale)</th></tr><tr><td headers="hd_h_ch3.tab5_1_1_1_1 hd_b_ch3.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4 (<a class="bibr" href="#ch3.appm.ref22" rid="ch3.appm.ref22">Langford 2013</a>, Leocani 2015, Markova 2018, <a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna 2011</a>)</td><td headers="hd_h_ch3.tab5_1_1_1_2 hd_b_ch3.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>3 Parallel RCTs</p>
|
|
<p>1 cross-over RCT</p>
|
|
</td><td headers="hd_h_ch3.tab5_1_1_1_3 hd_b_ch3.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">754</td><td headers="hd_h_ch3.tab5_1_1_1_4 hd_b_ch3.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD −0.78</p>
|
|
<p>(−1.51, −0.06)</p>
|
|
</td><td headers="hd_h_ch3.tab5_1_1_1_5 hd_b_ch3.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td><td headers="hd_h_ch3.tab5_1_1_1_6 hd_b_ch3.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours THC: CBD spray</td></tr><tr><th headers="hd_h_ch3.tab5_1_1_1_1 hd_h_ch3.tab5_1_1_1_2 hd_h_ch3.tab5_1_1_1_3 hd_h_ch3.tab5_1_1_1_4 hd_h_ch3.tab5_1_1_1_5 hd_h_ch3.tab5_1_1_1_6" id="hd_b_ch3.tab5_1_1_3_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Number of people with 30% or greater reduction in clinician-measured spasticity (Ashworth scale)</th></tr><tr><td headers="hd_h_ch3.tab5_1_1_1_1 hd_b_ch3.tab5_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna 2011</a>)</td><td headers="hd_h_ch3.tab5_1_1_1_2 hd_b_ch3.tab5_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.tab5_1_1_1_3 hd_b_ch3.tab5_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">241</td><td headers="hd_h_ch3.tab5_1_1_1_4 hd_b_ch3.tab5_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 0.69</p>
|
|
<p>(0.56, 0.85)</p>
|
|
</td><td headers="hd_h_ch3.tab5_1_1_1_5 hd_b_ch3.tab5_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td><td headers="hd_h_ch3.tab5_1_1_1_6 hd_b_ch3.tab5_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours THC: CBD spray</td></tr><tr><th headers="hd_h_ch3.tab5_1_1_1_1 hd_h_ch3.tab5_1_1_1_2 hd_h_ch3.tab5_1_1_1_3 hd_h_ch3.tab5_1_1_1_4 hd_h_ch3.tab5_1_1_1_5 hd_h_ch3.tab5_1_1_1_6" id="hd_b_ch3.tab5_1_1_5_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Number of people reporting 30% or greater reduction in spasticity (Numerical rating scale)</th></tr><tr><td headers="hd_h_ch3.tab5_1_1_1_1 hd_b_ch3.tab5_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 (Markova 2018, <a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna 2011</a>)</td><td headers="hd_h_ch3.tab5_1_1_1_2 hd_b_ch3.tab5_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.tab5_1_1_1_3 hd_b_ch3.tab5_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">347</td><td headers="hd_h_ch3.tab5_1_1_1_4 hd_b_ch3.tab5_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 0.55</p>
|
|
<p>(0.33, 0.92)</p>
|
|
</td><td headers="hd_h_ch3.tab5_1_1_1_5 hd_b_ch3.tab5_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td><td headers="hd_h_ch3.tab5_1_1_1_6 hd_b_ch3.tab5_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours THC: CBD spray</td></tr><tr><th headers="hd_h_ch3.tab5_1_1_1_1 hd_h_ch3.tab5_1_1_1_2 hd_h_ch3.tab5_1_1_1_3 hd_h_ch3.tab5_1_1_1_4 hd_h_ch3.tab5_1_1_1_5 hd_h_ch3.tab5_1_1_1_6" id="hd_b_ch3.tab5_1_1_7_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Treatment-related adverse events</th></tr><tr><td headers="hd_h_ch3.tab5_1_1_1_1 hd_b_ch3.tab5_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 (<a class="bibr" href="#ch3.appm.ref22" rid="ch3.appm.ref22">Langford 2013</a>, Markova 2018)</td><td headers="hd_h_ch3.tab5_1_1_1_2 hd_b_ch3.tab5_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.tab5_1_1_1_3 hd_b_ch3.tab5_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">445</td><td headers="hd_h_ch3.tab5_1_1_1_4 hd_b_ch3.tab5_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 1.20</p>
|
|
<p>(1.03, 1.40)</p>
|
|
</td><td headers="hd_h_ch3.tab5_1_1_1_5 hd_b_ch3.tab5_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">High</td><td headers="hd_h_ch3.tab5_1_1_1_6 hd_b_ch3.tab5_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours placebo</td></tr><tr><th headers="hd_h_ch3.tab5_1_1_1_1 hd_h_ch3.tab5_1_1_1_2 hd_h_ch3.tab5_1_1_1_3 hd_h_ch3.tab5_1_1_1_4 hd_h_ch3.tab5_1_1_1_5 hd_h_ch3.tab5_1_1_1_6" id="hd_b_ch3.tab5_1_1_9_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Withdrawal due to adverse events</th></tr><tr><td headers="hd_h_ch3.tab5_1_1_1_1 hd_b_ch3.tab5_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3 (<a class="bibr" href="#ch3.appm.ref22" rid="ch3.appm.ref22">Langford 2013</a>, Leocani 2015, <a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna 2011</a>)</td><td headers="hd_h_ch3.tab5_1_1_1_2 hd_b_ch3.tab5_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>2 Parallel RCTs</p>
|
|
<p>1 cross-over RCT</p>
|
|
</td><td headers="hd_h_ch3.tab5_1_1_1_3 hd_b_ch3.tab5_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">650</td><td headers="hd_h_ch3.tab5_1_1_1_4 hd_b_ch3.tab5_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 2.02</p>
|
|
<p>(1.05, 3.87)</p>
|
|
</td><td headers="hd_h_ch3.tab5_1_1_1_5 hd_b_ch3.tab5_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">High</td><td headers="hd_h_ch3.tab5_1_1_1_6 hd_b_ch3.tab5_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours placebo</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3tab6"><div id="ch3.tab6" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.tab6/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.tab6_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch3.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch3.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch3.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Effect size (95% CI)</th><th id="hd_h_ch3.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th><th id="hd_h_ch3.tab6_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Interpretation of effect</th></tr></thead><tbody><tr><th headers="hd_h_ch3.tab6_1_1_1_1 hd_h_ch3.tab6_1_1_1_2 hd_h_ch3.tab6_1_1_1_3 hd_h_ch3.tab6_1_1_1_4 hd_h_ch3.tab6_1_1_1_5 hd_h_ch3.tab6_1_1_1_6" id="hd_b_ch3.tab6_1_1_1_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Reduction in clinician-measured total body spasticity from baseline (Ashworth scale)</th></tr><tr><td headers="hd_h_ch3.tab6_1_1_1_1 hd_b_ch3.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 (<a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a>, Zajicek 2005)</td><td headers="hd_h_ch3.tab6_1_1_1_2 hd_b_ch3.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.tab6_1_1_1_3 hd_b_ch3.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">749</td><td headers="hd_h_ch3.tab6_1_1_1_4 hd_b_ch3.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD −1.38</p>
|
|
<p>(−2.47, −0.29)</p>
|
|
</td><td headers="hd_h_ch3.tab6_1_1_1_5 hd_b_ch3.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td><td headers="hd_h_ch3.tab6_1_1_1_6 hd_b_ch3.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours THC capsules</td></tr><tr><th headers="hd_h_ch3.tab6_1_1_1_1 hd_h_ch3.tab6_1_1_1_2 hd_h_ch3.tab6_1_1_1_3 hd_h_ch3.tab6_1_1_1_4 hd_h_ch3.tab6_1_1_1_5 hd_h_ch3.tab6_1_1_1_6" id="hd_b_ch3.tab6_1_1_3_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Withdrawals due to adverse events</th></tr><tr><td headers="hd_h_ch3.tab6_1_1_1_1 hd_b_ch3.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 (<a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a>, Zajicek 2005)</td><td headers="hd_h_ch3.tab6_1_1_1_2 hd_b_ch3.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.tab6_1_1_1_3 hd_b_ch3.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">823</td><td headers="hd_h_ch3.tab6_1_1_1_4 hd_b_ch3.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 3.55</p>
|
|
<p>(1.82, 6.91)</p>
|
|
</td><td headers="hd_h_ch3.tab6_1_1_1_5 hd_b_ch3.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td><td headers="hd_h_ch3.tab6_1_1_1_6 hd_b_ch3.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours placebo</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3tab7"><div id="ch3.tab7" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.tab7/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.tab7_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch3.tab7_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch3.tab7_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch3.tab7_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Effect size (95% CI)</th><th id="hd_h_ch3.tab7_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th><th id="hd_h_ch3.tab7_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Interpretation of effect</th></tr></thead><tbody><tr><th headers="hd_h_ch3.tab7_1_1_1_1 hd_h_ch3.tab7_1_1_1_2 hd_h_ch3.tab7_1_1_1_3 hd_h_ch3.tab7_1_1_1_4 hd_h_ch3.tab7_1_1_1_5 hd_h_ch3.tab7_1_1_1_6" id="hd_b_ch3.tab7_1_1_1_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Effect of spasticity on muscle stiffness (MSSS-88 subscale)</th></tr><tr><td headers="hd_h_ch3.tab7_1_1_1_1 hd_b_ch3.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Zajicek 2012)</td><td headers="hd_h_ch3.tab7_1_1_1_2 hd_b_ch3.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.tab7_1_1_1_3 hd_b_ch3.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">277</td><td headers="hd_h_ch3.tab7_1_1_1_4 hd_b_ch3.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD 3.70</p>
|
|
<p>(1.77, 5.63)</p>
|
|
</td><td headers="hd_h_ch3.tab7_1_1_1_5 hd_b_ch3.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td><td headers="hd_h_ch3.tab7_1_1_1_6 hd_b_ch3.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours THC:CBD capsules</td></tr><tr><th headers="hd_h_ch3.tab7_1_1_1_1 hd_h_ch3.tab7_1_1_1_2 hd_h_ch3.tab7_1_1_1_3 hd_h_ch3.tab7_1_1_1_4 hd_h_ch3.tab7_1_1_1_5 hd_h_ch3.tab7_1_1_1_6" id="hd_b_ch3.tab7_1_1_3_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Effect of spasticity on muscle spasms (MSSS-88 subscale)</th></tr><tr><td headers="hd_h_ch3.tab7_1_1_1_1 hd_b_ch3.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Zajicek 2012)</td><td headers="hd_h_ch3.tab7_1_1_1_2 hd_b_ch3.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.tab7_1_1_1_3 hd_b_ch3.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">277</td><td headers="hd_h_ch3.tab7_1_1_1_4 hd_b_ch3.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD 3.10</p>
|
|
<p>(0.85, 5.35)</p>
|
|
</td><td headers="hd_h_ch3.tab7_1_1_1_5 hd_b_ch3.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td><td headers="hd_h_ch3.tab7_1_1_1_6 hd_b_ch3.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours THC:CBD capsules</td></tr><tr><th headers="hd_h_ch3.tab7_1_1_1_1 hd_h_ch3.tab7_1_1_1_2 hd_h_ch3.tab7_1_1_1_3 hd_h_ch3.tab7_1_1_1_4 hd_h_ch3.tab7_1_1_1_5 hd_h_ch3.tab7_1_1_1_6" id="hd_b_ch3.tab7_1_1_5_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Effect of spasticity on ability to walk (MSSS-88 subscale)</th></tr><tr><td headers="hd_h_ch3.tab7_1_1_1_1 hd_b_ch3.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Zajicek 2012)</td><td headers="hd_h_ch3.tab7_1_1_1_2 hd_b_ch3.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.tab7_1_1_1_3 hd_b_ch3.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">277</td><td headers="hd_h_ch3.tab7_1_1_1_4 hd_b_ch3.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD 1.60</p>
|
|
<p>(0.43, 2.77)</p>
|
|
</td><td headers="hd_h_ch3.tab7_1_1_1_5 hd_b_ch3.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td><td headers="hd_h_ch3.tab7_1_1_1_6 hd_b_ch3.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours THC:CBD capsules</td></tr><tr><th headers="hd_h_ch3.tab7_1_1_1_1 hd_h_ch3.tab7_1_1_1_2 hd_h_ch3.tab7_1_1_1_3 hd_h_ch3.tab7_1_1_1_4 hd_h_ch3.tab7_1_1_1_5 hd_h_ch3.tab7_1_1_1_6" id="hd_b_ch3.tab7_1_1_7_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Effect of spasticity on body movement (MSSS-88 subscale)</th></tr><tr><td headers="hd_h_ch3.tab7_1_1_1_1 hd_b_ch3.tab7_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Zajicek 2012)</td><td headers="hd_h_ch3.tab7_1_1_1_2 hd_b_ch3.tab7_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.tab7_1_1_1_3 hd_b_ch3.tab7_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">277</td><td headers="hd_h_ch3.tab7_1_1_1_4 hd_b_ch3.tab7_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD 2.10</p>
|
|
<p>(0.26, 3.94)</p>
|
|
</td><td headers="hd_h_ch3.tab7_1_1_1_5 hd_b_ch3.tab7_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td><td headers="hd_h_ch3.tab7_1_1_1_6 hd_b_ch3.tab7_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours THC:CBD capsules</td></tr><tr><th headers="hd_h_ch3.tab7_1_1_1_1 hd_h_ch3.tab7_1_1_1_2 hd_h_ch3.tab7_1_1_1_3 hd_h_ch3.tab7_1_1_1_4 hd_h_ch3.tab7_1_1_1_5 hd_h_ch3.tab7_1_1_1_6" id="hd_b_ch3.tab7_1_1_9_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Treatment-related adverse events</th></tr><tr><td headers="hd_h_ch3.tab7_1_1_1_1 hd_b_ch3.tab7_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Zajicek 2012)</td><td headers="hd_h_ch3.tab7_1_1_1_2 hd_b_ch3.tab7_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.tab7_1_1_1_3 hd_b_ch3.tab7_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">277</td><td headers="hd_h_ch3.tab7_1_1_1_4 hd_b_ch3.tab7_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 1.25</p>
|
|
<p>(1.12, 1.39)</p>
|
|
</td><td headers="hd_h_ch3.tab7_1_1_1_5 hd_b_ch3.tab7_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td><td headers="hd_h_ch3.tab7_1_1_1_6 hd_b_ch3.tab7_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours placebo</td></tr><tr><th headers="hd_h_ch3.tab7_1_1_1_1 hd_h_ch3.tab7_1_1_1_2 hd_h_ch3.tab7_1_1_1_3 hd_h_ch3.tab7_1_1_1_4 hd_h_ch3.tab7_1_1_1_5 hd_h_ch3.tab7_1_1_1_6" id="hd_b_ch3.tab7_1_1_11_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Withdrawals due to adverse events</th></tr><tr><td headers="hd_h_ch3.tab7_1_1_1_1 hd_b_ch3.tab7_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3 (<a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a>, Zajicek 2005, Zajicek 2012)</td><td headers="hd_h_ch3.tab7_1_1_1_2 hd_b_ch3.tab7_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.tab7_1_1_1_3 hd_b_ch3.tab7_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1115</td><td headers="hd_h_ch3.tab7_1_1_1_4 hd_b_ch3.tab7_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 2.96</p>
|
|
<p>(1.81, 4.83)</p>
|
|
</td><td headers="hd_h_ch3.tab7_1_1_1_5 hd_b_ch3.tab7_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td><td headers="hd_h_ch3.tab7_1_1_1_6 hd_b_ch3.tab7_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours placebo</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3tab8"><div id="ch3.tab8" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.tab8/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.tab8_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch3.tab8_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch3.tab8_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch3.tab8_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Effect size (95% CI)</th><th id="hd_h_ch3.tab8_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th><th id="hd_h_ch3.tab8_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Interpretation of effect</th></tr></thead><tbody><tr><th headers="hd_h_ch3.tab8_1_1_1_1 hd_h_ch3.tab8_1_1_1_2 hd_h_ch3.tab8_1_1_1_3 hd_h_ch3.tab8_1_1_1_4 hd_h_ch3.tab8_1_1_1_5 hd_h_ch3.tab8_1_1_1_6" id="hd_b_ch3.tab8_1_1_1_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Reduction in clinician-measured spasticity from baseline (Modified Ashworth scale)</th></tr><tr><td headers="hd_h_ch3.tab8_1_1_1_1 hd_b_ch3.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Riva 2019)</td><td headers="hd_h_ch3.tab8_1_1_1_2 hd_b_ch3.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.tab8_1_1_1_3 hd_b_ch3.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">59</td><td headers="hd_h_ch3.tab8_1_1_1_4 hd_b_ch3.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD −0.27</p>
|
|
<p>(−0.51, −0.03)</p>
|
|
</td><td headers="hd_h_ch3.tab8_1_1_1_5 hd_b_ch3.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">High</td><td headers="hd_h_ch3.tab8_1_1_1_6 hd_b_ch3.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours THC:CBD spray</td></tr><tr><th headers="hd_h_ch3.tab8_1_1_1_1 hd_h_ch3.tab8_1_1_1_2 hd_h_ch3.tab8_1_1_1_3 hd_h_ch3.tab8_1_1_1_4 hd_h_ch3.tab8_1_1_1_5 hd_h_ch3.tab8_1_1_1_6" id="hd_b_ch3.tab8_1_1_3_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Total adverse events</th></tr><tr><td headers="hd_h_ch3.tab8_1_1_1_1 hd_b_ch3.tab8_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Riva 2019)</td><td headers="hd_h_ch3.tab8_1_1_1_2 hd_b_ch3.tab8_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.tab8_1_1_1_3 hd_b_ch3.tab8_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">59</td><td headers="hd_h_ch3.tab8_1_1_1_4 hd_b_ch3.tab8_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 2.84</p>
|
|
<p>(1.52, 5.33)</p>
|
|
</td><td headers="hd_h_ch3.tab8_1_1_1_5 hd_b_ch3.tab8_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">High</td><td headers="hd_h_ch3.tab8_1_1_1_6 hd_b_ch3.tab8_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours placebo</td></tr><tr><th headers="hd_h_ch3.tab8_1_1_1_1 hd_h_ch3.tab8_1_1_1_2 hd_h_ch3.tab8_1_1_1_3 hd_h_ch3.tab8_1_1_1_4 hd_h_ch3.tab8_1_1_1_5 hd_h_ch3.tab8_1_1_1_6" id="hd_b_ch3.tab8_1_1_5_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Treatment-related adverse events</th></tr><tr><td headers="hd_h_ch3.tab8_1_1_1_1 hd_b_ch3.tab8_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Riva 2019)</td><td headers="hd_h_ch3.tab8_1_1_1_2 hd_b_ch3.tab8_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.tab8_1_1_1_3 hd_b_ch3.tab8_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">59</td><td headers="hd_h_ch3.tab8_1_1_1_4 hd_b_ch3.tab8_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 5.43</p>
|
|
<p>(2.12, 13.90)</p>
|
|
</td><td headers="hd_h_ch3.tab8_1_1_1_5 hd_b_ch3.tab8_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">High</td><td headers="hd_h_ch3.tab8_1_1_1_6 hd_b_ch3.tab8_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours placebo</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3tab9"><div id="ch3.tab9" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.tab9/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.tab9_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch3.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch3.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch3.tab9_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Effect size (95% CI)</th><th id="hd_h_ch3.tab9_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th><th id="hd_h_ch3.tab9_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Interpretation of effect</th></tr></thead><tbody><tr><th headers="hd_h_ch3.tab9_1_1_1_1 hd_h_ch3.tab9_1_1_1_2 hd_h_ch3.tab9_1_1_1_3 hd_h_ch3.tab9_1_1_1_4 hd_h_ch3.tab9_1_1_1_5 hd_h_ch3.tab9_1_1_1_6" id="hd_b_ch3.tab9_1_1_1_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Reduction in clinician-measured spasticity from baseline (Ashworth scale)</th></tr><tr><td headers="hd_h_ch3.tab9_1_1_1_1 hd_b_ch3.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Pooyania 2010)</td><td headers="hd_h_ch3.tab9_1_1_1_2 hd_b_ch3.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cross-over RCT</td><td headers="hd_h_ch3.tab9_1_1_1_3 hd_b_ch3.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">22</td><td headers="hd_h_ch3.tab9_1_1_1_4 hd_b_ch3.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD −2.55</p>
|
|
<p>(−3.84, −1.26)</p>
|
|
</td><td headers="hd_h_ch3.tab9_1_1_1_5 hd_b_ch3.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td><td headers="hd_h_ch3.tab9_1_1_1_6 hd_b_ch3.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours THC capsules</td></tr></tbody></table></div></div></article><article data-type="boxed-text" id="figobch3box2"><div id="ch3.box2" class="box boxed-text-box whole_rhythm hide-overflow"><p>This evidence review supports <a href="/books/n/niceng144/?report=reader" class="toc-item">recommendations 1.3.1</a> and <a href="/books/n/niceng144/?report=reader" class="toc-item">1.3.2</a> and the research recommendation on spasticity.</p></div></article><article data-type="table-wrap" id="figobch3appatab1"><div id="ch3.appa.tab1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appa.tab1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appa.tab1_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Field (based on <a href="http://www.prisma-statement.org/Extensions/Protocols.aspx" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PRISMA-P</a></th><th id="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Content</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Review question</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>What is the clinical and cost effectiveness of cannabis-based medicinal products for people with spasticity?</p>
|
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<p>What are the adverse effects or complications of cannabis-based medicinal products for people with spasticity?</p>
|
|
<p>What are the contraindications, potential interactions and risks and cautions for use of cannabis-based medicinal products for people with spasticity?</p>
|
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<p>What are the individual patient monitoring requirements, treatment durations, reviewing and stopping criteria, including how should treatment be withdrawn or stopped, for use of cannabis-based medicinal products for people with spasticity?</p>
|
|
</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Type of review question</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Intervention</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Objective of the review</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">To determine the effectiveness, harms and cost-effectiveness of cannabis based medicinal products in reducing spasticity</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Eligibility criteria – population/disease/condition/issue/domain</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Adults, young people, children and babies.</p>
|
|
<p>Specific considerations will be given to:
|
|
<ul id="ch3.l17"><li id="ch3.lt39" class="half_rhythm"><div>Young people, children and babies</div></li><li id="ch3.lt40" class="half_rhythm"><div>Pregnant women and women who are breastfeeding</div></li><li id="ch3.lt41" class="half_rhythm"><div>People with existing substance misuse</div></li><li id="ch3.lt42" class="half_rhythm"><div>People with hepatic and renal failure</div></li></ul></p>
|
|
<p>The following definition of spasticity was used:</p>
|
|
<p>A specific form of increased muscle tone (hypertonia) where one or more of the following are present:
|
|
<ul id="ch3.l18"><li id="ch3.lt43" class="half_rhythm"><div>The resistance to externally imposed movement increases with increasing speed of stretch and varies with the direction of joint movement.</div></li><li id="ch3.lt44" class="half_rhythm"><div>The resistance to externally imposed movement increases rapidly beyond a threshold speed or joint angle</div></li></ul></p>
|
|
</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Eligibility criteria – intervention</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><p>Cannabis-based products for medicinal use (as per government definition):</p>
|
|
<p>A cannabis-based product for medicinal use that is a preparation or other product, other than one to which paragraph 5 of part 1 of schedule 4 applies, which:</p>
|
|
<p>is or contains cannabis, cannabis resin, cannabinol or a cannabinol derivative (not being dronabinol or its stereoisomers)</p>
|
|
<p>is produced for medicinal use in humans; and</p>
|
|
<p>is a medicinal product, or</p>
|
|
<p>a substance or preparation for use as an ingredient of, or in the production of an ingredient of, a medicinal product (<a href="http://www.legislation.gov.uk/uksi/2018/1055/made" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MDR 2018 regulations</a>)</p>
|
|
<p>Synthetic compounds which are identical in structure to naturally occurring cannabinoids such as delta-9-tetrahydrocannabinol (THC) for example dronabinol</p><p>Licensed products Sativex and nabilone</p><p>Plant-derived cannabinoids such as pure cannabidiol</p><p>For the purpose of this guideline, all the interventions above will be classed as cannabis-based medicinal products.</p></td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Eligibility criteria – comparator</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Placebo</p>
|
|
<p>Any relevant treatment (including physiotherapy, botulinum toxin, other management of symptoms)</p>
|
|
<p>Combination of treatments</p>
|
|
<p>Usual or standard care.</p>
|
|
</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Outcomes</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>30% or greater improvement in spasticity</p>
|
|
<p>Change in spasticity measured using any validated scale which measures spasticity.</p>
|
|
<p>Serious adverse events</p>
|
|
<p>Adverse events including but not limited to: sleep problems, fatigue, road traffic accidents, psychological distress, dizziness, headache, confusion state, paranoia, psychosis, substance dependence, diarrhoea at the start of treatment</p>
|
|
<p>Withdrawals due to adverse events</p>
|
|
<p>Substance abuse due to the use of cannabis-based medicinal product.</p>
|
|
<p>Misuse/diversion</p>
|
|
<p>Hepatic or renal failure</p>
|
|
<p>Outcomes requiring a narrative synthesis:</p>
|
|
<p>Contraindications as listed in exclusion criteria</p>
|
|
<p>Monitoring requirements, treatment durations, reviewing and stopping criteria, including how should treatment be withdrawn stopped as discussed in the methods of included studies.</p>
|
|
</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Eligibility criteria – study design</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>For adults:</p>
|
|
<p>RCTs</p>
|
|
<p>Systematic reviews of RCTs</p>
|
|
<p>The committee noted that a minimum of 5 RCTs were required to provide adequate evidence. If less than five RCTs identified, prospective cohort studies will be used.</p>
|
|
<p>For children:</p>
|
|
<p>RCTs</p>
|
|
<p>Systematic reviews of RCTs</p>
|
|
<p>If less than five RCTs identified, prospective and retrospective cohort studies will be used.</p>
|
|
<p>Additional information on safety concerns and contraindications will be obtained from the Summary of Product Characteristics and other relevant sources, such as the U.S Food and Drugs Administration.</p>
|
|
</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Other inclusion/exclusion criteria</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Inclusion</p>
|
|
<p>Cannabis-based products for the medicinal use when other treatments haven’t helped or have been discounted.</p>
|
|
<p>Exclusion</p>
|
|
<p>Synthetic cannabinoids In schedule 1 of the 2001 regulations,</p>
|
|
<p>Smoked cannabis-based products</p>
|
|
<p>Studies which do not report the doses or the concentration of cannabinoid constituents.</p>
|
|
<p>For randomised crossover studies, washout periods of less than 1 week.</p>
|
|
<p>Rigidity due to Parkinson’s disease. The committee noted that studies for Parkinson’s disease may be measuring rigidity rather than spasticity.</p>
|
|
</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">sub-group analysis</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Subgroups, where possible, will include:</p>
|
|
<p>Young people, children and babies</p>
|
|
<p>Pregnant women and women who are breastfeeding</p>
|
|
<p>People with existing substance abuse</p>
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<p>Spasticity in relation to multiple sclerosis (MS)</p>
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<p>People with hepatic and renal failure</p>
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</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Selection process – duplicate screening/selection/analysis</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10% of the abstracts will be reviewed by two reviewers, with any disagreements will be resolved by discussion or, if necessary, a third independent reviewer. If meaningful disagreements are found between the different reviewers, a further 10% of the abstracts will be reviewed by two reviewers, with this process continuing until agreement is achieved between the two reviewers. From this point, the remaining abstracts will be screened by a single reviewer.</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Data management (software)</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">See <a href="#ch3.appb">Appendix B</a>.</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Information sources – databases and dates</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Sources to be searched</p>
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<p>Clinical searches - Medline, Medline in Process, Medline EPub Ahead of Print, Embase, Cochrane CDSR, CENTRAL, DARE (legacy records), HTA, MHRA.</p>
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<p>Economic searches - Medline, Medline in Process, Medline EPub Ahead of Print, Embase, Econlit, NHS EED (legacy records) and HTA, with economic evaluations and quality of life filters applied.</p>
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<p>Supplementary search techniques</p>
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<p>None identified</p>
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<p>Limits</p>
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<p>Studies reported in English</p>
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<p>Study design RCT, SR and Observational filter will be applied (as agreed)</p>
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<p>Animal studies will be excluded from the search results</p>
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<p>Conference abstracts will be excluded from the search results</p>
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<p>No date limit will be set.</p>
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</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Identify if an update</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Author contacts</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Guideline updates team</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Highlight if amendment to previous protocol</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">This is a new protocol.</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Search strategy – for one database</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">For details please see <a href="#ch3.appc">Appendix C</a> of relevant chapter.</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Data collection process – forms/duplicate</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">A standardised evidence table format will be used, and published as <a href="#ch3.appd">Appendix D</a> (clinical evidence tables) or <a href="#ch3.apph">H</a> (economic evidence tables).</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Data items – define all variables to be collected</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">For details please see evidence tables in <a href="#ch3.appd">Appendix D</a> (clinical evidence tables) or <a href="#ch3.apph">H</a> (economic evidence tables).</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Methods for assessing bias at outcome/study level</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Study checklists were used to critically appraise individual studies. For details please see <a href="#ch3.apph">Appendix H</a> of <a href="https://www.nice.org.uk/process/pmg20/chapter/introduction-and-overview" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Developing NICE guidelines: the manual</a></p>
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<p>The following checklists will be used:</p>
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<p>Risk of bias of intervention studies - systematic reviews and meta-analyses will be assessed using the Risk of Bias in Systematic Reviews (ROBIS) checklist</p>
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<p>Risk of bias of intervention studies – randomised controlled trials (individual or cluster) will be assessed using the Cochrane risk of bias (RoB) 2.0 tool</p>
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<p>Risk of bias of cohort studies will be assessed using Cochrane ROBINS-I</p>
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<p>The risk of bias across all available evidence was evaluated for each outcome using an adaptation of the ‘Grading of Recommendations Assessment, Development and Evaluation (GRADE) toolbox’ developed by the international GRADE working group <a href="http://www.gradeworkinggroup.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://www<wbr style="display:inline-block"></wbr>​.gradeworkinggroup.org/</a></p>
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</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Criteria for quantitative synthesis</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">For details please see section 6 of <a href="https://www.nice.org.uk/article/pmg20/chapter/6-Reviewing-research-evidence#assessing-the-quality-of-the-evidence" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Developing NICE guidelines: the manual</a></td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Methods for quantitative analysis – combining studies and exploring (in)consistency</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">For details please see the <a href="#ch3.s1.2">methods and process</a> section of the main file.</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Meta-bias assessment – publication bias, selective reporting bias</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">For details please see section 6 of <a href="https://www.nice.org.uk/article/pmg20/chapter/6-Reviewing-research-evidence#assessing-the-quality-of-the-evidence" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Developing NICE guidelines: the manual</a>.</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Confidence in cumulative evidence</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">For details please see sections 6 of <a href="https://www.nice.org.uk/article/pmg20/chapter/1-Introduction-and-overview" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Developing NICE guidelines: the manual</a></td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rationale/context – what is known</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">For details please see the introduction to the evidence review in the main file.</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Describe contributions of authors and guarantor</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>A multidisciplinary committee [add link to history page of the guideline] developed the evidence review. The committee was convened by NICE Guideline Updates Team and chaired by Steve Pilling in line with section 3 of <a href="https://www.nice.org.uk/article/pmg20/chapter/1%20Introduction%20and%20overview" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Developing NICE guidelines: the manual</a>.</p>
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<p>Staff from NICE undertook systematic literature searches, appraised the evidence, conducted meta-analysis and cost-effectiveness analysis where appropriate, and drafted the evidence review in collaboration with the committee. For details please see <a href="https://www.nice.org.uk/process/pmg20/chapter/introduction-and-overview" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Developing NICE guidelines: the manual</a>.</p>
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</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Sources of funding/support</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">The NICE Guideline Updates Team is an internal team within NICE.</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Name of sponsor</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">The NICE Guideline Updates Team is an internal team within NICE.</td></tr><tr><td headers="hd_h_ch3.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Roles of sponsor</td><td headers="hd_h_ch3.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">The NICE Guideline Updates Team is an internal team within NICE.</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appbtab1"><div id="ch3.appb.tab1" class="table"><h3><span class="label">Table 1</span><span class="title">Rationale for downgrading quality of evidence for intervention studies</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appb.tab1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appb.tab1_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appb.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">GRADE criteria</th><th id="hd_h_ch3.appb.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reasons for downgrading quality</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appb.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Risk of bias</td><td headers="hd_h_ch3.appb.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Not serious: If less than 33.3% of the weight in a meta-analysis came from studies at moderate or high risk of bias, the overall outcome was not downgraded.</p>
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<p>Serious: If greater than 33.3% of the weight in a meta-analysis came from studies at moderate or high risk of bias, the outcome was downgraded one level.</p>
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<p>Very serious: If greater than 33.3% of the weight in a meta-analysis came from studies at high risk of bias, the outcome was downgraded two levels.</p>
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<p>Outcomes meeting the criteria for downgrading above were not downgraded if there was evidence the effect size was not meaningfully different between studies at high and low risk of bias.</p>
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</td></tr><tr><td headers="hd_h_ch3.appb.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Indirectness</td><td headers="hd_h_ch3.appb.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Not serious: If less than 33.3% of the weight in a meta-analysis came from partially indirect or indirect studies, the overall outcome was not downgraded.</p>
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<p>Serious: If greater than 33.3% of the weight in a meta-analysis came from partially indirect or indirect studies, the outcome was downgraded one level.</p>
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<p>Very serious: If greater than 33.3% of the weight in a meta-analysis came from indirect studies, the outcome was downgraded two levels.</p>
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<p>Outcomes meeting the criteria for downgrading above were not downgraded if there was evidence the effect size was not meaningfully different between direct and indirect studies.</p>
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</td></tr><tr><td headers="hd_h_ch3.appb.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Inconsistency</td><td headers="hd_h_ch3.appb.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Concerns about inconsistency of effects across studies, occurring when there is unexplained variability in the treatment effect demonstrated across studies (heterogeneity), after appropriate pre-specified subgroup analyses have been conducted. This was assessed using the I<sup>2</sup> statistic.</p>
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<p>N/A: Inconsistency was marked as not applicable if data on the outcome was only available from one study.</p>
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<p>Not serious: If the I<sup>2</sup> was less than 33.3%, the outcome was not downgraded.</p>
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<p>Serious: If the I<sup>2</sup> was between 33.3% and 66.7%, the outcome was downgraded one level.</p>
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<p>Very serious: If the I<sup>2</sup> was greater than 66.7%, the outcome was downgraded two levels.</p>
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<p>Outcomes meeting the criteria for downgrading above were not downgraded if there was evidence the effect size was not meaningfully different between studies with the smallest and largest effect sizes.</p>
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</td></tr><tr><td headers="hd_h_ch3.appb.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Imprecision</td><td headers="hd_h_ch3.appb.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>If the line of no effect was defined as an MID for the outcome, it was downgraded once if the 95% confidence interval for the effect size crossed the line of no effect (i.e. the outcome was not statistically significant), and twice if the sample size of the study was sufficiently small that it is not plausible any realistic effect size could have been detected.</p>
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<p>Outcomes meeting the criteria for downgrading above were not downgraded if the confidence interval was sufficiently narrow that the upper and lower bounds would correspond to clinically equivalent scenarios.</p>
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</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobch3appdfig1"><div id="ch3.appd.fig1" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appdf1&p=BOOKS&id=577084_ch3appdf1.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appdf1.jpg" alt="Image ch3appdf1" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch3appdfig2"><div id="ch3.appd.fig2" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appdf2&p=BOOKS&id=577084_ch3appdf2.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appdf2.jpg" alt="Image ch3appdf2" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch3appffig1"><div id="ch3.appf.fig1" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff1&p=BOOKS&id=577084_ch3appff1.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appff1.jpg" alt="Image ch3appff1" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch3appffig2"><div id="ch3.appf.fig2" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff2&p=BOOKS&id=577084_ch3appff2.jpg" target="tileshopwindow" class="inline_block 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img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appff9.jpg" alt="Image ch3appff9" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch3appffig10"><div id="ch3.appf.fig10" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff10&p=BOOKS&id=577084_ch3appff10.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appff10.jpg" alt="Image ch3appff10" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch3appffig11"><div id="ch3.appf.fig11" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff11&p=BOOKS&id=577084_ch3appff11.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appff11.jpg" alt="Image ch3appff11" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch3appffig12"><div id="ch3.appf.fig12" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff12&p=BOOKS&id=577084_ch3appff12.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appff12.jpg" alt="Image ch3appff12" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch3appffig13"><div id="ch3.appf.fig13" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff13&p=BOOKS&id=577084_ch3appff13.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appff13.jpg" alt="Image ch3appff13" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch3appffig14"><div id="ch3.appf.fig14" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff14&p=BOOKS&id=577084_ch3appff14.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appff14.jpg" alt="Image ch3appff14" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch3appffig15"><div id="ch3.appf.fig15" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff15&p=BOOKS&id=577084_ch3appff15.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appff15.jpg" alt="Image ch3appff15" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch3appffig16"><div id="ch3.appf.fig16" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff16&p=BOOKS&id=577084_ch3appff16.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appff16.jpg" alt="Image ch3appff16" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch3appffig17"><div id="ch3.appf.fig17" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff17&p=BOOKS&id=577084_ch3appff17.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appff17.jpg" alt="Image ch3appff17" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch3appffig18"><div id="ch3.appf.fig18" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff18&p=BOOKS&id=577084_ch3appff18.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appff18.jpg" alt="Image ch3appff18" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch3appffig19"><div id="ch3.appf.fig19" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff19&p=BOOKS&id=577084_ch3appff19.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appff19.jpg" alt="Image ch3appff19" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch3appffig20"><div id="ch3.appf.fig20" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff20&p=BOOKS&id=577084_ch3appff20.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appff20.jpg" alt="Image ch3appff20" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch3appffig21"><div id="ch3.appf.fig21" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff21&p=BOOKS&id=577084_ch3appff21.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appff21.jpg" alt="Image ch3appff21" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch3appffig22"><div id="ch3.appf.fig22" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff22&p=BOOKS&id=577084_ch3appff22.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appff22.jpg" alt="Image ch3appff22" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch3appffig23"><div id="ch3.appf.fig23" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch3appff23&p=BOOKS&id=577084_ch3appff23.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appff23.jpg" alt="Image ch3appff23" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="table-wrap" id="figobch3apphtab1"><div id="ch3.apph.tab1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.apph.tab1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.apph.tab1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ch3.apph.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch3.apph.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch3.apph.tab1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch3.apph.tab1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Effect size (95% CI)</th><th id="hd_h_ch3.apph.tab1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absolute risk (control)</th><th id="hd_h_ch3.apph.tab1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Absolute risk (intervention)</th><th id="hd_h_ch3.apph.tab1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Risk of bias</th><th id="hd_h_ch3.apph.tab1_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Inconsistency</th><th id="hd_h_ch3.apph.tab1_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Indirectness</th><th id="hd_h_ch3.apph.tab1_1_1_1_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Imprecision</th><th id="hd_h_ch3.apph.tab1_1_1_1_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th></tr></thead><tbody><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_1_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: Modified Ashworth scale (6 point scale) - Change from baseline (MD <0 favours THC:CBD spray)</th></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_1_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_2_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Dose higher than recommended</th></tr><tr><td headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td><td headers="hd_h_ch3.apph.tab1_1_1_1_2 hd_b_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.apph.tab1_1_1_1_3 hd_b_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">480</td><td headers="hd_h_ch3.apph.tab1_1_1_1_4 hd_b_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>MD 0.16</p>
|
|
<p>(−0.50, 0.83)</p>
|
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</td><td headers="hd_h_ch3.apph.tab1_1_1_1_5 hd_b_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab1_1_1_1_6 hd_b_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab1_1_1_1_7 hd_b_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_8 hd_b_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_9 hd_b_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_10 hd_b_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>6</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_11 hd_b_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_4_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Within recommended dose</th></tr><tr><td headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td><td headers="hd_h_ch3.apph.tab1_1_1_1_2 hd_b_ch3.apph.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.apph.tab1_1_1_1_3 hd_b_ch3.apph.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">347</td><td headers="hd_h_ch3.apph.tab1_1_1_1_4 hd_b_ch3.apph.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>MD −0.64</p>
|
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<p>(−1.94, 0.67)</p>
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|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_5 hd_b_ch3.apph.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab1_1_1_1_6 hd_b_ch3.apph.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab1_1_1_1_7 hd_b_ch3.apph.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_8 hd_b_ch3.apph.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>3</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_9 hd_b_ch3.apph.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_10 hd_b_ch3.apph.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>6</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_11 hd_b_ch3.apph.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_6_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: Ashworth scale (5 point scale) - Change from baseline (MD <0 favours THC:CBD spray)</th></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_6_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_7_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Dose higher than recommended</th></tr><tr><td headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_6_1 hd_b_ch3.apph.tab1_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>1</p>
|
|
<p>(<a class="bibr" href="#ch3.appm.ref9" rid="ch3.appm.ref9">Collin 2007</a>)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_2 hd_b_ch3.apph.tab1_1_1_6_1 hd_b_ch3.apph.tab1_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab1_1_1_1_3 hd_b_ch3.apph.tab1_1_1_6_1 hd_b_ch3.apph.tab1_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">184</td><td headers="hd_h_ch3.apph.tab1_1_1_1_4 hd_b_ch3.apph.tab1_1_1_6_1 hd_b_ch3.apph.tab1_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>MD −0.11</p>
|
|
<p>(−0.29, 0.07)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_5 hd_b_ch3.apph.tab1_1_1_6_1 hd_b_ch3.apph.tab1_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab1_1_1_1_6 hd_b_ch3.apph.tab1_1_1_6_1 hd_b_ch3.apph.tab1_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab1_1_1_1_7 hd_b_ch3.apph.tab1_1_1_6_1 hd_b_ch3.apph.tab1_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>7</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_8 hd_b_ch3.apph.tab1_1_1_6_1 hd_b_ch3.apph.tab1_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>5</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_9 hd_b_ch3.apph.tab1_1_1_6_1 hd_b_ch3.apph.tab1_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_10 hd_b_ch3.apph.tab1_1_1_6_1 hd_b_ch3.apph.tab1_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>6</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_11 hd_b_ch3.apph.tab1_1_1_6_1 hd_b_ch3.apph.tab1_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_9_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: Numerical rating scale (11 point scale) - Change from baseline (MD <0 favours THC:CBD spray)</th></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_9_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_10_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Dose higher than recommended</th></tr><tr><td headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_9_1 hd_b_ch3.apph.tab1_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3</td><td headers="hd_h_ch3.apph.tab1_1_1_1_2 hd_b_ch3.apph.tab1_1_1_9_1 hd_b_ch3.apph.tab1_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.apph.tab1_1_1_1_3 hd_b_ch3.apph.tab1_1_1_9_1 hd_b_ch3.apph.tab1_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">558</td><td headers="hd_h_ch3.apph.tab1_1_1_1_4 hd_b_ch3.apph.tab1_1_1_9_1 hd_b_ch3.apph.tab1_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD −0.76</p>
|
|
<p>(−1.50, −0.01)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_5 hd_b_ch3.apph.tab1_1_1_9_1 hd_b_ch3.apph.tab1_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab1_1_1_1_6 hd_b_ch3.apph.tab1_1_1_9_1 hd_b_ch3.apph.tab1_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab1_1_1_1_7 hd_b_ch3.apph.tab1_1_1_9_1 hd_b_ch3.apph.tab1_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_8 hd_b_ch3.apph.tab1_1_1_9_1 hd_b_ch3.apph.tab1_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup><sub>4</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_9 hd_b_ch3.apph.tab1_1_1_9_1 hd_b_ch3.apph.tab1_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_10 hd_b_ch3.apph.tab1_1_1_9_1 hd_b_ch3.apph.tab1_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>9</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_11 hd_b_ch3.apph.tab1_1_1_9_1 hd_b_ch3.apph.tab1_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_12_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Within recommended dose</th></tr><tr><td headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_12_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4</td><td headers="hd_h_ch3.apph.tab1_1_1_1_2 hd_b_ch3.apph.tab1_1_1_12_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3 Parallel RCTs 1 crossover RCT</td><td headers="hd_h_ch3.apph.tab1_1_1_1_3 hd_b_ch3.apph.tab1_1_1_12_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">754</td><td headers="hd_h_ch3.apph.tab1_1_1_1_4 hd_b_ch3.apph.tab1_1_1_12_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD −0.78</p>
|
|
<p>(−1.51, −0.06)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_5 hd_b_ch3.apph.tab1_1_1_12_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab1_1_1_1_6 hd_b_ch3.apph.tab1_1_1_12_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab1_1_1_1_7 hd_b_ch3.apph.tab1_1_1_12_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_8 hd_b_ch3.apph.tab1_1_1_12_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup><sub>4</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_9 hd_b_ch3.apph.tab1_1_1_12_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_10 hd_b_ch3.apph.tab1_1_1_12_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>9</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_11 hd_b_ch3.apph.tab1_1_1_12_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_14_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: Ashworth scale responder: >30% improvement in spasticity (RR <1 favours THC:CBD spray)</th></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_14_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_15_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Within recommended dose</th></tr><tr><td headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_14_1 hd_b_ch3.apph.tab1_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna 2011</a>)</td><td headers="hd_h_ch3.apph.tab1_1_1_1_2 hd_b_ch3.apph.tab1_1_1_14_1 hd_b_ch3.apph.tab1_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab1_1_1_1_3 hd_b_ch3.apph.tab1_1_1_14_1 hd_b_ch3.apph.tab1_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">241</td><td headers="hd_h_ch3.apph.tab1_1_1_1_4 hd_b_ch3.apph.tab1_1_1_14_1 hd_b_ch3.apph.tab1_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 0.69</p>
|
|
<p>(0.56, 0.85)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_5 hd_b_ch3.apph.tab1_1_1_14_1 hd_b_ch3.apph.tab1_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">50 per 100</td><td headers="hd_h_ch3.apph.tab1_1_1_1_6 hd_b_ch3.apph.tab1_1_1_14_1 hd_b_ch3.apph.tab1_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>73 per 100</p>
|
|
<p>(60, 90)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_7 hd_b_ch3.apph.tab1_1_1_14_1 hd_b_ch3.apph.tab1_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup><sub>8</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_8 hd_b_ch3.apph.tab1_1_1_14_1 hd_b_ch3.apph.tab1_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>5</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_9 hd_b_ch3.apph.tab1_1_1_14_1 hd_b_ch3.apph.tab1_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_10 hd_b_ch3.apph.tab1_1_1_14_1 hd_b_ch3.apph.tab1_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_11 hd_b_ch3.apph.tab1_1_1_14_1 hd_b_ch3.apph.tab1_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_17_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: Numerical rating scale responder: >30% improvement in spasticity (RR <1 favours THC:CBD spray)</th></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_17_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_18_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Dose higher than recommended</th></tr><tr><td headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_17_1 hd_b_ch3.apph.tab1_1_1_18_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td><td headers="hd_h_ch3.apph.tab1_1_1_1_2 hd_b_ch3.apph.tab1_1_1_17_1 hd_b_ch3.apph.tab1_1_1_18_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.apph.tab1_1_1_1_3 hd_b_ch3.apph.tab1_1_1_17_1 hd_b_ch3.apph.tab1_1_1_18_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">521</td><td headers="hd_h_ch3.apph.tab1_1_1_1_4 hd_b_ch3.apph.tab1_1_1_17_1 hd_b_ch3.apph.tab1_1_1_18_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 0.71</p>
|
|
<p>(0.53, 0.94)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_5 hd_b_ch3.apph.tab1_1_1_17_1 hd_b_ch3.apph.tab1_1_1_18_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">24 per 100</td><td headers="hd_h_ch3.apph.tab1_1_1_1_6 hd_b_ch3.apph.tab1_1_1_17_1 hd_b_ch3.apph.tab1_1_1_18_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>17 per 100</p>
|
|
<p>(13, 22)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_7 hd_b_ch3.apph.tab1_1_1_17_1 hd_b_ch3.apph.tab1_1_1_18_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_8 hd_b_ch3.apph.tab1_1_1_17_1 hd_b_ch3.apph.tab1_1_1_18_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_9 hd_b_ch3.apph.tab1_1_1_17_1 hd_b_ch3.apph.tab1_1_1_18_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_10 hd_b_ch3.apph.tab1_1_1_17_1 hd_b_ch3.apph.tab1_1_1_18_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_11 hd_b_ch3.apph.tab1_1_1_17_1 hd_b_ch3.apph.tab1_1_1_18_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_20_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Within recommended dose</th></tr><tr><td headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_20_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td><td headers="hd_h_ch3.apph.tab1_1_1_1_2 hd_b_ch3.apph.tab1_1_1_20_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.apph.tab1_1_1_1_3 hd_b_ch3.apph.tab1_1_1_20_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">347</td><td headers="hd_h_ch3.apph.tab1_1_1_1_4 hd_b_ch3.apph.tab1_1_1_20_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 0.55</p>
|
|
<p>(0.33, 0.92)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_5 hd_b_ch3.apph.tab1_1_1_20_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">45 per 100</td><td headers="hd_h_ch3.apph.tab1_1_1_1_6 hd_b_ch3.apph.tab1_1_1_20_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>82 per 100</p>
|
|
<p>(49, 137)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_7 hd_b_ch3.apph.tab1_1_1_20_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_8 hd_b_ch3.apph.tab1_1_1_20_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup><sub>4</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_9 hd_b_ch3.apph.tab1_1_1_20_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_10 hd_b_ch3.apph.tab1_1_1_20_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_11 hd_b_ch3.apph.tab1_1_1_20_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_22_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Total adverse events (RR<1 favours THC:CBD spray)</th></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_22_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_23_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Dose higher than recommended</th></tr><tr><td headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_22_1 hd_b_ch3.apph.tab1_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch3.appm.ref10" rid="ch3.appm.ref10">Collin 2010</a>)</td><td headers="hd_h_ch3.apph.tab1_1_1_1_2 hd_b_ch3.apph.tab1_1_1_22_1 hd_b_ch3.apph.tab1_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab1_1_1_1_3 hd_b_ch3.apph.tab1_1_1_22_1 hd_b_ch3.apph.tab1_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">288</td><td headers="hd_h_ch3.apph.tab1_1_1_1_4 hd_b_ch3.apph.tab1_1_1_22_1 hd_b_ch3.apph.tab1_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 1.20</p>
|
|
<p>(1.10, 1.32)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_5 hd_b_ch3.apph.tab1_1_1_22_1 hd_b_ch3.apph.tab1_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">78 per 100</td><td headers="hd_h_ch3.apph.tab1_1_1_1_6 hd_b_ch3.apph.tab1_1_1_22_1 hd_b_ch3.apph.tab1_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>93 per 100</p>
|
|
<p>(85, 100)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_7 hd_b_ch3.apph.tab1_1_1_22_1 hd_b_ch3.apph.tab1_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>7</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_8 hd_b_ch3.apph.tab1_1_1_22_1 hd_b_ch3.apph.tab1_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>5</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_9 hd_b_ch3.apph.tab1_1_1_22_1 hd_b_ch3.apph.tab1_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_10 hd_b_ch3.apph.tab1_1_1_22_1 hd_b_ch3.apph.tab1_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_11 hd_b_ch3.apph.tab1_1_1_22_1 hd_b_ch3.apph.tab1_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_25_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Within recommended dose</th></tr><tr><td headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td><td headers="hd_h_ch3.apph.tab1_1_1_1_2 hd_b_ch3.apph.tab1_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 Parallel RCT 1 cross-over RCT</td><td headers="hd_h_ch3.apph.tab1_1_1_1_3 hd_b_ch3.apph.tab1_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">143</td><td headers="hd_h_ch3.apph.tab1_1_1_1_4 hd_b_ch3.apph.tab1_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 1.44</p>
|
|
<p>(0.70, 2.98)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_5 hd_b_ch3.apph.tab1_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">42 per 100</td><td headers="hd_h_ch3.apph.tab1_1_1_1_6 hd_b_ch3.apph.tab1_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>60 per 100</p>
|
|
<p>(29, 124)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_7 hd_b_ch3.apph.tab1_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_8 hd_b_ch3.apph.tab1_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup><sub>4</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_9 hd_b_ch3.apph.tab1_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_10 hd_b_ch3.apph.tab1_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>6</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_11 hd_b_ch3.apph.tab1_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_27_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Treatment-related adverse events (RR<1 favours THC:CBD spray)</th></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_27_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_28_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Dose higher than recommended</th></tr><tr><td headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_27_1 hd_b_ch3.apph.tab1_1_1_28_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch3.appm.ref9" rid="ch3.appm.ref9">Collin 2007</a>)</td><td headers="hd_h_ch3.apph.tab1_1_1_1_2 hd_b_ch3.apph.tab1_1_1_27_1 hd_b_ch3.apph.tab1_1_1_28_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab1_1_1_1_3 hd_b_ch3.apph.tab1_1_1_27_1 hd_b_ch3.apph.tab1_1_1_28_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">184</td><td headers="hd_h_ch3.apph.tab1_1_1_1_4 hd_b_ch3.apph.tab1_1_1_27_1 hd_b_ch3.apph.tab1_1_1_28_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 1.18</p>
|
|
<p>(1.00, 1.40)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_5 hd_b_ch3.apph.tab1_1_1_27_1 hd_b_ch3.apph.tab1_1_1_28_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">72 per 100</td><td headers="hd_h_ch3.apph.tab1_1_1_1_6 hd_b_ch3.apph.tab1_1_1_27_1 hd_b_ch3.apph.tab1_1_1_28_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>85 per 100</p>
|
|
<p>(72, 101)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_7 hd_b_ch3.apph.tab1_1_1_27_1 hd_b_ch3.apph.tab1_1_1_28_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>7</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_8 hd_b_ch3.apph.tab1_1_1_27_1 hd_b_ch3.apph.tab1_1_1_28_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>5</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_9 hd_b_ch3.apph.tab1_1_1_27_1 hd_b_ch3.apph.tab1_1_1_28_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_10 hd_b_ch3.apph.tab1_1_1_27_1 hd_b_ch3.apph.tab1_1_1_28_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>6</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_11 hd_b_ch3.apph.tab1_1_1_27_1 hd_b_ch3.apph.tab1_1_1_28_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_30_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Within recommended dose</th></tr><tr><td headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_30_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td><td headers="hd_h_ch3.apph.tab1_1_1_1_2 hd_b_ch3.apph.tab1_1_1_30_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.apph.tab1_1_1_1_3 hd_b_ch3.apph.tab1_1_1_30_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">445</td><td headers="hd_h_ch3.apph.tab1_1_1_1_4 hd_b_ch3.apph.tab1_1_1_30_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 1.20</p>
|
|
<p>(1.03, 1.40)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_5 hd_b_ch3.apph.tab1_1_1_30_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">50 per 100</td><td headers="hd_h_ch3.apph.tab1_1_1_1_6 hd_b_ch3.apph.tab1_1_1_30_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>60 per 100</p>
|
|
<p>(52, 70)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_7 hd_b_ch3.apph.tab1_1_1_30_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_8 hd_b_ch3.apph.tab1_1_1_30_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_9 hd_b_ch3.apph.tab1_1_1_30_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_10 hd_b_ch3.apph.tab1_1_1_30_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_11 hd_b_ch3.apph.tab1_1_1_30_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">High</td></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_32_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Total serious adverse events (RR<1 favours THC:CBD spray)</th></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_32_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_33_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Dose higher than recommended</th></tr><tr><td headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_32_1 hd_b_ch3.apph.tab1_1_1_33_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch3.appm.ref9" rid="ch3.appm.ref9">Collin 2007</a>)</td><td headers="hd_h_ch3.apph.tab1_1_1_1_2 hd_b_ch3.apph.tab1_1_1_32_1 hd_b_ch3.apph.tab1_1_1_33_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab1_1_1_1_3 hd_b_ch3.apph.tab1_1_1_32_1 hd_b_ch3.apph.tab1_1_1_33_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">184</td><td headers="hd_h_ch3.apph.tab1_1_1_1_4 hd_b_ch3.apph.tab1_1_1_32_1 hd_b_ch3.apph.tab1_1_1_33_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 0.71</p>
|
|
<p>(0.16, 3.08)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_5 hd_b_ch3.apph.tab1_1_1_32_1 hd_b_ch3.apph.tab1_1_1_33_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5 per 100</td><td headers="hd_h_ch3.apph.tab1_1_1_1_6 hd_b_ch3.apph.tab1_1_1_32_1 hd_b_ch3.apph.tab1_1_1_33_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>3 per 100</p>
|
|
<p>(1, 14)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_7 hd_b_ch3.apph.tab1_1_1_32_1 hd_b_ch3.apph.tab1_1_1_33_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>7</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_8 hd_b_ch3.apph.tab1_1_1_32_1 hd_b_ch3.apph.tab1_1_1_33_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>5</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_9 hd_b_ch3.apph.tab1_1_1_32_1 hd_b_ch3.apph.tab1_1_1_33_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_10 hd_b_ch3.apph.tab1_1_1_32_1 hd_b_ch3.apph.tab1_1_1_33_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>6</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_11 hd_b_ch3.apph.tab1_1_1_32_1 hd_b_ch3.apph.tab1_1_1_33_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_35_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Within recommended dose</th></tr><tr><td headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_35_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Markova 2018)</td><td headers="hd_h_ch3.apph.tab1_1_1_1_2 hd_b_ch3.apph.tab1_1_1_35_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab1_1_1_1_3 hd_b_ch3.apph.tab1_1_1_35_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">106</td><td headers="hd_h_ch3.apph.tab1_1_1_1_4 hd_b_ch3.apph.tab1_1_1_35_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 1.00</p>
|
|
<p>(0.06, 15.57)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_5 hd_b_ch3.apph.tab1_1_1_35_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 per 100</td><td headers="hd_h_ch3.apph.tab1_1_1_1_6 hd_b_ch3.apph.tab1_1_1_35_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 per 100 (0, 29)</td><td headers="hd_h_ch3.apph.tab1_1_1_1_7 hd_b_ch3.apph.tab1_1_1_35_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup><sub>8</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_8 hd_b_ch3.apph.tab1_1_1_35_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>5</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_9 hd_b_ch3.apph.tab1_1_1_35_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_10 hd_b_ch3.apph.tab1_1_1_35_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>6</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_11 hd_b_ch3.apph.tab1_1_1_35_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_37_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Treatment-related serious adverse events (RR<1 favours THC:CBD spray)</th></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_37_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_38_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Within recommended dose</th></tr><tr><td headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_37_1 hd_b_ch3.apph.tab1_1_1_38_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch3.appm.ref22" rid="ch3.appm.ref22">Langford 2013</a>)</td><td headers="hd_h_ch3.apph.tab1_1_1_1_2 hd_b_ch3.apph.tab1_1_1_37_1 hd_b_ch3.apph.tab1_1_1_38_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab1_1_1_1_3 hd_b_ch3.apph.tab1_1_1_37_1 hd_b_ch3.apph.tab1_1_1_38_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">339</td><td headers="hd_h_ch3.apph.tab1_1_1_1_4 hd_b_ch3.apph.tab1_1_1_37_1 hd_b_ch3.apph.tab1_1_1_38_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 1.54</p>
|
|
<p>(0.81, 2.94)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_5 hd_b_ch3.apph.tab1_1_1_37_1 hd_b_ch3.apph.tab1_1_1_38_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">8 per 100</td><td headers="hd_h_ch3.apph.tab1_1_1_1_6 hd_b_ch3.apph.tab1_1_1_37_1 hd_b_ch3.apph.tab1_1_1_38_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>13 per 100</p>
|
|
<p>(7, 24)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_7 hd_b_ch3.apph.tab1_1_1_37_1 hd_b_ch3.apph.tab1_1_1_38_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_8 hd_b_ch3.apph.tab1_1_1_37_1 hd_b_ch3.apph.tab1_1_1_38_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>5</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_9 hd_b_ch3.apph.tab1_1_1_37_1 hd_b_ch3.apph.tab1_1_1_38_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_10 hd_b_ch3.apph.tab1_1_1_37_1 hd_b_ch3.apph.tab1_1_1_38_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>6</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_11 hd_b_ch3.apph.tab1_1_1_37_1 hd_b_ch3.apph.tab1_1_1_38_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_40_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Withdrawal due to adverse events (RR<1 favours THC:CBD spray)</th></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_40_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_41_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Dose higher than recommended</th></tr><tr><td headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_40_1 hd_b_ch3.apph.tab1_1_1_41_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3</td><td headers="hd_h_ch3.apph.tab1_1_1_1_2 hd_b_ch3.apph.tab1_1_1_40_1 hd_b_ch3.apph.tab1_1_1_41_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.apph.tab1_1_1_1_3 hd_b_ch3.apph.tab1_1_1_40_1 hd_b_ch3.apph.tab1_1_1_41_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">681</td><td headers="hd_h_ch3.apph.tab1_1_1_1_4 hd_b_ch3.apph.tab1_1_1_40_1 hd_b_ch3.apph.tab1_1_1_41_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 1.90</p>
|
|
<p>(0.84, 4.31)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_5 hd_b_ch3.apph.tab1_1_1_40_1 hd_b_ch3.apph.tab1_1_1_41_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3 per 100</td><td headers="hd_h_ch3.apph.tab1_1_1_1_6 hd_b_ch3.apph.tab1_1_1_40_1 hd_b_ch3.apph.tab1_1_1_41_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>5 per 100</p>
|
|
<p>(2, 11)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_7 hd_b_ch3.apph.tab1_1_1_40_1 hd_b_ch3.apph.tab1_1_1_41_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_8 hd_b_ch3.apph.tab1_1_1_40_1 hd_b_ch3.apph.tab1_1_1_41_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_9 hd_b_ch3.apph.tab1_1_1_40_1 hd_b_ch3.apph.tab1_1_1_41_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_10 hd_b_ch3.apph.tab1_1_1_40_1 hd_b_ch3.apph.tab1_1_1_41_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>6</sub></sup></td><td headers="hd_h_ch3.apph.tab1_1_1_1_11 hd_b_ch3.apph.tab1_1_1_40_1 hd_b_ch3.apph.tab1_1_1_41_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_h_ch3.apph.tab1_1_1_1_2 hd_h_ch3.apph.tab1_1_1_1_3 hd_h_ch3.apph.tab1_1_1_1_4 hd_h_ch3.apph.tab1_1_1_1_5 hd_h_ch3.apph.tab1_1_1_1_6 hd_h_ch3.apph.tab1_1_1_1_7 hd_h_ch3.apph.tab1_1_1_1_8 hd_h_ch3.apph.tab1_1_1_1_9 hd_h_ch3.apph.tab1_1_1_1_10 hd_h_ch3.apph.tab1_1_1_1_11" id="hd_b_ch3.apph.tab1_1_1_43_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Within recommended dose</th></tr><tr><td headers="hd_h_ch3.apph.tab1_1_1_1_1 hd_b_ch3.apph.tab1_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3</td><td headers="hd_h_ch3.apph.tab1_1_1_1_2 hd_b_ch3.apph.tab1_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>2 Parallel RCTs</p>
|
|
<p>1 crossover RCT</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_3 hd_b_ch3.apph.tab1_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">650</td><td headers="hd_h_ch3.apph.tab1_1_1_1_4 hd_b_ch3.apph.tab1_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 2.02</p>
|
|
<p>(1.05, 3.87)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_5 hd_b_ch3.apph.tab1_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4 per 100</td><td headers="hd_h_ch3.apph.tab1_1_1_1_6 hd_b_ch3.apph.tab1_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>8 per 100</p>
|
|
<p>(4, 14)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab1_1_1_1_7 hd_b_ch3.apph.tab1_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_8 hd_b_ch3.apph.tab1_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_9 hd_b_ch3.apph.tab1_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_10 hd_b_ch3.apph.tab1_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab1_1_1_1_11 hd_b_ch3.apph.tab1_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">High</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1</dt><dd><div id="ch3.apph.tab1_1"><p class="no_margin">> 33.3% of the weight in a meta-analysis came from studies at high risk of bias. Downgraded 2 levels</p></div></dd></dl><dl class="bkr_refwrap"><dt>2</dt><dd><div id="ch3.apph.tab1_2"><p class="no_margin">> 33.3% of the weight in a meta-analysis came from studies at moderate or high risk of bias. Downgraded 1 level</p></div></dd></dl><dl class="bkr_refwrap"><dt>3</dt><dd><div id="ch3.apph.tab1_3"><p class="no_margin">I<sub>2</sub> between 33.3% and 66.7%. Downgraded one level</p></div></dd></dl><dl class="bkr_refwrap"><dt>4</dt><dd><div id="ch3.apph.tab1_4"><p class="no_margin">I<sub>2</sub> > 66.7%. Downgraded two levels</p></div></dd></dl><dl class="bkr_refwrap"><dt>5</dt><dd><div id="ch3.apph.tab1_5"><p class="no_margin">Inconsistency N/A as only 1 study</p></div></dd></dl><dl class="bkr_refwrap"><dt>6</dt><dd><div id="ch3.apph.tab1_6"><p class="no_margin">95% confidence interval crosses line of no effect. Downgraded 1 level</p></div></dd></dl><dl class="bkr_refwrap"><dt>7</dt><dd><div id="ch3.apph.tab1_7"><p class="no_margin">Single study at moderate risk of bias. Downgraded 1 level</p></div></dd></dl><dl class="bkr_refwrap"><dt>8</dt><dd><div id="ch3.apph.tab1_8"><p class="no_margin">Single study at high risk of bias. Downgraded 2 levels</p></div></dd></dl><dl class="bkr_refwrap"><dt>9</dt><dd><div id="ch3.apph.tab1_9"><p class="no_margin">95% confidence interval crosses one end of the defined MID (−0.9).</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobch3apphtab2"><div id="ch3.apph.tab2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.apph.tab2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.apph.tab2_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ch3.apph.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch3.apph.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch3.apph.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch3.apph.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Effect size (95% CI)</th><th id="hd_h_ch3.apph.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absolute risk (control)</th><th id="hd_h_ch3.apph.tab2_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Absolute risk (intervention)</th><th id="hd_h_ch3.apph.tab2_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Risk of bias</th><th id="hd_h_ch3.apph.tab2_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Inconsistency</th><th id="hd_h_ch3.apph.tab2_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Indirectness</th><th id="hd_h_ch3.apph.tab2_1_1_1_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Imprecision</th><th id="hd_h_ch3.apph.tab2_1_1_1_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th></tr></thead><tbody><tr><th headers="hd_h_ch3.apph.tab2_1_1_1_1 hd_h_ch3.apph.tab2_1_1_1_2 hd_h_ch3.apph.tab2_1_1_1_3 hd_h_ch3.apph.tab2_1_1_1_4 hd_h_ch3.apph.tab2_1_1_1_5 hd_h_ch3.apph.tab2_1_1_1_6 hd_h_ch3.apph.tab2_1_1_1_7 hd_h_ch3.apph.tab2_1_1_1_8 hd_h_ch3.apph.tab2_1_1_1_9 hd_h_ch3.apph.tab2_1_1_1_10 hd_h_ch3.apph.tab2_1_1_1_11" id="hd_b_ch3.apph.tab2_1_1_1_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: Ashworth scale (5 point scale) - Change from baseline: Total score (MD <0 favours THC capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab2_1_1_1_1 hd_b_ch3.apph.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td><td headers="hd_h_ch3.apph.tab2_1_1_1_2 hd_b_ch3.apph.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.apph.tab2_1_1_1_3 hd_b_ch3.apph.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">749</td><td headers="hd_h_ch3.apph.tab2_1_1_1_4 hd_b_ch3.apph.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>MD −1.38</p>
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<p>(−2.47, −0.29)</p>
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</td><td headers="hd_h_ch3.apph.tab2_1_1_1_5 hd_b_ch3.apph.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab2_1_1_1_6 hd_b_ch3.apph.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab2_1_1_1_7 hd_b_ch3.apph.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>6</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_8 hd_b_ch3.apph.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab2_1_1_1_9 hd_b_ch3.apph.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab2_1_1_1_10 hd_b_ch3.apph.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab2_1_1_1_11 hd_b_ch3.apph.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr><tr><th headers="hd_h_ch3.apph.tab2_1_1_1_1 hd_h_ch3.apph.tab2_1_1_1_2 hd_h_ch3.apph.tab2_1_1_1_3 hd_h_ch3.apph.tab2_1_1_1_4 hd_h_ch3.apph.tab2_1_1_1_5 hd_h_ch3.apph.tab2_1_1_1_6 hd_h_ch3.apph.tab2_1_1_1_7 hd_h_ch3.apph.tab2_1_1_1_8 hd_h_ch3.apph.tab2_1_1_1_9 hd_h_ch3.apph.tab2_1_1_1_10 hd_h_ch3.apph.tab2_1_1_1_11" id="hd_b_ch3.apph.tab2_1_1_3_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: Ashworth scale (5 point scale) - Change from baseline: Upper body score (MD <0 favours THC capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab2_1_1_1_1 hd_b_ch3.apph.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a>)</td><td headers="hd_h_ch3.apph.tab2_1_1_1_2 hd_b_ch3.apph.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab2_1_1_1_3 hd_b_ch3.apph.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">419</td><td headers="hd_h_ch3.apph.tab2_1_1_1_4 hd_b_ch3.apph.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>MD −0.59</p>
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<p>(−1.43, 0.25)</p>
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</td><td headers="hd_h_ch3.apph.tab2_1_1_1_5 hd_b_ch3.apph.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab2_1_1_1_6 hd_b_ch3.apph.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab2_1_1_1_7 hd_b_ch3.apph.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_8 hd_b_ch3.apph.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>3</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_9 hd_b_ch3.apph.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab2_1_1_1_10 hd_b_ch3.apph.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>4</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_11 hd_b_ch3.apph.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch3.apph.tab2_1_1_1_1 hd_h_ch3.apph.tab2_1_1_1_2 hd_h_ch3.apph.tab2_1_1_1_3 hd_h_ch3.apph.tab2_1_1_1_4 hd_h_ch3.apph.tab2_1_1_1_5 hd_h_ch3.apph.tab2_1_1_1_6 hd_h_ch3.apph.tab2_1_1_1_7 hd_h_ch3.apph.tab2_1_1_1_8 hd_h_ch3.apph.tab2_1_1_1_9 hd_h_ch3.apph.tab2_1_1_1_10 hd_h_ch3.apph.tab2_1_1_1_11" id="hd_b_ch3.apph.tab2_1_1_5_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: Ashworth scale (5 point scale) - Change from baseline: Lower body score (MD <0 favours THC capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab2_1_1_1_1 hd_b_ch3.apph.tab2_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a>)</td><td headers="hd_h_ch3.apph.tab2_1_1_1_2 hd_b_ch3.apph.tab2_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab2_1_1_1_3 hd_b_ch3.apph.tab2_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">419</td><td headers="hd_h_ch3.apph.tab2_1_1_1_4 hd_b_ch3.apph.tab2_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>MD −0.35</p>
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<p>(−1.26, 0.56)</p>
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</td><td headers="hd_h_ch3.apph.tab2_1_1_1_5 hd_b_ch3.apph.tab2_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab2_1_1_1_6 hd_b_ch3.apph.tab2_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab2_1_1_1_7 hd_b_ch3.apph.tab2_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_8 hd_b_ch3.apph.tab2_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>3</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_9 hd_b_ch3.apph.tab2_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab2_1_1_1_10 hd_b_ch3.apph.tab2_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>4</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_11 hd_b_ch3.apph.tab2_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch3.apph.tab2_1_1_1_1 hd_h_ch3.apph.tab2_1_1_1_2 hd_h_ch3.apph.tab2_1_1_1_3 hd_h_ch3.apph.tab2_1_1_1_4 hd_h_ch3.apph.tab2_1_1_1_5 hd_h_ch3.apph.tab2_1_1_1_6 hd_h_ch3.apph.tab2_1_1_1_7 hd_h_ch3.apph.tab2_1_1_1_8 hd_h_ch3.apph.tab2_1_1_1_9 hd_h_ch3.apph.tab2_1_1_1_10 hd_h_ch3.apph.tab2_1_1_1_11" id="hd_b_ch3.apph.tab2_1_1_7_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: MSSS-88 - Change from baseline: Subscales 1–3 (Muscle stiffness/spasms, pain & discomfort; 52 items, 5 point scale) (MD >0 favours THC capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab2_1_1_1_1 hd_b_ch3.apph.tab2_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Ball 2015)</td><td headers="hd_h_ch3.apph.tab2_1_1_1_2 hd_b_ch3.apph.tab2_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab2_1_1_1_3 hd_b_ch3.apph.tab2_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">493</td><td headers="hd_h_ch3.apph.tab2_1_1_1_4 hd_b_ch3.apph.tab2_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>MD 0.34</p>
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<p>(−0.98, 1.66)</p>
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</td><td headers="hd_h_ch3.apph.tab2_1_1_1_5 hd_b_ch3.apph.tab2_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab2_1_1_1_6 hd_b_ch3.apph.tab2_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab2_1_1_1_7 hd_b_ch3.apph.tab2_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_8 hd_b_ch3.apph.tab2_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>3</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_9 hd_b_ch3.apph.tab2_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>5</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_10 hd_b_ch3.apph.tab2_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>4</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_11 hd_b_ch3.apph.tab2_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch3.apph.tab2_1_1_1_1 hd_h_ch3.apph.tab2_1_1_1_2 hd_h_ch3.apph.tab2_1_1_1_3 hd_h_ch3.apph.tab2_1_1_1_4 hd_h_ch3.apph.tab2_1_1_1_5 hd_h_ch3.apph.tab2_1_1_1_6 hd_h_ch3.apph.tab2_1_1_1_7 hd_h_ch3.apph.tab2_1_1_1_8 hd_h_ch3.apph.tab2_1_1_1_9 hd_h_ch3.apph.tab2_1_1_1_10 hd_h_ch3.apph.tab2_1_1_1_11" id="hd_b_ch3.apph.tab2_1_1_9_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: MSSS-88 - Change from baseline: Subscales 4–6 (Activity, walking & body movements; 50 items, 5 point scale) (MD >0 favours THC capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab2_1_1_1_1 hd_b_ch3.apph.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Ball 2015)</td><td headers="hd_h_ch3.apph.tab2_1_1_1_2 hd_b_ch3.apph.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab2_1_1_1_3 hd_b_ch3.apph.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">493</td><td headers="hd_h_ch3.apph.tab2_1_1_1_4 hd_b_ch3.apph.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>MD 0.03</p>
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<p>(−1.20, 1.26)</p>
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</td><td headers="hd_h_ch3.apph.tab2_1_1_1_5 hd_b_ch3.apph.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab2_1_1_1_6 hd_b_ch3.apph.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab2_1_1_1_7 hd_b_ch3.apph.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_8 hd_b_ch3.apph.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>3</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_9 hd_b_ch3.apph.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>5</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_10 hd_b_ch3.apph.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>4</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_11 hd_b_ch3.apph.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch3.apph.tab2_1_1_1_1 hd_h_ch3.apph.tab2_1_1_1_2 hd_h_ch3.apph.tab2_1_1_1_3 hd_h_ch3.apph.tab2_1_1_1_4 hd_h_ch3.apph.tab2_1_1_1_5 hd_h_ch3.apph.tab2_1_1_1_6 hd_h_ch3.apph.tab2_1_1_1_7 hd_h_ch3.apph.tab2_1_1_1_8 hd_h_ch3.apph.tab2_1_1_1_9 hd_h_ch3.apph.tab2_1_1_1_10 hd_h_ch3.apph.tab2_1_1_1_11" id="hd_b_ch3.apph.tab2_1_1_11_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: MSSS-88 - Change from baseline: Subscales 7–8 (Feelings & social functioning; 42 items, 5 point scale) (MD >0 favours THC capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab2_1_1_1_1 hd_b_ch3.apph.tab2_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Ball 2015)</td><td headers="hd_h_ch3.apph.tab2_1_1_1_2 hd_b_ch3.apph.tab2_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab2_1_1_1_3 hd_b_ch3.apph.tab2_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">493</td><td headers="hd_h_ch3.apph.tab2_1_1_1_4 hd_b_ch3.apph.tab2_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>MD −0.63</p>
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<p>(−1.56, 0.30)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab2_1_1_1_5 hd_b_ch3.apph.tab2_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab2_1_1_1_6 hd_b_ch3.apph.tab2_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab2_1_1_1_7 hd_b_ch3.apph.tab2_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_8 hd_b_ch3.apph.tab2_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>3</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_9 hd_b_ch3.apph.tab2_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>5</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_10 hd_b_ch3.apph.tab2_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>4</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_11 hd_b_ch3.apph.tab2_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch3.apph.tab2_1_1_1_1 hd_h_ch3.apph.tab2_1_1_1_2 hd_h_ch3.apph.tab2_1_1_1_3 hd_h_ch3.apph.tab2_1_1_1_4 hd_h_ch3.apph.tab2_1_1_1_5 hd_h_ch3.apph.tab2_1_1_1_6 hd_h_ch3.apph.tab2_1_1_1_7 hd_h_ch3.apph.tab2_1_1_1_8 hd_h_ch3.apph.tab2_1_1_1_9 hd_h_ch3.apph.tab2_1_1_1_10 hd_h_ch3.apph.tab2_1_1_1_11" id="hd_b_ch3.apph.tab2_1_1_13_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Total adverse events (RR<1 favours THC capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab2_1_1_1_1 hd_b_ch3.apph.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td><td headers="hd_h_ch3.apph.tab2_1_1_1_2 hd_b_ch3.apph.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.apph.tab2_1_1_1_3 hd_b_ch3.apph.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">838</td><td headers="hd_h_ch3.apph.tab2_1_1_1_4 hd_b_ch3.apph.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 1.03</p>
|
|
<p>(0.75, 1.43)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab2_1_1_1_5 hd_b_ch3.apph.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">69 per 100</td><td headers="hd_h_ch3.apph.tab2_1_1_1_6 hd_b_ch3.apph.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>72 per 100</p>
|
|
<p>(52, 99)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab2_1_1_1_7 hd_b_ch3.apph.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>6</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_8 hd_b_ch3.apph.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_9 hd_b_ch3.apph.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab2_1_1_1_10 hd_b_ch3.apph.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>4</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_11 hd_b_ch3.apph.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch3.apph.tab2_1_1_1_1 hd_h_ch3.apph.tab2_1_1_1_2 hd_h_ch3.apph.tab2_1_1_1_3 hd_h_ch3.apph.tab2_1_1_1_4 hd_h_ch3.apph.tab2_1_1_1_5 hd_h_ch3.apph.tab2_1_1_1_6 hd_h_ch3.apph.tab2_1_1_1_7 hd_h_ch3.apph.tab2_1_1_1_8 hd_h_ch3.apph.tab2_1_1_1_9 hd_h_ch3.apph.tab2_1_1_1_10 hd_h_ch3.apph.tab2_1_1_1_11" id="hd_b_ch3.apph.tab2_1_1_15_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Total serious adverse events (RR<1 favours THC capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab2_1_1_1_1 hd_b_ch3.apph.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td><td headers="hd_h_ch3.apph.tab2_1_1_1_2 hd_b_ch3.apph.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.apph.tab2_1_1_1_3 hd_b_ch3.apph.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">912</td><td headers="hd_h_ch3.apph.tab2_1_1_1_4 hd_b_ch3.apph.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 1.19</p>
|
|
<p>(0.93, 1.54)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab2_1_1_1_5 hd_b_ch3.apph.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">18 per 100</td><td headers="hd_h_ch3.apph.tab2_1_1_1_6 hd_b_ch3.apph.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>22 per 100</p>
|
|
<p>(17, 28)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab2_1_1_1_7 hd_b_ch3.apph.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>6</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_8 hd_b_ch3.apph.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab2_1_1_1_9 hd_b_ch3.apph.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>7</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_10 hd_b_ch3.apph.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>4</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_11 hd_b_ch3.apph.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch3.apph.tab2_1_1_1_1 hd_h_ch3.apph.tab2_1_1_1_2 hd_h_ch3.apph.tab2_1_1_1_3 hd_h_ch3.apph.tab2_1_1_1_4 hd_h_ch3.apph.tab2_1_1_1_5 hd_h_ch3.apph.tab2_1_1_1_6 hd_h_ch3.apph.tab2_1_1_1_7 hd_h_ch3.apph.tab2_1_1_1_8 hd_h_ch3.apph.tab2_1_1_1_9 hd_h_ch3.apph.tab2_1_1_1_10 hd_h_ch3.apph.tab2_1_1_1_11" id="hd_b_ch3.apph.tab2_1_1_17_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Withdrawals due to adverse events (RR<1 favours THC capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab2_1_1_1_1 hd_b_ch3.apph.tab2_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td><td headers="hd_h_ch3.apph.tab2_1_1_1_2 hd_b_ch3.apph.tab2_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.apph.tab2_1_1_1_3 hd_b_ch3.apph.tab2_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">823</td><td headers="hd_h_ch3.apph.tab2_1_1_1_4 hd_b_ch3.apph.tab2_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 3.55</p>
|
|
<p>(1.82, 6.91)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab2_1_1_1_5 hd_b_ch3.apph.tab2_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 per 100</td><td headers="hd_h_ch3.apph.tab2_1_1_1_6 hd_b_ch3.apph.tab2_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>8 per 100</p>
|
|
<p>(4, 16)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab2_1_1_1_7 hd_b_ch3.apph.tab2_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>6</sub></sup></td><td headers="hd_h_ch3.apph.tab2_1_1_1_8 hd_b_ch3.apph.tab2_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab2_1_1_1_9 hd_b_ch3.apph.tab2_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab2_1_1_1_10 hd_b_ch3.apph.tab2_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab2_1_1_1_11 hd_b_ch3.apph.tab2_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1</dt><dd><div id="ch3.apph.tab2_1"><p class="no_margin">Single study at moderate risk of bias. Downgraded 1 level</p></div></dd></dl><dl class="bkr_refwrap"><dt>2</dt><dd><div id="ch3.apph.tab2_2"><p class="no_margin">I<sup>2</sup> > 66.7%. Downgraded two levels</p></div></dd></dl><dl class="bkr_refwrap"><dt>3</dt><dd><div id="ch3.apph.tab2_3"><p class="no_margin">Inconsistency N/A as only 1 study</p></div></dd></dl><dl class="bkr_refwrap"><dt>4</dt><dd><div id="ch3.apph.tab2_4"><p class="no_margin">95% confidence interval crosses line of no effect. Downgraded 1 level</p></div></dd></dl><dl class="bkr_refwrap"><dt>5</dt><dd><div id="ch3.apph.tab2_5"><p class="no_margin">Single study which was partially indirect. Downgraded 1 level</p></div></dd></dl><dl class="bkr_refwrap"><dt>6</dt><dd><div id="ch3.apph.tab2_6"><p class="no_margin">> 33.3% of the weight in a meta-analysis came from studies at moderate or high risk of bias. Downgraded 1 level</p></div></dd></dl><dl class="bkr_refwrap"><dt>7</dt><dd><div id="ch3.apph.tab2_7"><p class="no_margin">> 33.3% of the weight in a meta-analysis came from studies which were partially indirect. Downgraded 1 level</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">8.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobch3apphtab3"><div id="ch3.apph.tab3" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.apph.tab3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.apph.tab3_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ch3.apph.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch3.apph.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch3.apph.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch3.apph.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Effect size (95% CI)</th><th id="hd_h_ch3.apph.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absolute risk (control)</th><th id="hd_h_ch3.apph.tab3_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Absolute risk (intervention)</th><th id="hd_h_ch3.apph.tab3_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Risk of bias</th><th id="hd_h_ch3.apph.tab3_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Inconsistency</th><th id="hd_h_ch3.apph.tab3_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Indirectness</th><th id="hd_h_ch3.apph.tab3_1_1_1_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Imprecision</th><th id="hd_h_ch3.apph.tab3_1_1_1_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th></tr></thead><tbody><tr><th headers="hd_h_ch3.apph.tab3_1_1_1_1 hd_h_ch3.apph.tab3_1_1_1_2 hd_h_ch3.apph.tab3_1_1_1_3 hd_h_ch3.apph.tab3_1_1_1_4 hd_h_ch3.apph.tab3_1_1_1_5 hd_h_ch3.apph.tab3_1_1_1_6 hd_h_ch3.apph.tab3_1_1_1_7 hd_h_ch3.apph.tab3_1_1_1_8 hd_h_ch3.apph.tab3_1_1_1_9 hd_h_ch3.apph.tab3_1_1_1_10 hd_h_ch3.apph.tab3_1_1_1_11" id="hd_b_ch3.apph.tab3_1_1_1_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: Numerical rating scale (11 point scale) - Change from baseline (MD <0 favours THC capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab3_1_1_1_1 hd_b_ch3.apph.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (van Amerongen 2018)</td><td headers="hd_h_ch3.apph.tab3_1_1_1_2 hd_b_ch3.apph.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab3_1_1_1_3 hd_b_ch3.apph.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">24</td><td headers="hd_h_ch3.apph.tab3_1_1_1_4 hd_b_ch3.apph.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD −0.38</p>
|
|
<p>(−1.30, 0.54)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab3_1_1_1_5 hd_b_ch3.apph.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab3_1_1_1_6 hd_b_ch3.apph.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab3_1_1_1_7 hd_b_ch3.apph.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab3_1_1_1_8 hd_b_ch3.apph.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab3_1_1_1_9 hd_b_ch3.apph.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab3_1_1_1_10 hd_b_ch3.apph.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>3</sub></sup></td><td headers="hd_h_ch3.apph.tab3_1_1_1_11 hd_b_ch3.apph.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch3.apph.tab3_1_1_1_1 hd_h_ch3.apph.tab3_1_1_1_2 hd_h_ch3.apph.tab3_1_1_1_3 hd_h_ch3.apph.tab3_1_1_1_4 hd_h_ch3.apph.tab3_1_1_1_5 hd_h_ch3.apph.tab3_1_1_1_6 hd_h_ch3.apph.tab3_1_1_1_7 hd_h_ch3.apph.tab3_1_1_1_8 hd_h_ch3.apph.tab3_1_1_1_9 hd_h_ch3.apph.tab3_1_1_1_10 hd_h_ch3.apph.tab3_1_1_1_11" id="hd_b_ch3.apph.tab3_1_1_3_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Total adverse events (RR<1 favours THC capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab3_1_1_1_1 hd_b_ch3.apph.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (van Amerongen 2018)</td><td headers="hd_h_ch3.apph.tab3_1_1_1_2 hd_b_ch3.apph.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab3_1_1_1_3 hd_b_ch3.apph.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">24</td><td headers="hd_h_ch3.apph.tab3_1_1_1_4 hd_b_ch3.apph.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 1.43</p>
|
|
<p>(0.83, 2.45)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab3_1_1_1_5 hd_b_ch3.apph.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">58 per 100</td><td headers="hd_h_ch3.apph.tab3_1_1_1_6 hd_b_ch3.apph.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>83 per 100</p>
|
|
<p>(48, 100)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab3_1_1_1_7 hd_b_ch3.apph.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab3_1_1_1_8 hd_b_ch3.apph.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab3_1_1_1_9 hd_b_ch3.apph.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab3_1_1_1_10 hd_b_ch3.apph.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>3</sub></sup></td><td headers="hd_h_ch3.apph.tab3_1_1_1_11 hd_b_ch3.apph.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch3.apph.tab3_1_1_1_1 hd_h_ch3.apph.tab3_1_1_1_2 hd_h_ch3.apph.tab3_1_1_1_3 hd_h_ch3.apph.tab3_1_1_1_4 hd_h_ch3.apph.tab3_1_1_1_5 hd_h_ch3.apph.tab3_1_1_1_6 hd_h_ch3.apph.tab3_1_1_1_7 hd_h_ch3.apph.tab3_1_1_1_8 hd_h_ch3.apph.tab3_1_1_1_9 hd_h_ch3.apph.tab3_1_1_1_10 hd_h_ch3.apph.tab3_1_1_1_11" id="hd_b_ch3.apph.tab3_1_1_5_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Withdrawals due to adverse events (RR<1 favours THC capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab3_1_1_1_1 hd_b_ch3.apph.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (van Amerongen 2018)</td><td headers="hd_h_ch3.apph.tab3_1_1_1_2 hd_b_ch3.apph.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab3_1_1_1_3 hd_b_ch3.apph.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">24</td><td headers="hd_h_ch3.apph.tab3_1_1_1_4 hd_b_ch3.apph.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>RR 3.00</p>
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<p>(0.13, 67.06)</p>
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</td><td headers="hd_h_ch3.apph.tab3_1_1_1_5 hd_b_ch3.apph.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4 per 100</td><td headers="hd_h_ch3.apph.tab3_1_1_1_6 hd_b_ch3.apph.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>13 per 100</p>
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<p>(1, 100)</p>
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</td><td headers="hd_h_ch3.apph.tab3_1_1_1_7 hd_b_ch3.apph.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab3_1_1_1_8 hd_b_ch3.apph.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab3_1_1_1_9 hd_b_ch3.apph.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab3_1_1_1_10 hd_b_ch3.apph.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>3</sub></sup></td><td headers="hd_h_ch3.apph.tab3_1_1_1_11 hd_b_ch3.apph.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1</dt><dd><div id="ch3.apph.tab3_1"><p class="no_margin">Single study at moderate risk of bias. Downgraded 1 level</p></div></dd></dl><dl class="bkr_refwrap"><dt>2</dt><dd><div id="ch3.apph.tab3_2"><p class="no_margin">Inconsistency N/A as only 1 study</p></div></dd></dl><dl class="bkr_refwrap"><dt>3</dt><dd><div id="ch3.apph.tab3_3"><p class="no_margin">95% confidence interval crosses line of no effect. Downgraded 1 level</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobch3apphtab4"><div id="ch3.apph.tab4" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.apph.tab4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.apph.tab4_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ch3.apph.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch3.apph.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch3.apph.tab4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch3.apph.tab4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Effect size (95% CI)</th><th id="hd_h_ch3.apph.tab4_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Absolute risk (control)</th><th id="hd_h_ch3.apph.tab4_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absolute risk (intervention)</th><th id="hd_h_ch3.apph.tab4_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Risk of bias</th><th id="hd_h_ch3.apph.tab4_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Inconsistency</th><th id="hd_h_ch3.apph.tab4_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Indirectness</th><th id="hd_h_ch3.apph.tab4_1_1_1_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Imprecision</th><th id="hd_h_ch3.apph.tab4_1_1_1_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th></tr></thead><tbody><tr><th headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_h_ch3.apph.tab4_1_1_1_2 hd_h_ch3.apph.tab4_1_1_1_3 hd_h_ch3.apph.tab4_1_1_1_4 hd_h_ch3.apph.tab4_1_1_1_5 hd_h_ch3.apph.tab4_1_1_1_6 hd_h_ch3.apph.tab4_1_1_1_7 hd_h_ch3.apph.tab4_1_1_1_8 hd_h_ch3.apph.tab4_1_1_1_9 hd_h_ch3.apph.tab4_1_1_1_10 hd_h_ch3.apph.tab4_1_1_1_11" id="hd_b_ch3.apph.tab4_1_1_1_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: Ashworth scale (5 point scale) - Change from baseline: Total score (MD <0 favours THC:CBD capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_b_ch3.apph.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td><td headers="hd_h_ch3.apph.tab4_1_1_1_2 hd_b_ch3.apph.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.apph.tab4_1_1_1_3 hd_b_ch3.apph.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">772</td><td headers="hd_h_ch3.apph.tab4_1_1_1_4 hd_b_ch3.apph.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD −0.32</p>
|
|
<p>(−1.31, 0.66)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab4_1_1_1_5 hd_b_ch3.apph.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_6 hd_b_ch3.apph.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_7 hd_b_ch3.apph.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>5</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_8 hd_b_ch3.apph.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_9 hd_b_ch3.apph.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_10 hd_b_ch3.apph.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>3</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_11 hd_b_ch3.apph.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_h_ch3.apph.tab4_1_1_1_2 hd_h_ch3.apph.tab4_1_1_1_3 hd_h_ch3.apph.tab4_1_1_1_4 hd_h_ch3.apph.tab4_1_1_1_5 hd_h_ch3.apph.tab4_1_1_1_6 hd_h_ch3.apph.tab4_1_1_1_7 hd_h_ch3.apph.tab4_1_1_1_8 hd_h_ch3.apph.tab4_1_1_1_9 hd_h_ch3.apph.tab4_1_1_1_10 hd_h_ch3.apph.tab4_1_1_1_11" id="hd_b_ch3.apph.tab4_1_1_3_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: Ashworth scale (5 point scale) - Change from baseline: Upper body score (MD <0 favours THC:CBD capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_b_ch3.apph.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a>)</td><td headers="hd_h_ch3.apph.tab4_1_1_1_2 hd_b_ch3.apph.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab4_1_1_1_3 hd_b_ch3.apph.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">424</td><td headers="hd_h_ch3.apph.tab4_1_1_1_4 hd_b_ch3.apph.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD −0.06</p>
|
|
<p>(−0.84, 0.72)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab4_1_1_1_5 hd_b_ch3.apph.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_6 hd_b_ch3.apph.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_7 hd_b_ch3.apph.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_8 hd_b_ch3.apph.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_9 hd_b_ch3.apph.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_10 hd_b_ch3.apph.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>3</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_11 hd_b_ch3.apph.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_h_ch3.apph.tab4_1_1_1_2 hd_h_ch3.apph.tab4_1_1_1_3 hd_h_ch3.apph.tab4_1_1_1_4 hd_h_ch3.apph.tab4_1_1_1_5 hd_h_ch3.apph.tab4_1_1_1_6 hd_h_ch3.apph.tab4_1_1_1_7 hd_h_ch3.apph.tab4_1_1_1_8 hd_h_ch3.apph.tab4_1_1_1_9 hd_h_ch3.apph.tab4_1_1_1_10 hd_h_ch3.apph.tab4_1_1_1_11" id="hd_b_ch3.apph.tab4_1_1_5_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: Ashworth scale (5 point scale) - Change from baseline: Lower body score (MD <0 favours THC:CBD capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_b_ch3.apph.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a>)</td><td headers="hd_h_ch3.apph.tab4_1_1_1_2 hd_b_ch3.apph.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab4_1_1_1_3 hd_b_ch3.apph.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">424</td><td headers="hd_h_ch3.apph.tab4_1_1_1_4 hd_b_ch3.apph.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD −0.25</p>
|
|
<p>(−1.07, 0.57)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab4_1_1_1_5 hd_b_ch3.apph.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_6 hd_b_ch3.apph.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_7 hd_b_ch3.apph.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_8 hd_b_ch3.apph.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_9 hd_b_ch3.apph.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_10 hd_b_ch3.apph.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>3</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_11 hd_b_ch3.apph.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_h_ch3.apph.tab4_1_1_1_2 hd_h_ch3.apph.tab4_1_1_1_3 hd_h_ch3.apph.tab4_1_1_1_4 hd_h_ch3.apph.tab4_1_1_1_5 hd_h_ch3.apph.tab4_1_1_1_6 hd_h_ch3.apph.tab4_1_1_1_7 hd_h_ch3.apph.tab4_1_1_1_8 hd_h_ch3.apph.tab4_1_1_1_9 hd_h_ch3.apph.tab4_1_1_1_10 hd_h_ch3.apph.tab4_1_1_1_11" id="hd_b_ch3.apph.tab4_1_1_7_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: MSSS-88 - Change from baseline: Subscale 1 (Muscle stiffness; 19 items, 5 point scale)) (MD >0 favours THC:CBD capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_b_ch3.apph.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Zajicek 2012)</td><td headers="hd_h_ch3.apph.tab4_1_1_1_2 hd_b_ch3.apph.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab4_1_1_1_3 hd_b_ch3.apph.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">277</td><td headers="hd_h_ch3.apph.tab4_1_1_1_4 hd_b_ch3.apph.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD 3.70</p>
|
|
<p>(1.77, 5.63)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab4_1_1_1_5 hd_b_ch3.apph.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_6 hd_b_ch3.apph.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_7 hd_b_ch3.apph.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_8 hd_b_ch3.apph.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_9 hd_b_ch3.apph.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_10 hd_b_ch3.apph.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_11 hd_b_ch3.apph.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr><tr><th headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_h_ch3.apph.tab4_1_1_1_2 hd_h_ch3.apph.tab4_1_1_1_3 hd_h_ch3.apph.tab4_1_1_1_4 hd_h_ch3.apph.tab4_1_1_1_5 hd_h_ch3.apph.tab4_1_1_1_6 hd_h_ch3.apph.tab4_1_1_1_7 hd_h_ch3.apph.tab4_1_1_1_8 hd_h_ch3.apph.tab4_1_1_1_9 hd_h_ch3.apph.tab4_1_1_1_10 hd_h_ch3.apph.tab4_1_1_1_11" id="hd_b_ch3.apph.tab4_1_1_9_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: MSSS-88 - Change from baseline: Subscale 2 (Pain/discomfort; 10 items, 5 point scale) (MD >0 favours THC:CBD capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_b_ch3.apph.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Zajicek 2012)</td><td headers="hd_h_ch3.apph.tab4_1_1_1_2 hd_b_ch3.apph.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab4_1_1_1_3 hd_b_ch3.apph.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">277</td><td headers="hd_h_ch3.apph.tab4_1_1_1_4 hd_b_ch3.apph.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD 1.40</p>
|
|
<p>(−0.08, 2.88)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab4_1_1_1_5 hd_b_ch3.apph.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_6 hd_b_ch3.apph.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_7 hd_b_ch3.apph.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_8 hd_b_ch3.apph.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_9 hd_b_ch3.apph.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_10 hd_b_ch3.apph.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>3</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_11 hd_b_ch3.apph.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_h_ch3.apph.tab4_1_1_1_2 hd_h_ch3.apph.tab4_1_1_1_3 hd_h_ch3.apph.tab4_1_1_1_4 hd_h_ch3.apph.tab4_1_1_1_5 hd_h_ch3.apph.tab4_1_1_1_6 hd_h_ch3.apph.tab4_1_1_1_7 hd_h_ch3.apph.tab4_1_1_1_8 hd_h_ch3.apph.tab4_1_1_1_9 hd_h_ch3.apph.tab4_1_1_1_10 hd_h_ch3.apph.tab4_1_1_1_11" id="hd_b_ch3.apph.tab4_1_1_11_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: MSSS-88 - Change from baseline: Subscale 3 (Muscle spasms; 23 items, 5 point scale) (MD >0 favours THC:CBD capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_b_ch3.apph.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Zajicek 2012)</td><td headers="hd_h_ch3.apph.tab4_1_1_1_2 hd_b_ch3.apph.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab4_1_1_1_3 hd_b_ch3.apph.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">277</td><td headers="hd_h_ch3.apph.tab4_1_1_1_4 hd_b_ch3.apph.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD 3.10</p>
|
|
<p>(0.85, 5.35)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab4_1_1_1_5 hd_b_ch3.apph.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_6 hd_b_ch3.apph.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_7 hd_b_ch3.apph.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_8 hd_b_ch3.apph.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_9 hd_b_ch3.apph.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_10 hd_b_ch3.apph.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_11 hd_b_ch3.apph.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr><tr><th headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_h_ch3.apph.tab4_1_1_1_2 hd_h_ch3.apph.tab4_1_1_1_3 hd_h_ch3.apph.tab4_1_1_1_4 hd_h_ch3.apph.tab4_1_1_1_5 hd_h_ch3.apph.tab4_1_1_1_6 hd_h_ch3.apph.tab4_1_1_1_7 hd_h_ch3.apph.tab4_1_1_1_8 hd_h_ch3.apph.tab4_1_1_1_9 hd_h_ch3.apph.tab4_1_1_1_10 hd_h_ch3.apph.tab4_1_1_1_11" id="hd_b_ch3.apph.tab4_1_1_13_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: MSSS-88 - Change from baseline: Subscale 4 (Daily activities; 14 items, 5 point scale) (MD >0 favours THC:CBD capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_b_ch3.apph.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Zajicek 2012)</td><td headers="hd_h_ch3.apph.tab4_1_1_1_2 hd_b_ch3.apph.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab4_1_1_1_3 hd_b_ch3.apph.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">277</td><td headers="hd_h_ch3.apph.tab4_1_1_1_4 hd_b_ch3.apph.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD −0.30</p>
|
|
<p>(−2.21, 1.61)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab4_1_1_1_5 hd_b_ch3.apph.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_6 hd_b_ch3.apph.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_7 hd_b_ch3.apph.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_8 hd_b_ch3.apph.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_9 hd_b_ch3.apph.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_10 hd_b_ch3.apph.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>3</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_11 hd_b_ch3.apph.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_h_ch3.apph.tab4_1_1_1_2 hd_h_ch3.apph.tab4_1_1_1_3 hd_h_ch3.apph.tab4_1_1_1_4 hd_h_ch3.apph.tab4_1_1_1_5 hd_h_ch3.apph.tab4_1_1_1_6 hd_h_ch3.apph.tab4_1_1_1_7 hd_h_ch3.apph.tab4_1_1_1_8 hd_h_ch3.apph.tab4_1_1_1_9 hd_h_ch3.apph.tab4_1_1_1_10 hd_h_ch3.apph.tab4_1_1_1_11" id="hd_b_ch3.apph.tab4_1_1_15_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: MSSS-88 - Change from baseline: Subscale 5 (Ability to walk; 15 items, 5 point scale) (MD >0 favours THC:CBD capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_b_ch3.apph.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Zajicek 2012)</td><td headers="hd_h_ch3.apph.tab4_1_1_1_2 hd_b_ch3.apph.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab4_1_1_1_3 hd_b_ch3.apph.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">277</td><td headers="hd_h_ch3.apph.tab4_1_1_1_4 hd_b_ch3.apph.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD 1.60</p>
|
|
<p>(0.43, 2.77)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab4_1_1_1_5 hd_b_ch3.apph.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_6 hd_b_ch3.apph.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_7 hd_b_ch3.apph.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_8 hd_b_ch3.apph.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_9 hd_b_ch3.apph.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_10 hd_b_ch3.apph.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_11 hd_b_ch3.apph.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr><tr><th headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_h_ch3.apph.tab4_1_1_1_2 hd_h_ch3.apph.tab4_1_1_1_3 hd_h_ch3.apph.tab4_1_1_1_4 hd_h_ch3.apph.tab4_1_1_1_5 hd_h_ch3.apph.tab4_1_1_1_6 hd_h_ch3.apph.tab4_1_1_1_7 hd_h_ch3.apph.tab4_1_1_1_8 hd_h_ch3.apph.tab4_1_1_1_9 hd_h_ch3.apph.tab4_1_1_1_10 hd_h_ch3.apph.tab4_1_1_1_11" id="hd_b_ch3.apph.tab4_1_1_17_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: MSSS-88 - Change from baseline: Subscale 6 (Body movement; 21 items, 5 point scale) (MD >0 favours THC:CBD capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_b_ch3.apph.tab4_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Zajicek 2012)</td><td headers="hd_h_ch3.apph.tab4_1_1_1_2 hd_b_ch3.apph.tab4_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab4_1_1_1_3 hd_b_ch3.apph.tab4_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">277</td><td headers="hd_h_ch3.apph.tab4_1_1_1_4 hd_b_ch3.apph.tab4_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD 2.10</p>
|
|
<p>(0.26, 3.94)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab4_1_1_1_5 hd_b_ch3.apph.tab4_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_6 hd_b_ch3.apph.tab4_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_7 hd_b_ch3.apph.tab4_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_8 hd_b_ch3.apph.tab4_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_9 hd_b_ch3.apph.tab4_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_10 hd_b_ch3.apph.tab4_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_11 hd_b_ch3.apph.tab4_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr><tr><th headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_h_ch3.apph.tab4_1_1_1_2 hd_h_ch3.apph.tab4_1_1_1_3 hd_h_ch3.apph.tab4_1_1_1_4 hd_h_ch3.apph.tab4_1_1_1_5 hd_h_ch3.apph.tab4_1_1_1_6 hd_h_ch3.apph.tab4_1_1_1_7 hd_h_ch3.apph.tab4_1_1_1_8 hd_h_ch3.apph.tab4_1_1_1_9 hd_h_ch3.apph.tab4_1_1_1_10 hd_h_ch3.apph.tab4_1_1_1_11" id="hd_b_ch3.apph.tab4_1_1_19_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: MSSS-88 - Change from baseline: Subscale 7 (Feelings; 26 items, 5 point scale) (MD >0 favours THC:CBD capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_b_ch3.apph.tab4_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Zajicek 2012)</td><td headers="hd_h_ch3.apph.tab4_1_1_1_2 hd_b_ch3.apph.tab4_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab4_1_1_1_3 hd_b_ch3.apph.tab4_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">277</td><td headers="hd_h_ch3.apph.tab4_1_1_1_4 hd_b_ch3.apph.tab4_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD 0.30</p>
|
|
<p>(−1.82, 2.42)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab4_1_1_1_5 hd_b_ch3.apph.tab4_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_6 hd_b_ch3.apph.tab4_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_7 hd_b_ch3.apph.tab4_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_8 hd_b_ch3.apph.tab4_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_9 hd_b_ch3.apph.tab4_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_10 hd_b_ch3.apph.tab4_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>3</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_11 hd_b_ch3.apph.tab4_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_h_ch3.apph.tab4_1_1_1_2 hd_h_ch3.apph.tab4_1_1_1_3 hd_h_ch3.apph.tab4_1_1_1_4 hd_h_ch3.apph.tab4_1_1_1_5 hd_h_ch3.apph.tab4_1_1_1_6 hd_h_ch3.apph.tab4_1_1_1_7 hd_h_ch3.apph.tab4_1_1_1_8 hd_h_ch3.apph.tab4_1_1_1_9 hd_h_ch3.apph.tab4_1_1_1_10 hd_h_ch3.apph.tab4_1_1_1_11" id="hd_b_ch3.apph.tab4_1_1_21_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: MSSS-88 - Change from baseline: Subscale 8 (Social functioning; 16 items, 5 point scale) (MD >0 favours THC:CBD capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_b_ch3.apph.tab4_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Zajicek 2012)</td><td headers="hd_h_ch3.apph.tab4_1_1_1_2 hd_b_ch3.apph.tab4_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab4_1_1_1_3 hd_b_ch3.apph.tab4_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">277</td><td headers="hd_h_ch3.apph.tab4_1_1_1_4 hd_b_ch3.apph.tab4_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD 0.20</p>
|
|
<p>(−1.19, 1.59)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab4_1_1_1_5 hd_b_ch3.apph.tab4_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_6 hd_b_ch3.apph.tab4_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab4_1_1_1_7 hd_b_ch3.apph.tab4_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_8 hd_b_ch3.apph.tab4_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_9 hd_b_ch3.apph.tab4_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_10 hd_b_ch3.apph.tab4_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>3</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_11 hd_b_ch3.apph.tab4_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_h_ch3.apph.tab4_1_1_1_2 hd_h_ch3.apph.tab4_1_1_1_3 hd_h_ch3.apph.tab4_1_1_1_4 hd_h_ch3.apph.tab4_1_1_1_5 hd_h_ch3.apph.tab4_1_1_1_6 hd_h_ch3.apph.tab4_1_1_1_7 hd_h_ch3.apph.tab4_1_1_1_8 hd_h_ch3.apph.tab4_1_1_1_9 hd_h_ch3.apph.tab4_1_1_1_10 hd_h_ch3.apph.tab4_1_1_1_11" id="hd_b_ch3.apph.tab4_1_1_23_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Total adverse events (RR<1 favours THC:CBD capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_b_ch3.apph.tab4_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td><td headers="hd_h_ch3.apph.tab4_1_1_1_2 hd_b_ch3.apph.tab4_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.apph.tab4_1_1_1_3 hd_b_ch3.apph.tab4_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">848</td><td headers="hd_h_ch3.apph.tab4_1_1_1_4 hd_b_ch3.apph.tab4_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>RR 1.09</p>
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<p>(0.91, 1.31)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab4_1_1_1_5 hd_b_ch3.apph.tab4_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">69 per 100</td><td headers="hd_h_ch3.apph.tab4_1_1_1_6 hd_b_ch3.apph.tab4_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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|
<p>76 per 100</p>
|
|
<p>(63, 91)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab4_1_1_1_7 hd_b_ch3.apph.tab4_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_8 hd_b_ch3.apph.tab4_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>4</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_9 hd_b_ch3.apph.tab4_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_10 hd_b_ch3.apph.tab4_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>3</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_11 hd_b_ch3.apph.tab4_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_h_ch3.apph.tab4_1_1_1_2 hd_h_ch3.apph.tab4_1_1_1_3 hd_h_ch3.apph.tab4_1_1_1_4 hd_h_ch3.apph.tab4_1_1_1_5 hd_h_ch3.apph.tab4_1_1_1_6 hd_h_ch3.apph.tab4_1_1_1_7 hd_h_ch3.apph.tab4_1_1_1_8 hd_h_ch3.apph.tab4_1_1_1_9 hd_h_ch3.apph.tab4_1_1_1_10 hd_h_ch3.apph.tab4_1_1_1_11" id="hd_b_ch3.apph.tab4_1_1_25_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Treatment-related adverse events (RR<1 favours THC:CBD capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_b_ch3.apph.tab4_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Zajicek 2012)</td><td headers="hd_h_ch3.apph.tab4_1_1_1_2 hd_b_ch3.apph.tab4_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab4_1_1_1_3 hd_b_ch3.apph.tab4_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">277</td><td headers="hd_h_ch3.apph.tab4_1_1_1_4 hd_b_ch3.apph.tab4_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>RR 1.25</p>
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<p>(1.12, 1.39)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab4_1_1_1_5 hd_b_ch3.apph.tab4_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">75 per 100</td><td headers="hd_h_ch3.apph.tab4_1_1_1_6 hd_b_ch3.apph.tab4_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>93 per 100</p>
|
|
<p>(84, 104)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab4_1_1_1_7 hd_b_ch3.apph.tab4_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_8 hd_b_ch3.apph.tab4_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_9 hd_b_ch3.apph.tab4_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_10 hd_b_ch3.apph.tab4_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_11 hd_b_ch3.apph.tab4_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr><tr><th headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_h_ch3.apph.tab4_1_1_1_2 hd_h_ch3.apph.tab4_1_1_1_3 hd_h_ch3.apph.tab4_1_1_1_4 hd_h_ch3.apph.tab4_1_1_1_5 hd_h_ch3.apph.tab4_1_1_1_6 hd_h_ch3.apph.tab4_1_1_1_7 hd_h_ch3.apph.tab4_1_1_1_8 hd_h_ch3.apph.tab4_1_1_1_9 hd_h_ch3.apph.tab4_1_1_1_10 hd_h_ch3.apph.tab4_1_1_1_11" id="hd_b_ch3.apph.tab4_1_1_27_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Total serious adverse events (RR<1 favours THC capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_b_ch3.apph.tab4_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td><td headers="hd_h_ch3.apph.tab4_1_1_1_2 hd_b_ch3.apph.tab4_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.apph.tab4_1_1_1_3 hd_b_ch3.apph.tab4_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">701</td><td headers="hd_h_ch3.apph.tab4_1_1_1_4 hd_b_ch3.apph.tab4_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 1.30</p>
|
|
<p>(0.80, 2.12)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab4_1_1_1_5 hd_b_ch3.apph.tab4_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7 per 100</td><td headers="hd_h_ch3.apph.tab4_1_1_1_6 hd_b_ch3.apph.tab4_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>10 per 100</p>
|
|
<p>(6, 16)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab4_1_1_1_7 hd_b_ch3.apph.tab4_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>5</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_8 hd_b_ch3.apph.tab4_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_9 hd_b_ch3.apph.tab4_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_10 hd_b_ch3.apph.tab4_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>3</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_11 hd_b_ch3.apph.tab4_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_h_ch3.apph.tab4_1_1_1_2 hd_h_ch3.apph.tab4_1_1_1_3 hd_h_ch3.apph.tab4_1_1_1_4 hd_h_ch3.apph.tab4_1_1_1_5 hd_h_ch3.apph.tab4_1_1_1_6 hd_h_ch3.apph.tab4_1_1_1_7 hd_h_ch3.apph.tab4_1_1_1_8 hd_h_ch3.apph.tab4_1_1_1_9 hd_h_ch3.apph.tab4_1_1_1_10 hd_h_ch3.apph.tab4_1_1_1_11" id="hd_b_ch3.apph.tab4_1_1_29_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Withdrawals due to adverse events (RR<1 favours THC capsules)</th></tr><tr><td headers="hd_h_ch3.apph.tab4_1_1_1_1 hd_b_ch3.apph.tab4_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3</td><td headers="hd_h_ch3.apph.tab4_1_1_1_2 hd_b_ch3.apph.tab4_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs</td><td headers="hd_h_ch3.apph.tab4_1_1_1_3 hd_b_ch3.apph.tab4_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1115</td><td headers="hd_h_ch3.apph.tab4_1_1_1_4 hd_b_ch3.apph.tab4_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 2.96</p>
|
|
<p>(1.81, 4.83)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab4_1_1_1_5 hd_b_ch3.apph.tab4_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3 per 100</td><td headers="hd_h_ch3.apph.tab4_1_1_1_6 hd_b_ch3.apph.tab4_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>10 per 100</p>
|
|
<p>(6, 17)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab4_1_1_1_7 hd_b_ch3.apph.tab4_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>5</sub></sup></td><td headers="hd_h_ch3.apph.tab4_1_1_1_8 hd_b_ch3.apph.tab4_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_9 hd_b_ch3.apph.tab4_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_10 hd_b_ch3.apph.tab4_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab4_1_1_1_11 hd_b_ch3.apph.tab4_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1</dt><dd><div id="ch3.apph.tab4_1"><p class="no_margin">Single study at moderate risk of bias. Downgraded 1 level</p></div></dd></dl><dl class="bkr_refwrap"><dt>2</dt><dd><div id="ch3.apph.tab4_2"><p class="no_margin">Inconsistency N/A as only 1 study</p></div></dd></dl><dl class="bkr_refwrap"><dt>3</dt><dd><div id="ch3.apph.tab4_3"><p class="no_margin">95% confidence interval crosses line of no effect. Downgraded 1 level</p></div></dd></dl><dl class="bkr_refwrap"><dt>4</dt><dd><div id="ch3.apph.tab4_4"><p class="no_margin">I<sup>2</sup> between 33.3% and 66.7%. Downgraded one level</p></div></dd></dl><dl class="bkr_refwrap"><dt>5</dt><dd><div id="ch3.apph.tab4_5"><p class="no_margin">> 33.3% of the weight in a meta-analysis came from studies at moderate or high risk of bias. Downgraded 1 level</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobch3apphtab5"><div id="ch3.apph.tab5" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.apph.tab5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.apph.tab5_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ch3.apph.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch3.apph.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch3.apph.tab5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch3.apph.tab5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Effect size (95% CI)</th><th id="hd_h_ch3.apph.tab5_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absolute risk (control)</th><th id="hd_h_ch3.apph.tab5_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Absolute risk (intervention)</th><th id="hd_h_ch3.apph.tab5_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Risk of bias</th><th id="hd_h_ch3.apph.tab5_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Inconsistency</th><th id="hd_h_ch3.apph.tab5_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Indirectness</th><th id="hd_h_ch3.apph.tab5_1_1_1_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Imprecision</th><th id="hd_h_ch3.apph.tab5_1_1_1_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th></tr></thead><tbody><tr><th headers="hd_h_ch3.apph.tab5_1_1_1_1 hd_h_ch3.apph.tab5_1_1_1_2 hd_h_ch3.apph.tab5_1_1_1_3 hd_h_ch3.apph.tab5_1_1_1_4 hd_h_ch3.apph.tab5_1_1_1_5 hd_h_ch3.apph.tab5_1_1_1_6 hd_h_ch3.apph.tab5_1_1_1_7 hd_h_ch3.apph.tab5_1_1_1_8 hd_h_ch3.apph.tab5_1_1_1_9 hd_h_ch3.apph.tab5_1_1_1_10 hd_h_ch3.apph.tab5_1_1_1_11" id="hd_b_ch3.apph.tab5_1_1_1_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: Modified Ashworth scale (6 point scale) - Change from baseline: Total score (MD <0 favours THC:CBD spray)</th></tr><tr><td headers="hd_h_ch3.apph.tab5_1_1_1_1 hd_b_ch3.apph.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Riva 2019)</td><td headers="hd_h_ch3.apph.tab5_1_1_1_2 hd_b_ch3.apph.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab5_1_1_1_3 hd_b_ch3.apph.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">59</td><td headers="hd_h_ch3.apph.tab5_1_1_1_4 hd_b_ch3.apph.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>MD −0.27</p>
|
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<p>(−0.51, −0.03)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab5_1_1_1_5 hd_b_ch3.apph.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab5_1_1_1_6 hd_b_ch3.apph.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab5_1_1_1_7 hd_b_ch3.apph.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab5_1_1_1_8 hd_b_ch3.apph.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab5_1_1_1_9 hd_b_ch3.apph.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab5_1_1_1_10 hd_b_ch3.apph.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab5_1_1_1_11 hd_b_ch3.apph.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">High</td></tr><tr><th headers="hd_h_ch3.apph.tab5_1_1_1_1 hd_h_ch3.apph.tab5_1_1_1_2 hd_h_ch3.apph.tab5_1_1_1_3 hd_h_ch3.apph.tab5_1_1_1_4 hd_h_ch3.apph.tab5_1_1_1_5 hd_h_ch3.apph.tab5_1_1_1_6 hd_h_ch3.apph.tab5_1_1_1_7 hd_h_ch3.apph.tab5_1_1_1_8 hd_h_ch3.apph.tab5_1_1_1_9 hd_h_ch3.apph.tab5_1_1_1_10 hd_h_ch3.apph.tab5_1_1_1_11" id="hd_b_ch3.apph.tab5_1_1_3_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: Numerical rating scale (11 point scale) - Change from baseline (MD <0 favours THC:CBD spray)</th></tr><tr><td headers="hd_h_ch3.apph.tab5_1_1_1_1 hd_b_ch3.apph.tab5_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Riva 2019)</td><td headers="hd_h_ch3.apph.tab5_1_1_1_2 hd_b_ch3.apph.tab5_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab5_1_1_1_3 hd_b_ch3.apph.tab5_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">59</td><td headers="hd_h_ch3.apph.tab5_1_1_1_4 hd_b_ch3.apph.tab5_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD −0.20</p>
|
|
<p>(−1.13, 0.73)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab5_1_1_1_5 hd_b_ch3.apph.tab5_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab5_1_1_1_6 hd_b_ch3.apph.tab5_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab5_1_1_1_7 hd_b_ch3.apph.tab5_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab5_1_1_1_8 hd_b_ch3.apph.tab5_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab5_1_1_1_9 hd_b_ch3.apph.tab5_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab5_1_1_1_10 hd_b_ch3.apph.tab5_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab5_1_1_1_11 hd_b_ch3.apph.tab5_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr><tr><th headers="hd_h_ch3.apph.tab5_1_1_1_1 hd_h_ch3.apph.tab5_1_1_1_2 hd_h_ch3.apph.tab5_1_1_1_3 hd_h_ch3.apph.tab5_1_1_1_4 hd_h_ch3.apph.tab5_1_1_1_5 hd_h_ch3.apph.tab5_1_1_1_6 hd_h_ch3.apph.tab5_1_1_1_7 hd_h_ch3.apph.tab5_1_1_1_8 hd_h_ch3.apph.tab5_1_1_1_9 hd_h_ch3.apph.tab5_1_1_1_10 hd_h_ch3.apph.tab5_1_1_1_11" id="hd_b_ch3.apph.tab5_1_1_5_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Total adverse events (RR <1 favours THC:CBD oromucosal spray)</th></tr><tr><td headers="hd_h_ch3.apph.tab5_1_1_1_1 hd_b_ch3.apph.tab5_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Riva 2019)</td><td headers="hd_h_ch3.apph.tab5_1_1_1_2 hd_b_ch3.apph.tab5_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab5_1_1_1_3 hd_b_ch3.apph.tab5_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">59</td><td headers="hd_h_ch3.apph.tab5_1_1_1_4 hd_b_ch3.apph.tab5_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 2.84</p>
|
|
<p>(1.52, 5.33)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab5_1_1_1_5 hd_b_ch3.apph.tab5_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">27 per 100</td><td headers="hd_h_ch3.apph.tab5_1_1_1_6 hd_b_ch3.apph.tab5_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>76 per 100</p>
|
|
<p>(41, 100)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab5_1_1_1_7 hd_b_ch3.apph.tab5_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab5_1_1_1_8 hd_b_ch3.apph.tab5_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab5_1_1_1_9 hd_b_ch3.apph.tab5_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab5_1_1_1_10 hd_b_ch3.apph.tab5_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab5_1_1_1_11 hd_b_ch3.apph.tab5_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">High</td></tr><tr><th headers="hd_h_ch3.apph.tab5_1_1_1_1 hd_h_ch3.apph.tab5_1_1_1_2 hd_h_ch3.apph.tab5_1_1_1_3 hd_h_ch3.apph.tab5_1_1_1_4 hd_h_ch3.apph.tab5_1_1_1_5 hd_h_ch3.apph.tab5_1_1_1_6 hd_h_ch3.apph.tab5_1_1_1_7 hd_h_ch3.apph.tab5_1_1_1_8 hd_h_ch3.apph.tab5_1_1_1_9 hd_h_ch3.apph.tab5_1_1_1_10 hd_h_ch3.apph.tab5_1_1_1_11" id="hd_b_ch3.apph.tab5_1_1_7_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Treatment-related adverse events (RR <1 favours THC:CBD spray)</th></tr><tr><td headers="hd_h_ch3.apph.tab5_1_1_1_1 hd_b_ch3.apph.tab5_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Riva 2019)</td><td headers="hd_h_ch3.apph.tab5_1_1_1_2 hd_b_ch3.apph.tab5_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch3.apph.tab5_1_1_1_3 hd_b_ch3.apph.tab5_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">59</td><td headers="hd_h_ch3.apph.tab5_1_1_1_4 hd_b_ch3.apph.tab5_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>RR 5.43</p>
|
|
<p>(2.12, 13.90)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab5_1_1_1_5 hd_b_ch3.apph.tab5_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">13 per 100</td><td headers="hd_h_ch3.apph.tab5_1_1_1_6 hd_b_ch3.apph.tab5_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>72 per 100</p>
|
|
<p>(28, 100)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab5_1_1_1_7 hd_b_ch3.apph.tab5_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab5_1_1_1_8 hd_b_ch3.apph.tab5_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab5_1_1_1_9 hd_b_ch3.apph.tab5_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab5_1_1_1_10 hd_b_ch3.apph.tab5_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab5_1_1_1_11 hd_b_ch3.apph.tab5_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">High</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1</dt><dd><div id="ch3.apph.tab5_1"><p class="no_margin">Inconsistency N/A as only 1 study</p></div></dd></dl><dl class="bkr_refwrap"><dt>2</dt><dd><div id="ch3.apph.tab5_2"><p class="no_margin">95% confidence interval crosses line of no effect. Downgraded 1 level</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobch3apphtab6"><div id="ch3.apph.tab6" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.apph.tab6/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.apph.tab6_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ch3.apph.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch3.apph.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch3.apph.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch3.apph.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Effect size (95% CI)</th><th id="hd_h_ch3.apph.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Absolute risk (control)</th><th id="hd_h_ch3.apph.tab6_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absolute risk (intervention)</th><th id="hd_h_ch3.apph.tab6_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Risk of bias</th><th id="hd_h_ch3.apph.tab6_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Inconsistency</th><th id="hd_h_ch3.apph.tab6_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Indirectness</th><th id="hd_h_ch3.apph.tab6_1_1_1_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Imprecision</th><th id="hd_h_ch3.apph.tab6_1_1_1_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th></tr></thead><tbody><tr><th headers="hd_h_ch3.apph.tab6_1_1_1_1 hd_h_ch3.apph.tab6_1_1_1_2 hd_h_ch3.apph.tab6_1_1_1_3 hd_h_ch3.apph.tab6_1_1_1_4 hd_h_ch3.apph.tab6_1_1_1_5 hd_h_ch3.apph.tab6_1_1_1_6 hd_h_ch3.apph.tab6_1_1_1_7 hd_h_ch3.apph.tab6_1_1_1_8 hd_h_ch3.apph.tab6_1_1_1_9 hd_h_ch3.apph.tab6_1_1_1_10 hd_h_ch3.apph.tab6_1_1_1_11" id="hd_b_ch3.apph.tab6_1_1_1_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: Ashworth scale (5 point scale) - Change from baseline: Total score (MD <0 favours nabilone)</th></tr><tr><td headers="hd_h_ch3.apph.tab6_1_1_1_1 hd_b_ch3.apph.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Wissel 2006)</td><td headers="hd_h_ch3.apph.tab6_1_1_1_2 hd_b_ch3.apph.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cross-over RCT</td><td headers="hd_h_ch3.apph.tab6_1_1_1_3 hd_b_ch3.apph.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">26</td><td headers="hd_h_ch3.apph.tab6_1_1_1_4 hd_b_ch3.apph.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD −0.35</p>
|
|
<p>(−1.14, 0.45)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab6_1_1_1_5 hd_b_ch3.apph.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab6_1_1_1_6 hd_b_ch3.apph.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab6_1_1_1_7 hd_b_ch3.apph.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab6_1_1_1_8 hd_b_ch3.apph.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab6_1_1_1_9 hd_b_ch3.apph.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab6_1_1_1_10 hd_b_ch3.apph.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>3</sub></sup></td><td headers="hd_h_ch3.apph.tab6_1_1_1_11 hd_b_ch3.apph.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1</dt><dd><div id="ch3.apph.tab6_1"><p class="no_margin">Single study at high risk of bias. Downgraded 2 levels</p></div></dd></dl><dl class="bkr_refwrap"><dt>2</dt><dd><div id="ch3.apph.tab6_2"><p class="no_margin">Inconsistency N/A as only 1 study</p></div></dd></dl><dl class="bkr_refwrap"><dt>3</dt><dd><div id="ch3.apph.tab6_3"><p class="no_margin">95% confidence interval crosses line of no effect. Downgraded 1 level</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobch3apphtab7"><div id="ch3.apph.tab7" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.apph.tab7/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.apph.tab7_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ch3.apph.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch3.apph.tab7_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch3.apph.tab7_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch3.apph.tab7_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Effect size (95% CI)</th><th id="hd_h_ch3.apph.tab7_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Absolute risk (control)</th><th id="hd_h_ch3.apph.tab7_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Absolute risk (intervention)</th><th id="hd_h_ch3.apph.tab7_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Risk of bias</th><th id="hd_h_ch3.apph.tab7_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Inconsistency</th><th id="hd_h_ch3.apph.tab7_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Indirectness</th><th id="hd_h_ch3.apph.tab7_1_1_1_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Imprecision</th><th id="hd_h_ch3.apph.tab7_1_1_1_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th></tr></thead><tbody><tr><th headers="hd_h_ch3.apph.tab7_1_1_1_1 hd_h_ch3.apph.tab7_1_1_1_2 hd_h_ch3.apph.tab7_1_1_1_3 hd_h_ch3.apph.tab7_1_1_1_4 hd_h_ch3.apph.tab7_1_1_1_5 hd_h_ch3.apph.tab7_1_1_1_6 hd_h_ch3.apph.tab7_1_1_1_7 hd_h_ch3.apph.tab7_1_1_1_8 hd_h_ch3.apph.tab7_1_1_1_9 hd_h_ch3.apph.tab7_1_1_1_10 hd_h_ch3.apph.tab7_1_1_1_11" id="hd_b_ch3.apph.tab7_1_1_1_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: Ashworth scale (5 point scale) - Change from baseline: Total score (MD <0 favours nabilone)</th></tr><tr><td headers="hd_h_ch3.apph.tab7_1_1_1_1 hd_b_ch3.apph.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Pooyania 2010)</td><td headers="hd_h_ch3.apph.tab7_1_1_1_2 hd_b_ch3.apph.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cross-over RCT</td><td headers="hd_h_ch3.apph.tab7_1_1_1_3 hd_b_ch3.apph.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">22</td><td headers="hd_h_ch3.apph.tab7_1_1_1_4 hd_b_ch3.apph.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD −2.55</p>
|
|
<p>(−3.84, −1.26)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab7_1_1_1_5 hd_b_ch3.apph.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab7_1_1_1_6 hd_b_ch3.apph.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab7_1_1_1_7 hd_b_ch3.apph.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab7_1_1_1_8 hd_b_ch3.apph.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab7_1_1_1_9 hd_b_ch3.apph.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab7_1_1_1_10 hd_b_ch3.apph.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab7_1_1_1_11 hd_b_ch3.apph.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr><tr><th headers="hd_h_ch3.apph.tab7_1_1_1_1 hd_h_ch3.apph.tab7_1_1_1_2 hd_h_ch3.apph.tab7_1_1_1_3 hd_h_ch3.apph.tab7_1_1_1_4 hd_h_ch3.apph.tab7_1_1_1_5 hd_h_ch3.apph.tab7_1_1_1_6 hd_h_ch3.apph.tab7_1_1_1_7 hd_h_ch3.apph.tab7_1_1_1_8 hd_h_ch3.apph.tab7_1_1_1_9 hd_h_ch3.apph.tab7_1_1_1_10 hd_h_ch3.apph.tab7_1_1_1_11" id="hd_b_ch3.apph.tab7_1_1_3_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: Ashworth scale (5 point scale) - Change from baseline: Most involved muscle group (MD <0 favours nabilone)</th></tr><tr><td headers="hd_h_ch3.apph.tab7_1_1_1_1 hd_b_ch3.apph.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Pooyania 2010)</td><td headers="hd_h_ch3.apph.tab7_1_1_1_2 hd_b_ch3.apph.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cross-over RCT</td><td headers="hd_h_ch3.apph.tab7_1_1_1_3 hd_b_ch3.apph.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">22</td><td headers="hd_h_ch3.apph.tab7_1_1_1_4 hd_b_ch3.apph.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD −0.91</p>
|
|
<p>(−1.44, −0.38)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab7_1_1_1_5 hd_b_ch3.apph.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab7_1_1_1_6 hd_b_ch3.apph.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab7_1_1_1_7 hd_b_ch3.apph.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab7_1_1_1_8 hd_b_ch3.apph.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab7_1_1_1_9 hd_b_ch3.apph.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab7_1_1_1_10 hd_b_ch3.apph.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab7_1_1_1_11 hd_b_ch3.apph.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr><tr><th headers="hd_h_ch3.apph.tab7_1_1_1_1 hd_h_ch3.apph.tab7_1_1_1_2 hd_h_ch3.apph.tab7_1_1_1_3 hd_h_ch3.apph.tab7_1_1_1_4 hd_h_ch3.apph.tab7_1_1_1_5 hd_h_ch3.apph.tab7_1_1_1_6 hd_h_ch3.apph.tab7_1_1_1_7 hd_h_ch3.apph.tab7_1_1_1_8 hd_h_ch3.apph.tab7_1_1_1_9 hd_h_ch3.apph.tab7_1_1_1_10 hd_h_ch3.apph.tab7_1_1_1_11" id="hd_b_ch3.apph.tab7_1_1_5_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:middle;">Spasticity: Visual analogue scale (100 point scale) - Change from baseline (MD <0 favours nabilone)</th></tr><tr><td headers="hd_h_ch3.apph.tab7_1_1_1_1 hd_b_ch3.apph.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (Pooyania 2010)</td><td headers="hd_h_ch3.apph.tab7_1_1_1_2 hd_b_ch3.apph.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cross-over RCT</td><td headers="hd_h_ch3.apph.tab7_1_1_1_3 hd_b_ch3.apph.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">22</td><td headers="hd_h_ch3.apph.tab7_1_1_1_4 hd_b_ch3.apph.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>MD −9.09</p>
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|
<p>(−18.61, 0.43)</p>
|
|
</td><td headers="hd_h_ch3.apph.tab7_1_1_1_5 hd_b_ch3.apph.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab7_1_1_1_6 hd_b_ch3.apph.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_ch3.apph.tab7_1_1_1_7 hd_b_ch3.apph.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>1</sub></sup></td><td headers="hd_h_ch3.apph.tab7_1_1_1_8 hd_b_ch3.apph.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A<sup><sub>2</sub></sup></td><td headers="hd_h_ch3.apph.tab7_1_1_1_9 hd_b_ch3.apph.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch3.apph.tab7_1_1_1_10 hd_b_ch3.apph.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup><sub>3</sub></sup></td><td headers="hd_h_ch3.apph.tab7_1_1_1_11 hd_b_ch3.apph.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1</dt><dd><div id="ch3.apph.tab7_1"><p class="no_margin">Single study at moderate risk of bias. Downgraded 1 level</p></div></dd></dl><dl class="bkr_refwrap"><dt>2</dt><dd><div id="ch3.apph.tab7_2"><p class="no_margin">Inconsistency N/A as only 1 study</p></div></dd></dl><dl class="bkr_refwrap"><dt>3</dt><dd><div id="ch3.apph.tab7_3"><p class="no_margin">95% confidence interval crosses line of no effect. Downgraded 1 level</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobch3appitab1"><div id="ch3.appi.tab1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appi.tab1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appi.tab1_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appi.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study</th><th id="hd_h_ch3.appi.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Adverse events reported</th></tr></thead><tbody><tr><th headers="hd_h_ch3.appi.tab1_1_1_1_1 hd_h_ch3.appi.tab1_1_1_1_2" id="hd_b_ch3.appi.tab1_1_1_1_1" colspan="2" rowspan="1" style="text-align:left;vertical-align:bottom;">Dose higher than recommended</th></tr><tr><td headers="hd_h_ch3.appi.tab1_1_1_1_1 hd_b_ch3.appi.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref9" rid="ch3.appm.ref9">Collin 2007</a>
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</td><td headers="hd_h_ch3.appi.tab1_1_1_1_2 hd_b_ch3.appi.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Treatment-related adverse events experienced by more than 4 participants</p>
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<p>THC: CBD spray: Dizziness 32%; Fatigue 11%; Urinary tract infection 11%; Dry mouth 9%; Balance impaired 7%; Nausea 7%; Headache 7%; Diarrhoea 6%; Oral pain 5%; Somnolence 5%; Confusion 5%; Depressed mood 5%; Constipation 4%; Disorientation 4%; Dysgeusia 4%; Disturbance in attention 3%; Euphoric mood 3%; Blurred vision 3%; Weakness 3%; Limb pain 3%</p>
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<p>Placebo: Dizziness 11%; Fatigue 6%; Urinary tract infection 9%; Dry mouth 6%; Balance impaired 2%; Nausea 6%; Headache 6%; Diarrhoea 3%; Oral pain 10%; Somnolence 2%; Confusion 3%; Constipation 2%; Disorientation 2%; Dysgeusia 2%; Euphoric mood 3%; Weakness 2%; Limb pain 2%</p>
|
|
</td></tr><tr><td headers="hd_h_ch3.appi.tab1_1_1_1_1 hd_b_ch3.appi.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref10" rid="ch3.appm.ref10">Collin 2010</a>
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</td><td headers="hd_h_ch3.appi.tab1_1_1_1_2 hd_b_ch3.appi.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Total adverse events experienced by ≥10% participants</p>
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<p>THC: CBD spray: Nervous system disorders 69% (Dizziness 32%; Somnolence 14%; Spasticity 10%); General disorders 46% (Fatigue 25%; Asthenia 16%); Gastrointestinal disorders 35% (Nausea 32%; Dry mouth 14%); Infections 22% (Urinary tract infection NOS 11%); Psychiatric disorders 17%; Musculoskeletal and connective tissue disorders 14%; Ear and labyrinth disorders 11% (Vertigo 11%)</p>
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<p>Placebo: Nervous system disorders 78% (Dizziness 34%; Somnolence 10%; Spasticity 4%); General disorders 28% (Fatigue 19%; Asthenia 6%); Gastrointestinal disorders 20% (Nausea 10%; Dry mouth 4%); Infections 22% (Urinary tract infection NOS 12%); Psychiatric disorders 11%; Musculoskeletal and connective tissue disorders 9%; Ear and labyrinth disorders 4% (Vertigo 4%)</p>
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<p>Most commonly reported treatment-related adverse events which showed a higher incidence in the active treatment group than placebo:</p>
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<p>THC: CBD spray: Dizziness 32%; Fatigue 23%; Somnolence 14%; Nausea 14%; Asthenia 13%; Vertigo 11%</p>
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<p>Placebo: Dizziness 10%; Fatigue 16%; Somnolence 4%; Nausea 5%; Asthenia 6%; Vertigo 4%</p>
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</td></tr><tr><td headers="hd_h_ch3.appi.tab1_1_1_1_1 hd_b_ch3.appi.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Wade 2004</td><td headers="hd_h_ch3.appi.tab1_1_1_1_2 hd_b_ch3.appi.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Treatment-related adverse events with >4% incidence</p>
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<p>THC: CBD spray: Dizziness 33%; Disturbance in attention 9%; Headache 9%; Fatigue 15%; Somnolence 9%; Disorientation 8%; Feeling drunk 5%; Vertigo 6%; Application site discomfort 26%; Nausea 9%; Diarrhoea 8%; Mouth ulceration 5%</p>
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<p>Placebo: Dizziness 13%; Headache 16%; Fatigue 4%; Somnolence 1%; Application site discomfort 23%; Nausea 6%; Diarrhoea 3%; Mouth ulceration 1%</p>
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</td></tr><tr><th headers="hd_h_ch3.appi.tab1_1_1_1_1 hd_h_ch3.appi.tab1_1_1_1_2" id="hd_b_ch3.appi.tab1_1_1_5_1" colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;">Within recommended dose</th></tr><tr><td headers="hd_h_ch3.appi.tab1_1_1_1_1 hd_b_ch3.appi.tab1_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref22" rid="ch3.appm.ref22">Langford 2013</a>
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</td><td headers="hd_h_ch3.appi.tab1_1_1_1_2 hd_b_ch3.appi.tab1_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Treatment-related adverse events experienced by ≥3% participants (Phase A)</p>
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<p>THC: CBD spray: Ear and labyrinth disorder 12% (Vertigo 9%); Eye disorder 4% (Blurred vision 2%); Gastrointestinal disorder 32% (Nausea 8%; Dry mouth 7%; Diarrhoea 4%; Vomiting 3%); General disorders 24% (Fatigue 10%; Feeling abnormal 3%); Infections and infestations (20%); Musculoskeletal and connective tissue disorders 10% (Muscular weakness 1%); Nervous system disorders 44% (Dizziness 20%; Somnolence 10%; Headache 4%; Disturbance in attention 4%; Dysgeusia 4%; Memory impairment 4%; Balance disorder 3%; Psychomotor skills impaired 3%; Neuralgia 1%); Psychiatric disorders 16% (Depression 1%); Respiratory, thoracic and mediastinal disorders 5% (Pharyngolaryngeal pain 1%)</p>
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<p>Placebo: Ear and labyrinth disorder 5% (Vertigo 3%); Eye disorder 3% (Blurred vision 1%); Gastrointestinal disorder 23% (Nausea 4%; Dry mouth 6%; Diarrhoea 3%; Vomiting 3%); General disorders 17% (Fatigue 5%; Feeling abnormal 1%; Pain 1%); Infections and infestations (16%); Musculoskeletal and connective tissue disorders 12% (Pain in extremity 1%; Muscular weakness 1%); Nervous system disorders 30% (Dizziness 4%; Somnolence 2%; Headache 3%; Disturbance in attention 1%; Dysgeusia 1%; Memory impairment 1%; Balance disorder 1%; Neuralgia 1%); Psychiatric disorders 7%; Respiratory, thoracic and mediastinal disorders 6% (Pharyngolaryngeal pain 1%)</p>
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</td></tr><tr><td headers="hd_h_ch3.appi.tab1_1_1_1_1 hd_b_ch3.appi.tab1_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Leocani 2015</td><td headers="hd_h_ch3.appi.tab1_1_1_1_2 hd_b_ch3.appi.tab1_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>THC: CBD spray: Dizziness 21%; Lower limb weakness 6%; Vertigo 3%; Hypotension 6%; Hypertension 3%; Pharyngodia 3%</p>
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<p>Placebo: Dizziness 6%; Lower limb weakness 3%; Vertigo 3%; Somnolence 3%; Fever 3%</p>
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</td></tr><tr><td headers="hd_h_ch3.appi.tab1_1_1_1_1 hd_b_ch3.appi.tab1_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Markova 2018</td><td headers="hd_h_ch3.appi.tab1_1_1_1_2 hd_b_ch3.appi.tab1_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>Most frequently reported treatment-related adverse events experienced in Phase A (enriched enrolment)</p>
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<p>THC: CBD spray: Vertigo 7%; Somnolence 2%; Dizziness 2%; Diarrhoea 2%; Nausea 2%</p>
|
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<p>Total serious adverse events in Phase B (RCT)</p>
|
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<p>THC: CBD spray: haematuria</p>
|
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<p>Placebo: Tubulointerstitial nephristis</p>
|
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</td></tr><tr><td headers="hd_h_ch3.appi.tab1_1_1_1_1 hd_b_ch3.appi.tab1_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna 2011</a>
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</td><td headers="hd_h_ch3.appi.tab1_1_1_1_2 hd_b_ch3.appi.tab1_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Total adverse events experienced by ≥3% participants</p>
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<p>Phase A (enriched enrolment) THC: CBD spray: Ear and labyrinth disorders 4% (Vertigo 4%); Gastrointestinal disorders 13% (Dry mouth 4%; Nausea 4%; Diarrhoea 1%; Upper abdominal pain 1%); General disorders 14% (Fatigue 6%); Infections and infestations 7% (Urinary tract infection 3%; Naso-pharyngitis 1%); Musculo-skeletal and connective tissue 5% (Muscle spasms 1%; Back pain 0.2%; Pain in extremity 0.2%); Nervous system disorders 26% (Dizziness 14%; Somnolence 5%; Headache 2%; Spasticity 2%; MS relapse 1%); Psychiatric disorders 8% (Euphoric mood 1%)</p>
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<p>Phase B (RCT) THC: CBD spray: Ear and labyrinth disorders 6% (Vertigo 6%); Gastrointestinal disorders 15% (Dry mouth 3%; Nausea 4%; Diarrhoea 2%; Upper abdominal pain 3%); General disorders 14% (Fatigue 5%); Infections and infestations 15% (Urinary tract infection 7%; Naso-pharyngitis 3%); Musculo-skeletal and connective tissue 15% (Muscle spasms 6%; Back pain 4%); Nervous system disorders 15% (Dizziness 3%; Somnolence 3%; Headache 2%; Spasticity 2%; MS relapse 3%); Psychiatric disorders 11% (Euphoric mood 3%)</p>
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<p>Phase B (RCT) Placebo: Ear and labyrinth disorders 1% (Vertigo 1%); Gastrointestinal disorders 10% (Dry mouth 1%; Nausea 2%; Diarrhoea 5%); General disorders 8% (Fatigue 1%); Infections and infestations 22% (Urinary tract infection 10%; Naso-pharyngitis 3%); Musculo-skeletal and connective tissue 15% (Muscle spasms 7%; Back pain 3%; Pain in extremity 4%); Nervous system disorders 13% (Somnolence 1%; Headache 4%; Spasticity 3%; MS relapse 1%); Psychiatric disorders 6% (Euphoric mood 1%)</p>
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</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appitab2"><div id="ch3.appi.tab2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appi.tab2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appi.tab2_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appi.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study</th><th id="hd_h_ch3.appi.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Adverse events reported</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appi.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Ball 2015</td><td headers="hd_h_ch3.appi.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Adverse events experienced by ≥10% participants</p>
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<p>THC: Falls and injuries 31%; Mobility, balance and co-ordination problems 33%; Infections (excluding urinary tract) 29%; Fatigue and tiredness 25%; Dizziness and light-headedness 32%; Muscle disorders (spasticity, stiffness, spasms or tremor) 24%; Muscle weakness 22%; Dissociative and thinking or perception disorders 30%; Depression 20%; Musculoskeletal pain and aches 15%; Constipation, diarrhoea, faecal incontinence 17%; Joint disorders 14%; Urinary tract infections 13%</p>
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<p>Placebo: Falls and injuries 31%; Mobility, balance and co-ordination problems 26%; Infections (excluding urinary tract) 29%; Fatigue and tiredness 23%; Dizziness and light-headedness 7%; Muscle disorders (spasticity, stiffness, spasms or tremor) 23%; Muscle weakness 20%; Dissociative and thinking or perception disorders 4%; Depression 16%; Musculoskeletal pain and aches 25%; Constipation, diarrhoea, faecal incontinence 13%; Joint disorders 17%; Urinary tract infections 17%</p>
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<p>Serious adverse events</p>
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<p>THC: Death 2%; Hospital admission 32%; Life-threatening or important medical event 3%</p>
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<p>Placebo: Death 0.6%; Hospital admission 27%; Life-threatening or important medical event 2%</p>
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</td></tr><tr><td headers="hd_h_ch3.appi.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a>
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</td><td headers="hd_h_ch3.appi.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>Adverse events</p>
|
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<p>THC: Bladder 24%; Gastrointestinal 30%; Pain 26%; Depression or anxiety 10%; Vision 6%; Infection 15%; Dizzy or lightheadedness 59%; Dry mouth 26%; Weakness or reduced mobility 25%; Sleep 35%; Spasms or stiffness 34%; Tremor or lack of coordination 12%; Numbness of paraesthesia 9%; Miscellaneous 28%; Improvement in symptoms 1%</p>
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<p>Placebo: Bladder 23%; Gastrointestinal 20%; Pain 32%; Depression or anxiety 8%; Vision 2%; Infection 17%; Dizzy or lightheadedness 18%; Dry mouth 7%; Weakness or reduced mobility 20%; Sleep 33%; Spasms or stiffness 33%; Tremor or lack of coordination 8%; Numbness of paraesthesia 7%; Miscellaneous 22%; Improvement in symptoms 0.5%</p>
|
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<p>Serious adverse events</p>
|
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<p>THC: MS relapse or possible relapse 0.5%; Urinary tract infection 2%; Pneumonia 1%; Blocked/insertion of suprapubic catheter 0.5%; Other 6%</p>
|
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<p>Placebo: MS relapse or possible relapse 4%; Urinary tract infection 2%; Pneumonia 0.5%; Blocked/insertion of suprapubic catheter 1%; Constipation 2%; Grand mal seizures 0.5%; Other 1%</p>
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</td></tr><tr><td headers="hd_h_ch3.appi.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Zajicek 2005</td><td headers="hd_h_ch3.appi.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>Adverse events</p>
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<p>THC: Bladder 16%; Depression or anxiety 6%; Dizziness or lightheadedness 9%; Dry mouth 2%; Falls 5%; Fatigue or sleep disturbance 8%; Gastrointestinal 12%; Infection 11%; Memory or concentration 2%; Miscellaneous 9%; MS relapse or exacerbation 6%; Numbness or paraesthesia 5%; Other skin problem 1%; Pain 13%; Pressure sores 0.5%; Spasms or stiffness 17%; Tremor or lack of coordination 5%; Vision symptoms 2%; Weakness or reduced mobility 12%</p>
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<p>Placebo: Bladder 24%; Depression or anxiety 5%; Dizziness or lightheadedness 3%; Dry mouth 1%; Falls 4%; Fatigue or sleep disturbance 11%; Gastrointestinal 9%; Infection 14%; Memory or concentration 1%; Miscellaneous 9%; MS relapse or exacerbation 6%; Numbness or paraesthesia 4%; Other skin problem 7%; Pain 13%; Pressure sores 3%; Spasms or stiffness 19%; Tremor or lack of coordination 2%; Vision symptoms 0.5%; Weakness or reduced mobility 18%</p>
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<p>Serious adverse events</p>
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<p>THC: Relapse/possible relapse 5%; Urinary tract infection 1%; Other 5%</p>
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<p>Placebo: Relapse/possible relapse 2%; Urinary tract infection 2%; Pneumonia/chest infection 1%; Seizure 1%; Limb fracture 0.5%; Other 4%</p>
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</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appitab3"><div id="ch3.appi.tab3" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appi.tab3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appi.tab3_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appi.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study</th><th id="hd_h_ch3.appi.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Adverse events reported</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appi.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Van Amerongen 2018</td><td headers="hd_h_ch3.appi.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Adverse events reported more than once</p>
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<p>THC: Nervous system (Dizziness 58%; Headache 50%; Somnolence 25%; Muscular weakness 33%; Spasticity 25%; Paresthesia 17%; Tremor 17%; Tinnitus 17%); Psychiatric/mood (Euphoric mood 33%; Insomnia 8%); General disorders (Fatigue 17%; Feeling abnormal 8%; Feeling hot 17%); Gastrointestinal (Dry mouth 17%; Increased appetite 8%)</p>
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<p>Placebo: Nervous system (Dizziness 8%; Headache 25%; Somnolence 17%; Muscular weakness 8%; Spasticity 25%); Psychiatric/mood (Euphoric mood 33%; Insomnia 8%); General disorders (Fatigue 25%; Feeling abnormal 17%; Feeling hot 17%); Gastrointestinal (Nausea 8%)</p>
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</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appitab4"><div id="ch3.appi.tab4" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appi.tab4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appi.tab4_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appi.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study</th><th id="hd_h_ch3.appi.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Adverse events reported</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appi.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a>
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</td><td headers="hd_h_ch3.appi.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Adverse events</p>
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<p>Cannabis extract: Bladder 26%; Gastrointestinal 37%; Pain 24%; Depression or anxiety 9%; Vision 8%; Infection 16%; Dizzy or lightheadedness 50%; Dry mouth 20%; Weakness or reduced mobility 23%; Sleep 40%; Spasms or stiffness 33%; Tremor or lack of coordination 10%; Numbness of paraesthesia 7%; Miscellaneous 30%; Improvement in symptoms 1%</p>
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<p>Placebo: Bladder 23%; Gastrointestinal 20%; Pain 32%; Depression or anxiety 8%; Vision 2%; Infection 17%; Dizzy or lightheadedness 18%; Dry mouth 7%; Weakness or reduced mobility 20%; Sleep 33%; Spasms or stiffness 33%; Tremor or lack of coordination 8%; Numbness of paraesthesia 7%; Miscellaneous 22%; Improvement in symptoms 0.5%</p>
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<p>Serious adverse events</p>
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<p>Cannabis extract: MS relapse or possible relapse 0.5%; Urinary tract infection 0.5%; Pneumonia 0.5%; Blocked/insertion of suprapubic catheter 0.5%; Constipation 0.5%; Grand mal seizures 0.5%; Other 3%</p>
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<p>Placebo: MS relapse or possible relapse 4%; Urinary tract infection 2%; Pneumonia 0.5%; Blocked/insertion of suprapubic catheter 1%; Constipation 2%; Grand mal seizures 0.5%; Other 1%</p>
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</td></tr><tr><td headers="hd_h_ch3.appi.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Zajicek 2005</td><td headers="hd_h_ch3.appi.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Adverse events</p>
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<p>Cannabis extract: Bladder 18%; Depression or anxiety 6%; Dizziness or light-headedness 13%; Dry mouth 1%; Falls 7%; Fatigue or sleep disturbance 8%; Gastrointestinal 15%; Infection 15%; Memory or concentration 2%; Miscellaneous 11%; MS relapse or exacerbation 8%; Numbness or paraesthesia 5%; Other skin problem 5%; Pain 23%; Pressure sores 1%; Spasms or stiffness 21%; Tremor or lack of coordination 2%; Vision symptoms 2%; Weakness or reduced mobility 14%</p>
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<p>Placebo: Bladder 24%; Depression or anxiety 5%; Dizziness or lightheadedness 3%; Dry mouth 1%; Falls 4%; Fatigue or sleep disturbance 11%; Gastrointestinal 9%; Infection 14%; Memory or concentration 1%; Miscellaneous 9%; MS relapse or exacerbation 6%; Numbness or paraesthesia 4%; Other skin problem 7%; Pain 13%; Pressure sores 3%; Spasms or stiffness 19%; Tremor or lack of coordination 2%; Vision symptoms 0.5%; Weakness or reduced mobility 18%</p>
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<p>Serious adverse events</p>
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<p>Cannabis extract: Relapse/possible relapse 4%; Urinary tract infection 1%; Pneumonia/chest infection 3%; Seizure 0.5%; Insertion of baclofen pump 1%; Limb fracture 0.5%; Other 2%</p>
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<p>Placebo: Relapse/possible relapse 2%; Urinary tract infection 2%; Pneumonia/chest infection 1%; Seizure 1%; Limb fracture 0.5%; Other 4%</p>
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</td></tr><tr><td headers="hd_h_ch3.appi.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Zajicek 2012</td><td headers="hd_h_ch3.appi.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Adverse events experienced by ≥10% participants</p>
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<p>Cannabis extract: Dizziness 46%; Urinary tract infection 15%; Dry mouth 23%; Headache 11%; Asthenia 13%; Fatigue 14%</p>
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<p>Placebo: Dizziness 7%; Urinary tract infection 12%; Dry mouth 8%; Headache 12%; Asthenia 8%; Fatigue 6%</p>
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</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appitab5"><div id="ch3.appi.tab5" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appi.tab5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appi.tab5_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appi.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study</th><th id="hd_h_ch3.appi.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Adverse events reported</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appi.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Riva 2019</td><td headers="hd_h_ch3.appi.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Most common adverse events</p>
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<p>THC: CBD spray: General disorders (Asthenia 24%; Malaise 3%); Nervous system disorders (Dizziness 7%; Balance disorder 3%; Memory impairment 3%; Somnolence 17%; Syncope 7%; Tremors 3%; Spasticity 3%); Psychiatric disorders (Anxiety 3%; Agitation 3%); Vertigo 17%; Blurred vision 3%; Palpitations 3%; Gastrointestinal disorders (Dry mouth 3%; Nausea 10%; Oral pain 3%); Fall 3%</p>
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<p>Placebo: General disorders (Asthenia 3%); Nervous system disorders (Somnolence 3%); Gastrointestinal disorders (Dry mouth 3%; Oral mucosal disorder 3%); Skin and subcutaneous tissue disorders (Erythema 3%; Skin exfoliation 3%; Pruritus 3%)</p>
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</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appitab6"><div id="ch3.appi.tab6" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appi.tab6/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appi.tab6_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study</th><th id="hd_h_ch3.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Adverse events reported</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Wissel 2006</td><td headers="hd_h_ch3.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Adverse events</p>
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<p>THC: Drowsiness (15%); Slight weakness in lower limbs</p>
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<p>Placebo: Drowsiness (8%); Slight dysphagia (8%)</p>
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<p>Severe adverse events</p>
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<p>THC: MS relapse (8%); Lower limb weakness (8%)</p>
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<p>Placebo: No severe adverse events</p>
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</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appitab7"><div id="ch3.appi.tab7" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appi.tab7/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appi.tab7_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appi.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study</th><th id="hd_h_ch3.appi.tab7_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Adverse events reported</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appi.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Pooyania 2010</td><td headers="hd_h_ch3.appi.tab7_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>THC: Drowsiness 27%; Dry mouth and asthenia 18%; Mild vertigo 18%; Mild ataxia, headache and lack of motivation 9%</p>
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<p>Adverse events not reported for placebo</p>
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</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appjtab1"><div id="ch3.appj.tab1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appj.tab1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appj.tab1_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Study</th><th id="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reason for exclusion</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Abo Youssef, Nadim, Schneider, Marc P., Mordasini, Livio et al. (2017) Cannabinoids for treating neurogenic lower urinary tract dysfunction in patients with multiple sclerosis: a systematic review and meta-analysis. BJU international 119(4): 515–521</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">The relevant symptoms are not included</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Anonymous (2014) Delta-9-tetrahydrocannabinol + cannabidiol (New Drug). Prescrire International 23(150): 145–148</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not a relevant study design</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Anonymous (2014) Delta-9-tetrahydrocannabinol + cannabidiol. A reasonable option for some patients with multiple sclerosis. Prescrire international 23(150): 145–8</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Narrative review</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Aragona, Massimiliano, Onesti, Emanuela, Tomassini, Valentina et al. (2009) Psychopathological and cognitive effects of therapeutic cannabinoids in multiple sclerosis: a double-blind, placebo controlled, crossover study. Clinical neuropharmacology 32(1): 41–7</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">The relevant symptoms are not included</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beard, S.; Hunn, A.; Wight, J. (2004) Treatments for spasticity and pain in multiple sclerosis: a systematic review. Health Technology Assessment: 24</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">No outcomes of interest</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Behm, Kate and Morgan, Prue (2018) The effect of symptom-controlling medication on gait outcomes in people with multiple sclerosis: a systematic review. Disability and rehabilitation 40(15): 1733–1744</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Review article. The bibliography was reviewed for possible includes</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bravo-Soto, Gonzalo A. and Juri, Carlos (2017) Are cannabinoids effective for Parkinson’s disease?. Son efectivos los cannabinoides en la enfermedad de Parkinson? 17(suppl2): e6974</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">The relevant symptoms are not included</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Conte, Antonella, Bettolo, Chiara Marini, Onesti, Emanuela et al. (2009) Cannabinoid-induced effects on the nociceptive system: a neurophysiological study in patients with secondary progressive multiple sclerosis. European journal of pain (London, England) 13(5): 472–7</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Experimental pain model and used electrophysiological outcomes</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">da Rovare, Victoria P., Magalhaes, Gabriel P. A., Jardini, Guilherme D. A. et al. (2017) Cannabinoids for spasticity due to multiple sclerosis or paraplegia: A systematic review and meta-analysis of randomized clinical trials. Complementary therapies in medicine 34: 170–185</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Review article. The bibliography was reviewed for possible includes</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Devinsky, O., Nabbout, R., Miller, I. et al. (2017) Maintenance of long-term safety and efficacy of cannabidiol (CBD) treatment in dravet syndrome (DS): results of the open-label extension (OLE) trial (GWPCARE 5). Developmental medicine and child neurology. Conference: 44th annual conference of the british paediatric neurology association, BPNA 2018. United kingdom 59(supplement4): 126</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Conference abstract</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Farzaei, Mohammad Hosein, Shahpiri, Zahra, Bahramsoltani, Roodabeh et al. (2017) Efficacy and Tolerability of Phytomedicines in Multiple Sclerosis Patients: A Review. CNS drugs 31(10): 867–889</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Review article. The bibliography was reviewed for possible includes</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Flachenecker, Peter (2013) A new multiple sclerosis spasticity treatment option: effect in everyday clinical practice and cost-effectiveness in Germany. Expert review of neurotherapeutics 13(3suppl1): 15–9</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Observational study. No control group</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Flachenecker, Peter; Henze, Thomas; Zettl, Uwe K. (2014) Nabiximols (THC/CBD oromucosal spray, Sativex) in clinical practice--results of a multicenter, noninterventional study (MOVE 2) in patients with multiple sclerosis spasticity. European neurology 71(56): 271–9</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Observational study. No control group</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fox, P. and Zajicek, J. (2001) A multicentre randomised controlled trial of cannabinoids in multiple sclerosis. JNS 187(suppl1)</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">This article is no longer available from any source</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fox, P., Bain, P. G., Glickman, S. et al. (2004) The effect of cannabis on tremor in patients with multiple sclerosis. Neurology 62(7): 1105–9</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">The relevant symptoms are not included</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Freeman, R. M., Adekanmi, O., Waterfield, M. R. et al. (2006) The effect of cannabis on urge incontinence in patients with multiple sclerosis: a multicentre, randomised placebo-controlled trial (CAMS-LUTS). International urogynecology journal and pelvic floor dysfunction 17(6): 636–41</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">The relevant symptoms are not included</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fu, Xiying, Wang, Yanqiao, Wang, Can et al. (2018) A mixed treatment comparison on efficacy and safety of treatments for spasticity caused by multiple sclerosis: a systematic review and network meta-analysis. Clinical rehabilitation 32(6): 713–721</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Review article. The bibliography was reviewed for possible includes</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gras, Adrien and Broughton, Julie (2016) A cost-effectiveness model for the use of a cannabis-derived oromucosal spray for the treatment of spasticity in multiple sclerosis. Expert review of pharmacoeconomics & outcomes research 16(6): 771–779</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cost-effectiveness model</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Green, Anita J. and De-Vries, Kay (2010) Cannabis use in palliative care - an examination of the evidence and the implications for nurses. Journal of clinical nursing 19(1718): 2454–62</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Review article. The bibliography was reviewed for possible includes</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Grotenhermen, F. (2004) Cannabinoids do not reduce objective measurements in muscle spasticity, but people with multiple sclerosis perceive some benefit. Evidence-Based Healthcare 8(3): 159–161</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Letter to the editor</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Haupts, M., Jonas, A., Witte, K. et al. (2015) Influence of optimized anti-spastic pre-treatment on the efficacy and tolerability of THC: CBD oromucosal spray in multiple sclerosis spasticity patients. A post-hoc RCT data analyses. Multiple sclerosis (houndmills, basingstoke, england) 23(11suppl1): 708–709</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Post-hoc data that does not provide any additional information on the outcomes of interest</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Haupts, M., Vila, C., Jonas, A. et al. (2016) Influence of Previous Failed Antispasticity Therapy on the Efficacy and Tolerability of THC: CBD Oromucosal Spray for Multiple Sclerosis Spasticity. European neurology 75(56): 236–243</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Conference abstract</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Herzog, Samuel, Shanahan, Marian, Grimison, Peter et al. (2018) Systematic Review of the Costs and Benefits of Prescribed Cannabis-Based Medicines for the Management of Chronic Illness: Lessons from Multiple Sclerosis. PharmacoEconomics 36(1): 67–78</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">No outcomes of interest</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hobart, J. C. and Zajicek, J. P. (2012) Cannabis as a symptomatic treatment for MS: clinically meaningful MUSEC to the stiffness and walking problems of people with MS. Multiple sclerosis. 18(4suppl1): 247</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Conference abstract</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Izquierdo, Guillermo (2017) Multiple sclerosis symptoms and spasticity management: new data. Neurodegenerative disease management 7(6s): 7–11</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Review article. The bibliography was reviewed for possible includes</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Katona, S., Kaminski, E., Sanders, H. et al. (2005) Cannabinoid influence on cytokine profile in multiple sclerosis. Clinical and experimental immunology 140(3): 580–5</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">No outcomes of interest</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Keating, Gillian M. (2017) Delta-9-Tetrahydrocannabinol/Cannabidiol Oromucosal Spray (Sativex): A Review in Multiple Sclerosis-Related Spasticity. Drugs 77(5): 563–574</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Narrative review</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Killestein, J., Hoogervorst, E. L. J., Reif, M. et al. (2002) Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Neurology 58(9): 1404–7</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Data not in an extractable format</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Lakhan, Shaheen E. and Rowland, Marie (2009) Whole plant cannabis extracts in the treatment of spasticity in multiple sclerosis: a systematic review. BMC neurology 9: 59</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Review article. The bibliography was reviewed for possible includes</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Leocani, L., Nuara, A., Houdayer, E. et al. (2014) Effect of THC-CBD oromucosal spray (Sativex) on measures of spasticity in multiple sclerosis: a doubleblind, placebo-controlled, crossover study. Multiple sclerosis (houndmills, basingstoke, england) 20(1suppl1): 498</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Conference abstract</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Lus, G., Cantello, R., Danni, M. C. et al. (2017) “Taste”, a pilot study: palatability and oral cavity tolerability of Sativex and possible improvement measures in multiple sclerosis patients with resistant spasticity. Multiple sclerosis journal. Conference: 7th joint ECTRIMS-ACTRIMS, MSPARIS2017. France 23(3supplement1): 996–997</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Conference abstract</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Lus, G., Cantello, R., Danni, M. C. et al. (2018) Palatability and oral cavity tolerability of THC: CBD oromucosal spray and possible improvement measures in multiple sclerosis patients with resistant spasticity: a pilot study. Neurodegenerative disease management 8(2): 105–113</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">The relevant symptoms are not included</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Maccarrone, Mauro, Maldonado, Rafael, Casas, Miguel et al. (2017) Cannabinoids therapeutic use: what is our current understanding following the introduction of THC, THC:CBD oromucosal spray and others?. Expert review of clinical pharmacology 10(4): 443–455</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Narrative review</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Marinelli, L., Balestrino, M., Mori, L. et al. (2017) A randomized controlled cross-over double blind study protocol on THC/CBD oromucosal spray as an add-on therapy for post-stroke spasticity. Clinical neurophysiology. Conference: 62nd national congress of the italian society for clinical neurophysiology. Italy 128(12): e421</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Conference abstract</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Markova, J. (2017) Sativex as Add-on therapy Vs. further optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity double blind randomized clinical trial. Multiple sclerosis journal. Conference: 7th joint ECTRIMS-ACTRIMS, MSPARIS2017. France 23(3supplement1): 990</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Conference abstract</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Markova, Jolana (2019) Newest evidence for tetrahydrocannabinol:cannabidiol oromucosal spray from randomized clinical trials. Neurodegenerative disease management</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Review article. The bibliography was reviewed for possible includes</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Maurer, M., Henn, V., Dittrich, A. et al. (1990) Delta-9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial. European archives of psychiatry and clinical neuroscience 240(1): 1–4</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Case study with one patient</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Meuth, Sven G.; Vila, Carlos; Dechant, Kerry L. (2015) Effect of Sativex on spasticity-associated symptoms in patients with multiple sclerosis. Expert review of neurotherapeutics 15(8): 909–18</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Narrative review</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Meza, Rodrigo, Pena, Javier, Garcia, Karen et al. (2017) Are cannabinoids effective in multiple sclerosis?. 17(suppl1): e6865</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Non-English language article</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Ng, Louisa, Khan, Fary, Young, Carolyn A. et al. (2017) Symptomatic treatments for amyotrophic lateral sclerosis/motor neuron disease. The Cochrane database of systematic reviews 1: cd011776</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">No outcomes of interest</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nielsen, Suzanne, Germanos, Rada, Weier, Megan et al. (2018) The Use of Cannabis and Cannabinoids in Treating Symptoms of Multiple Sclerosis: a Systematic Review of Reviews. Current neurology and neuroscience reports 18(2): 8</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Review article. The bibliography was reviewed for possible includes</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Notcutt, W., Langford, R., Davies, P. et al. (2012) A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex (nabiximols). Multiple sclerosis (Houndmills, Basingstoke, England) 18(2): 219–28</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Withdrawal study</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Otero-Romero, Susana, Sastre-Garriga, Jaume, Comi, Giancarlo et al. (2016) Pharmacological management of spasticity in multiple sclerosis: Systematic review and consensus paper. Multiple sclerosis (Houndmills, Basingstoke, England) 22(11): 1386–1396</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Review article. The bibliography was reviewed for possible includes</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Paisley, S., Beard, S., Hunn, A. et al. (2002) Clinical effectiveness of oral treatments for spasticity in multiple sclerosis: a systematic review. Multiple Sclerosis 8(4): 319–329</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">No outcomes of interest</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Paolicelli, D., Direnzo, V., Manni, A. et al. (2015) Long-Term Data of Efficacy, Safety, and Tolerability in a Real-Life Setting of THC/CBD Oromucosal Spray-Treated Multiple Sclerosis Patients. Journal of Clinical Pharmacology</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Observational study. No control group</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Petro, D. J. and Ellenberger, C., Jr. (1981) Treatment of human spasticity with delta 9-tetrahydrocannabinol. Journal of clinical pharmacology 21(s1): 413S–416S</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Unclear what scale was used to assess spasticity</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rog, David J. (2010) Cannabis-based medicines in multiple sclerosis--a review of clinical studies. Immunobiology 215(8): 658–72</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Review article. The bibliography was reviewed for possible includes</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Sacca, F., Pane, C., Carotenuto, A. et al. (2016) The use of medical-grade Cannabis (Bedrocan) in patients non-responders to nabiximols (sativex). Multiple sclerosis (Houndmills, Basingstoke, England)</p>
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<p>conference32ndcongressoftheeuropeancommitteefortreatmentandresearchinmultiplescl erosisectrims2016unitedkingdomconferencestart20160914conferenceend2016091722: 686</p>
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</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Conference abstract</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serpell, Michael G.; Notcutt, William; Collin, Christine (2013) Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis. Journal of neurology 260(1): 285–95</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Observational study. No control group</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Shakespeare, D. T.; Boggild, M.; Young, C. (2003) Anti-spasticity agents for multiple sclerosis. The Cochrane database of systematic reviews: cd001332</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Review article. The bibliography was reviewed for possible includes</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Slof, J. and Gras, A. (2012) Sativex in multiple sclerosis spasticity: A cost-effectiveness model. Expert Review of Pharmacoeconomics and Outcomes Research 12(4): 525–538</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cost-effectiveness model</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Syed, Yahiya Y.; McKeage, Kate; Scott, Lesley J. (2014) Delta-9-tetrahydrocannabinol/cannabidiol (Sativex): a review of its use in patients with moderate to severe spasticity due to multiple sclerosis. Drugs 74(5): 563–78</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Review article. The bibliography was reviewed for possible includes</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Thaera, Greg M., Wellik, Kay E., Carter, Jonathan L. et al. (2009) Do cannabinoids reduce multiple sclerosis-related spasticity?. The neurologist 15(6): 369–71</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Review article. The bibliography was reviewed for possible includes</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Turner, S.; Kumar, R.; Fairhurst, C. (2017) Safety, efficacy and tolerability of oro-mucosal tetrahydrocannabinol/cannabidiol therapy to reduce spasticity in children and adolescents. results of a multicentre, double blind placebo controlled trial. Developmental medicine and child neurology. Conference: 44th annual conference of the british paediatric neurology association, BPNA 2018. United kingdom 59(supplement4): 12–13</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Conference abstract</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Ungerleider, J. T., Andyrsiak, T., Fairbanks, L. et al. (1987) Delta-9-THC in the treatment of spasticity associated with multiple sclerosis. Advances in alcohol & substance abuse 7(1): 39–50</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Unclear what scale was used to assess spasticity</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Van Amerongen, G., Beumer, T., Killestein, J. et al. (2014) Individualized dosing of a novel oral DELTA9-THC formulation improves subjective spasticity and pain in patients with progressive multiple sclerosis. Multiple sclerosis (houndmills, basingstoke, england) 20(1suppl1): 478–479</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Conference abstract</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Vaney, C., Heinzel-Gutenbrunner, M., Jobin, P. et al. (2004) Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, crossover study. Multiple sclerosis (Houndmills, Basingstoke, England) 10(4): 417–24</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cross-over trial with inadequate washout period (<1 week)</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Vermersch, Patrick (2011) Sativex() (tetrahydrocannabinol + cannabidiol), an endocannabinoid system modulator: basic features and main clinical data. Expert review of neurotherapeutics 11(4suppl): 15–9</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Narrative review</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Wade, D. T., Makela, P. M., House, H. et al. (2006) Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England) 12(5): 639–45</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Single-arm follow-up study</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Wade, Derick T., Collin, Christine, Stott, Colin et al. (2010) Meta-analysis of the efficacy and safety of Sativex (nabiximols), on spasticity in people with multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England) 16(6): 707–14</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary publication of existing studies without additional data</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Wright, S.; Vachova, M. M.; Novakova, I. (2013) The effect of long-term treatment with a prescription cannabisbased THC: CBD oromucosal spray on cognitive function and mood: a 12 month double blind placebo-controlled study in people with spasticity due to multiple sclerosis. Multiple sclerosis. 19(11suppl1): 572–573</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Conference abstract</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Zajicek, J.; Ball, S.; Wright, D.; Vickery, J. et al. (2013) Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial. The Lancet. 12(9): 857–865</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">The relevant symptoms are not included</td></tr><tr><td headers="hd_h_ch3.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Zettl, Uwe K., Rommer, Paulus, Hipp, Petra et al. (2016) Evidence for the efficacy and effectiveness of THC-CBD oromucosal spray in symptom management of patients with spasticity due to multiple sclerosis. Therapeutic advances in neurological disorders 9(1): 9–30</td><td headers="hd_h_ch3.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Narrative review</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appjtab2"><div id="ch3.appj.tab2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appj.tab2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appj.tab2_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appj.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Study</th><th id="hd_h_ch3.appj.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reason for exclusion</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appj.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bellnier, T., Brown, G. W., & Ortega, T. R. (2018). Preliminary evaluation of the efficacy, safety, and costs associated with the treatment of chronic pain with medical cannabis. The mental health clinician, 8(3): 110–115.</td><td headers="hd_h_ch3.appj.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not a cost-utility analysis</td></tr><tr><td headers="hd_h_ch3.appj.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Flachenecker P. (2013). A new multiple sclerosis spasticity treatment option: effect in everyday clinical practice and cost-effectiveness in Germany. Expert Rev Neurother, 13(3 Suppl 1):15–19.</td><td headers="hd_h_ch3.appj.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Non-UK evaluation</td></tr><tr><td headers="hd_h_ch3.appj.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Herzog, S., Shanahan, M., Grimison, P., Tran, A., Wong, N., Lintzeris, N., Simes, J., Stockler, M., Morton, R. L. (2018). Systematic Review of the Costs and Benefits of Prescribed Cannabis-Based Medicines for the Management of Chronic Illness: Lessons from Multiple Sclerosis. Pharmacoeconomics, 36(1):67–78.</td><td headers="hd_h_ch3.appj.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Systematic review</td></tr><tr><td headers="hd_h_ch3.appj.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Slof, J., Gras, A. (2012). Sativex in multiple sclerosis spasticity: a cost-effectiveness model. Expert Rev Pharmacoecon Outcomes Res, 12(4):439–441.</td><td headers="hd_h_ch3.appj.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Non-UK evaluation</td></tr><tr><td headers="hd_h_ch3.appj.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Lu, L., Pearce, H., Roome, C., Shearer, J., Lang, I. A., Stein, K. (2015). Erratum to: cost effectiveness of Oromucosal cannabis-based medicine (Sativex(®)) for spasticity in multiple sclerosis. Pharmacoeconomics, 33(6):611.</td><td headers="hd_h_ch3.appj.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Erratum</td></tr><tr><td headers="hd_h_ch3.appj.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Slof, J., Ruiz, L., Vila, C. (2015). Cost-effectiveness of Sativex in multiple sclerosis spasticity: new data and application to Italy. Expert Rev Pharmacoecon Outcomes Res, 15(3):379–391.</td><td headers="hd_h_ch3.appj.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Editorial</td></tr><tr><td headers="hd_h_ch3.appj.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Ball, S., Vickery, J., Hobart, J., Wright, D., Green, C., Shearer, J., Nunn, A., Cano, M. G., MacManus, D., Miller, D., Mallik, S., Zajicek, J. (2015). The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial: a randomised double-blind placebo-controlled parallel-group multicentre trial and economic evaluation of cannabinoids to slow progression in multiple sclerosis. Health technology assessment (Winchester, England), 19(12), vii–187.</td><td headers="hd_h_ch3.appj.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Evaluation of cannabis to slow MS progression, rather than to treat spasticity</td></tr><tr><td headers="hd_h_ch3.appj.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bellnier, T., Brown, G. W., & Ortega, T. R. (2018). Preliminary evaluation of the efficacy, safety, and costs associated with the treatment of chronic pain with medical cannabis. The mental health clinician, 8(3): 110–115.</td><td headers="hd_h_ch3.appj.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not a cost-utility analysis</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appktab1"><div id="ch3.appk.tab1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appk.tab1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appk.tab1_lrgtbl__"><table><tbody><tr><th id="hd_b_ch3.appk.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PICO</th><td headers="hd_b_ch3.appk.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><p><b>Population:</b> Adults and children with spasticity who haven’t fully responded to optimal treatment</p><p>Specific subgroups:
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<ul id="ch3.l30"><li id="ch3.lt218" class="half_rhythm"><div>People with cerebral palsy</div></li></ul></p>
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<p><b>Interventions:</b></p>
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<p>Cannabis based product defined as:
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<ol id="ch3.l31"><li id="ch3.lt219" class="half_rhythm"><div>A cannabis-based product for medicinal use that is a preparation or other product, other than one to which paragraph 5 of part 1 of schedule 4 applies, which:
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<ul id="ch3.l32"><li id="ch3.lt220" class="half_rhythm"><div>is or contains cannabis, cannabis resin, cannabinol or a cannabinol derivative (not being dronabinol or its stereoisomers)</div></li><li id="ch3.lt221" class="half_rhythm"><div>is produced for medicinal use in humans; and</div></li><li id="ch3.lt222" class="half_rhythm"><div>is a medicinal product, or</div></li><li id="ch3.lt223" class="half_rhythm"><div>a substance or preparation for use as an ingredient of, or in the production of an ingredient of, a medicinal product (MDR 2018 regulations)</div></li></ul></div></li><li id="ch3.lt224" class="half_rhythm"><div>Synthetic compounds which are identical in structure to naturally occurring cannabinoids such as delta-9-tetrahydrocannabinol (THC) for example dronabinol</div></li><li id="ch3.lt225" class="half_rhythm"><div>Licensed products nabilone</div></li><li id="ch3.lt226" class="half_rhythm"><div>Plant-derived cannabinoids such as pure cannabidiol</div></li></ol></p>
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<p><b>Cannabis based product used as an adjunct to optimal therapy</b></p>
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<p><b>Comparator:</b> Placebo, Optimal therapy</p>
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<p><b>Outcomes:</b>
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<ul id="ch3.l33"><li id="ch3.lt227" class="half_rhythm"><div>30% or greater improvement in spasticity</div></li><li id="ch3.lt228" class="half_rhythm"><div>Change in spasticity measured using any validated scale which measures spasticity</div></li><li id="ch3.lt229" class="half_rhythm"><div>Quality of life using any validated scale for spasticity</div></li><li id="ch3.lt230" class="half_rhythm"><div>Serious adverse events</div></li><li id="ch3.lt231" class="half_rhythm"><div>Adverse events including but not limited to: sleep problems, fatigue, road traffic accidents, psychological distress, dizziness, headache, confusion state, paranoia, psychosis, substance dependence, diarrhoea at the start of treatment</div></li><li id="ch3.lt232" class="half_rhythm"><div>Withdrawals due to adverse events</div></li><li id="ch3.lt233" class="half_rhythm"><div>Substance abuse due to the use of cannabis-based medicinal product.</div></li><li id="ch3.lt234" class="half_rhythm"><div>Misuse/diversion</div></li><li id="ch3.lt235" class="half_rhythm"><div>Hepatic or renal failure</div></li></ul></p></td></tr><tr><th id="hd_b_ch3.appk.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Current evidence base</th><td headers="hd_b_ch3.appk.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">16 RCTS (13 parallel RCTS, 3 crossover RCTs)</td></tr><tr><th id="hd_b_ch3.appk.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Study design</th><td headers="hd_b_ch3.appk.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Randomised controlled trial</td></tr><tr><th id="hd_b_ch3.appk.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Other comments</th><td headers="hd_b_ch3.appk.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Study should be adequately powered.</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobch3appmfig1"><div id="ch3.appm.fig1" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%201.%20Histogram%20of%20response%20in%20patients%20treated%20with%20CBD%3ATHC.&p=BOOKS&id=577084_ch3appmf1.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appmf1.jpg" alt="Figure 1. Histogram of response in patients treated with CBD:THC." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 1</span><span class="title">Histogram of response in patients treated with CBD:THC</span></h3></div></article><article data-type="table-wrap" id="figobch3appmtab1"><div id="ch3.appm.tab1" class="table"><h3><span class="label">Table 2</span><span class="title">Comparison of Relative Risks derived from Simulations and RCTs</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab1_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Outcome</th><th id="hd_h_ch3.appm.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sativex</th><th id="hd_h_ch3.appm.tab1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Placebo</th><th id="hd_h_ch3.appm.tab1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">RR</th></tr><tr><th headers="hd_h_ch3.appm.tab1_1_1_1_1 hd_h_ch3.appm.tab1_1_1_1_2 hd_h_ch3.appm.tab1_1_1_1_3 hd_h_ch3.appm.tab1_1_1_1_4" id="hd_h_ch3.appm.tab1_1_1_2_1" colspan="4" rowspan="1" style="text-align:left;vertical-align:bottom;">Estimated using continuous outcomes</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appm.tab1_1_1_1_1 hd_h_ch3.appm.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Proportion achieving ≥30% reduction</td><td headers="hd_h_ch3.appm.tab1_1_1_1_2 hd_h_ch3.appm.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">35%</td><td headers="hd_h_ch3.appm.tab1_1_1_1_3 hd_h_ch3.appm.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">31%</td><td headers="hd_h_ch3.appm.tab1_1_1_1_4 hd_h_ch3.appm.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
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<b>1.12</b>
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</td></tr><tr><td headers="hd_h_ch3.appm.tab1_1_1_1_1 hd_h_ch3.appm.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Proportion achieving ≥50% reduction</td><td headers="hd_h_ch3.appm.tab1_1_1_1_2 hd_h_ch3.appm.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">17%</td><td headers="hd_h_ch3.appm.tab1_1_1_1_3 hd_h_ch3.appm.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">15%</td><td headers="hd_h_ch3.appm.tab1_1_1_1_4 hd_h_ch3.appm.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
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<b>1.14</b>
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</td></tr><tr><th headers="hd_h_ch3.appm.tab1_1_1_1_1 hd_h_ch3.appm.tab1_1_1_2_1 hd_h_ch3.appm.tab1_1_1_1_2 hd_h_ch3.appm.tab1_1_1_1_3 hd_h_ch3.appm.tab1_1_1_1_4" id="hd_b_ch3.appm.tab1_1_1_3_1" colspan="4" rowspan="1" style="text-align:left;vertical-align:bottom;">Taken directly from <a class="bibr" href="#ch3.appm.ref10" rid="ch3.appm.ref10">Collin 2010</a></th></tr><tr><td headers="hd_h_ch3.appm.tab1_1_1_1_1 hd_h_ch3.appm.tab1_1_1_2_1 hd_b_ch3.appm.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Proportion achieving ≥30% reduction</td><td headers="hd_h_ch3.appm.tab1_1_1_1_2 hd_h_ch3.appm.tab1_1_1_2_1 hd_b_ch3.appm.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">31%</td><td headers="hd_h_ch3.appm.tab1_1_1_1_3 hd_h_ch3.appm.tab1_1_1_2_1 hd_b_ch3.appm.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">25%</td><td headers="hd_h_ch3.appm.tab1_1_1_1_4 hd_h_ch3.appm.tab1_1_1_2_1 hd_b_ch3.appm.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
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<b>1.24</b>
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</td></tr><tr><td headers="hd_h_ch3.appm.tab1_1_1_1_1 hd_h_ch3.appm.tab1_1_1_2_1 hd_b_ch3.appm.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Proportion achieving ≥50% reduction</td><td headers="hd_h_ch3.appm.tab1_1_1_1_2 hd_h_ch3.appm.tab1_1_1_2_1 hd_b_ch3.appm.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">-</td><td headers="hd_h_ch3.appm.tab1_1_1_1_3 hd_h_ch3.appm.tab1_1_1_2_1 hd_b_ch3.appm.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">-</td><td headers="hd_h_ch3.appm.tab1_1_1_1_4 hd_h_ch3.appm.tab1_1_1_2_1 hd_b_ch3.appm.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
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<b>-</b>
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</td></tr></tbody></table><table><thead><tr><th id="hd_h_ch3.appm.tab1_1_2_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Outcome</th><th id="hd_h_ch3.appm.tab1_1_2_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sativex</th><th id="hd_h_ch3.appm.tab1_1_2_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Placebo</th><th id="hd_h_ch3.appm.tab1_1_2_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">RR</th></tr><tr><th headers="hd_h_ch3.appm.tab1_1_2_1_1 hd_h_ch3.appm.tab1_1_2_1_2 hd_h_ch3.appm.tab1_1_2_1_3 hd_h_ch3.appm.tab1_1_2_1_4" id="hd_h_ch3.appm.tab1_1_2_2_1" colspan="4" rowspan="1" style="text-align:left;vertical-align:bottom;">Estimated using continuous outcomes</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appm.tab1_1_2_1_1 hd_h_ch3.appm.tab1_1_2_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Proportion achieving ≥30% reduction</td><td headers="hd_h_ch3.appm.tab1_1_2_1_2 hd_h_ch3.appm.tab1_1_2_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">41%</td><td headers="hd_h_ch3.appm.tab1_1_2_1_3 hd_h_ch3.appm.tab1_1_2_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">28%</td><td headers="hd_h_ch3.appm.tab1_1_2_1_4 hd_h_ch3.appm.tab1_1_2_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
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<b>1.44</b>
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</td></tr><tr><td headers="hd_h_ch3.appm.tab1_1_2_1_1 hd_h_ch3.appm.tab1_1_2_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Proportion achieving ≥50% reduction</td><td headers="hd_h_ch3.appm.tab1_1_2_1_2 hd_h_ch3.appm.tab1_1_2_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">23%</td><td headers="hd_h_ch3.appm.tab1_1_2_1_3 hd_h_ch3.appm.tab1_1_2_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">14%</td><td headers="hd_h_ch3.appm.tab1_1_2_1_4 hd_h_ch3.appm.tab1_1_2_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
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<b>1.69</b>
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</td></tr><tr><th headers="hd_h_ch3.appm.tab1_1_2_1_1 hd_h_ch3.appm.tab1_1_2_2_1 hd_h_ch3.appm.tab1_1_2_1_2 hd_h_ch3.appm.tab1_1_2_1_3 hd_h_ch3.appm.tab1_1_2_1_4" id="hd_b_ch3.appm.tab1_1_2_3_1" colspan="4" rowspan="1" style="text-align:left;vertical-align:bottom;">Taken directly from <a class="bibr" href="#ch3.appm.ref9" rid="ch3.appm.ref9">Collin 2007</a></th></tr><tr><td headers="hd_h_ch3.appm.tab1_1_2_1_1 hd_h_ch3.appm.tab1_1_2_2_1 hd_b_ch3.appm.tab1_1_2_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Proportion achieving ≥30% reduction</td><td headers="hd_h_ch3.appm.tab1_1_2_1_2 hd_h_ch3.appm.tab1_1_2_2_1 hd_b_ch3.appm.tab1_1_2_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">40%</td><td headers="hd_h_ch3.appm.tab1_1_2_1_3 hd_h_ch3.appm.tab1_1_2_2_1 hd_b_ch3.appm.tab1_1_2_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">22%</td><td headers="hd_h_ch3.appm.tab1_1_2_1_4 hd_h_ch3.appm.tab1_1_2_2_1 hd_b_ch3.appm.tab1_1_2_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
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<b>1.83</b>
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</td></tr><tr><td headers="hd_h_ch3.appm.tab1_1_2_1_1 hd_h_ch3.appm.tab1_1_2_2_1 hd_b_ch3.appm.tab1_1_2_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Proportion achieving ≥50% reduction</td><td headers="hd_h_ch3.appm.tab1_1_2_1_2 hd_h_ch3.appm.tab1_1_2_2_1 hd_b_ch3.appm.tab1_1_2_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">18%</td><td headers="hd_h_ch3.appm.tab1_1_2_1_3 hd_h_ch3.appm.tab1_1_2_2_1 hd_b_ch3.appm.tab1_1_2_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">9%</td><td headers="hd_h_ch3.appm.tab1_1_2_1_4 hd_h_ch3.appm.tab1_1_2_2_1 hd_b_ch3.appm.tab1_1_2_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
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<b>1.86</b>
|
|
</td></tr></tbody></table><table><thead><tr><th id="hd_h_ch3.appm.tab1_1_3_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Outcome</th><th id="hd_h_ch3.appm.tab1_1_3_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sativex</th><th id="hd_h_ch3.appm.tab1_1_3_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Placebo</th><th id="hd_h_ch3.appm.tab1_1_3_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">RR</th></tr><tr><th headers="hd_h_ch3.appm.tab1_1_3_1_1 hd_h_ch3.appm.tab1_1_3_1_2 hd_h_ch3.appm.tab1_1_3_1_3 hd_h_ch3.appm.tab1_1_3_1_4" id="hd_h_ch3.appm.tab1_1_3_2_1" colspan="4" rowspan="1" style="text-align:left;vertical-align:bottom;">Estimated using continuous outcomes</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appm.tab1_1_3_1_1 hd_h_ch3.appm.tab1_1_3_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Proportion achieving ≥30% reduction</td><td headers="hd_h_ch3.appm.tab1_1_3_1_2 hd_h_ch3.appm.tab1_1_3_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">77%</td><td headers="hd_h_ch3.appm.tab1_1_3_1_3 hd_h_ch3.appm.tab1_1_3_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">38%</td><td headers="hd_h_ch3.appm.tab1_1_3_1_4 hd_h_ch3.appm.tab1_1_3_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
|
|
<b>2.02</b>
|
|
</td></tr><tr><td headers="hd_h_ch3.appm.tab1_1_3_1_1 hd_h_ch3.appm.tab1_1_3_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Proportion achieving ≥50% reduction</td><td headers="hd_h_ch3.appm.tab1_1_3_1_2 hd_h_ch3.appm.tab1_1_3_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">55%</td><td headers="hd_h_ch3.appm.tab1_1_3_1_3 hd_h_ch3.appm.tab1_1_3_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">9%</td><td headers="hd_h_ch3.appm.tab1_1_3_1_4 hd_h_ch3.appm.tab1_1_3_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
|
|
<b>5.94</b>
|
|
</td></tr><tr><th headers="hd_h_ch3.appm.tab1_1_3_1_1 hd_h_ch3.appm.tab1_1_3_2_1 hd_h_ch3.appm.tab1_1_3_1_2 hd_h_ch3.appm.tab1_1_3_1_3 hd_h_ch3.appm.tab1_1_3_1_4" id="hd_b_ch3.appm.tab1_1_3_3_1" colspan="4" rowspan="1" style="text-align:left;vertical-align:bottom;">Taken directly from Markova 2018</th></tr><tr><td headers="hd_h_ch3.appm.tab1_1_3_1_1 hd_h_ch3.appm.tab1_1_3_2_1 hd_b_ch3.appm.tab1_1_3_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Proportion achieving ≥30% reduction</td><td headers="hd_h_ch3.appm.tab1_1_3_1_2 hd_h_ch3.appm.tab1_1_3_2_1 hd_b_ch3.appm.tab1_1_3_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">77%</td><td headers="hd_h_ch3.appm.tab1_1_3_1_3 hd_h_ch3.appm.tab1_1_3_2_1 hd_b_ch3.appm.tab1_1_3_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">32%</td><td headers="hd_h_ch3.appm.tab1_1_3_1_4 hd_h_ch3.appm.tab1_1_3_2_1 hd_b_ch3.appm.tab1_1_3_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
|
|
<b>2.41</b>
|
|
</td></tr><tr><td headers="hd_h_ch3.appm.tab1_1_3_1_1 hd_h_ch3.appm.tab1_1_3_2_1 hd_b_ch3.appm.tab1_1_3_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Proportion achieving ≥50% reduction</td><td headers="hd_h_ch3.appm.tab1_1_3_1_2 hd_h_ch3.appm.tab1_1_3_2_1 hd_b_ch3.appm.tab1_1_3_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">-</td><td headers="hd_h_ch3.appm.tab1_1_3_1_3 hd_h_ch3.appm.tab1_1_3_2_1 hd_b_ch3.appm.tab1_1_3_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">-</td><td headers="hd_h_ch3.appm.tab1_1_3_1_4 hd_h_ch3.appm.tab1_1_3_2_1 hd_b_ch3.appm.tab1_1_3_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
|
|
<b>-</b>
|
|
</td></tr></tbody></table><table><thead><tr><th id="hd_h_ch3.appm.tab1_1_4_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Outcome</th><th id="hd_h_ch3.appm.tab1_1_4_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sativex</th><th id="hd_h_ch3.appm.tab1_1_4_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Placebo</th><th id="hd_h_ch3.appm.tab1_1_4_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">RR</th></tr><tr><th headers="hd_h_ch3.appm.tab1_1_4_1_1 hd_h_ch3.appm.tab1_1_4_1_2 hd_h_ch3.appm.tab1_1_4_1_3 hd_h_ch3.appm.tab1_1_4_1_4" id="hd_h_ch3.appm.tab1_1_4_2_1" colspan="4" rowspan="1" style="text-align:left;vertical-align:bottom;">Estimated using continuous outcomes</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appm.tab1_1_4_1_1 hd_h_ch3.appm.tab1_1_4_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Proportion achieving ≥30% reduction</td><td headers="hd_h_ch3.appm.tab1_1_4_1_2 hd_h_ch3.appm.tab1_1_4_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">75%</td><td headers="hd_h_ch3.appm.tab1_1_4_1_3 hd_h_ch3.appm.tab1_1_4_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">53%</td><td headers="hd_h_ch3.appm.tab1_1_4_1_4 hd_h_ch3.appm.tab1_1_4_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
|
|
<b>1.41</b>
|
|
</td></tr><tr><td headers="hd_h_ch3.appm.tab1_1_4_1_1 hd_h_ch3.appm.tab1_1_4_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Proportion achieving ≥50% reduction</td><td headers="hd_h_ch3.appm.tab1_1_4_1_2 hd_h_ch3.appm.tab1_1_4_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">39%</td><td headers="hd_h_ch3.appm.tab1_1_4_1_3 hd_h_ch3.appm.tab1_1_4_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">20%</td><td headers="hd_h_ch3.appm.tab1_1_4_1_4 hd_h_ch3.appm.tab1_1_4_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
|
|
<b>1.95</b>
|
|
</td></tr><tr><th headers="hd_h_ch3.appm.tab1_1_4_1_1 hd_h_ch3.appm.tab1_1_4_2_1 hd_h_ch3.appm.tab1_1_4_1_2 hd_h_ch3.appm.tab1_1_4_1_3 hd_h_ch3.appm.tab1_1_4_1_4" id="hd_b_ch3.appm.tab1_1_4_3_1" colspan="4" rowspan="1" style="text-align:left;vertical-align:bottom;">Taken directly from <a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna 2011</a></th></tr><tr><td headers="hd_h_ch3.appm.tab1_1_4_1_1 hd_h_ch3.appm.tab1_1_4_2_1 hd_b_ch3.appm.tab1_1_4_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Proportion achieving ≥30% reduction</td><td headers="hd_h_ch3.appm.tab1_1_4_1_2 hd_h_ch3.appm.tab1_1_4_2_1 hd_b_ch3.appm.tab1_1_4_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">74%</td><td headers="hd_h_ch3.appm.tab1_1_4_1_3 hd_h_ch3.appm.tab1_1_4_2_1 hd_b_ch3.appm.tab1_1_4_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">51%</td><td headers="hd_h_ch3.appm.tab1_1_4_1_4 hd_h_ch3.appm.tab1_1_4_2_1 hd_b_ch3.appm.tab1_1_4_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
|
|
<b>1.45</b>
|
|
</td></tr><tr><td headers="hd_h_ch3.appm.tab1_1_4_1_1 hd_h_ch3.appm.tab1_1_4_2_1 hd_b_ch3.appm.tab1_1_4_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Proportion achieving ≥50% reduction</td><td headers="hd_h_ch3.appm.tab1_1_4_1_2 hd_h_ch3.appm.tab1_1_4_2_1 hd_b_ch3.appm.tab1_1_4_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">45%</td><td headers="hd_h_ch3.appm.tab1_1_4_1_3 hd_h_ch3.appm.tab1_1_4_2_1 hd_b_ch3.appm.tab1_1_4_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">33%</td><td headers="hd_h_ch3.appm.tab1_1_4_1_4 hd_h_ch3.appm.tab1_1_4_2_1 hd_b_ch3.appm.tab1_1_4_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">
|
|
<b>1.36</b>
|
|
</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobch3appmfig2"><div id="ch3.appm.fig2" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%202.%20Model%20structure.&p=BOOKS&id=577084_ch3appmf2.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appmf2.jpg" alt="Figure 2. Model structure." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 2</span><span class="title">Model structure</span></h3></div></article><article data-type="table-wrap" id="figobch3appmtab2"><div id="ch3.appm.tab2" class="table"><h3><span class="label">Table 3</span><span class="title">Treatment effects in ORs</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab2_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab2_1_1_1_1" rowspan="2" colspan="1" headers="hd_h_ch3.appm.tab2_1_1_1_1" style="text-align:left;vertical-align:middle;"></th><th id="hd_h_ch3.appm.tab2_1_1_1_2" colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;">ORs</th></tr><tr><th headers="hd_h_ch3.appm.tab2_1_1_1_2" id="hd_h_ch3.appm.tab2_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mean</th><th headers="hd_h_ch3.appm.tab2_1_1_1_2" id="hd_h_ch3.appm.tab2_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">95% CI</th></tr></thead><tbody><tr><th headers="hd_h_ch3.appm.tab2_1_1_1_1" id="hd_b_ch3.appm.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">THC: CBD spray all doses</th><td headers="hd_h_ch3.appm.tab2_1_1_1_2 hd_h_ch3.appm.tab2_1_1_2_1 hd_b_ch3.appm.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.61</td><td headers="hd_h_ch3.appm.tab2_1_1_1_2 hd_h_ch3.appm.tab2_1_1_2_2 hd_b_ch3.appm.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.40 – 4.86</td></tr><tr><th headers="hd_h_ch3.appm.tab2_1_1_1_1" id="hd_b_ch3.appm.tab2_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">THC: CBD spray within the licensed dose</th><td headers="hd_h_ch3.appm.tab2_1_1_1_2 hd_h_ch3.appm.tab2_1_1_2_1 hd_b_ch3.appm.tab2_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.17</td><td headers="hd_h_ch3.appm.tab2_1_1_1_2 hd_h_ch3.appm.tab2_1_1_2_2 hd_b_ch3.appm.tab2_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.60 – 10.83</td></tr><tr><th headers="hd_h_ch3.appm.tab2_1_1_1_1" id="hd_b_ch3.appm.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">THC: CBD spray high dose</th><td headers="hd_h_ch3.appm.tab2_1_1_1_2 hd_h_ch3.appm.tab2_1_1_2_1 hd_b_ch3.appm.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.61</td><td headers="hd_h_ch3.appm.tab2_1_1_1_2 hd_h_ch3.appm.tab2_1_1_2_2 hd_b_ch3.appm.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.09 – 2.38</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appmtab3"><div id="ch3.appm.tab3" class="table"><h3><span class="label">Table 4</span><span class="title">Response in Cannabis and SoC arms of the model</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab3_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Data Source for Cannabis Response</th><th id="hd_h_ch3.appm.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Cannabis Response</th><th id="hd_h_ch3.appm.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">SoC response (OR = 1/2.61)</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appm.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cannabis response from <a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina 2017</a>/ Patti 2016</td><td headers="hd_h_ch3.appm.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">28.3%</td><td headers="hd_h_ch3.appm.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">13.1%</td></tr><tr><td headers="hd_h_ch3.appm.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cannabis response (meta-analysis of 2 non-enriched studies, random effect)</td><td headers="hd_h_ch3.appm.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">35.2%</td><td headers="hd_h_ch3.appm.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">17.2%</td></tr><tr><td headers="hd_h_ch3.appm.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cannabis response (meta-analysis of 4 studies (enriched corrected), random effect)</td><td headers="hd_h_ch3.appm.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">36.4%</td><td headers="hd_h_ch3.appm.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">18.0%</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appmtab4"><div id="ch3.appm.tab4" class="table"><h3><span class="label">Table 5</span><span class="title">Model fit statistics for discontinuation survival curve</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab4_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Parametric Survival Regression</th><th id="hd_h_ch3.appm.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AIC</th><th id="hd_h_ch3.appm.tab4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">BIC</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appm.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Weibull</td><td headers="hd_h_ch3.appm.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2641</td><td headers="hd_h_ch3.appm.tab4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2652</td></tr><tr><td headers="hd_h_ch3.appm.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Exponential</td><td headers="hd_h_ch3.appm.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3145</td><td headers="hd_h_ch3.appm.tab4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3150</td></tr><tr><td headers="hd_h_ch3.appm.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<b>
|
|
<u>Gompertz</u>
|
|
</b>
|
|
</td><td headers="hd_h_ch3.appm.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<b>
|
|
<u>2412</u>
|
|
</b>
|
|
</td><td headers="hd_h_ch3.appm.tab4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<b>
|
|
<u>2422</u>
|
|
</b>
|
|
</td></tr><tr><td headers="hd_h_ch3.appm.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2497</td><td headers="hd_h_ch3.appm.tab4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2512</td></tr><tr><td headers="hd_h_ch3.appm.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Lognormal</td><td headers="hd_h_ch3.appm.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2588</td><td headers="hd_h_ch3.appm.tab4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2599</td></tr><tr><td headers="hd_h_ch3.appm.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Loglogistic</td><td headers="hd_h_ch3.appm.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2625</td><td headers="hd_h_ch3.appm.tab4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2635</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobch3appmfig3"><div id="ch3.appm.fig3" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%203.%20Cumulative%20Hazard%20Curves%20from%20Competing%20Risks%20Model.&p=BOOKS&id=577084_ch3appmf3.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appmf3.jpg" alt="Figure 3. Cumulative Hazard Curves from Competing Risks Model." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 3</span><span class="title">Cumulative Hazard Curves from Competing Risks Model</span></h3></div></article><article data-type="fig" id="figobch3appmfig4"><div id="ch3.appm.fig4" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%204.%20Proportion%20of%20patients%20remained%20as%20responders%20over%20time.&p=BOOKS&id=577084_ch3appmf4.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appmf4.jpg" alt="Figure 4. Proportion of patients remained as responders over time." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 4</span><span class="title">Proportion of patients remained as responders over time</span></h3></div></article><article data-type="table-wrap" id="figobch3appmtab5"><div id="ch3.appm.tab5" class="table"><h3><span class="label">Table 6</span><span class="title">Frequency of most important non-serious AEs (for determining proportions)</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab5_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th id="hd_h_ch3.appm.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Number of events</th><th id="hd_h_ch3.appm.tab5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">%</th></tr></thead><tbody><tr><th headers="hd_h_ch3.appm.tab5_1_1_1_1" id="hd_b_ch3.appm.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dizziness</th><td headers="hd_h_ch3.appm.tab5_1_1_1_2 hd_b_ch3.appm.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">714</td><td headers="hd_h_ch3.appm.tab5_1_1_1_3 hd_b_ch3.appm.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">56.76%</td></tr><tr><th headers="hd_h_ch3.appm.tab5_1_1_1_1" id="hd_b_ch3.appm.tab5_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dry mouth</th><td headers="hd_h_ch3.appm.tab5_1_1_1_2 hd_b_ch3.appm.tab5_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">239</td><td headers="hd_h_ch3.appm.tab5_1_1_1_3 hd_b_ch3.appm.tab5_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">19.00%</td></tr><tr><th headers="hd_h_ch3.appm.tab5_1_1_1_1" id="hd_b_ch3.appm.tab5_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fatigue</th><td headers="hd_h_ch3.appm.tab5_1_1_1_2 hd_b_ch3.appm.tab5_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">109</td><td headers="hd_h_ch3.appm.tab5_1_1_1_3 hd_b_ch3.appm.tab5_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">8.66%</td></tr><tr><th headers="hd_h_ch3.appm.tab5_1_1_1_1" id="hd_b_ch3.appm.tab5_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Headache</th><td headers="hd_h_ch3.appm.tab5_1_1_1_2 hd_b_ch3.appm.tab5_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">79</td><td headers="hd_h_ch3.appm.tab5_1_1_1_3 hd_b_ch3.appm.tab5_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.28%</td></tr><tr><th headers="hd_h_ch3.appm.tab5_1_1_1_1" id="hd_b_ch3.appm.tab5_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nausea</th><td headers="hd_h_ch3.appm.tab5_1_1_1_2 hd_b_ch3.appm.tab5_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">117</td><td headers="hd_h_ch3.appm.tab5_1_1_1_3 hd_b_ch3.appm.tab5_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">9.30%</td></tr><tr><th headers="hd_h_ch3.appm.tab5_1_1_1_1" id="hd_b_ch3.appm.tab5_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Total</th><td headers="hd_h_ch3.appm.tab5_1_1_1_2 hd_b_ch3.appm.tab5_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1,258</td><td headers="hd_h_ch3.appm.tab5_1_1_1_3 hd_b_ch3.appm.tab5_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">100%</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appmtab6"><div id="ch3.appm.tab6" class="table"><h3><span class="label">Table 7</span><span class="title">Adverse event rates per cycle</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab6/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab6_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;"></th><th id="hd_h_ch3.appm.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Cannabis + SoC per cycle</th><th id="hd_h_ch3.appm.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">SoC per cycle</th><th id="hd_h_ch3.appm.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Cannabis + SoC per year</th><th id="hd_h_ch3.appm.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">SoC per year</th></tr></thead><tbody><tr><th headers="hd_h_ch3.appm.tab6_1_1_1_1" id="hd_b_ch3.appm.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dizziness</th><td headers="hd_h_ch3.appm.tab6_1_1_1_2 hd_b_ch3.appm.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.45</td><td headers="hd_h_ch3.appm.tab6_1_1_1_3 hd_b_ch3.appm.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.30</td><td headers="hd_h_ch3.appm.tab6_1_1_1_4 hd_b_ch3.appm.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5.89</td><td headers="hd_h_ch3.appm.tab6_1_1_1_5 hd_b_ch3.appm.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3.90</td></tr><tr><th headers="hd_h_ch3.appm.tab6_1_1_1_1" id="hd_b_ch3.appm.tab6_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dry mouth</th><td headers="hd_h_ch3.appm.tab6_1_1_1_2 hd_b_ch3.appm.tab6_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.15</td><td headers="hd_h_ch3.appm.tab6_1_1_1_3 hd_b_ch3.appm.tab6_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.10</td><td headers="hd_h_ch3.appm.tab6_1_1_1_4 hd_b_ch3.appm.tab6_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.97</td><td headers="hd_h_ch3.appm.tab6_1_1_1_5 hd_b_ch3.appm.tab6_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.31</td></tr><tr><th headers="hd_h_ch3.appm.tab6_1_1_1_1" id="hd_b_ch3.appm.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fatigue</th><td headers="hd_h_ch3.appm.tab6_1_1_1_2 hd_b_ch3.appm.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.07</td><td headers="hd_h_ch3.appm.tab6_1_1_1_3 hd_b_ch3.appm.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.05</td><td headers="hd_h_ch3.appm.tab6_1_1_1_4 hd_b_ch3.appm.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.90</td><td headers="hd_h_ch3.appm.tab6_1_1_1_5 hd_b_ch3.appm.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.60</td></tr><tr><th headers="hd_h_ch3.appm.tab6_1_1_1_1" id="hd_b_ch3.appm.tab6_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Headache</th><td headers="hd_h_ch3.appm.tab6_1_1_1_2 hd_b_ch3.appm.tab6_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.05</td><td headers="hd_h_ch3.appm.tab6_1_1_1_3 hd_b_ch3.appm.tab6_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.03</td><td headers="hd_h_ch3.appm.tab6_1_1_1_4 hd_b_ch3.appm.tab6_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.65</td><td headers="hd_h_ch3.appm.tab6_1_1_1_5 hd_b_ch3.appm.tab6_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.43</td></tr><tr><th headers="hd_h_ch3.appm.tab6_1_1_1_1" id="hd_b_ch3.appm.tab6_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nausea</th><td headers="hd_h_ch3.appm.tab6_1_1_1_2 hd_b_ch3.appm.tab6_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.07</td><td headers="hd_h_ch3.appm.tab6_1_1_1_3 hd_b_ch3.appm.tab6_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.05</td><td headers="hd_h_ch3.appm.tab6_1_1_1_4 hd_b_ch3.appm.tab6_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.96</td><td headers="hd_h_ch3.appm.tab6_1_1_1_5 hd_b_ch3.appm.tab6_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.64</td></tr><tr><th headers="hd_h_ch3.appm.tab6_1_1_1_1" id="hd_b_ch3.appm.tab6_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious adverse event</th><td headers="hd_h_ch3.appm.tab6_1_1_1_2 hd_b_ch3.appm.tab6_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.03</td><td headers="hd_h_ch3.appm.tab6_1_1_1_3 hd_b_ch3.appm.tab6_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.02</td><td headers="hd_h_ch3.appm.tab6_1_1_1_4 hd_b_ch3.appm.tab6_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.37</td><td headers="hd_h_ch3.appm.tab6_1_1_1_5 hd_b_ch3.appm.tab6_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.25</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appmtab7"><div id="ch3.appm.tab7" class="table"><h3><span class="label">Table 8</span><span class="title">Utility regression model</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab7/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab7_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th id="hd_h_ch3.appm.tab7_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Coefficients</th></tr></thead><tbody><tr><th headers="hd_h_ch3.appm.tab7_1_1_1_1" id="hd_b_ch3.appm.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Constant</th><td headers="hd_h_ch3.appm.tab7_1_1_1_2 hd_b_ch3.appm.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.9229</td></tr><tr><th headers="hd_h_ch3.appm.tab7_1_1_1_1" id="hd_b_ch3.appm.tab7_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS</th><td headers="hd_h_ch3.appm.tab7_1_1_1_2 hd_b_ch3.appm.tab7_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.0505</td></tr><tr><th headers="hd_h_ch3.appm.tab7_1_1_1_1" id="hd_b_ch3.appm.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">EDSS 5</th><td headers="hd_h_ch3.appm.tab7_1_1_1_2 hd_b_ch3.appm.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.0293</td></tr><tr><th headers="hd_h_ch3.appm.tab7_1_1_1_1" id="hd_b_ch3.appm.tab7_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">EDSS 5.5</th><td headers="hd_h_ch3.appm.tab7_1_1_1_2 hd_b_ch3.appm.tab7_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.3417</td></tr><tr><th headers="hd_h_ch3.appm.tab7_1_1_1_1" id="hd_b_ch3.appm.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">EDSS 6</th><td headers="hd_h_ch3.appm.tab7_1_1_1_2 hd_b_ch3.appm.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.1305</td></tr><tr><th headers="hd_h_ch3.appm.tab7_1_1_1_1" id="hd_b_ch3.appm.tab7_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">EDSS 6.5</th><td headers="hd_h_ch3.appm.tab7_1_1_1_2 hd_b_ch3.appm.tab7_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.2521</td></tr><tr><th headers="hd_h_ch3.appm.tab7_1_1_1_1" id="hd_b_ch3.appm.tab7_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">EDSS 7</th><td headers="hd_h_ch3.appm.tab7_1_1_1_2 hd_b_ch3.appm.tab7_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.3353</td></tr><tr><th headers="hd_h_ch3.appm.tab7_1_1_1_1" id="hd_b_ch3.appm.tab7_1_1_8_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">EDSS 7.5</th><td headers="hd_h_ch3.appm.tab7_1_1_1_2 hd_b_ch3.appm.tab7_1_1_8_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.526</td></tr><tr><th headers="hd_h_ch3.appm.tab7_1_1_1_1" id="hd_b_ch3.appm.tab7_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">EDSS 8</th><td headers="hd_h_ch3.appm.tab7_1_1_1_2 hd_b_ch3.appm.tab7_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.8124</td></tr><tr><th headers="hd_h_ch3.appm.tab7_1_1_1_1" id="hd_b_ch3.appm.tab7_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">EDSS 8.5</th><td headers="hd_h_ch3.appm.tab7_1_1_1_2 hd_b_ch3.appm.tab7_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.9408</td></tr><tr><th headers="hd_h_ch3.appm.tab7_1_1_1_1" id="hd_b_ch3.appm.tab7_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">EDSS 9</th><td headers="hd_h_ch3.appm.tab7_1_1_1_2 hd_b_ch3.appm.tab7_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.7648</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appmtab8"><div id="ch3.appm.tab8" class="table"><h3><span class="label">Table 9</span><span class="title">Options for utility values at each spasticity NRS level</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab8/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab8_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th id="hd_h_ch3.appm.tab8_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Option 1</th><th id="hd_h_ch3.appm.tab8_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Option 2</th><th id="hd_h_ch3.appm.tab8_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Option 3</th><th id="hd_h_ch3.appm.tab8_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Option 4</th><th id="hd_h_ch3.appm.tab8_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Option 5</th></tr></thead><tbody><tr><th headers="hd_h_ch3.appm.tab8_1_1_1_1" id="hd_b_ch3.appm.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 1</th><td headers="hd_h_ch3.appm.tab8_1_1_1_2 hd_b_ch3.appm.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.872</td><td headers="hd_h_ch3.appm.tab8_1_1_1_3 hd_b_ch3.appm.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.872</td><td headers="hd_h_ch3.appm.tab8_1_1_1_4 hd_b_ch3.appm.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.972</td><td headers="hd_h_ch3.appm.tab8_1_1_1_5 hd_b_ch3.appm.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.872</td><td headers="hd_h_ch3.appm.tab8_1_1_1_6 hd_b_ch3.appm.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.620</td></tr><tr><th headers="hd_h_ch3.appm.tab8_1_1_1_1" id="hd_b_ch3.appm.tab8_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 2</th><td headers="hd_h_ch3.appm.tab8_1_1_1_2 hd_b_ch3.appm.tab8_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.782</td><td headers="hd_h_ch3.appm.tab8_1_1_1_3 hd_b_ch3.appm.tab8_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.719</td><td headers="hd_h_ch3.appm.tab8_1_1_1_4 hd_b_ch3.appm.tab8_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.862</td><td headers="hd_h_ch3.appm.tab8_1_1_1_5 hd_b_ch3.appm.tab8_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.822</td><td headers="hd_h_ch3.appm.tab8_1_1_1_6 hd_b_ch3.appm.tab8_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.570</td></tr><tr><th headers="hd_h_ch3.appm.tab8_1_1_1_1" id="hd_b_ch3.appm.tab8_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 3</th><td headers="hd_h_ch3.appm.tab8_1_1_1_2 hd_b_ch3.appm.tab8_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.709</td><td headers="hd_h_ch3.appm.tab8_1_1_1_3 hd_b_ch3.appm.tab8_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.648</td><td headers="hd_h_ch3.appm.tab8_1_1_1_4 hd_b_ch3.appm.tab8_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.752</td><td headers="hd_h_ch3.appm.tab8_1_1_1_5 hd_b_ch3.appm.tab8_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.771</td><td headers="hd_h_ch3.appm.tab8_1_1_1_6 hd_b_ch3.appm.tab8_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.519</td></tr><tr><th headers="hd_h_ch3.appm.tab8_1_1_1_1" id="hd_b_ch3.appm.tab8_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 4</th><td headers="hd_h_ch3.appm.tab8_1_1_1_2 hd_b_ch3.appm.tab8_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.591</td><td headers="hd_h_ch3.appm.tab8_1_1_1_3 hd_b_ch3.appm.tab8_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.506</td><td headers="hd_h_ch3.appm.tab8_1_1_1_4 hd_b_ch3.appm.tab8_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.642</td><td headers="hd_h_ch3.appm.tab8_1_1_1_5 hd_b_ch3.appm.tab8_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.721</td><td headers="hd_h_ch3.appm.tab8_1_1_1_6 hd_b_ch3.appm.tab8_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.469</td></tr><tr><th headers="hd_h_ch3.appm.tab8_1_1_1_1" id="hd_b_ch3.appm.tab8_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 5</th><td headers="hd_h_ch3.appm.tab8_1_1_1_2 hd_b_ch3.appm.tab8_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.517</td><td headers="hd_h_ch3.appm.tab8_1_1_1_3 hd_b_ch3.appm.tab8_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.436</td><td headers="hd_h_ch3.appm.tab8_1_1_1_4 hd_b_ch3.appm.tab8_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.532</td><td headers="hd_h_ch3.appm.tab8_1_1_1_5 hd_b_ch3.appm.tab8_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.670</td><td headers="hd_h_ch3.appm.tab8_1_1_1_6 hd_b_ch3.appm.tab8_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.418</td></tr><tr><th headers="hd_h_ch3.appm.tab8_1_1_1_1" id="hd_b_ch3.appm.tab8_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 6</th><td headers="hd_h_ch3.appm.tab8_1_1_1_2 hd_b_ch3.appm.tab8_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.423</td><td headers="hd_h_ch3.appm.tab8_1_1_1_3 hd_b_ch3.appm.tab8_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.374</td><td headers="hd_h_ch3.appm.tab8_1_1_1_4 hd_b_ch3.appm.tab8_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.422</td><td headers="hd_h_ch3.appm.tab8_1_1_1_5 hd_b_ch3.appm.tab8_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.620</td><td headers="hd_h_ch3.appm.tab8_1_1_1_6 hd_b_ch3.appm.tab8_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.368</td></tr><tr><th headers="hd_h_ch3.appm.tab8_1_1_1_1" id="hd_b_ch3.appm.tab8_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 7</th><td headers="hd_h_ch3.appm.tab8_1_1_1_2 hd_b_ch3.appm.tab8_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.315</td><td headers="hd_h_ch3.appm.tab8_1_1_1_3 hd_b_ch3.appm.tab8_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.293</td><td headers="hd_h_ch3.appm.tab8_1_1_1_4 hd_b_ch3.appm.tab8_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.312</td><td headers="hd_h_ch3.appm.tab8_1_1_1_5 hd_b_ch3.appm.tab8_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.569</td><td headers="hd_h_ch3.appm.tab8_1_1_1_6 hd_b_ch3.appm.tab8_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.317</td></tr><tr><th headers="hd_h_ch3.appm.tab8_1_1_1_1" id="hd_b_ch3.appm.tab8_1_1_8_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 8</th><td headers="hd_h_ch3.appm.tab8_1_1_1_2 hd_b_ch3.appm.tab8_1_1_8_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.210</td><td headers="hd_h_ch3.appm.tab8_1_1_1_3 hd_b_ch3.appm.tab8_1_1_8_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.223</td><td headers="hd_h_ch3.appm.tab8_1_1_1_4 hd_b_ch3.appm.tab8_1_1_8_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.202</td><td headers="hd_h_ch3.appm.tab8_1_1_1_5 hd_b_ch3.appm.tab8_1_1_8_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.519</td><td headers="hd_h_ch3.appm.tab8_1_1_1_6 hd_b_ch3.appm.tab8_1_1_8_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.267</td></tr><tr><th headers="hd_h_ch3.appm.tab8_1_1_1_1" id="hd_b_ch3.appm.tab8_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 9</th><td headers="hd_h_ch3.appm.tab8_1_1_1_2 hd_b_ch3.appm.tab8_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.110</td><td headers="hd_h_ch3.appm.tab8_1_1_1_3 hd_b_ch3.appm.tab8_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.131</td><td headers="hd_h_ch3.appm.tab8_1_1_1_4 hd_b_ch3.appm.tab8_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.092</td><td headers="hd_h_ch3.appm.tab8_1_1_1_5 hd_b_ch3.appm.tab8_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.468</td><td headers="hd_h_ch3.appm.tab8_1_1_1_6 hd_b_ch3.appm.tab8_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.216</td></tr><tr><th headers="hd_h_ch3.appm.tab8_1_1_1_1" id="hd_b_ch3.appm.tab8_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 10</th><td headers="hd_h_ch3.appm.tab8_1_1_1_2 hd_b_ch3.appm.tab8_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.025</td><td headers="hd_h_ch3.appm.tab8_1_1_1_3 hd_b_ch3.appm.tab8_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.056</td><td headers="hd_h_ch3.appm.tab8_1_1_1_4 hd_b_ch3.appm.tab8_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.018</td><td headers="hd_h_ch3.appm.tab8_1_1_1_5 hd_b_ch3.appm.tab8_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.418</td><td headers="hd_h_ch3.appm.tab8_1_1_1_6 hd_b_ch3.appm.tab8_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.166</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobch3appmfig5"><div id="ch3.appm.fig5" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%205.%20Beta%20distribution%20of%20baseline%20NRS%20score%20for%20calculating%20costs%20and%20utilities.&p=BOOKS&id=577084_ch3appmf5.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appmf5.jpg" alt="Figure 5. Beta distribution of baseline NRS score for calculating costs and utilities." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 5</span><span class="title">Beta distribution of baseline NRS score for calculating costs and utilities</span></h3></div></article><article data-type="table-wrap" id="figobch3appmtab9"><div id="ch3.appm.tab9" class="table"><h3><span class="label">Table 10</span><span class="title">Model fit data for >30% responders survival curve</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab9/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab9_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Parametric Survival Regression</th><th id="hd_h_ch3.appm.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AIC</th><th id="hd_h_ch3.appm.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">BIC</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appm.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Weibull</td><td headers="hd_h_ch3.appm.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1118</td><td headers="hd_h_ch3.appm.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1126</td></tr><tr><td headers="hd_h_ch3.appm.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Exponential</td><td headers="hd_h_ch3.appm.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1139</td><td headers="hd_h_ch3.appm.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1143</td></tr><tr><td headers="hd_h_ch3.appm.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gompertz</td><td headers="hd_h_ch3.appm.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1136</td><td headers="hd_h_ch3.appm.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1144</td></tr><tr><td headers="hd_h_ch3.appm.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>
|
|
<u>Gamma</u>
|
|
</b>
|
|
</td><td headers="hd_h_ch3.appm.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>
|
|
<u>1106</u>
|
|
</b>
|
|
</td><td headers="hd_h_ch3.appm.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>
|
|
<u>1118</u>
|
|
</b>
|
|
</td></tr><tr><td headers="hd_h_ch3.appm.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lognormal</td><td headers="hd_h_ch3.appm.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1122</td><td headers="hd_h_ch3.appm.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1130</td></tr><tr><td headers="hd_h_ch3.appm.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Loglogistic</td><td headers="hd_h_ch3.appm.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1122</td><td headers="hd_h_ch3.appm.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1129</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobch3appmfig6"><div id="ch3.appm.fig6" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%206.%20%25%20of%20patients%20had%20NRS%20improvement%20by%20at%20least%2030%25.&p=BOOKS&id=577084_ch3appmf6.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appmf6.jpg" alt="Figure 6. % of patients had NRS improvement by at least 30%." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 6</span><span class="title">% of patients had NRS improvement by at least 30%</span></h3></div></article><article data-type="table-wrap" id="figobch3appmtab10"><div id="ch3.appm.tab10" class="table"><h3><span class="label">Table 11</span><span class="title">Options for “response among responders” curve</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab10/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab10_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab10_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Response among responders</th><th id="hd_h_ch3.appm.tab10_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">30% cutoff</th><th id="hd_h_ch3.appm.tab10_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">28% cutoff</th><th id="hd_h_ch3.appm.tab10_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">25% cutoff</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appm.tab10_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">30–34%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">26%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">25%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">29%</td></tr><tr><td headers="hd_h_ch3.appm.tab10_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">35–49%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">27%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">32%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">30%</td></tr><tr><td headers="hd_h_ch3.appm.tab10_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">40–44%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">18%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">17%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">16%</td></tr><tr><td headers="hd_h_ch3.appm.tab10_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">45–49%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">11%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">9%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">9%</td></tr><tr><td headers="hd_h_ch3.appm.tab10_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">50–54%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">7%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5%</td></tr><tr><td headers="hd_h_ch3.appm.tab10_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">55–59%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">4%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3%</td></tr><tr><td headers="hd_h_ch3.appm.tab10_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">60–64%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2%</td></tr><tr><td headers="hd_h_ch3.appm.tab10_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">65–69%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1%</td></tr><tr><td headers="hd_h_ch3.appm.tab10_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">70–74%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1%</td></tr><tr><td headers="hd_h_ch3.appm.tab10_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">75–79%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1%</td></tr><tr><td headers="hd_h_ch3.appm.tab10_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">80–84%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1%</td></tr><tr><td headers="hd_h_ch3.appm.tab10_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">85–89%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0%</td></tr><tr><td headers="hd_h_ch3.appm.tab10_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">90–94%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0%</td></tr><tr><td headers="hd_h_ch3.appm.tab10_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">95–100%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0%</td><td headers="hd_h_ch3.appm.tab10_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0%</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appmtab11"><div id="ch3.appm.tab11" class="table"><h3><span class="label">Table 12</span><span class="title">AE disutility and duration of the events</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab11/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab11_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th id="hd_h_ch3.appm.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Utility decrement</th><th id="hd_h_ch3.appm.tab11_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Duration (days)</th></tr></thead><tbody><tr><th headers="hd_h_ch3.appm.tab11_1_1_1_1" id="hd_b_ch3.appm.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dizziness</th><td headers="hd_h_ch3.appm.tab11_1_1_1_2 hd_b_ch3.appm.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.02</td><td headers="hd_h_ch3.appm.tab11_1_1_1_3 hd_b_ch3.appm.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3.00</td></tr><tr><th headers="hd_h_ch3.appm.tab11_1_1_1_1" id="hd_b_ch3.appm.tab11_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dry mouth</th><td headers="hd_h_ch3.appm.tab11_1_1_1_2 hd_b_ch3.appm.tab11_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.02</td><td headers="hd_h_ch3.appm.tab11_1_1_1_3 hd_b_ch3.appm.tab11_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">7.00</td></tr><tr><th headers="hd_h_ch3.appm.tab11_1_1_1_1" id="hd_b_ch3.appm.tab11_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Fatigue</th><td headers="hd_h_ch3.appm.tab11_1_1_1_2 hd_b_ch3.appm.tab11_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.02</td><td headers="hd_h_ch3.appm.tab11_1_1_1_3 hd_b_ch3.appm.tab11_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">7.00</td></tr><tr><th headers="hd_h_ch3.appm.tab11_1_1_1_1" id="hd_b_ch3.appm.tab11_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Headache</th><td headers="hd_h_ch3.appm.tab11_1_1_1_2 hd_b_ch3.appm.tab11_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.04</td><td headers="hd_h_ch3.appm.tab11_1_1_1_3 hd_b_ch3.appm.tab11_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3.00</td></tr><tr><th headers="hd_h_ch3.appm.tab11_1_1_1_1" id="hd_b_ch3.appm.tab11_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nausea</th><td headers="hd_h_ch3.appm.tab11_1_1_1_2 hd_b_ch3.appm.tab11_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.06</td><td headers="hd_h_ch3.appm.tab11_1_1_1_3 hd_b_ch3.appm.tab11_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3.00</td></tr><tr><th headers="hd_h_ch3.appm.tab11_1_1_1_1" id="hd_b_ch3.appm.tab11_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Serious AE</th><td headers="hd_h_ch3.appm.tab11_1_1_1_2 hd_b_ch3.appm.tab11_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.10</td><td headers="hd_h_ch3.appm.tab11_1_1_1_3 hd_b_ch3.appm.tab11_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3.00</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appmtab12"><div id="ch3.appm.tab12" class="table"><h3><span class="label">Table 13</span><span class="title">AE disutility per event</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab12/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab12_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab12_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;"></th><th id="hd_h_ch3.appm.tab12_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">QALY losses</th></tr></thead><tbody><tr><th headers="hd_h_ch3.appm.tab12_1_1_1_1" id="hd_b_ch3.appm.tab12_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dizziness</th><td headers="hd_h_ch3.appm.tab12_1_1_1_2 hd_b_ch3.appm.tab12_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.00018</td></tr><tr><th headers="hd_h_ch3.appm.tab12_1_1_1_1" id="hd_b_ch3.appm.tab12_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dry mouth</th><td headers="hd_h_ch3.appm.tab12_1_1_1_2 hd_b_ch3.appm.tab12_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.00042</td></tr><tr><th headers="hd_h_ch3.appm.tab12_1_1_1_1" id="hd_b_ch3.appm.tab12_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Fatigue</th><td headers="hd_h_ch3.appm.tab12_1_1_1_2 hd_b_ch3.appm.tab12_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.00042</td></tr><tr><th headers="hd_h_ch3.appm.tab12_1_1_1_1" id="hd_b_ch3.appm.tab12_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Headache</th><td headers="hd_h_ch3.appm.tab12_1_1_1_2 hd_b_ch3.appm.tab12_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.00035</td></tr><tr><th headers="hd_h_ch3.appm.tab12_1_1_1_1" id="hd_b_ch3.appm.tab12_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nausea</th><td headers="hd_h_ch3.appm.tab12_1_1_1_2 hd_b_ch3.appm.tab12_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.00051</td></tr><tr><th headers="hd_h_ch3.appm.tab12_1_1_1_1" id="hd_b_ch3.appm.tab12_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Serious AE</th><td headers="hd_h_ch3.appm.tab12_1_1_1_2 hd_b_ch3.appm.tab12_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.00078</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appmtab13"><div id="ch3.appm.tab13" class="table"><h3><span class="label">Table 14</span><span class="title">Medicinal cannabis costs</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab13/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab13_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ch3.appm.tab13_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Drug name</th><th id="hd_h_ch3.appm.tab13_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Ingredients</th><th id="hd_h_ch3.appm.tab13_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Pack size</th><th id="hd_h_ch3.appm.tab13_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Price (country)</th><th id="hd_h_ch3.appm.tab13_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Cost per day (£, min to max)</th><th id="hd_h_ch3.appm.tab13_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Licensed dosage</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appm.tab13_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Sativex oromucosal spray a</td><td headers="hd_h_ch3.appm.tab13_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nabiximols: Cannabidiol (CBD) 2.5 mg & Dronabinol (THC) 2.7 mg per 1 dose</td><td headers="hd_h_ch3.appm.tab13_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">270 doses</td><td headers="hd_h_ch3.appm.tab13_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£300(UK)</td><td headers="hd_h_ch3.appm.tab13_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.39 to 16.67</td><td headers="hd_h_ch3.appm.tab13_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Starting from 1 spray a day, increased by 1 spray per day. Maximum 12 sprays per day (adults only)</td></tr><tr><td headers="hd_h_ch3.appm.tab13_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nabilone b</td><td headers="hd_h_ch3.appm.tab13_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nabilone (synthetic THC) 1 mg</td><td headers="hd_h_ch3.appm.tab13_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">20 capsules</td><td headers="hd_h_ch3.appm.tab13_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£196 (UK)</td><td headers="hd_h_ch3.appm.tab13_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">19.60 to 58.80</td><td headers="hd_h_ch3.appm.tab13_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1mg or 2mg twice a day, maximum daily dose of 6 mg (adults only). The first dose should be administered the night before initiation of chemotherapy, and the second dose should be given one to three hours before the first dose of the oncolytic agent is administered. It may be administered throughout each cycle of chemotherapy and, if necessary, for 48 hours after the last dose of each cycle.</td></tr><tr><td headers="hd_h_ch3.appm.tab13_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">EPIDIOLEX® c</td><td headers="hd_h_ch3.appm.tab13_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cannabidiol (CBD) 100 mg/ mL oral solution</td><td headers="hd_h_ch3.appm.tab13_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">100 mL</td><td headers="hd_h_ch3.appm.tab13_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">$1,235 (US)</td><td headers="hd_h_ch3.appm.tab13_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10.84 to 43.38</td><td headers="hd_h_ch3.appm.tab13_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Starting dose 2.5 mg/kg twice daily for one week then 5 mg/kg twice daily, can be increased up to maximum 10 mg/kg twice daily (patients 2+ years old)</td></tr><tr><td headers="hd_h_ch3.appm.tab13_1_1_1_1" rowspan="3" colspan="1" style="text-align:left;vertical-align:top;">Dronabinol d</td><td headers="hd_h_ch3.appm.tab13_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dronabinol (THC) 2.5 mg</td><td headers="hd_h_ch3.appm.tab13_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">60 capsules</td><td headers="hd_h_ch3.appm.tab13_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">$2.14 per capsule (US)</td><td headers="hd_h_ch3.appm.tab13_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">26.11 to 39.16</td><td headers="hd_h_ch3.appm.tab13_1_1_1_6" rowspan="3" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Anorexia associated with weight loss with AIDS - 2.5 mg twice daily (adults only)</p>
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<p>Nausea and vomiting associated with chemotherapy - 5 mg/m2 1–3 hours prior to chemotherapy then every 2–4 hours after chemotherapy for a total of 4 to 6 doses per day. (adults only)</p>
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</td></tr><tr><td headers="hd_h_ch3.appm.tab13_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dronabinol (THC) 5 mg</td><td headers="hd_h_ch3.appm.tab13_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">60 capsules</td><td headers="hd_h_ch3.appm.tab13_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">$3.97 per capsule (US)</td><td headers="hd_h_ch3.appm.tab13_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">24.27 to 36.40</td></tr><tr><td headers="hd_h_ch3.appm.tab13_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dronabinol (THC) 10 mg</td><td headers="hd_h_ch3.appm.tab13_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">60 capsules</td><td headers="hd_h_ch3.appm.tab13_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">$7.08 per capsule (US)</td><td headers="hd_h_ch3.appm.tab13_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">21.64 to 32.45</td></tr><tr><td headers="hd_h_ch3.appm.tab13_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dronabinol (SYNDROS®) e</td><td headers="hd_h_ch3.appm.tab13_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dronabinol (THC) 5mg/ mL oral solution</td><td headers="hd_h_ch3.appm.tab13_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">30 mL</td><td headers="hd_h_ch3.appm.tab13_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">$1226.49 (US)</td><td headers="hd_h_ch3.appm.tab13_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">187.74 to 281.61</td><td headers="hd_h_ch3.appm.tab13_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Anorexia associated with weight loss with AIDS - 2.1mg twice daily (adults only)</p>
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<p>Nausea and vomiting associated with chemotherapy - 4.2 mg/m2 1–3 hours prior to chemotherapy then every 2–4 hours after chemotherapy for a total of 4 to 6 doses per day. (adults only)</p>
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</td></tr><tr><td headers="hd_h_ch3.appm.tab13_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bedica® THC 2.0% oil f</td><td headers="hd_h_ch3.appm.tab13_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">14% THC and <1% CBD 0.05 ml = 1 mg THC</td><td headers="hd_h_ch3.appm.tab13_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10 mL</td><td headers="hd_h_ch3.appm.tab13_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">€46.78 (Netherlands)</td><td headers="hd_h_ch3.appm.tab13_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.60</td><td headers="hd_h_ch3.appm.tab13_1_1_1_6" rowspan="4" colspan="1" style="text-align:left;vertical-align:top;">Epilepsy case study: 1 mg Bedica (THC) three times a day and 150 mg Bedrolite (CBD) twice a day</td></tr><tr><td headers="hd_h_ch3.appm.tab13_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bediol® CBD 2.0%/THC 1.3% oil f</td><td headers="hd_h_ch3.appm.tab13_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.3% THC and 8% CBD 0.05 ml = 1 mg CBD and 0.65 mg THC</td><td headers="hd_h_ch3.appm.tab13_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10 mL</td><td headers="hd_h_ch3.appm.tab13_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">€46.78 (Netherlands)</td><td headers="hd_h_ch3.appm.tab13_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ch3.appm.tab13_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bedrolite® CBD 2.0% oil f</td><td headers="hd_h_ch3.appm.tab13_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><1% THC and 9% CBD 0.05 ml = 1 mg CBD</td><td headers="hd_h_ch3.appm.tab13_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10 mL</td><td headers="hd_h_ch3.appm.tab13_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">€20.51 (Netherlands)</td><td headers="hd_h_ch3.appm.tab13_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">26.49</td></tr><tr><td headers="hd_h_ch3.appm.tab13_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bedrolite® CBD 10% oil f</td><td headers="hd_h_ch3.appm.tab13_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><1% THC and 9% CBD 0.05 ml = 5 mg CBD</td><td headers="hd_h_ch3.appm.tab13_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10 mL</td><td headers="hd_h_ch3.appm.tab13_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">€77.12 (Netherlands)</td><td headers="hd_h_ch3.appm.tab13_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">19.92</td></tr><tr><td headers="hd_h_ch3.appm.tab13_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Tilray 2:100 (TIL-TC150) g</td><td headers="hd_h_ch3.appm.tab13_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CBD: THC = 50:1; 2 mg/mL THC and 100 mg/mL CBD</td><td headers="hd_h_ch3.appm.tab13_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">40 mL</td><td headers="hd_h_ch3.appm.tab13_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CAD $390 (Canada)</td><td headers="hd_h_ch3.appm.tab13_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.56 to 20.47</td><td headers="hd_h_ch3.appm.tab13_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">From open-label trial by McCoy et al. 2018: 2 mg/kg/day CBD (0.04 mg/kg/day THC) divided twice daily with weekly titration by 2 mg/kg/day every 7 days up to a maximum dose of 16 mg/kg/day CBD (0.32 mg/kg/day THC)</td></tr><tr><td headers="hd_h_ch3.appm.tab13_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Avidekel™ oil h</td><td headers="hd_h_ch3.appm.tab13_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>1% THC and 16–19% CBD (THC <2 mg/mL, CBD 20–25 mg/mL)</td><td headers="hd_h_ch3.appm.tab13_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">40 mL</td><td headers="hd_h_ch3.appm.tab13_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CAD $120 (Canada)</td><td headers="hd_h_ch3.appm.tab13_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3.15 to 78.74</td><td headers="hd_h_ch3.appm.tab13_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">From observational studies by Hausman-Kedem et al. 2018 (mix of Avidekel and Cheesepie [EP1]): 2–5 mg/kg/day, dosage increments were performed until maximum dose of 50 mg/kg per day of CBD</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Sativex: Price: NHS Drug Tariff <a href="http://www.drugtariff.nhsbsa.nhs.uk/#/00710361-DA/DA00710133/Part%20VIIIA%20products%20D" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://www.drugtariff.nhsbsa.nhs.uk/#/00710361-DA/DA00710133/Part%20VIIIA%20products%20D</a>; Dosing: eMC <a href="https://www.medicines.org.uk/emc/product/602#INDICATIONS" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.medicines.org.uk/emc/product/602#INDICATIONS</a> accessed on 6 March 2019; THC: CBD spray discount: Sativex NHS Pay for Responder scheme(3 × 10ml vial; 90 doses per vial; 270 doses per pack and pay for responder only): <a href="http://sativex.co.uk/static/documents/NHS_Pay-for-Responder_scheme_order_form.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://sativex.co.uk/static/documents/NHS_Pay-for-Responder_scheme_order_form.pdf</a></p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Nabilone: Price: NHS Drug Tariff <a href="http://www.drugtariff.nhsbsa.nhs.uk/#/00710361-DA/DA00709784/Part%20VIIIA%20products%20N" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://www.drugtariff.nhsbsa.nhs.uk/#/00710361-DA/DA00709784/Part%20VIIIA%20products%20N</a> accessed on 6 March 2019; Dosing: eMC <a href="https://www.medicines.org.uk/emc/product/6176#INDICATIONS" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.medicines.org.uk/emc/product/6176#INDICATIONS</a> accessed on 6 March 2019</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">EPIDIOLEX: Price: GW Pharmaceuticals documents FORM 8-K for US Securities and Exchange Commission <a href="http://ir.gwpharm.com/static-files/fcc5c52a-910d-4db2-a0da-accaf9e5c35f" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://ir.gwpharm.com/static-files/fcc5c52a-910d-4db2-a0da-accaf9e5c35f</a> accessed on 7 March 2019; Dosing: FDA label <a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf</a> accessed on 6 March 2019</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Dronabinol: Price: US NADAC (National Average Drug Acquisition Cost) effective date 20 February 2019 <a href="https://healthdata.gov/dataset/nadac-national-average-drug-acquisition-cost" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://healthdata.gov/dataset/nadac-national-average-drug-acquisition-cost</a> CSV file, accessed on 7 March 2017; Dosing: FDA labels <a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018651s029lbl.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018651s029lbl.pdf</a> accessed on 6 March 2019</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">SYNDROS: Price: <a href="https://www.drugs.com/price-guide/syndros" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.drugs.com/price-guide/syndros</a>, accessed on 7 March 2017; Dosing: FDA labels <a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205525s007lbl.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205525s007lbl.pdf</a> accessed on 6 March 2019</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Bedrocan products: Price: <a href="https://www.cannabiszorg.nl/en/#products" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.cannabiszorg.nl/en/#products</a> accessed on 21 March 2019; Bedica THC 2% (assume it is Bedrocan’s Indica) <a href="https://www.cannabiszorg.nl/en/product/thc-20-indica/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.cannabiszorg.nl/en/product/thc-20-indica/</a>; Bediol CBD 2.0%/THC 1.3% <a href="https://www.cannabiszorg.nl/en/product/cbd-20-thc-13-sativa/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.cannabiszorg.nl/en/product/cbd-20-thc-13-sativa/</a>; Bedrolite CBD 2% and 10% <a href="https://www.cannabiszorg.nl/en/product/cbd-from-purified-cbd/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.cannabiszorg.nl/en/product/cbd-from-purified-cbd/</a>; CBD and THC concentration strength: <a href="https://www.transvaalapotheek.nl/wp-content/uploads/2017/12/Patient-leaflet-Cannabis-oil-1.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.transvaalapotheek.nl/wp-content/uploads/2017/12/Patient-leaflet-Cannabis-oil-1.pdf</a>; Dosing: Personal communication (Dr David Spraggett on 19 March 2019)</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Tilray 2:100: Price: <a href="https://www.livingwithpain.ca/unbranded/sneaky2100.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.livingwithpain.ca/unbranded/sneaky2100.html</a> and Tilray Twitter <a href="https://twitter.com/tilray/status/997189798715711490" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://twitter.com/tilray/status/997189798715711490</a> accessed on 8 March 2019; Dosing: McCoy et al. A prospective open-label trial of a CBD/THC cannabis oil in dravet syndrome. Ann Clin Transl Neurol. 2018 Aug 1;5(9):1077–1088.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Avidekel: Price: <a href="http://www.gardenofcannabis.ca/product/avidekel-oil/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://www.gardenofcannabis.ca/product/avidekel-oil/</a> and <a href="https://hmed.ca/wp-content/uploads/2018/07/MedReleaf-Titration-Guide-July-2018.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://hmed.ca/wp-content/uploads/2018/07/MedReleaf-Titration-Guide-July-2018.pdf</a> accessed on 8 March 2019; Dosing: Hausman-Kedem et al. Efficacy of CBD-enriched medical cannabis for the treatment of refractory epilepsy in children and adolescents - An observational, longitudinal study. Brain Dev. 2018 Aug;40(7):544–551.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobch3appmtab14"><div id="ch3.appm.tab14" class="table"><h3><span class="label">Table 15</span><span class="title">spasticity management costs by NRS (based on <a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson et al. 2015</a>)</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab14/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab14_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab14_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></th><th id="hd_h_ch3.appm.tab14_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NRS 0–2</th><th id="hd_h_ch3.appm.tab14_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NRS 2–4</th><th id="hd_h_ch3.appm.tab14_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NRS 4–6</th><th id="hd_h_ch3.appm.tab14_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NRS 6–8</th><th id="hd_h_ch3.appm.tab14_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NRS 8–10</th></tr></thead><tbody><tr><th headers="hd_h_ch3.appm.tab14_1_1_1_1" id="hd_b_ch3.appm.tab14_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Community-based visits (annual)</th><td headers="hd_h_ch3.appm.tab14_1_1_1_2 hd_b_ch3.appm.tab14_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£42.62</td><td headers="hd_h_ch3.appm.tab14_1_1_1_3 hd_b_ch3.appm.tab14_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£59.26</td><td headers="hd_h_ch3.appm.tab14_1_1_1_4 hd_b_ch3.appm.tab14_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£120.59</td><td headers="hd_h_ch3.appm.tab14_1_1_1_5 hd_b_ch3.appm.tab14_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£457.41</td><td headers="hd_h_ch3.appm.tab14_1_1_1_6 hd_b_ch3.appm.tab14_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£903.38</td></tr><tr><th headers="hd_h_ch3.appm.tab14_1_1_1_1" id="hd_b_ch3.appm.tab14_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Outpatient clinic visits (annual)</th><td headers="hd_h_ch3.appm.tab14_1_1_1_2 hd_b_ch3.appm.tab14_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£149.70</td><td headers="hd_h_ch3.appm.tab14_1_1_1_3 hd_b_ch3.appm.tab14_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£640.37</td><td headers="hd_h_ch3.appm.tab14_1_1_1_4 hd_b_ch3.appm.tab14_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1,588.45</td><td headers="hd_h_ch3.appm.tab14_1_1_1_5 hd_b_ch3.appm.tab14_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£2,155.01</td><td headers="hd_h_ch3.appm.tab14_1_1_1_6 hd_b_ch3.appm.tab14_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£2,756.92</td></tr><tr><th headers="hd_h_ch3.appm.tab14_1_1_1_1" id="hd_b_ch3.appm.tab14_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">A&E visits (annual)</th><td headers="hd_h_ch3.appm.tab14_1_1_1_2 hd_b_ch3.appm.tab14_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£4.16</td><td headers="hd_h_ch3.appm.tab14_1_1_1_3 hd_b_ch3.appm.tab14_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£10.40</td><td headers="hd_h_ch3.appm.tab14_1_1_1_4 hd_b_ch3.appm.tab14_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£29.11</td><td headers="hd_h_ch3.appm.tab14_1_1_1_5 hd_b_ch3.appm.tab14_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£38.46</td><td headers="hd_h_ch3.appm.tab14_1_1_1_6 hd_b_ch3.appm.tab14_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£61.33</td></tr><tr><th headers="hd_h_ch3.appm.tab14_1_1_1_1" id="hd_b_ch3.appm.tab14_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hospital admissions (annual)</th><td headers="hd_h_ch3.appm.tab14_1_1_1_2 hd_b_ch3.appm.tab14_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£7.28</td><td headers="hd_h_ch3.appm.tab14_1_1_1_3 hd_b_ch3.appm.tab14_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£45.74</td><td headers="hd_h_ch3.appm.tab14_1_1_1_4 hd_b_ch3.appm.tab14_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£152.82</td><td headers="hd_h_ch3.appm.tab14_1_1_1_5 hd_b_ch3.appm.tab14_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£485.48</td><td headers="hd_h_ch3.appm.tab14_1_1_1_6 hd_b_ch3.appm.tab14_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£920.01</td></tr><tr><th headers="hd_h_ch3.appm.tab14_1_1_1_1" id="hd_b_ch3.appm.tab14_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Home care visits (annual)</th><td headers="hd_h_ch3.appm.tab14_1_1_1_2 hd_b_ch3.appm.tab14_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1.04</td><td headers="hd_h_ch3.appm.tab14_1_1_1_3 hd_b_ch3.appm.tab14_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1,692.41</td><td headers="hd_h_ch3.appm.tab14_1_1_1_4 hd_b_ch3.appm.tab14_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£6,720.77</td><td headers="hd_h_ch3.appm.tab14_1_1_1_5 hd_b_ch3.appm.tab14_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£17,261.92</td><td headers="hd_h_ch3.appm.tab14_1_1_1_6 hd_b_ch3.appm.tab14_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£29,521.47</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appmtab15"><div id="ch3.appm.tab15" class="table"><h3><span class="label">Table 16</span><span class="title">Proportion of funding bodies for home care visits</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab15/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab15_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab15_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th id="hd_h_ch3.appm.tab15_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion</th></tr></thead><tbody><tr><th headers="hd_h_ch3.appm.tab15_1_1_1_1" id="hd_b_ch3.appm.tab15_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Self-funded</th><td headers="hd_h_ch3.appm.tab15_1_1_1_2 hd_b_ch3.appm.tab15_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.4340</td></tr><tr><th headers="hd_h_ch3.appm.tab15_1_1_1_1" id="hd_b_ch3.appm.tab15_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Part self- part NHS/PSS-funded</th><td headers="hd_h_ch3.appm.tab15_1_1_1_2 hd_b_ch3.appm.tab15_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.1390</td></tr><tr><th headers="hd_h_ch3.appm.tab15_1_1_1_1" id="hd_b_ch3.appm.tab15_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PSS funded</th><td headers="hd_h_ch3.appm.tab15_1_1_1_2 hd_b_ch3.appm.tab15_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.3550</td></tr><tr><th headers="hd_h_ch3.appm.tab15_1_1_1_1" id="hd_b_ch3.appm.tab15_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NHS continuing care funded</th><td headers="hd_h_ch3.appm.tab15_1_1_1_2 hd_b_ch3.appm.tab15_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.0720</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appmtab16"><div id="ch3.appm.tab16" class="table"><h3><span class="label">Table 17</span><span class="title">resource use of AE management</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab16/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab16_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab16_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></th><th id="hd_h_ch3.appm.tab16_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Unit cost</th><th id="hd_h_ch3.appm.tab16_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Source</th></tr></thead><tbody><tr><th headers="hd_h_ch3.appm.tab16_1_1_1_1" id="hd_b_ch3.appm.tab16_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GP visit</th><td headers="hd_h_ch3.appm.tab16_1_1_1_2 hd_b_ch3.appm.tab16_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£37.00</td><td headers="hd_h_ch3.appm.tab16_1_1_1_3 hd_b_ch3.appm.tab16_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PSSRU (<a class="bibr" href="#ch3.appm.ref11" rid="ch3.appm.ref11">Curtis and Burns, 2018</a>)</td></tr><tr><th headers="hd_h_ch3.appm.tab16_1_1_1_1" id="hd_b_ch3.appm.tab16_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">A&E visit</th><td headers="hd_h_ch3.appm.tab16_1_1_1_2 hd_b_ch3.appm.tab16_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£225.82</td><td headers="hd_h_ch3.appm.tab16_1_1_1_3 hd_b_ch3.appm.tab16_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NHS Reference costs - Weighted average of emergency medicine costs (excluding dental care, no investigation with no significant treatment, and dead on arrival)</td></tr><tr><th headers="hd_h_ch3.appm.tab16_1_1_1_1" id="hd_b_ch3.appm.tab16_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Ambulance</th><td headers="hd_h_ch3.appm.tab16_1_1_1_2 hd_b_ch3.appm.tab16_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£251.93</td><td headers="hd_h_ch3.appm.tab16_1_1_1_3 hd_b_ch3.appm.tab16_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NHS Reference costs - see and treat and convey</td></tr><tr><th headers="hd_h_ch3.appm.tab16_1_1_1_1" id="hd_b_ch3.appm.tab16_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Inpatient stay</th><td headers="hd_h_ch3.appm.tab16_1_1_1_2 hd_b_ch3.appm.tab16_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1,590.00</td><td headers="hd_h_ch3.appm.tab16_1_1_1_3 hd_b_ch3.appm.tab16_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NHS Reference Costs 2016/2017</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appmtab17"><div id="ch3.appm.tab17" class="table"><h3><span class="label">Table 18</span><span class="title">Resource use costs per AE</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab17/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab17_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab17_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th id="hd_h_ch3.appm.tab17_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cost</th></tr></thead><tbody><tr><th headers="hd_h_ch3.appm.tab17_1_1_1_1" id="hd_b_ch3.appm.tab17_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dizziness</th><td headers="hd_h_ch3.appm.tab17_1_1_1_2 hd_b_ch3.appm.tab17_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£18.50</td></tr><tr><th headers="hd_h_ch3.appm.tab17_1_1_1_1" id="hd_b_ch3.appm.tab17_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dry mouth</th><td headers="hd_h_ch3.appm.tab17_1_1_1_2 hd_b_ch3.appm.tab17_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£18.50</td></tr><tr><th headers="hd_h_ch3.appm.tab17_1_1_1_1" id="hd_b_ch3.appm.tab17_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Fatigue</th><td headers="hd_h_ch3.appm.tab17_1_1_1_2 hd_b_ch3.appm.tab17_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£18.50</td></tr><tr><th headers="hd_h_ch3.appm.tab17_1_1_1_1" id="hd_b_ch3.appm.tab17_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Headache</th><td headers="hd_h_ch3.appm.tab17_1_1_1_2 hd_b_ch3.appm.tab17_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£18.50</td></tr><tr><th headers="hd_h_ch3.appm.tab17_1_1_1_1" id="hd_b_ch3.appm.tab17_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nausea</th><td headers="hd_h_ch3.appm.tab17_1_1_1_2 hd_b_ch3.appm.tab17_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£18.50</td></tr><tr><th headers="hd_h_ch3.appm.tab17_1_1_1_1" id="hd_b_ch3.appm.tab17_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Serious adverse event</th><td headers="hd_h_ch3.appm.tab17_1_1_1_2 hd_b_ch3.appm.tab17_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£686.31</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appmtab18"><div id="ch3.appm.tab18" class="table"><h3><span class="label">Table 19</span><span class="title">OR of response at 20% cut-off</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab18/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab18_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab18_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;"></th><th id="hd_h_ch3.appm.tab18_1_1_1_2" colspan="2" rowspan="1" style="text-align:left;vertical-align:bottom;">THC:CBD Spray</th><th id="hd_h_ch3.appm.tab18_1_1_1_3" colspan="2" rowspan="1" style="text-align:left;vertical-align:bottom;">Placebo</th><th id="hd_h_ch3.appm.tab18_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;"></th><th id="hd_h_ch3.appm.tab18_1_1_1_5" colspan="2" rowspan="1" style="text-align:left;vertical-align:bottom;">OR from RevMan</th></tr></thead><tbody><tr><th headers="hd_h_ch3.appm.tab18_1_1_1_1" id="hd_b_ch3.appm.tab18_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Study</th><td headers="hd_h_ch3.appm.tab18_1_1_1_2 hd_b_ch3.appm.tab18_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">R</td><td headers="hd_h_ch3.appm.tab18_1_1_1_2 hd_b_ch3.appm.tab18_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N</td><td headers="hd_h_ch3.appm.tab18_1_1_1_3 hd_b_ch3.appm.tab18_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">R</td><td headers="hd_h_ch3.appm.tab18_1_1_1_3 hd_b_ch3.appm.tab18_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N</td><td headers="hd_h_ch3.appm.tab18_1_1_1_4 hd_b_ch3.appm.tab18_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Time (weeks)</td><td headers="hd_h_ch3.appm.tab18_1_1_1_5 hd_b_ch3.appm.tab18_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Mean</td><td headers="hd_h_ch3.appm.tab18_1_1_1_5 hd_b_ch3.appm.tab18_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">95% CI</td></tr><tr><th headers="hd_h_ch3.appm.tab18_1_1_1_1" id="hd_b_ch3.appm.tab18_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Markova 2018</th><td headers="hd_h_ch3.appm.tab18_1_1_1_2 hd_b_ch3.appm.tab18_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">43</td><td headers="hd_h_ch3.appm.tab18_1_1_1_2 hd_b_ch3.appm.tab18_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">53</td><td headers="hd_h_ch3.appm.tab18_1_1_1_3 hd_b_ch3.appm.tab18_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">24</td><td headers="hd_h_ch3.appm.tab18_1_1_1_3 hd_b_ch3.appm.tab18_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">53</td><td headers="hd_h_ch3.appm.tab18_1_1_1_4 hd_b_ch3.appm.tab18_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4</td><td headers="hd_h_ch3.appm.tab18_1_1_1_5 hd_b_ch3.appm.tab18_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5.20</td><td headers="hd_h_ch3.appm.tab18_1_1_1_5 hd_b_ch3.appm.tab18_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.17–12.47</td></tr><tr><th headers="hd_h_ch3.appm.tab18_1_1_1_1" id="hd_b_ch3.appm.tab18_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref20" rid="ch3.appm.ref20">Haupts 2016</a> post hoc of <a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna 2011</a></th><td headers="hd_h_ch3.appm.tab18_1_1_1_2 hd_b_ch3.appm.tab18_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">107</td><td headers="hd_h_ch3.appm.tab18_1_1_1_2 hd_b_ch3.appm.tab18_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">124</td><td headers="hd_h_ch3.appm.tab18_1_1_1_3 hd_b_ch3.appm.tab18_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">77</td><td headers="hd_h_ch3.appm.tab18_1_1_1_3 hd_b_ch3.appm.tab18_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">117</td><td headers="hd_h_ch3.appm.tab18_1_1_1_4 hd_b_ch3.appm.tab18_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">12</td><td headers="hd_h_ch3.appm.tab18_1_1_1_5 hd_b_ch3.appm.tab18_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3.27</td><td headers="hd_h_ch3.appm.tab18_1_1_1_5 hd_b_ch3.appm.tab18_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.73–6.19</td></tr><tr><th headers="hd_h_ch3.appm.tab18_1_1_1_1 hd_h_ch3.appm.tab18_1_1_1_2 hd_h_ch3.appm.tab18_1_1_1_3 hd_h_ch3.appm.tab18_1_1_1_4" id="hd_b_ch3.appm.tab18_1_1_4_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:top;">Fixed Effects Meta-analysis</th><td headers="hd_h_ch3.appm.tab18_1_1_1_5 hd_b_ch3.appm.tab18_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3.84</td><td headers="hd_h_ch3.appm.tab18_1_1_1_5 hd_b_ch3.appm.tab18_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.29–6.42</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appmtab19"><div id="ch3.appm.tab19" class="table"><h3><span class="label">Table 20</span><span class="title">Proportion of responders in each response category (>=20%)</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab19/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab19_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab19_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">NRS response category among responders (>=20%)</th><th id="hd_h_ch3.appm.tab19_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Percentage of responders in category</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appm.tab19_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.2 - 0.26</td><td headers="hd_h_ch3.appm.tab19_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">27%</td></tr><tr><td headers="hd_h_ch3.appm.tab19_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.26 - 0.31</td><td headers="hd_h_ch3.appm.tab19_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">30%</td></tr><tr><td headers="hd_h_ch3.appm.tab19_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.31 - 0.37</td><td headers="hd_h_ch3.appm.tab19_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">18%</td></tr><tr><td headers="hd_h_ch3.appm.tab19_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.37 - 0.43</td><td headers="hd_h_ch3.appm.tab19_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10%</td></tr><tr><td headers="hd_h_ch3.appm.tab19_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.43 - 0.49</td><td headers="hd_h_ch3.appm.tab19_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6%</td></tr><tr><td headers="hd_h_ch3.appm.tab19_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.49 - 0.54</td><td headers="hd_h_ch3.appm.tab19_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3%</td></tr><tr><td headers="hd_h_ch3.appm.tab19_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.54 - 0.6</td><td headers="hd_h_ch3.appm.tab19_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2%</td></tr><tr><td headers="hd_h_ch3.appm.tab19_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.6 - 0.66</td><td headers="hd_h_ch3.appm.tab19_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1%</td></tr><tr><td headers="hd_h_ch3.appm.tab19_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.66 - 0.71</td><td headers="hd_h_ch3.appm.tab19_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1%</td></tr><tr><td headers="hd_h_ch3.appm.tab19_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.71 - 0.77</td><td headers="hd_h_ch3.appm.tab19_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1%</td></tr><tr><td headers="hd_h_ch3.appm.tab19_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.77 - 0.83</td><td headers="hd_h_ch3.appm.tab19_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0%</td></tr><tr><td headers="hd_h_ch3.appm.tab19_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.83 - 0.89</td><td headers="hd_h_ch3.appm.tab19_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0%</td></tr><tr><td headers="hd_h_ch3.appm.tab19_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.89 - 0.94</td><td headers="hd_h_ch3.appm.tab19_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0%</td></tr><tr><td headers="hd_h_ch3.appm.tab19_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.94 - 1</td><td headers="hd_h_ch3.appm.tab19_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0%</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appmtab20"><div id="ch3.appm.tab20" class="table"><h3><span class="label">Table 21</span><span class="title">parameters in the probabilistic sensitivity analysis</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab20/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab20_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Parameter</th><th id="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">mean</th><th id="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">SE</th><th id="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Lo/Min</th><th id="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Hi/Max</th><th id="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Source</th><th id="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Dist</th><th id="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Param1</th><th id="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Param2</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Baseline population: starting age</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">51.00</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.17</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">21.00</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">84.00</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina 2017</a>
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</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=1904.473</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.027</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Baseline population: sex (% male)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.47</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.45</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.50</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina 2017</a>
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</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=756</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=841</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Spasticity NRS at baseline</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7.50</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.04</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina 2017</a>
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</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Multivariate normal</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">EDSS at baseline</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.40</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.03</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated from <a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina 2017</a></td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Multivariate normal</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cannabis response from <a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina 2017</a>/ Patti 2016</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.283</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.012</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.25979</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.30643</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina 2017</a>; Patti 2016</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=404.717</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=1026.283</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cannabis response (meta-analysis of 2 non-enriched studies, random effect)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.3516</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.0441</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.26777</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.44027</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Meta-analysis</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=40.864</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=75.359</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">THC: CBD spray Response (meta-analysis of 4 studies, random effect)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.36</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.0281</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.31</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.42</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Meta-analysis</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=106.273</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=185.846</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Placebo response (<a class="bibr" href="#ch3.appm.ref42" rid="ch3.appm.ref42">Wade 2010</a>)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.26</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.03</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.21</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.31</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref42" rid="ch3.appm.ref42">Wade 2010</a>
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</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=77</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=219</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Odds ratio vs. placebo - response: THC: CBD spray - Within Dose</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.17</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.49</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.60</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10.83</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Clinical review: meta-analysis random effect</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Lognormal</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">μ=1.428</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">σ=0.488</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Odds ratio vs. placebo - response: THC: CBD spray - Higher Dose</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.61</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.20</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.09</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.38</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Clinical review: meta-analysis fixed effect</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Lognormal</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">μ=0.476</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">σ=0.199</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Odds ratio vs. placebo - response: THC: CBD spray - All Doses</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.61</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.32</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.40</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.86</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Clinical review: meta-analysis random effect</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Lognormal</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">μ=0.959</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">σ=0.317</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SMR of MS versus general population</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.80</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.74</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.87</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref26" rid="ch3.appm.ref26">Manouchehrinia 2016</a>
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</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Lognormal</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">μ=1.030</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">σ=0.012</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Competing Risks Model (Messina)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"> shape</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−4.609</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated from <a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina 2017</a></td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Multivariate normal</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"> rate</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−0.786</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated from <a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina 2017</a></td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Multivariate normal</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"> trans</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−0.053</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated from <a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina 2017</a></td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Multivariate normal</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"> shape(trans)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.615</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated from <a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina 2017</a></td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Multivariate normal</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HR for discontinuation: placebo vs. cannabis</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.48</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.06</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.38</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.62</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Lognormal</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">μ=−0.730</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">σ=0.061</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Non-serious adverse event rate (Cannabis) per year</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10.370</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.311</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.79539</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">18.39036</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref44" rid="ch3.appm.ref44">Wang 2008</a>
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</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=2.339</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.311</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Non-serious adverse event rate (Placebo) per year</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.870</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.382</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.50438</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">13.74420</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref44" rid="ch3.appm.ref44">Wang 2008</a>
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</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=1.927</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.382</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious adverse event rate (Cannabis) per year</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.370</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.038</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.34365</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.39838</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref44" rid="ch3.appm.ref44">Wang 2008</a>
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</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−α=0.994</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.038</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious adverse event rate (Placebo) per year</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.250</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.056</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.22406</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.27895</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref44" rid="ch3.appm.ref44">Wang 2008</a>
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</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−α=1.386</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.056</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">% of AE which are dizziness</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.57</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.54</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.59</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref44" rid="ch3.appm.ref44">Wang 2008</a>
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</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=714</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=544</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">% of AE which are dry mouth</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.19</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.17</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.21</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref44" rid="ch3.appm.ref44">Wang 2008</a>
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</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=239</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=1019</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">% of AE which are fatigue</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.09</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.07</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.10</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref44" rid="ch3.appm.ref44">Wang 2008</a>
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</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=109</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=1149</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">% of AE which are headache</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.06</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.05</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.08</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref44" rid="ch3.appm.ref44">Wang 2008</a>
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</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=79</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=1179</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">% of AE which are nausea</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.09</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.08</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.11</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref44" rid="ch3.appm.ref44">Wang 2008</a>
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</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=117</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=1141</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">THC: CBD spray: initial dose per day: pooled from RCTs</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">8.55</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.72</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">8.48</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">8.61</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Pooled from RCTs (<a class="bibr" href="#ch3.appm.ref9" rid="ch3.appm.ref9">Collin 2007</a>, <a class="bibr" href="#ch3.appm.ref10" rid="ch3.appm.ref10">Collin 2010</a>, <a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna 2011</a> phase B, Markova 2018 phase B)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=66496.133</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.000</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">THC: CBD spray: initial doses per day: <a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina 2017</a></td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.80</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.07</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.67</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.93</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina 2017</a> T1</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=10923.858</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.001</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">THC: CBD spray: subsequent dose per day: up to 12 weeks</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.5</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.07</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.37</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.63</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina 2017</a> T2 (12 weeks)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=9981.250</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.001</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">THC: CBD spray: subsequent dose per day: >12 weeks</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.3</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.07</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.16</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.44</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina 2017</a> T3 (24 weeks)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=8084.813</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.001</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Oral dronabinol: doses per day</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.30</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.23</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5.85</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.75</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref45" rid="ch3.appm.ref45">Zajicek 2003</a>
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</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=756.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.008</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">% of non-responders continuing cannabis treatment</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.10</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.05102</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.2</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=3.357</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=30.216</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Resource use: State 1 (NRS 0–2):</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Community-based visits (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">42.62</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">8.52</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">25.91</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">59.33</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=1.705</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Outpatient clinic visits (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">149.70</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">29.94</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">91.02</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">208.38</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=5.988</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">A&E visits (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.16</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.83</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.53</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5.79</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.166</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hospital admissions (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7.28</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.46</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.42</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10.13</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.291</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Home care visits (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.04</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.21</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.63</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.45</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.042</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Resource use: State 2 (NRS 2–4):</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Community-based visits (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">59.26</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">11.85</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">36.03</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">82.48</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=2.370</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Outpatient clinic visits (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">640.37</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">128.07</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">389.35</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">891.39</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=25.615</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">A&E visits (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10.40</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.08</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.32</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">14.47</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.416</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hospital admissions (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">45.74</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">9.15</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">27.81</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">63.67</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=1.830</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Home care visits (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1692.41</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">338.48</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1029.00</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2355.82</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=67.696</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Resource use: State 3 (NRS 4–6):</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Community-based visits (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">120.59</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">24.12</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">73.32</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">167.86</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=4.824</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Outpatient clinic visits (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1588.45</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">317.69</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">965.79</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2211.11</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=63.538</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">A&E visits (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">29.11</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5.82</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">17.70</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">40.52</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=1.164</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hospital admissions (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">152.82</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">30.56</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">92.91</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">212.72</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=6.113</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Home care visits (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6720.77</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1344.15</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4086.27</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">9355.26</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=268.831</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Resource use: State 4 (NRS 6–8):</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Community-based visits (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">457.41</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">91.48</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">278.11</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">636.71</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=18.296</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Outpatient clinic visits (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2155.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">431.00</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1310.26</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2999.76</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=86.200</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">A&E visits (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">38.46</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7.69</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">23.39</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">53.54</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=1.539</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hospital admissions (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">485.48</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">97.10</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">295.17</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">675.78</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=19.419</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Home care visits (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">17261.92</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3452.38</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10495.37</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">24028.47</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=690.477</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Resource use: State 5 (NRS 8–10):</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Community-based visits (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">903.38</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">180.68</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">549.26</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1257.50</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=36.135</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Outpatient clinic visits (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2756.92</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">551.38</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1676.23</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3837.61</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=110.277</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">A&E visits (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">61.33</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">12.27</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">37.29</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">85.38</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=2.453</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hospital admissions (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">920.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">184.00</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">559.37</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1280.65</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=36.800</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Home care visits (annual)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">29521.47</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5904.29</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">17949.27</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">41093.67</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref40" rid="ch3.appm.ref40">Stevenson 2015</a>: 2013 price inflated to 2017/18 price using PSSRU 2018 HCHS inflation index</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=1180.859</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Distribution of home care funding categories</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Self-funded</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.43</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.04</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.35</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.52</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parkinson’s guideline</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dirichlet</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=0.367</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Part self- part NHS/PSS-funded</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.14</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.11</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.17</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parkinson’s guideline</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=0.159</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PSS funded</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.36</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.04</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.29</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.42</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parkinson’s guideline</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=0.322</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NHS continuing care funded</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.07</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.06</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.09</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parkinson’s guideline</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=0.084</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Proportion of costs that are spasticity related</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.5</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.1</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.31</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.69</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=12.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=12.000</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dizziness - proportion of patients who visit GP</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.50</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.05</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.40</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.60</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=50</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=50</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dry mouth - proportion of patients who visit GP</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.50</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.05</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.40</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.60</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=50</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=50</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fatigue - proportion of patients who visit GP</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.50</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.05</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.40</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.60</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=50</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=50</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Headache - proportion of patients who visit GP</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.50</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.05</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.40</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.60</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=50</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=50</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nausea - proportion of patients who visit GP</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.50</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.05</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.40</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.60</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=50</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=50</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious adverse event - proportion of patients who require ambulance journey to A&E</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.25</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.03</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.20</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.30</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=75</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=224</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious adverse event - proportion of patients who require an inpatient stay</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.25</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.03</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.20</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.30</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=75</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=224</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Population utility (aged 50–59) from study country (Sweden)</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.82</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.81</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.83</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Svensson 2013, <a class="bibr" href="#ch3.appm.ref8" rid="ch3.appm.ref8">Burstrom 2001</a></td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=2469</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=542</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">QoL decrements: Dizziness</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.02</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.02</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.05</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref19" rid="ch3.appm.ref19">Hagiwara 2018</a> - assumed to be equivalent to disutility of fatigue</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=1.874</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.012</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">QoL decrements:Dry mouth</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.02</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.02</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.05</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref19" rid="ch3.appm.ref19">Hagiwara 2018</a> - assumed to be equivalent to disutility of fatigue</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=1.874</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.012</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">QoL decrements: Fatigue</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.02</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.02</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.05</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref19" rid="ch3.appm.ref19">Hagiwara 2018</a>
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</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=1.874</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.012</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">QoL decrements: Headache</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.04</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.02</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.08</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref2" rid="ch3.appm.ref2">Ara and Brazier 2011</a>
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</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=6.377</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.007</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">QoL decrements: Nausea</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.06</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.02</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.03</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.10</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref19" rid="ch3.appm.ref19">Hagiwara 2018</a>
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</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=9.708</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.006</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">QoL decrements: Serious adverse event</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.10</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.07</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−0.05</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.24</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a class="bibr" href="#ch3.appm.ref19" rid="ch3.appm.ref19">Hagiwara 2018</a> - grade 2 vomiting</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=1.638</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.058</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adverse event durations (days): Dizziness</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3.00</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.60</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.82</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.18</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.120</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adverse event durations (days): Dry mouth</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7.00</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.40</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.26</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">9.74</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.280</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adverse event durations (days): Fatigue</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7.00</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.40</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.26</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">9.74</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.280</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adverse event durations (days): Headache</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3.00</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.60</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.82</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.18</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.120</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adverse event durations (days): Nausea</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3.00</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.60</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.82</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.18</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.120</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adverse event durations (days): Serious adverse event</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3.00</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.60</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.82</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.18</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gamma</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=25.000</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=0.120</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">EQ-5D in men</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">age < 25</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.94</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.92</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.96</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref21" rid="ch3.appm.ref21">Kind et al. 1999</a>
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</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=470.313</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=30.020</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">24 < age < 35</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.93</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.91</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.95</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref21" rid="ch3.appm.ref21">Kind et al. 1999</a>
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</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=779.507</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=58.673</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">34 < age < 45</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.91</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.89</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.93</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref21" rid="ch3.appm.ref21">Kind et al. 1999</a>
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|
</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=659.278</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=65.203</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">44 < age < 55</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.84</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.02</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.80</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.87</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch3.appm.ref21" rid="ch3.appm.ref21">Kind et al. 1999</a>
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|
</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=341.410</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=65.030</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">54 < age < 65</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.78</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.02</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.74</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.82</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch3.appm.ref21" rid="ch3.appm.ref21">Kind et al. 1999</a>
|
|
</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=333.840</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=94.160</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">64 < age < 75</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.78</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.02</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.74</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.82</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch3.appm.ref21" rid="ch3.appm.ref21">Kind et al. 1999</a>
|
|
</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=388.472</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=109.569</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">74 < age</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.75</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.03</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.70</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.80</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch3.appm.ref21" rid="ch3.appm.ref21">Kind et al. 1999</a>
|
|
</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=192.968</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=64.323</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">EQ-5D in women</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">age < 25</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.94</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.92</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.96</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch3.appm.ref21" rid="ch3.appm.ref21">Kind et al. 1999</a>
|
|
</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=647.033</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=41.300</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">24 < age < 35</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.93</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.92</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.94</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch3.appm.ref21" rid="ch3.appm.ref21">Kind et al. 1999</a>
|
|
</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=1137.278</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=85.602</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">34 < age < 45</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.91</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.89</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.93</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch3.appm.ref21" rid="ch3.appm.ref21">Kind et al. 1999</a>
|
|
</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=1009.372</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=99.828</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">44 < age < 55</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.85</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.01</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.82</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.88</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch3.appm.ref21" rid="ch3.appm.ref21">Kind et al. 1999</a>
|
|
</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=546.147</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=96.379</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">54 < age < 65</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.81</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.02</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.78</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.84</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch3.appm.ref21" rid="ch3.appm.ref21">Kind et al. 1999</a>
|
|
</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=530.282</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=124.387</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">64 < age < 75</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.78</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.02</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.75</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.81</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch3.appm.ref21" rid="ch3.appm.ref21">Kind et al. 1999</a>
|
|
</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=556.028</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=156.828</td></tr><tr><td headers="hd_h_ch3.appm.tab20_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">74 < age</td><td headers="hd_h_ch3.appm.tab20_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.71</td><td headers="hd_h_ch3.appm.tab20_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.02</td><td headers="hd_h_ch3.appm.tab20_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.67</td><td headers="hd_h_ch3.appm.tab20_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.75</td><td headers="hd_h_ch3.appm.tab20_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch3.appm.ref21" rid="ch3.appm.ref21">Kind et al. 1999</a>
|
|
</td><td headers="hd_h_ch3.appm.tab20_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beta</td><td headers="hd_h_ch3.appm.tab20_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">α=412.389</td><td headers="hd_h_ch3.appm.tab20_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">β=168.441</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch3appmtab21"><div id="ch3.appm.tab21" class="table"><h3><span class="label">Table 22</span><span class="title">Base case results</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab21/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab21_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab21_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;"></th><th id="hd_h_ch3.appm.tab21_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">SoC</th><th id="hd_h_ch3.appm.tab21_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">THC: CBD spray + SoC</th><th id="hd_h_ch3.appm.tab21_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Incremental</th></tr></thead><tbody><tr><th headers="hd_h_ch3.appm.tab21_1_1_1_1" id="hd_b_ch3.appm.tab21_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">LYs</th><td headers="hd_h_ch3.appm.tab21_1_1_1_2 hd_b_ch3.appm.tab21_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.506</td><td headers="hd_h_ch3.appm.tab21_1_1_1_3 hd_b_ch3.appm.tab21_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.506</td><td headers="hd_h_ch3.appm.tab21_1_1_1_4 hd_b_ch3.appm.tab21_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.000</td></tr><tr><th headers="hd_h_ch3.appm.tab21_1_1_1_1" id="hd_b_ch3.appm.tab21_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">QALYs</th><td headers="hd_h_ch3.appm.tab21_1_1_1_2 hd_b_ch3.appm.tab21_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.286</td><td headers="hd_h_ch3.appm.tab21_1_1_1_3 hd_b_ch3.appm.tab21_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.367</td><td headers="hd_h_ch3.appm.tab21_1_1_1_4 hd_b_ch3.appm.tab21_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.081</td></tr><tr><th headers="hd_h_ch3.appm.tab21_1_1_1_1" id="hd_b_ch3.appm.tab21_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Total costs</th><td headers="hd_h_ch3.appm.tab21_1_1_1_2 hd_b_ch3.appm.tab21_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£30,630</td><td headers="hd_h_ch3.appm.tab21_1_1_1_3 hd_b_ch3.appm.tab21_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£32,210</td><td headers="hd_h_ch3.appm.tab21_1_1_1_4 hd_b_ch3.appm.tab21_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1,580</td></tr><tr><th headers="hd_h_ch3.appm.tab21_1_1_1_1" id="hd_b_ch3.appm.tab21_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"> Treatment cost</th><td headers="hd_h_ch3.appm.tab21_1_1_1_2 hd_b_ch3.appm.tab21_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£0</td><td headers="hd_h_ch3.appm.tab21_1_1_1_3 hd_b_ch3.appm.tab21_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£3,377</td><td headers="hd_h_ch3.appm.tab21_1_1_1_4 hd_b_ch3.appm.tab21_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£3,377</td></tr><tr><th headers="hd_h_ch3.appm.tab21_1_1_1_1" id="hd_b_ch3.appm.tab21_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"> AE cost</th><td headers="hd_h_ch3.appm.tab21_1_1_1_2 hd_b_ch3.appm.tab21_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1,345</td><td headers="hd_h_ch3.appm.tab21_1_1_1_3 hd_b_ch3.appm.tab21_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£2,008</td><td headers="hd_h_ch3.appm.tab21_1_1_1_4 hd_b_ch3.appm.tab21_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£663</td></tr><tr><th headers="hd_h_ch3.appm.tab21_1_1_1_1" id="hd_b_ch3.appm.tab21_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"> Management cost</th><td headers="hd_h_ch3.appm.tab21_1_1_1_2 hd_b_ch3.appm.tab21_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£29,284</td><td headers="hd_h_ch3.appm.tab21_1_1_1_3 hd_b_ch3.appm.tab21_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£26,825</td><td headers="hd_h_ch3.appm.tab21_1_1_1_4 hd_b_ch3.appm.tab21_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−£2,460</td></tr><tr><th headers="hd_h_ch3.appm.tab21_1_1_1_1" id="hd_b_ch3.appm.tab21_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ICER</th><td headers="hd_h_ch3.appm.tab21_1_1_1_2 hd_b_ch3.appm.tab21_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab21_1_1_1_3 hd_b_ch3.appm.tab21_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch3.appm.tab21_1_1_1_4 hd_b_ch3.appm.tab21_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£19,512</td></tr><tr><th headers="hd_h_ch3.appm.tab21_1_1_1_1" id="hd_b_ch3.appm.tab21_1_1_8_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Net monetary benefit @ £20k/QALY)</th><td headers="hd_h_ch3.appm.tab21_1_1_1_2 hd_b_ch3.appm.tab21_1_1_8_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">−£4,907</td><td headers="hd_h_ch3.appm.tab21_1_1_1_3 hd_b_ch3.appm.tab21_1_1_8_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">−£4,868</td><td headers="hd_h_ch3.appm.tab21_1_1_1_4 hd_b_ch3.appm.tab21_1_1_8_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;"></td></tr></tbody></table></div></div></article><article data-type="fig" id="figobch3appmfig7"><div id="ch3.appm.fig7" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%207.%20PSA%20scatterplot.&p=BOOKS&id=577084_ch3appmf7.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appmf7.jpg" alt="Figure 7. PSA scatterplot." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 7</span><span class="title">PSA scatterplot</span></h3></div></article><article data-type="fig" id="figobch3appmfig8"><div id="ch3.appm.fig8" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%208.%20Cost-effectiveness%20acceptability%20curve.&p=BOOKS&id=577084_ch3appmf8.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appmf8.jpg" alt="Figure 8. Cost-effectiveness acceptability curve." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 8</span><span class="title">Cost-effectiveness acceptability curve</span></h3></div></article><article data-type="table-wrap" id="figobch3appmtab22"><div id="ch3.appm.tab22" class="table"><h3><span class="label">Table 23</span><span class="title">scenario analyses</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appm.tab22/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appm.tab22_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Scenario</th><th id="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Incremental cost</th><th id="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Incremental QALYs</th><th id="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">ICER</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Base case</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1,580</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.081</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #92d050;text-align:left;vertical-align:top;">£19,512</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Odds ratio from enriched design RCTs only, within licensed dose (<a class="bibr" href="#ch3.appm.ref35" rid="ch3.appm.ref35">Novotna 2011</a>; Markova 2018)</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£693</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.111</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #92d050;text-align:left;vertical-align:top;">£6,260</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Odds ratio from <a class="bibr" href="#ch3.appm.ref9" rid="ch3.appm.ref9">Collin 2007</a>, <a class="bibr" href="#ch3.appm.ref10" rid="ch3.appm.ref10">2010</a> (unrestricted dose) only</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£2,876</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.038</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #d99594;text-align:left;vertical-align:top;">£76,300</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Discontinuation rates (loss of response) the same in both arms</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1,330</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.089</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #92d050;text-align:left;vertical-align:top;">£14,890</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Discontinuation rates (loss of response the same in both arms and set at 10% rate per year)</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1,329</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.089</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #92d050;text-align:left;vertical-align:top;">£14,958</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">No discontinuation in treatment response in SoC</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1,891</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.071</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #ffc000;text-align:left;vertical-align:top;">£26,762</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">No natural progression in NRS</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1,879</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.075</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #ffc000;text-align:left;vertical-align:top;">£25,013</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Lower initial THC: CBD spray dose (6.8 sprays/ day from <a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina 2017</a> T1)</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1,570</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.081</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #92d050;text-align:left;vertical-align:top;">£19,383</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Allow decreasing Sativex dose after 24 weeks</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1,134</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.081</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #92d050;text-align:left;vertical-align:top;">£14,001</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Maximum constant THC: CBD spray dose (12 sprays/ day)</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£4,722</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.081</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #d99594;text-align:left;vertical-align:top;">£58,302</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Constant THC: CBD spray dose (6.8 sprays/ day from <a class="bibr" href="#ch3.appm.ref28" rid="ch3.appm.ref28">Messina 2017</a> T1)</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1,840</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.081</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #ffc000;text-align:left;vertical-align:top;">£22,715</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Lower constant THC: CBD spray dose (5.4 sprays/ day from <a class="bibr" href="#ch3.appm.ref17" rid="ch3.appm.ref17">Etges 2016</a>)</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1,064</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.081</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #92d050;text-align:left;vertical-align:top;">£13,134</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">QoL: assume correlation (0.34) between NRS and EDSS</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1,580</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.164</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #92d050;text-align:left;vertical-align:top;">£9,612</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">QoL: assume correlation (0.17) between NRS and EDSS</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1,580</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.125</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #92d050;text-align:left;vertical-align:top;">£12,670</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">QoL: assume 5% decrement by NRS alone</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1,580</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.081</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #92d050;text-align:left;vertical-align:top;">£19,615</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">QoL: Assume 10% decrement by NRS</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1,580</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.179</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #92d050;text-align:left;vertical-align:top;">£8,851</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Utility data from <a class="bibr" href="#ch3.appm.ref23" rid="ch3.appm.ref23">Lu 2012</a> and no NRS progression (response utility = 0.57, no response utility = 0.48)</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1,879</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.044</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #d99594;text-align:left;vertical-align:top;">£42,344</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10 years time horizon</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£2,728</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.149</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #92d050;text-align:left;vertical-align:top;">£18,325</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">20 years time horizon</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£4,301</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.239</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #92d050;text-align:left;vertical-align:top;">£17,999</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">30 years time horizon</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£4,994</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.277</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #92d050;text-align:left;vertical-align:top;">£18,026</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dronabinol costs + SoC vs SoC</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£3,565</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.081</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #d99594;text-align:left;vertical-align:top;">£44,017</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nabilone costs + SoC vs SoC</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£8,426</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.081</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #d99594;text-align:left;vertical-align:top;">£104,028</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Background management costs doubled</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−£879</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.081</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #92d050;text-align:left;vertical-align:top;">dominant</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Background management costs halved</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£2,810</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.081</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #d99594;text-align:left;vertical-align:top;">£34,695</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cannabis response = meta-analysis of 2 non-enriched RCTs</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£914</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.122</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #92d050;text-align:left;vertical-align:top;">£7,500</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cannabis response = meta-analysis of 2 non-enriched RCTs + 2 enriched RCTs (corrected for run-in phase)</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£796</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.129</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #92d050;text-align:left;vertical-align:top;">£6,163</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">THC:CBD is not free for patients in first cycle or with sub-threshold response</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£1,929</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.081</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #ffc000;text-align:left;vertical-align:top;">£23,810</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assume 20% of non-responders continuing receiving cannabis treatment</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£2,451</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.081</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #d99594;text-align:left;vertical-align:top;">£30,265</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assume 0% of non-responders continuing receiving cannabis treatment</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£709</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.081</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #92d050;text-align:left;vertical-align:top;">£8,759</td></tr><tr><td headers="hd_h_ch3.appm.tab22_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assume 20% improvement as response criteria for continuing treatment</td><td headers="hd_h_ch3.appm.tab22_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£3,083</td><td headers="hd_h_ch3.appm.tab22_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.123</td><td headers="hd_h_ch3.appm.tab22_1_1_1_4" rowspan="1" colspan="1" style="background-color: #ffc000;text-align:left;vertical-align:top;">£24,992</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobch3appmfig9"><div id="ch3.appm.fig9" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%209.%20Tornado%20diagram%20of%20one-way%20sensitivity%20analysis%20at%20the%20%A320%2C000%2FQALY%20threshold.&p=BOOKS&id=577084_ch3appmf9.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appmf9.jpg" alt="Figure 9. Tornado diagram of one-way sensitivity analysis at the £20,000/QALY threshold." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 9</span><span class="title">Tornado diagram of one-way sensitivity analysis at the £20,000/QALY threshold</span></h3></div></article><article data-type="fig" id="figobch3appmfig10"><div id="ch3.appm.fig10" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%2010.%20Tornado%20diagram%20of%20one-way%20sensitivity%20analysis%20at%20the%20%A330%2C000%2FQALY%20threshold.&p=BOOKS&id=577084_ch3appmf10.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appmf10.jpg" alt="Figure 10. Tornado diagram of one-way sensitivity analysis at the £30,000/QALY threshold." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 10</span><span class="title">Tornado diagram of one-way sensitivity analysis at the £30,000/QALY threshold</span></h3></div></article><article data-type="fig-group" id="figobch3appmfig11all"><div id="ch3.appm.fig11all" class="figure bk_fig"><h3><span class="label">Figure 11</span><span class="title">Results of Two-way sensitivity analyses</span></h3><p id="ch3.appm.fig11"><a href="/books/NBK577084/figure/ch3.appm.fig11/?report=objectonly" target="object" rid-ob="figobch3appmfig11" class="figpopup">Treatment response of cannabis vs. standard of care at £20,000 threshold</a></p><p id="ch3.appm.fig12"><a href="/books/NBK577084/figure/ch3.appm.fig12/?report=objectonly" target="object" rid-ob="figobch3appmfig12" class="figpopup">Treatment response of cannabis vs. standard of care at £30,000 threshold</a></p><p id="ch3.appm.fig13"><a href="/books/NBK577084/figure/ch3.appm.fig13/?report=objectonly" target="object" rid-ob="figobch3appmfig13" class="figpopup">Utility of responder vs. non-responder at £20,000 threshold</a></p><p id="ch3.appm.fig14"><a href="/books/NBK577084/figure/ch3.appm.fig14/?report=objectonly" target="object" rid-ob="figobch3appmfig14" class="figpopup">Utility of responder vs. non-responder at £30,000 threshold</a></p><p id="ch3.appm.fig15"><a href="/books/NBK577084/figure/ch3.appm.fig15/?report=objectonly" target="object" rid-ob="figobch3appmfig15" class="figpopup">THC:CBD spray (Sativex) dose per day vs. % of resource use attributable to spasticity at £20,000 threshold</a></p><p id="ch3.appm.fig16"><a href="/books/NBK577084/figure/ch3.appm.fig16/?report=objectonly" target="object" rid-ob="figobch3appmfig16" class="figpopup">THC:CBD spray (Sativex) dose per day vs. % of resource use attributable to spasticity at £30,000 threshold</a></p></div></article><article data-type="fig" id="figobch3appmfig17"><div id="ch3.appm.fig17" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%2012.%20Threshold%20analysis%20on%20placebo%20response%20(fixed%20value%20for%20cannabis%20response).&p=BOOKS&id=577084_ch3appmf17.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appmf17.jpg" alt="Figure 12. Threshold analysis on placebo response (fixed value for cannabis response)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 12</span><span class="title">Threshold analysis on placebo response (fixed value for cannabis response)</span></h3></div></article><article data-type="fig" id="figobch3appmfig18"><div id="ch3.appm.fig18" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%2013.%20Threshold%20analysis%20on%20cannabis%20response%20(fixed%20value%20for%20placebo%20response).&p=BOOKS&id=577084_ch3appmf18.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appmf18.jpg" alt="Figure 13. Threshold analysis on cannabis response (fixed value for placebo response)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 13</span><span class="title">Threshold analysis on cannabis response (fixed value for placebo response)</span></h3></div></article><article data-type="fig" id="figobch3appmfig19"><div id="ch3.appm.fig19" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%2014.%20Threshold%20analysis%20on%20OR%20vs%20placebo.&p=BOOKS&id=577084_ch3appmf19.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appmf19.jpg" alt="Figure 14. Threshold analysis on OR vs placebo." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 14</span><span class="title">Threshold analysis on OR vs placebo</span></h3></div></article><article data-type="fig" id="figobch3appmfig20"><div id="ch3.appm.fig20" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%2015.%20Threshold%20analysis%20on%20THC%3A%20CBD%20spray%20pack%20cost.&p=BOOKS&id=577084_ch3appmf20.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appmf20.jpg" alt="Figure 15. Threshold analysis on THC: CBD spray pack cost." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 15</span><span class="title">Threshold analysis on THC: CBD spray pack cost</span></h3></div></article><article data-type="fig" id="figobch3appmfig21"><div id="ch3.appm.fig21" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%2016.%20Threshold%20analysis%20on%20proportion%20of%20management%20costs%20that%20are%20spasticity%20related.&p=BOOKS&id=577084_ch3appmf21.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK577084/bin/ch3appmf21.jpg" alt="Figure 16. Threshold analysis on proportion of management costs that are spasticity related." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 16</span><span class="title">Threshold analysis on proportion of management costs that are spasticity related</span></h3></div></article><article data-type="table-wrap" id="figobch3appntab1"><div id="ch3.appn.tab1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577084/table/ch3.appn.tab1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch3.appn.tab1_lrgtbl__"><table><thead><tr><th id="hd_h_ch3.appn.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Study</th></tr></thead><tbody><tr><td headers="hd_h_ch3.appn.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Ball, Susan, Vickery, Jane, Hobart, Jeremy et al. (2015) The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial: a randomised double-blind placebo-controlled parallel-group multicentre trial and economic evaluation of cannabinoids to slow progression in multiple sclerosis. Health technology assessment (Winchester, England) 19(12): vii–187</td></tr><tr><td headers="hd_h_ch3.appn.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Collin, C., Davies, P., Mutiboko, I. K. et al. (2007) Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. European journal of neurology 14(3): 290–6</td></tr><tr><td headers="hd_h_ch3.appn.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Collin, C., Ehler, E., Waberzinek, G. et al. (2010) A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurological research 32(5): 451–9</td></tr><tr><td headers="hd_h_ch3.appn.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Langford, R. M., Mares, J., Novotna, A. et al. (2013) A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis. Journal of neurology 260(4): 984–97</td></tr><tr><td headers="hd_h_ch3.appn.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Leocani, L., Nuara, A., Houdayer, E. et al. (2015) Sativex and clinical-neurophysiological measures of spasticity in progressive multiple sclerosis. Journal of neurology 262(11): 2520–2527</td></tr><tr><td headers="hd_h_ch3.appn.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Markova, Jolana, Essner, Ute, Akmaz, Bulent et al. (2018) Sativex as add-on therapy vs. further optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity: a double-blind, placebo-controlled randomised clinical trial. The International journal of neuroscience: 1–10</td></tr><tr><td headers="hd_h_ch3.appn.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Novotna, A., Mares, J., Ratcliffe, S. et al. (2011) A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. European journal of neurology 18(9): 1122–31</td></tr><tr><td headers="hd_h_ch3.appn.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Pooyania, Sepideh, Ethans, Karen, Szturm, Tony et al. (2010) A randomized, double-blinded, crossover pilot study assessing the effect of nabilone on spasticity in persons with spinal cord injury. Archives of physical medicine and rehabilitation 91(5): 703–7</td></tr><tr><td headers="hd_h_ch3.appn.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Riva, Nilo, Mora, Gabriele, Soraru, Gianni et al. (2018) Safety and efficacy of nabiximols on spasticity symptoms in patients with motor neuron disease (CANALS): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial. The Lancet. Neurology</td></tr><tr><td headers="hd_h_ch3.appn.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">van Amerongen, Guido, Kanhai, Kawita, Baakman, Anne Catrien et al. (2018) Effects on Spasticity and Neuropathic Pain of an Oral Formulation of DELTA9-tetrahydrocannabinol in Patients WithProgressive Multiple Sclerosis. Clinical therapeutics 40(9): 1467–1482</td></tr><tr><td headers="hd_h_ch3.appn.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Wade, Derick T., Makela, Petra, Robson, Philip et al. (2004) Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Multiple sclerosis (Houndmills, Basingstoke, England) 10(4): 434–41</td></tr><tr><td headers="hd_h_ch3.appn.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Wissel, Jorg, Haydn, Tanja, Muller, Jorg et al. (2006) Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain: a double-blind placebo-controlled cross-over trial. Journal of neurology 253(10): 1337–41</td></tr><tr><td headers="hd_h_ch3.appn.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Zajicek, J. P., Sanders, H. P., Wright, D. E. et al. (2005) Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. Journal of neurology, neurosurgery, and psychiatry 76(12): 1664–9</td></tr><tr><td headers="hd_h_ch3.appn.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Zajicek, John Peter, Hobart, Jeremy C., Slade, Anita et al. (2012) Multiple sclerosis and extract of cannabis: results of the MUSEC trial. Journal of neurology, neurosurgery, and psychiatry 83(11): 1125–32</td></tr><tr><td headers="hd_h_ch3.appn.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Zajicek, John, Fox, Patrick, Sanders, Hilary et al. (2003) Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet (London, England) 362(9395): 1517–26</td></tr></tbody></table></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript" src="/core/mathjax/2.7.9/MathJax.js?config=TeX-AMS-MML_SVG"> </script></div></div>
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