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id="_NBK577083_"><span itemprop="name">Evidence review for chronic pain</span></h1><div class="subtitle">Cannabis-based medicinal products</div><p><b>Evidence review B</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="ch2.s1"><h2 id="_ch2_s1_">Effectiveness of cannabis-based medicinal products for the treatment of chronic pain</h2><div id="ch2.s1.1"><h3>Introduction</h3><p>Chronic pain has recently been <a href="https://icd.who.int/en/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">defined by the ICD-11</a> as pain that persists or recurs for longer than 3 months. Chronic primary pain is defined as pain in one or more anatomical regions that persists or recurs for longer than 3 months and is associated with significant emotional distress or functional disability. Chronic secondary pain syndromes are linked to other diseases as the underlying cause, where pain becomes a problem in its own right. In practice, the division between acute and chronic pain can be difficult to establish. This is particularly true in children and young people, and the committee felt that the looser (non-temporal) term ‘persistent pain’ is more commonly used in this group.</p><p>According to the British Medical Association briefing paper <a href="https://www.bma.org.uk/collective-voice/policy-and-research/public-and-population-health/analgesics-use" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">chronic pain: supporting safer prescribing of analgesics</a>, chronic pain affects about 13% of adults in the UK, and about 8% of children experience severe pain. NICE has published a <a href="https://www.nice.org.uk/advice/ktt21" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">summary on the evidence base on medicines optimisation in chronic pain</a>. A NICE guideline on <a href="https://www.nice.org.uk/guidance/indevelopment/gid-ng10069" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">chronic pain: assessment and management</a> is in development. This guideline is intended to be used alongside existing NICE guidance for specific conditions that cause pain, including <a href="https://www.nice.org.uk/guidance/cg150" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">headaches</a>, <a href="https://www.nice.org.uk/guidance/ng59" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">low back pain and sciatica</a>, <a href="https://www.nice.org.uk/guidance/ng100" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rheumatoid arthritis</a>, <a href="https://www.nice.org.uk/guidance/indevelopment/gid-ng10127" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">osteoarthritis</a>, <a href="https://www.nice.org.uk/guidance/ng65" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">spondyloarthritis</a>, <a href="https://www.nice.org.uk/guidance/ng73" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">endometriosis</a> and <a href="https://www.nice.org.uk/guidance/cg61" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">irritable bowel syndrome</a>.</p><p>The aim of this review was to find out how effective cannabis-based medicinal products are in managing chronic pain, particularly when conventional treatment options have failed or not been tolerated. The review looked into the safety profile (including complications and contraindications) and examined what individual patient requirements, treatment durations, reviewing and stopping criteria need to be considered when prescribing cannabis-based medicinal products.</p></div><div id="ch2.s1.2"><h3>Review question</h3><p>What is the clinical and cost effectiveness of cannabis-based medicinal products for people with chronic pain?</p><p>This review question also answered the following as part of the evidence review:
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<ul id="ch2.l1"><li id="ch2.lt1" class="half_rhythm"><div>What is the clinical and cost effectiveness of cannabis-based medicinal products for people with chronic pain?</div></li><li id="ch2.lt2" class="half_rhythm"><div>What are the adverse effects or complications of cannabis-based medicinal products for people with chronic pain?</div></li><li id="ch2.lt3" class="half_rhythm"><div>What are the contraindications, potential interactions and risks and cautions for use of cannabis-based medicinal products for people with chronic pain?</div></li><li id="ch2.lt4" class="half_rhythm"><div>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 chronic pain?</div></li></ul></p><p>The review protocol for this review question is in <a href="#ch2.appa">Appendix A</a>. The PICO table below formed part of the search strategy to identify studies associated with chronic pain.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2tab1"><a href="/books/NBK577083/table/ch2.tab1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2tab1" rid-ob="figobch2tab1"><img class="small-thumb" src="/books/NBK577083/table/ch2.tab1/?report=thumb" src-large="/books/NBK577083/table/ch2.tab1/?report=previmg" alt="PICO table." /></a><div class="icnblk_cntnt"><h4 id="ch2.tab1"><a href="/books/NBK577083/table/ch2.tab1/?report=objectonly" target="object" rid-ob="figobch2tab1">Table</a></h4><p class="float-caption no_bottom_margin">PICO table. </p></div></div></div><div id="ch2.s1.3"><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 (2018)</a>. Methods specific to this review question are described in the review protocol in <a href="#ch2.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 in the treatment of intractable nausea and vomiting, chronic pain, spasticity and severe treatment-resistant epilepsy. The review protocol highlighted in <a class="figpopup" href="/books/NBK577083/table/ch2.appb.tab1/?report=objectonly" target="object" rid-figpopup="figch2appbtab1" rid-ob="figobch2appbtab1">Table 1</a> and <a href="#ch2.appa">Appendix A</a> was used to identify studies associated with chronic pain.</p><p>For the adult population, randomised controlled trials (RCTs) and systematic review of RCTs were considered. The review protocol also specified that in the event of fewer than 5 RCTs being identified, prospective cohort studies would also be considered for inclusion.</p><p>For children, RCTs and systematic review 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. This is because the committee highlighted that there may be fewer studies performed in children.</p><p>Additional information on safety concerns and contraindications were 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:
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<ul id="ch2.l6"><li id="ch2.lt25" class="half_rhythm"><div>Examined the use of synthetic cannabinoids in schedule 1 of the 2001 regulations,</div></li><li id="ch2.lt26" class="half_rhythm"><div>Examined the use of smoked cannabis-based products</div></li><li id="ch2.lt27" class="half_rhythm"><div>Did not clearly report the amount of cannabis-based constituents in the intervention</div></li></ul></p><p>The review protocol specified that where possible for adults, data would be stratified according to the ICD-11 definition of pain as primary or secondary pain. For primary pain, data was analysed according to whether it was chronic widespread pain, complex regional pain syndrome, chronic primary visceral pain or chronic primary musculoskeletal pain.</p><p>For secondary pain, the data was analysed according to whether it is chronic cancer-related pain, chronic postsurgical or posttraumatic pain, chronic neuropathic pain, chronic secondary visceral pain and chronic secondary musculoskeletal pain.</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>The committee agreed that the clinical outcome that matters most is mean change in pain intensity. This is widely used and easily understood. The next most important outcomes were the proportion of patients who experienced pain relief of 30% or 50% or more from baseline. These are also direct measurements of pain. However, the committee felt that they are less descriptive outcomes; information is lost when converting continuous data into dichotomous data.</p><p>The next most important outcome is functional impairment caused by pain. This is arguably a more useful measurement compared to pain intensity because it captures the effect that pain has on people’s lives. However, functional impairment caused by pain is not measured often and when measured, it is usually measured in an inconsistent way across studies. Therefore, average pain intensity is more useful for meta-analysing outcomes across studies compared to functional impairment caused by pain.</p><p>After these direct measurements of pain, the committee were most interested in opioid sparing with a view to reducing adverse events caused by opioids.</p><p>The next most important clinical outcomes are those which are influenced by pain but are also influenced by other factors that may be unrelated to pain, such as mood. These outcomes include Patient Global Impression of Change and measurements of quality of life.</p></div><div id="ch2.s1.4"><h3>Clinical evidence</h3><p>A total of 19,491 RCTs and systematic reviews were identified from the search. After removing duplicates, 9,341 references were screened on their titles and abstracts. 292 studies were obtained and reviewed against the inclusion criteria as described in the review protocol for chronic pain (<a href="#ch2.appa">Appendix A</a>). Overall, 20 RCTs (14 parallel and 6 crossover) were included (see <a href="#ch2.appe">Appendix E</a> for evidence tables). 272 references were excluded because they did not meet the eligibility criteria.</p><p>Because fewer than 5 RCTs were found for children, an additional search was conducted for observational studies. A total of 5,975 observational studies were identified from the search. After removing duplicates, 4,028 references were screened on their titles and abstracts. No studies were identified as being potentially relevant to chronic pain.</p><p>See <a href="#ch2.appe">Appendix E</a> for evidence tables and <a href="#ch2.appj">Appendix J</a> for excluded studies.</p><p>There were 20 RCTs, see <a class="figpopup" href="/books/NBK577083/table/ch2.appi.tab1/?report=objectonly" target="object" rid-figpopup="figch2appitab1" rid-ob="figobch2appitab1">table 2</a>, summary of included studies.</p><p>No studies were identified which included the following subgroups:
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<ul id="ch2.l7"><li id="ch2.lt28" class="half_rhythm"><div>Pregnant women and women who are breastfeeding People with hepatic or renal failure</div></li></ul></p><div id="ch2.s1.4.1"><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.</p><p>With regard to crossover studies, the committee identified 1 week as an adequate washout period. It should be noted that this could lead to symptoms of THC withdrawal, including heightened anxiety, which might obscure any potential analgesic effect of the study product.</p><p>See <a href="#ch2.appg">Appendix G</a> for full GRADE tables and <a href="#ch2.appf">Appendix F</a> for forest plots in situations where data have been meta-analysed.</p></div><div id="ch2.s1.4.2"><h4>Interventions</h4><p>Of the 20 studies included, 5 looked at treatment of cancer pain. The included studies looked at the following interventions:
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<ul id="ch2.l8"><li id="ch2.lt29" class="half_rhythm"><div>Oromucosal spray containing 2.7 mg THC and 2.5 mg CBD per 100 microlitre actuation. This is abbreviated in this document to THC:CBD spray.</div></li><li id="ch2.lt30" class="half_rhythm"><div>Oromucosal spray containing 2.7 mg THC only per 100 microlitre actuation</div></li></ul></p><p>Of the 20 studies included, 7 looked at treatment of neuropathic pain (including multiple sclerosis, peripheral neuropathic pain and neuropathic pain characterised by allodynia). The included studies looked at the following interventions:
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<ul id="ch2.l9"><li id="ch2.lt31" class="half_rhythm"><div>Oromucosal spray containing THC:CBD</div></li><li id="ch2.lt32" class="half_rhythm"><div>Oral delta-9-THC (dronabinol)</div></li></ul></p><p>Of the 20 studies included, 3 looked at treatment of musculoskeletal pain (including rheumatoid arthritis, cramps and spasticity). The included studies looked at the following interventions:
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<ul id="ch2.l10"><li id="ch2.lt33" class="half_rhythm"><div>Oromucosal spray containing THC:CBD</div></li><li id="ch2.lt34" class="half_rhythm"><div>Oral delta-9-THC (dronabinol)</div></li><li id="ch2.lt35" class="half_rhythm"><div>Oral nabilone</div></li></ul></p><p>Of the 20 studies included, 3 looked at treatment of visceral pain (including abdominal pain and oesophageal functional chest pain). The included studies looked at the following intervention:
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<ul id="ch2.l11"><li id="ch2.lt36" class="half_rhythm"><div>Oral delta-9-THC (dronabinol)</div></li></ul></p><p>Of the 20 studies included, 2 looked at treatment of widespread pain (fibromyalgia). The included studies looked at the following interventions:
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<ul id="ch2.l12"><li id="ch2.lt37" class="half_rhythm"><div>Oral nabilone</div></li><li id="ch2.lt38" class="half_rhythm"><div>Vaporised 22.4 mg THC and <1 mg CBD</div></li><li id="ch2.lt39" class="half_rhythm"><div>Vaporised 13.4 mg THC and 17.8 mg CBD</div></li><li id="ch2.lt40" class="half_rhythm"><div>Vaporised <1 mg THC and 18.4 mg CBD</div></li></ul></p></div><div id="ch2.s1.4.3"><h4>Summary of clinical studies included in the evidence review</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2tab2"><a href="/books/NBK577083/table/ch2.tab2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2tab2" rid-ob="figobch2tab2"><img class="small-thumb" src="/books/NBK577083/table/ch2.tab2/?report=thumb" src-large="/books/NBK577083/table/ch2.tab2/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.tab2"><a href="/books/NBK577083/table/ch2.tab2/?report=objectonly" target="object" rid-ob="figobch2tab2">Table</a></h4><p class="float-caption no_bottom_margin">
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Blake 2006
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Parallel RCT</p></div></div><p>See <a href="#ch2.appe">Appendix E</a> for evidence tables and <a href="#ch2.apph">Appendix H</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 the table below:</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2tab3"><a href="/books/NBK577083/table/ch2.tab3/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2tab3" rid-ob="figobch2tab3"><img class="small-thumb" src="/books/NBK577083/table/ch2.tab3/?report=thumb" src-large="/books/NBK577083/table/ch2.tab3/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.tab3"><a href="/books/NBK577083/table/ch2.tab3/?report=objectonly" target="object" rid-ob="figobch2tab3">Table</a></h4><p class="float-caption no_bottom_margin">Oromucosal spray 2.7 mg THC with 2.5 mg CBD per 100 microlitre actuation (n=5)</p></div></div></div></div><div id="ch2.s1.5"><h3>Economic evidence</h3><div id="ch2.s1.5.1"><h4>Included studies</h4><p>No economic studies were included in this review.</p></div><div id="ch2.s1.5.2"><h4>Excluded studies</h4><p>A global search conducted for this guideline returned 1,863 hits. 1 full paper was ordered for this review question and subsequently excluded. More detail is available in <a href="#ch2.appj">Appendix J</a>.</p></div><div id="ch2.s1.5.3"><h4>Summary of studies included in the economic evidence review</h4><p>No studies included.</p></div><div id="ch2.s1.5.4"><h4>Economic model</h4><p>A de novo economic model was developed to address this review question. The model considered the CBMPs + the Standard of Care (SoC) versus the SoC alone. Subgroup analyses were conducted for specific treatments and for specific types of chronic pain where data were available to do so.</p><p>The economic model was comprised of five health states in each arm; on treatment response (OTR), on treatment no response (OTNR), discontinued with response (DR), discontinued with no response (DNR) and dead. In the SoC arm the “on treatment” states were nominal only, simply reflecting different levels of change from baseline observed in the underpinning trials. The model was run in monthly cycles over a lifetime time horizon and costs and QALYs were discounted at 3.5% per year.</p><p>Patients were categorised into one of the health states after one model cycle by combining the distribution of pain at baseline with the continuous outcomes from the clinical review for this question. Patients with a >30% response were assumed to remain as responders until they discontinued or died. The model calculated costs and QALYs from the distribution of pain scores within each health state, with lower pain scores having higher QoL and lower background management costs. Costs and QALYs associated with adverse events were also included, along with the costs of downstream radiofrequency denervation for the low back pain subgroup.</p><p>For all treatment and condition specific subgroups the model produced ICERs far in excess of the usually accepted £20,000–£30,000/QALY range. This was principally due to the modest treatment effects and the high and ongoing cost of treatment with CBMPs. The model had a number of limitations including the lack of long term data on almost all parameters but no plausible variations in any of the model’s input parameters produced ICERs close to £20,000–£30,000/QALY.</p><p>Details of the <i>de novo</i> economic model developed for this review question are available in <a href="#ch2.appi">Appendix I</a>.</p></div></div><div id="ch2.s1.6"><h3>Summary of evidence</h3><p>The summary of evidence reflects the evidence on effectiveness of cannabis-based medicinal products. Evidence summarises are stratified by population and reflect evidence that was significant. Further information on adverse events is also provided. The format of the summary of evidence is explained in the methods in <a href="#ch2.appb">Appendix B</a>. Further information on adverse events is provided in <a href="#ch2.appi">Appendix I</a>.</p><div id="ch2.s1.6.1"><h4>THC:CBD spray vs placebo</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2tab4"><a href="/books/NBK577083/table/ch2.tab4/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2tab4" rid-ob="figobch2tab4"><img class="small-thumb" src="/books/NBK577083/table/ch2.tab4/?report=thumb" src-large="/books/NBK577083/table/ch2.tab4/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.tab4"><a href="/books/NBK577083/table/ch2.tab4/?report=objectonly" target="object" rid-ob="figobch2tab4">Table</a></h4></div></div><p>Commonly reported adverse events for THC:CBD spray included: dizziness, somnolence, nausea, vertigo and fatigue.</p><p>Further details of the quality assessments can be found <a href="#ch2.appg.s1">here in the GRADE tables</a>.</p><p>Subgroups were analysed and can been seen <a href="#ch2.appf.s1">here in the forest plots</a>.</p></div><div id="ch2.s1.6.2"><h4>Oral delta-9-THC (dronabinol), 7.5 to 16 mg per 24 hours vs placebo</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2tab5"><a href="/books/NBK577083/table/ch2.tab5/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2tab5" rid-ob="figobch2tab5"><img class="small-thumb" src="/books/NBK577083/table/ch2.tab5/?report=thumb" src-large="/books/NBK577083/table/ch2.tab5/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.tab5"><a href="/books/NBK577083/table/ch2.tab5/?report=objectonly" target="object" rid-ob="figobch2tab5">Table</a></h4></div></div><p>Commonly reported adverse events for oral delta-9-THC (dronabinol) included: dizziness, vertigo, fatigue, nausea and headache.</p><p>Further details of the quality assessments can be found <a href="#ch2.appg.s2">here in the GRADE tables</a>.</p><p>Subgroups were analysed and can been seen <a href="#ch2.appf.s2">here in the forest plots</a>.</p></div><div id="ch2.s1.6.3"><h4>Oral nabilone, 1 to 2 mg per 24 hours vs placebo</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2tab6"><a href="/books/NBK577083/table/ch2.tab6/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2tab6" rid-ob="figobch2tab6"><img class="small-thumb" src="/books/NBK577083/table/ch2.tab6/?report=thumb" src-large="/books/NBK577083/table/ch2.tab6/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.tab6"><a href="/books/NBK577083/table/ch2.tab6/?report=objectonly" target="object" rid-ob="figobch2tab6">Table</a></h4></div></div><p>Commonly reported adverse events for oral nabilone included: drowsiness, dry mouth, ataxia, confusion and headache.</p><p>Further details of the quality assessments can be found <a href="#ch2.appf.s3">here in the GRADE tables</a>.</p><p>Subgroups were analysed and can been seen <a href="#ch2.appf.s3">here in the forest plots</a>.</p></div><div id="ch2.s1.6.4"><h4>Oromucosal spray 2.7 mg THC only per 100 microlitre actuation, maximum 48 actuations per 24 hours vs placebo</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2tab7"><a href="/books/NBK577083/table/ch2.tab7/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2tab7" rid-ob="figobch2tab7"><img class="small-thumb" src="/books/NBK577083/table/ch2.tab7/?report=thumb" src-large="/books/NBK577083/table/ch2.tab7/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.tab7"><a href="/books/NBK577083/table/ch2.tab7/?report=objectonly" target="object" rid-ob="figobch2tab7">Table</a></h4></div></div><p>Commonly reported adverse events for THC spray included: somnolence, dizziness, nausea, vomiting and confusion.</p><p>Further details of the quality assessments can be found <a href="#ch2.appg.s4">here in the GRADE tables</a>.</p></div><div id="ch2.s1.6.5"><h4>Vaporised 13.4 mg THC and 17.8 mg CBD vs placebo</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2tab8"><a href="/books/NBK577083/table/ch2.tab8/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2tab8" rid-ob="figobch2tab8"><img class="small-thumb" src="/books/NBK577083/table/ch2.tab8/?report=thumb" src-large="/books/NBK577083/table/ch2.tab8/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.tab8"><a href="/books/NBK577083/table/ch2.tab8/?report=objectonly" target="object" rid-ob="figobch2tab8">Table</a></h4></div></div><p>Commonly reported adverse events for vaporised THC:CBD included: drug high, coughing, sore throat, bad taste and nausea.</p><p>Further details of the quality assessments can be found <a href="#ch2.appg.s6">here in the GRADE tables</a>.</p><p>See <a href="#ch2.appk">Appendix K</a> for further information on the research questions’ PICOs.</p></div></div><div id="ch2.s1.7"><h3>The committee’s discussion of the evidence</h3><div id="ch2.s1.7.1"><h4>Interpreting the evidence</h4><div id="ch2.s1.7.1.1"><h5>The outcomes that matter most</h5><p>Outcomes were discussed <i>a priori</i>. After reviewing the evidence, the opinion of the committee did not change. Outcomes that matter most are discussed in the <a href="#ch2.s1.3">Methods and process</a> section.</p></div><div id="ch2.s1.7.1.2"><h5>The quality of the evidence</h5><p>There was limited evidence of high quality. The main reason for this is that the maintenance dose duration is relatively short in most studies. The committee agreed that a maintenance dose duration of up to 6 weeks is unrealistic for assessing chronic pain treatments. Additionally, many studies did not provide details of methods for randomisation or blinding.</p><p>The majority of the RCTs are for CBD in combination with THC. There was only one RCT for THC alone and two for nabilone. There was no evidence for CBD alone and the preparation that had CBD with a small amount of THC (<1 mg) was poor quality.</p></div><div id="ch2.s1.7.1.3"><h5>Benefits and harms</h5><p>There is evidence to suggest that CBD reduces chronic pain: Nabilone reduced functional impairment caused by pain compared with placebo in a population of 33 participants who had fibromyalgia. THC reduced mean functional impairment caused by pain in a population of 96 participants who had cancer. However, where cannabis-based medicinal products reduced chronic pain, the benefit is small and economic analysis shows that this compares poorly with the high costs of the intervention (see below).</p><p>There was high quality evidence which could not differentiate reduction in pain intensity between dronabinol and placebo in a population of 389 participants who had multiple sclerosis, abdominal pain or cramps.</p><p>The data could not differentiate THC:CBD for functional pain, change in opioid dose or quality of life. However, the committee considered these are outcomes to be less important compared with mean pain intensity which could not be differentiated between THC:CBD and placebo.</p><p>With regard to research recommendation 1, people who have fibromyalgia or persistent treatment-resistant neuropathic pain are often prescribed high doses of analgesia over long periods of time. This can be associated with adverse events including nausea, drowsiness, mood disturbance and fatigue. It is hoped that CBD might have an opioid-sparing effect and therefore reduce the incidence of adverse events such as these. The committee noted that of this significant population with chronic pain, around 15% are referred for specialist pain management. They also noted that this population is usually on many medications, including opioids and treatments for neuropathic pain. In this population, it is unclear whether cannabis-based medicinal products could improve safety by reducing doses of other medicines. Therefore, a research recommendation was made. The committee defined standard treatment as WHO pain ladder step 3: opioids plus adjuvants. RCTs should have at least 6 months follow-up to reflect the chronic nature of these conditions.</p><p>With regard to research recommendation 2, there is currently no evidence that explores whether the addition of cannabis-based medicinal products as an adjunct to standard care improves the pain experience in children with rare conditions experiencing persistent pain symptoms, for example children with intractable cancer-related pain or chronic pain associated with specific diseases such as epidermolysis bullosa. The reason for the lack of research so far is probably because there are relatively few children with these conditions. In addition, opioids may not control pain effectively in these conditions and may cause adverse effects. Therefore, a research recommendation was made. The committee defined ‘intractable cancer-related pain’ as cancer-related pain that does not respond to multiple interventions including non- pharmacological and drug therapies sufficiently to enable a reasonable quality of life. The committee defined standard care in this context as tertiary specialist pain/palliative care management. An additional benefit from such research could be a reduction in resource use.</p><p>The committee felt that CBD has the potential to be cost effective for all these research populations if they could be robustly demonstrated to improve quality of life and reduce resource use associated with complex conditions requiring standard tertiary specialist pain/palliative care management. For example, if children and young people with chronic pain achieved benefits sufficient for them to be able to receive their care in an outpatient rather than an inpatient setting.</p><p>See <a href="#ch2.appk">Appendix K</a> for further information on the research questions’ PICOs.</p></div></div><div id="ch2.s1.7.2"><h4>Cost effectiveness and resource use</h4><p>No published health economic analyses met the inclusion criteria for this review, but this area was prioritised for de novo economic modelling because the potential eligible population, and therefore potential resource impact, were deemed to be large. The committee considered that outcomes measuring change in pain were the most important in the clinical review and thought it important that the economic model structure should be directly tied to these outcomes. The clinical review provided both continuous (11 studies) and dichotomous (4 studies) data. A continuous model structure was chosen because continuous outcome data were more plentiful, because the continuous data approximated the dichotomous data very well under the assumption that treatment response was normally distributed and because it allowed the model to tie pain to costs and quality of life in a more detailed way.</p><p>The intermediate results from the model showed that ~54% of people in the cannabis arm and ~46% of people in the placebo arm achieved a 30% reduction in pain from baseline, while ~31% and ~25% achieved a treatment response of 50% respectively, which was similar to data observed in the clinical trials. Following an initial period of some treatment discontinuation, mean pain scores across the cohorts in both model arms settled into a steady state somewhat lower than the baseline level. The committee noted that adverse events contributed relatively little in terms of costs or quality of life decrements and that there were some savings in pain management costs associated with the treatment effect. These savings were small in comparison to the costs of cannabis based medicinal products (CBMPs), however. Net avoidance of invasive long-term treatments in the cannabis arm also contributed a negligible amount to cost savings.</p><p>Using THC:CBD spray, which is the cheapest CBMP with a publicly available price, the model produced an incremental cost-effectiveness ratio (ICER) of over £150,000/QALY gained over the standard of care, a value far higher than the commonly accepted decision threshold of £20,000–£30,000/QALY gained. The committee concluded that this finding was not surprising as CBMPs are not expected to extend life or be fundamentally disease modifying, treatment effects relating to symptom alleviation are modest (about a 0.4 improvement in pain on a 0 to 10 scale on average) and the cost of the treatments is high.</p><p>The committee noted the limitations of the model, including that only short term data were available from RCTs, that there were no robust estimates of resource use associated with different pain scores, that data on some parameters were extrapolated from indirect sources, that there were no good data linking either cannabis or pain scores to the downstream treatments that had been included in the model and that good quality data were lacking in some subgroups. These limitations were explored in sensitivity analyses showing that even under extreme assumptions, the model never produced ICERs close to those normally considered cost-effective. Furthermore, the probabilistic sensitivity analysis showed a 0% probability that CBMPs are cost-effective – using NICE’s ‘threshold’ of £20,000 to £30,000 per QALY over which treatments are not likely to be recommended for use in the NHS.</p><p>Overall, the committee considered the economic model to be directly applicable with minor limitations for decision-making. They considered that the CBMPs that they had seen evidence for would have to be around 8 times more effective (accrue 1.22 QALYs compared with 0.162 QALY in the base case) or 6 times less expensive (or some equivalent combination) or associated with very significant pain management savings for the average patient to bring the ICER down to an acceptable level. The committee was aware that given the findings from the clinical evidence, the additional effectiveness is unrealistic. Given how unlikely it would be to observe changes of this scale they concluded that, at current prices, these CBMPs do not represent an effective use of resources in the management of chronic pain. They therefore decided to make a recommendation against their use in the specific populations that were considered in the evidence base for this review. They discussed gaps in the evidence and made a series of recommendations for research into the use of CBMPs in specialised settings. Poor quality evidence on CBD alone was included in this review and the committee were aware of anecdotal evidence that many people with chronic pain are accessing this outside the NHS and reporting benefit. They therefore thought it important to include this intervention in their recommendations for research. They also noted that, although the clinical review had found some evidence showing no difference in opiate use between cannabis and standard of care, the trials were too short in duration to be reliable. As a matter of theory, this outcome might importantly influence decisions to prescribe CBMPs and could also influence their cost-effectiveness in certain populations. They therefore highlighted this is an outcome of interest.</p><div id="ch2.box1" 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 1.2.1</a> to <a href="/books/n/niceng144/?report=reader" class="toc-item">1.2.3</a> and the research recommendations on fibromyalgia or persistent treatment-resistant neuropathic pain in adults and chronic pain in children and young people.</p></div></div></div></div><div id="ch2.s2"><h2 id="_ch2_s2_">Glossary</h2><div id="ch2.s2.1"><h3>Cannabis-based medicinal products</h3><p>In this guideline cannabis-based medicinal products include:
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<ul id="ch2.l13"><li id="ch2.lt41" 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="ch2.lt42" class="half_rhythm"><div>the licensed products delta-9-tetrahydrocannibinol and cannabidiol (Sativex) and nabilone</div></li><li id="ch2.lt43" class="half_rhythm"><div>plant-derived cannabinoids such as pure cannabidiol (CBD)</div></li><li id="ch2.lt44" 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="appendixesappgroup2"><h2 id="_appendixesappgroup2_">Appendices</h2><div id="ch2.appa"><h3>Appendix A. Review protocols</h3><div id="ch2.appa.s1"><h4>Review protocol for effectiveness of cannabis based medicinal products for people with chronic pain</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2appatab1"><a href="/books/NBK577083/table/ch2.appa.tab1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2appatab1" rid-ob="figobch2appatab1"><img class="small-thumb" src="/books/NBK577083/table/ch2.appa.tab1/?report=thumb" src-large="/books/NBK577083/table/ch2.appa.tab1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.appa.tab1"><a href="/books/NBK577083/table/ch2.appa.tab1/?report=objectonly" target="object" rid-ob="figobch2appatab1">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 chronic pain? What are the adverse effects or complications of cannabis-based medicinal products for people with chronic pain?</p></div></div></div></div><div id="ch2.appb"><h3>Appendix B. Methods</h3><div id="ch2.appb.s1"><h4>Priority screening</h4><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="ch2.appb.s2"><h4>Evidence synthesis and meta-analyses</h4><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.</p><p>Because most of the studies reported odds ratios which could not be converted to risk ratios, all dichotomous outcomes were reported as odds ratios for consistency. Due to the nature of the data reported in the studies, absolute risks could not be calculated for the outcomes.</p></div><div id="ch2.appb.s3"><h4>Evidence of effectiveness of interventions</h4><div id="ch2.appb.s3.1"><h5>Quality assessment</h5><p>Individual RCTs and quasi-randomised controlled trials were quality assessed using the Cochrane Risk of Bias Tool. Each individual study was classified into one of the following three groups:
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<ul id="ch2.l27"><li id="ch2.lt92" 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="ch2.lt93" class="half_rhythm"><div>Moderate 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="ch2.lt94" 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="ch2.l28"><li id="ch2.lt95" class="half_rhythm"><div>Direct – No important deviations from the protocol in population, intervention, comparator and/or outcomes.</div></li><li id="ch2.lt96" 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="ch2.lt97" 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="ch2.appb.s3.2"><h5>Methods for combining intervention evidence</h5><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>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 deemed to be inappropriate if one or both of the following conditions was met:
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<ul id="ch2.l29"><li id="ch2.lt98" class="half_rhythm"><div>Significant between study heterogeneity in methodology, population, intervention or comparator was identified by the reviewer in advance of data analysis. In analysis which included subgroups from more than 1 ICD classification of pain, random-effects were fitted to account for differences in populations.</div></li><li id="ch2.lt99" 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>Where data for multiple subgroups (i.e. different doses of medicinal cannabis) were combined, this was done in accordance to the advice given in the Cochrane Handbook for Systematic Reviews of Interventions.</p><p>Meta-analyses were performed in Cochrane Review Manager V5.3.</p><p>Numerical Rating Scale (NRS) is used to score pain intensity on a scale of 0 to 10. Visual Analog Scale (VAS) is used to score pain intensity on a scale of 0 to 100. The committee agreed that if a study only uses VAS, we should transform it to NRS by dividing the score by 10.</p><div id="ch2.appb.s3.2.1"><h5>Combining groups within studies</h5><p>When combining the arms of studies, we used Cochrane’s advice and formula for combining groups. In doing so, we assumed equal SD for the placebo and intervention arm.</p></div><div id="ch2.appb.s3.2.2"><h5>Minimal clinically important differences (MIDs)</h5><p>The guideline committee were asked to prospectively specify outcomes where they felt a consensus MID could be defined from their experience. The committee specified a key outcome is participant reported pain relief of 30% or greater. This is in line with the recommended measure of minimal important difference in pain intensity (IMMPACT 2005). For this measure, other dichotomous measures and measures of functional pain, the committee agreed that any statistically significant difference in outcomes would be of interest to them. Therefore, it was decided that the line of no effect was to be used as the MID (OR = 1 and mean or median difference = 0). For mean difference measures between arms reported on the visual analogue scale (VAS) or numerical rating scale (NRS), a clinically important difference of −0.8 was used. This is the same MID used by the Cochrane Pain, Palliative and Supportive Care Group (Mücke 2018) and similar to the median average MID for pain intensity reported in a systematic review of chronic pain intensity MIDs (Olsen 2018).</p><p>Therefore, a mean difference and confidence interval below −0.8 would show a clinical benefit to reduction in pain intensity in the treatment arm compared to the comparator.</p></div></div><div id="ch2.appb.s3.3"><h5>GRADE for pairwise meta-analyses of interventional evidence</h5><p>GRADE was used to assess the quality of evidence for the selected outcomes as specified 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 (2018)</a>’. 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/NBK577083/table/ch2.appb.tab1/?report=objectonly" target="object" rid-figpopup="figch2appbtab1" rid-ob="figobch2appbtab1">Table 1</a>.</p><p id="ch2.appb.tab1"><a href="/books/NBK577083/table/ch2.appb.tab1/?report=objectonly" target="object" rid-ob="figobch2appbtab1" 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="ch2.l30"><li id="ch2.lt100" 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="ch2.lt101" class="half_rhythm"><div>Data showing a dose-response gradient.</div></li><li id="ch2.lt102" 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="ch2.appb.s3.4"><h5>Summary of evidence</h5><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, 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></div><div id="ch2.appc"><h3>Appendix C. Literature search strategies</h3><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="ch2.l31"><li id="ch2.lt103" class="half_rhythm"><div>Medical Marijuana/</div></li><li id="ch2.lt104" class="half_rhythm"><div>cannabinoids/ or cannabidiol/ or cannabinol/ or cannabis/</div></li><li id="ch2.lt105" 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="ch2.lt106" class="half_rhythm"><div>(epidiolex* or cannabidiol* or cannabinoid*).tw.</div></li><li id="ch2.lt107" class="half_rhythm"><div>(sativex or THC:CBD spray or tetrabinex or nabidiolex).tw.</div></li><li id="ch2.lt108" class="half_rhythm"><div>(nabilone or cesamet).tw.</div></li><li id="ch2.lt109" class="half_rhythm"><div>(tilray* or bedrocan* or bedrobinol* or bedica* or bediol* or bedrolite*).tw.</div></li><li id="ch2.lt110" class="half_rhythm"><div>Dronabinol/</div></li><li id="ch2.lt111" class="half_rhythm"><div>(dronabinol* or marinol* or syndros*).tw.</div></li><li id="ch2.lt112" class="half_rhythm"><div>(9-ene-tetrahydrocannabinol* or 9enetetrahydrocannabinol*).tw.</div></li><li id="ch2.lt113" class="half_rhythm"><div>(THC or tetrahydrocannabinol*).tw.</div></li><li id="ch2.lt114" class="half_rhythm"><div>(“delta(1)-thc*” or “delta(1)-tetrahydrocannabinol*” or “delta(9)-thc*” or “delta(9)-tetrahydrocannabinol*”).tw.</div></li><li id="ch2.lt115" 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="ch2.lt116" 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="ch2.lt117" class="half_rhythm"><div>THCa.tw.</div></li><li id="ch2.lt118" class="half_rhythm"><div>CBDa.tw.</div></li><li id="ch2.lt119" class="half_rhythm"><div>cannabinol*.tw.</div></li><li id="ch2.lt120" class="half_rhythm"><div>cannabigerol*.tw.</div></li><li id="ch2.lt121" class="half_rhythm"><div>cannabichromene*.tw.</div></li><li id="ch2.lt122" class="half_rhythm"><div>(tetrahydrocannabivarin* or THCV).tw.</div></li><li id="ch2.lt123" class="half_rhythm"><div>(cannabidivarin* or CBDV).tw.</div></li><li id="ch2.lt124" class="half_rhythm"><div>or/1–21</div></li><li id="ch2.lt125" class="half_rhythm"><div>animals/ not humans/</div></li><li id="ch2.lt126" class="half_rhythm"><div>22 not 23</div></li><li id="ch2.lt127" class="half_rhythm"><div>limit 24 to english language</div></li><li id="ch2.lt128" class="half_rhythm"><div>Randomized Controlled Trial.pt.</div></li><li id="ch2.lt129" class="half_rhythm"><div>Controlled Clinical Trial.pt.</div></li><li id="ch2.lt130" class="half_rhythm"><div>Clinical Trial.pt.</div></li><li id="ch2.lt131" class="half_rhythm"><div>exp Clinical Trials as Topic/</div></li><li id="ch2.lt132" class="half_rhythm"><div>Placebos/</div></li><li id="ch2.lt133" class="half_rhythm"><div>Random Allocation/</div></li><li id="ch2.lt134" class="half_rhythm"><div>Double-Blind Method/</div></li><li id="ch2.lt135" class="half_rhythm"><div>Single-Blind Method/</div></li><li id="ch2.lt136" class="half_rhythm"><div>Cross-Over Studies/</div></li><li id="ch2.lt137" class="half_rhythm"><div>((random$ or control$ or clinical$) adj3 (trial$ or stud$)).tw.</div></li><li id="ch2.lt138" class="half_rhythm"><div>(random$ adj3 allocat$).tw.</div></li><li id="ch2.lt139" class="half_rhythm"><div>placebo$.tw.</div></li><li id="ch2.lt140" class="half_rhythm"><div>((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).tw.</div></li><li id="ch2.lt141" class="half_rhythm"><div>(crossover$ or (cross adj over$)).tw.</div></li><li id="ch2.lt142" class="half_rhythm"><div>or/20–33</div></li><li id="ch2.lt143" class="half_rhythm"><div>Meta-Analysis.pt.</div></li><li id="ch2.lt144" class="half_rhythm"><div>Network Meta-Analysis/</div></li><li id="ch2.lt145" class="half_rhythm"><div>Meta-Analysis as Topic/</div></li><li id="ch2.lt146" class="half_rhythm"><div>Review.pt.</div></li><li id="ch2.lt147" class="half_rhythm"><div>exp Review Literature as Topic/</div></li><li id="ch2.lt148" class="half_rhythm"><div>(metaanaly$ or metanaly$ or (meta adj3 analy$)).tw.</div></li><li id="ch2.lt149" class="half_rhythm"><div>(review$ or overview$).ti.</div></li><li id="ch2.lt150" class="half_rhythm"><div>(systematic$ adj5 (review$ or overview$)).tw.</div></li><li id="ch2.lt151" class="half_rhythm"><div>((quantitative$ or qualitative$) adj5 (review$ or overview$)).tw.</div></li><li id="ch2.lt152" class="half_rhythm"><div>((studies or trial$) adj2 (review$ or overview$)).tw.</div></li><li id="ch2.lt153" class="half_rhythm"><div>(integrat$ adj3 (research or review$ or literature)).tw.</div></li><li id="ch2.lt154" class="half_rhythm"><div>(pool$ adj2 (analy$ or data)).tw.</div></li><li id="ch2.lt155" class="half_rhythm"><div>(handsearch$ or (hand adj3 search$)).tw.</div></li><li id="ch2.lt156" class="half_rhythm"><div>(manual$ adj3 search$).tw.</div></li><li id="ch2.lt157" class="half_rhythm"><div>or/35–48</div></li><li id="ch2.lt158" class="half_rhythm"><div>34 or 49</div></li><li id="ch2.lt159" class="half_rhythm"><div>19 and 50</div></li><li id="ch2.lt160" class="half_rhythm"><div>Observational Studies as Topic/</div></li><li id="ch2.lt161" class="half_rhythm"><div>Observational Study/</div></li><li id="ch2.lt162" class="half_rhythm"><div>Epidemiologic Studies/</div></li><li id="ch2.lt163" class="half_rhythm"><div>exp Case-Control Studies/</div></li><li id="ch2.lt164" class="half_rhythm"><div>exp Cohort Studies/</div></li><li id="ch2.lt165" class="half_rhythm"><div>Cross-Sectional Studies/</div></li><li id="ch2.lt166" class="half_rhythm"><div>Controlled Before-After Studies/</div></li><li id="ch2.lt167" class="half_rhythm"><div>Historically Controlled Study/</div></li><li id="ch2.lt168" class="half_rhythm"><div>Interrupted Time Series Analysis/</div></li><li id="ch2.lt169" class="half_rhythm"><div>Comparative Study.pt.</div></li><li id="ch2.lt170" class="half_rhythm"><div>case control$.tw.</div></li><li id="ch2.lt171" class="half_rhythm"><div>case series.tw.</div></li><li id="ch2.lt172" class="half_rhythm"><div>(cohort adj (study or studies)).tw.</div></li><li id="ch2.lt173" class="half_rhythm"><div>cohort analy$.tw.</div></li><li id="ch2.lt174" class="half_rhythm"><div>(follow up adj (study or studies)).tw.</div></li><li id="ch2.lt175" class="half_rhythm"><div>(observational adj (study or studies)).tw.</div></li><li id="ch2.lt176" class="half_rhythm"><div>longitudinal.tw.</div></li><li id="ch2.lt177" class="half_rhythm"><div>prospective.tw.</div></li><li id="ch2.lt178" class="half_rhythm"><div>retrospective.tw.</div></li><li id="ch2.lt179" class="half_rhythm"><div>cross sectional.tw.</div></li><li id="ch2.lt180" class="half_rhythm"><div>or/26–45</div></li><li id="ch2.lt181" class="half_rhythm"><div>25 and 46</div></li><li id="ch2.lt182" 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
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<ol id="ch2.l32"><li id="ch2.lt183" class="half_rhythm"><div>Economics/</div></li><li id="ch2.lt184" class="half_rhythm"><div>exp “Costs and Cost Analysis”/</div></li><li id="ch2.lt185" class="half_rhythm"><div>Economics, Dental/</div></li><li id="ch2.lt186" class="half_rhythm"><div>exp Economics, Hospital/</div></li><li id="ch2.lt187" class="half_rhythm"><div>exp Economics, Medical/</div></li><li id="ch2.lt188" class="half_rhythm"><div>Economics, Nursing/</div></li><li id="ch2.lt189" class="half_rhythm"><div>Economics, Pharmaceutical/</div></li><li id="ch2.lt190" class="half_rhythm"><div>Budgets/</div></li><li id="ch2.lt191" class="half_rhythm"><div>exp Models, Economic/</div></li><li id="ch2.lt192" class="half_rhythm"><div>Markov Chains/</div></li><li id="ch2.lt193" class="half_rhythm"><div>Monte Carlo Method/</div></li><li id="ch2.lt194" class="half_rhythm"><div>Decision Trees/</div></li><li id="ch2.lt195" class="half_rhythm"><div>econom$.tw.</div></li><li id="ch2.lt196" class="half_rhythm"><div>cba.tw.</div></li><li id="ch2.lt197" class="half_rhythm"><div>cea.tw.</div></li><li id="ch2.lt198" class="half_rhythm"><div>cua.tw.</div></li><li id="ch2.lt199" class="half_rhythm"><div>markov$.tw.</div></li><li id="ch2.lt200" class="half_rhythm"><div>(monte adj carlo).tw.</div></li><li id="ch2.lt201" class="half_rhythm"><div>(decision adj3 (tree$ or analys$)).tw.</div></li><li id="ch2.lt202" class="half_rhythm"><div>(cost or costs or costing$ or costly or costed).tw.</div></li><li id="ch2.lt203" class="half_rhythm"><div>(price$ or pricing$).tw.</div></li><li id="ch2.lt204" class="half_rhythm"><div>budget$.tw.</div></li><li id="ch2.lt205" class="half_rhythm"><div>expenditure$.tw.</div></li><li id="ch2.lt206" class="half_rhythm"><div>(value adj3 (money or monetary)).tw.</div></li><li id="ch2.lt207" class="half_rhythm"><div>(pharmacoeconomic$ or (pharmaco adj economic$)).tw.</div></li><li id="ch2.lt208" class="half_rhythm"><div>or/1–25</div></li></ol></p><p>Quality of Life
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<ol id="ch2.l33"><li id="ch2.lt209" class="half_rhythm"><div>“Quality of Life”/</div></li><li id="ch2.lt210" class="half_rhythm"><div>quality of life.tw.</div></li><li id="ch2.lt211" class="half_rhythm"><div>“Value of Life”/</div></li><li id="ch2.lt212" class="half_rhythm"><div>Quality-Adjusted Life Years/</div></li><li id="ch2.lt213" class="half_rhythm"><div>quality adjusted life.tw.</div></li><li id="ch2.lt214" class="half_rhythm"><div>(qaly$ or qald$ or qale$ or qtime$).tw.</div></li><li id="ch2.lt215" class="half_rhythm"><div>disability adjusted life.tw.</div></li><li id="ch2.lt216" class="half_rhythm"><div>daly$.tw.</div></li><li id="ch2.lt217" class="half_rhythm"><div>Health Status Indicators/</div></li><li id="ch2.lt218" 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="ch2.lt219" 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="ch2.lt220" 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="ch2.lt221" 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="ch2.lt222" 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="ch2.lt223" class="half_rhythm"><div>(euroqol or euro qol or eq5d or eq 5d).tw.</div></li><li id="ch2.lt224" class="half_rhythm"><div>(qol or hql or hqol or hrqol).tw.</div></li><li id="ch2.lt225" class="half_rhythm"><div>(hye or hyes).tw.</div></li><li id="ch2.lt226" class="half_rhythm"><div>health$ year$ equivalent$.tw.</div></li><li id="ch2.lt227" class="half_rhythm"><div>utilit$.tw.</div></li><li id="ch2.lt228" class="half_rhythm"><div>(hui or hui1 or hui2 or hui3).tw.</div></li><li id="ch2.lt229" class="half_rhythm"><div>disutili$.tw.</div></li><li id="ch2.lt230" class="half_rhythm"><div>rosser.tw.</div></li><li id="ch2.lt231" class="half_rhythm"><div>quality of wellbeing.tw.</div></li><li id="ch2.lt232" class="half_rhythm"><div>quality of well-being.tw.</div></li><li id="ch2.lt233" class="half_rhythm"><div>qwb.tw.</div></li><li id="ch2.lt234" class="half_rhythm"><div>willingness to pay.tw.</div></li><li id="ch2.lt235" class="half_rhythm"><div>standard gamble$.tw.</div></li><li id="ch2.lt236" class="half_rhythm"><div>time trade off.tw.</div></li><li id="ch2.lt237" class="half_rhythm"><div>time tradeoff.tw.</div></li><li id="ch2.lt238" class="half_rhythm"><div>tto.tw.</div></li><li id="ch2.lt239" class="half_rhythm"><div>or/1–30</div></li></ol></p><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="ch2.l34" class="simple-list"><li id="ch2.lt240" class="half_rhythm"><div>Sativex</div></li><li id="ch2.lt241" class="half_rhythm"><div>Dronabinol</div></li><li id="ch2.lt242" class="half_rhythm"><div>Epidiolex</div></li><li id="ch2.lt243" class="half_rhythm"><div>THC:CBD spray</div></li><li id="ch2.lt244" class="half_rhythm"><div>Abalone</div></li><li id="ch2.lt245" class="half_rhythm"><div>Tetrabinex</div></li><li id="ch2.lt246" class="half_rhythm"><div>Nabidiolex</div></li><li id="ch2.lt247" class="half_rhythm"><div>Cesamet</div></li><li id="ch2.lt248" class="half_rhythm"><div>Tilray</div></li><li id="ch2.lt249" class="half_rhythm"><div>Bedrocan</div></li><li id="ch2.lt250" class="half_rhythm"><div>Bedrobinol</div></li><li id="ch2.lt251" class="half_rhythm"><div>Bedica</div></li><li id="ch2.lt252" class="half_rhythm"><div>Bediol</div></li><li id="ch2.lt253" class="half_rhythm"><div>Bedrolite</div></li><li id="ch2.lt254" class="half_rhythm"><div>Marinol</div></li><li id="ch2.lt255" class="half_rhythm"><div>Syndros</div></li><li id="ch2.lt256" class="half_rhythm"><div>THC</div></li><li id="ch2.lt257" class="half_rhythm"><div>Tetrahydrocannabinol</div></li><li id="ch2.lt258" class="half_rhythm"><div>Cannabinol</div></li><li id="ch2.lt259" class="half_rhythm"><div>Cannibigerol</div></li><li id="ch2.lt260" class="half_rhythm"><div>Cannabichromene</div></li><li id="ch2.lt261" class="half_rhythm"><div>Tetrahydrocannabivarin</div></li><li id="ch2.lt262" class="half_rhythm"><div>Cannabidivarin</div></li></ul><p>Quality of Life
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<ol id="ch2.l35"><li id="ch2.lt263" class="half_rhythm"><div>“Quality of Life”/</div></li><li id="ch2.lt264" class="half_rhythm"><div>quality of life.tw.</div></li><li id="ch2.lt265" class="half_rhythm"><div>“Value of Life”/</div></li><li id="ch2.lt266" class="half_rhythm"><div>Quality-Adjusted Life Years/</div></li><li id="ch2.lt267" class="half_rhythm"><div>quality adjusted life.tw.</div></li><li id="ch2.lt268" class="half_rhythm"><div>(qaly$ or qald$ or qale$ or qtime$).tw.</div></li><li id="ch2.lt269" class="half_rhythm"><div>disability adjusted life.tw.</div></li><li id="ch2.lt270" class="half_rhythm"><div>daly$.tw.</div></li><li id="ch2.lt271" class="half_rhythm"><div>Health Status Indicators/ (22343)</div></li><li id="ch2.lt272" 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="ch2.lt273" 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="ch2.lt274" 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="ch2.lt275" 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="ch2.lt276" 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="ch2.lt277" class="half_rhythm"><div>(euroqol or euro qol or eq5d or eq 5d).tw.</div></li><li id="ch2.lt278" class="half_rhythm"><div>(qol or hql or hqol or hrqol).tw.</div></li><li id="ch2.lt279" class="half_rhythm"><div>(hye or hyes).tw.</div></li><li id="ch2.lt280" class="half_rhythm"><div>health$ year$ equivalent$.tw.</div></li><li id="ch2.lt281" class="half_rhythm"><div>utilit$.tw.</div></li><li id="ch2.lt282" class="half_rhythm"><div>(hui or hui1 or hui2 or hui3).tw.</div></li><li id="ch2.lt283" class="half_rhythm"><div>disutili$.tw.</div></li><li id="ch2.lt284" class="half_rhythm"><div>rosser.tw.</div></li><li id="ch2.lt285" class="half_rhythm"><div>quality of wellbeing.tw.</div></li><li id="ch2.lt286" class="half_rhythm"><div>quality of well-being.tw.</div></li><li id="ch2.lt287" class="half_rhythm"><div>qwb.tw.</div></li><li id="ch2.lt288" class="half_rhythm"><div>willingness to pay.tw.</div></li><li id="ch2.lt289" class="half_rhythm"><div>standard gamble$.tw.</div></li><li id="ch2.lt290" class="half_rhythm"><div>time trade off.tw.</div></li><li id="ch2.lt291" class="half_rhythm"><div>time tradeoff.tw.</div></li><li id="ch2.lt292" class="half_rhythm"><div>tto.tw.</div></li><li id="ch2.lt293" class="half_rhythm"><div>or/1–30</div></li></ol></p><div id="ch2.appc.s1"><h4>MHRA search</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2appctab1"><a href="/books/NBK577083/table/ch2.appc.tab1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2appctab1" rid-ob="figobch2appctab1"><img class="small-thumb" src="/books/NBK577083/table/ch2.appc.tab1/?report=thumb" src-large="/books/NBK577083/table/ch2.appc.tab1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.appc.tab1"><a href="/books/NBK577083/table/ch2.appc.tab1/?report=objectonly" target="object" rid-ob="figobch2appctab1">Table</a></h4><p class="float-caption no_bottom_margin">Alerts and recalls for drugs and medical devices Drug safety update</p></div></div></div><div id="ch2.appc.s2"><h4>Search history – observational studies</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2appctab2"><a href="/books/NBK577083/table/ch2.appc.tab2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2appctab2" rid-ob="figobch2appctab2"><img class="small-thumb" src="/books/NBK577083/table/ch2.appc.tab2/?report=thumb" src-large="/books/NBK577083/table/ch2.appc.tab2/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.appc.tab2"><a href="/books/NBK577083/table/ch2.appc.tab2/?report=objectonly" target="object" rid-ob="figobch2appctab2">Table</a></h4></div></div></div><div id="ch2.appc.s3"><h4>Search history – observational studies: Medline search</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2appctab3"><a href="/books/NBK577083/table/ch2.appc.tab3/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2appctab3" rid-ob="figobch2appctab3"><img class="small-thumb" src="/books/NBK577083/table/ch2.appc.tab3/?report=thumb" src-large="/books/NBK577083/table/ch2.appc.tab3/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.appc.tab3"><a href="/books/NBK577083/table/ch2.appc.tab3/?report=objectonly" target="object" rid-ob="figobch2appctab3">Table</a></h4></div></div></div></div><div id="ch2.appd"><h3>Appendix D. Clinical evidence study selection</h3><div id="ch2.appd.s1"><h4>RCTs and systematic reviews of RCTs search</h4><div id="ch2.appd.fig1" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appdf1&p=BOOKS&id=577083_ch2appdf1.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/NBK577083/bin/ch2appdf1.jpg" alt="Image ch2appdf1" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch2.appd.s2"><h4>Observational studies search for children</h4><div id="ch2.appd.fig2" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appdf2&p=BOOKS&id=577083_ch2appdf2.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/NBK577083/bin/ch2appdf2.jpg" alt="Image ch2appdf2" class="tileshop" title="Click on image to zoom" /></a></div></div></div></div><div id="ch2.appe"><h3>Appendix E. Clinical evidence table</h3><div id="ch2.appe.s1"><h4>E.1. Parallel RCTs</h4><p id="ch2.appe.et1"><a href="/books/NBK577083/bin/ch2-appe-et1.pdf" class="bk_dwnld_icn bk_dwnld_pdf">Download PDF</a><span class="small"> (1.6M)</span></p></div><div id="ch2.appe.s2"><h4>E.2. Crossover RCTs</h4><p id="ch2.appe.et2"><a href="/books/NBK577083/bin/ch2-appe-et2.pdf" class="bk_dwnld_icn bk_dwnld_pdf">Download PDF</a><span class="small"> (1.4M)</span></p></div></div><div id="ch2.appf"><h3>Appendix F. Forest plots</h3><div id="ch2.appf.s1"><h4>THC:CBD spray vs placebo</h4><div id="ch2.appf.s1.1"><h5>Proportion of people who experienced pain relief of 30% or more from baseline</h5><div id="ch2.appf.fig1" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff1&p=BOOKS&id=577083_ch2appff1.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/NBK577083/bin/ch2appff1.jpg" alt="Image ch2appff1" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch2.appf.s1.2"><h5>Proportion of people who experienced pain relief of 50% or more from baseline</h5><div id="ch2.appf.fig2" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff2&p=BOOKS&id=577083_ch2appff2.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/NBK577083/bin/ch2appff2.jpg" alt="Image ch2appff2" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch2.appf.s1.3"><h5>Mean average pain intensity: Numerical Rating Scale (0 to 10) or Visual Analogue Scale (0 to 100)/10 converted to NRS</h5><div id="ch2.appf.fig3" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff3&p=BOOKS&id=577083_ch2appff3.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/NBK577083/bin/ch2appff3.jpg" alt="Image ch2appff3" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch2.appf.s1.4"><h5>Functional impairment caused by pain: Brief Pain Inventory - Short Form</h5><div id="ch2.appf.fig4" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff4&p=BOOKS&id=577083_ch2appff4.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/NBK577083/bin/ch2appff4.jpg" alt="Image ch2appff4" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch2.appf.s1.5"><h5>Change in analgesics: daily change in total dose, morphine equivalents</h5><div id="ch2.appf.fig5" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff5&p=BOOKS&id=577083_ch2appff5.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/NBK577083/bin/ch2appff5.jpg" alt="Image ch2appff5" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch2.appf.s1.6"><h5>Change in analgesics: daily change in breakthrough dose, morphine equivalents</h5><div id="ch2.appf.fig6" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff6&p=BOOKS&id=577083_ch2appff6.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/NBK577083/bin/ch2appff6.jpg" alt="Image ch2appff6" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch2.appf.s1.7"><h5>Change in analgesics: daily change in breakthrough dose, morphine equivalents</h5><div id="ch2.appf.fig7" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff7&p=BOOKS&id=577083_ch2appff7.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/NBK577083/bin/ch2appff7.jpg" alt="Image ch2appff7" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch2.appf.s1.8"><h5>Patient Global Impression of Change (dichotomous)</h5><div id="ch2.appf.fig8" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff8&p=BOOKS&id=577083_ch2appff8.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/NBK577083/bin/ch2appff8.jpg" alt="Image ch2appff8" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch2.appf.s1.9"><h5>Patient Global Impression of Change (continuous)</h5><div id="ch2.appf.fig9" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff9&p=BOOKS&id=577083_ch2appff9.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/NBK577083/bin/ch2appff9.jpg" alt="Image ch2appff9" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch2.appf.s1.10"><h5>Quality of life: EQ-5D index</h5><div id="ch2.appf.fig10" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff10&p=BOOKS&id=577083_ch2appff10.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/NBK577083/bin/ch2appff10.jpg" alt="Image ch2appff10" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch2.appf.s1.11"><h5>People experiencing adverse events, all-causality</h5><div id="ch2.appf.fig11" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff11&p=BOOKS&id=577083_ch2appff11.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/NBK577083/bin/ch2appff11.jpg" alt="Image ch2appff11" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch2.appf.s1.12"><h5>People experiencing serious adverse events, all-causality</h5><div id="ch2.appf.fig12" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff12&p=BOOKS&id=577083_ch2appff12.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/NBK577083/bin/ch2appff12.jpg" alt="Image ch2appff12" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch2.appf.s1.13"><h5>People experiencing serious adverse events, treatment-related</h5><div id="ch2.appf.fig13" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff13&p=BOOKS&id=577083_ch2appff13.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/NBK577083/bin/ch2appff13.jpg" alt="Image ch2appff13" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch2.appf.s1.14"><h5>Withdrawals due to adverse events, all-causality</h5><div id="ch2.appf.fig14" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff14&p=BOOKS&id=577083_ch2appff14.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/NBK577083/bin/ch2appff14.jpg" alt="Image ch2appff14" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch2.appf.s1.15"><h5>Adverse events: psychosis, such as hallucinations, delusions, confused and disturbed thoughts, or lack of insight and self-awareness</h5><div id="ch2.appf.fig15" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff15&p=BOOKS&id=577083_ch2appff15.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/NBK577083/bin/ch2appff15.jpg" alt="Image ch2appff15" class="tileshop" title="Click on image to zoom" /></a></div></div></div></div><div id="ch2.appf.s2"><h4>Oral delta-9-THC (dronabinol), 7.5 to 16 mg per 24 hours vs placebo</h4><div id="ch2.appf.s2.1"><h5>Mean average pain intensity: Numerical Rating Scale’ (0 to 10) or Visual Analogue Scale (0 to 100)/10 converted to NRS</h5><div id="ch2.appf.fig16" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff16&p=BOOKS&id=577083_ch2appff16.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/NBK577083/bin/ch2appff16.jpg" alt="Image ch2appff16" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch2.appf.s2.2"><h5>People experiencing adverse events, all-causality</h5><div id="ch2.appf.fig17" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff17&p=BOOKS&id=577083_ch2appff17.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/NBK577083/bin/ch2appff17.jpg" alt="Image ch2appff17" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch2.appf.s2.3"><h5>People experiencing serious adverse events, all-causality</h5><div id="ch2.appf.fig18" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff18&p=BOOKS&id=577083_ch2appff18.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/NBK577083/bin/ch2appff18.jpg" alt="Image ch2appff18" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch2.appf.s2.4"><h5>Withdrawals due to adverse events, all-causality</h5><div id="ch2.appf.fig19" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff19&p=BOOKS&id=577083_ch2appff19.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/NBK577083/bin/ch2appff19.jpg" alt="Image ch2appff19" class="tileshop" title="Click on image to zoom" /></a></div></div></div></div><div id="ch2.appf.s3"><h4>Oral nabilone, 1 to 2 mg per 24 hours vs placebo</h4><div id="ch2.appf.s3.1"><h5>People experiencing adverse events, all-causality</h5><div id="ch2.appf.fig20" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff20&p=BOOKS&id=577083_ch2appff20.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/NBK577083/bin/ch2appff20.jpg" alt="Image ch2appff20" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div id="ch2.appf.s3.2"><h5>Withdrawals due to adverse events, all-causality</h5><div id="ch2.appf.fig21" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff21&p=BOOKS&id=577083_ch2appff21.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/NBK577083/bin/ch2appff21.jpg" alt="Image ch2appff21" class="tileshop" title="Click on image to zoom" /></a></div></div></div></div></div><div id="ch2.appg"><h3>Appendix G. GRADE tables</h3><div id="ch2.appg.s1"><h4>THC:CBD spray vs placebo</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2appgtab1"><a href="/books/NBK577083/table/ch2.appg.tab1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2appgtab1" rid-ob="figobch2appgtab1"><img class="small-thumb" src="/books/NBK577083/table/ch2.appg.tab1/?report=thumb" src-large="/books/NBK577083/table/ch2.appg.tab1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.appg.tab1"><a href="/books/NBK577083/table/ch2.appg.tab1/?report=objectonly" target="object" rid-ob="figobch2appgtab1">Table</a></h4></div></div></div><div id="ch2.appg.s2"><h4>Oral delta-9-THC (dronabinol), 7.5 to 16 mg per 24 hours vs placebo</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2appgtab2"><a href="/books/NBK577083/table/ch2.appg.tab2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2appgtab2" rid-ob="figobch2appgtab2"><img class="small-thumb" src="/books/NBK577083/table/ch2.appg.tab2/?report=thumb" src-large="/books/NBK577083/table/ch2.appg.tab2/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.appg.tab2"><a href="/books/NBK577083/table/ch2.appg.tab2/?report=objectonly" target="object" rid-ob="figobch2appgtab2">Table</a></h4></div></div></div><div id="ch2.appg.s3"><h4>Oral nabilone 1 to 2 mg per 24 hours vs placebo</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2appgtab3"><a href="/books/NBK577083/table/ch2.appg.tab3/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2appgtab3" rid-ob="figobch2appgtab3"><img class="small-thumb" src="/books/NBK577083/table/ch2.appg.tab3/?report=thumb" src-large="/books/NBK577083/table/ch2.appg.tab3/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.appg.tab3"><a href="/books/NBK577083/table/ch2.appg.tab3/?report=objectonly" target="object" rid-ob="figobch2appgtab3">Table</a></h4></div></div></div><div id="ch2.appg.s4"><h4>Oromucosal spray 2.7 mg THC only per 100 microlitre actuation, maximum 48 actuations per 24 hours vs placebo</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2appgtab4"><a href="/books/NBK577083/table/ch2.appg.tab4/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2appgtab4" rid-ob="figobch2appgtab4"><img class="small-thumb" src="/books/NBK577083/table/ch2.appg.tab4/?report=thumb" src-large="/books/NBK577083/table/ch2.appg.tab4/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.appg.tab4"><a href="/books/NBK577083/table/ch2.appg.tab4/?report=objectonly" target="object" rid-ob="figobch2appgtab4">Table</a></h4></div></div></div><div id="ch2.appg.s5"><h4>Vaporised 22.4 mg THC and <1 mg CBD vs placebo</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2appgtab5"><a href="/books/NBK577083/table/ch2.appg.tab5/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2appgtab5" rid-ob="figobch2appgtab5"><img class="small-thumb" src="/books/NBK577083/table/ch2.appg.tab5/?report=thumb" src-large="/books/NBK577083/table/ch2.appg.tab5/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.appg.tab5"><a href="/books/NBK577083/table/ch2.appg.tab5/?report=objectonly" target="object" rid-ob="figobch2appgtab5">Table</a></h4></div></div></div><div id="ch2.appg.s6"><h4>Vaporised 13.4 mg THC and 17.8 mg CBD vs placebo</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2appgtab6"><a href="/books/NBK577083/table/ch2.appg.tab6/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2appgtab6" rid-ob="figobch2appgtab6"><img class="small-thumb" src="/books/NBK577083/table/ch2.appg.tab6/?report=thumb" src-large="/books/NBK577083/table/ch2.appg.tab6/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.appg.tab6"><a href="/books/NBK577083/table/ch2.appg.tab6/?report=objectonly" target="object" rid-ob="figobch2appgtab6">Table</a></h4></div></div></div><div id="ch2.appg.s7"><h4>Vaporised <1 mg THC and 18.4 mg CBD vs placebo</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2appgtab7"><a href="/books/NBK577083/table/ch2.appg.tab7/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2appgtab7" rid-ob="figobch2appgtab7"><img class="small-thumb" src="/books/NBK577083/table/ch2.appg.tab7/?report=thumb" src-large="/books/NBK577083/table/ch2.appg.tab7/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.appg.tab7"><a href="/books/NBK577083/table/ch2.appg.tab7/?report=objectonly" target="object" rid-ob="figobch2appgtab7">Table</a></h4></div></div></div></div><div id="ch2.apph"><h3>Appendix H. Adverse events</h3><div id="ch2.apph.s1"><h4>THC:CBD spray vs placebo</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2apphtab1"><a href="/books/NBK577083/table/ch2.apph.tab1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2apphtab1" rid-ob="figobch2apphtab1"><img class="small-thumb" src="/books/NBK577083/table/ch2.apph.tab1/?report=thumb" src-large="/books/NBK577083/table/ch2.apph.tab1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.apph.tab1"><a href="/books/NBK577083/table/ch2.apph.tab1/?report=objectonly" target="object" rid-ob="figobch2apphtab1">Table</a></h4><p class="float-caption no_bottom_margin">Phase A (standard parallel RCT) Treatment-related: all severities</p></div></div></div><div id="ch2.apph.s2"><h4>Oral delta-9-THC (dronabinol), 7.5 to 16 mg per 24 hours vs placebo</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2apphtab2"><a href="/books/NBK577083/table/ch2.apph.tab2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2apphtab2" rid-ob="figobch2apphtab2"><img class="small-thumb" src="/books/NBK577083/table/ch2.apph.tab2/?report=thumb" src-large="/books/NBK577083/table/ch2.apph.tab2/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.apph.tab2"><a href="/books/NBK577083/table/ch2.apph.tab2/?report=objectonly" target="object" rid-ob="figobch2apphtab2">Table</a></h4><p class="float-caption no_bottom_margin">All-causality in ≥5% of patients Delta-9-THC (124 patients in the arm): dizziness (25), vertigo (14), fatigue (10), dry mouth (9), adverse drug reaction (8), nausea (6), headache (5), diarrhoea (3), withdrawal syndrome (0), neuralgia (0), insomnia <a href="/books/NBK577083/table/ch2.apph.tab2/?report=objectonly" target="object" rid-ob="figobch2apphtab2">(more...)</a></p></div></div></div><div id="ch2.apph.s3"><h4>Oral nabilone (1 to 2 mg per 24 hours vs placebo)</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2apphtab3"><a href="/books/NBK577083/table/ch2.apph.tab3/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2apphtab3" rid-ob="figobch2apphtab3"><img class="small-thumb" src="/books/NBK577083/table/ch2.apph.tab3/?report=thumb" src-large="/books/NBK577083/table/ch2.apph.tab3/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.apph.tab3"><a href="/books/NBK577083/table/ch2.apph.tab3/?report=objectonly" target="object" rid-ob="figobch2apphtab3">Table</a></h4><p class="float-caption no_bottom_margin">All-causality Nabilone (13 patients in the arm): one moderate transient weakness of the lower limbs (1), mild drowsiness (2), acute relapse of multiple sclerosis (1)</p></div></div></div><div id="ch2.apph.s4"><h4>Oromucosal spray THC only per 100 microlitre actuation, maximum 48 actuations per 24 hours vs placebo</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2apphtab4"><a href="/books/NBK577083/table/ch2.apph.tab4/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2apphtab4" rid-ob="figobch2apphtab4"><img class="small-thumb" src="/books/NBK577083/table/ch2.apph.tab4/?report=thumb" src-large="/books/NBK577083/table/ch2.apph.tab4/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.apph.tab4"><a href="/books/NBK577083/table/ch2.apph.tab4/?report=objectonly" target="object" rid-ob="figobch2apphtab4">Table</a></h4><p class="float-caption no_bottom_margin">Treatment-related reported by ≥3 patients THC (58 patients in the arm): somnolence (8), dizziness (7), confusion (1), nausea (4), vomiting (4), raised gamma GT (5), hypercalcaemia (0), hypotension (0).</p></div></div></div><div id="ch2.apph.s5"><h4>Vaporised 22.4 mg THC and <1 mg CBD vs placebo</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2apphtab5"><a href="/books/NBK577083/table/ch2.apph.tab5/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2apphtab5" rid-ob="figobch2apphtab5"><img class="small-thumb" src="/books/NBK577083/table/ch2.apph.tab5/?report=thumb" src-large="/books/NBK577083/table/ch2.apph.tab5/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.apph.tab5"><a href="/books/NBK577083/table/ch2.apph.tab5/?report=objectonly" target="object" rid-ob="figobch2apphtab5">Table</a></h4><p class="float-caption no_bottom_margin">All-causality THC and CBD (20 patients in the arm): Drug high (16), coughing (14), sore throat (2), bad taste (5), dyspnoea (0), dizzy (3), headache (1), nausea (3), vomiting (0), sleepy (1)</p></div></div></div><div id="ch2.apph.s6"><h4>Vaporised 13.4 mg THC and 17.8 mg CBD vs placebo</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2apphtab6"><a href="/books/NBK577083/table/ch2.apph.tab6/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2apphtab6" rid-ob="figobch2apphtab6"><img class="small-thumb" src="/books/NBK577083/table/ch2.apph.tab6/?report=thumb" src-large="/books/NBK577083/table/ch2.apph.tab6/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.apph.tab6"><a href="/books/NBK577083/table/ch2.apph.tab6/?report=objectonly" target="object" rid-ob="figobch2apphtab6">Table</a></h4><p class="float-caption no_bottom_margin">All-causality THC and CBD (20 patients in the arm): Drug high (16), coughing (14), sore throat (7), bad taste (6), dyspnoea (1), dizzy (4), headache (2), nausea (6), vomiting (0), sleepy (0)</p></div></div></div><div id="ch2.apph.s7"><h4>Vaporised <1 mg THC and 18.4 mg CBD vs placebo</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2apphtab7"><a href="/books/NBK577083/table/ch2.apph.tab7/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2apphtab7" rid-ob="figobch2apphtab7"><img class="small-thumb" src="/books/NBK577083/table/ch2.apph.tab7/?report=thumb" src-large="/books/NBK577083/table/ch2.apph.tab7/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.apph.tab7"><a href="/books/NBK577083/table/ch2.apph.tab7/?report=objectonly" target="object" rid-ob="figobch2apphtab7">Table</a></h4><p class="float-caption no_bottom_margin">All-causality THC and CBD (20 patients in the arm): Drug high (8), coughing (13), sore throat (1), bad taste (5), dyspnoea (0), dizzy (2), headache (3), nausea (1), vomiting (1), sleepy (1)</p></div></div></div></div><div id="ch2.appi"><h3>Appendix I. Health economic analysis</h3><div id="ch2.appi.s1"><h4>Introduction</h4><p>Chronic pain is common in the UK general population but has a heterogeneous aetiology. A recent epidemiological study found that roughly 43.5%, 28 million people in the UK general population were expected to have “severe and chronic pain that is unresponsive to treatment”. Treatment options vary widely depending on the cause of the pain but their effectiveness and side effects vary widely and there is very significant unmet clinical need in the population group whose pain is not adequately controlled by these conventional options. Some chronic pain patients self treat with cannabis based products purchased as health food supplements or online and there is widespread interest in whether Cannabis Based Medicinal Products (CBMPs) should be prescribed on the NHS. However, it is currently very rare for patients with chronic pain to be treated with CBMPs on the NHS.</p><p>The CBMPs that are currently on the market could cost several thousand pounds per patient per year, based on publicly available sources for price. This, along with the considerations above meant that the potential resource impact of a positive recommendation in this area could be extremely high. The committee therefore prioritised this question for <i>de novo</i> economic modelling as any positive recommendation would need to be underpinned by robust health economic evaluation.</p></div><div id="ch2.appi.s2"><h4>Methods</h4><div id="ch2.appi.s2.1"><h5>Decision problem</h5><p>The population of interest were people with chronic pain whose pain was not adequately controlled by conventional management. Since no CBMPs have a licence for treating chronic pain, it would not be appropriate to compare them to conventional management. Instead the model has 2 strategies, CBMP + usual care and usual care.</p><p>In the base case, the model considers all people with chronic pain as an aggregated group, which is broken down by pain aetiological subgroups in sensitivity analysis. The different aetiologies, decided upon by the committee following review of the available clinical evidence, were neuropathic pain, cancer pain and musculoskeletal pain. Separate analyses were conducted for different CBMPs; THC:CBD spray, oral dronabinol, oral nabilone and oromucosal THC.</p></div><div id="ch2.appi.s2.2"><h5>Model Structure</h5><p>The committee indicated that if CBMPs were to be used in the chronic pain population, they would be trialled for a month and discontinued if patients did not achieve a 30% reduction in pain from baseline as this is a well accepted Minimally Clinically Important Difference (MCID) in this population and a threshold that had been reported by studies in the clinical review. They indicated that a small proportion of patients who did not achieve a treatment response of 30% would remain on treatment if they felt they were getting some benefit from it. The 30% improvement threshold is based on the expert opinion at the committee. This parameter is only used to determine the continuation of treatment. The treatment response is based on the absolute NRS changes in the model.</p><p>We built a decision analytic model with five Markov states in each model arm; on treatment response (OTR), on treatment no response (OTNR), discontinued with response (DR), discontinued with no response (DNR) and dead. After being initially assigned to a Markov state through treatment effects, patients could transition from OTR to DR and from OTNR to DNR and patients could die from any state but no other transitions were possible (<a class="figpopup" href="/books/NBK577083/figure/ch2.appi.fig1/?report=objectonly" target="object" rid-figpopup="figch2appifig1" rid-ob="figobch2appifig1">Figure 1</a>). We adopted the same structure as this for the placebo arm because it is logical to operationalise the treatment and placebo effects within the same model structure, but people do not incur treatment cost in the usual care arm of the model despite nominally occupying a nominal “on treatment” state. This structural choice is not expected to have affected any of the results as the total distribution of patients’ pain scores within the usual care arm of the model is unaffected by grouping patients with higher and lower distributions into arbitrary Markov states in this way.</p><p id="ch2.appi.fig1"><a href="/books/NBK577083/figure/ch2.appi.fig1/?report=objectonly" target="object" rid-ob="figobch2appifig1" class="figpopup">Figure 1. Model structure (for both model arms)</a></p></div><div id="ch2.appi.s2.3"><h5>Effect Engine</h5><div id="ch2.appi.s2.3.1"><h5>Distribution of treatment effects</h5><p>We chose to model treatment effects within our model using continuous (mean changes in pain score) rather than dichotomous (proportion of people achieving a 30% response) data on treatment effects from the clinical review. This decision was made firstly because more trials reported mean changes in pain score rather than proportions of people achieving at least a 30% improvement in pain and secondly because it provided a more detailed breakdown of treatment effects for us to examine the influence of CBMPs on costs and quality of life across the whole distribution of pain scores at different time points in the model.</p><p>We assumed that treatment effects would be normally distributed and tested this assumption by conducting simulations. There were two studies from the clinical review that allowed us to test how well normally distributed treatment effects would match empirically observed dichotomous outcomes, (<a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a> and <a class="bibr" href="#ch2.appl.ref11" rid="ch2.appl.ref11">Portenoy 2012</a>). These were two of the larger studies included in the systematic review. Using the Langford data, we assumed baseline pain was normally distributed (we did not need to truncate this data to fit between 0 and 10 because of the relatively tight confidence intervals) and simulated 60,000 theoretical patients based on baseline mean and SD pain score. We then added a placebo or active treatment effect to each theoretical patient, randomly assigning values from a normal distribution with mean and SD taken from the change from baseline data in that study. Using the simulated data, we calculated the proportion of patients that received a 30% and 50% improvement in pain and compared them to the data from the trial. The results are in <a class="figpopup" href="/books/NBK577083/table/ch2.appi.tab1/?report=objectonly" target="object" rid-figpopup="figch2appitab1" rid-ob="figobch2appitab1">Table 2</a>.</p><p id="ch2.appi.tab1"><a href="/books/NBK577083/table/ch2.appi.tab1/?report=objectonly" target="object" rid-ob="figobch2appitab1" class="figpopup">Table 2. Langford 2013 response data compared with normal distribution estimates</a></p><p>We then repeated this process for the <a class="bibr" href="#ch2.appl.ref11" rid="ch2.appl.ref11">Portenoy 2012</a> data, which provided dichotomous response data at many more levels of response. The data are in <a class="figpopup" href="/books/NBK577083/figure/ch2.appi.fig2/?report=objectonly" target="object" rid-figpopup="figch2appifig2" rid-ob="figobch2appifig2">Figure 2</a>.</p><p id="ch2.appi.fig2"><a href="/books/NBK577083/figure/ch2.appi.fig2/?report=objectonly" target="object" rid-ob="figobch2appifig2" class="figpopup">Figure 2. Portenoy response data compared with normal distribution estimates</a></p><p>Based on the fit of these data and their experience, the committee felt that it was clinically plausible that treatment effects are well approximated by a normal distribution.</p></div><div id="ch2.appi.s2.3.2"><h5>Application of treatment effects</h5><p>As detailed in the Natural History section below, the distribution of baseline pain in both model arms was calculated using a beta distribution to assign patients into 200 ‘bins’ representing each 0.05 pain increment from 0.025 to 9.975 on the NRS scale.</p><p>We calculated patients’ pain scores after treatment by combining the beta distribution of baseline score and the normal distribution for treatment effects. We were then able to use the normally distributed treatment effects to calculate the proportion of patients moving from each bin to every other bin.</p><p>Separate post-treatments distributions were then calculated for patients who achieved a >=30% treatment response and those who did not. This was implemented by calculating whether the difference between 2 bins was >=30% or not when combining distributions. This also allowed calculation of the proportion of the overall cohort achieving a treatment response. Calculating the pain distribution of those who had achieved a >=30% response and those who had not was important for assigning costs and utility values to those continuing treatment with CBMPs beyond the first cycle of the model.</p><p>We also calculated distributions for patients who discontinued due to lack of treatment response and patients who did achieve a response but discontinued for other reasons. We made the assumption that patients who did not continue treatment would drop back to baseline in both arms of the model. These two distributions combined are therefore equivalent to the distribution at baseline, but divided into patients who would have achieved a treatment response, and those who would not. The separation of these distributions was necessary because 10% of partial responders are assumed to continue with treatment and because we assumed that patients discontinuing from the OTR health state would transition to the DR health state and patients discontinuing from the OTNR health state would discontinue to the DNR health state.</p></div><div id="ch2.appi.s2.3.3"><h5>Cycle Length, Discount Rate and Time Horizon</h5><p>We adopted a 4-week cycle length as treatment effects were often reported over this time in clinical trials. We adopted a discount rate of 3.5% for both costs and benefits and a lifetime time horizon in line with the NICE reference case. The data available to populate the model were typically short term so we adopted a shorter time horizon in sensitivity analysis.</p></div></div><div id="ch2.appi.s2.4"><h5>Input parameters</h5><div id="ch2.appi.s2.4.1"><h5>Natural History</h5><p>The distribution of baseline pain in both model arms was calculated using a beta distribution to assign patients into 200 ‘bins’ representing each 0.05 pain increment from 0.025 to 9.975 on the NRS scale. We used this distribution because it is not possible for a person to have a pain score below 0 or above 10. Using the ‘method of moments’ formulae, we converted the mean and SD of baseline pain from a large epidemiological study (<a class="bibr" href="#ch2.appl.ref23" rid="ch2.appl.ref23">Farrar 2001</a>) to the alpha and beta parameters necessary for the distribution. We also used the average age and sex from this study to calculate utility values associated with each NRS score (see <a href="#ch2.appi.s2.4.8">Utilities</a> section).</p><p>In the base case, the assumption was made that pain score does not change over time (unless in response to treatment). This assumption was relaxed in sensitivity analysis by including capacity for increasing or decreasing pain score. Since a linearly changing score would mean that almost all of the cohort would end up with a pain score of either 0 or 10, we modelled the natural history such that pain asymptotically approaches 0 and 10. This was achieved by first specifying a “mean change in pain score per year”. This was used to calculate a “hazard ratio”, by dividing baseline pain score and pain score after 1 year by 10, converting into instantaneous “rates”, and taking the ratio between the two. The resulting value was converted to a HR per cycle of the model. This was then applied to pain scores in each cycle, by converting scores into “rates”, applying the “HR” and then converting back to pain scores.</p><p id="ch2.appi.tab2"><a href="/books/NBK577083/table/ch2.appi.tab2/?report=objectonly" target="object" rid-ob="figobch2appitab2" class="figpopup">Table 3. Baseline Characteristics</a></p></div><div id="ch2.appi.s2.4.2"><h5>Treatment effects</h5><p>We obtained treatment effect data from the systematic review for this review question for four separate cannabis based medicinal products (<a class="figpopup" href="/books/NBK577083/table/ch2.appi.tab3/?report=objectonly" target="object" rid-figpopup="figch2appitab3" rid-ob="figobch2appitab3">Table 4</a>). These were either derived from single studies or from meta-analyses. Response in the SoC arm of the model was set equal to the control arm from Langford, the largest study in the review, in the base case. Treatment effect data were added to response in the SoC arm to calculate response in the cannabis arm. See <a href="#ch2.appe">appendix E</a> and <a href="#ch2.appf">AppendixF</a> for details.</p><p id="ch2.appi.tab3"><a href="/books/NBK577083/table/ch2.appi.tab3/?report=objectonly" target="object" rid-ob="figobch2appitab3" class="figpopup">Table 4. Baseline response and treatment effect data from the clinical review</a></p></div><div id="ch2.appi.s2.4.3"><h5>Discontinuation from Response</h5><p>No direct, long term data on discontinuation were available for this population so we explored several options in the model. In the base case, discontinuation from response data were obtained from a large, publicly available individual patient dataset (<a class="bibr" href="#ch2.appl.ref24" rid="ch2.appl.ref24">Messina et al. 2017</a>) on patients with advanced MS being treated with THC:CBD spray. 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. Based on AIC/BIC statistics we selected a gompertz parametric curve to use within our economic model.</p><p id="ch2.appi.tab4"><a href="/books/NBK577083/table/ch2.appi.tab4/?report=objectonly" target="object" rid-ob="figobch2appitab4" class="figpopup">Table 5. Model fit statistics for discontinuation survival curve</a></p><p>While this dataset relates to the MS population rather than the population with chronic pain, the results indicate that THC:CBD spray is generally well tolerated and that treatment benefit appears to persist, with 80% of responders still being on treatment after 2 years. The most common reasons for discontinuation among those that responded were lack of effectiveness, adverse events or a combination of the two. We set up the model to use an alternative discount rate of 3.1% per cycle, calculated from <a class="bibr" href="#ch2.appl.ref25" rid="ch2.appl.ref25">Hoggart 2015</a>, a study that was specific to cannabis use in chronic pain in scenario analysis.</p><p>In the base case we applied the discontinuation curve equally to responders in both the standard of care and active treatment arms of the model but explored no discontinuation and differential discontinuation in sensitivity analysis. For the differential discontinuation we modelled discontinuation by application of a hazard ratio. The hazard ratio was derived by creating an identical dataset to that in <a class="bibr" href="#ch2.appl.ref24" rid="ch2.appl.ref24">Messina 2017</a> but treating all patients who discontinued for adverse events alone as censors. This dataset was compared with the original using a cox proportional hazards model (HR = 0.482, se=0.06, proportional hazards assumption not rejected). The interpretation of this is that lower discontinuation would be expected in the standard of care arm because people cannot discontinue from pain response through adverse events alone. We included another option which fitted a competing risks model to the 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="#ch2.fn1">a</a></sup> but used a gompertz model instead of the Weibull example given. 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. The competing risks model produced survival estimates that were very similar to those produced using the hazard ratio method outlined above. 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 particular 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.</p><p id="ch2.appi.fig3"><a href="/books/NBK577083/figure/ch2.appi.fig3/?report=objectonly" target="object" rid-ob="figobch2appifig3" class="figpopup">Figure 3. Discontinuation from THC:CBD spray in responders and simulated non-responders [the placebo=1 group] (Messina 2017)</a></p></div><div id="ch2.appi.s2.4.4"><h5>Mortality</h5><p>There is no data available on whether treatment with CBMPs affect mortality and they are not expected to be fundamentally disease modifying. We therefore did not vary mortality by model arm but modelled overall mortality by applying an SMR of 1.32 (0.08) for people with chronic pain from an epidemiological study (<a class="bibr" href="#ch2.appl.ref26" rid="ch2.appl.ref26">Torrance 2006</a>) to standard population level life tables published by the Office for National Statistics.</p></div><div id="ch2.appi.s2.4.5"><h5>Downstream treatments</h5><p>While CBMPs are not expected to be fundamentally disease modifying, and the clinical review identified no randomised evidence that their use spares other medication, we were interested in whether their potential to reduce or delay invasive treatments would influence the results of the economic model. The committee advised us that the only invasive treatment that was common enough to potentially influence the model’s results was radiofrequency denervation (RFD) for people with chronic low back pain. This section is therefore only relevant when considering the patient population with low back pain. This part of the model was switched off for other subgroups.</p><p>Theoretically, any patient with chronic low back pain and an NRS greater than 5 is eligible for RFD and the committee estimated that around 10% of the eligible population might be trialled for RFD per year. The methodology for applying the costs and benefits of RFD was adapted from that employed in the <a href="https://www.nice.org.uk/guidance/ng59" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NICE guideline on Low back pain and sciatica in over 16s: assessment and management</a>..</p><p>The trial for RFD consists of administration of a diagnostic block which is either positive or negative and to which some patients receive a HRQoL benefit (modelled as the same level of benefit as full RFD, as in the low back pain analysis) for prolonged response for the duration of that response. Negative patients will not receive RFD and 10% of positive patients will decline it. RFD and prolonged response to diagnostic block are implemented as a series of simultaneous tunnel states (i.e. they exist in parallel to the main on treatment/off treatment states). In each cycle, the % of patients with a pain score >5 is calculated using patient distributions, and this is used to determine the number of patients who undergo diagnostic block. Because of the tunnel state structure, the model ensures patients who are already in RFD or prolonged diagnostic block states cannot undergo diagnostic block again.</p><p>The QALY gain for RFD is determined by first applying the treatment effects from the NG59 model uniformly (having no specific evidence of non-uniformity) to each level of baseline pain within the initial distribution. The weighted average utility difference between the resulting distribution and the initial distribution is then taken and applied to the proportion of people who respond to diagnostic blocks or are in receipt of RFC benefit in any given cycle, with the treatment effect of RFD lasting two years. 10% of people who receive the full two years of RFD benefit were assumed to undergo repeat RFD after this time. The relevant parameters are in <a class="figpopup" href="/books/NBK577083/table/ch2.appi.tab5/?report=objectonly" target="object" rid-figpopup="figch2appitab5" rid-ob="figobch2appitab5">Table 6</a>.</p><p id="ch2.appi.tab5"><a href="/books/NBK577083/table/ch2.appi.tab5/?report=objectonly" target="object" rid-ob="figobch2appitab5" class="figpopup">Table 6. Radiofrequency Denervation Parameters</a></p></div><div id="ch2.appi.s2.4.6"><h5>Adverse Events</h5><p>We obtained adverse event and serious adverse event rates from a systematic review of patients being treated with CBMPs (<a class="bibr" href="#ch2.appl.ref27" rid="ch2.appl.ref27">Wang 2008</a>) and used these data to calculate the events that occurred per cycle in the model. A wide range of non-serious adverse events were reported in this study but for simplicity we assumed them to be distributed among the five most important events selected by the committee; dizziness, dry mouth, fatigue, headache and nausea. We re-scaled the incidence of these five adverse events so that their sum matched the total event rate. Serious adverse events were assumed to be homogenous.</p><p>We assumed that all adverse events would be short term in nature, lasting only a few days and sourced temporary health related quality of life decrements from studies that reported the five most important adverse events selected by the committee. A quality of life decrement for grade 2 vomiting was used as a surrogate for serious adverse events because this was the most common non-condition specific adverse event reported in the <a class="bibr" href="#ch2.appl.ref27" rid="ch2.appl.ref27">Wang 2008</a> study. Grade 2 events are often not classified as serious in papers outside the CBMP field so it is possible that we may have slightly underestimated the QoL decrement associated with treatment related adverse events. 50% of non serious adverse events were assumed to incur a GP appointment and serious adverse events were assumed to incur an A&E visit, with 50% incurring a trip in an ambulance.</p><p>To obtain the adverse events for each Markov state in both arms of the model where patients were not on treatment, we multiplied the per cycle event rates for serious and non-serious AEs by the reciprocal of relative risks associated with different forms of CBMP in the clinical review. For patients in the on-treatment states these adverse event rates are unadjusted.</p><p>The above assumptions are subject to very serious limitations but, taken together, provide a rough estimate of the scale of the effect that adverse events have on the cost-effectiveness results. Sensitivity analyses including and excluding adverse events and varying input data to the extremes of their confidence intervals were undertaken. Since the only evidence we had indicated that adverse events are relatively rare and short term in nature, they are not expected to materially affect the cost-effectiveness of CBMPs.</p><p id="ch2.appi.tab6"><a href="/books/NBK577083/table/ch2.appi.tab6/?report=objectonly" target="object" rid-ob="figobch2appitab6" class="figpopup">Table 7. Adverse event parameters</a></p></div><div id="ch2.appi.s2.4.7"><h5>Costs</h5><p>Treatment costs for THC:CBD spray and nabilone were taken from the Drug Tariff with daily doses being taken from representative studies from the clinical review (<a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a> and <a class="bibr" href="#ch2.appl.ref15" rid="ch2.appl.ref15">Skrabek 2008</a> respectively). There are currently no publicly available UK prices for dronabinol or for the various Bedrocan products but the overall cost per patient is expected to be higher than that for THC:CBD spray.</p><p id="ch2.appi.tab7"><a href="/books/NBK577083/table/ch2.appi.tab7/?report=objectonly" target="object" rid-ob="figobch2appitab7" class="figpopup">Table 8. CBMP Costs</a></p><p>The committee informed us that patients treated with CBMPs might expect to receive four additional outpatient visits within the first year and two outpatient visits in subsequent years to monitor their medication. Outpatient visits were costed at £147 (NHS Reference Costs 2017/18 - non-admitted face-to-face consultant-led attendance, follow-up – pain management).</p><p>In line with methodology that had been employed in modelling the spasticity question for this guideline, we assigned resource use to different levels of pain NRS. The committee confirmed that this approach was reasonable and considered that improvement in pain levels might lead to a resource saving in pain management costs. From their clinical experience they estimated the number of community based visits, outpatient clinic visits, A&E visits, hospital admissions and home care visits associated with five broad pain levels, NRS 0–2, NRS 2–4, NRS 4–6, NRS 6–8, NRS 8–10. The overlapping naming is caused by dividing an 11-point scale by five. The overall management cost for a given Markov state in a given cycle is the weighted average of their pain distribution rounded to the nearest fifth of the NRS scale multiplied by these costs. Given the uncertainty inherent in estimating background management costs in this way, these parameters were subject to extreme sensitivity analyses. We adjusted home care costs to account for the proportion that were self funded using data from <a href="https://www.nice.org.uk/guidance/ng71/evidence/appendix-f-he-report-pdf-4538466259" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NICE’s guideline on Parkinson’s disease health economics report</a>.</p><p>Adverse event costs are discussed in that section.</p><p id="ch2.appi.tab8"><a href="/books/NBK577083/table/ch2.appi.tab8/?report=objectonly" target="object" rid-ob="figobch2appitab8" class="figpopup">Table 9. Background pain management costs by NRS stage</a></p></div><div id="ch2.appi.s2.4.8"><h5>Utilities</h5><p>Utilities associated with each NRS pain level were sourced from a utility study that included 2,719 patients with chronic neuropathic pain (<a class="bibr" href="#ch2.appl.ref28" rid="ch2.appl.ref28">Gu 2012</a>). This study provided dummy variable regression coefficients for each NRS level as well as age, gender and the constant. As well as having been collected from a large and broadly representative sample, the committee agreed that these data had face validity. The per cycle QALYs for each Markov state were the weighted average of the pain distribution and these utility values, with pain scores for the individual bins being rounded to the nearest integer.</p><p>Adverse event disutilities were obtained from a utility study which aimed to estimate the disutility associated with a series of common adverse events in patients with breast cancer. The patient group is clearly indirect and, as shown in the table below, several assumptions were necessary to operationalise adverse events in the model but as AEs were typically short term and non-severe, these limitations are not expected to materially influence the model’s results. Please see the <a href="#ch2.appi.s2.4.6">adverse events</a> section for the relevant input data.</p><p id="ch2.appi.tab9"><a href="/books/NBK577083/table/ch2.appi.tab9/?report=objectonly" target="object" rid-ob="figobch2appitab9" class="figpopup">Table 10. Utility regression model coefficients for chronic pain</a></p></div><div id="ch2.appi.s2.4.9"><h5>Sensitivity and scenario analyses</h5><p>A large number of one-way and multi-way deterministic sensitivity analyses were conducted in order to test how sensitive the model’s conclusions were to uncertainties in its input parameters. Probabilistic sensitivity analysis, where the model was run thousands of times with input parameters being sampled from appropriate probability distributions was also conducted to test the sensitivity of the model to combined statistical uncertainty. Pre-specified scenario analysis were:-
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<ol id="ch2.l37"><li id="ch2.lt296" class="half_rhythm"><div>Using the costs and effects of nabilone instead of THC:CBD spray</div></li><li id="ch2.lt297" class="half_rhythm"><div>Using treatment effect data for the neuropathic pain subgroup</div></li><li id="ch2.lt298" class="half_rhythm"><div>Using treatment effect data for the cancer pain subgroup</div></li><li id="ch2.lt299" class="half_rhythm"><div>Using treatment effect data for the musculoskeletal pain subgroup</div></li><li id="ch2.lt300" class="half_rhythm"><div>Using discontinuation data from the <a class="bibr" href="#ch2.appl.ref25" rid="ch2.appl.ref25">Hoggart 2015</a> chronic pain study instead of the <a class="bibr" href="#ch2.appl.ref24" rid="ch2.appl.ref24">Messina 2017</a> MS individual patient data</div></li><li id="ch2.lt301" class="half_rhythm"><div>Using control arm response from <a class="bibr" href="#ch2.appl.ref11" rid="ch2.appl.ref11">Portenoy 2012</a> instead of <a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a></div></li><li id="ch2.lt302" class="half_rhythm"><div>Excluding the background management costs for chronic pain</div></li><li id="ch2.lt303" class="half_rhythm"><div>Not allowing a proportion of sub<30% responders to continue with treatment</div></li><li id="ch2.lt304" class="half_rhythm"><div>Including RFD as a downstream treatment for low back pain</div></li><li id="ch2.lt305" class="half_rhythm"><div>Declining the treatment effect over time by reducing mean pain to match placebo</div></li><li id="ch2.lt306" class="half_rhythm"><div>Declining the placebo effect (change from baseline) in both arms so that pain returns to baseline after 2 years</div></li><li id="ch2.lt307" class="half_rhythm"><div>Allowing differential discontinuation from response in the standard of care arm equalling the hazard ratio</div></li><li id="ch2.lt308" class="half_rhythm"><div>Assuming no discontinuation from response in either arm</div></li><li id="ch2.lt309" class="half_rhythm"><div>All adverse events halved</div></li><li id="ch2.lt310" class="half_rhythm"><div>All adverse events doubled</div></li><li id="ch2.lt311" class="half_rhythm"><div>All pain management costs halved</div></li><li id="ch2.lt312" class="half_rhythm"><div>All pain management costs doubled</div></li><li id="ch2.lt313" class="half_rhythm"><div>All QoL coefficients set to high limits of confidence intervals</div></li><li id="ch2.lt314" class="half_rhythm"><div>All QoL coefficients set to low limits of confidence intervals</div></li><li id="ch2.lt315" class="half_rhythm"><div>Competing risks model from Messina for discontinuation</div></li><li id="ch2.lt316" class="half_rhythm"><div>−0.55 treatment effect to force the model to produce a mean difference equal to the input treatment effect of −0.44</div></li></ol></p></div></div></div><div id="ch2.appi.s3"><h4>Results</h4><p>The results section will focus on treatment with THC:CBD spray unless otherwise noted as this is the treatment with the most robust clinical evidence. The patient group will be all patients with chronic pain unless otherwise noted.</p><div id="ch2.appi.s3.1"><h5>Intermediate Results</h5><p>The model’s intermediate results show that after the initial trial of treatment period, 54% of patients in the cannabis arm and 46% of patients in the standard of care arm achieved a 30% reduction from baseline while 31% and 25% achieved a 50% reduction respectively. These data were similar to data observed in the clinical trials. There is some discontinuation from response and then the model settles into a steady state where about 43% and 37% of patients remain as responders respectively (see <a class="figpopup" href="/books/NBK577083/figure/ch2.appi.fig4/?report=objectonly" target="object" rid-figpopup="figch2appifig4" rid-ob="figobch2appifig4">Figure 4</a>). Similarly, the graph of mean cohort pain over time shows an initial drop, followed by a slight increase and then a steady state of 4.9 for the cannabis arm and 5.2 for the standard of care with the slight increase being the result of the aforementioned discontinuation (see <a class="figpopup" href="/books/NBK577083/figure/ch2.appi.fig4/?report=objectonly" target="object" rid-figpopup="figch2appifig4" rid-ob="figobch2appifig4">Figure 4</a>). This is somewhat lower than the mean treatment effect and that is because only patients with a 30% improvement are assumed to continue treatment and carry on receiving the benefits. All other patients drop back to baseline after ending treatment. We set up a sensitivity analysis to increase the mean difference between the arms to match the input effectiveness data.</p><p id="ch2.appi.fig4"><a href="/books/NBK577083/figure/ch2.appi.fig4/?report=objectonly" target="object" rid-ob="figobch2appifig4" class="figpopup">Figure 4. Intermediate model results</a></p><p>The relatively small difference between the intermediate outcomes in the model reflects the modest effectiveness of cannabis observed in the clinical review.</p><p id="ch2.appi.fig5"><a href="/books/NBK577083/figure/ch2.appi.fig5/?report=objectonly" target="object" rid-ob="figobch2appifig5" class="figpopup">Figure 5. Total lifetime undiscounted costs by broad area and model arm</a></p><p>It can be seen from <a class="figpopup" href="/books/NBK577083/figure/ch2.appi.fig5/?report=objectonly" target="object" rid-figpopup="figch2appifig5" rid-ob="figobch2appifig5">Figure 5</a> that cannabis only results in very small resource savings through reduction in pain scores and small increases in adverse event costs. These values are overwhelmed by the cost of cannabis treatment, however, along with a modest increase in monitoring costs.</p></div><div id="ch2.appi.s3.2"><h5>Cost-utility Results</h5><p>In the base case (THC:CBD spray costs and effects, overall chronic pain population, discontinuation data from <a class="bibr" href="#ch2.appl.ref24" rid="ch2.appl.ref24">Messina 2017</a>, SoC response from <a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a>, no treatment effect or SoC decline over time, no differential discontinuation from response, lifetime time horizon, discounting at 3.5% for both costs and benefits) the model produced incremental costs of £24,474 and incremental QALYs of 0.162 and therefore an ICER of £151,431/QALY gained.</p><p>The results for the mean of the probabilistic sensitivity analysis were very similar to this and that analysis found a 100% probability that cannabis is more effective, a 100% probability that it is more expensive and a 0.0% probability that cannabis is cost effective over standard care at the commonly accepted thresholds of £20,000 and £30,000/QALY gained.</p><p id="ch2.appi.tab10"><a href="/books/NBK577083/table/ch2.appi.tab10/?report=objectonly" target="object" rid-ob="figobch2appitab10" class="figpopup">Table 11. Cost-utility analysis results</a></p><p id="ch2.appi.fig6"><a href="/books/NBK577083/figure/ch2.appi.fig6/?report=objectonly" target="object" rid-ob="figobch2appifig6" class="figpopup">Figure 6. Probabilistic Sensitivity Analysis Scatterplot</a></p></div><div id="ch2.appi.s3.3"><h5>Sensitivity and scenario analysis results</h5><p>The tornado diagram in <a class="figpopup" href="/books/NBK577083/figure/ch2.appi.fig7/?report=objectonly" target="object" rid-figpopup="figch2appifig7" rid-ob="figobch2appifig7">Figure 7</a> shows how the ICER changes in response to high and low values in important input parameters. The high and low values are typically limits of confidence intervals or other values selected to represent extreme scenarios. It can be seen from this diagram that no plausible variations in individual model parameters meaningfully affect the ICER.</p><p id="ch2.appi.fig7"><a href="/books/NBK577083/figure/ch2.appi.fig7/?report=objectonly" target="object" rid-ob="figobch2appifig7" class="figpopup">Figure 7. Tornado Diagram (most influential parameters)</a></p><p>Scenario analyses either involve changing the source data of input parameters, the structural assumptions of the model or groups of input parameters to represent, for example, ‘best’ and ‘worst’ case results. Full descriptions of the scenario analyses are available in that section above.</p><p id="ch2.appi.tab11"><a href="/books/NBK577083/table/ch2.appi.tab11/?report=objectonly" target="object" rid-ob="figobch2appitab11" class="figpopup">Table 12. Results of scenario analyses</a></p><p>It can be seen from <a class="figpopup" href="/books/NBK577083/table/ch2.appi.tab11/?report=objectonly" target="object" rid-figpopup="figch2appitab11" rid-ob="figobch2appitab11">Table 12</a> that no scenario analyses bring the ICER close to £20,000–£30,000 per QALY gained. The ICER is lower for nabilone than for THC:CBD spray, but the clinical effectiveness data are much more uncertain and only available for a patient group with ‘widespread pain’.</p></div></div><div id="ch2.appi.s4"><h4>Discussion</h4><p>The economic model was characterised by a number of limitations; the clinical input data were of low quality, input parameters were largely drawn from short term trials and extrapolated into the longer term, adverse events and background pain management incorporated several committee assumptions relating to their associated costs and HRQoL effects, costing the standard of care was ignored as cannabis was modelled as an add-on treatment and the only data we had on opioid sparing showed no effect and we had no data on pain progression or the behaviour of the placebo effect over time. Nevertheless, no plausible variations in any of the model parameters or structural assumptions produced ICERs remotely near the commonly accepted cost-effectiveness threshold of £20,000–£30,000 per QALY gained. This is principally because the CBMPs that are currently on the market and for which there is any clinical evidence are quite expensive, costing upwards of £4,000 per patient per year and only provide very modest clinical benefits. Indeed, these products would have to either be around 8 times more effective (accrue 1.22 QALYs compared with 0.162 QALY in the base case) or around 6 times less expensive or some equivalent combination of the 2 for the model to produce ICERs within the range normally accepted by NICE committees. The committee was aware that given the findings from the clinical evidence, the additional effectiveness is unrealistic.</p><p>There are a number of products not examined by this analysis because no data were available on their effectiveness or UK price; pure CBD oil, Bedrocan products and dronabinol have been omitted but could be included in an updated version of the model once such data become available.</p></div></div><div id="ch2.appj"><h3>Appendix J. Excluded studies</h3><div id="ch2.appj.s1"><h4>Clinical studies</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2appjtab1"><a href="/books/NBK577083/table/ch2.appj.tab1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2appjtab1" rid-ob="figobch2appjtab1"><img class="small-thumb" src="/books/NBK577083/table/ch2.appj.tab1/?report=thumb" src-large="/books/NBK577083/table/ch2.appj.tab1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.appj.tab1"><a href="/books/NBK577083/table/ch2.appj.tab1/?report=objectonly" target="object" rid-ob="figobch2appjtab1">Table</a></h4><p class="float-caption no_bottom_margin">No outcomes of interest
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<i>[The results are in a format that it’s not possible to data extract: All the data is either given as a narrative account or in form of graphs. This also includes adverse events.]</i>
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</p></div></div></div><div id="ch2.appj.s2"><h4>Economic studies</h4></div></div><div id="ch2.appk"><h3>Appendix K. Research recommendations</h3><dl id="ch2.l38" class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd id="ch2.lt317"><p class="no_top_margin">
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<b>For adults with fibromyalgia or persistent treatment-resistant neuropathic pain, what is the clinical and cost effectiveness of cannabidiol (CBD containing no or traces of THC) as an add-on to standard treatment?</b>
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</p></dd></dl></dl><p>There are no RCTs that compare CBD (either as a pure product or containing traces of THC) with standard treatment to standard treatment for fibromyalgia or for persistent treatment-resistant neuropathic pain. Cannabis could be a cost-effective treatment for these conditions because it could reduce resource use.</p><p>The committee agreed that a follow-up period of 6 months is a realistic duration for assessing chronic pain treatments.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2appktab1"><a href="/books/NBK577083/table/ch2.appk.tab1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2appktab1" rid-ob="figobch2appktab1"><img class="small-thumb" src="/books/NBK577083/table/ch2.appk.tab1/?report=thumb" src-large="/books/NBK577083/table/ch2.appk.tab1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.appk.tab1"><a href="/books/NBK577083/table/ch2.appk.tab1/?report=objectonly" target="object" rid-ob="figobch2appktab1">Table</a></h4><p class="float-caption no_bottom_margin"><i>Population:</i> Adults with fibromyalgia or persistent treatment-resistant neuropathic pain being managed by a pain specialist using standard treatment <i>Intervention</i>: CBD (either as a pure product or containing traces of THC)</p></div></div><dl id="ch2.l41" class="temp-labeled-list"><dl class="bkr_refwrap"><dt>2.</dt><dd id="ch2.lt335"><p class="no_top_margin">
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<b>In children and young people with intractable cancer-related pain and pain associated with specific diseases (such as epidermolysis bullosa), what is the clinical and cost effectiveness of cannabis-based medicinal products as an add-on treatment to improve symptoms in comparison to treatment with standard care?</b>
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</p></dd></dl></dl><p>There is currently no evidence that explores whether the addition of cannabis-based medicinal products as an adjunct to standard care improves symptoms for children and young people with intractable cancer-related pain and pain associated with specific diseases, such as epidermolysis bullosa. The reason for the lack of research so far is probably because there are relatively few children and young people with these conditions. In addition, there is concern regarding the use of high dose opioids for children and young people because it often causes adverse events. Therefore, a research recommendation was made. The committee defined ‘intractable cancer-related pain’ as cancer-related pain that does not respond to multiple drugs sufficiently to enable a reasonable quality of life and/or the child to be discharged home. The committee defined standard care as tertiary specialist pain/palliative management. An additional benefit from such research could be a reduction in resource use.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figch2appktab2"><a href="/books/NBK577083/table/ch2.appk.tab2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figch2appktab2" rid-ob="figobch2appktab2"><img class="small-thumb" src="/books/NBK577083/table/ch2.appk.tab2/?report=thumb" src-large="/books/NBK577083/table/ch2.appk.tab2/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ch2.appk.tab2"><a href="/books/NBK577083/table/ch2.appk.tab2/?report=objectonly" target="object" rid-ob="figobch2appktab2">Table</a></h4><p class="float-caption no_bottom_margin"><i>Population:</i> Children with intractable cancer-related pain (intractable cancer-related pain was defined by the committee as cancer-related pain which does not respond to multiple interventions including non-pharmacological and drug therapies sufficiently <a href="/books/NBK577083/table/ch2.appk.tab2/?report=objectonly" target="object" rid-ob="figobch2appktab2">(more...)</a></p></div></div></div><div id="ch2.appl"><h3>Appendix L. Reference list of included studies</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref1">Blake, D. R., Robson, P., Ho, M.
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et al. (2006) Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford, England)
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45(1): 50–2 [<a href="https://pubmed.ncbi.nlm.nih.gov/16282192" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16282192</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref2">de Vries, Marjan, Van Rijckevorsel, Dagmar C. M., Vissers, Kris C. P.
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et al. (2016) Single dose delta-9-tetrahydrocannabinol in chronic pancreatitis patients: analgesic efficacy, pharmacokinetics and tolerability. British journal of clinical pharmacology
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81(3): 525–37 [<a href="/pmc/articles/PMC4767190/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4767190</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26505163" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26505163</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref3">de Vries, Marjan, van Rijckevorsel, Dagmar C. M., Vissers, Kris C. P.
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et al. (2017) Tetrahydrocannabinol Does Not Reduce Pain in Patients with Chronic Abdominal Pain in a Phase 2 Placebo-controlled Study. Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association
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15(7): 1079–1086.e4 [<a href="https://pubmed.ncbi.nlm.nih.gov/27720917" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27720917</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref4">Fallon, Marie T., Albert Lux, Eberhard, McQuade, Robert
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et al. (2017) Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies. British journal of pain
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11(3): 119–133 [<a href="/pmc/articles/PMC5521351/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5521351</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28785408" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28785408</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref5">Johnson, Jeremy R., Burnell-Nugent, Mary, Lossignol, Dominique
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et al. (2010) Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. Journal of pain and symptom management
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39(2): 167–79 [<a href="https://pubmed.ncbi.nlm.nih.gov/19896326" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19896326</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref6">Langford, R. M., Mares, J., Novotna, A.
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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
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260(4): 984–97 [<a href="https://pubmed.ncbi.nlm.nih.gov/23180178" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23180178</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref7">Lichtman, Aron H., Lux, Eberhard Albert, McQuade, Robert
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et al. (2018) Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as an Adjunctive Therapy in Advanced Cancer Patients with Chronic Uncontrolled Pain. Journal of pain and symptom management
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55(2): 179–188.e1 [<a href="https://pubmed.ncbi.nlm.nih.gov/28923526" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28923526</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref8">Lynch, Mary E.; Cesar-Rittenberg, Paula; Hohmann, Andrea G. (2014) A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. Journal of pain and symptom management
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47(1): 166–73 [<a href="https://pubmed.ncbi.nlm.nih.gov/23742737" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23742737</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref9">Malik, Z., Bayman, L., Valestin, J.
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et al. (2017) Dronabinol increases pain threshold in patients with functional chest pain: a pilot double-blind placebo-controlled trial. Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus
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30(2): 1–8 [<a href="https://pubmed.ncbi.nlm.nih.gov/26822791" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26822791</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref10">Nurmikko, Turo J., Serpell, Mick G., Hoggart, Barbara
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et al. (2007) Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain
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133(13): 210–20 [<a href="https://pubmed.ncbi.nlm.nih.gov/17997224" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17997224</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref11">Portenoy, Russell K., Ganae-Motan, Elena Doina, Allende, Silvia
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et al. (2012) Nabiximols for opioid-treated cancer patients with poorly controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. The journal of Pain: Official journal of the American Pain Society
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13(5): 438–49 [<a href="https://pubmed.ncbi.nlm.nih.gov/22483680" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22483680</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref12">Rog, David J., Nurmikko, Turo J., Friede, Tim
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et al. (2005) Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology
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65(6): 812–9 [<a href="https://pubmed.ncbi.nlm.nih.gov/16186518" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16186518</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref13">Schimrigk, Sebastian, Marziniak, Martin, Neubauer, Christine
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et al. (2017) Dronabinol Is a Safe Long-Term Treatment Option for Neuropathic Pain Patients. European neurology
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78(56): 320–329 [<a href="/pmc/articles/PMC5804828/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5804828</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29073592" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29073592</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref14">Serpell, M., Ratcliffe, S., Hovorka, J.
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et al. (2014) A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. European journal of pain (London, England)
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18(7): 999–1012 [<a href="https://pubmed.ncbi.nlm.nih.gov/24420962" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24420962</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref15">Skrabek, Ryan Quinlan, Galimova, Lena, Ethans, Karen
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et al. (2008) Nabilone for the treatment of pain in fibromyalgia. The journal of Pain: official journal of the American Pain Society
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9(2): 164–73 [<a href="https://pubmed.ncbi.nlm.nih.gov/17974490" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17974490</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref16">Svendsen, Kristina B.; Jensen, Troels S.; Bach, Flemming W. (2004) Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double-blind placebo-controlled crossover trial. BMJ (Clinical research ed.) 329(7460): 253 [<a href="/pmc/articles/PMC498019/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC498019</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/15258006" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15258006</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref17">van de Donk, Tine, Niesters, Marieke, Kowal, Mikael A.
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et al. (2019) An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia. Pain [<a href="/pmc/articles/PMC6430597/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6430597</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30585986" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30585986</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref18">Wade, Derick T., Makela, Petra, Robson, Philip
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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)
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10(4): 434–41 [<a href="https://pubmed.ncbi.nlm.nih.gov/15327042" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15327042</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref19">Weber, M.; Goldman, B.; Truniger, S. (2010) Tetrahydrocannabinol (THC) for cramps in amyotrophic lateral sclerosis: a randomised, double-blind crossover trial. Journal of neurology, neurosurgery, and psychiatry
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81(10): 1135–40 [<a href="https://pubmed.ncbi.nlm.nih.gov/20498181" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20498181</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref20">Wissel, Jorg, Haydn, Tanja, Muller, Jorg
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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
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253(10): 1337–41 [<a href="https://pubmed.ncbi.nlm.nih.gov/16988792" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16988792</span></a>]</div></p></li><div id="ch2.appl.rl.r1.1"><h4>Other references</h4><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref21">Dworkin, Robert H., et al. (2005) Core outcome measures for chronic pain clinical trials: IMMPACT recommendations.” Pain
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113(1): 9–19. [<a href="https://pubmed.ncbi.nlm.nih.gov/15621359" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15621359</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref22">Dworkin, Robert H., et al. (2009) Interpreting the clinical importance of group differences in chronic pain clinical trials: IMMPACT recommendations. Pain
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146(3): 238–244. [<a href="https://pubmed.ncbi.nlm.nih.gov/19836888" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19836888</span></a>]</div></p></li><div id="ch2.appl.rl.r1.1.1"><h5>References used solely in the economic model</h5><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref23">Farrar, J
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et al (2001) Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain
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94: 149–158 [<a href="https://pubmed.ncbi.nlm.nih.gov/11690728" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11690728</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref24">Messina, S.
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et al., 2017. Sativex in resistant multiple sclerosis spasticity: Discontinuation study in a large population of Italian patients (SA.FE. study).. PloS one, 12(8), p. e0180651 [<a href="/pmc/articles/PMC5538735/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5538735</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28763462" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28763462</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref25">Hoggart
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et al. 2015. A multicentre, open-label, follow-on study to assess the long-term maintenance of effect, tolerance and safety of THC/CBD oromucosal spray in the management of neuropathic pain. Journal of Neurology
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262(1) [<a href="https://pubmed.ncbi.nlm.nih.gov/25270679" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25270679</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref26">Torrance
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et al
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2006. The Epidemiology of Chronic Pain of Predominantly Neuropathic Origin. Results From a General Population Survey. The Journal of Pain
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7(4) [<a href="https://pubmed.ncbi.nlm.nih.gov/16618472" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16618472</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="ch2.appl.ref27">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="ch2.appl.ref28">Gu
|
|
et al
|
|
2012. Estimating Preference-Based EQ-5D Health State Utilities or Item Responses from Neuropathic Pain Scores. Patient
|
|
5(3) [<a href="https://pubmed.ncbi.nlm.nih.gov/22765255" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22765255</span></a>]</div></p></li></ul></div></ul></div></ul></div></div><div><h2 id="NBK577083_footnotes">Footnotes</h2><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ch2.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="figch2appifig1"><img alt="Image ch2appif1" src-large="/books/NBK577083/bin/ch2appif1.jpg" /></div><div style="display:none" id="figch2appifig2"><img alt="Image ch2appif2" src-large="/books/NBK577083/bin/ch2appif2.jpg" /></div><div style="display:none" id="figch2appifig4"><img alt="Image ch2appif4" src-large="/books/NBK577083/bin/ch2appif4.jpg" /></div><div style="display:none" id="figch2appifig5"><img alt="Image ch2appif5" src-large="/books/NBK577083/bin/ch2appif5.jpg" /></div><div style="display:none" id="figch2appifig7"><img alt="Image ch2appif7" src-large="/books/NBK577083/bin/ch2appif7.jpg" /></div></div></div><div class="fm-sec"><div><p>Final</p></div><div><p>Evidence review underpinning recommendations 1.2.1 to 1.2.3 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: NBK577083</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/35107907" title="PubMed record of this title" ref="pagearea=meta&targetsite=entrez&targetcat=link&targettype=pubmed">35107907</a></span></div></div><div class="small-screen-prev"></div><div class="small-screen-next"></div></article><article data-type="table-wrap" id="figobch2tab1"><div id="ch2.tab1" class="table"><h3><span class="title">PICO table</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.tab1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.tab1_lrgtbl__"><table><tbody><tr><th id="hd_b_ch2.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Population</th><td headers="hd_b_ch2.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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|
<p>Adults, young people, children and babies with chronic pain.</p>
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<p>Specific considerations were given to:
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|
<ul id="ch2.l2"><li id="ch2.lt5" class="half_rhythm"><div>Young people, children and babies</div></li><li id="ch2.lt6" class="half_rhythm"><div>Pregnant women and women who are breastfeeding</div></li><li id="ch2.lt7" class="half_rhythm"><div>People with existing substance abuse</div></li><li id="ch2.lt8" class="half_rhythm"><div>People with hepatic and renal failure</div></li></ul></p>
|
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</td></tr><tr><th id="hd_b_ch2.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Interventions</th><td headers="hd_b_ch2.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cannabis-based medicinal product</td></tr><tr><th id="hd_b_ch2.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Comparator</th><td headers="hd_b_ch2.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<ul id="ch2.l3"><li id="ch2.lt9" class="half_rhythm"><div>Placebo</div></li></ul></td></tr><tr><th id="hd_b_ch2.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Outcomes</th><td headers="hd_b_ch2.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<ul id="ch2.l4"><li id="ch2.lt10" class="half_rhythm"><div>Participant reported pain relief of 30% or greater</div></li><li id="ch2.lt11" class="half_rhythm"><div>Participant reported pain relief of 50% or greater (to assist the economic analysis)</div></li><li id="ch2.lt12" class="half_rhythm"><div>Reduction in analgesics required</div></li><li id="ch2.lt13" class="half_rhythm"><div>Change in pain intensity using Numerical Rating Scale’, or Visual Analogue Scale’</div></li><li id="ch2.lt14" class="half_rhythm"><div>Functional impairment specific to the type of pain. For neuropathic pain: McGill Pain Questionnaire. For nociceptive pain: Brief Pain Inventory.</div></li><li id="ch2.lt15" class="half_rhythm"><div>Participant/Patient/Subject Global Impression of Change (PGIC or SGIG) scale</div></li><li id="ch2.lt16" class="half_rhythm"><div>Quality of life score using SF-36 or EQ-5D</div></li><li id="ch2.lt17" class="half_rhythm"><div>Serious adverse events</div></li><li id="ch2.lt18" 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="ch2.lt19" class="half_rhythm"><div>Withdrawals due to adverse events</div></li><li id="ch2.lt20" class="half_rhythm"><div>Complications due to adverse events</div></li><li id="ch2.lt21" class="half_rhythm"><div>Substance abuse due to the use of cannabis-based medicinal product.</div></li><li id="ch2.lt22" class="half_rhythm"><div>Misuse/diversion</div></li><li id="ch2.lt23" class="half_rhythm"><div>Hepatic and renal failure</div></li></ul>
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|
Outcomes requiring a narrative synthesis:
|
|
<ul id="ch2.l5"><li id="ch2.lt24" class="half_rhythm"><div>Contraindications as listed in exclusion criteria</div></li></ul>
|
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Monitoring requirements, treatment durations, reviewing and stopping criteria, including how should treatment be withdrawn stopped as discussed in the methods of individual RCTs</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch2tab2"><div id="ch2.tab2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.tab2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.tab2_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference</th><th id="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Population</th><th id="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Intervention(s) and placebo</th><th id="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Outcomes</th><th id="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Limitations</th></tr></thead><tbody><tr><td headers="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>
|
|
<a class="bibr" href="#ch2.appl.ref1" rid="ch2.appl.ref1">Blake 2006</a>
|
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</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Secondary pain: musculoskeletal (rheumatoid arthritis)</p>
|
|
<p>Mean age (SD)</p>
|
|
<p>Intervention: 60.9 (10.6)</p>
|
|
<p>Placebo: 64.9 (8.5)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oromucosal spray THC:CBD spray (n=30)</p>
|
|
<p>Titration period: 12 days</p>
|
|
<p>Maintenance dose: up to 6 actuations</p>
|
|
<p>Mean dose with variance: 5.4 actuations (SD 0.84)</p>
|
|
<p>Follow-up: 3 weeks</p>
|
|
<p>Placebo (n=27)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Mean average pain intensity</p>
|
|
<p>Functional impairment caused by pain: McGill Pain Questionnaire - Short Form, total intensity of pain</p>
|
|
<p>Patients experiencing serious adverse events, all-causality</p>
|
|
<p>Patients experiencing serious adverse events, treatment-related</p>
|
|
<p>Withdrawals due to adverse events, all-causality</p>
|
|
<p>Withdrawals due to adverse events, treatment-related</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>No information on the blinding method</p>
|
|
<p>Follow-up <6 months<sup>1</sup></p>
|
|
</td></tr><tr><td headers="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>
|
|
<a class="bibr" href="#ch2.appl.ref3" rid="ch2.appl.ref3">de Vries 2017</a>
|
|
</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Secondary pain: visceral (abdominal pain)</p>
|
|
<p>Mean age (SD)</p>
|
|
<p>Intervention: 53 (9)</p>
|
|
<p>Placebo: 53 (9)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oral delta-9-THC (dronabiniol) (n=21)</p>
|
|
<p>Titration period: 6–10 days</p>
|
|
<p>Maintenance dose: 8 mg, three times a day</p>
|
|
<p>Mean dose with variance: 5/21 had 5 mg, three times a day</p>
|
|
<p>Follow-up: 41 days</p>
|
|
<p>Placebo (n=29)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Mean average pain intensity</p>
|
|
<p>Withdrawals due to adverse events, all-causality</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Incomplete reporting of outcomes</p>
|
|
<p>Follow-up <6 months<sup>1</sup></p>
|
|
</td></tr><tr><td headers="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>
|
|
<a class="bibr" href="#ch2.appl.ref4" rid="ch2.appl.ref4">Fallon 2017</a>
|
|
</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Secondary pain: cancer</p>
|
|
<p>Mean age (SD)</p>
|
|
<p>Intervention: 60.0 (11.0)</p>
|
|
<p>Placebo: 59.6 (11.0)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oromucosal spray THC:CBD spray (n=136)</p>
|
|
<p>Titration period: 2 weeks</p>
|
|
<p>Maintenance dose: Up to 10 actuations</p>
|
|
<p>Mean dose with variance: 6.3 actuations variance not given</p>
|
|
<p>Follow-up: 3 weeks</p>
|
|
<p>Placebo (n=158)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Mean average pain intensity</p>
|
|
<p>Change in analgesics: daily change in total dose, morphine equivalents</p>
|
|
<p>Change in analgesics: daily change in breakthrough dose, morphine equivalents</p>
|
|
<p>Change in analgesics: daily change in maintenance dose, morphine equivalents</p>
|
|
<p>Patient Global Impression of Change (continuous)</p>
|
|
<p>Patients experiencing adverse events, all-causality</p>
|
|
<p>Patients experiencing serious adverse events, all-causality</p>
|
|
<p>Patients experiencing serious adverse events, treatment-related</p>
|
|
<p>Withdrawals due to adverse events, all-causality</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>No details regarding how randomisation and blinding took place (and all outcomes have a subjective aspect)</p>
|
|
<p>Follow-up <6 months<sup>1</sup></p>
|
|
</td></tr><tr><td headers="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>
|
|
<a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>
|
|
</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Secondary pain: cancer</p>
|
|
<p>Mean age (SD)</p>
|
|
<p>THC + CBD: 59.4 (12.1)</p>
|
|
<p>THC: 61.3 (12.5)</p>
|
|
<p>Placebo: 60.1 (12.3)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oromucosal spray 2.7 mg THC with 2.5 mg CBD per 100 microlitre actuation (n=48)</p>
|
|
<p>Titration period: 1 week</p>
|
|
<p>Maintenance dose: Up to 48 actuations</p>
|
|
<p>Mean dose with variance: 8.79 actuations (SD 5.14)</p>
|
|
<p>Follow-up: 2 weeks</p>
|
|
<p>Oromucosal spray 2.7 mg THC only per 100 microlitre actuation (n=45)</p>
|
|
<p>Titration period: 1 week</p>
|
|
<p>Maintenance dose: Up to 48 actuations</p>
|
|
<p>Mean dose with variance: 8.34 actuations (SD 5.17)</p>
|
|
<p>Follow-up: 2 weeks</p>
|
|
<p>Placebo (n=51)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Proportion of patients who experienced pain relief of 30% or more from baseline</p>
|
|
<p>Mean average pain intensity</p>
|
|
<p>Functional impairment caused by pain: Brief Pain Inventory - Short Form</p>
|
|
<p>Change in analgesics: daily change in breakthrough dose, morphine equivalents</p>
|
|
<p>Change in analgesics: daily change in maintenance dose, morphine equivalents</p>
|
|
<p>Quality of life: mean QLQ-C30 global health status</p>
|
|
<p>Patients experiencing serious adverse events, all-causality</p>
|
|
<p>Patients experiencing serious adverse events, treatment-related</p>
|
|
<p>Withdrawals due to adverse events, all-causality</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>No information provided on randomisation nor blinding. The THC + CBD arm has a much lower baseline morphine dose</p>
|
|
<p>Follow-up <6 months<sup>1</sup></p>
|
|
</td></tr><tr><td headers="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>
|
|
<a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a>
|
|
</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Secondary pain: neuropathic (Multiple sclerosis)</p>
|
|
<p>Mean age (SD)</p>
|
|
<p>THC + CBD: 48.42 (10.43)</p>
|
|
<p>Placebo: 49.51 (10.50)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oromucosal spray 2.7 mg THC with 2.5 mg CBD per 100 microlitre actuation (n=141)</p>
|
|
<p>Titration period: 1 week</p>
|
|
<p>Maintenance dose: Up to 12 actuations</p>
|
|
<p>Mean dose with variance: 8.8 actuations (SD 3.87)</p>
|
|
<p>Follow-up: 2 weeks</p>
|
|
<p>Placebo (n=156)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Proportion of patients who experienced pain relief of 30% or more from baseline</p>
|
|
<p>Proportion of patients who experienced pain relief of 50% or more from baseline</p>
|
|
<p>Mean average pain intensity</p>
|
|
<p>Functional impairment caused by pain: Brief Pain Inventory - Short Form</p>
|
|
<p>Change in analgesics: breakthrough daily change in paracetamol, units not provided</p>
|
|
<p>Patient Global Impression of Change (dichotomous)</p>
|
|
<p>Quality of life: EQ-5D index</p>
|
|
<p>Patients experiencing adverse events, all-causality</p>
|
|
<p>Patients experiencing serious adverse events, all-causality</p>
|
|
<p>Withdrawals due to adverse events, all-causality</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Follow-up <6 months<sup>1</sup></td></tr><tr><td headers="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>
|
|
<a class="bibr" href="#ch2.appl.ref7" rid="ch2.appl.ref7">Lichtman 2018</a>
|
|
</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Secondary pain: cancer</p>
|
|
<p>Mean age (SD)</p>
|
|
<p>Intervention: 59.2 (12.0)</p>
|
|
<p>Placebo: 60.7 (11.1)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oromucosal spray 2.7 mg THC with 2.5 mg CBD per 100 microlitre actuation (n=141)</p>
|
|
<p>Titration period: 2 weeks</p>
|
|
<p>Maintenance dose: Up to 10 actuations</p>
|
|
<p>Mean dose with variance: 6.4 actuations variance not given</p>
|
|
<p>Follow-up: 3 weeks</p>
|
|
<p>Placebo (n=150)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Mean average pain intensity</p>
|
|
<p>Change in analgesics: daily change in total dose, morphine equivalents</p>
|
|
<p>Change in analgesics: daily change in breakthrough dose, morphine equivalents</p>
|
|
<p>Change in analgesics: daily change in maintenance dose, morphine equivalents</p>
|
|
<p>Patient Global Impression of Change (continuous)</p>
|
|
<p>Patients experiencing adverse events, all-causality</p>
|
|
<p>Patients experiencing serious adverse events, all-causality</p>
|
|
<p>Patients experiencing serious adverse events, treatment-related</p>
|
|
<p>Withdrawals due to adverse events, all-causality</p>
|
|
<p>Adverse events: psychosis, such as hallucinations, delusions, confused and disturbed thoughts, or lack of insight and self-awareness, all-causality</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>No information on randomisation and blinding. High dropout rates: 30% in the THC + CBD arm and 20% in the placebo arm.</p>
|
|
<p>Follow-up <6 months<sup>1</sup></p>
|
|
</td></tr><tr><td headers="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>
|
|
<a class="bibr" href="#ch2.appl.ref9" rid="ch2.appl.ref9">Malik 2017</a>
|
|
</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Secondary pain: visceral (Functional chest pain: oesophageal)</p>
|
|
<p>Mean age (SD)</p>
|
|
<p>Intervention: 46</p>
|
|
<p>Placebo: 35.5</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oral delta-9-THC (dronabiniol) (n=7)</p>
|
|
<p>Titration period: none</p>
|
|
<p>Maintenance dose: 5 mg twice a day</p>
|
|
<p>Mean dose with variance: Not given</p>
|
|
<p>Follow-up: 4 weeks</p>
|
|
<p>Placebo (n=6)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adverse events</td><td headers="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Follow-up <6 months<sup>1</sup></td></tr><tr><td headers="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>
|
|
<a class="bibr" href="#ch2.appl.ref10" rid="ch2.appl.ref10">Nurnikko 2007</a>
|
|
</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Secondary pain: neuropathic (Neuropathic pain characterised by allodynia)</p>
|
|
<p>Mean age (SD)</p>
|
|
<p>Intervention: 52.4 (15.8)</p>
|
|
<p>Placebo: 54.3 (15.2)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oromucosal spray 2.7 mg THC with 2.5 mg CBD per 100 microlitre actuation (n=50)</p>
|
|
<p>Titration period: 7–10 days</p>
|
|
<p>Maintenance dose: Up to 48 actuations</p>
|
|
<p>Mean dose with variance: 10.9 actuations (SD 6.8)</p>
|
|
<p>Follow-up: 5 weeks</p>
|
|
<p>Placebo (n=55)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Mean average pain intensity</p>
|
|
<p>Functional impairment caused by pain: Pain Disability Index</p>
|
|
<p>Patients experiencing adverse events, all-causality</p>
|
|
<p>Patients experiencing serious adverse events, all-causality</p>
|
|
<p>Patients experiencing serious adverse events, treatment-related</p>
|
|
<p>Withdrawals due to adverse events, all-causality</p>
|
|
<p>Adverse events: psychosis, such as hallucinations, delusions, confused and disturbed thoughts, or lack of insight and self-awareness, all-causality</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Follow-up <6 months<sup>1</sup></td></tr><tr><td headers="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>
|
|
<a class="bibr" href="#ch2.appl.ref11" rid="ch2.appl.ref11">Portenoy 2012</a>
|
|
</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Secondary pain: cancer</p>
|
|
<p>Mean age (SD)</p>
|
|
<p>1–4 sprays: 59 (12.3)</p>
|
|
<p>5–10 sprays: 59 (13.1)</p>
|
|
<p>11–16 sprays: 58 (11.2)</p>
|
|
<p>Placebo: 56 (12.2)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oromucosal spray 2.7 mg THC with 2.5 mg CBD per 100 microlitre actuation (n=197)</p>
|
|
<p>Titration period: 1 week</p>
|
|
<p>Maintenance dose: Up to 16 actuations</p>
|
|
<p>Mean dose with variance: ~1/3 had 1–5, ~1/3 had 6–10, ~1/3 had 11–16</p>
|
|
<p>Follow-up: 4 weeks</p>
|
|
<p>Placebo (n=66)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Proportion of patients who experienced pain relief of 30% or more from baseline</p>
|
|
<p>Mean average pain intensity</p>
|
|
<p>Patients experiencing adverse events, all-causality</p>
|
|
<p>Patients experiencing serious adverse events, all-causality</p>
|
|
<p>Patients experiencing serious adverse events, treatment-related</p>
|
|
<p>Withdrawals due to adverse events, all-causality</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Follow-up <6 months<sup>1</sup></td></tr><tr><td headers="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>
|
|
<a class="bibr" href="#ch2.appl.ref12" rid="ch2.appl.ref12">Rog 2005</a>
|
|
</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Secondary pain: neuropathic (Multiple sclerosis)</p>
|
|
<p>Mean age (SD)</p>
|
|
<p>Intervention: 50.3 (6.7)</p>
|
|
<p>Placebo: 48.1 (9.7)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oromucosal spray 2.7 mg THC with 2.5 mg CBD per 100 microlitre actuation (n=32)</p>
|
|
<p>Titration period: 4–5 days?</p>
|
|
<p>Maintenance dose: Up to 48 actuations</p>
|
|
<p>Mean dose with variance: 9.6 actuations (range 2 to 25)</p>
|
|
<p>Follow-up: 5 weeks</p>
|
|
<p>Placebo (n=32)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Mean average pain intensity</p>
|
|
<p>Patients experiencing adverse events, all-causality</p>
|
|
<p>Patients experiencing serious adverse events, all-causality</p>
|
|
<p>Withdrawals due to adverse events, all-causality</p>
|
|
<p>Adverse events: psychosis, such as hallucinations, delusions, confused and disturbed thoughts, or lack of insight and self-awareness, all-causality</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Follow-up <6 months<sup>1</sup></td></tr><tr><td headers="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>
|
|
<a class="bibr" href="#ch2.appl.ref13" rid="ch2.appl.ref13">Schimrigk 2017</a>
|
|
</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Secondary pain: neuropathic (Multiple sclerosis)</p>
|
|
<p>Mean age (SD)</p>
|
|
<p>Intervention: 48.4 (9.6)</p>
|
|
<p>Placebo: 47.0 (9.7)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oral delta-9-THC (dronabiniol) (n=105)</p>
|
|
<p>Titration period: 4 weeks</p>
|
|
<p>Maintenance dose: 7.5 to 15 mg per day</p>
|
|
<p>Mean dose with variance: 12.7 mg ± 2.9 mg (range 0 to 15.9 mg)</p>
|
|
<p>Follow-up: 12 weeks</p>
|
|
<p>Placebo (n=104)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Mean average pain intensity</p>
|
|
<p>Patients experiencing adverse events, all-causality</p>
|
|
<p>Patients experiencing adverse events, treatment-related</p>
|
|
<p>Patients experiencing serious adverse events, all-causality</p>
|
|
<p>Patients experiencing serious adverse events, treatment-related</p>
|
|
<p>Withdrawals due to adverse events, all-causality</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Follow-up <6 months<sup>1</sup></td></tr><tr><td headers="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>
|
|
<a class="bibr" href="#ch2.appl.ref14" rid="ch2.appl.ref14">Serpell 2014</a>
|
|
</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Secondary pain: neuropathic (Peripheral neuropathic pain)</p>
|
|
<p>Mean age (SD)</p>
|
|
<p>Intervention: 57.6 (14.4)</p>
|
|
<p>Placebo: 57.0 (14.1)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oromucosal spray 2.7 mg THC with 2.5 mg CBD per 100 microlitre actuation (n=79)</p>
|
|
<p>Titration period: 3–4 days?</p>
|
|
<p>Maintenance dose: Up to 24 actuations</p>
|
|
<p>Mean dose with variance: 8.9 actuations variance not given</p>
|
|
<p>Follow-up: 15 weeks</p>
|
|
<p>Placebo (n=94)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Proportion of patients who experienced pain relief of 30% or more from baseline</p>
|
|
<p>Proportion of patients who experienced pain relief of 50% or more from baseline</p>
|
|
<p>Mean average pain intensity</p>
|
|
<p>Functional impairment caused by pain: Brief Pain Inventory - Short Form</p>
|
|
<p>Change in analgesics: daily change in paracetamol, number of rescue (breakthrough) medication paracetamol tablets</p>
|
|
<p>Patient Global Impression of Change (dichotomous)</p>
|
|
<p>Quality of life: EQ-5D index</p>
|
|
<p>Patients experiencing serious adverse events, all-causality</p>
|
|
<p>Patients experiencing serious adverse events, treatment-related</p>
|
|
<p>Withdrawals due to adverse events, all-causality</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Cannabis arm dropout rate being 40%; staff were assigning patients to arms. Therefore, there was no allocation concealment. Sealed envelopes were used</p>
|
|
<p>Follow-up <6 months<sup>1</sup></p>
|
|
</td></tr><tr><td headers="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>
|
|
<a class="bibr" href="#ch2.appl.ref15" rid="ch2.appl.ref15">Skrabek 2008</a>
|
|
</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Primary pain: widespread (Fibromyalgia)</p>
|
|
<p>Mean age (SD)</p>
|
|
<p>Intervention: 47.5 (9.13)</p>
|
|
<p>Placebo: 50.11 (5.96)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oral nabilone (synthetic mimic of THC) (n=15)</p>
|
|
<p>Titration period: 3 weeks</p>
|
|
<p>Maintenance dose: 1 mg twice a day</p>
|
|
<p>Mean dose with variance: All who completed had 1 mg twice a day</p>
|
|
<p>Follow-up: 1 week</p>
|
|
<p>Placebo (n=18)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Mean average pain intensity</p>
|
|
<p>Functional impairment caused by pain: Fibromyalgia Impact Questionnaire</p>
|
|
<p>Patients experiencing adverse events, all-causality</p>
|
|
<p>Withdrawals due to adverse events, all-causality</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Very little information on the randomisation method and blinding</p>
|
|
<p>Follow-up <6 months<sup>1</sup></p>
|
|
</td></tr><tr><td headers="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>
|
|
<a class="bibr" href="#ch2.appl.ref18" rid="ch2.appl.ref18">Wade 2004</a>
|
|
</p>
|
|
<p>Parallel RCT</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Secondary pain: neuropathic (Multiple sclerosis)</p>
|
|
<p>Mean age (SD)</p>
|
|
<p>THC/CBD: 51.0 (9.4)</p>
|
|
<p>Placebo: 50.4 (9.3)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oromucosal spray 2.7 mg THC with 2.5 mg CBD per 100 microlitre actuation (n=77)</p>
|
|
<p>Titration period: Not given</p>
|
|
<p>Maintenance dose: Up to 48 actuations</p>
|
|
<p>Mean dose with variance: Mean ~26 actuations (SE±2)</p>
|
|
<p>Follow-up: 6 weeks</p>
|
|
<p>Placebo (n=77)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Mean average pain intensity</p>
|
|
<p>Withdrawals due to adverse events, all-causality</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Allocation sequence was probably not concealed</p>
|
|
<p>Follow-up <6 months<sup>1</sup></p>
|
|
</td></tr><tr><td headers="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>de Vries 2015</p>
|
|
<p>Crossover RCT</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Secondary pain: visceral (Abdominal pain)</p>
|
|
<p>Mean age (SD)</p>
|
|
<p>51.8 (9.3)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oral delta-9-THC (dronabiniol) (n=12)</p>
|
|
<p>Titration period: None</p>
|
|
<p>Maintenance dose: 8 mg single dose</p>
|
|
<p>Mean dose with variance: Not given</p>
|
|
<p>Follow-up: None</p>
|
|
<p>Placebo (n=10)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Mean average pain intensity</p>
|
|
<p>Patients experiencing adverse events, all-causality</p>
|
|
<p>Withdrawals due to adverse events, all-causality</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Only a single dose was given. This is not a realistic way to assess chronic pain treatment.</td></tr><tr><td headers="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>
|
|
<a class="bibr" href="#ch2.appl.ref8" rid="ch2.appl.ref8">Lynch 2014</a>
|
|
</p>
|
|
<p>Crossover RCT</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Secondary pain: cancer</p>
|
|
<p>Mean age (SD)</p>
|
|
<p>Not provided</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oromucosal spray 2.7 mg THC with 2.5 mg CBD per 100 microlitre actuation (n=18)</p>
|
|
<p>Titration period: 6–12 days</p>
|
|
<p>Maintenance dose: Up to 12 actuations</p>
|
|
<p>Mean dose with variance: 8 actuations (range 3 to 12)</p>
|
|
<p>Follow-up: 4 weeks</p>
|
|
<p>Placebo (n=18)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Mean average pain intensity</p>
|
|
<p>Quality of life: SF-36 physical</p>
|
|
<p>Quality of life: SF-36 mental</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Follow-up <6 months<sup>1</sup></td></tr><tr><td headers="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>
|
|
<a class="bibr" href="#ch2.appl.ref16" rid="ch2.appl.ref16">Svendsen 2004</a>
|
|
</p>
|
|
<p>Crossover RCT</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Secondary pain: neuropathic (Multiple sclerosis)</p>
|
|
<p>Mean age (SD)</p>
|
|
<p>50 (range 23–55)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oral delta-9-THC (dronabiniol) (n=12)</p>
|
|
<p>Titration period: 6 days</p>
|
|
<p>Maintenance dose: 5 mg twice a day</p>
|
|
<p>Mean dose with variance: 3/12 had 7.5 mg 1/12 had 5 mg</p>
|
|
<p>Follow-up: 18–21 days</p>
|
|
<p>Placebo (n=12)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Median average pain intensity</p>
|
|
<p>Quality of life: SF-36 median average</p>
|
|
<p>Patients experiencing adverse events, all-causality</p>
|
|
<p>Patients experiencing serious adverse events, all-causality</p>
|
|
<p>Withdrawals due to adverse events, all-causality</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Follow-up <6 months<sup>1</sup></td></tr><tr><td headers="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>
|
|
<a class="bibr" href="#ch2.appl.ref17" rid="ch2.appl.ref17">van de Donk 2019</a>
|
|
</p>
|
|
<p>Crossover RCT</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Primary pain: widespread (Fibromyalgia)</p>
|
|
<p>Mean age (SD)</p>
|
|
<p>39 ± 13 years</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Vaporised 22.4 mg THC and <1 mg CBD (n=20)</p>
|
|
<p>Titration period: None</p>
|
|
<p>Maintenance dose: Single dose</p>
|
|
<p>Mean dose with variance: All had 22.4mg THC and <1mg CBD</p>
|
|
<p>Follow-up: 3 hours</p>
|
|
<p>Vaporised 13.4 mg THC and 17.8 mg CBD (n=20)</p>
|
|
<p>Titration period: None</p>
|
|
<p>Maintenance dose: Single dose</p>
|
|
<p>Mean dose with variance: All had 22.4mg THC and <1mg CBD</p>
|
|
<p>Follow-up: 3 hours</p>
|
|
<p>Vaporised <1 mg THC and 18.4 mg CBD (n=20)</p>
|
|
<p>Titration period: None</p>
|
|
<p>Maintenance dose: Single dose</p>
|
|
<p>Mean dose with variance: All had 22.4mg THC and <1mg CBD</p>
|
|
<p>Follow-up: 3 hours</p>
|
|
<p>Placebo (n=20)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Mean average pain intensity</p>
|
|
<p>Proportion of patients who experienced pain relief of 30% or more from baseline</p>
|
|
<p>Proportion of patients who experienced pain relief of 50% or more from baseline</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>The incidence of patients experiencing adverse events was not reported. Data for the proportion of patients who experienced pain relief of 30% or 50% or more from baseline was not provided in an extractable format for 2 of the 3 interventions</p>
|
|
<p>Only one dose given and outcomes were recorded 3 hours afterwards. This is not a realistic way of assessing chronic pain treatment.</p>
|
|
</td></tr><tr><td headers="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>
|
|
<a class="bibr" href="#ch2.appl.ref19" rid="ch2.appl.ref19">Weber 2010</a>
|
|
</p>
|
|
<p>Crossover RCT</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Secondary pain: musculoskeletal (Cramps)</p>
|
|
<p>Mean age (SD)</p>
|
|
<p>57 (12)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oral delta-9-THC (dronabiniol) (n=11)</p>
|
|
<p>Titration period: No dose titration.</p>
|
|
<p>Maintenance dose: 5mg twice daily</p>
|
|
<p>Mean dose with variance: 6 drops equivalent to 5 mg taken twice daily (10mg total).</p>
|
|
<p>Follow-up: 2 weeks</p>
|
|
<p>Placebo (n=11)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Mean average pain intensity</p>
|
|
<p>Patients experiencing adverse events, all-causality</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Follow-up <6 months<sup>1</sup></td></tr><tr><td headers="hd_h_ch2.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>
|
|
<a class="bibr" href="#ch2.appl.ref20" rid="ch2.appl.ref20">Wissel 2006</a>
|
|
</p>
|
|
<p>Crossover RCT</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Secondary pain: musculoskeletal (Spasticity)</p>
|
|
<p>Mean age (SD)</p>
|
|
<p>44.8 (14.3)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oral nabilone (synthetic mimic of THC) (n=13)</p>
|
|
<p>Titration period: 1 week</p>
|
|
<p>Maintenance dose: Up to 48 actuations</p>
|
|
<p>Mean dose with variance: 8.34 actuations (SD 5.17)</p>
|
|
<p>Follow-up: 2 weeks</p>
|
|
<p>Placebo (n=13)</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Median average pain intensity</p>
|
|
<p>Patients experiencing adverse events, all-causality</p>
|
|
<p>Patients experiencing serious adverse events, all-causality</p>
|
|
<p>Withdrawals due to adverse events, all-causality</p>
|
|
</td><td headers="hd_h_ch2.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>No information provided on randomisation, blinding nor baseline characteristics</p>
|
|
<p>Follow-up <6 months<sup>1</sup></p>
|
|
</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="ch2.tab2_1"><p class="no_margin">The committee agreed that a follow-up period of 6 months is a realistic duration for assessing chronic pain treatments. This was agreed when making research recommendations after the evidence had been presented. Therefore, this did not influence our risk of bias assessments. Nevertheless, a follow-up period of <6 months is a study limitation.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobch2tab3"><div id="ch2.tab3" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.tab3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.tab3_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.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_ch2.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Indication</th><th id="hd_h_ch2.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Dose and duration</th><th id="hd_h_ch2.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Patient monitoring</th><th id="hd_h_ch2.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_ch2.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oromucosal spray 2.7 mg THC with 2.5 mg CBD per 100 microlitre actuation</p>
|
|
<p>(n=5)</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cancer</td><td headers="hd_h_ch2.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Up to between 10 to 48 actuations</p>
|
|
<p>For 2–4 weeks</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Three studies did not describe patient monitoring. For one study, patients were contacted by phone for follow-up safety evaluations 2 weeks after the final dose. For another study there were “Study visits throughout the trial”.</td><td headers="hd_h_ch2.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">No study had stopping criteria.</td></tr><tr><td headers="hd_h_ch2.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oromucosal spray 2.7 mg THC with 2.5 mg CBD per 100 microlitre actuation</p>
|
|
<p>(n=5)</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Neuropathic pain (including multiple sclerosis, peripheral neuropathic pain and neuropathic pain characterised by allodynia)</td><td headers="hd_h_ch2.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Up to between 12 to 48 actuations</p>
|
|
<p>For 2–15 weeks</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>One study described a phone call, performed by nursing staff, 14 to 20 days after the 5-week follow-up trial was initiated.</p>
|
|
<p>Another study explained that during the initial dose titration phase, patients recorded the time and number of actuations per day, in a dosing diary. Regular telephone contact was maintained according to individual patient requirements and a brief safety visit was conducted after two weeks.</p>
|
|
<p>Another study described that periodic telephone monitoring was undertaken at pre-arranged times during home dosing to check the patient’s condition and to answer any queries.</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">No study had stopping criteria.</td></tr><tr><td headers="hd_h_ch2.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oromucosal spray 2.7 mg THC with 2.5 mg CBD per 100 microlitre actuation</p>
|
|
<p>(n=1)</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Musculoskeletal pain (rheumatoid arthritis)</td><td headers="hd_h_ch2.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Up to 6 actuations</p>
|
|
<p>For 3 weeks</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not described</td><td headers="hd_h_ch2.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">None</td></tr><tr><td headers="hd_h_ch2.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oral delta-9-THC (dronabiniol)</p>
|
|
<p>(n=2)</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Neuropathic pain (multiple sclerosis)</td><td headers="hd_h_ch2.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Maximum doses were 15 mg per day and 5 mg twice a day</p>
|
|
<p>For 18 days to 12 weeks</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">In one study, for safety analysis, vital signs, laboratory parameters, (serious) AEs (SAEs) including (serious) adverse reactions (SARs) were regularly assessed.</td><td headers="hd_h_ch2.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">No study had stopping criteria.</td></tr><tr><td headers="hd_h_ch2.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oral delta-9-THC (dronabiniol)</p>
|
|
<p>(n=2)</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Visceral pain (abdominal pain and oesophageal functional pain)</td><td headers="hd_h_ch2.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Maximum doses were 8 mg single dose, 5 mg twice a day, 8 mg three times a day</p>
|
|
<p>For no duration (single dose) to 4 weeks</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">For the study that had a 4-week duration, efficacy and safety assessments were conducted preceding medication intake on day 1, after 15 treatment days, and 50–52 treatment days. Several phone calls were performed by the investigators during and after the treatment period (days 4–5, 9–10, 21–23, 28–30, 38–40, and 59–61) to evaluate the tolerability, safety, and compliance.</td><td headers="hd_h_ch2.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">No study had stopping criteria.</td></tr><tr><td headers="hd_h_ch2.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oral delta-9-THC (dronabiniol)</p>
|
|
<p>(n=1)</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Musculoskeletal pain (cramps)</td><td headers="hd_h_ch2.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Maximum dose was 5 mg twice a day</p>
|
|
<p>For 2 weeks</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not described</td><td headers="hd_h_ch2.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">None</td></tr><tr><td headers="hd_h_ch2.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oral nabilone</p>
|
|
<p>(n=1)</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Widespread pain (fibromyalgia)</td><td headers="hd_h_ch2.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Maximum dose was 1 mg twice a day</p>
|
|
<p>For 1 week</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not described</td><td headers="hd_h_ch2.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">None</td></tr><tr><td headers="hd_h_ch2.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oral nabilone</p>
|
|
<p>(n=1)</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Musculoskeletal pain (spasticity)</td><td headers="hd_h_ch2.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Maximum dose was 1 mg once a day</p>
|
|
<p>For 3 weeks</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">There were clinic visits where monitoring occurred. However, the timing of these is not provided.</td><td headers="hd_h_ch2.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">None</td></tr><tr><td headers="hd_h_ch2.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Oromucosal spray 2.7 mg THC only per 100 microlitre actuation</p>
|
|
<p>(n=1)</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cancer</td><td headers="hd_h_ch2.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Up to 48 actuations</p>
|
|
<p>For 2 weeks</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">“Study visits throughout the trial”</td><td headers="hd_h_ch2.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">None</td></tr><tr><td headers="hd_h_ch2.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Vaporised 22.4 mg THC and <1 mg CBD</p>
|
|
<p>(n=1)</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Widespread pain (fibromyalgia)</td><td headers="hd_h_ch2.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Complete content was inhaled by all</p>
|
|
<p>Single dose</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A (single dose)</td><td headers="hd_h_ch2.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td></tr><tr><td headers="hd_h_ch2.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Vaporised 13.4 mg THC and 17.8 mg CBD</p>
|
|
<p>(n=1)</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Widespread pain (fibromyalgia)</td><td headers="hd_h_ch2.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Complete content was inhaled by all</p>
|
|
<p>Single dose</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td></tr><tr><td headers="hd_h_ch2.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Vaporised <1 mg THC and 18.4 mg CBD</p>
|
|
<p>(n=1)</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Widespread pain (fibromyalgia)</td><td headers="hd_h_ch2.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Complete content was inhaled by all</p>
|
|
<p>Single dose</p>
|
|
</td><td headers="hd_h_ch2.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch2tab4"><div id="ch2.tab4" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.tab4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.tab4_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ch2.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch2.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch2.tab4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch2.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_ch2.tab4_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th><th id="hd_h_ch2.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_ch2.tab4_1_1_1_1 hd_h_ch2.tab4_1_1_1_2 hd_h_ch2.tab4_1_1_1_3 hd_h_ch2.tab4_1_1_1_4 hd_h_ch2.tab4_1_1_1_5 hd_h_ch2.tab4_1_1_1_6" id="hd_b_ch2.tab4_1_1_1_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Proportion of people who experienced pain relief of 30% or more from baseline for neuropathic and cancer pain (values greater than 1 favour THC + CBD)</th></tr><tr><td headers="hd_h_ch2.tab4_1_1_1_1 hd_b_ch2.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4 (<a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a>, <a class="bibr" href="#ch2.appl.ref14" rid="ch2.appl.ref14">Serpell 2014</a>, <a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>, <a class="bibr" href="#ch2.appl.ref11" rid="ch2.appl.ref11">Portenoy 2012</a>)</td><td headers="hd_h_ch2.tab4_1_1_1_2 hd_b_ch2.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.tab4_1_1_1_3 hd_b_ch2.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">826</td><td headers="hd_h_ch2.tab4_1_1_1_4 hd_b_ch2.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 1.49 (1.10, 2.01)</td><td headers="hd_h_ch2.tab4_1_1_1_5 hd_b_ch2.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td><td headers="hd_h_ch2.tab4_1_1_1_6 hd_b_ch2.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours THC + CBD</td></tr><tr><th headers="hd_h_ch2.tab4_1_1_1_1 hd_h_ch2.tab4_1_1_1_2 hd_h_ch2.tab4_1_1_1_3 hd_h_ch2.tab4_1_1_1_4 hd_h_ch2.tab4_1_1_1_5 hd_h_ch2.tab4_1_1_1_6" id="hd_b_ch2.tab4_1_1_3_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Functional impairment caused by pain: Pain Disability Index for neuropathic pain (0 to 70). Dose: up to 48 actuations (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.tab4_1_1_1_1 hd_b_ch2.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref10" rid="ch2.appl.ref10">Nurmikko 2007</a>)</td><td headers="hd_h_ch2.tab4_1_1_1_2 hd_b_ch2.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.tab4_1_1_1_3 hd_b_ch2.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">105</td><td headers="hd_h_ch2.tab4_1_1_1_4 hd_b_ch2.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD −5.85 (−9.61, −2.09)</td><td headers="hd_h_ch2.tab4_1_1_1_5 hd_b_ch2.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">High</td><td headers="hd_h_ch2.tab4_1_1_1_6 hd_b_ch2.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours THC + CBD</td></tr><tr><th headers="hd_h_ch2.tab4_1_1_1_1 hd_h_ch2.tab4_1_1_1_2 hd_h_ch2.tab4_1_1_1_3 hd_h_ch2.tab4_1_1_1_4 hd_h_ch2.tab4_1_1_1_5 hd_h_ch2.tab4_1_1_1_6" id="hd_b_ch2.tab4_1_1_5_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Patient Global Impression of Change (dichotomous<sup>1</sup>) for neuropathic pain (multiple sclerosis / peripheral neuropathic pain). Dose: up to 24 actuations (values greater than 1 favour THC + CBD)</th></tr><tr><td headers="hd_h_ch2.tab4_1_1_1_1 hd_b_ch2.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 (<a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a>, <a class="bibr" href="#ch2.appl.ref14" rid="ch2.appl.ref14">Serpell 2014</a>)</td><td headers="hd_h_ch2.tab4_1_1_1_2 hd_b_ch2.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.tab4_1_1_1_3 hd_b_ch2.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">470</td><td headers="hd_h_ch2.tab4_1_1_1_4 hd_b_ch2.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 1.58 (1.16, 2.15)</td><td headers="hd_h_ch2.tab4_1_1_1_5 hd_b_ch2.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td><td headers="hd_h_ch2.tab4_1_1_1_6 hd_b_ch2.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours THC + CBD</td></tr><tr><th headers="hd_h_ch2.tab4_1_1_1_1 hd_h_ch2.tab4_1_1_1_2 hd_h_ch2.tab4_1_1_1_3 hd_h_ch2.tab4_1_1_1_4 hd_h_ch2.tab4_1_1_1_5 hd_h_ch2.tab4_1_1_1_6" id="hd_b_ch2.tab4_1_1_7_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Patient Global Impression of Change (continuous) for cancer pain. Dose: up to 10 actuations (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.tab4_1_1_1_1 hd_b_ch2.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 (<a class="bibr" href="#ch2.appl.ref4" rid="ch2.appl.ref4">Fallon 2017</a>, <a class="bibr" href="#ch2.appl.ref7" rid="ch2.appl.ref7">Lichtman 2018</a>)</td><td headers="hd_h_ch2.tab4_1_1_1_2 hd_b_ch2.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.tab4_1_1_1_3 hd_b_ch2.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">585</td><td headers="hd_h_ch2.tab4_1_1_1_4 hd_b_ch2.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD −0.26 (−0.43, −0.09)</td><td headers="hd_h_ch2.tab4_1_1_1_5 hd_b_ch2.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td><td headers="hd_h_ch2.tab4_1_1_1_6 hd_b_ch2.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours THC + CBD</td></tr><tr><th headers="hd_h_ch2.tab4_1_1_1_1 hd_h_ch2.tab4_1_1_1_2 hd_h_ch2.tab4_1_1_1_3 hd_h_ch2.tab4_1_1_1_4 hd_h_ch2.tab4_1_1_1_5 hd_h_ch2.tab4_1_1_1_6" id="hd_b_ch2.tab4_1_1_9_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Quality of life: SF-36 physical for cancer pain. Dose: up to 12 actuations (values greater than 0 favour THC + CBD)</th></tr><tr><td headers="hd_h_ch2.tab4_1_1_1_1 hd_b_ch2.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref8" rid="ch2.appl.ref8">Lynch 2014</a>)</td><td headers="hd_h_ch2.tab4_1_1_1_2 hd_b_ch2.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Crossover RCT</td><td headers="hd_h_ch2.tab4_1_1_1_3 hd_b_ch2.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">16</td><td headers="hd_h_ch2.tab4_1_1_1_4 hd_b_ch2.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD −11.00 (−17.13, −4.87)</td><td headers="hd_h_ch2.tab4_1_1_1_5 hd_b_ch2.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td><td headers="hd_h_ch2.tab4_1_1_1_6 hd_b_ch2.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours placebo</td></tr><tr><th headers="hd_h_ch2.tab4_1_1_1_1 hd_h_ch2.tab4_1_1_1_2 hd_h_ch2.tab4_1_1_1_3 hd_h_ch2.tab4_1_1_1_4 hd_h_ch2.tab4_1_1_1_5 hd_h_ch2.tab4_1_1_1_6" id="hd_b_ch2.tab4_1_1_11_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Quality of life: SF-36 mental for cancer pain. Dose: up to 12 actuations (values greater than 0 favour THC + CBD)</th></tr><tr><td headers="hd_h_ch2.tab4_1_1_1_1 hd_b_ch2.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref8" rid="ch2.appl.ref8">Lynch 2014</a>)</td><td headers="hd_h_ch2.tab4_1_1_1_2 hd_b_ch2.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Crossover RCT</td><td headers="hd_h_ch2.tab4_1_1_1_3 hd_b_ch2.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">16</td><td headers="hd_h_ch2.tab4_1_1_1_4 hd_b_ch2.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD 10.95 (4.02, 17.88)</td><td headers="hd_h_ch2.tab4_1_1_1_5 hd_b_ch2.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td><td headers="hd_h_ch2.tab4_1_1_1_6 hd_b_ch2.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours THC + CBD</td></tr><tr><th headers="hd_h_ch2.tab4_1_1_1_1 hd_h_ch2.tab4_1_1_1_2 hd_h_ch2.tab4_1_1_1_3 hd_h_ch2.tab4_1_1_1_4 hd_h_ch2.tab4_1_1_1_5 hd_h_ch2.tab4_1_1_1_6" id="hd_b_ch2.tab4_1_1_13_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">People experiencing adverse events, all-causality for multiple sclerosis, neuropathic pain characterised by allodynia and cancer pain (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.tab4_1_1_1_1 hd_b_ch2.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6 (<a class="bibr" href="#ch2.appl.ref12" rid="ch2.appl.ref12">Rog 2005</a>, <a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a>
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<a class="bibr" href="#ch2.appl.ref10" rid="ch2.appl.ref10">Nurmikko 2007</a>, <a class="bibr" href="#ch2.appl.ref11" rid="ch2.appl.ref11">Portenoy 2012</a>, <a class="bibr" href="#ch2.appl.ref7" rid="ch2.appl.ref7">Lichtman 2018</a>, <a class="bibr" href="#ch2.appl.ref4" rid="ch2.appl.ref4">Fallon 2017</a>)</td><td headers="hd_h_ch2.tab4_1_1_1_2 hd_b_ch2.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.tab4_1_1_1_3 hd_b_ch2.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1,665</td><td headers="hd_h_ch2.tab4_1_1_1_4 hd_b_ch2.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 1.5 (1.20, 1.87)</td><td headers="hd_h_ch2.tab4_1_1_1_5 hd_b_ch2.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td><td headers="hd_h_ch2.tab4_1_1_1_6 hd_b_ch2.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours placebo</td></tr><tr><th headers="hd_h_ch2.tab4_1_1_1_1 hd_h_ch2.tab4_1_1_1_2 hd_h_ch2.tab4_1_1_1_3 hd_h_ch2.tab4_1_1_1_4 hd_h_ch2.tab4_1_1_1_5 hd_h_ch2.tab4_1_1_1_6" id="hd_b_ch2.tab4_1_1_15_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Withdrawals due to adverse events, all-causality for neuropathic, cancer and musculoskeletal pain (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.tab4_1_1_1_1 hd_b_ch2.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10 (<a class="bibr" href="#ch2.appl.ref18" rid="ch2.appl.ref18">Wade 2004</a>, <a class="bibr" href="#ch2.appl.ref14" rid="ch2.appl.ref14">Serpell 2014</a>, <a class="bibr" href="#ch2.appl.ref12" rid="ch2.appl.ref12">Rog 2005</a>, <a class="bibr" href="#ch2.appl.ref10" rid="ch2.appl.ref10">Nurmikko 2007</a>, <a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a>, <a class="bibr" href="#ch2.appl.ref11" rid="ch2.appl.ref11">Portenoy 2012</a>, <a class="bibr" href="#ch2.appl.ref7" rid="ch2.appl.ref7">Lichtman 2018</a>, <a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>, <a class="bibr" href="#ch2.appl.ref4" rid="ch2.appl.ref4">Fallon 2017</a>, <a class="bibr" href="#ch2.appl.ref1" rid="ch2.appl.ref1">Blake 2006</a>)</td><td headers="hd_h_ch2.tab4_1_1_1_2 hd_b_ch2.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.tab4_1_1_1_3 hd_b_ch2.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2,267</td><td headers="hd_h_ch2.tab4_1_1_1_4 hd_b_ch2.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 1.74 (1.18, 2.56)</td><td headers="hd_h_ch2.tab4_1_1_1_5 hd_b_ch2.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td><td headers="hd_h_ch2.tab4_1_1_1_6 hd_b_ch2.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours placebo</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="ch2.tab4_1"><p class="no_margin">For the PGIC outcome, the two treatment groups were compared using ordinal logistic regression and the proportional odds model, incorporating centre group.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobch2tab5"><div id="ch2.tab5" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.tab5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.tab5_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch2.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch2.tab5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch2.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_ch2.tab5_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th><th id="hd_h_ch2.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_ch2.tab5_1_1_1_1 hd_h_ch2.tab5_1_1_1_2 hd_h_ch2.tab5_1_1_1_3 hd_h_ch2.tab5_1_1_1_4 hd_h_ch2.tab5_1_1_1_5 hd_h_ch2.tab5_1_1_1_6" id="hd_b_ch2.tab5_1_1_1_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">People experiencing adverse events, treatment-related for neuropathic pain (multiple sclerosis) (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.tab5_1_1_1_1 hd_b_ch2.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref13" rid="ch2.appl.ref13">Schimrigk 2017</a>)</td><td headers="hd_h_ch2.tab5_1_1_1_2 hd_b_ch2.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.tab5_1_1_1_3 hd_b_ch2.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">240</td><td headers="hd_h_ch2.tab5_1_1_1_4 hd_b_ch2.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 2.87 (1.66, 4.94)</td><td headers="hd_h_ch2.tab5_1_1_1_5 hd_b_ch2.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">High</td><td headers="hd_h_ch2.tab5_1_1_1_6 hd_b_ch2.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours placebo</td></tr><tr><th headers="hd_h_ch2.tab5_1_1_1_1 hd_h_ch2.tab5_1_1_1_2 hd_h_ch2.tab5_1_1_1_3 hd_h_ch2.tab5_1_1_1_4 hd_h_ch2.tab5_1_1_1_5 hd_h_ch2.tab5_1_1_1_6" id="hd_b_ch2.tab5_1_1_3_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">People experiencing serious adverse events, all-causality for neuropathic pain (multiple sclerosis) (values greater than 1 favour placebo)</th></tr><tr><th headers="hd_h_ch2.tab5_1_1_1_1 hd_b_ch2.tab5_1_1_3_1 hd_h_ch2.tab5_1_1_1_2 hd_h_ch2.tab5_1_1_1_3 hd_h_ch2.tab5_1_1_1_4 hd_h_ch2.tab5_1_1_1_5 hd_h_ch2.tab5_1_1_1_6" id="hd_b_ch2.tab5_1_1_4_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Withdrawals due to adverse events, all-causality for neuropathic and visceral pain (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.tab5_1_1_1_1 hd_b_ch2.tab5_1_1_3_1 hd_b_ch2.tab5_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4 (<a class="bibr" href="#ch2.appl.ref13" rid="ch2.appl.ref13">Schimrigk 2017</a>, <a class="bibr" href="#ch2.appl.ref16" rid="ch2.appl.ref16">Svendsen 2004</a>, de Vries 2015, <a class="bibr" href="#ch2.appl.ref3" rid="ch2.appl.ref3">de Vries 2017</a>)</td><td headers="hd_h_ch2.tab5_1_1_1_2 hd_b_ch2.tab5_1_1_3_1 hd_b_ch2.tab5_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs and 1 crossover RCT</td><td headers="hd_h_ch2.tab5_1_1_1_3 hd_b_ch2.tab5_1_1_3_1 hd_b_ch2.tab5_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">398</td><td headers="hd_h_ch2.tab5_1_1_1_4 hd_b_ch2.tab5_1_1_3_1 hd_b_ch2.tab5_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 6.08 (1.83, 20.23)</td><td headers="hd_h_ch2.tab5_1_1_1_5 hd_b_ch2.tab5_1_1_3_1 hd_b_ch2.tab5_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td><td headers="hd_h_ch2.tab5_1_1_1_6 hd_b_ch2.tab5_1_1_3_1 hd_b_ch2.tab5_1_1_4_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="figobch2tab6"><div id="ch2.tab6" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.tab6/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.tab6_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch2.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch2.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch2.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_ch2.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th><th id="hd_h_ch2.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_ch2.tab6_1_1_1_1 hd_h_ch2.tab6_1_1_1_2 hd_h_ch2.tab6_1_1_1_3 hd_h_ch2.tab6_1_1_1_4 hd_h_ch2.tab6_1_1_1_5 hd_h_ch2.tab6_1_1_1_6" id="hd_b_ch2.tab6_1_1_1_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Functional impairment caused by pain: Fibromyalgia Impact Questionnaire for widespread pain (fibromyalgia) (0 to 100) (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.tab6_1_1_1_1 hd_b_ch2.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref15" rid="ch2.appl.ref15">Skrabek 2008</a>)</td><td headers="hd_h_ch2.tab6_1_1_1_2 hd_b_ch2.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.tab6_1_1_1_3 hd_b_ch2.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">33</td><td headers="hd_h_ch2.tab6_1_1_1_4 hd_b_ch2.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD −10.76 (−18.45, −3.07)</td><td headers="hd_h_ch2.tab6_1_1_1_5 hd_b_ch2.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td><td headers="hd_h_ch2.tab6_1_1_1_6 hd_b_ch2.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Favours nabilone</td></tr><tr><th headers="hd_h_ch2.tab6_1_1_1_1 hd_h_ch2.tab6_1_1_1_2 hd_h_ch2.tab6_1_1_1_3 hd_h_ch2.tab6_1_1_1_4 hd_h_ch2.tab6_1_1_1_5 hd_h_ch2.tab6_1_1_1_6" id="hd_b_ch2.tab6_1_1_3_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">People experiencing adverse events, all-causality for musculoskeletal and widespread pain (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.tab6_1_1_1_1 hd_b_ch2.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 (<a class="bibr" href="#ch2.appl.ref15" rid="ch2.appl.ref15">Skrabek 2008</a>, <a class="bibr" href="#ch2.appl.ref20" rid="ch2.appl.ref20">Wissel 2006</a>)</td><td headers="hd_h_ch2.tab6_1_1_1_2 hd_b_ch2.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT and crossover RCT</td><td headers="hd_h_ch2.tab6_1_1_1_3 hd_b_ch2.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">46</td><td headers="hd_h_ch2.tab6_1_1_1_4 hd_b_ch2.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 1.60 (1.06, 2.42)</td><td headers="hd_h_ch2.tab6_1_1_1_5 hd_b_ch2.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td><td headers="hd_h_ch2.tab6_1_1_1_6 hd_b_ch2.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="figobch2tab7"><div id="ch2.tab7" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.tab7/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.tab7_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch2.tab7_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch2.tab7_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch2.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_ch2.tab7_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th><th id="hd_h_ch2.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_ch2.tab7_1_1_1_1 hd_h_ch2.tab7_1_1_1_2 hd_h_ch2.tab7_1_1_1_3 hd_h_ch2.tab7_1_1_1_4 hd_h_ch2.tab7_1_1_1_5 hd_h_ch2.tab7_1_1_1_6" id="hd_b_ch2.tab7_1_1_1_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Functional impairment caused by pain: Brief Pain Inventory - Short Form (0 to 10) for cancer pain (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.tab7_1_1_1_1 hd_b_ch2.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1 (<a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>)</td><td headers="hd_h_ch2.tab7_1_1_1_2 hd_b_ch2.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Parallel RCT</td><td headers="hd_h_ch2.tab7_1_1_1_3 hd_b_ch2.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">96</td><td headers="hd_h_ch2.tab7_1_1_1_4 hd_b_ch2.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MD −4.07 (−8.05, −0.09)</td><td headers="hd_h_ch2.tab7_1_1_1_5 hd_b_ch2.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Low</td><td headers="hd_h_ch2.tab7_1_1_1_6 hd_b_ch2.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Favours placebo</td></tr><tr><th headers="hd_h_ch2.tab7_1_1_1_1 hd_h_ch2.tab7_1_1_1_2 hd_h_ch2.tab7_1_1_1_3 hd_h_ch2.tab7_1_1_1_4 hd_h_ch2.tab7_1_1_1_5 hd_h_ch2.tab7_1_1_1_6" id="hd_b_ch2.tab7_1_1_3_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Change in analgesics: daily total dose change, morphine equivalents for cancer pain (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.tab7_1_1_1_1 hd_b_ch2.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1 (<a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>)</td><td headers="hd_h_ch2.tab7_1_1_1_2 hd_b_ch2.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Parallel RCT</td><td headers="hd_h_ch2.tab7_1_1_1_3 hd_b_ch2.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">96</td><td headers="hd_h_ch2.tab7_1_1_1_4 hd_b_ch2.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MD 68.30 (3.74, 132.86)</td><td headers="hd_h_ch2.tab7_1_1_1_5 hd_b_ch2.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Low</td><td headers="hd_h_ch2.tab7_1_1_1_6 hd_b_ch2.tab7_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Favours placebo</td></tr><tr><th headers="hd_h_ch2.tab7_1_1_1_1 hd_h_ch2.tab7_1_1_1_2 hd_h_ch2.tab7_1_1_1_3 hd_h_ch2.tab7_1_1_1_4 hd_h_ch2.tab7_1_1_1_5 hd_h_ch2.tab7_1_1_1_6" id="hd_b_ch2.tab7_1_1_5_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">People experiencing serious adverse events (all-causality) for cancer pain (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.tab7_1_1_1_1 hd_b_ch2.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1 (<a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>)</td><td headers="hd_h_ch2.tab7_1_1_1_2 hd_b_ch2.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Parallel RCT</td><td headers="hd_h_ch2.tab7_1_1_1_3 hd_b_ch2.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">117</td><td headers="hd_h_ch2.tab7_1_1_1_4 hd_b_ch2.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">OR 3.34 (1.27, 8.78)</td><td headers="hd_h_ch2.tab7_1_1_1_5 hd_b_ch2.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Low</td><td headers="hd_h_ch2.tab7_1_1_1_6 hd_b_ch2.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Favours placebo</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch2tab8"><div id="ch2.tab8" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.tab8/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.tab8_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch2.tab8_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch2.tab8_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch2.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_ch2.tab8_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th><th id="hd_h_ch2.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_ch2.tab8_1_1_1_1 hd_h_ch2.tab8_1_1_1_2 hd_h_ch2.tab8_1_1_1_3 hd_h_ch2.tab8_1_1_1_4 hd_h_ch2.tab8_1_1_1_5 hd_h_ch2.tab8_1_1_1_6" id="hd_b_ch2.tab8_1_1_1_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:middle;">Proportion of people who experienced pain relief of 30% or more from baseline (fibromyalgia) (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.tab8_1_1_1_1 hd_b_ch2.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1 (<a class="bibr" href="#ch2.appl.ref17" rid="ch2.appl.ref17">van de Donk 2019</a>)</td><td headers="hd_h_ch2.tab8_1_1_1_2 hd_b_ch2.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Crossover RCT</td><td headers="hd_h_ch2.tab8_1_1_1_3 hd_b_ch2.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">20</td><td headers="hd_h_ch2.tab8_1_1_1_4 hd_b_ch2.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">OR 7.36 (1.35, 40.55)</td><td headers="hd_h_ch2.tab8_1_1_1_5 hd_b_ch2.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Very low</td><td headers="hd_h_ch2.tab8_1_1_1_6 hd_b_ch2.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Favours THC + CBD</td></tr></tbody></table></div></div></article><article data-type="boxed-text" id="figobch2box1"><div id="ch2.box1" 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 1.2.1</a> to <a href="/books/n/niceng144/?report=reader" class="toc-item">1.2.3</a> and the research recommendations on fibromyalgia or persistent treatment-resistant neuropathic pain in adults and chronic pain in children and young people.</p></div></article><article data-type="table-wrap" id="figobch2appatab1"><div id="ch2.appa.tab1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appa.tab1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appa.tab1_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">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_ch2.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Content</th></tr></thead><tbody><tr><td headers="hd_h_ch2.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Review question</td><td headers="hd_h_ch2.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>What is the clinical and cost effectiveness of cannabis-based medicinal products for people with chronic pain?</p>
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<p>What are the adverse effects or complications of cannabis-based medicinal products for people with chronic pain?</p>
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<p>What are the contraindications, potential interactions and risks and cautions for use of cannabis-based medicinal products for people with chronic pain?</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 chronic pain?</p>
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</td></tr><tr><td headers="hd_h_ch2.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_ch2.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_ch2.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_ch2.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 chronic pain in adults and persisting pain in children.</td></tr><tr><td headers="hd_h_ch2.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Eligibility criteria – population/disease/condition/issue/do main</td><td headers="hd_h_ch2.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Adults, young people, children and babies.</p>
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<p>Specific considerations were given to:
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<ul id="ch2.l14"><li id="ch2.lt45" class="half_rhythm"><div>Young people, children and babies</div></li><li id="ch2.lt46" class="half_rhythm"><div>Pregnant women and women who are breastfeeding</div></li><li id="ch2.lt47" class="half_rhythm"><div>People with existing substance abuse</div></li><li id="ch2.lt48" class="half_rhythm"><div>People with hepatic and renal failure</div></li></ul>
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Chronic pain for adults is defined as pain lasting for 3 months or longer.</p>
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<p>The committee agreed that any pain in children which is not acute is considered as chronic pain. The term ‘persisting pain’ may be more used in a paediatric population than ‘chronic pain’.</p>
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</td></tr><tr><td headers="hd_h_ch2.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_ch2.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<ol id="ch2.l15"><li id="ch2.lt49" 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="ch2.l16"><li id="ch2.lt50" 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="ch2.lt51" class="half_rhythm"><div>is produced for medicinal use in humans; and</div></li><li id="ch2.lt52" class="half_rhythm"><div>is a medicinal product, or</div></li><li id="ch2.lt53" 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 (<a href="http://www.legislation.gov.uk/uksi/2018/1055/made" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MDR 2018 regulations</a>)</div></li></ul></div></li><li id="ch2.lt54" 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="ch2.lt55" class="half_rhythm"><div>Licensed products Sativex and nabilone</div></li><li id="ch2.lt56" class="half_rhythm"><div>Plant-derived cannabinoids such as pure cannabidiol</div></li></ol>
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For the purpose of this guideline, all the interventions above were classed as cannabis-based medicinal products.</td></tr><tr><td headers="hd_h_ch2.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_ch2.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Placebo</td></tr><tr><td headers="hd_h_ch2.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Outcomes</td><td headers="hd_h_ch2.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<ul id="ch2.l17"><li id="ch2.lt57" class="half_rhythm"><div>Participant reported pain relief of 30% or greater</div></li><li id="ch2.lt58" class="half_rhythm"><div>Participant reported pain relief of 50% or greater (to assist the economic analysis)</div></li><li id="ch2.lt59" class="half_rhythm"><div>Reduction in analgesics required</div></li><li id="ch2.lt60" class="half_rhythm"><div>Change in pain intensity using Numerical Rating Scale’, or Visual Analogue Scale’</div></li><li id="ch2.lt61" class="half_rhythm"><div>Functional impairment specific to the type of pain. For neuropathic pain: McGill Pain Questionnaire. For nociceptive pain: Brief Pain Inventory.</div></li><li id="ch2.lt62" class="half_rhythm"><div>Participant/Patient/Subject Global Impression of Change (PGIC or SGIG) scale</div></li><li id="ch2.lt63" class="half_rhythm"><div>Quality of life score using SF-36 or EQ-5D.</div></li><li id="ch2.lt64" class="half_rhythm"><div>Serious adverse events</div></li><li id="ch2.lt65" 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="ch2.lt66" class="half_rhythm"><div>Withdrawals due to adverse events</div></li><li id="ch2.lt67" class="half_rhythm"><div>Complications due to adverse events</div></li><li id="ch2.lt68" class="half_rhythm"><div>Substance abuse due to the use of cannabis-based medicinal product.</div></li><li id="ch2.lt69" class="half_rhythm"><div>Misuse/diversion</div></li><li id="ch2.lt70" 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="ch2.l18"><li id="ch2.lt71" class="half_rhythm"><div>Contraindications as listed in exclusion criteria</div><div>Monitoring requirements, treatment durations, reviewing and stopping criteria, including how should treatment be withdrawn stopped as discussed in the methods of individual RCTs</div></li></ul></td></tr><tr><td headers="hd_h_ch2.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_ch2.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>For adults:
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<ul id="ch2.l19"><li id="ch2.lt72" class="half_rhythm"><div>RCTs</div></li><li id="ch2.lt73" class="half_rhythm"><div>Systematic reviews of RCTs</div></li></ul>
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If less than five RCTs identified, prospective cohort studies were to be used.</p>
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<p>For children:
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<ul id="ch2.l20"><li id="ch2.lt74" class="half_rhythm"><div>RCTs</div></li><li id="ch2.lt75" class="half_rhythm"><div>Systematic reviews of RCTs</div></li></ul>
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If less than five RCTs identified, prospective and retrospective cohort studies were to be used.</p>
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<p>Additional information on safety concerns and contraindications were obtained from the Summary of Product Characteristics and other relevant sources, such as the U.S Food and Drugs Administration.</p>
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</td></tr><tr><td headers="hd_h_ch2.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_ch2.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Inclusion</p>
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<p>Cannabis-based products for the medicinal use when other treatments haven’t helped or have been discounted.</p>
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<p>Exclusion
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<ul id="ch2.l21"><li id="ch2.lt76" class="half_rhythm"><div>Synthetic cannabinoids in schedule 1 of the 2001 regulations,</div></li><li id="ch2.lt77" class="half_rhythm"><div>Smoked cannabis-based products</div></li><li id="ch2.lt78" class="half_rhythm"><div>Studies which do not report the doses or the concentration of cannabinoid constituents.</div></li><li id="ch2.lt79" class="half_rhythm"><div>Headaches and orofacial pain. However, headaches caused by cancer were included.</div></li><li id="ch2.lt80" class="half_rhythm"><div>For randomised crossover studies, washout periods of less than 1 week.</div></li></ul></p>
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</td></tr><tr><td headers="hd_h_ch2.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_ch2.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Where possible for adults, data were stratified according to the ICD-11 definition of pain as primary or secondary pain. For primary pain, data was analysed according to whether it was chronic widespread pain, complex regional pain syndrome, chronic primary visceral pain or chronic primary musculoskeletal pain.</p>
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<p>For secondary pain, data was analysed according to whether it was chronic cancer-related pain, chronic postsurgical or posttraumatic pain, chronic neuropathic pain, chronic secondary visceral pain or chronic secondary musculoskeletal pain.</p>
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<p>Subgroups, where possible, included:
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<ul id="ch2.l22"><li id="ch2.lt81" class="half_rhythm"><div>Young people, children and babies</div></li><li id="ch2.lt82" class="half_rhythm"><div>Pregnant women and women who are breastfeeding</div></li><li id="ch2.lt83" class="half_rhythm"><div>People with existing substance abuse</div></li></ul></p>
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</td></tr><tr><td headers="hd_h_ch2.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_ch2.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10% of the abstracts was reviewed by two reviewers, with any disagreements being resolved by discussion or, if necessary, a third independent reviewer. If meaningful disagreements were found between the different reviewers, a further 10% of the abstracts was reviewed by two reviewers, with this process continuing until agreement was achieved between the two reviewers. From this point, the remaining abstracts were screened by a single reviewer.</td></tr><tr><td headers="hd_h_ch2.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_ch2.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">See <a href="#ch2.appb">Appendix B</a>.</td></tr><tr><td headers="hd_h_ch2.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_ch2.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>Sources to be searched</b>
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<ul id="ch2.l23"><li id="ch2.lt84" class="half_rhythm"><div>Clinical searches - Medline, Medline in Process, Medline EPub Ahead of Print, Embase, Cochrane CDSR, CENTRAL, DARE (legacy records), HTA, MHRA.
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<ul id="ch2.l24" class="circle"><li id="ch2.lt85" class="half_rhythm"><div>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.</div></li></ul></div></li></ul>
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<b>Supplementary search techniques</b>
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<ul id="ch2.l25"><li id="ch2.lt86" class="half_rhythm"><div>None identified</div></li></ul>
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<b>Limits</b>
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<ul id="ch2.l26"><li id="ch2.lt87" class="half_rhythm"><div>Studies reported in English</div></li><li id="ch2.lt88" class="half_rhythm"><div>Study design RCT, SR and Observational filter was applied (as agreed)</div></li><li id="ch2.lt89" class="half_rhythm"><div>Animal studies were excluded from the search results</div></li><li id="ch2.lt90" class="half_rhythm"><div>Conference abstracts were excluded from the search results</div></li><li id="ch2.lt91" class="half_rhythm"><div>No date limit was set.</div></li></ul></td></tr><tr><td headers="hd_h_ch2.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_ch2.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_ch2.appa.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Author contacts</td><td headers="hd_h_ch2.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_ch2.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_ch2.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_ch2.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_ch2.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">For details please see <a href="#ch2.appc">appendix C</a> of relevant chapter.</td></tr><tr><td headers="hd_h_ch2.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_ch2.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">A standardised evidence table format was used, and published as <a href="#ch2.appd">appendix D</a> (clinical evidence tables) or <a href="#ch2.apph">Appendix H</a>H (economic evidence tables).</td></tr><tr><td headers="hd_h_ch2.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_ch2.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="#ch2.appd">appendix D</a> (clinical evidence tables) or <a href="#ch2.apph">H</a> (economic evidence tables).</td></tr><tr><td headers="hd_h_ch2.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_ch2.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="#ch2.apph">appendix H</a> of <a href="https://www.nice.org.uk/process/pmg20/resources/appendix-h-pdf-2549710190" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Developing NICE guidelines: the manual</a></p>
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<p>The following checklists were used:</p>
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<p>Risk of bias of intervention studies - systematic reviews and meta-analyses were assessed using the <a href="http://www.bristol.ac.uk/media-library/sites/social-community-medicine/robis/robisguidancedocument.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Risk of Bias in Systematic Reviews (ROBIS) checklist</a></p>
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<p>Risk of bias of intervention studies – randomised controlled trials (individual or cluster) were assessed using the <a href="https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Cochrane risk of bias (RoB) 2.0 tool</a></p>
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<p>Risk of bias of cohort studies were assessed using <a href="https://sites.google.com/site/riskofbiastool/welcome/home" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Cochrane ROBINS-I</a></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_ch2.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_ch2.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="http://file://nice.nhs.uk/Data/Clinical%20Practice/1-GuidelineUpdatesTeam/Technical%20Team/Methods%20documents/2018%20methods%20manual/developing-nice-guidelines-the-manual-pdf-NEW.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Developing NICE guidelines: the manual</a></td></tr><tr><td headers="hd_h_ch2.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_ch2.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">For details please see the <a href="#ch2.s1.3">methods and process</a> section of the main file.</td></tr><tr><td headers="hd_h_ch2.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_ch2.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">For details please see section 6.2 of <a href="http://file://nice.nhs.uk/Data/Clinical%20Practice/1-GuidelineUpdatesTeam/Technical%20Team/Methods%20documents/2018%20methods%20manual/developing-nice-guidelines-the-manual-pdf-NEW.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Developing NICE guidelines: the manual</a>.</td></tr><tr><td headers="hd_h_ch2.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_ch2.appa.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">For details please see sections 6 and 9 of <a href="http://file://nice.nhs.uk/Data/Clinical%20Practice/1-GuidelineUpdatesTeam/Technical%20Team/Methods%20documents/2018%20methods%20manual/developing-nice-guidelines-the-manual-pdf-NEW.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Developing NICE guidelines: the manual</a></td></tr><tr><td headers="hd_h_ch2.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_ch2.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_ch2.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_ch2.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 [add name of developer] and chaired by [add name of Chair] in line with section 3 of <a href="http://file://nice.nhs.uk/Data/Clinical%20Practice/1-GuidelineUpdatesTeam/Technical%20Team/Methods%20documents/2018%20methods%20manual/developing-nice-guidelines-the-manual-pdf-NEW.pdf" 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="http://file://nice.nhs.uk/Data/Clinical%20Practice/1-GuidelineUpdatesTeam/Technical%20Team/Methods%20documents/2018%20methods%20manual/developing-nice-guidelines-the-manual-pdf-NEW.pdf" 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_ch2.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_ch2.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_ch2.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_ch2.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_ch2.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_ch2.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="figobch2appbtab1"><div id="ch2.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/NBK577083/table/ch2.appb.tab1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appb.tab1_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.appb.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">GRADE criteria</th><th id="hd_h_ch2.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_ch2.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_ch2.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_ch2.appb.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Indirectness</td><td headers="hd_h_ch2.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_ch2.appb.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Inconsistency</td><td headers="hd_h_ch2.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_ch2.appb.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Imprecision</td><td headers="hd_h_ch2.appb.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>For outcomes where the line of no effect was defined as the MID, 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 (<40 participants). For outcomes with specified MIDs (−0.9 for pain intensity reported on the NRS or VAS scales), these were downgraded once if the 95% confidence interval for the effect size crossed one MID. The sample size was also considered as a factor for downgrading for imprecision.</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="table-wrap" id="figobch2appctab1"><div id="ch2.appc.tab1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appc.tab1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appc.tab1_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Database: MHRA
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<ul id="ch2.l36"><li id="ch2.lt294" class="half_rhythm"><div><a href="https://www.gov.uk/drug-device-alerts" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Alerts and recalls for drugs and medical devices</a></div></li><li id="ch2.lt295" class="half_rhythm"><div><a href="https://www.gov.uk/drug-safety-update" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Drug safety update</a></div></li></ul></th></tr></thead><tbody><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Strategy used:</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Sativex</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dronabinol</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Epidiolex</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">THC:CBD spray</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nabilone</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Tetrabinex</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nabidiolex</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cesamet</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Tilray</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bedrocan</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bedrobinol</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bedica</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bediol</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bedrolite</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Marinol</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Syndros</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">THC</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Tetrahydrocannabinol</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cannabinol</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cannibigerol</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cannabichromene</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Tetrahydrocannabivarin</td></tr><tr><td headers="hd_h_ch2.appc.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cannabidivarin</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch2appctab2"><div id="ch2.appc.tab2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appc.tab2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appc.tab2_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.appc.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Databases</th><th id="hd_h_ch2.appc.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Date searched</th><th id="hd_h_ch2.appc.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Version/files</th><th id="hd_h_ch2.appc.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">No. retrieved</th><th id="hd_h_ch2.appc.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">RefMan data</th></tr></thead><tbody><tr><td headers="hd_h_ch2.appc.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="http://ovidsp.uk.ovid.com/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Embase (Ovid)</a>
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</td><td headers="hd_h_ch2.appc.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">20/12/2018</td><td headers="hd_h_ch2.appc.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1974 to 2018 December 18</td><td headers="hd_h_ch2.appc.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2011</td><td headers="hd_h_ch2.appc.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2427–4437</td></tr><tr><td headers="hd_h_ch2.appc.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="http://ovidsp.uk.ovid.com/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MEDLINE (Ovid)</a>
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</td><td headers="hd_h_ch2.appc.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">20/12/2018</td><td headers="hd_h_ch2.appc.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1946 to December 19, 2018</td><td headers="hd_h_ch2.appc.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2264</td><td headers="hd_h_ch2.appc.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1–2264</td></tr><tr><td headers="hd_h_ch2.appc.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="http://ovidsp.uk.ovid.com/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MEDLINE In-Process (Ovid)</a>
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</td><td headers="hd_h_ch2.appc.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">20/12/2018</td><td headers="hd_h_ch2.appc.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">December 19, 2018</td><td headers="hd_h_ch2.appc.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">132</td><td headers="hd_h_ch2.appc.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2265–2396</td></tr><tr><td headers="hd_h_ch2.appc.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MEDLINE epubs (Ovid)</td><td headers="hd_h_ch2.appc.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">20/12/2018</td><td headers="hd_h_ch2.appc.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">December 19, 2018</td><td headers="hd_h_ch2.appc.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">30</td><td headers="hd_h_ch2.appc.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2397–2426</td></tr><tr><td headers="hd_h_ch2.appc.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MHRA</a> – Drug Safety Alerts<sup>2</sup></td><td headers="hd_h_ch2.appc.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appc.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appc.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appc.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch2appctab3"><div id="ch2.appc.tab3" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appc.tab3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appc.tab3_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Database: MEDLINE</th></tr></thead><tbody><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Strategy used:</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Database: Ovid MEDLINE(R) <1946 to December 18, 2018></td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Search Strategy:</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">------------------------------------------------------------</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1 Medical Marijuana/ (732)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2 cannabinoids/ or cannabidiol/ or cannabinol/ or cannabis/ (14684)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3 ((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 THC or tetrahydrocannabinol* or 9-delta-tetra-hydrocannabinol* or “9 delta tetra hydrocannabinol” or compound*)).tw. (5770)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">4 (epidiolex* or cannabidiol* or cannabinoid*).tw. (15896)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5 (sativex or THC:CBD spray or tetrabinex or nabidiolex).tw. (173)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">6 (nabilone or cesamet).tw. (237)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">7 (tilray* or bedrocan* or bedrobinol* or bedica* or bediol* or bedrolite*).tw. (7)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">8 or/1–7 (25311)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">9 Observational Studies as Topic/ (3464)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10 Observational Study/ (55720)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">11 Epidemiologic Studies/ (7826)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">12 exp Case-Control Studies/ (960041)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">13 exp Cohort Studies/ (1807116)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">14 Cross-Sectional Studies/ (281284)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">15 Controlled Before-After Studies/ (366)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">16 Historically Controlled Study/ (146)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">17 Interrupted Time Series Analysis/ (512)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">18 Comparative Study.pt. (1816843)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">19 case control$.tw. (101282)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">20 case series.tw. (51003)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">21 (cohort adj (study or studies)).tw. (138635)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">22 cohort analy$.tw. (5562)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">23 (follow up adj (study or studies)).tw. (42522)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">24 (observational adj (study or studies)).tw. (71051)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">25 longitudinal.tw. (179685)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">26 prospective.tw. (445972)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">27 retrospective.tw. (382273)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">28 cross sectional.tw. (241222)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">29 or/9–28 (4036363)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">30 8 and 29 (3359)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">31 animals/ not humans/ (4493878)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">32 30 not 31 (2413)</td></tr><tr><td headers="hd_h_ch2.appc.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">33 limit 32 to english language (2270)</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobch2appdfig1"><div id="ch2.appd.fig1" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appdf1&p=BOOKS&id=577083_ch2appdf1.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/NBK577083/bin/ch2appdf1.jpg" alt="Image ch2appdf1" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appdfig2"><div id="ch2.appd.fig2" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appdf2&p=BOOKS&id=577083_ch2appdf2.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/NBK577083/bin/ch2appdf2.jpg" alt="Image ch2appdf2" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig1"><div id="ch2.appf.fig1" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff1&p=BOOKS&id=577083_ch2appff1.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/NBK577083/bin/ch2appff1.jpg" alt="Image ch2appff1" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig2"><div id="ch2.appf.fig2" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff2&p=BOOKS&id=577083_ch2appff2.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/NBK577083/bin/ch2appff2.jpg" alt="Image ch2appff2" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig3"><div id="ch2.appf.fig3" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff3&p=BOOKS&id=577083_ch2appff3.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/NBK577083/bin/ch2appff3.jpg" alt="Image ch2appff3" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig4"><div id="ch2.appf.fig4" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff4&p=BOOKS&id=577083_ch2appff4.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/NBK577083/bin/ch2appff4.jpg" alt="Image ch2appff4" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig5"><div id="ch2.appf.fig5" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff5&p=BOOKS&id=577083_ch2appff5.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/NBK577083/bin/ch2appff5.jpg" alt="Image ch2appff5" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig6"><div id="ch2.appf.fig6" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff6&p=BOOKS&id=577083_ch2appff6.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/NBK577083/bin/ch2appff6.jpg" alt="Image ch2appff6" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig7"><div id="ch2.appf.fig7" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff7&p=BOOKS&id=577083_ch2appff7.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/NBK577083/bin/ch2appff7.jpg" alt="Image ch2appff7" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig8"><div id="ch2.appf.fig8" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff8&p=BOOKS&id=577083_ch2appff8.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/NBK577083/bin/ch2appff8.jpg" alt="Image ch2appff8" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig9"><div id="ch2.appf.fig9" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff9&p=BOOKS&id=577083_ch2appff9.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/NBK577083/bin/ch2appff9.jpg" alt="Image ch2appff9" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig10"><div id="ch2.appf.fig10" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff10&p=BOOKS&id=577083_ch2appff10.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/NBK577083/bin/ch2appff10.jpg" alt="Image ch2appff10" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig11"><div id="ch2.appf.fig11" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff11&p=BOOKS&id=577083_ch2appff11.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/NBK577083/bin/ch2appff11.jpg" alt="Image ch2appff11" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig12"><div id="ch2.appf.fig12" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff12&p=BOOKS&id=577083_ch2appff12.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/NBK577083/bin/ch2appff12.jpg" alt="Image ch2appff12" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig13"><div id="ch2.appf.fig13" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff13&p=BOOKS&id=577083_ch2appff13.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/NBK577083/bin/ch2appff13.jpg" alt="Image ch2appff13" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig14"><div id="ch2.appf.fig14" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff14&p=BOOKS&id=577083_ch2appff14.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/NBK577083/bin/ch2appff14.jpg" alt="Image ch2appff14" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig15"><div id="ch2.appf.fig15" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff15&p=BOOKS&id=577083_ch2appff15.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/NBK577083/bin/ch2appff15.jpg" alt="Image ch2appff15" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig16"><div id="ch2.appf.fig16" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff16&p=BOOKS&id=577083_ch2appff16.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/NBK577083/bin/ch2appff16.jpg" alt="Image ch2appff16" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig17"><div id="ch2.appf.fig17" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff17&p=BOOKS&id=577083_ch2appff17.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/NBK577083/bin/ch2appff17.jpg" alt="Image ch2appff17" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig18"><div id="ch2.appf.fig18" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff18&p=BOOKS&id=577083_ch2appff18.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/NBK577083/bin/ch2appff18.jpg" alt="Image ch2appff18" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig19"><div id="ch2.appf.fig19" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff19&p=BOOKS&id=577083_ch2appff19.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/NBK577083/bin/ch2appff19.jpg" alt="Image ch2appff19" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig20"><div id="ch2.appf.fig20" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff20&p=BOOKS&id=577083_ch2appff20.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/NBK577083/bin/ch2appff20.jpg" alt="Image ch2appff20" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobch2appffig21"><div id="ch2.appf.fig21" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ch2appff21&p=BOOKS&id=577083_ch2appff21.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/NBK577083/bin/ch2appff21.jpg" alt="Image ch2appff21" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="table-wrap" id="figobch2appgtab1"><div id="ch2.appg.tab1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appg.tab1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appg.tab1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ch2.appg.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch2.appg.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch2.appg.tab1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch2.appg.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_ch2.appg.tab1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Risk of bias</th><th id="hd_h_ch2.appg.tab1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Inconsistency</th><th id="hd_h_ch2.appg.tab1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Indirectness</th><th id="hd_h_ch2.appg.tab1_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Imprecision</th><th id="hd_h_ch2.appg.tab1_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th></tr></thead><tbody><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_1_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Proportion of people who experienced pain relief of 30% or more from baseline for neuropathic and cancer pain (values greater than 1 favour THC + CBD)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4 (<a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a>, <a class="bibr" href="#ch2.appl.ref14" rid="ch2.appl.ref14">Serpell 2014</a>, <a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>, <a class="bibr" href="#ch2.appl.ref11" rid="ch2.appl.ref11">Portenoy 2012</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">826</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 1.49 (1.10, 2.01)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup><sup>,</sup><sup>2</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_3_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Proportion of people who experienced pain relief of 50% or more from baseline for neuropathic pain (multiple sclerosis). Dose: up to 24 actuations (values greater than 1 favour THC + CBD)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 (<a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a>, <a class="bibr" href="#ch2.appl.ref14" rid="ch2.appl.ref14">Serpell 2014</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">470</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 1.19 (0.76, 1.86)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>4</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_5_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Mean average pain intensity: Numerical Rating Scale (0 to 10) or Visual Analogue Scale (0 to 100)/10 converted to NRS for neuropathic, cancer and musculoskeletal pain (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">11 (<a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a>, <a class="bibr" href="#ch2.appl.ref10" rid="ch2.appl.ref10">Nurmikko 2007</a>, <a class="bibr" href="#ch2.appl.ref12" rid="ch2.appl.ref12">Rog 2005</a>, <a class="bibr" href="#ch2.appl.ref14" rid="ch2.appl.ref14">Serpell 2014</a>, <a class="bibr" href="#ch2.appl.ref18" rid="ch2.appl.ref18">Wade 2004</a>, <a class="bibr" href="#ch2.appl.ref4" rid="ch2.appl.ref4">Fallon 2017</a>, <a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>, <a class="bibr" href="#ch2.appl.ref7" rid="ch2.appl.ref7">Lichtman 2018</a>, <a class="bibr" href="#ch2.appl.ref8" rid="ch2.appl.ref8">Lynch 2014</a>, <a class="bibr" href="#ch2.appl.ref11" rid="ch2.appl.ref11">Portenoy 2012</a>, <a class="bibr" href="#ch2.appl.ref1" rid="ch2.appl.ref1">Blake 2006</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs and 1 crossover RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1,833</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD −0.44 (−0.70, −0.18)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup><sup>,</sup><sup>2</sup><sup>,</sup><sup>5</sup><sup>,</sup><sup>6</sup><sup>,</sup><sup>7</sup><sup>,</sup><sup>8</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>3</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_7_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Functional impairment caused by pain: Pain Disability Index (0 to 70) for neuropathic pain. Dose: up to 48 actuations (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref10" rid="ch2.appl.ref10">Nurmikko 2007</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">105</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD −5.85 (−9.61, −2.09)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">High</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_9_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Impairment caused by pain: McGill Pain Questionnaire - Short Form (0 to 45), total intensity of pain for musculoskeletal pain (rheumatoid arthritis). Dose: up to 6 actuations (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref1" rid="ch2.appl.ref1">Blake 2006</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">57</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD 3.00 (−2.64, 8.64)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>8</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>4</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_11_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Functional impairment caused by pain: Brief Pain Inventory - Short Form (0 to 10) for neuropathic and cancer pain (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3 (<a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a>, <a class="bibr" href="#ch2.appl.ref14" rid="ch2.appl.ref14">Serpell 2014</a>, <a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">569</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD −0.26 (−0.72, 0.20)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup><sup>,</sup><sup>2</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>4</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_13_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Change in analgesics: daily change in paracetamol, number of rescue (breakthrough) medication paracetamol tablets for neuropathic pain (peripheral neuropathic pain). Dose: up to 24 actuations (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref14" rid="ch2.appl.ref14">Serpell 2014</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">173</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD −0.38 (−0.85, 0.09)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>4</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_15_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Change in analgesics: daily change in total dose, morphine equivalents for cancer pain. Dose: up to 10 actuations (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 (<a class="bibr" href="#ch2.appl.ref4" rid="ch2.appl.ref4">Fallon 2017</a>, <a class="bibr" href="#ch2.appl.ref7" rid="ch2.appl.ref7">Lichtman 2018</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">585</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD −0.74 (−22.16, 20.68)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>6</sup><sup>,</sup><sup>7</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>4</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_17_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Change in analgesics: breakthrough daily change in paracetamol, units not provided for neuropathic pain (multiple sclerosis). Dose: up to 12 actuations (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">297</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD −0.24 (−0.57, 0.09)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>4</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_19_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Change in analgesics: daily change in breakthrough dose, morphine equivalents for cancer pain. Dose: up to 48 actuations (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">99</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD −0.04 (−0.23, 0.15)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>2</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>4</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_21_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Change in analgesics: daily change in breakthrough dose, morphine equivalents for cancer pain. Dose: up to 10 actuations (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 (<a class="bibr" href="#ch2.appl.ref4" rid="ch2.appl.ref4">Fallon 2017</a>, <a class="bibr" href="#ch2.appl.ref7" rid="ch2.appl.ref7">Lichtman 2018</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">585</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD 1.26 (−5.12, 7.64)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>6</sup><sup>,</sup><sup>7</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>4</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_23_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Change in analgesics: daily change in maintenance dose, morphine equivalents for cancer pain. Dose: up to 48 actuations (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3 (<a class="bibr" href="#ch2.appl.ref4" rid="ch2.appl.ref4">Fallon 2017</a>, <a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>, <a class="bibr" href="#ch2.appl.ref7" rid="ch2.appl.ref7">Lichtman 2018</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">359</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD 1.48 (−17.22, 20.19)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>2</sup><sup>,</sup><sup>6</sup><sup>,</sup><sup>7</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>4</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_25_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Patient Global Impression of Change (dichotomous<sup>9</sup>) for neuropathic pain (multiple sclerosis / peripheral neuropathic pain). Dose: up to 24 actuations (values greater than 1 favour THC + CBD)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 (<a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a>, <a class="bibr" href="#ch2.appl.ref14" rid="ch2.appl.ref14">Serpell 2014</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">470</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 1.58 (1.16, 2.15)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_27_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Patient Global Impression of Change (continuous) for cancer pain. Dose: up to 10 actuations (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 (<a class="bibr" href="#ch2.appl.ref4" rid="ch2.appl.ref4">Fallon 2017</a>, <a class="bibr" href="#ch2.appl.ref7" rid="ch2.appl.ref7">Lichtman 2018</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">585</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD −0.26 (−0.43, −0.09)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>6</sup><sup>,</sup><sup>7</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_29_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Quality of life: mean QLQ-C30 global health status for cancer pain. Dose: up to 48 actuations (values greater than 0 favour THC + CBD)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">99</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD 2.47 (−3.81, 8.75)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>2</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>4</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_31_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Quality of life: EQ-5D index for neuropathic pain (multiple sclerosis / peripheral neuropathic pain). Dose: up to 24 actuations (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_31_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 (<a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a>, <a class="bibr" href="#ch2.appl.ref14" rid="ch2.appl.ref14">Serpell 2014</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_31_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_31_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">470</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_31_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD −0.01 (−0.03, 0.01)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_31_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_31_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_31_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_31_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>4</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_31_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_33_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Quality of life: SF-36 physical for cancer pain. Dose: up to 12 actuations (values greater than 0 favour THC + CBD)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_33_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref8" rid="ch2.appl.ref8">Lynch 2014</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_33_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Crossover RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_33_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">16</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_33_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD −11.00 (−17.13, −4.87)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_33_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_33_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_33_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_33_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>10</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_33_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_35_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Quality of life: SF-36 mental for cancer pain. Dose: up to 12 actuations (values greater than 0 favour THC + CBD)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_35_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref8" rid="ch2.appl.ref8">Lynch 2014</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_35_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Crossover RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_35_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">16</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_35_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD 10.95 (4.02, 17.88)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_35_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_35_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_35_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_35_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>10</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_35_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_37_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">People experiencing adverse events, all-causality for multiple sclerosis, neuropathic pain characterised by allodynia and cancer pain (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_37_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6 (<a class="bibr" href="#ch2.appl.ref12" rid="ch2.appl.ref12">Rog 2005</a>, <a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a>
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<a class="bibr" href="#ch2.appl.ref10" rid="ch2.appl.ref10">Nurmikko 2007</a>, <a class="bibr" href="#ch2.appl.ref11" rid="ch2.appl.ref11">Portenoy 2012</a>, <a class="bibr" href="#ch2.appl.ref7" rid="ch2.appl.ref7">Lichtman 2018</a>, <a class="bibr" href="#ch2.appl.ref4" rid="ch2.appl.ref4">Fallon 2017</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_37_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_37_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1,665</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_37_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 1.5 (1.20, 1.87)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_37_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>6</sup><sup>,</sup><sup>7</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_37_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_37_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_37_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_37_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_39_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">People experiencing serious adverse events, all-causality for neuropathic, cancer and musculoskeletal pain (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_39_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">9 (<a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a>, <a class="bibr" href="#ch2.appl.ref10" rid="ch2.appl.ref10">Nurmikko 2007</a>, <a class="bibr" href="#ch2.appl.ref12" rid="ch2.appl.ref12">Rog 2005</a>, <a class="bibr" href="#ch2.appl.ref14" rid="ch2.appl.ref14">Serpell 2014</a>, <a class="bibr" href="#ch2.appl.ref4" rid="ch2.appl.ref4">Fallon 2017</a>, <a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>, <a class="bibr" href="#ch2.appl.ref7" rid="ch2.appl.ref7">Lichtman 2018</a>, <a class="bibr" href="#ch2.appl.ref11" rid="ch2.appl.ref11">Portenoy 2012</a>, <a class="bibr" href="#ch2.appl.ref1" rid="ch2.appl.ref1">Blake 2006</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_39_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_39_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1,643</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_39_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 1.19 (0.85, 1.66)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_39_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>2</sup><sup>,</sup><sup>6</sup><sup>,</sup><sup>7</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_39_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>3</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_39_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_39_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>4</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_39_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_41_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">People experiencing serious adverse events, treatment-related for neuropathic, cancer and musculoskeletal pain (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_41_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7 (<a class="bibr" href="#ch2.appl.ref10" rid="ch2.appl.ref10">Nurmikko 2007</a>, <a class="bibr" href="#ch2.appl.ref14" rid="ch2.appl.ref14">Serpell 2014</a>
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|
<a class="bibr" href="#ch2.appl.ref4" rid="ch2.appl.ref4">Fallon 2017</a>, <a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>, <a class="bibr" href="#ch2.appl.ref7" rid="ch2.appl.ref7">Lichtman 2018</a>, <a class="bibr" href="#ch2.appl.ref11" rid="ch2.appl.ref11">Portenoy 2012</a>, <a class="bibr" href="#ch2.appl.ref1" rid="ch2.appl.ref1">Blake 2006</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_41_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_41_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1,282</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_41_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 1.29 (0.81, 2.06)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_41_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup><sup>,</sup><sup>2</sup><sup>,</sup><sup>6</sup><sup>,</sup><sup>7</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_41_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_41_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_41_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>4</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_41_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_43_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Withdrawals due to adverse events, all-causality for neuropathic, cancer and musculoskeletal pain (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10 (<a class="bibr" href="#ch2.appl.ref18" rid="ch2.appl.ref18">Wade 2004</a>, <a class="bibr" href="#ch2.appl.ref14" rid="ch2.appl.ref14">Serpell 2014</a>, <a class="bibr" href="#ch2.appl.ref12" rid="ch2.appl.ref12">Rog 2005</a>, <a class="bibr" href="#ch2.appl.ref10" rid="ch2.appl.ref10">Nurmikko 2007</a>, <a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a>, <a class="bibr" href="#ch2.appl.ref11" rid="ch2.appl.ref11">Portenoy 2012</a>, <a class="bibr" href="#ch2.appl.ref7" rid="ch2.appl.ref7">Lichtman 2018</a>, <a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>, <a class="bibr" href="#ch2.appl.ref4" rid="ch2.appl.ref4">Fallon 2017</a>, <a class="bibr" href="#ch2.appl.ref1" rid="ch2.appl.ref1">Blake 2006</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2,267</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 1.74 (1.18, 2.56)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup><sup>,</sup><sup>2</sup><sup>,</sup><sup>5</sup><sup>,</sup><sup>6</sup><sup>,</sup><sup>7</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>3</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_45_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Withdrawals due to adverse events, treatment-related for musculoskeletal pain (rheumatoid arthritis). Dose: up to 6 actuations (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_45_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref1" rid="ch2.appl.ref1">Blake 2006</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_45_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_45_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">57</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_45_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 0.86 (0.16, 4.65)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_45_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_45_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_45_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_45_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>4</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_45_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr><tr><th headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_h_ch2.appg.tab1_1_1_1_2 hd_h_ch2.appg.tab1_1_1_1_3 hd_h_ch2.appg.tab1_1_1_1_4 hd_h_ch2.appg.tab1_1_1_1_5 hd_h_ch2.appg.tab1_1_1_1_6 hd_h_ch2.appg.tab1_1_1_1_7 hd_h_ch2.appg.tab1_1_1_1_8 hd_h_ch2.appg.tab1_1_1_1_9" id="hd_b_ch2.appg.tab1_1_1_47_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Adverse events: psychosis, such as hallucinations, delusions, confused and disturbed thoughts, or lack of insight and self-awareness, all-causality for neuropathic and cancer pain (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab1_1_1_1_1 hd_b_ch2.appg.tab1_1_1_47_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3 (<a class="bibr" href="#ch2.appl.ref10" rid="ch2.appl.ref10">Nurnikko 2007</a>, <a class="bibr" href="#ch2.appl.ref12" rid="ch2.appl.ref12">Rog 2005</a>, <a class="bibr" href="#ch2.appl.ref7" rid="ch2.appl.ref7">Lichtman 2018</a>)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_2 hd_b_ch2.appg.tab1_1_1_47_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab1_1_1_1_3 hd_b_ch2.appg.tab1_1_1_47_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">588</td><td headers="hd_h_ch2.appg.tab1_1_1_1_4 hd_b_ch2.appg.tab1_1_1_47_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 2.97 (0.46, 19.07)</td><td headers="hd_h_ch2.appg.tab1_1_1_1_5 hd_b_ch2.appg.tab1_1_1_47_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>7</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_6 hd_b_ch2.appg.tab1_1_1_47_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_7 hd_b_ch2.appg.tab1_1_1_47_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab1_1_1_1_8 hd_b_ch2.appg.tab1_1_1_47_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>4</sup></td><td headers="hd_h_ch2.appg.tab1_1_1_1_9 hd_b_ch2.appg.tab1_1_1_47_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="ch2.appg.tab1_1"><p class="no_margin">Downgrade 2 levels for very serious risk of bias due to <a class="bibr" href="#ch2.appl.ref14" rid="ch2.appl.ref14">Serpell 2014</a> cannabis arm dropout rate being 40%; staff were assigning patients to arms. Therefore, there was no allocation concealment. Sealed envelopes were used.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2</dt><dd><div id="ch2.appg.tab1_2"><p class="no_margin">Downgrade 2 levels for very serious risk of bias due to <a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>: No information provided on randomisation nor blinding. The THC + CBD arm has a much lower baseline morphine dose.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3</dt><dd><div id="ch2.appg.tab1_3"><p class="no_margin">Downgrade 1 level because I<sup>2</sup> is between 33.3% and 66.7%</p></div></dd></dl><dl class="bkr_refwrap"><dt>4</dt><dd><div id="ch2.appg.tab1_4"><p class="no_margin">Downgrade 1 level because the 95% confidence interval crosses the line of no effect.</p></div></dd></dl><dl class="bkr_refwrap"><dt>5</dt><dd><div id="ch2.appg.tab1_5"><p class="no_margin">Downgrade 1 level because allocation sequence was probably not concealed in <a class="bibr" href="#ch2.appl.ref18" rid="ch2.appl.ref18">Wade 2004</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>6</dt><dd><div id="ch2.appg.tab1_6"><p class="no_margin">Downgrade 2 levels: <a class="bibr" href="#ch2.appl.ref4" rid="ch2.appl.ref4">Fallon 2017</a> has no details regarding how randomisation and blinding took place (and all outcomes have a subjective aspect).</p></div></dd></dl><dl class="bkr_refwrap"><dt>7</dt><dd><div id="ch2.appg.tab1_7"><p class="no_margin">Downgrade 2 levels: <a class="bibr" href="#ch2.appl.ref7" rid="ch2.appl.ref7">Lichtman 2018</a> has no information on randomisation and blinding. High dropout rates: 30% in the THC + CBD arm and 20% in the placebo arm.</p></div></dd></dl><dl class="bkr_refwrap"><dt>8</dt><dd><div id="ch2.appg.tab1_8"><p class="no_margin">Downgrade 1 level: <a class="bibr" href="#ch2.appl.ref1" rid="ch2.appl.ref1">Blake 2006</a> has no information on the blinding method.</p></div></dd></dl><dl class="bkr_refwrap"><dt>9</dt><dd><div id="ch2.appg.tab1_9"><p class="no_margin">For the PGIC outcome, the two treatment groups were compared using ordinal logistic regression and the proportional odds model, incorporating centre group.</p></div></dd></dl><dl class="bkr_refwrap"><dt>10</dt><dd><div id="ch2.appg.tab1_10"><p class="no_margin">Downgrade 1 level: sample size is relatively small (<40 people).</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobch2appgtab2"><div id="ch2.appg.tab2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appg.tab2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appg.tab2_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ch2.appg.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch2.appg.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch2.appg.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch2.appg.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_ch2.appg.tab2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Risk of bias</th><th id="hd_h_ch2.appg.tab2_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Inconsistency</th><th id="hd_h_ch2.appg.tab2_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Indirectness</th><th id="hd_h_ch2.appg.tab2_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Imprecision</th><th id="hd_h_ch2.appg.tab2_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th></tr></thead><tbody><tr><th headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_h_ch2.appg.tab2_1_1_1_2 hd_h_ch2.appg.tab2_1_1_1_3 hd_h_ch2.appg.tab2_1_1_1_4 hd_h_ch2.appg.tab2_1_1_1_5 hd_h_ch2.appg.tab2_1_1_1_6 hd_h_ch2.appg.tab2_1_1_1_7 hd_h_ch2.appg.tab2_1_1_1_8 hd_h_ch2.appg.tab2_1_1_1_9" id="hd_b_ch2.appg.tab2_1_1_1_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Mean average pain intensity: Numerical Rating Scale’ (0 to 10) or Visual Analogue Scale (0 to 100)/10 converted to NRS neuropathic, visceral and musculoskeletal pain (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_b_ch2.appg.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4 (<a class="bibr" href="#ch2.appl.ref13" rid="ch2.appl.ref13">Schimrigk 2017</a>, <a class="bibr" href="#ch2.appl.ref3" rid="ch2.appl.ref3">de Vries 2017</a>, de Vries 2015 <a class="bibr" href="#ch2.appl.ref19" rid="ch2.appl.ref19">Weber 2010</a>)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_2 hd_b_ch2.appg.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs and 1 crossover RCT</td><td headers="hd_h_ch2.appg.tab2_1_1_1_3 hd_b_ch2.appg.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">389</td><td headers="hd_h_ch2.appg.tab2_1_1_1_4 hd_b_ch2.appg.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD 0.10 (−0.23, 0.43)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_5 hd_b_ch2.appg.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_6 hd_b_ch2.appg.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_7 hd_b_ch2.appg.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_8 hd_b_ch2.appg.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_9 hd_b_ch2.appg.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">High</td></tr><tr><th headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_h_ch2.appg.tab2_1_1_1_2 hd_h_ch2.appg.tab2_1_1_1_3 hd_h_ch2.appg.tab2_1_1_1_4 hd_h_ch2.appg.tab2_1_1_1_5 hd_h_ch2.appg.tab2_1_1_1_6 hd_h_ch2.appg.tab2_1_1_1_7 hd_h_ch2.appg.tab2_1_1_1_8 hd_h_ch2.appg.tab2_1_1_1_9" id="hd_b_ch2.appg.tab2_1_1_3_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Median average pain intensity: Numerical Rating Scale (0 to 10) for neuropathic pain (multiple sclerosis) (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_b_ch2.appg.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref16" rid="ch2.appl.ref16">Svendsen 2004</a>)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_2 hd_b_ch2.appg.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Crossover RCT</td><td headers="hd_h_ch2.appg.tab2_1_1_1_3 hd_b_ch2.appg.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">24</td><td headers="hd_h_ch2.appg.tab2_1_1_1_4 hd_b_ch2.appg.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Median difference (IQR) −0.6 (−1.8, 0)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_5 hd_b_ch2.appg.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_6 hd_b_ch2.appg.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab2_1_1_1_7 hd_b_ch2.appg.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_8 hd_b_ch2.appg.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab2_1_1_1_9 hd_b_ch2.appg.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_h_ch2.appg.tab2_1_1_1_2 hd_h_ch2.appg.tab2_1_1_1_3 hd_h_ch2.appg.tab2_1_1_1_4 hd_h_ch2.appg.tab2_1_1_1_5 hd_h_ch2.appg.tab2_1_1_1_6 hd_h_ch2.appg.tab2_1_1_1_7 hd_h_ch2.appg.tab2_1_1_1_8 hd_h_ch2.appg.tab2_1_1_1_9" id="hd_b_ch2.appg.tab2_1_1_5_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Quality of life: SF-36 median average for neuropathic pain (multiple sclerosis): physical functioning (values greater than 0 favour dronabinol)</th></tr><tr><td headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_b_ch2.appg.tab2_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref16" rid="ch2.appl.ref16">Svendsen 2004</a>)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_2 hd_b_ch2.appg.tab2_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Crossover RCT</td><td headers="hd_h_ch2.appg.tab2_1_1_1_3 hd_b_ch2.appg.tab2_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">23</td><td headers="hd_h_ch2.appg.tab2_1_1_1_4 hd_b_ch2.appg.tab2_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Median difference (IQR) 5.0 (0, 7.5)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_5 hd_b_ch2.appg.tab2_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_6 hd_b_ch2.appg.tab2_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab2_1_1_1_7 hd_b_ch2.appg.tab2_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_8 hd_b_ch2.appg.tab2_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab2_1_1_1_9 hd_b_ch2.appg.tab2_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_h_ch2.appg.tab2_1_1_1_2 hd_h_ch2.appg.tab2_1_1_1_3 hd_h_ch2.appg.tab2_1_1_1_4 hd_h_ch2.appg.tab2_1_1_1_5 hd_h_ch2.appg.tab2_1_1_1_6 hd_h_ch2.appg.tab2_1_1_1_7 hd_h_ch2.appg.tab2_1_1_1_8 hd_h_ch2.appg.tab2_1_1_1_9" id="hd_b_ch2.appg.tab2_1_1_7_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Quality of life: SF-36 median average for neuropathic pain (multiple sclerosis): role physical (values greater than 0 favour dronabinol)</th></tr><tr><td headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_b_ch2.appg.tab2_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref16" rid="ch2.appl.ref16">Svendsen 2004</a>)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_2 hd_b_ch2.appg.tab2_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Crossover RCT</td><td headers="hd_h_ch2.appg.tab2_1_1_1_3 hd_b_ch2.appg.tab2_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">23</td><td headers="hd_h_ch2.appg.tab2_1_1_1_4 hd_b_ch2.appg.tab2_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Median difference (IQR) 0 (−25.0, 12.5)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_5 hd_b_ch2.appg.tab2_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_6 hd_b_ch2.appg.tab2_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab2_1_1_1_7 hd_b_ch2.appg.tab2_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_8 hd_b_ch2.appg.tab2_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab2_1_1_1_9 hd_b_ch2.appg.tab2_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_h_ch2.appg.tab2_1_1_1_2 hd_h_ch2.appg.tab2_1_1_1_3 hd_h_ch2.appg.tab2_1_1_1_4 hd_h_ch2.appg.tab2_1_1_1_5 hd_h_ch2.appg.tab2_1_1_1_6 hd_h_ch2.appg.tab2_1_1_1_7 hd_h_ch2.appg.tab2_1_1_1_8 hd_h_ch2.appg.tab2_1_1_1_9" id="hd_b_ch2.appg.tab2_1_1_9_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Quality of life: SF-36 median average for neuropathic pain (multiple sclerosis): bodily pain (values greater than 0 favour dronabinol)</th></tr><tr><td headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_b_ch2.appg.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref16" rid="ch2.appl.ref16">Svendsen 2004</a>)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_2 hd_b_ch2.appg.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Crossover RCT</td><td headers="hd_h_ch2.appg.tab2_1_1_1_3 hd_b_ch2.appg.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">23</td><td headers="hd_h_ch2.appg.tab2_1_1_1_4 hd_b_ch2.appg.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Median difference (IQR) 9.8 (0, 21.5)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_5 hd_b_ch2.appg.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_6 hd_b_ch2.appg.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab2_1_1_1_7 hd_b_ch2.appg.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_8 hd_b_ch2.appg.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab2_1_1_1_9 hd_b_ch2.appg.tab2_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Low</td></tr><tr><th headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_h_ch2.appg.tab2_1_1_1_2 hd_h_ch2.appg.tab2_1_1_1_3 hd_h_ch2.appg.tab2_1_1_1_4 hd_h_ch2.appg.tab2_1_1_1_5 hd_h_ch2.appg.tab2_1_1_1_6 hd_h_ch2.appg.tab2_1_1_1_7 hd_h_ch2.appg.tab2_1_1_1_8 hd_h_ch2.appg.tab2_1_1_1_9" id="hd_b_ch2.appg.tab2_1_1_11_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Quality of life: SF-36 median average for neuropathic pain (multiple sclerosis): general health (values greater than 0 favour dronabinol)</th></tr><tr><td headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_b_ch2.appg.tab2_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref16" rid="ch2.appl.ref16">Svendsen 2004</a>)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_2 hd_b_ch2.appg.tab2_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Crossover RCT</td><td headers="hd_h_ch2.appg.tab2_1_1_1_3 hd_b_ch2.appg.tab2_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">23</td><td headers="hd_h_ch2.appg.tab2_1_1_1_4 hd_b_ch2.appg.tab2_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Median difference (IQR) 0 (6.0, 5.0)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_5 hd_b_ch2.appg.tab2_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_6 hd_b_ch2.appg.tab2_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab2_1_1_1_7 hd_b_ch2.appg.tab2_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_8 hd_b_ch2.appg.tab2_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab2_1_1_1_9 hd_b_ch2.appg.tab2_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_h_ch2.appg.tab2_1_1_1_2 hd_h_ch2.appg.tab2_1_1_1_3 hd_h_ch2.appg.tab2_1_1_1_4 hd_h_ch2.appg.tab2_1_1_1_5 hd_h_ch2.appg.tab2_1_1_1_6 hd_h_ch2.appg.tab2_1_1_1_7 hd_h_ch2.appg.tab2_1_1_1_8 hd_h_ch2.appg.tab2_1_1_1_9" id="hd_b_ch2.appg.tab2_1_1_13_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Quality of life: SF-36 median average for neuropathic pain (multiple sclerosis): vitality (values greater than 0 favour dronabinol)</th></tr><tr><td headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_b_ch2.appg.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref16" rid="ch2.appl.ref16">Svendsen 2004</a>)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_2 hd_b_ch2.appg.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Crossover RCT</td><td headers="hd_h_ch2.appg.tab2_1_1_1_3 hd_b_ch2.appg.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">23</td><td headers="hd_h_ch2.appg.tab2_1_1_1_4 hd_b_ch2.appg.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Median difference (IQR) 2.5 (−5, 10.0)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_5 hd_b_ch2.appg.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_6 hd_b_ch2.appg.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab2_1_1_1_7 hd_b_ch2.appg.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_8 hd_b_ch2.appg.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab2_1_1_1_9 hd_b_ch2.appg.tab2_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_h_ch2.appg.tab2_1_1_1_2 hd_h_ch2.appg.tab2_1_1_1_3 hd_h_ch2.appg.tab2_1_1_1_4 hd_h_ch2.appg.tab2_1_1_1_5 hd_h_ch2.appg.tab2_1_1_1_6 hd_h_ch2.appg.tab2_1_1_1_7 hd_h_ch2.appg.tab2_1_1_1_8 hd_h_ch2.appg.tab2_1_1_1_9" id="hd_b_ch2.appg.tab2_1_1_15_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Quality of life: SF-36 median average for neuropathic pain (multiple sclerosis): social functioning (values greater than 0 favour dronabinol)</th></tr><tr><td headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_b_ch2.appg.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref16" rid="ch2.appl.ref16">Svendsen 2004</a>)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_2 hd_b_ch2.appg.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Crossover RCT</td><td headers="hd_h_ch2.appg.tab2_1_1_1_3 hd_b_ch2.appg.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">23</td><td headers="hd_h_ch2.appg.tab2_1_1_1_4 hd_b_ch2.appg.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Median difference (IQR) 6.3 (0, 12.5)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_5 hd_b_ch2.appg.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_6 hd_b_ch2.appg.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab2_1_1_1_7 hd_b_ch2.appg.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_8 hd_b_ch2.appg.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab2_1_1_1_9 hd_b_ch2.appg.tab2_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_h_ch2.appg.tab2_1_1_1_2 hd_h_ch2.appg.tab2_1_1_1_3 hd_h_ch2.appg.tab2_1_1_1_4 hd_h_ch2.appg.tab2_1_1_1_5 hd_h_ch2.appg.tab2_1_1_1_6 hd_h_ch2.appg.tab2_1_1_1_7 hd_h_ch2.appg.tab2_1_1_1_8 hd_h_ch2.appg.tab2_1_1_1_9" id="hd_b_ch2.appg.tab2_1_1_17_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Quality of life: SF-36 median average for neuropathic pain (multiple sclerosis): mental health (values greater than 0 favour dronabinol)</th></tr><tr><td headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_b_ch2.appg.tab2_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref16" rid="ch2.appl.ref16">Svendsen 2004</a>)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_2 hd_b_ch2.appg.tab2_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Crossover RCT</td><td headers="hd_h_ch2.appg.tab2_1_1_1_3 hd_b_ch2.appg.tab2_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">23</td><td headers="hd_h_ch2.appg.tab2_1_1_1_4 hd_b_ch2.appg.tab2_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Median difference (IQR) 8.0 (0, 12.0)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_5 hd_b_ch2.appg.tab2_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_6 hd_b_ch2.appg.tab2_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab2_1_1_1_7 hd_b_ch2.appg.tab2_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_8 hd_b_ch2.appg.tab2_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab2_1_1_1_9 hd_b_ch2.appg.tab2_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_h_ch2.appg.tab2_1_1_1_2 hd_h_ch2.appg.tab2_1_1_1_3 hd_h_ch2.appg.tab2_1_1_1_4 hd_h_ch2.appg.tab2_1_1_1_5 hd_h_ch2.appg.tab2_1_1_1_6 hd_h_ch2.appg.tab2_1_1_1_7 hd_h_ch2.appg.tab2_1_1_1_8 hd_h_ch2.appg.tab2_1_1_1_9" id="hd_b_ch2.appg.tab2_1_1_19_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Quality of life: SF-36 median average for neuropathic pain (multiple sclerosis): role emotional (values greater than 0 favour dronabinol)</th></tr><tr><td headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_b_ch2.appg.tab2_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref16" rid="ch2.appl.ref16">Svendsen 2004</a>)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_2 hd_b_ch2.appg.tab2_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Crossover RCT</td><td headers="hd_h_ch2.appg.tab2_1_1_1_3 hd_b_ch2.appg.tab2_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">23</td><td headers="hd_h_ch2.appg.tab2_1_1_1_4 hd_b_ch2.appg.tab2_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Median difference (IQR) 0 (−33, 0)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_5 hd_b_ch2.appg.tab2_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_6 hd_b_ch2.appg.tab2_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab2_1_1_1_7 hd_b_ch2.appg.tab2_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_8 hd_b_ch2.appg.tab2_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab2_1_1_1_9 hd_b_ch2.appg.tab2_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_h_ch2.appg.tab2_1_1_1_2 hd_h_ch2.appg.tab2_1_1_1_3 hd_h_ch2.appg.tab2_1_1_1_4 hd_h_ch2.appg.tab2_1_1_1_5 hd_h_ch2.appg.tab2_1_1_1_6 hd_h_ch2.appg.tab2_1_1_1_7 hd_h_ch2.appg.tab2_1_1_1_8 hd_h_ch2.appg.tab2_1_1_1_9" id="hd_b_ch2.appg.tab2_1_1_21_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">People experiencing adverse events, all-causality for neuropathic, visceral and musculoskeletal pain (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_b_ch2.appg.tab2_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 (<a class="bibr" href="#ch2.appl.ref13" rid="ch2.appl.ref13">Schimrigk 2017</a>, <a class="bibr" href="#ch2.appl.ref16" rid="ch2.appl.ref16">Svendsen 2004</a>, de Vries 2015, <a class="bibr" href="#ch2.appl.ref19" rid="ch2.appl.ref19">Weber 2010</a>)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_2 hd_b_ch2.appg.tab2_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab2_1_1_1_3 hd_b_ch2.appg.tab2_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">390</td><td headers="hd_h_ch2.appg.tab2_1_1_1_4 hd_b_ch2.appg.tab2_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 2.7 (0.63, 11.68)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_5 hd_b_ch2.appg.tab2_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_6 hd_b_ch2.appg.tab2_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>3</sup></td><td headers="hd_h_ch2.appg.tab2_1_1_1_7 hd_b_ch2.appg.tab2_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_8 hd_b_ch2.appg.tab2_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>2</sup></td><td headers="hd_h_ch2.appg.tab2_1_1_1_9 hd_b_ch2.appg.tab2_1_1_21_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_h_ch2.appg.tab2_1_1_1_2 hd_h_ch2.appg.tab2_1_1_1_3 hd_h_ch2.appg.tab2_1_1_1_4 hd_h_ch2.appg.tab2_1_1_1_5 hd_h_ch2.appg.tab2_1_1_1_6 hd_h_ch2.appg.tab2_1_1_1_7 hd_h_ch2.appg.tab2_1_1_1_8 hd_h_ch2.appg.tab2_1_1_1_9" id="hd_b_ch2.appg.tab2_1_1_23_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">People experiencing adverse events, treatment-related for neuropathic pain (multiple sclerosis) (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_b_ch2.appg.tab2_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref13" rid="ch2.appl.ref13">Schimrigk 2017</a>)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_2 hd_b_ch2.appg.tab2_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab2_1_1_1_3 hd_b_ch2.appg.tab2_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">240</td><td headers="hd_h_ch2.appg.tab2_1_1_1_4 hd_b_ch2.appg.tab2_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 2.87 (1.66, 4.94)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_5 hd_b_ch2.appg.tab2_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_6 hd_b_ch2.appg.tab2_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab2_1_1_1_7 hd_b_ch2.appg.tab2_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_8 hd_b_ch2.appg.tab2_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_9 hd_b_ch2.appg.tab2_1_1_23_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">High</td></tr><tr><th headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_h_ch2.appg.tab2_1_1_1_2 hd_h_ch2.appg.tab2_1_1_1_3 hd_h_ch2.appg.tab2_1_1_1_4 hd_h_ch2.appg.tab2_1_1_1_5 hd_h_ch2.appg.tab2_1_1_1_6 hd_h_ch2.appg.tab2_1_1_1_7 hd_h_ch2.appg.tab2_1_1_1_8 hd_h_ch2.appg.tab2_1_1_1_9" id="hd_b_ch2.appg.tab2_1_1_25_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">People experiencing serious adverse events, all-causality for neuropathic pain (multiple sclerosis) (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_b_ch2.appg.tab2_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 (<a class="bibr" href="#ch2.appl.ref13" rid="ch2.appl.ref13">Schimrigk 2017</a>, <a class="bibr" href="#ch2.appl.ref16" rid="ch2.appl.ref16">Svendsen 2004</a>)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_2 hd_b_ch2.appg.tab2_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT and crossover RCT</td><td headers="hd_h_ch2.appg.tab2_1_1_1_3 hd_b_ch2.appg.tab2_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">288</td><td headers="hd_h_ch2.appg.tab2_1_1_1_4 hd_b_ch2.appg.tab2_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 1.86 (0.76, 4.53)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_5 hd_b_ch2.appg.tab2_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_6 hd_b_ch2.appg.tab2_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_7 hd_b_ch2.appg.tab2_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_8 hd_b_ch2.appg.tab2_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>2</sup></td><td headers="hd_h_ch2.appg.tab2_1_1_1_9 hd_b_ch2.appg.tab2_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr><tr><th headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_h_ch2.appg.tab2_1_1_1_2 hd_h_ch2.appg.tab2_1_1_1_3 hd_h_ch2.appg.tab2_1_1_1_4 hd_h_ch2.appg.tab2_1_1_1_5 hd_h_ch2.appg.tab2_1_1_1_6 hd_h_ch2.appg.tab2_1_1_1_7 hd_h_ch2.appg.tab2_1_1_1_8 hd_h_ch2.appg.tab2_1_1_1_9" id="hd_b_ch2.appg.tab2_1_1_27_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">People experiencing serious adverse events, treatment-related for neuropathic pain (multiple sclerosis (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_b_ch2.appg.tab2_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref13" rid="ch2.appl.ref13">Schimrigk 2017</a>)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_2 hd_b_ch2.appg.tab2_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab2_1_1_1_3 hd_b_ch2.appg.tab2_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">240</td><td headers="hd_h_ch2.appg.tab2_1_1_1_4 hd_b_ch2.appg.tab2_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 2.83 (0.11, 70.17)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_5 hd_b_ch2.appg.tab2_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_6 hd_b_ch2.appg.tab2_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab2_1_1_1_7 hd_b_ch2.appg.tab2_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_8 hd_b_ch2.appg.tab2_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>2</sup></td><td headers="hd_h_ch2.appg.tab2_1_1_1_9 hd_b_ch2.appg.tab2_1_1_27_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Moderate</td></tr><tr><th headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_h_ch2.appg.tab2_1_1_1_2 hd_h_ch2.appg.tab2_1_1_1_3 hd_h_ch2.appg.tab2_1_1_1_4 hd_h_ch2.appg.tab2_1_1_1_5 hd_h_ch2.appg.tab2_1_1_1_6 hd_h_ch2.appg.tab2_1_1_1_7 hd_h_ch2.appg.tab2_1_1_1_8 hd_h_ch2.appg.tab2_1_1_1_9" id="hd_b_ch2.appg.tab2_1_1_29_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Withdrawals due to adverse events, all-causality for neuropathic and visceral pain (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab2_1_1_1_1 hd_b_ch2.appg.tab2_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4 (<a class="bibr" href="#ch2.appl.ref13" rid="ch2.appl.ref13">Schimrigk 2017</a>, <a class="bibr" href="#ch2.appl.ref16" rid="ch2.appl.ref16">Svendsen 2004</a>, de Vries 2015, <a class="bibr" href="#ch2.appl.ref3" rid="ch2.appl.ref3">de Vries 2017</a>)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_2 hd_b_ch2.appg.tab2_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCTs and 1 crossover RCT</td><td headers="hd_h_ch2.appg.tab2_1_1_1_3 hd_b_ch2.appg.tab2_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">398</td><td headers="hd_h_ch2.appg.tab2_1_1_1_4 hd_b_ch2.appg.tab2_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 6.08 (1.83, 20.23)</td><td headers="hd_h_ch2.appg.tab2_1_1_1_5 hd_b_ch2.appg.tab2_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>4</sup></td><td headers="hd_h_ch2.appg.tab2_1_1_1_6 hd_b_ch2.appg.tab2_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_7 hd_b_ch2.appg.tab2_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_8 hd_b_ch2.appg.tab2_1_1_29_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab2_1_1_1_9 hd_b_ch2.appg.tab2_1_1_29_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="ch2.appg.tab2_1"><p class="no_margin">Downgrade 2 levels as imprecision could not be assessed (confidence interval not available). Furthermore, the sample size is relatively small (<40 people)</p></div></dd></dl><dl class="bkr_refwrap"><dt>2</dt><dd><div id="ch2.appg.tab2_2"><p class="no_margin">Downgrade 1 level because the 95% confidence interval crosses the line of no effect.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3</dt><dd><div id="ch2.appg.tab2_3"><p class="no_margin">Downgrade 2 levels because the I<sup>2</sup> is greater than 66.7%</p></div></dd></dl><dl class="bkr_refwrap"><dt>4</dt><dd><div id="ch2.appg.tab2_4"><p class="no_margin">Downgrade 2 levels because in de <a class="bibr" href="#ch2.appl.ref3" rid="ch2.appl.ref3">Vries 2017</a> there was incomplete reporting of outcomes</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobch2appgtab3"><div id="ch2.appg.tab3" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appg.tab3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appg.tab3_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ch2.appg.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch2.appg.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch2.appg.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch2.appg.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_ch2.appg.tab3_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Risk of bias</th><th id="hd_h_ch2.appg.tab3_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Inconsistency</th><th id="hd_h_ch2.appg.tab3_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Indirectness</th><th id="hd_h_ch2.appg.tab3_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Imprecision</th><th id="hd_h_ch2.appg.tab3_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th></tr></thead><tbody><tr><th headers="hd_h_ch2.appg.tab3_1_1_1_1 hd_h_ch2.appg.tab3_1_1_1_2 hd_h_ch2.appg.tab3_1_1_1_3 hd_h_ch2.appg.tab3_1_1_1_4 hd_h_ch2.appg.tab3_1_1_1_5 hd_h_ch2.appg.tab3_1_1_1_6 hd_h_ch2.appg.tab3_1_1_1_7 hd_h_ch2.appg.tab3_1_1_1_8 hd_h_ch2.appg.tab3_1_1_1_9" id="hd_b_ch2.appg.tab3_1_1_1_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Mean average pain intensity: Numerical Rating Scale’ (0 to 10) or Visual Analogue Scale (0 to 100)/10 converted to NRS for widespread pain (fibromyalgia) (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab3_1_1_1_1 hd_b_ch2.appg.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref15" rid="ch2.appl.ref15">Skrabek 2008</a>)</td><td headers="hd_h_ch2.appg.tab3_1_1_1_2 hd_b_ch2.appg.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab3_1_1_1_3 hd_b_ch2.appg.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">33</td><td headers="hd_h_ch2.appg.tab3_1_1_1_4 hd_b_ch2.appg.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD −1.43 (−2.80, −0.06)</td><td headers="hd_h_ch2.appg.tab3_1_1_1_5 hd_b_ch2.appg.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab3_1_1_1_6 hd_b_ch2.appg.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab3_1_1_1_7 hd_b_ch2.appg.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab3_1_1_1_8 hd_b_ch2.appg.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>2</sup></td><td headers="hd_h_ch2.appg.tab3_1_1_1_9 hd_b_ch2.appg.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab3_1_1_1_1 hd_h_ch2.appg.tab3_1_1_1_2 hd_h_ch2.appg.tab3_1_1_1_3 hd_h_ch2.appg.tab3_1_1_1_4 hd_h_ch2.appg.tab3_1_1_1_5 hd_h_ch2.appg.tab3_1_1_1_6 hd_h_ch2.appg.tab3_1_1_1_7 hd_h_ch2.appg.tab3_1_1_1_8 hd_h_ch2.appg.tab3_1_1_1_9" id="hd_b_ch2.appg.tab3_1_1_3_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Median average pain intensity: Numerical Rating Scale (0 to 10) for musculoskeletal pain (spasticity) (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab3_1_1_1_1 hd_b_ch2.appg.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref20" rid="ch2.appl.ref20">Wissel 2006</a>)</td><td headers="hd_h_ch2.appg.tab3_1_1_1_2 hd_b_ch2.appg.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Crossover RCT</td><td headers="hd_h_ch2.appg.tab3_1_1_1_3 hd_b_ch2.appg.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">11</td><td headers="hd_h_ch2.appg.tab3_1_1_1_4 hd_b_ch2.appg.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Median difference −2 (p-value <0.05)</td><td headers="hd_h_ch2.appg.tab3_1_1_1_5 hd_b_ch2.appg.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>3</sup></td><td headers="hd_h_ch2.appg.tab3_1_1_1_6 hd_b_ch2.appg.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab3_1_1_1_7 hd_b_ch2.appg.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab3_1_1_1_8 hd_b_ch2.appg.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>4</sup></td><td headers="hd_h_ch2.appg.tab3_1_1_1_9 hd_b_ch2.appg.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab3_1_1_1_1 hd_h_ch2.appg.tab3_1_1_1_2 hd_h_ch2.appg.tab3_1_1_1_3 hd_h_ch2.appg.tab3_1_1_1_4 hd_h_ch2.appg.tab3_1_1_1_5 hd_h_ch2.appg.tab3_1_1_1_6 hd_h_ch2.appg.tab3_1_1_1_7 hd_h_ch2.appg.tab3_1_1_1_8 hd_h_ch2.appg.tab3_1_1_1_9" id="hd_b_ch2.appg.tab3_1_1_5_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Functional impairment caused by pain: Fibromyalgia Impact Questionnaire for widespread pain (fibromyalgia) (0 to 100) (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab3_1_1_1_1 hd_b_ch2.appg.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref15" rid="ch2.appl.ref15">Skrabek 2008</a>)</td><td headers="hd_h_ch2.appg.tab3_1_1_1_2 hd_b_ch2.appg.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab3_1_1_1_3 hd_b_ch2.appg.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">33</td><td headers="hd_h_ch2.appg.tab3_1_1_1_4 hd_b_ch2.appg.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD −10.76 (−18.45, −3.07)</td><td headers="hd_h_ch2.appg.tab3_1_1_1_5 hd_b_ch2.appg.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab3_1_1_1_6 hd_b_ch2.appg.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab3_1_1_1_7 hd_b_ch2.appg.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab3_1_1_1_8 hd_b_ch2.appg.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>7</sup></td><td headers="hd_h_ch2.appg.tab3_1_1_1_9 hd_b_ch2.appg.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch2.appg.tab3_1_1_1_1 hd_h_ch2.appg.tab3_1_1_1_2 hd_h_ch2.appg.tab3_1_1_1_3 hd_h_ch2.appg.tab3_1_1_1_4 hd_h_ch2.appg.tab3_1_1_1_5 hd_h_ch2.appg.tab3_1_1_1_6 hd_h_ch2.appg.tab3_1_1_1_7 hd_h_ch2.appg.tab3_1_1_1_8 hd_h_ch2.appg.tab3_1_1_1_9" id="hd_b_ch2.appg.tab3_1_1_7_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">People experiencing adverse events, all-causality for musculoskeletal and widespread pain (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab3_1_1_1_1 hd_b_ch2.appg.tab3_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 (<a class="bibr" href="#ch2.appl.ref15" rid="ch2.appl.ref15">Skrabek 2008</a>, <a class="bibr" href="#ch2.appl.ref20" rid="ch2.appl.ref20">Wissel 2006</a>)</td><td headers="hd_h_ch2.appg.tab3_1_1_1_2 hd_b_ch2.appg.tab3_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT and crossover RCT</td><td headers="hd_h_ch2.appg.tab3_1_1_1_3 hd_b_ch2.appg.tab3_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">46</td><td headers="hd_h_ch2.appg.tab3_1_1_1_4 hd_b_ch2.appg.tab3_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 1.60 (1.06, 2.42)</td><td headers="hd_h_ch2.appg.tab3_1_1_1_5 hd_b_ch2.appg.tab3_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup><sup>,</sup><sup>3</sup></td><td headers="hd_h_ch2.appg.tab3_1_1_1_6 hd_b_ch2.appg.tab3_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab3_1_1_1_7 hd_b_ch2.appg.tab3_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab3_1_1_1_8 hd_b_ch2.appg.tab3_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab3_1_1_1_9 hd_b_ch2.appg.tab3_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch2.appg.tab3_1_1_1_1 hd_h_ch2.appg.tab3_1_1_1_2 hd_h_ch2.appg.tab3_1_1_1_3 hd_h_ch2.appg.tab3_1_1_1_4 hd_h_ch2.appg.tab3_1_1_1_5 hd_h_ch2.appg.tab3_1_1_1_6 hd_h_ch2.appg.tab3_1_1_1_7 hd_h_ch2.appg.tab3_1_1_1_8 hd_h_ch2.appg.tab3_1_1_1_9" id="hd_b_ch2.appg.tab3_1_1_9_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">People experiencing serious adverse events, all-causality for musculoskeletal pain (spasticity) (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab3_1_1_1_1 hd_b_ch2.appg.tab3_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref20" rid="ch2.appl.ref20">Wissel 2006</a>)</td><td headers="hd_h_ch2.appg.tab3_1_1_1_2 hd_b_ch2.appg.tab3_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Crossover RCT</td><td headers="hd_h_ch2.appg.tab3_1_1_1_3 hd_b_ch2.appg.tab3_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">13</td><td headers="hd_h_ch2.appg.tab3_1_1_1_4 hd_b_ch2.appg.tab3_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 5.87 (0.25, 135.15)</td><td headers="hd_h_ch2.appg.tab3_1_1_1_5 hd_b_ch2.appg.tab3_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>3</sup></td><td headers="hd_h_ch2.appg.tab3_1_1_1_6 hd_b_ch2.appg.tab3_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab3_1_1_1_7 hd_b_ch2.appg.tab3_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab3_1_1_1_8 hd_b_ch2.appg.tab3_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>5</sup></td><td headers="hd_h_ch2.appg.tab3_1_1_1_9 hd_b_ch2.appg.tab3_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab3_1_1_1_1 hd_h_ch2.appg.tab3_1_1_1_2 hd_h_ch2.appg.tab3_1_1_1_3 hd_h_ch2.appg.tab3_1_1_1_4 hd_h_ch2.appg.tab3_1_1_1_5 hd_h_ch2.appg.tab3_1_1_1_6 hd_h_ch2.appg.tab3_1_1_1_7 hd_h_ch2.appg.tab3_1_1_1_8 hd_h_ch2.appg.tab3_1_1_1_9" id="hd_b_ch2.appg.tab3_1_1_11_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Withdrawals due to adverse events, all-causality for musculoskeletal and widespread pain (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab3_1_1_1_1 hd_b_ch2.appg.tab3_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2 (<a class="bibr" href="#ch2.appl.ref15" rid="ch2.appl.ref15">Skrabek 2008</a>, <a class="bibr" href="#ch2.appl.ref20" rid="ch2.appl.ref20">Wissel 2006</a>)</td><td headers="hd_h_ch2.appg.tab3_1_1_1_2 hd_b_ch2.appg.tab3_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT and crossover RCT</td><td headers="hd_h_ch2.appg.tab3_1_1_1_3 hd_b_ch2.appg.tab3_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">53</td><td headers="hd_h_ch2.appg.tab3_1_1_1_4 hd_b_ch2.appg.tab3_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 4.10 (0.62, 26.99)</td><td headers="hd_h_ch2.appg.tab3_1_1_1_5 hd_b_ch2.appg.tab3_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup><sup>,</sup><sup>3</sup></td><td headers="hd_h_ch2.appg.tab3_1_1_1_6 hd_b_ch2.appg.tab3_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab3_1_1_1_7 hd_b_ch2.appg.tab3_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab3_1_1_1_8 hd_b_ch2.appg.tab3_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>6</sup></td><td headers="hd_h_ch2.appg.tab3_1_1_1_9 hd_b_ch2.appg.tab3_1_1_11_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="ch2.appg.tab3_1"><p class="no_margin">Downgrade 1 level for <a class="bibr" href="#ch2.appl.ref15" rid="ch2.appl.ref15">Skrabek 2008</a>: very little information on the randomisation method and blinding.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2</dt><dd><div id="ch2.appg.tab3_2"><p class="no_margin">Downgrade 2 levels: the 95% confidence interval for the effect size crosses the MID (−0.8) and the sample size is <40.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3</dt><dd><div id="ch2.appg.tab3_3"><p class="no_margin">Downgrade 2 levels for <a class="bibr" href="#ch2.appl.ref20" rid="ch2.appl.ref20">Wissel 2006</a>: no information provided on randomisation, blinding nor baseline characteristics.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4</dt><dd><div id="ch2.appg.tab3_4"><p class="no_margin">Downgrade 2 levels for <a class="bibr" href="#ch2.appl.ref20" rid="ch2.appl.ref20">Wissel 2006</a>: uncertainty of precision as only p-value is available with no 95% CI and the sample size is very small (<40 people).</p></div></dd></dl><dl class="bkr_refwrap"><dt>5</dt><dd><div id="ch2.appg.tab3_5"><p class="no_margin">Downgrade 2 levels: because the 95% confidence interval crosses the line of no effect and the sample size is small (<40 people).</p></div></dd></dl><dl class="bkr_refwrap"><dt>6</dt><dd><div id="ch2.appg.tab3_6"><p class="no_margin">Downgrade 1 level: the 95% confidence interval for the effect size crosses the line of no effect.</p></div></dd></dl><dl class="bkr_refwrap"><dt>7</dt><dd><div id="ch2.appg.tab3_7"><p class="no_margin">Downgrade 1 level: sample size is small (<40 people).</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobch2appgtab4"><div id="ch2.appg.tab4" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appg.tab4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appg.tab4_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ch2.appg.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch2.appg.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch2.appg.tab4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch2.appg.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_ch2.appg.tab4_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Risk of bias</th><th id="hd_h_ch2.appg.tab4_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Inconsistency</th><th id="hd_h_ch2.appg.tab4_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Indirectness</th><th id="hd_h_ch2.appg.tab4_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Imprecision</th><th id="hd_h_ch2.appg.tab4_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th></tr></thead><tbody><tr><th headers="hd_h_ch2.appg.tab4_1_1_1_1 hd_h_ch2.appg.tab4_1_1_1_2 hd_h_ch2.appg.tab4_1_1_1_3 hd_h_ch2.appg.tab4_1_1_1_4 hd_h_ch2.appg.tab4_1_1_1_5 hd_h_ch2.appg.tab4_1_1_1_6 hd_h_ch2.appg.tab4_1_1_1_7 hd_h_ch2.appg.tab4_1_1_1_8 hd_h_ch2.appg.tab4_1_1_1_9" id="hd_b_ch2.appg.tab4_1_1_1_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Proportion of people who experienced pain relief of 30% or more from baseline for cancer pain (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab4_1_1_1_1 hd_b_ch2.appg.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>)</td><td headers="hd_h_ch2.appg.tab4_1_1_1_2 hd_b_ch2.appg.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab4_1_1_1_3 hd_b_ch2.appg.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">117</td><td headers="hd_h_ch2.appg.tab4_1_1_1_4 hd_b_ch2.appg.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 1.02 (0.42, 2.51)</td><td headers="hd_h_ch2.appg.tab4_1_1_1_5 hd_b_ch2.appg.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab4_1_1_1_6 hd_b_ch2.appg.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab4_1_1_1_7 hd_b_ch2.appg.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab4_1_1_1_8 hd_b_ch2.appg.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>2</sup></td><td headers="hd_h_ch2.appg.tab4_1_1_1_9 hd_b_ch2.appg.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab4_1_1_1_1 hd_h_ch2.appg.tab4_1_1_1_2 hd_h_ch2.appg.tab4_1_1_1_3 hd_h_ch2.appg.tab4_1_1_1_4 hd_h_ch2.appg.tab4_1_1_1_5 hd_h_ch2.appg.tab4_1_1_1_6 hd_h_ch2.appg.tab4_1_1_1_7 hd_h_ch2.appg.tab4_1_1_1_8 hd_h_ch2.appg.tab4_1_1_1_9" id="hd_b_ch2.appg.tab4_1_1_3_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Mean average pain intensity: Numerical Rating Scale’ (0 to 10) or Visual Analogue Scale (0 to 100)/10 for cancer pain (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab4_1_1_1_1 hd_b_ch2.appg.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>)</td><td headers="hd_h_ch2.appg.tab4_1_1_1_2 hd_b_ch2.appg.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab4_1_1_1_3 hd_b_ch2.appg.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">96</td><td headers="hd_h_ch2.appg.tab4_1_1_1_4 hd_b_ch2.appg.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD −0.32 (−0.86, 0.22)</td><td headers="hd_h_ch2.appg.tab4_1_1_1_5 hd_b_ch2.appg.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab4_1_1_1_6 hd_b_ch2.appg.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab4_1_1_1_7 hd_b_ch2.appg.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab4_1_1_1_8 hd_b_ch2.appg.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab4_1_1_1_9 hd_b_ch2.appg.tab4_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch2.appg.tab4_1_1_1_1 hd_h_ch2.appg.tab4_1_1_1_2 hd_h_ch2.appg.tab4_1_1_1_3 hd_h_ch2.appg.tab4_1_1_1_4 hd_h_ch2.appg.tab4_1_1_1_5 hd_h_ch2.appg.tab4_1_1_1_6 hd_h_ch2.appg.tab4_1_1_1_7 hd_h_ch2.appg.tab4_1_1_1_8 hd_h_ch2.appg.tab4_1_1_1_9" id="hd_b_ch2.appg.tab4_1_1_5_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Functional impairment caused by pain: Brief Pain Inventory - Short Form for cancer pain (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab4_1_1_1_1 hd_b_ch2.appg.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>)</td><td headers="hd_h_ch2.appg.tab4_1_1_1_2 hd_b_ch2.appg.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab4_1_1_1_3 hd_b_ch2.appg.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">96</td><td headers="hd_h_ch2.appg.tab4_1_1_1_4 hd_b_ch2.appg.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD −4.07 (−8.05, −0.09)</td><td headers="hd_h_ch2.appg.tab4_1_1_1_5 hd_b_ch2.appg.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab4_1_1_1_6 hd_b_ch2.appg.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab4_1_1_1_7 hd_b_ch2.appg.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab4_1_1_1_8 hd_b_ch2.appg.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab4_1_1_1_9 hd_b_ch2.appg.tab4_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch2.appg.tab4_1_1_1_1 hd_h_ch2.appg.tab4_1_1_1_2 hd_h_ch2.appg.tab4_1_1_1_3 hd_h_ch2.appg.tab4_1_1_1_4 hd_h_ch2.appg.tab4_1_1_1_5 hd_h_ch2.appg.tab4_1_1_1_6 hd_h_ch2.appg.tab4_1_1_1_7 hd_h_ch2.appg.tab4_1_1_1_8 hd_h_ch2.appg.tab4_1_1_1_9" id="hd_b_ch2.appg.tab4_1_1_7_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Change in analgesics: daily total dose change, morphine equivalents for cancer pain (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab4_1_1_1_1 hd_b_ch2.appg.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>)</td><td headers="hd_h_ch2.appg.tab4_1_1_1_2 hd_b_ch2.appg.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab4_1_1_1_3 hd_b_ch2.appg.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">96</td><td headers="hd_h_ch2.appg.tab4_1_1_1_4 hd_b_ch2.appg.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD 68.30 (3.74, 132.86)</td><td headers="hd_h_ch2.appg.tab4_1_1_1_5 hd_b_ch2.appg.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab4_1_1_1_6 hd_b_ch2.appg.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab4_1_1_1_7 hd_b_ch2.appg.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab4_1_1_1_8 hd_b_ch2.appg.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab4_1_1_1_9 hd_b_ch2.appg.tab4_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch2.appg.tab4_1_1_1_1 hd_h_ch2.appg.tab4_1_1_1_2 hd_h_ch2.appg.tab4_1_1_1_3 hd_h_ch2.appg.tab4_1_1_1_4 hd_h_ch2.appg.tab4_1_1_1_5 hd_h_ch2.appg.tab4_1_1_1_6 hd_h_ch2.appg.tab4_1_1_1_7 hd_h_ch2.appg.tab4_1_1_1_8 hd_h_ch2.appg.tab4_1_1_1_9" id="hd_b_ch2.appg.tab4_1_1_9_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Quality of life: mean QLQ-C30 global health status for cancer pain (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab4_1_1_1_1 hd_b_ch2.appg.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>)</td><td headers="hd_h_ch2.appg.tab4_1_1_1_2 hd_b_ch2.appg.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab4_1_1_1_3 hd_b_ch2.appg.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">96</td><td headers="hd_h_ch2.appg.tab4_1_1_1_4 hd_b_ch2.appg.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD 0.84 (−5.42, 7.10)</td><td headers="hd_h_ch2.appg.tab4_1_1_1_5 hd_b_ch2.appg.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab4_1_1_1_6 hd_b_ch2.appg.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab4_1_1_1_7 hd_b_ch2.appg.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab4_1_1_1_8 hd_b_ch2.appg.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>2</sup></td><td headers="hd_h_ch2.appg.tab4_1_1_1_9 hd_b_ch2.appg.tab4_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab4_1_1_1_1 hd_h_ch2.appg.tab4_1_1_1_2 hd_h_ch2.appg.tab4_1_1_1_3 hd_h_ch2.appg.tab4_1_1_1_4 hd_h_ch2.appg.tab4_1_1_1_5 hd_h_ch2.appg.tab4_1_1_1_6 hd_h_ch2.appg.tab4_1_1_1_7 hd_h_ch2.appg.tab4_1_1_1_8 hd_h_ch2.appg.tab4_1_1_1_9" id="hd_b_ch2.appg.tab4_1_1_11_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Change in analgesics: daily change in maintenance (background) dose, morphine equivalents for cancer pain (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab4_1_1_1_1 hd_b_ch2.appg.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>)</td><td headers="hd_h_ch2.appg.tab4_1_1_1_2 hd_b_ch2.appg.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab4_1_1_1_3 hd_b_ch2.appg.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">96</td><td headers="hd_h_ch2.appg.tab4_1_1_1_4 hd_b_ch2.appg.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD 68.30 (−2.58, 139.18)</td><td headers="hd_h_ch2.appg.tab4_1_1_1_5 hd_b_ch2.appg.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab4_1_1_1_6 hd_b_ch2.appg.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab4_1_1_1_7 hd_b_ch2.appg.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab4_1_1_1_8 hd_b_ch2.appg.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>2</sup></td><td headers="hd_h_ch2.appg.tab4_1_1_1_9 hd_b_ch2.appg.tab4_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab4_1_1_1_1 hd_h_ch2.appg.tab4_1_1_1_2 hd_h_ch2.appg.tab4_1_1_1_3 hd_h_ch2.appg.tab4_1_1_1_4 hd_h_ch2.appg.tab4_1_1_1_5 hd_h_ch2.appg.tab4_1_1_1_6 hd_h_ch2.appg.tab4_1_1_1_7 hd_h_ch2.appg.tab4_1_1_1_8 hd_h_ch2.appg.tab4_1_1_1_9" id="hd_b_ch2.appg.tab4_1_1_13_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Change in analgesics: daily change in breakthrough dose, morphine equivalents for cancer pain (values greater than 0 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab4_1_1_1_1 hd_b_ch2.appg.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>)</td><td headers="hd_h_ch2.appg.tab4_1_1_1_2 hd_b_ch2.appg.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab4_1_1_1_3 hd_b_ch2.appg.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">96</td><td headers="hd_h_ch2.appg.tab4_1_1_1_4 hd_b_ch2.appg.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD 0.01 (−0.14, 0.16)</td><td headers="hd_h_ch2.appg.tab4_1_1_1_5 hd_b_ch2.appg.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab4_1_1_1_6 hd_b_ch2.appg.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab4_1_1_1_7 hd_b_ch2.appg.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab4_1_1_1_8 hd_b_ch2.appg.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>2</sup></td><td headers="hd_h_ch2.appg.tab4_1_1_1_9 hd_b_ch2.appg.tab4_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab4_1_1_1_1 hd_h_ch2.appg.tab4_1_1_1_2 hd_h_ch2.appg.tab4_1_1_1_3 hd_h_ch2.appg.tab4_1_1_1_4 hd_h_ch2.appg.tab4_1_1_1_5 hd_h_ch2.appg.tab4_1_1_1_6 hd_h_ch2.appg.tab4_1_1_1_7 hd_h_ch2.appg.tab4_1_1_1_8 hd_h_ch2.appg.tab4_1_1_1_9" id="hd_b_ch2.appg.tab4_1_1_15_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">People experiencing serious adverse events (all-causality) for cancer pain (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab4_1_1_1_1 hd_b_ch2.appg.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>)</td><td headers="hd_h_ch2.appg.tab4_1_1_1_2 hd_b_ch2.appg.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab4_1_1_1_3 hd_b_ch2.appg.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">117</td><td headers="hd_h_ch2.appg.tab4_1_1_1_4 hd_b_ch2.appg.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 3.34 (1.27, 8.78)</td><td headers="hd_h_ch2.appg.tab4_1_1_1_5 hd_b_ch2.appg.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab4_1_1_1_6 hd_b_ch2.appg.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab4_1_1_1_7 hd_b_ch2.appg.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab4_1_1_1_8 hd_b_ch2.appg.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab4_1_1_1_9 hd_b_ch2.appg.tab4_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low</td></tr><tr><th headers="hd_h_ch2.appg.tab4_1_1_1_1 hd_h_ch2.appg.tab4_1_1_1_2 hd_h_ch2.appg.tab4_1_1_1_3 hd_h_ch2.appg.tab4_1_1_1_4 hd_h_ch2.appg.tab4_1_1_1_5 hd_h_ch2.appg.tab4_1_1_1_6 hd_h_ch2.appg.tab4_1_1_1_7 hd_h_ch2.appg.tab4_1_1_1_8 hd_h_ch2.appg.tab4_1_1_1_9" id="hd_b_ch2.appg.tab4_1_1_17_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">People experiencing serious adverse events (treatment-related) for cancer pain (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab4_1_1_1_1 hd_b_ch2.appg.tab4_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>)</td><td headers="hd_h_ch2.appg.tab4_1_1_1_2 hd_b_ch2.appg.tab4_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab4_1_1_1_3 hd_b_ch2.appg.tab4_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">117</td><td headers="hd_h_ch2.appg.tab4_1_1_1_4 hd_b_ch2.appg.tab4_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 3.10 (0.12, 77.78)</td><td headers="hd_h_ch2.appg.tab4_1_1_1_5 hd_b_ch2.appg.tab4_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab4_1_1_1_6 hd_b_ch2.appg.tab4_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab4_1_1_1_7 hd_b_ch2.appg.tab4_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab4_1_1_1_8 hd_b_ch2.appg.tab4_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>2</sup></td><td headers="hd_h_ch2.appg.tab4_1_1_1_9 hd_b_ch2.appg.tab4_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab4_1_1_1_1 hd_h_ch2.appg.tab4_1_1_1_2 hd_h_ch2.appg.tab4_1_1_1_3 hd_h_ch2.appg.tab4_1_1_1_4 hd_h_ch2.appg.tab4_1_1_1_5 hd_h_ch2.appg.tab4_1_1_1_6 hd_h_ch2.appg.tab4_1_1_1_7 hd_h_ch2.appg.tab4_1_1_1_8 hd_h_ch2.appg.tab4_1_1_1_9" id="hd_b_ch2.appg.tab4_1_1_19_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Withdrawals due to adverse events (all-causality) for cancer pain (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab4_1_1_1_1 hd_b_ch2.appg.tab4_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>)</td><td headers="hd_h_ch2.appg.tab4_1_1_1_2 hd_b_ch2.appg.tab4_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parallel RCT</td><td headers="hd_h_ch2.appg.tab4_1_1_1_3 hd_b_ch2.appg.tab4_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">117</td><td headers="hd_h_ch2.appg.tab4_1_1_1_4 hd_b_ch2.appg.tab4_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 2.56 (0.63, 10.44)</td><td headers="hd_h_ch2.appg.tab4_1_1_1_5 hd_b_ch2.appg.tab4_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab4_1_1_1_6 hd_b_ch2.appg.tab4_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab4_1_1_1_7 hd_b_ch2.appg.tab4_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not serious</td><td headers="hd_h_ch2.appg.tab4_1_1_1_8 hd_b_ch2.appg.tab4_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>2</sup></td><td headers="hd_h_ch2.appg.tab4_1_1_1_9 hd_b_ch2.appg.tab4_1_1_19_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="ch2.appg.tab4_1"><p class="no_margin">Downgrade 2 levels for very serious risk of bias due to <a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>: No information provided on randomisation nor blinding. The THC + CBD arm has a much lower baseline morphine dose.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2</dt><dd><div id="ch2.appg.tab4_2"><p class="no_margin">Downgrade 1 level: the 95% confidence interval for the effect size crosses the line of no effect</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobch2appgtab5"><div id="ch2.appg.tab5" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appg.tab5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appg.tab5_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ch2.appg.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch2.appg.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch2.appg.tab5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch2.appg.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_ch2.appg.tab5_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Risk of bias</th><th id="hd_h_ch2.appg.tab5_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Inconsistency</th><th id="hd_h_ch2.appg.tab5_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Indirectness</th><th id="hd_h_ch2.appg.tab5_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Imprecision</th><th id="hd_h_ch2.appg.tab5_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th></tr></thead><tbody><tr><th headers="hd_h_ch2.appg.tab5_1_1_1_1 hd_h_ch2.appg.tab5_1_1_1_2 hd_h_ch2.appg.tab5_1_1_1_3 hd_h_ch2.appg.tab5_1_1_1_4 hd_h_ch2.appg.tab5_1_1_1_5 hd_h_ch2.appg.tab5_1_1_1_6 hd_h_ch2.appg.tab5_1_1_1_7 hd_h_ch2.appg.tab5_1_1_1_8 hd_h_ch2.appg.tab5_1_1_1_9" id="hd_b_ch2.appg.tab5_1_1_1_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Mean average pain intensity: Numerical Rating Scale’ (0 to 10) or Visual Analogue Scale (0 to 100)/10 converted to NRS (fibromyalgia) (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab5_1_1_1_1 hd_b_ch2.appg.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref17" rid="ch2.appl.ref17">van de Donk 2019</a>)</td><td headers="hd_h_ch2.appg.tab5_1_1_1_2 hd_b_ch2.appg.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Crossover RCT</td><td headers="hd_h_ch2.appg.tab5_1_1_1_3 hd_b_ch2.appg.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">20</td><td headers="hd_h_ch2.appg.tab5_1_1_1_4 hd_b_ch2.appg.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD 0.03 (−0.96, 1.02)</td><td headers="hd_h_ch2.appg.tab5_1_1_1_5 hd_b_ch2.appg.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab5_1_1_1_6 hd_b_ch2.appg.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab5_1_1_1_7 hd_b_ch2.appg.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>2</sup></td><td headers="hd_h_ch2.appg.tab5_1_1_1_8 hd_b_ch2.appg.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>3</sup></td><td headers="hd_h_ch2.appg.tab5_1_1_1_9 hd_b_ch2.appg.tab5_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="ch2.appg.tab5_1"><p class="no_margin">Downgrade 2 levels: <a class="bibr" href="#ch2.appl.ref17" rid="ch2.appl.ref17">van de Donk 2019</a> had missing outcome data.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2</dt><dd><div id="ch2.appg.tab5_2"><p class="no_margin">Downgrade 2 levels: <a class="bibr" href="#ch2.appl.ref17" rid="ch2.appl.ref17">van de Donk 2019</a> involved giving only 1 dose and follow-up 3 hours later. This is not a realistic assessment for chronic pain management.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3</dt><dd><div id="ch2.appg.tab5_3"><p class="no_margin">Downgrade 1 level: sample size <40</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobch2appgtab6"><div id="ch2.appg.tab6" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appg.tab6/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appg.tab6_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ch2.appg.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch2.appg.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch2.appg.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch2.appg.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_ch2.appg.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Risk of bias</th><th id="hd_h_ch2.appg.tab6_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Inconsistency</th><th id="hd_h_ch2.appg.tab6_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Indirectness</th><th id="hd_h_ch2.appg.tab6_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Imprecision</th><th id="hd_h_ch2.appg.tab6_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th></tr></thead><tbody><tr><th headers="hd_h_ch2.appg.tab6_1_1_1_1 hd_h_ch2.appg.tab6_1_1_1_2 hd_h_ch2.appg.tab6_1_1_1_3 hd_h_ch2.appg.tab6_1_1_1_4 hd_h_ch2.appg.tab6_1_1_1_5 hd_h_ch2.appg.tab6_1_1_1_6 hd_h_ch2.appg.tab6_1_1_1_7 hd_h_ch2.appg.tab6_1_1_1_8 hd_h_ch2.appg.tab6_1_1_1_9" id="hd_b_ch2.appg.tab6_1_1_1_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Mean average pain intensity: Numerical Rating Scale’ (0 to 10) or Visual Analogue Scale (0 to 100)/10 converted to NRS (fibromyalgia) (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab6_1_1_1_1 hd_b_ch2.appg.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref17" rid="ch2.appl.ref17">van de Donk 2019</a>)</td><td headers="hd_h_ch2.appg.tab6_1_1_1_2 hd_b_ch2.appg.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Crossover RCT</td><td headers="hd_h_ch2.appg.tab6_1_1_1_3 hd_b_ch2.appg.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">20</td><td headers="hd_h_ch2.appg.tab6_1_1_1_4 hd_b_ch2.appg.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD −0.06 (−0.99, 0.87)</td><td headers="hd_h_ch2.appg.tab6_1_1_1_5 hd_b_ch2.appg.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab6_1_1_1_6 hd_b_ch2.appg.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab6_1_1_1_7 hd_b_ch2.appg.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>2</sup></td><td headers="hd_h_ch2.appg.tab6_1_1_1_8 hd_b_ch2.appg.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>3</sup></td><td headers="hd_h_ch2.appg.tab6_1_1_1_9 hd_b_ch2.appg.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab6_1_1_1_1 hd_h_ch2.appg.tab6_1_1_1_2 hd_h_ch2.appg.tab6_1_1_1_3 hd_h_ch2.appg.tab6_1_1_1_4 hd_h_ch2.appg.tab6_1_1_1_5 hd_h_ch2.appg.tab6_1_1_1_6 hd_h_ch2.appg.tab6_1_1_1_7 hd_h_ch2.appg.tab6_1_1_1_8 hd_h_ch2.appg.tab6_1_1_1_9" id="hd_b_ch2.appg.tab6_1_1_3_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Proportion of people who experienced pain relief of 30% or more from baseline (fibromyalgia) (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab6_1_1_1_1 hd_b_ch2.appg.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref17" rid="ch2.appl.ref17">van de Donk 2019</a>)</td><td headers="hd_h_ch2.appg.tab6_1_1_1_2 hd_b_ch2.appg.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Crossover RCT</td><td headers="hd_h_ch2.appg.tab6_1_1_1_3 hd_b_ch2.appg.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">20</td><td headers="hd_h_ch2.appg.tab6_1_1_1_4 hd_b_ch2.appg.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 7.36 (1.35, 40.55)</td><td headers="hd_h_ch2.appg.tab6_1_1_1_5 hd_b_ch2.appg.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab6_1_1_1_6 hd_b_ch2.appg.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab6_1_1_1_7 hd_b_ch2.appg.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>2</sup></td><td headers="hd_h_ch2.appg.tab6_1_1_1_8 hd_b_ch2.appg.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>4</sup></td><td headers="hd_h_ch2.appg.tab6_1_1_1_9 hd_b_ch2.appg.tab6_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very low</td></tr><tr><th headers="hd_h_ch2.appg.tab6_1_1_1_1 hd_h_ch2.appg.tab6_1_1_1_2 hd_h_ch2.appg.tab6_1_1_1_3 hd_h_ch2.appg.tab6_1_1_1_4 hd_h_ch2.appg.tab6_1_1_1_5 hd_h_ch2.appg.tab6_1_1_1_6 hd_h_ch2.appg.tab6_1_1_1_7 hd_h_ch2.appg.tab6_1_1_1_8 hd_h_ch2.appg.tab6_1_1_1_9" id="hd_b_ch2.appg.tab6_1_1_5_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Proportion of people who experienced pain relief of 50% or more from baseline (fibromyalgia) (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab6_1_1_1_1 hd_b_ch2.appg.tab6_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref17" rid="ch2.appl.ref17">van de Donk 2019</a>)</td><td headers="hd_h_ch2.appg.tab6_1_1_1_2 hd_b_ch2.appg.tab6_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Crossover RCT</td><td headers="hd_h_ch2.appg.tab6_1_1_1_3 hd_b_ch2.appg.tab6_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">20</td><td headers="hd_h_ch2.appg.tab6_1_1_1_4 hd_b_ch2.appg.tab6_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OR 1.91 (0.52, 7.01)</td><td headers="hd_h_ch2.appg.tab6_1_1_1_5 hd_b_ch2.appg.tab6_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab6_1_1_1_6 hd_b_ch2.appg.tab6_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab6_1_1_1_7 hd_b_ch2.appg.tab6_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>2</sup></td><td headers="hd_h_ch2.appg.tab6_1_1_1_8 hd_b_ch2.appg.tab6_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>5</sup></td><td headers="hd_h_ch2.appg.tab6_1_1_1_9 hd_b_ch2.appg.tab6_1_1_5_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="ch2.appg.tab6_1"><p class="no_margin">Downgrade 2 levels: <a class="bibr" href="#ch2.appl.ref17" rid="ch2.appl.ref17">van de Donk 2019</a> had missing outcome data.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2</dt><dd><div id="ch2.appg.tab6_2"><p class="no_margin">Downgrade 2 levels: <a class="bibr" href="#ch2.appl.ref17" rid="ch2.appl.ref17">van de Donk 2019</a> involved giving only 1 dose and follow-up 3 hours later. This is not a realistic assessment for chronic pain management.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3</dt><dd><div id="ch2.appg.tab6_3"><p class="no_margin">Downgrade 2 levels: the 95% confidence interval for the effect size crosses the MID (−0.8) and the sample size is relatively small (<40 people).</p></div></dd></dl><dl class="bkr_refwrap"><dt>4</dt><dd><div id="ch2.appg.tab6_4"><p class="no_margin">Downgrade 1 level: sample size is relatively small (<40 people).</p></div></dd></dl><dl class="bkr_refwrap"><dt>5</dt><dd><div id="ch2.appg.tab6_5"><p class="no_margin">Downgrade 2 levels: the 95% confidence interval for the effect size crosses the MID (−0.9) and the sample size is relatively small (<40 people).</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobch2appgtab7"><div id="ch2.appg.tab7" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appg.tab7/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appg.tab7_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ch2.appg.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">No. of studies</th><th id="hd_h_ch2.appg.tab7_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Study design</th><th id="hd_h_ch2.appg.tab7_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Sample size</th><th id="hd_h_ch2.appg.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_ch2.appg.tab7_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Risk of bias</th><th id="hd_h_ch2.appg.tab7_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Inconsistency</th><th id="hd_h_ch2.appg.tab7_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Indirectness</th><th id="hd_h_ch2.appg.tab7_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Imprecision</th><th id="hd_h_ch2.appg.tab7_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Quality</th></tr></thead><tbody><tr><th headers="hd_h_ch2.appg.tab7_1_1_1_1 hd_h_ch2.appg.tab7_1_1_1_2 hd_h_ch2.appg.tab7_1_1_1_3 hd_h_ch2.appg.tab7_1_1_1_4 hd_h_ch2.appg.tab7_1_1_1_5 hd_h_ch2.appg.tab7_1_1_1_6 hd_h_ch2.appg.tab7_1_1_1_7 hd_h_ch2.appg.tab7_1_1_1_8 hd_h_ch2.appg.tab7_1_1_1_9" id="hd_b_ch2.appg.tab7_1_1_1_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:middle;">Mean average pain intensity: Numerical Rating Scale’ (0 to 10) or Visual Analogue Scale (0 to 100)/10 converted to NRS (fibromyalgia) (values greater than 1 favour placebo)</th></tr><tr><td headers="hd_h_ch2.appg.tab7_1_1_1_1 hd_b_ch2.appg.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 (<a class="bibr" href="#ch2.appl.ref17" rid="ch2.appl.ref17">van de Donk 2019</a>)</td><td headers="hd_h_ch2.appg.tab7_1_1_1_2 hd_b_ch2.appg.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Crossover RCT</td><td headers="hd_h_ch2.appg.tab7_1_1_1_3 hd_b_ch2.appg.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">20</td><td headers="hd_h_ch2.appg.tab7_1_1_1_4 hd_b_ch2.appg.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MD 0.00 (−0.99, 0.99)</td><td headers="hd_h_ch2.appg.tab7_1_1_1_5 hd_b_ch2.appg.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>1</sup></td><td headers="hd_h_ch2.appg.tab7_1_1_1_6 hd_b_ch2.appg.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ch2.appg.tab7_1_1_1_7 hd_b_ch2.appg.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Very serious<sup>2</sup></td><td headers="hd_h_ch2.appg.tab7_1_1_1_8 hd_b_ch2.appg.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious<sup>3</sup></td><td headers="hd_h_ch2.appg.tab7_1_1_1_9 hd_b_ch2.appg.tab7_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="ch2.appg.tab7_1"><p class="no_margin">Downgrade 2 levels: <a class="bibr" href="#ch2.appl.ref17" rid="ch2.appl.ref17">van de Donk 2019</a> had missing outcome data.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2</dt><dd><div id="ch2.appg.tab7_2"><p class="no_margin">Downgrade 2 levels: <a class="bibr" href="#ch2.appl.ref17" rid="ch2.appl.ref17">van de Donk 2019</a> involved giving only 1 dose and follow-up 3 hours later. This is not a realistic assessment for chronic pain management.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3</dt><dd><div id="ch2.appg.tab7_3"><p class="no_margin">Downgrade 1 level: the sample size is relatively small (<40 people).</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobch2apphtab1"><div id="ch2.apph.tab1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.apph.tab1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.apph.tab1_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.apph.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Study</th><th id="hd_h_ch2.apph.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Subgroup</th><th id="hd_h_ch2.apph.tab1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adverse events reported</th></tr></thead><tbody><tr><td headers="hd_h_ch2.apph.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a>
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</td><td headers="hd_h_ch2.apph.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Neuropathic pain: multiple sclerosis</td><td headers="hd_h_ch2.apph.tab1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Phase A (standard parallel RCT)</p>
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<p>Treatment-related: all severities</p>
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<p>THC + CBD (167 patients in the arm): cardiac disorders (0), Ear and labyrinth disorders (20) including vertigo (15); Eye disorders (7) including vision blurred (4); Gastrointestinal disorders (54) including nausea (13), dry mouth (12), diarrhoea (7), vomiting (5); General disorders and administration site conditions (40) including: fatigue (16), feeling abnormal (5), pain (0); Infections and infestations (34); Musculoskeletal and connective tissue disorders (17) including pain in extremity (0), muscular weakness (1); Nervous system disorders (73) including dizziness (34), somnolence (16), headache (7), disturbance in attention (6), dysgeusia (6), memory impairment (6), balance disorder (5), psychomotor skills impaired (5), neuralgia (1); Psychiatric disorders (27) including: depression (2); Respiratory, thoracic and mediastinal disorders (8) including: pharyngolaryngeal pain (2).</p>
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<p>Placebo (172 patients in the arm): cardiac disorders (1), Ear and labyrinth disorders (9) including vertigo (6); Eye disorders (5) including vision blurred (1); Gastrointestinal disorders (40) including nausea (7), dry mouth (10), diarrhoea (5), vomiting (5); General disorders and administration site conditions (30) including: fatigue (9), feeling abnormal (2), pain (1); Infections and infestations (27); Musculoskeletal and connective tissue disorders (20) including pain in extremity (1), muscular weakness (1); Nervous system disorders (51) including dizziness (7), somnolence (3), headache (6), disturbance in attention (1), dysgeusia (1), memory impairment (1), balance disorder (2), psychomotor skills impaired (0), neuralgia (1); Psychiatric disorders (12) including: depression (0); Respiratory, thoracic and mediastinal disorders (11) including: pharyngolaryngeal pain (1).</p>
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<p>Treatment-related: severe</p>
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<p>THC + CBD (167 patients in the arm): serious disorientation (1), suicidal ideation (1).</p>
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<p>Placebo (172 patients in the arm): suicidal ideation (1).</p>
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<p>Phase B (withdrawal RCT)</p>
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<p>Treatment-related: all severities</p>
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<p>THC + CBD (21 patients in the arm): General disorders and administration site conditions (1) including: mucosal erosion (0), fatigue (0), feeling abnormal (0), pain (0); Investigations (0) including hepatic enzyme increased (0); Musculoskeletal and connective tissue disorders (0); Nervous system disorders (0); Psychiatric disorders (1) including: depression (1), insomnia (0); Skin and subcutaneous tissue disorders (0) including dry skin (0).</p>
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<p>Placebo (21 patients in the arm): General disorders and administration site conditions (0) including: mucosal erosion (0), fatigue (0), feeling abnormal (0), pain (0); Investigations (1) including hepatic enzyme increased (1); Musculoskeletal and connective tissue disorders (1); Nervous system disorders (2); Psychiatric disorders (1) including: depression (0), insomnia (1); Skin and subcutaneous tissue disorders (1) including dry skin (1).</p>
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<p>Severe adverse events</p>
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<p>All-causality</p>
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<p>THC + CBD (21 patients in the arm): serious disorientation (1), suicidal ideation (1)</p>
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<p>Placebo (21 patients in the arm): serious disorientation (0), suicidal ideation (1), accidental injury (1)</p>
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<p>Treatment-related</p>
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<p>THC + CBD (21 patients in the arm): serious disorientation (1), suicidal ideation (1)</p>
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<p>Placebo (21 patients in the arm): serious disorientation (0), suicidal ideation (1)</p>
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</td></tr><tr><td headers="hd_h_ch2.apph.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch2.appl.ref12" rid="ch2.appl.ref12">Rog 2005</a>
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</td><td headers="hd_h_ch2.apph.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Neuropathic pain: multiple sclerosis</td><td headers="hd_h_ch2.apph.tab1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>All-causality</p>
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<p>THC + CBD (34 patients in the arm): Nervous system including: dizziness (18), somnolence (3), disturbance in attention (2), headache (1); Psychiatric including: dissociation (3), euphoria (2); Gastrointestinal including: dry mouth (4), nausea (3), glossodynia (1), mouth ulceration (1), vomiting (1), dyspepsia (0), oral pain (0); General and administration site conditions including: falls (3), weakness (3), fatigue (2), feeling abnormal (1), feeling drunk (1), thirst (1), application site burning (0), chest discomfort (0); Respiratory including: pharyngitis (2), hoarseness (1), throat irritation (1), dyspnoea (0).</p>
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<p>Placebo (32 patients in the arm): Nervous system including: dizziness (5), somnolence (0), disturbance in attention (0), headache (3); Psychiatric including: dissociation (0), euphoria (0); Gastrointestinal including: dry mouth (0), nausea (2), glossodynia (3), mouth ulceration (0), vomiting (0), dyspepsia (1), oral pain (3); General and administration site conditions including: falls (2), weakness (0), fatigue (2), feeling abnormal (0), feeling drunk (1), thirst (0), application site burning (1), chest discomfort (1); Respiratory including: pharyngitis (1), hoarseness (0), throat irritation (0), dyspnoea (1).</p>
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<p>There were no serious adverse events</p>
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</td></tr><tr><td headers="hd_h_ch2.apph.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch2.appl.ref18" rid="ch2.appl.ref18">Wade 2004</a>
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</td><td headers="hd_h_ch2.apph.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Neuropathic pain: multiple sclerosis</td><td headers="hd_h_ch2.apph.tab1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Treatment-related</p>
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<p>THC + CBD (80 patients in the arm): dizziness (26), disturbance in attention (7), headache (7), fatigue (12), somnolence (7), disorientation (6), feeling drunk (4), vertigo (5), application site discomfort (21), nausea (7), diarrhoea (6), mouth ulceration (4).</p>
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<p>Placebo (80 patients in the arm): dizziness (10), disturbance in attention (0), headache (13), fatigue (3), somnolence (1), disorientation (0), feeling drunk (0), vertigo (0), application site discomfort (18), nausea (5), diarrhoea (2), mouth ulceration (1).</p>
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<p>There was no mention of serious adverse events</p>
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</td></tr><tr><td headers="hd_h_ch2.apph.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Selvarajah 2010</td><td headers="hd_h_ch2.apph.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Neuropathic pain: diabetic neuropathy</td><td headers="hd_h_ch2.apph.tab1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adverse events were not reported.</td></tr><tr><td headers="hd_h_ch2.apph.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch2.appl.ref10" rid="ch2.appl.ref10">Nurmikko 2007</a>
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</td><td headers="hd_h_ch2.apph.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Neuropathic pain: characterised by allodynia</td><td headers="hd_h_ch2.apph.tab1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Treatment-related adverse events experienced by 3 or more patients (approximately 5%) receiving THC + CBD compared with placebo</p>
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<p>THC + CBD (63 patients in the arm): dizziness (18), nausea (14), fatigue (13), dry mouth (11), vomiting (8), feeling drunk (6), headache (6), diarrhoea (4), nasopharyngitis (4), anorexia (4), somnolence (4), abdominal pain upper (3), disturbance in attention (3), memory impairment (3).</p>
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<p>Placebo (62 patients in the arm): dizziness (9), nausea (7), fatigue (5), dry mouth (3), vomiting (3), feeling drunk (1), headache (9), diarrhoea (0), nasopharyngitis (2), anorexia (0), somnolence (1), abdominal pain upper (1), disturbance in attention (0), memory impairment (0).</p>
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<p>Serious adverse events (treatment-related)</p>
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<p>THC + CBD (63 patients in the arm): Severe symptoms suggesting involvement of the nervous system (7), emotional stress associated with paranoid thinking (1).</p>
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<p>Placebo (62 patients in the arm): Severe symptoms suggesting involvement of the nervous system (5), confusion (1).</p>
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<p>Serious adverse events (all-causality)</p>
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<p>THC + CBD (63 patients in the arm): Severe symptoms suggesting involvement of the nervous system (7), emotional stress associated with paranoid thinking (1), transient ischemic attack (1)</p>
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<p>Placebo (62 patients in the arm): Severe symptoms suggesting involvement of the nervous system (5), confusion (1).</p>
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</td></tr><tr><td headers="hd_h_ch2.apph.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch2.appl.ref14" rid="ch2.appl.ref14">Serpell 2014</a>
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</td><td headers="hd_h_ch2.apph.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Neuropathic pain: peripheral neuropathic pain</td><td headers="hd_h_ch2.apph.tab1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>All-causality with an incidence of 3% or greater</p>
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<p>THC + CBD (128 patients in the arm): Nervous system disorders (79) including: dizziness (52), dysgeusia (14), headache (13), disturbance in attention (8), neuropathy peripheral (6), tremor (6), somnolence (5), balance disorder (4), memory impairment (4), sedation (4); Gastrointestinal disorders (60) including: nausea (23), vomiting (13), diarrhoea (12), dry mouth (11), abdominal pain upper (6), dyspepsia (6), constipation (4), mouth ulceration (4), oral pain (4); General disorders and administration site conditions including (45): fatigue (20), feeling drunk (8), application site pain (7); Psychiatric disorders (36) including: dissociation (9), disorientation (8), depression (6), anxiety (4), panic attack (4); Infections and infestations including (35): nasopharyngitis (9), gastroenteritis (4), lower respiratory tract infection (4); Metabolism and nutrition disorders (15) including: increased appetite (6), anorexia (4); Respiratory, thoracic and mediastinal disorders (15) including: pharyngolaryngeal pain (7), dyspnoea (4); Musculoskeletal and connective tissue disorders (11); Injury, poisoning and procedural complications (9); Skin and subcutaneous tissue disorders (9) including: rash (5); Eye disorders (7); Ear and labyrinth disorders (6) including: vertigo (5); Vascular disorders (4); Investigations (3); Neoplasms benign, malignant and unspecified (incl. cysts and polyps) (3); Renal and urinary disorders (3); Cardiac disorders (2); Reproductive system and breast disorders (2); Immune system disorders (1); Blood and lymphatic system disorders (0).</p>
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<p>Placebo (118 patients in the arm): Nervous system disorders (34) including: dizziness (12), dysgeusia (2), headache (9), disturbance in attention (2), neuropathy peripheral (4), tremor (0), somnolence (2), balance disorder (2), memory impairment (2), sedation (0); Gastrointestinal disorders (43) including: nausea (14), vomiting (7), diarrhoea (6), dry mouth (4), abdominal pain upper (1), dyspepsia (4), constipation (2), mouth ulceration (6), oral pain (3); General disorders and administration site conditions including (30): fatigue (8), feeling drunk (3), application site pain (2); Psychiatric disorders (11) including: dissociation (0), disorientation (0), depression (0), anxiety (1), panic attack (1); Infections and infestations including (26): nasopharyngitis (8), gastroenteritis (1), lower respiratory tract infection (3); Metabolism and nutrition disorders (6) including: increased appetite (1), anorexia (1); Respiratory, thoracic and mediastinal disorders (16) including: pharyngolaryngeal pain (5), dyspnoea (3); Musculoskeletal and connective tissue disorders (8); Injury, poisoning and procedural complications (6); Skin and subcutaneous tissue disorders (9) including: rash (4); Eye disorders (6); Ear and labyrinth disorders (1) including: vertigo (0); Vascular disorders (5); Investigations (3); Neoplasms benign, malignant and unspecified (incl. cysts and polyps) (1); Renal and urinary disorders (2); Cardiac disorders (2); Reproductive system and breast disorders (1); Immune system disorders (0); Blood and lymphatic system disorders (2).</p>
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<p>Treatment-related with an incidence of 3% or greater</p>
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<p>THC + CBD (128 patients in the arm): Nervous system disorders (73) including: dizziness (50), dysgeusia (14), headache (8), disturbance in attention (8), neuropathy peripheral (3), tremor (4), somnolence (5), balance disorder (4), memory impairment (4), sedation (4); Gastrointestinal disorders (48) including: nausea (22), vomiting (6), diarrhoea (8), dry mouth (11), abdominal pain upper (4), dyspepsia (1), constipation (2), mouth ulceration (4), oral pain (4); General disorders and administration site conditions including (38): fatigue (19), feeling drunk (8), application site pain (7); Psychiatric disorders (30) including: dissociation (9), disorientation (8), depression (3), anxiety (3), panic attack (3); Infections and infestations including (1): nasopharyngitis (1), gastroenteritis (0), lower respiratory tract infection (0); Metabolism and nutrition disorders (10) including: increased appetite (6), anorexia (1); Respiratory, thoracic and mediastinal disorders (7) including: pharyngolaryngeal pain (2), dyspnoea (1); Musculoskeletal and connective tissue disorders (2); Injury, poisoning and procedural complications (2); Skin and subcutaneous tissue disorders (2) including: rash (1); Eye disorders (5); Ear and labyrinth disorders (5) including: vertigo (5); Vascular disorders (3); Investigations (2); Neoplasms benign, malignant and unspecified (incl. cysts and polyps) (0); Renal and urinary disorders (0); Cardiac disorders (1); Reproductive system and breast disorders (0); Immune system disorders (0); Blood and lymphatic system disorders (0).</p>
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<p>Placebo (118 patients in the arm): Nervous system disorders (20) including: dizziness (11), dysgeusia (2), headache (7), disturbance in attention (1), neuropathy peripheral (0), tremor (0), somnolence (2), balance disorder (2), memory impairment (2), sedation (0); Gastrointestinal disorders (30) including: nausea (9), vomiting (3), diarrhoea (2), dry mouth (4), abdominal pain upper (0), dyspepsia (3), constipation (0), mouth ulceration (6), oral pain (3); General disorders and administration site conditions including (23): fatigue (5), feeling drunk (3), application site pain (2); Psychiatric disorders (4) including: dissociation (0), disorientation (0), depression (0), anxiety (1), panic attack (0); Infections and infestations including (3): nasopharyngitis (1), gastroenteritis (0), lower respiratory tract infection (0); Metabolism and nutrition disorders (5) including: increased appetite (1), anorexia (1); Respiratory, thoracic and mediastinal disorders (5) including: pharyngolaryngeal pain (5), dyspnoea (0); Musculoskeletal and connective tissue disorders (1); Injury, poisoning and procedural complications (0); Skin and subcutaneous tissue disorders (2) including: rash (0); Eye disorders (3); Ear and labyrinth disorders (1) including: vertigo (0); Vascular disorders (2); Investigations (2); Neoplasms benign, malignant and unspecified (incl. cysts and polyps) (0); Renal and urinary disorders (1); Cardiac disorders (0); Reproductive system and breast disorders (0); Immune system disorders (0); Blood and lymphatic system disorders (0).</p>
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<p>Serious adverse events</p>
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<p>All-causality</p>
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<p>THC + CBD (128 patients in the arm): 10 (no details provided)</p>
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<p>Placebo (118 patients in the arm): 6 (no details provided)</p>
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<p>Treatment-related</p>
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<p>THC + CBD (128 patients in the arm): 0</p>
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<p>Placebo (118 patients in the arm): 1 (no details provided)</p>
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</td></tr><tr><td headers="hd_h_ch2.apph.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch2.appl.ref8" rid="ch2.appl.ref8">Lynch 2014</a>
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</td><td headers="hd_h_ch2.apph.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Chemotherapy: neuropathic pain + possible nociceptive</td><td headers="hd_h_ch2.apph.tab1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Treatment-related</p>
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|
<p>THC + CBD (128 patients in the arm): fatigue (7), dry mouth (5), dizziness (6), nausea (6), increased appetite (2), diarrhoea (2), decreased appetite (1), feeling “stoned” (1), anxiety (1), panic attack (1), headache (2), confusion (1), “fuzzy thinking” or “foggy brain” (2).</p>
|
|
<p>Placebo (118 patients in the arm): fatigue (0), dry mouth (1), dizziness (0), nausea (1), increased appetite (0), diarrhoea (0), decreased appetite (0), feeling “stoned” (0), anxiety (0), panic attack (0), headache (0), confusion (0), “fuzzy thinking” or “foggy brain” (0).</p>
|
|
<p>There were no serious adverse events</p>
|
|
</td></tr><tr><td headers="hd_h_ch2.apph.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch2.appl.ref4" rid="ch2.appl.ref4">Fallon 2017</a>
|
|
</td><td headers="hd_h_ch2.apph.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nociceptive pain: cancer pain</td><td headers="hd_h_ch2.apph.tab1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>All-causality in ≥5%</p>
|
|
<p>THC + CBD (199 patients in the arm): neoplasm progression (32), somnolence (24), nausea (19), vomiting (18), dizziness (16), constipation (10).</p>
|
|
<p>Placebo (198 patients in the arm): neoplasm progression (36), somnolence (8), nausea (16), vomiting (13), dizziness (9), constipation (13).</p>
|
|
<p>Treatment-related in ≥5%</p>
|
|
<p>THC + CBD (199 patients in the arm): somnolence (18), dizziness (15), nausea (10).</p>
|
|
<p>Placebo (198 patients in the arm): somnolence (6), dizziness (6), nausea (8).</p>
|
|
<p>Serious adverse events</p>
|
|
<p>All-causality</p>
|
|
<p>THC + CBD (199 patients in the arm): 35 in total including: neoplasm progression (23), constipation (1), moderate disorientation and moderate somnolence (1)</p>
|
|
<p>Placebo (198 patients in the arm): 44 in total including: neoplasm progression (31)</p>
|
|
<p>Treatment-related</p>
|
|
<p>THC + CBD (199 patients in the arm): 2 including: constipation (1), moderate disorientation and moderate somnolence (1)</p>
|
|
<p>Placebo (198 patients in the arm): 0</p>
|
|
</td></tr><tr><td headers="hd_h_ch2.apph.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>
|
|
</td><td headers="hd_h_ch2.apph.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nociceptive pain: cancer pain</td><td headers="hd_h_ch2.apph.tab1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Treatment-related reported by ≥3 patients</p>
|
|
<p>THC + CBD (60 patients in the arm): somnolence (8), dizziness (7), confusion (4), nausea (6), vomiting (3), raised gamma GT (2), hypercalcaemia (0), hypotension (3).</p>
|
|
<p>Placebo (59 patients in the arm): somnolence (6), dizziness (3), confusion (1), nausea (4), vomiting (2), raised gamma GT (1), hypercalcaemia (3), hypotension (0).</p>
|
|
<p>Serious adverse event</p>
|
|
<p>All-causality</p>
|
|
<p>THC + CBD (60 patients in the arm): progression of cancer (8), urinary retention (1), tumour-related pain (1), worsened nausea (1), weakness (1), tumour haemorrhage (1), somnolence (1)</p>
|
|
<p>Placebo (59 patients in the arm): progression of cancer (7)</p>
|
|
<p>Treatment-related</p>
|
|
<p>THC + CBD (60 patients in the arm): 0</p>
|
|
<p>Placebo (59 patients in the arm): 0</p>
|
|
</td></tr><tr><td headers="hd_h_ch2.apph.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch2.appl.ref7" rid="ch2.appl.ref7">Lichtman 2018</a>
|
|
</td><td headers="hd_h_ch2.apph.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nociceptive pain: cancer pain</td><td headers="hd_h_ch2.apph.tab1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>All-causality in ≥5% of patients</p>
|
|
<p>THC + CBD (199 patients in the arm): neoplasm progression (37), nausea (31), vomiting (16), dizziness (16), decreased appetite (14), fatigue (12), constipation (11).</p>
|
|
<p>Placebo (198 patients in the arm): neoplasm progression (34), nausea (21), vomiting (13), dizziness (8), decreased appetite (12), fatigue (10), constipation (13).</p>
|
|
<p>Treatment-related in ≥5% of patients</p>
|
|
<p>THC + CBD (199 patients in the arm): nausea (17), dizziness (15).</p>
|
|
<p>Placebo (198 patients in the arm): nausea (10), dizziness (5).</p>
|
|
<p>Severe adverse events</p>
|
|
<p>All-causality in ≥5% of patients</p>
|
|
<p>THC + CBD (199 patients in the arm): neoplasm progression (32), disorientation (1), visual hallucination (1), pancytopenia (1), pulmonary embolus (1)</p>
|
|
<p>Placebo (198 patients in the arm): neoplasm progression (25), vomiting (1), suicide (1)</p>
|
|
<p>Treatment-related in ≥5% of patients</p>
|
|
<p>THC + CBD (199 patients in the arm): 0</p>
|
|
<p>Placebo (198 patients in the arm): 0</p>
|
|
</td></tr><tr><td headers="hd_h_ch2.apph.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch2.appl.ref11" rid="ch2.appl.ref11">Portenoy 2012</a>
|
|
</td><td headers="hd_h_ch2.apph.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nociceptive pain: cancer pain</td><td headers="hd_h_ch2.apph.tab1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Treatment-related in ≥5% of patients</p>
|
|
<p>All-causality</p>
|
|
<p>THC + CBD all doses combined (268 patients in the arm):</p>
|
|
<p>neoplasm progression (47), nausea (59), dizziness (51), vomiting (42), somnolence (39), disorientation (18), anorexia (22), constipation (20), dry mouth (22), anaemia (19), diarrhoea (17), dysgeusia (11), headache (15), asthenia (18), hallucination (8), decreased appetite (11), fatigue (13), pain (11), insomnia (8), stomatitis (10), weight decreased (8).</p>
|
|
<p>THC + CBD 1–4 sprays (91 patients in the arm): neoplasm progression (24), nausea (16), dizziness (10), vomiting (9), somnolence (8), disorientation (5), anorexia (6), constipation (4), dry mouth (7), anaemia (6), diarrhoea (5), dysgeusia (1), headache (5), asthenia (6), hallucination (1), decreased appetite (4), fatigue (4), pain (4), insomnia (2), stomatitis (5), weight decreased (5).</p>
|
|
<p>THC + CBD 6–10 sprays (87 patients in the arm): neoplasm progression (11), nausea (18), dizziness (21), vomiting (14), somnolence (16), disorientation (5), anorexia (5), constipation (10), dry mouth (8), anaemia (5), diarrhoea (4), dysgeusia (7), headache (6), asthenia (7), hallucination (1), decreased appetite (5), fatigue (4), pain (2), insomnia (2), stomatitis (2), weight decreased (1).</p>
|
|
<p>THC + CBD 11–16 sprays (90 patients in the arm): neoplasm progression (12), nausea (25), dizziness (20), vomiting (19), somnolence (15), disorientation (8), anorexia (11), constipation (6), dry mouth (7), anaemia (8), diarrhoea (8), dysgeusia (3), headache (4), asthenia (5), hallucination (6), decreased appetite (2), fatigue (5), pain (5), insomnia (4), stomatitis (3), weight decreased (2).</p>
|
|
<p>Placebo (91 patients in the arm): neoplasm progression (13), nausea (12), dizziness (12), vomiting (7), somnolence (4), disorientation (1), anorexia (10), constipation (7), dry mouth (7), anaemia (4), diarrhoea (4), dysgeusia (2), headache (1), asthenia (6), hallucination (5), decreased appetite (2), fatigue (4), pain (2), insomnia (5), stomatitis (0), weight decreased (2).</p>
|
|
<p>Serious adverse events</p>
|
|
<p>THC + CBD all doses combined (268 patients in the arm): deaths (56), blood disorders (4), cardiac disorders (0), gastrointestinal disorders (8), general disorders and administration site conditions (9), hepatobiliary disorders (2), infections and infestations (11), injury, poisoning and procedural complications (2), investigations (1), metabolism and nutrition disorders (5), musculoskeletal & connective tissue disorders (0), neoplasms, benign, malignant and unspecified (51), nervous system disorders (5), psychiatric disorders (4), renal and urinary disorders (4), respiratory, thoracic and mediastinal disorders (4), vascular disorders (4).</p>
|
|
<p>THC + CBD 1–4 sprays (91 patients in the arm): deaths (25), blood disorders (4), cardiac disorders (0), gastrointestinal disorders (1), general disorders and administration site conditions (4), hepatobiliary disorders (0), infections and infestations (4), injury, poisoning and procedural complications (1), investigations (0), metabolism and nutrition disorders (1), musculoskeletal & connective tissue disorders (0), neoplasms, benign, malignant and unspecified (26), nervous system disorders (1), psychiatric disorders (1), renal and urinary disorders (0), respiratory, thoracic and mediastinal disorders (1), vascular disorders (0).</p>
|
|
<p>THC + CBD 6–10 sprays (87 patients in the arm): deaths (14), blood disorders (0), cardiac disorders (0), gastrointestinal disorders (0), general disorders and administration site conditions (1), hepatobiliary disorders (1), infections and infestations (5), injury, poisoning and procedural complications (1), investigations (0), metabolism and nutrition disorders (1), musculoskeletal & connective tissue disorders (0), neoplasms, benign, malignant and unspecified (12), nervous system disorders (1), psychiatric disorders (1), renal and urinary disorders (0), respiratory, thoracic and mediastinal disorders (2), vascular disorders (0).</p>
|
|
<p>THC + CBD 11–16 sprays (90 patients in the arm): deaths (17), blood disorders (0), cardiac disorders (0), gastrointestinal disorders (4), general disorders and administration site conditions (4), hepatobiliary disorders (1), infections and infestations (2), injury, poisoning and procedural complications (0), investigations (1), metabolism and nutrition disorders (3), musculoskeletal & connective tissue disorders (0), neoplasms, benign, malignant and unspecified (51), nervous system disorders (3), psychiatric disorders (2), renal and urinary disorders (4), respiratory, thoracic and mediastinal disorders (1), vascular disorders (3).</p>
|
|
<p>Placebo (91 patients in the arm): deaths (16), blood disorders (2), cardiac disorders (1), gastrointestinal disorders (2), general disorders and administration site conditions (2), hepatobiliary disorders (2), infections and infestations (2), injury, poisoning and procedural complications (1), investigations (0), metabolism and nutrition disorders (1), musculoskeletal & connective tissue disorders (1), neoplasms, benign, malignant and unspecified (15), nervous system disorders (0), psychiatric disorders (0), renal and urinary disorders (1), respiratory, thoracic and mediastinal disorders (1), vascular disorders (1).</p>
|
|
</td></tr><tr><td headers="hd_h_ch2.apph.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch2.appl.ref1" rid="ch2.appl.ref1">Blake 2006</a>
|
|
</td><td headers="hd_h_ch2.apph.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nociceptive pain: rheumatoid arthritis</td><td headers="hd_h_ch2.apph.tab1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Treatment-related in more than 1 patient</p>
|
|
<p>THC + CBD (31 patients in the arm): dizziness (all mild) (8), light-headedness (3), dry mouth (4), nausea (2), arthritic pains (1), constipation (1), drowsiness (1), fall (2), headache (1), palpitations (0), vomiting (0).</p>
|
|
<p>Placebo (27 patients in the arm): dizziness (all mild) (1), light-headedness (1), dry mouth (0), nausea (1), arthritic pains (1), constipation (1), drowsiness (1), fall (0), headache (1), palpitations (2), vomiting (2).</p>
|
|
<p>Serious adverse events</p>
|
|
<p>All-causality</p>
|
|
<p>THC + CBD (31 patients in the arm): constipation (1), malaise (1).</p>
|
|
<p>Placebo (27 patients in the arm): unspecified (6)</p>
|
|
<p>Treatment-related</p>
|
|
<p>THC + CBD (31 patients in the arm): constipation (1), malaise (1).</p>
|
|
<p>Placebo (27 patients in the arm): unspecified (2)</p>
|
|
</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch2apphtab2"><div id="ch2.apph.tab2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.apph.tab2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.apph.tab2_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.apph.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Study</th><th id="hd_h_ch2.apph.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Subgroup</th><th id="hd_h_ch2.apph.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adverse events reported</th></tr></thead><tbody><tr><td headers="hd_h_ch2.apph.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch2.appl.ref13" rid="ch2.appl.ref13">Schimrigk 2017</a>
|
|
</td><td headers="hd_h_ch2.apph.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Neuropathic pain: multiple sclerosis</td><td headers="hd_h_ch2.apph.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>All-causality in ≥5% of patients</p>
|
|
<p>Delta-9-THC (124 patients in the arm): dizziness (25), vertigo (14), fatigue (10), dry mouth (9), adverse drug reaction (8), nausea (6), headache (5), diarrhoea (3), withdrawal syndrome (0), neuralgia (0), insomnia (1).</p>
|
|
<p>Placebo (116 patients in the arm): dizziness (5), vertigo (3), fatigue (5), dry mouth (1), adverse drug reaction (0), nausea (4), headache (6), diarrhoea (0), withdrawal syndrome (0), neuralgia (0), insomnia (0).</p>
|
|
<p>Serious adverse events</p>
|
|
<p>All-causality</p>
|
|
<p>Delta-9-THC (124 patients in the arm): (17)</p>
|
|
<p>Placebo (116 patients in the arm): (10)</p>
|
|
<p>Treatment-related</p>
|
|
<p>Delta-9-THC (124 patients in the arm): (2)</p>
|
|
<p>Placebo (116 patients in the arm): (0)</p>
|
|
</td></tr><tr><td headers="hd_h_ch2.apph.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch2.appl.ref16" rid="ch2.appl.ref16">Svendsen 2004</a>
|
|
</td><td headers="hd_h_ch2.apph.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Neuropathic pain: multiple sclerosis</td><td headers="hd_h_ch2.apph.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>All-causality</p>
|
|
<p>Delta-9-THC (24 patients in the arm): Central nervous system (19) including: dizziness or light-headedness (14), tiredness or drowsiness (10), fatigue (1), balance difficulty (2), headache (6), migraine (1), speech disorders (1), feeling of drunkenness (2), sleep difficulty (1), multiple sclerosis aggravated (1); Musculoskeletal system (9) including: myalgia (6), muscle weakness (3), limb heaviness (1), distortion of wrist (1); Gastro-intestinal disorders (5) including: mouth dryness (3), nausea (3), abdominal pain (0); Cardiovascular disorders (4) including: palpitations (4); Psychiatric disorders (3) including: euphoria (3), hyperactivity (1), nervousness (0); endocrine disorders (1) including: hot flushes (1); Vision disorders (0) including: diplopia (0); Whole body (4) including: anorexia (1), weight decrease (1), fever (0), chills (1), upper airway infection (1), tenderness in nose (1).</p>
|
|
<p>Placebo (24 patients in the arm): Central nervous system (8) including: dizziness or light-headedness (4), tiredness or drowsiness (6), fatigue (0), balance difficulty (0), headache (1), migraine (0), speech disorders (0), feeling of drunkenness (0), sleep difficulty (2), multiple sclerosis aggravated (2); Musculoskeletal system (2) including: myalgia (1), muscle weakness (1), limb heaviness (0), distortion of wrist (0); Gastrointestinal disorders (4) including: mouth dryness (0), nausea (4), abdominal pain (1); Cardiovascular disorders (2) including: palpitations (2); Psychiatric disorders (1) including: euphoria (0), hyperactivity (0), nervousness (1); endocrine disorders (0) including: hot flushes (0); Vision disorders (1) including: diplopia (1); Whole body (2) including: anorexia (0), weight decrease (0), fever (1), chills (0), upper airway infection (1), tenderness in nose (0).</p>
|
|
<p>Serious adverse events</p>
|
|
<p>All-causality</p>
|
|
<p>Delta-9-THC (24 patients in the arm): (3)</p>
|
|
<p>Placebo (24 patients in the arm): (1)</p>
|
|
</td></tr><tr><td headers="hd_h_ch2.apph.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch2.appl.ref3" rid="ch2.appl.ref3">de Vries 2017</a>
|
|
</td><td headers="hd_h_ch2.apph.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nociceptive pain: abdominal pain</td><td headers="hd_h_ch2.apph.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Treatment-related in ≥10% Patients</p>
|
|
<p>Delta-9-THC (24 patients in the arm): General: decreased appetite (6), increased appetite (7); Nervous system disorders: amnesia (4), balance disorder (3), disturbance in attention (4), dizziness (24), dysgeusia (3), headache (14), somnolence (15); Psychiatric disorders: confusional state (3), depressed mood (3), euphoric mood (4), irritability (2), sluggishness (3); Gastrointestinal system disorders: abdominal pain (3), constipation (4), diarrhoea (3), dry mouth (9), nausea (13); Skin and subcutaneous tissue disorders: hyperhidrosis (8), rash (0); Musculoskeletal and connective tissue disorders: tremor (1); Vision disorders: visual impairment (4).</p>
|
|
<p>Placebo (24 patients in the arm): General: decreased appetite (1), increased appetite (6); Nervous system disorders: amnesia (1), balance disorder (4), disturbance in attention (0), dizziness (11), dysgeusia (1), headache (18), somnolence (11); Psychiatric disorders: confusional state (3), depressed mood (2), euphoric mood (2), irritability (2), sluggishness (0); Gastrointestinal system disorders: abdominal pain (0), constipation (5), diarrhoea (2), dry mouth (2), nausea (5); Skin and subcutaneous tissue disorders: hyperhidrosis (5), rash (5); Musculoskeletal and connective tissue disorders: tremor (4); Vision disorders: visual impairment (1).</p>
|
|
<p>Details of the 5 serious adverse events were not reported</p>
|
|
</td></tr><tr><td headers="hd_h_ch2.apph.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">De Vries 2015</td><td headers="hd_h_ch2.apph.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nociceptive pain: abdominal pain</td><td headers="hd_h_ch2.apph.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>Treatment-related</p>
|
|
<p>Delta-9-THC (24 patients in the arm): General: fatigue (7); Nervous system symptoms: somnolence (8), dizziness (4), headache (2), balance disorder (2), amnesia (1), paraesthesia (2), depressed level of consciousness (0); Psychiatric symptoms: confusional state (2), indifference (1), euphoric mood (4), derealization (1), disorientation (1), tension (1), Gastro-intestinal system symptoms: nausea (3), vomiting (1), steatorrhoea (1), constipation (0), abdominal discomfort (1), dry mouth (5), throat irritation (1); Vision symptoms: visual impairment (3); Cardiac symptoms: heart rate increased (1); Eye symptoms: dry eye (1), photophobia (1).</p>
|
|
<p>Placebo (22 patients in the arm): General: fatigue (8); Nervous system symptoms: somnolence (11), dizziness (6), headache (3), balance disorder (0), amnesia (0), paraesthesia (1), depressed level of consciousness (1); Psychiatric symptoms: confusional state (0), indifference (0), euphoric mood (2), derealization (0), disorientation (0), tension (0), Gastro-intestinal system symptoms: nausea (1), vomiting (0), steatorrhoea (0), constipation (1), abdominal discomfort (0), dry mouth (0), throat irritation (0); Vision symptoms: visual impairment (1); Cardiac symptoms: heart rate increased (1); Eye symptoms: dry eye (0), photophobia (0).0</p>
|
|
<p>There were no serious adverse events</p>
|
|
</td></tr><tr><td headers="hd_h_ch2.apph.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch2.appl.ref9" rid="ch2.appl.ref9">Malik 2017</a>
|
|
</td><td headers="hd_h_ch2.apph.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nociceptive pain: functional chest pain (oesophageal)</td><td headers="hd_h_ch2.apph.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<p>All-causality</p>
|
|
<p>Delta-9-THC (10 patients in the arm): transient headache, fatigue (2), transient loose stools (1)</p>
|
|
<p>Placebo (9 patients in the arm): transient nausea and loose stools (2)</p>
|
|
<p>There were no serious adverse events</p>
|
|
</td></tr><tr><td headers="hd_h_ch2.apph.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch2.appl.ref19" rid="ch2.appl.ref19">Weber 2010</a>
|
|
</td><td headers="hd_h_ch2.apph.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nociceptive pain: cramps</td><td headers="hd_h_ch2.apph.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">“Two serious adverse events occurred. Both patients were admitted to hospital. One patient developed pneumonia during the wash-out period (after THC period) and later died; the other developed deep venous thrombosis before the THC period. These adverse events were felt not to be study-related. None of the remaining patients withdrew from the study. One patient experienced mild dizziness while on THC (sequence 0/1). The patient continued the study with half the dosage. Otherwise, none of the patients reported any side effects.”</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch2apphtab3"><div id="ch2.apph.tab3" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.apph.tab3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.apph.tab3_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.apph.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Study</th><th id="hd_h_ch2.apph.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Subgroup</th><th id="hd_h_ch2.apph.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adverse events reported</th></tr></thead><tbody><tr><td headers="hd_h_ch2.apph.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch2.appl.ref20" rid="ch2.appl.ref20">Wissel 2006</a>
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</td><td headers="hd_h_ch2.apph.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nociceptive pain: spasticity</td><td headers="hd_h_ch2.apph.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>All-causality</p>
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<p>Nabilone (13 patients in the arm): one moderate transient weakness of the lower limbs (1), mild drowsiness (2), acute relapse of multiple sclerosis (1)</p>
|
|
<p>Placebo (13 patients in the arm): mild drowsiness (1), mild dysphagia (1)</p>
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<p>Severe adverse events</p>
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<p>All-causality</p>
|
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<p>Nabilone (13 patients in the arm): acute relapse (1), exacerbation of weakness (1)</p>
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<p>Placebo (13 patients in the arm): 0</p>
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</td></tr><tr><td headers="hd_h_ch2.apph.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch2.appl.ref15" rid="ch2.appl.ref15">Skrabek 2008</a>
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</td><td headers="hd_h_ch2.apph.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Uncertain aetiology: fibromyalgia</td><td headers="hd_h_ch2.apph.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>All-causality at week 2</p>
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<p>Nabilone (18 patients in the arm): drowsiness (7), dry mouth (5), vertigo (2), ataxia (3), confusion (3), decreased concentration (1), disassociation (2), orthostatic hypotension (1), anorexia (1), headache (3), blurred vision (1), dysphoria (2), depression (0), euphoria (0), lightheaded (1), psychological high (1), nightmares (1), sensory disturbance (1), tachycardia (0), hallucination (0).</p>
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<p>Placebo (20 patients in the arm): drowsiness (3), dry mouth (5), vertigo (0), ataxia (0), confusion (0), decreased concentration (0), disassociation (0), orthostatic hypotension (0), anorexia (0), headache (2), blurred vision (1), dysphoria (0), depression (0), euphoria (0), lightheaded (0), psychological high (1), nightmares (0), sensory disturbance (0), tachycardia (0), hallucination (0).</p>
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<p>All-causality at week 4</p>
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<p>Nabilone (15 patients in the arm): drowsiness (7), dry mouth (5), vertigo (4), ataxia (3), confusion (2), decreased concentration (2), disassociation (2), orthostatic hypotension (2), anorexia (2), headache (1), blurred vision (0), dysphoria (1), depression (0), euphoria (1), lightheaded (0), psychological high (0), nightmares (0), sensory disturbance (1), tachycardia (0), hallucination (0).</p>
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<p>Placebo (18 patients in the arm): drowsiness (1), dry mouth (1), vertigo (0), ataxia (1), confusion (1), decreased concentration (1), disassociation (0), orthostatic hypotension (1), anorexia (1), headache (3), blurred vision (0), dysphoria (0), depression (1), euphoria (1), lightheaded (0), psychological high (0), nightmares (1), sensory disturbance (0), tachycardia (1), hallucination (0).</p>
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</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch2apphtab4"><div id="ch2.apph.tab4" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.apph.tab4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.apph.tab4_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.apph.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Study</th><th id="hd_h_ch2.apph.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Subgroup</th><th id="hd_h_ch2.apph.tab4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adverse events reported</th></tr></thead><tbody><tr><td headers="hd_h_ch2.apph.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch2.appl.ref5" rid="ch2.appl.ref5">Johnson 2010</a>
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</td><td headers="hd_h_ch2.apph.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nociceptive pain: cancer pain</td><td headers="hd_h_ch2.apph.tab4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Treatment-related reported by ≥3 patients</p>
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<p>THC (58 patients in the arm): somnolence (8), dizziness (7), confusion (1), nausea (4), vomiting (4), raised gamma GT (5), hypercalcaemia (0), hypotension (0).</p>
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<p>Placebo (59 patients in the arm): somnolence (6), dizziness (3), confusion (1), nausea (4), vomiting (2), raised gamma GT (1), hypercalcaemia (3), hypotension (0).</p>
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<p>Serious adverse event</p>
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<p>All-causality</p>
|
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<p>THC (58 patients in the arm): progression of cancer (8), metastases to the brain (1), gastric ulcer haemorrhage (1), syncope (1), bronchopneumonia (1), hyperglycaemia (1), confusion (1), oral candidiasis (1), somnolence (1), tremor (1), disorientation (1).</p>
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<p>Placebo (59 patients in the arm): progression of cancer (7)</p>
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<p>Treatment-related</p>
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<p>THC (58 patients in the arm): syncope (1)</p>
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<p>Placebo (59 patients in the arm): 0</p>
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</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch2apphtab5"><div id="ch2.apph.tab5" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.apph.tab5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.apph.tab5_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.apph.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Study</th><th id="hd_h_ch2.apph.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Subgroup</th><th id="hd_h_ch2.apph.tab5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adverse events reported</th></tr></thead><tbody><tr><td headers="hd_h_ch2.apph.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch2.appl.ref17" rid="ch2.appl.ref17">van de Donk 2019</a>
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</td><td headers="hd_h_ch2.apph.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Uncertain aetiology: fibromyalgia</td><td headers="hd_h_ch2.apph.tab5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>All-causality</p>
|
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<p>THC and CBD (20 patients in the arm): Drug high (16), coughing (14), sore throat (2), bad taste (5), dyspnoea (0), dizzy (3), headache (1), nausea (3), vomiting (0), sleepy (1)</p>
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<p>Placebo (20 patients in the arm): Drug high (2), coughing (0), sore throat (0), bad taste (0), dyspnoea (0), dizzy (0), headache (1), nausea (0), vomiting (0), sleepy (0)</p>
|
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<p>No serious adverse events</p>
|
|
</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch2apphtab6"><div id="ch2.apph.tab6" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.apph.tab6/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.apph.tab6_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.apph.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Study</th><th id="hd_h_ch2.apph.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Subgroup</th><th id="hd_h_ch2.apph.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adverse events reported</th></tr></thead><tbody><tr><td headers="hd_h_ch2.apph.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch2.appl.ref17" rid="ch2.appl.ref17">van de Donk 2019</a>
|
|
</td><td headers="hd_h_ch2.apph.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Uncertain aetiology: fibromyalgia</td><td headers="hd_h_ch2.apph.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>All-causality</p>
|
|
<p>THC and CBD (20 patients in the arm): Drug high (16), coughing (14), sore throat (7), bad taste (6), dyspnoea (1), dizzy (4), headache (2), nausea (6), vomiting (0), sleepy (0)</p>
|
|
<p>Placebo (20 patients in the arm): Drug high (2), coughing (0), sore throat (0), bad taste (0), dyspnoea (0), dizzy (0), headache (1), nausea (0), vomiting (0), sleepy (0)</p>
|
|
<p>No serious adverse events</p>
|
|
</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch2apphtab7"><div id="ch2.apph.tab7" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.apph.tab7/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.apph.tab7_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.apph.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Study</th><th id="hd_h_ch2.apph.tab7_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Subgroup</th><th id="hd_h_ch2.apph.tab7_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adverse events reported</th></tr></thead><tbody><tr><td headers="hd_h_ch2.apph.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a class="bibr" href="#ch2.appl.ref17" rid="ch2.appl.ref17">van de Donk 2019</a>
|
|
</td><td headers="hd_h_ch2.apph.tab7_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Uncertain aetiology: fibromyalgia</td><td headers="hd_h_ch2.apph.tab7_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<p>All-causality</p>
|
|
<p>THC and CBD (20 patients in the arm): Drug high (8), coughing (13), sore throat (1), bad taste (5), dyspnoea (0), dizzy (2), headache (3), nausea (1), vomiting (1), sleepy (1)</p>
|
|
<p>Placebo (20 patients in the arm): Drug high (2), coughing (0), sore throat (0), bad taste (0), dyspnoea (0), dizzy (0), headache (1), nausea (0), vomiting (0), sleepy (0)</p>
|
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<p>No serious adverse events</p>
|
|
</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobch2appifig1"><div id="ch2.appi.fig1" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%201.%20Model%20structure%20(for%20both%20model%20arms).&p=BOOKS&id=577083_ch2appif1.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/NBK577083/bin/ch2appif1.jpg" alt="Figure 1. Model structure (for both model arms)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 1</span><span class="title">Model structure (for both model arms)</span></h3></div></article><article data-type="table-wrap" id="figobch2appitab1"><div id="ch2.appi.tab1" class="table"><h3><span class="label">Table 2</span><span class="title"><a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a> response data compared with normal distribution estimates</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appi.tab1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appi.tab1_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.appi.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Outcome</th><th id="hd_h_ch2.appi.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reported by study</th><th id="hd_h_ch2.appi.tab1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Estimated</th></tr></thead><tbody><tr><th headers="hd_h_ch2.appi.tab1_1_1_1_1 hd_h_ch2.appi.tab1_1_1_1_2" id="hd_b_ch2.appi.tab1_1_1_1_1" colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;">Patients achieving 30% pain reduction</th><th headers="hd_h_ch2.appi.tab1_1_1_1_3" id="hd_b_ch2.appi.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th></tr><tr><td headers="hd_h_ch2.appi.tab1_1_1_1_1 hd_b_ch2.appi.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">THC:CBD spray</td><td headers="hd_h_ch2.appi.tab1_1_1_1_2 hd_b_ch2.appi.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">50%</td><td headers="hd_h_ch2.appi.tab1_1_1_1_3 hd_b_ch2.appi.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">49%</td></tr><tr><td headers="hd_h_ch2.appi.tab1_1_1_1_1 hd_b_ch2.appi.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Placebo</td><td headers="hd_h_ch2.appi.tab1_1_1_1_2 hd_b_ch2.appi.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">45%</td><td headers="hd_h_ch2.appi.tab1_1_1_1_3 hd_b_ch2.appi.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">46%</td></tr><tr><th headers="hd_h_ch2.appi.tab1_1_1_1_1 hd_h_ch2.appi.tab1_1_1_1_2" id="hd_b_ch2.appi.tab1_1_1_4_1" colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;">Patients achieving 50% pain reduction</th><th headers="hd_h_ch2.appi.tab1_1_1_1_3" id="hd_b_ch2.appi.tab1_1_1_4_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th></tr><tr><td headers="hd_h_ch2.appi.tab1_1_1_1_1 hd_b_ch2.appi.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">THC:CBD spray</td><td headers="hd_h_ch2.appi.tab1_1_1_1_2 hd_b_ch2.appi.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">30%</td><td headers="hd_h_ch2.appi.tab1_1_1_1_3 hd_b_ch2.appi.tab1_1_1_4_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">28%</td></tr><tr><td headers="hd_h_ch2.appi.tab1_1_1_1_1 hd_b_ch2.appi.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Placebo</td><td headers="hd_h_ch2.appi.tab1_1_1_1_2 hd_b_ch2.appi.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">28%</td><td headers="hd_h_ch2.appi.tab1_1_1_1_3 hd_b_ch2.appi.tab1_1_1_4_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">25%</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobch2appifig2"><div id="ch2.appi.fig2" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%202.%20Portenoy%20response%20data%20compared%20with%20normal%20distribution%20estimates.&p=BOOKS&id=577083_ch2appif2.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/NBK577083/bin/ch2appif2.jpg" alt="Figure 2. Portenoy response data compared with normal distribution estimates." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 2</span><span class="title">Portenoy response data compared with normal distribution estimates</span></h3></div></article><article data-type="table-wrap" id="figobch2appitab2"><div id="ch2.appi.tab2" class="table"><h3><span class="label">Table 3</span><span class="title">Baseline Characteristics</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appi.tab2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appi.tab2_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.appi.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Parameter</th><th id="hd_h_ch2.appi.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mean</th><th id="hd_h_ch2.appi.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">SD</th><th id="hd_h_ch2.appi.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Source</th></tr></thead><tbody><tr><td headers="hd_h_ch2.appi.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Age</td><td headers="hd_h_ch2.appi.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">60.32</td><td headers="hd_h_ch2.appi.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10.93</td><td headers="hd_h_ch2.appi.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a class="bibr" href="#ch2.appl.ref23" rid="ch2.appl.ref23">Farrar 2001</a>
|
|
</td></tr><tr><td headers="hd_h_ch2.appi.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% male</td><td headers="hd_h_ch2.appi.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">46%</td><td headers="hd_h_ch2.appi.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ch2.appi.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<a class="bibr" href="#ch2.appl.ref23" rid="ch2.appl.ref23">Farrar 2001</a>
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|
</td></tr><tr><td headers="hd_h_ch2.appi.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pain NRS at baseline</td><td headers="hd_h_ch2.appi.tab2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">6.52</td><td headers="hd_h_ch2.appi.tab2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1.43</td><td headers="hd_h_ch2.appi.tab2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#ch2.appl.ref23" rid="ch2.appl.ref23">Farrar 2001</a>
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</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch2appitab3"><div id="ch2.appi.tab3" class="table"><h3><span class="label">Table 4</span><span class="title">Baseline response and treatment effect data from the clinical review</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appi.tab3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appi.tab3_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.appi.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th id="hd_h_ch2.appi.tab3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mean</th><th id="hd_h_ch2.appi.tab3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lower CI</th><th id="hd_h_ch2.appi.tab3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Upper CI</th></tr></thead><tbody><tr><th headers="hd_h_ch2.appi.tab3_1_1_1_1 hd_h_ch2.appi.tab3_1_1_1_2 hd_h_ch2.appi.tab3_1_1_1_3 hd_h_ch2.appi.tab3_1_1_1_4" id="hd_b_ch2.appi.tab3_1_1_1_1" colspan="4" rowspan="1" style="text-align:left;vertical-align:middle;">Treatment response in control arm</th></tr><tr><th headers="hd_h_ch2.appi.tab3_1_1_1_1" id="hd_b_ch2.appi.tab3_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a>
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</th><td headers="hd_h_ch2.appi.tab3_1_1_1_2 hd_b_ch2.appi.tab3_1_1_2_1 hd_b_ch2.appi.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−1.76</td><td headers="hd_h_ch2.appi.tab3_1_1_1_3 hd_b_ch2.appi.tab3_1_1_2_1 hd_b_ch2.appi.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−2.11465</td><td headers="hd_h_ch2.appi.tab3_1_1_1_4 hd_b_ch2.appi.tab3_1_1_2_1 hd_b_ch2.appi.tab3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−1.40535</td></tr><tr><th headers="hd_h_ch2.appi.tab3_1_1_1_1" id="hd_b_ch2.appi.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#ch2.appl.ref11" rid="ch2.appl.ref11">Portenoy 2012</a>
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</th><td headers="hd_h_ch2.appi.tab3_1_1_1_2 hd_b_ch2.appi.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.8</td><td headers="hd_h_ch2.appi.tab3_1_1_1_3 hd_b_ch2.appi.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−1.17394</td><td headers="hd_h_ch2.appi.tab3_1_1_1_4 hd_b_ch2.appi.tab3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.42606</td></tr><tr><th headers="hd_h_ch2.appi.tab3_1_1_1_1 hd_b_ch2.appi.tab3_1_1_3_1 hd_h_ch2.appi.tab3_1_1_1_2 hd_h_ch2.appi.tab3_1_1_1_3 hd_h_ch2.appi.tab3_1_1_1_4" id="hd_b_ch2.appi.tab3_1_1_4_1" colspan="4" rowspan="1" style="text-align:left;vertical-align:middle;">THC:CBD spray</th></tr><tr><th headers="hd_h_ch2.appi.tab3_1_1_1_1" id="hd_b_ch2.appi.tab3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Overall</th><td headers="hd_h_ch2.appi.tab3_1_1_1_2 hd_b_ch2.appi.tab3_1_1_5_1 hd_b_ch2.appi.tab3_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.44</td><td headers="hd_h_ch2.appi.tab3_1_1_1_3 hd_b_ch2.appi.tab3_1_1_5_1 hd_b_ch2.appi.tab3_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.7</td><td headers="hd_h_ch2.appi.tab3_1_1_1_4 hd_b_ch2.appi.tab3_1_1_5_1 hd_b_ch2.appi.tab3_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.18</td></tr><tr><th headers="hd_h_ch2.appi.tab3_1_1_1_1" id="hd_b_ch2.appi.tab3_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neuropathic pain</th><td headers="hd_h_ch2.appi.tab3_1_1_1_2 hd_b_ch2.appi.tab3_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.52</td><td headers="hd_h_ch2.appi.tab3_1_1_1_3 hd_b_ch2.appi.tab3_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.99</td><td headers="hd_h_ch2.appi.tab3_1_1_1_4 hd_b_ch2.appi.tab3_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.06</td></tr><tr><th headers="hd_h_ch2.appi.tab3_1_1_1_1" id="hd_b_ch2.appi.tab3_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cancer pain</th><td headers="hd_h_ch2.appi.tab3_1_1_1_2 hd_b_ch2.appi.tab3_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.33</td><td headers="hd_h_ch2.appi.tab3_1_1_1_3 hd_b_ch2.appi.tab3_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.66</td><td headers="hd_h_ch2.appi.tab3_1_1_1_4 hd_b_ch2.appi.tab3_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0</td></tr><tr><th headers="hd_h_ch2.appi.tab3_1_1_1_1" id="hd_b_ch2.appi.tab3_1_1_8_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Musculoskeletal pain</th><td headers="hd_h_ch2.appi.tab3_1_1_1_2 hd_b_ch2.appi.tab3_1_1_8_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.95</td><td headers="hd_h_ch2.appi.tab3_1_1_1_3 hd_b_ch2.appi.tab3_1_1_8_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−1.85</td><td headers="hd_h_ch2.appi.tab3_1_1_1_4 hd_b_ch2.appi.tab3_1_1_8_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.05</td></tr><tr><th headers="hd_h_ch2.appi.tab3_1_1_1_1 hd_b_ch2.appi.tab3_1_1_8_1 hd_h_ch2.appi.tab3_1_1_1_2 hd_h_ch2.appi.tab3_1_1_1_3 hd_h_ch2.appi.tab3_1_1_1_4" id="hd_b_ch2.appi.tab3_1_1_9_1" colspan="4" rowspan="1" style="text-align:left;vertical-align:middle;">Oral dronabinol</th></tr><tr><th headers="hd_h_ch2.appi.tab3_1_1_1_1" id="hd_b_ch2.appi.tab3_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Overall</th><td headers="hd_h_ch2.appi.tab3_1_1_1_2 hd_b_ch2.appi.tab3_1_1_10_1 hd_b_ch2.appi.tab3_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.1</td><td headers="hd_h_ch2.appi.tab3_1_1_1_3 hd_b_ch2.appi.tab3_1_1_10_1 hd_b_ch2.appi.tab3_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.23</td><td headers="hd_h_ch2.appi.tab3_1_1_1_4 hd_b_ch2.appi.tab3_1_1_10_1 hd_b_ch2.appi.tab3_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.43</td></tr><tr><th headers="hd_h_ch2.appi.tab3_1_1_1_1" id="hd_b_ch2.appi.tab3_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neuropathic pain</th><td headers="hd_h_ch2.appi.tab3_1_1_1_2 hd_b_ch2.appi.tab3_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.11</td><td headers="hd_h_ch2.appi.tab3_1_1_1_3 hd_b_ch2.appi.tab3_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.41</td><td headers="hd_h_ch2.appi.tab3_1_1_1_4 hd_b_ch2.appi.tab3_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.63</td></tr><tr><th headers="hd_h_ch2.appi.tab3_1_1_1_1" id="hd_b_ch2.appi.tab3_1_1_12_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Visceral pain</th><td headers="hd_h_ch2.appi.tab3_1_1_1_2 hd_b_ch2.appi.tab3_1_1_12_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.1</td><td headers="hd_h_ch2.appi.tab3_1_1_1_3 hd_b_ch2.appi.tab3_1_1_12_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.77</td><td headers="hd_h_ch2.appi.tab3_1_1_1_4 hd_b_ch2.appi.tab3_1_1_12_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.57</td></tr><tr><th headers="hd_h_ch2.appi.tab3_1_1_1_1" id="hd_b_ch2.appi.tab3_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Musculoskeletal pain</th><td headers="hd_h_ch2.appi.tab3_1_1_1_2 hd_b_ch2.appi.tab3_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.24</td><td headers="hd_h_ch2.appi.tab3_1_1_1_3 hd_b_ch2.appi.tab3_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.32</td><td headers="hd_h_ch2.appi.tab3_1_1_1_4 hd_b_ch2.appi.tab3_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.8</td></tr><tr><th headers="hd_h_ch2.appi.tab3_1_1_1_1 hd_b_ch2.appi.tab3_1_1_13_1 hd_h_ch2.appi.tab3_1_1_1_2 hd_h_ch2.appi.tab3_1_1_1_3 hd_h_ch2.appi.tab3_1_1_1_4" id="hd_b_ch2.appi.tab3_1_1_14_1" colspan="4" rowspan="1" style="text-align:left;vertical-align:middle;">Oral nabilone</th></tr><tr><th headers="hd_h_ch2.appi.tab3_1_1_1_1" id="hd_b_ch2.appi.tab3_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Widespread pain</th><td headers="hd_h_ch2.appi.tab3_1_1_1_2 hd_b_ch2.appi.tab3_1_1_15_1 hd_b_ch2.appi.tab3_1_1_14_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−1.43</td><td headers="hd_h_ch2.appi.tab3_1_1_1_3 hd_b_ch2.appi.tab3_1_1_15_1 hd_b_ch2.appi.tab3_1_1_14_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−2.8</td><td headers="hd_h_ch2.appi.tab3_1_1_1_4 hd_b_ch2.appi.tab3_1_1_15_1 hd_b_ch2.appi.tab3_1_1_14_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.06</td></tr><tr><th headers="hd_h_ch2.appi.tab3_1_1_1_1 hd_b_ch2.appi.tab3_1_1_15_1 hd_h_ch2.appi.tab3_1_1_1_2 hd_h_ch2.appi.tab3_1_1_1_3 hd_h_ch2.appi.tab3_1_1_1_4" id="hd_b_ch2.appi.tab3_1_1_16_1" colspan="4" rowspan="1" style="text-align:left;vertical-align:middle;">THC - oromucosal spray</th></tr><tr><th headers="hd_h_ch2.appi.tab3_1_1_1_1" id="hd_b_ch2.appi.tab3_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cancer pain</th><td headers="hd_h_ch2.appi.tab3_1_1_1_2 hd_b_ch2.appi.tab3_1_1_17_1 hd_b_ch2.appi.tab3_1_1_16_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.32</td><td headers="hd_h_ch2.appi.tab3_1_1_1_3 hd_b_ch2.appi.tab3_1_1_17_1 hd_b_ch2.appi.tab3_1_1_16_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.86</td><td headers="hd_h_ch2.appi.tab3_1_1_1_4 hd_b_ch2.appi.tab3_1_1_17_1 hd_b_ch2.appi.tab3_1_1_16_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.22</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch2appitab4"><div id="ch2.appi.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/NBK577083/table/ch2.appi.tab4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appi.tab4_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.appi.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Parametric Survival Regression</th><th id="hd_h_ch2.appi.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AIC</th><th id="hd_h_ch2.appi.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_ch2.appi.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Weibull</td><td headers="hd_h_ch2.appi.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2641</td><td headers="hd_h_ch2.appi.tab4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2652</td></tr><tr><td headers="hd_h_ch2.appi.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Exponential</td><td headers="hd_h_ch2.appi.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3145</td><td headers="hd_h_ch2.appi.tab4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3150</td></tr><tr><td headers="hd_h_ch2.appi.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gompertz</td><td headers="hd_h_ch2.appi.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2412</td><td headers="hd_h_ch2.appi.tab4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2422</td></tr><tr><td headers="hd_h_ch2.appi.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gamma</td><td headers="hd_h_ch2.appi.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2497</td><td headers="hd_h_ch2.appi.tab4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2512</td></tr><tr><td headers="hd_h_ch2.appi.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lognormal</td><td headers="hd_h_ch2.appi.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2588</td><td headers="hd_h_ch2.appi.tab4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2599</td></tr><tr><td headers="hd_h_ch2.appi.tab4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Loglogistic</td><td headers="hd_h_ch2.appi.tab4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2625</td><td headers="hd_h_ch2.appi.tab4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2635</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobch2appifig3"><div id="ch2.appi.fig3" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%203.%20Discontinuation%20from%20THC%3ACBD%20spray%20in%20responders%20and%20simulated%20non-responders%20%5Bthe%20placebo%3D1%20group%5D%20(Messina%202017).&p=BOOKS&id=577083_ch2appif3.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/NBK577083/bin/ch2appif3.jpg" alt="Figure 3. Discontinuation from THC:CBD spray in responders and simulated non-responders [the placebo=1 group] (Messina 2017)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 3</span><span class="title">Discontinuation from THC:CBD spray in responders and simulated non-responders [the placebo=1 group] (<a class="bibr" href="#ch2.appl.ref24" rid="ch2.appl.ref24">Messina 2017</a>)</span></h3></div></article><article data-type="table-wrap" id="figobch2appitab5"><div id="ch2.appi.tab5" class="table"><h3><span class="label">Table 6</span><span class="title">Radiofrequency Denervation Parameters</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appi.tab5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appi.tab5_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.appi.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Parameter</th><th id="hd_h_ch2.appi.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mean</th><th id="hd_h_ch2.appi.tab5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lower CI</th><th id="hd_h_ch2.appi.tab5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Upper CI</th><th id="hd_h_ch2.appi.tab5_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Source</th></tr></thead><tbody><tr><td headers="hd_h_ch2.appi.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Threshold for consideration of RFD (pain score)</td><td headers="hd_h_ch2.appi.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5</td><td headers="hd_h_ch2.appi.tab5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">4</td><td headers="hd_h_ch2.appi.tab5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">6</td><td headers="hd_h_ch2.appi.tab5_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NG59</td></tr><tr><td headers="hd_h_ch2.appi.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of eligible patients in whom RFD is considered - per annum</td><td headers="hd_h_ch2.appi.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10%</td><td headers="hd_h_ch2.appi.tab5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">8%</td><td headers="hd_h_ch2.appi.tab5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">12%</td><td headers="hd_h_ch2.appi.tab5_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Probability of a positive diagnostic block</td><td headers="hd_h_ch2.appi.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">69%</td><td headers="hd_h_ch2.appi.tab5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ch2.appi.tab5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ch2.appi.tab5_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NG59</td></tr><tr><td headers="hd_h_ch2.appi.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Probability of a prolonged response to diagnostic block</td><td headers="hd_h_ch2.appi.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">15%</td><td headers="hd_h_ch2.appi.tab5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ch2.appi.tab5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ch2.appi.tab5_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NG59</td></tr><tr><td headers="hd_h_ch2.appi.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Probability of declining RFD after successful diagnostic block</td><td headers="hd_h_ch2.appi.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10%</td><td headers="hd_h_ch2.appi.tab5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ch2.appi.tab5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ch2.appi.tab5_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NG59</td></tr><tr><td headers="hd_h_ch2.appi.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of patients repeating successful RFD</td><td headers="hd_h_ch2.appi.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10%</td><td headers="hd_h_ch2.appi.tab5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ch2.appi.tab5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ch2.appi.tab5_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NG59</td></tr><tr><td headers="hd_h_ch2.appi.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Initial appointment</td><td headers="hd_h_ch2.appi.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£168</td><td headers="hd_h_ch2.appi.tab5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£135</td><td headers="hd_h_ch2.appi.tab5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£201</td><td headers="hd_h_ch2.appi.tab5_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NG59</td></tr><tr><td headers="hd_h_ch2.appi.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Diagnostic block procedure</td><td headers="hd_h_ch2.appi.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£546</td><td headers="hd_h_ch2.appi.tab5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£439</td><td headers="hd_h_ch2.appi.tab5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£653</td><td headers="hd_h_ch2.appi.tab5_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NG59</td></tr><tr><td headers="hd_h_ch2.appi.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Follow-up visit</td><td headers="hd_h_ch2.appi.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£121</td><td headers="hd_h_ch2.appi.tab5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£97</td><td headers="hd_h_ch2.appi.tab5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£145</td><td headers="hd_h_ch2.appi.tab5_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NG59</td></tr><tr><td headers="hd_h_ch2.appi.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Radiofrequency denervation procedure</td><td headers="hd_h_ch2.appi.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£618</td><td headers="hd_h_ch2.appi.tab5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£497</td><td headers="hd_h_ch2.appi.tab5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£739</td><td headers="hd_h_ch2.appi.tab5_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NG59</td></tr><tr><td headers="hd_h_ch2.appi.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">QoL gain from RFD < 4 months</td><td headers="hd_h_ch2.appi.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.091481</td><td headers="hd_h_ch2.appi.tab5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ch2.appi.tab5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ch2.appi.tab5_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Calculated</td></tr><tr><td headers="hd_h_ch2.appi.tab5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">QoL gain from RFD > 4 months</td><td headers="hd_h_ch2.appi.tab5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.078471</td><td headers="hd_h_ch2.appi.tab5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ch2.appi.tab5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ch2.appi.tab5_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Calculated</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch2appitab6"><div id="ch2.appi.tab6" class="table"><h3><span class="label">Table 7</span><span class="title">Adverse event parameters</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appi.tab6/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appi.tab6_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adverse events</th><th id="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Parameter</th><th id="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lower CI</th><th id="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Upper CI</th><th id="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th></tr></thead><tbody><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Event rates per year</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Non-serious adverse events</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10.37</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10.0708</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10.6692</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch2.appl.ref27" rid="ch2.appl.ref27">Wang 2008</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious adverse events</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.37</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.313484</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.426516</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch2.appl.ref27" rid="ch2.appl.ref27">Wang 2008</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Non-serious adverse events Placebo</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.87</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.626473</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7.113527</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Wang 2009</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious adverse events Placebo</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.25</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.203544</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.296456</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Wang 2010</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Frequency of individual events</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">% of events which are dizziness</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">56.8%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch2.appl.ref27" rid="ch2.appl.ref27">Wang 2008</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">% of events which are dry mouth</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">19.0%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch2.appl.ref27" rid="ch2.appl.ref27">Wang 2008</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">% of events which are fatigue</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">8.7%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch2.appl.ref27" rid="ch2.appl.ref27">Wang 2008</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">% of events which are headache</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.3%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch2.appl.ref27" rid="ch2.appl.ref27">Wang 2008</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">% of events which are nausea</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">9.3 %</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch2.appl.ref27" rid="ch2.appl.ref27">Wang 2008</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Event rates per cycle</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dizziness</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.451504</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dry mouth</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.151134</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fatigue</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.068927</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Headache</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.049956</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nausea</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.073986</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious adverse events</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.028384</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Event rates per cycle</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dizziness</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.299116</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dry mouth</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.100124</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fatigue</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.045663</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Headache</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.033095</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nausea</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.049015</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious adverse events</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.019178</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adverse event costs</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Unit costs</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GP visit</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">37</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PSSRU - GP consultation including direct staff costs and qualification costs</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">A&E visit</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">225.8232</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Reference costs - Weighted average of emergency medicine costs (excluding dental care, no investigation with no significant treatment, and dead on arrival)</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Ambulance</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">251.9343</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Reference costs - see and treat and convey</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Resource use</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_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_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">50%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">40%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">60%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab6_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_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">50%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">40%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">60%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab6_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_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">50%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">40%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">60%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab6_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_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">50%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">40%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">60%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab6_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_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">50%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">40%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">60%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab6_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_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">50%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">40%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">60%</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cost per event</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dizziness</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">18.5</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dry mouth</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">18.5</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fatigue</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">18.5</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Headache</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">18.5</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nausea</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">18.5</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious adverse event</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">351.7904</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adverse event disutilities</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">QoL decrements</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dizziness</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.022</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−0.009</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.054</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hagiwara 2018 - assumed to be equivalent to disutility of fatigue</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dry mouth</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.022</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−0.009</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.054</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hagiwara 2018 - assumed to be equivalent to disutility of fatigue</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fatigue</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.022</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−0.009</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.054</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hagiwara 2018</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Headache</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.043</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.155573</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.264427</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Stafford 2012 - equivalent to mild migraine</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nausea</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.062</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.025</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.103</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hagiwara 2018</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious adverse event</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.095</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−0.05</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.241</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hagiwara 2018 - grade 2 vomiting</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adverse event durations (days)</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dizziness</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.824022</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.175978</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dry mouth</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.25605</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">9.74395</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fatigue</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.25605</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">9.74395</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Headache</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.824022</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.175978</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nausea</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.824022</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.175978</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious adverse event</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.824022</td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.175978</td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">QALY losses</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dizziness</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.000181</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dry mouth</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.000422</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fatigue</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.000422</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Headache</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.000353</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nausea</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.00051</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated</td></tr><tr><td headers="hd_h_ch2.appi.tab6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serious adverse event</td><td headers="hd_h_ch2.appi.tab6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.000781</td><td headers="hd_h_ch2.appi.tab6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch2appitab7"><div id="ch2.appi.tab7" class="table"><h3><span class="label">Table 8</span><span class="title">CBMP Costs</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appi.tab7/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appi.tab7_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.appi.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cannabis treatment costs</th><th id="hd_h_ch2.appi.tab7_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mean</th><th id="hd_h_ch2.appi.tab7_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lower CI</th><th id="hd_h_ch2.appi.tab7_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Upper CI</th><th id="hd_h_ch2.appi.tab7_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Source</th></tr></thead><tbody><tr><th headers="hd_h_ch2.appi.tab7_1_1_1_1" id="hd_b_ch2.appi.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">THC:CBD spray</th><th headers="hd_h_ch2.appi.tab7_1_1_1_2" id="hd_b_ch2.appi.tab7_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th headers="hd_h_ch2.appi.tab7_1_1_1_3" id="hd_b_ch2.appi.tab7_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th headers="hd_h_ch2.appi.tab7_1_1_1_4" id="hd_b_ch2.appi.tab7_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th headers="hd_h_ch2.appi.tab7_1_1_1_5" id="hd_b_ch2.appi.tab7_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th></tr><tr><td headers="hd_h_ch2.appi.tab7_1_1_1_1 hd_b_ch2.appi.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cost per pack</td><td headers="hd_h_ch2.appi.tab7_1_1_1_2 hd_b_ch2.appi.tab7_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£300</td><td headers="hd_h_ch2.appi.tab7_1_1_1_3 hd_b_ch2.appi.tab7_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab7_1_1_1_4 hd_b_ch2.appi.tab7_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab7_1_1_1_5 hd_b_ch2.appi.tab7_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Drug Tariff</td></tr><tr><td headers="hd_h_ch2.appi.tab7_1_1_1_1 hd_b_ch2.appi.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Doses per day</td><td headers="hd_h_ch2.appi.tab7_1_1_1_2 hd_b_ch2.appi.tab7_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">8.8</td><td headers="hd_h_ch2.appi.tab7_1_1_1_3 hd_b_ch2.appi.tab7_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">8.16</td><td headers="hd_h_ch2.appi.tab7_1_1_1_4 hd_b_ch2.appi.tab7_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">9.43</td><td headers="hd_h_ch2.appi.tab7_1_1_1_5 hd_b_ch2.appi.tab7_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab7_1_1_1_1 hd_b_ch2.appi.tab7_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cost per cycle</td><td headers="hd_h_ch2.appi.tab7_1_1_1_2 hd_b_ch2.appi.tab7_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£ 342.2</td><td headers="hd_h_ch2.appi.tab7_1_1_1_3 hd_b_ch2.appi.tab7_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab7_1_1_1_4 hd_b_ch2.appi.tab7_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab7_1_1_1_5 hd_b_ch2.appi.tab7_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated</td></tr><tr><th headers="hd_h_ch2.appi.tab7_1_1_1_1" id="hd_b_ch2.appi.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nabilone</th><th headers="hd_h_ch2.appi.tab7_1_1_1_2" id="hd_b_ch2.appi.tab7_1_1_5_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th headers="hd_h_ch2.appi.tab7_1_1_1_3" id="hd_b_ch2.appi.tab7_1_1_5_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th headers="hd_h_ch2.appi.tab7_1_1_1_4" id="hd_b_ch2.appi.tab7_1_1_5_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th headers="hd_h_ch2.appi.tab7_1_1_1_5" id="hd_b_ch2.appi.tab7_1_1_5_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th></tr><tr><td headers="hd_h_ch2.appi.tab7_1_1_1_1 hd_b_ch2.appi.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cost per pack</td><td headers="hd_h_ch2.appi.tab7_1_1_1_2 hd_b_ch2.appi.tab7_1_1_5_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£196</td><td headers="hd_h_ch2.appi.tab7_1_1_1_3 hd_b_ch2.appi.tab7_1_1_5_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab7_1_1_1_4 hd_b_ch2.appi.tab7_1_1_5_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab7_1_1_1_5 hd_b_ch2.appi.tab7_1_1_5_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Drug Tariff (March 2019)</td></tr><tr><td headers="hd_h_ch2.appi.tab7_1_1_1_1 hd_b_ch2.appi.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Doses per day</td><td headers="hd_h_ch2.appi.tab7_1_1_1_2 hd_b_ch2.appi.tab7_1_1_5_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td><td headers="hd_h_ch2.appi.tab7_1_1_1_3 hd_b_ch2.appi.tab7_1_1_5_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab7_1_1_1_4 hd_b_ch2.appi.tab7_1_1_5_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab7_1_1_1_5 hd_b_ch2.appi.tab7_1_1_5_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a class="bibr" href="#ch2.appl.ref15" rid="ch2.appl.ref15">Skrabek 2008</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab7_1_1_1_1 hd_b_ch2.appi.tab7_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cost per cycle</td><td headers="hd_h_ch2.appi.tab7_1_1_1_2 hd_b_ch2.appi.tab7_1_1_5_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£548.8</td><td headers="hd_h_ch2.appi.tab7_1_1_1_3 hd_b_ch2.appi.tab7_1_1_5_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab7_1_1_1_4 hd_b_ch2.appi.tab7_1_1_5_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab7_1_1_1_5 hd_b_ch2.appi.tab7_1_1_5_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch2appitab8"><div id="ch2.appi.tab8" class="table"><h3><span class="label">Table 9</span><span class="title">Background pain management costs by NRS stage</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appi.tab8/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appi.tab8_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.appi.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unit costs</th><th id="hd_h_ch2.appi.tab8_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Parameter</th><th id="hd_h_ch2.appi.tab8_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Source</th></tr></thead><tbody><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GP visit</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£37.00</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PSSRU - GP consultation including direct staff costs and qualification costs</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Outpatient visit</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£147.00</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NHS Reference costs - non-admitted face-to-face consultant-led attendance, follow-up - pain management</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">A&E visit</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£225.82</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Reference costs - Weighted average of emergency medicine costs (excluding dental care, no investigation with no significant treatment, and dead on arrival)</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hospital admission</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£2,071.39</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Reference costs - Weighted average of elective long stay, non-elective long stay and non-elective short stay for pain procedure HRGs: AB12Z, AB13Z, AB14Z, AB15Z, AB16Z, AB17Z, AB18Z, AB19Z, AB20Z, AB21Z, AB22Z, AB24Z</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Home care visitor - cost per hour</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£27.29</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PSSRU 2018 - Cost per hour for home care worker (based on the price multipliers for independent sector home care provided for social services) - weighted average of weekday and weekend cost</td></tr><tr><th headers="hd_h_ch2.appi.tab8_1_1_1_1" id="hd_b_ch2.appi.tab8_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Resource use per state</th><th headers="hd_h_ch2.appi.tab8_1_1_1_2" id="hd_b_ch2.appi.tab8_1_1_6_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th headers="hd_h_ch2.appi.tab8_1_1_1_3" id="hd_b_ch2.appi.tab8_1_1_6_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th></tr><tr><th headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_6_1" id="hd_b_ch2.appi.tab8_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">State 1 (NRS 0–2)</th><th headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_6_2" id="hd_b_ch2.appi.tab8_1_1_7_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_6_3" id="hd_b_ch2.appi.tab8_1_1_7_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_6_1 hd_b_ch2.appi.tab8_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Community-based visits (annual)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_6_2 hd_b_ch2.appi.tab8_1_1_7_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_6_3 hd_b_ch2.appi.tab8_1_1_7_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_6_1 hd_b_ch2.appi.tab8_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Outpatient clinic visits (annual)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_6_2 hd_b_ch2.appi.tab8_1_1_7_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_6_3 hd_b_ch2.appi.tab8_1_1_7_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_6_1 hd_b_ch2.appi.tab8_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">A&E visits (annual)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_6_2 hd_b_ch2.appi.tab8_1_1_7_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_6_3 hd_b_ch2.appi.tab8_1_1_7_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_6_1 hd_b_ch2.appi.tab8_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hospital admissions (annual)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_6_2 hd_b_ch2.appi.tab8_1_1_7_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_6_3 hd_b_ch2.appi.tab8_1_1_7_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_6_1 hd_b_ch2.appi.tab8_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Home care visits (weekly)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_6_2 hd_b_ch2.appi.tab8_1_1_7_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_6_3 hd_b_ch2.appi.tab8_1_1_7_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><th headers="hd_h_ch2.appi.tab8_1_1_1_1" id="hd_b_ch2.appi.tab8_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">State 2 (NRS 2–4)</th><th headers="hd_h_ch2.appi.tab8_1_1_1_2" id="hd_b_ch2.appi.tab8_1_1_13_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th headers="hd_h_ch2.appi.tab8_1_1_1_3" id="hd_b_ch2.appi.tab8_1_1_13_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Community-based visits (annual)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_13_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_13_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Outpatient clinic visits (annual)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_13_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_13_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">A&E visits (annual)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_13_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_13_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hospital admissions (annual)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_13_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_13_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Home care visits (weekly)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_13_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_13_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><th headers="hd_h_ch2.appi.tab8_1_1_1_1" id="hd_b_ch2.appi.tab8_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">State 3 (NRS 4–6)</th><th headers="hd_h_ch2.appi.tab8_1_1_1_2" id="hd_b_ch2.appi.tab8_1_1_19_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th headers="hd_h_ch2.appi.tab8_1_1_1_3" id="hd_b_ch2.appi.tab8_1_1_19_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Community-based visits (annual)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_19_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_19_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Outpatient clinic visits (annual)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_19_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_19_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">A&E visits (annual)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_19_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_19_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hospital admissions (annual)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_19_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.5</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_19_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_19_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Home care visits (weekly)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_19_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_19_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><th headers="hd_h_ch2.appi.tab8_1_1_1_1" id="hd_b_ch2.appi.tab8_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">State 4 (NRS 6–8)</th><th headers="hd_h_ch2.appi.tab8_1_1_1_2" id="hd_b_ch2.appi.tab8_1_1_25_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th headers="hd_h_ch2.appi.tab8_1_1_1_3" id="hd_b_ch2.appi.tab8_1_1_25_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Community-based visits (annual)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_25_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_25_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Outpatient clinic visits (annual)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_25_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_25_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">A&E visits (annual)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_25_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_25_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hospital admissions (annual)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_25_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_25_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_25_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Home care visits (weekly)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_25_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_25_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><th headers="hd_h_ch2.appi.tab8_1_1_1_1" id="hd_b_ch2.appi.tab8_1_1_31_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">State 5 (NRS 8–10)</th><th headers="hd_h_ch2.appi.tab8_1_1_1_2" id="hd_b_ch2.appi.tab8_1_1_31_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th headers="hd_h_ch2.appi.tab8_1_1_1_3" id="hd_b_ch2.appi.tab8_1_1_31_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_31_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Community-based visits (annual)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_31_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">12</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_31_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_31_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Outpatient clinic visits (annual)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_31_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">8</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_31_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_31_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">A&E visits (annual)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_31_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_31_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_31_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hospital admissions (annual)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_31_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_31_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_31_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Home care visits (weekly)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_31_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_31_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Committee assumption</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_31_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Home care funding sources</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_31_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_31_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><th headers="hd_h_ch2.appi.tab8_1_1_1_1" id="hd_b_ch2.appi.tab8_1_1_38_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distribution of funding categories</th><th headers="hd_h_ch2.appi.tab8_1_1_1_2" id="hd_b_ch2.appi.tab8_1_1_38_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th headers="hd_h_ch2.appi.tab8_1_1_1_3" id="hd_b_ch2.appi.tab8_1_1_38_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_38_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Self-funded</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_38_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.434</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_38_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parkinson’s guideline</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_38_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Part self- part NHS/PSS-funded</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_38_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.139</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_38_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parkinson’s guideline</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_38_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PSS funded</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_38_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.355</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_38_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parkinson’s guideline</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_38_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NHS continuing care funded</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_38_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.072</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_38_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Parkinson’s guideline</td></tr><tr><th headers="hd_h_ch2.appi.tab8_1_1_1_1" id="hd_b_ch2.appi.tab8_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Part-self funded care</th><th headers="hd_h_ch2.appi.tab8_1_1_1_2" id="hd_b_ch2.appi.tab8_1_1_43_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th headers="hd_h_ch2.appi.tab8_1_1_1_3" id="hd_b_ch2.appi.tab8_1_1_43_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_43_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Proportion of part self-funded care paid for by patients</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_43_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.5</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_43_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assumption</td></tr><tr><th headers="hd_h_ch2.appi.tab8_1_1_1_1" id="hd_b_ch2.appi.tab8_1_1_45_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cost per cycle</th><th headers="hd_h_ch2.appi.tab8_1_1_1_2" id="hd_b_ch2.appi.tab8_1_1_45_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th headers="hd_h_ch2.appi.tab8_1_1_1_3" id="hd_b_ch2.appi.tab8_1_1_45_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_45_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">State 1 (NRS 0–2)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_45_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£0.00</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_45_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_45_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">State 2 (NRS 2–4)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_45_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£11.28</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_45_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_45_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">State 3 (NRS 4–6)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_45_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£119.33</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_45_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_45_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">State 4 (NRS 6–8)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_45_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£238.65</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_45_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated</td></tr><tr><td headers="hd_h_ch2.appi.tab8_1_1_1_1 hd_b_ch2.appi.tab8_1_1_45_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">State 5 (NRS 8–10)</td><td headers="hd_h_ch2.appi.tab8_1_1_1_2 hd_b_ch2.appi.tab8_1_1_45_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">£565.41</td><td headers="hd_h_ch2.appi.tab8_1_1_1_3 hd_b_ch2.appi.tab8_1_1_45_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calculated</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch2appitab9"><div id="ch2.appi.tab9" class="table"><h3><span class="label">Table 10</span><span class="title">Utility regression model coefficients for chronic pain</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appi.tab9/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appi.tab9_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.appi.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Regression equation - effect of NRS on EQ-5D</th><th id="hd_h_ch2.appi.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mean</th><th id="hd_h_ch2.appi.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lower CI</th><th id="hd_h_ch2.appi.tab9_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Upper CI</th><th id="hd_h_ch2.appi.tab9_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Source</th></tr></thead><tbody><tr><td headers="hd_h_ch2.appi.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Constant</td><td headers="hd_h_ch2.appi.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.684</td><td headers="hd_h_ch2.appi.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.617</td><td headers="hd_h_ch2.appi.tab9_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.751</td><td headers="hd_h_ch2.appi.tab9_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#ch2.appl.ref28" rid="ch2.appl.ref28">Gu 2012</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 0</td><td headers="hd_h_ch2.appi.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.000</td><td headers="hd_h_ch2.appi.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ch2.appi.tab9_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ch2.appi.tab9_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#ch2.appl.ref28" rid="ch2.appl.ref28">Gu 2012</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 1</td><td headers="hd_h_ch2.appi.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.005</td><td headers="hd_h_ch2.appi.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.062</td><td headers="hd_h_ch2.appi.tab9_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.052</td><td headers="hd_h_ch2.appi.tab9_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#ch2.appl.ref28" rid="ch2.appl.ref28">Gu 2012</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 2</td><td headers="hd_h_ch2.appi.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.088</td><td headers="hd_h_ch2.appi.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.143</td><td headers="hd_h_ch2.appi.tab9_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.033</td><td headers="hd_h_ch2.appi.tab9_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#ch2.appl.ref28" rid="ch2.appl.ref28">Gu 2012</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 3</td><td headers="hd_h_ch2.appi.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.098</td><td headers="hd_h_ch2.appi.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.151</td><td headers="hd_h_ch2.appi.tab9_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.045</td><td headers="hd_h_ch2.appi.tab9_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#ch2.appl.ref28" rid="ch2.appl.ref28">Gu 2012</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 4</td><td headers="hd_h_ch2.appi.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.138</td><td headers="hd_h_ch2.appi.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.191</td><td headers="hd_h_ch2.appi.tab9_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.085</td><td headers="hd_h_ch2.appi.tab9_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#ch2.appl.ref28" rid="ch2.appl.ref28">Gu 2012</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 5</td><td headers="hd_h_ch2.appi.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.152</td><td headers="hd_h_ch2.appi.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.205</td><td headers="hd_h_ch2.appi.tab9_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.099</td><td headers="hd_h_ch2.appi.tab9_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#ch2.appl.ref28" rid="ch2.appl.ref28">Gu 2012</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 6</td><td headers="hd_h_ch2.appi.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.188</td><td headers="hd_h_ch2.appi.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.239</td><td headers="hd_h_ch2.appi.tab9_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.137</td><td headers="hd_h_ch2.appi.tab9_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#ch2.appl.ref28" rid="ch2.appl.ref28">Gu 2012</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 7</td><td headers="hd_h_ch2.appi.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.260</td><td headers="hd_h_ch2.appi.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.313</td><td headers="hd_h_ch2.appi.tab9_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.207</td><td headers="hd_h_ch2.appi.tab9_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#ch2.appl.ref28" rid="ch2.appl.ref28">Gu 2012</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 8</td><td headers="hd_h_ch2.appi.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.328</td><td headers="hd_h_ch2.appi.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.381</td><td headers="hd_h_ch2.appi.tab9_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.275</td><td headers="hd_h_ch2.appi.tab9_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#ch2.appl.ref28" rid="ch2.appl.ref28">Gu 2012</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 9</td><td headers="hd_h_ch2.appi.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.398</td><td headers="hd_h_ch2.appi.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.461</td><td headers="hd_h_ch2.appi.tab9_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.335</td><td headers="hd_h_ch2.appi.tab9_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#ch2.appl.ref28" rid="ch2.appl.ref28">Gu 2012</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NRS 10</td><td headers="hd_h_ch2.appi.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.464</td><td headers="hd_h_ch2.appi.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.525</td><td headers="hd_h_ch2.appi.tab9_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.403</td><td headers="hd_h_ch2.appi.tab9_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#ch2.appl.ref28" rid="ch2.appl.ref28">Gu 2012</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Age</td><td headers="hd_h_ch2.appi.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.003</td><td headers="hd_h_ch2.appi.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.001</td><td headers="hd_h_ch2.appi.tab9_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.005</td><td headers="hd_h_ch2.appi.tab9_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#ch2.appl.ref28" rid="ch2.appl.ref28">Gu 2012</a>
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</td></tr><tr><td headers="hd_h_ch2.appi.tab9_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gender</td><td headers="hd_h_ch2.appi.tab9_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.034</td><td headers="hd_h_ch2.appi.tab9_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.048</td><td headers="hd_h_ch2.appi.tab9_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−0.020</td><td headers="hd_h_ch2.appi.tab9_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#ch2.appl.ref28" rid="ch2.appl.ref28">Gu 2012</a>
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</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobch2appifig4"><div id="ch2.appi.fig4" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%204.%20Intermediate%20model%20results.&p=BOOKS&id=577083_ch2appif4.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/NBK577083/bin/ch2appif4.jpg" alt="Figure 4. Intermediate model results." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 4</span><span class="title">Intermediate model results</span></h3></div></article><article data-type="fig" id="figobch2appifig5"><div id="ch2.appi.fig5" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%205.%20Total%20lifetime%20undiscounted%20costs%20by%20broad%20area%20and%20model%20arm.&p=BOOKS&id=577083_ch2appif5.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/NBK577083/bin/ch2appif5.jpg" alt="Figure 5. Total lifetime undiscounted costs by broad area and model arm." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 5</span><span class="title">Total lifetime undiscounted costs by broad area and model arm</span></h3></div></article><article data-type="table-wrap" id="figobch2appitab10"><div id="ch2.appi.tab10" class="table"><h3><span class="label">Table 11</span><span class="title">Cost-utility analysis results</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appi.tab10/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appi.tab10_lrgtbl__"><table><tbody><tr><th id="hd_b_ch2.appi.tab10_1_1_1_1" colspan="5" rowspan="1" style="text-align:left;vertical-align:middle;">Deterministic</th><th id="hd_b_ch2.appi.tab10_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th></tr><tr><th headers="hd_b_ch2.appi.tab10_1_1_1_1" id="hd_b_ch2.appi.tab10_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Strategy</th><th headers="hd_b_ch2.appi.tab10_1_1_1_1" id="hd_b_ch2.appi.tab10_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Costs</th><th headers="hd_b_ch2.appi.tab10_1_1_1_1" id="hd_b_ch2.appi.tab10_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">QALYs</th><th headers="hd_b_ch2.appi.tab10_1_1_1_1" id="hd_b_ch2.appi.tab10_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Inc costs</th><th headers="hd_b_ch2.appi.tab10_1_1_1_1" id="hd_b_ch2.appi.tab10_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Inc QALYs</th><th headers="hd_b_ch2.appi.tab10_1_1_1_2" id="hd_b_ch2.appi.tab10_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ICER</th></tr><tr><td headers="hd_b_ch2.appi.tab10_1_1_1_1 hd_b_ch2.appi.tab10_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard of Care</td><td headers="hd_b_ch2.appi.tab10_1_1_1_1 hd_b_ch2.appi.tab10_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£39,233</td><td headers="hd_b_ch2.appi.tab10_1_1_1_1 hd_b_ch2.appi.tab10_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10.480</td><td headers="hd_b_ch2.appi.tab10_1_1_1_1 hd_b_ch2.appi.tab10_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_b_ch2.appi.tab10_1_1_1_1 hd_b_ch2.appi.tab10_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_b_ch2.appi.tab10_1_1_1_2 hd_b_ch2.appi.tab10_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_b_ch2.appi.tab10_1_1_1_1 hd_b_ch2.appi.tab10_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cannabis</td><td headers="hd_b_ch2.appi.tab10_1_1_1_1 hd_b_ch2.appi.tab10_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£63,706</td><td headers="hd_b_ch2.appi.tab10_1_1_1_1 hd_b_ch2.appi.tab10_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10.642</td><td headers="hd_b_ch2.appi.tab10_1_1_1_1 hd_b_ch2.appi.tab10_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£24,474</td><td headers="hd_b_ch2.appi.tab10_1_1_1_1 hd_b_ch2.appi.tab10_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.162</td><td headers="hd_b_ch2.appi.tab10_1_1_1_2 hd_b_ch2.appi.tab10_1_1_2_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£151,431</td></tr><tr><th id="hd_b_ch2.appi.tab10_1_1_5_1" colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;">Mean of Probabilistic</th><th id="hd_b_ch2.appi.tab10_1_1_5_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th id="hd_b_ch2.appi.tab10_1_1_5_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th id="hd_b_ch2.appi.tab10_1_1_5_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th><th id="hd_b_ch2.appi.tab10_1_1_5_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th></tr><tr><th headers="hd_b_ch2.appi.tab10_1_1_5_1" id="hd_b_ch2.appi.tab10_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Strategy</th><th headers="hd_b_ch2.appi.tab10_1_1_5_1" id="hd_b_ch2.appi.tab10_1_1_6_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Costs</th><th headers="hd_b_ch2.appi.tab10_1_1_5_2" id="hd_b_ch2.appi.tab10_1_1_6_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">QALYs</th><th headers="hd_b_ch2.appi.tab10_1_1_5_3" id="hd_b_ch2.appi.tab10_1_1_6_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Inc costs</th><th headers="hd_b_ch2.appi.tab10_1_1_5_4" id="hd_b_ch2.appi.tab10_1_1_6_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Inc QALYs</th><th headers="hd_b_ch2.appi.tab10_1_1_5_5" id="hd_b_ch2.appi.tab10_1_1_6_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></th></tr><tr><td headers="hd_b_ch2.appi.tab10_1_1_5_1 hd_b_ch2.appi.tab10_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard of Care</td><td headers="hd_b_ch2.appi.tab10_1_1_5_1 hd_b_ch2.appi.tab10_1_1_6_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£39,414</td><td headers="hd_b_ch2.appi.tab10_1_1_5_2 hd_b_ch2.appi.tab10_1_1_6_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10.442</td><td headers="hd_b_ch2.appi.tab10_1_1_5_3 hd_b_ch2.appi.tab10_1_1_6_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_b_ch2.appi.tab10_1_1_5_4 hd_b_ch2.appi.tab10_1_1_6_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_b_ch2.appi.tab10_1_1_5_5 hd_b_ch2.appi.tab10_1_1_6_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_b_ch2.appi.tab10_1_1_5_1 hd_b_ch2.appi.tab10_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cannabis</td><td headers="hd_b_ch2.appi.tab10_1_1_5_1 hd_b_ch2.appi.tab10_1_1_6_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£63,924</td><td headers="hd_b_ch2.appi.tab10_1_1_5_2 hd_b_ch2.appi.tab10_1_1_6_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10.606</td><td headers="hd_b_ch2.appi.tab10_1_1_5_3 hd_b_ch2.appi.tab10_1_1_6_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£24,510</td><td headers="hd_b_ch2.appi.tab10_1_1_5_4 hd_b_ch2.appi.tab10_1_1_6_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.164</td><td headers="hd_b_ch2.appi.tab10_1_1_5_5 hd_b_ch2.appi.tab10_1_1_6_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£149,454</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobch2appifig6"><div id="ch2.appi.fig6" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%206.%20Probabilistic%20Sensitivity%20Analysis%20Scatterplot.&p=BOOKS&id=577083_ch2appif6.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/NBK577083/bin/ch2appif6.jpg" alt="Figure 6. Probabilistic Sensitivity Analysis Scatterplot." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 6</span><span class="title">Probabilistic Sensitivity Analysis Scatterplot</span></h3></div></article><article data-type="fig" id="figobch2appifig7"><div id="ch2.appi.fig7" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%207.%20Tornado%20Diagram%20(most%20influential%20parameters).&p=BOOKS&id=577083_ch2appif7.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/NBK577083/bin/ch2appif7.jpg" alt="Figure 7. Tornado Diagram (most influential parameters)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 7</span><span class="title">Tornado Diagram (most influential parameters)</span></h3></div></article><article data-type="table-wrap" id="figobch2appitab11"><div id="ch2.appi.tab11" class="table"><h3><span class="label">Table 12</span><span class="title">Results of scenario analyses</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appi.tab11/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appi.tab11_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Scenario</th><th id="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ICER (cannabis vs SoC)</th></tr></thead><tbody><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1. Using the costs and effects of nabilone instead of nabiximols</td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£102,343</td></tr><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2. Using treatment effect data in the neuropathic pain subgroup</td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£127,321</td></tr><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3. Using treatment effect data for the cancer pain subgroup</td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£204,846</td></tr><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">4. Using treatment effect data for the musculoskeletal pain subgroup</td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£68,759</td></tr><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5. Using discontinuation data from the <a class="bibr" href="#ch2.appl.ref25" rid="ch2.appl.ref25">Hoggart 2015</a> chronic pain study instead of the <a class="bibr" href="#ch2.appl.ref24" rid="ch2.appl.ref24">Messina 2017</a> MS individual patient data</td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£135,190</td></tr><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">6. Using control arm response from <a class="bibr" href="#ch2.appl.ref11" rid="ch2.appl.ref11">Portenoy 2012</a> instead of <a class="bibr" href="#ch2.appl.ref6" rid="ch2.appl.ref6">Langford 2013</a></td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£107,943</td></tr><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">7. Excluding the background management costs for chronic pain</td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£169,064</td></tr><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">8. Not allowing a proportion of sub<30% responders to continue with treatment</td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£141,779</td></tr><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">9. Including RFD as a downstream treatment for musceloskeletal pain</td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£153,671</td></tr><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10. Declining the treatment effect over time by reducing mean pain to match placebo</td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£1,072,864</td></tr><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">11. Declining the placebo effect (change from baseline) in both arms so that pain returns to baseline after 2 years</td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£106,026</td></tr><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">12. Allowing differential discontinuation from response in the standard of care arm equalling the hazard ratio</td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£386,084</td></tr><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">13. Assuming no discontinuation from response in either arm</td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£217,680</td></tr><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">14. All adverse events halved</td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£148,993</td></tr><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">15. All adverse events doubled</td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£156,683</td></tr><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">16. All pain management costs halved</td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£160,248</td></tr><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">17. All pain management costs doubled</td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£133,797</td></tr><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">18. All QoL coefficients set to high limits of confidence intervals</td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£164,453</td></tr><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">19. All QoL coefficients set to low limits of confidence intervals</td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£140,320</td></tr><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">20. Competing risks model from Messina for discontinuation</td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£414,759</td></tr><tr><td headers="hd_h_ch2.appi.tab11_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">21. −0.55 treatment effect to produce −0.44 intermediate outcome</td><td headers="hd_h_ch2.appi.tab11_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">£120,153</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch2appjtab1"><div id="ch2.appj.tab1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appj.tab1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appj.tab1_lrgtbl__"><table><thead><tr><th id="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Study</th><th id="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Alharbi, G. S.; Chen, L. C.; Knaggs, R. (2016) Efficacy of anticonvulsant, antidepressant and opioid in treating neuropathic pain - A systematic review and meta-analysis. Pharmacoepidemiology and drug safety. Conference: 32nd international conference on pharmacoepidemiology and therapeutic risk management. Ireland. Conference start: 20160825. Conference end: 20160828 25: 582</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Allan, G. Michael, Finley, Caitlin R., Ton, Joey et al. (2018) Systematic review of systematic reviews for medical cannabinoids: Pain, nausea and vomiting, spasticity, and harms. Canadian family physician Medecin de famille canadien 64(2): e78–e94</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Allende-Salazar, Ruben F. and Rada, Gabriel (2017) Are cannabinoids an effective treatment for chronic non-cancer pain? Son los cannabinoides un tratamiento efectivo para el dolor cronico no asociado a cancer? 17(suppl2): e6972</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Andreae, Michael H., Carter, George M., Shaparin, Naum et al. (2015) Inhaled Cannabis for Chronic Neuropathic Pain: A Meta-analysis of Individual Patient Data. The journal of pain: official journal of the American Pain Society 16(12): 1221–1232</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Smoked cannabis</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Aviram, J. and Samuelly-Leichtag, G. (2017) Efficacy of Cannabis-Based Medicines for Pain Management: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Pain physician 20(6): E755–E796</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beaulieu, Pierre (2006) Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Canadian journal of anaesthesia = Journal canadien d’anesthesie 53(8): 769–75</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Study is on acute postoperative pain</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Beaulieu, Pierre, Boulanger, Aline, Desroches, Julie et al. (2016) Medical cannabis: considerations for the anesthesiologist and pain physician. Canadian journal of anaesthesia = Journal canadien d’anesthesie 63(5): 608–24</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Berman, Jonathan S.; Symonds, Catherine; Birch, Rolfe (2004) Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain 112(3): 299–306</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bestard, Jennifer A. and Toth, Cory C. (2011) An open-label comparison of nabilone and gabapentin as adjuvant therapy or monotherapy in the management of neuropathic pain in patients with peripheral neuropathy. Pain practice: the official journal of World Institute of Pain 11(4): 353–68</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Non-randomised observational study</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Blake, Alexia, Wan, Bo Angela, Malek, Leila et al. (2017) A selective review of medical cannabis in cancer pain management. Annals of palliative medicine 6(suppl2): S215–S222</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Boychuk, Darrell G., Goddard, Greg, Mauro, Giovanni et al. (2015) The effectiveness of cannabinoids in the management of chronic nonmalignant neuropathic pain: a systematic review. Journal of oral & facial pain and headache 29(1): 7–14</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Campbell, F. A., Tramer, M. R., Carroll, D. et al. (2001) Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. British Medical Journal 323(7303): 13–16</td><td headers="hd_h_ch2.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_ch2.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_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Corey, Susan (2005) Recent developments in the therapeutic potential of cannabinoids. Puerto Rico health sciences journal 24(1): 19–26</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cote, Mathieu, Trudel, Mathieu, Wang, Changshu et al. (2016) Improving Quality of Life with Nabilone During Radiotherapy Treatments for Head and Neck Cancers: A Randomized Double-Blind Placebo-Controlled Trial. The Annals of otology, rhinology, and laryngology 125(4): 317–24</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>No outcomes of interest</p>
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<p>
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<i>[The results are in a format that it’s not possible to data extract: All the data is either given as a narrative account or in form of graphs. This also includes adverse events.]</i>
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</p>
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</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cunetti, L., Manzo, L., Peyraube, R. et al. (2018) Chronic Pain Treatment with Cannabidiol in Kidney Transplant Patients in Uruguay. Transplantation proceedings 50(2): 461–464</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Davies, B. H., Weatherstone, R. M., Graham, J. D. et al. (1974) A pilot study of orally administered DELTA(1)-trans-tetrahydrocannabinol in the management of patients undergoing radiotherapy for carcinoma of the bronchus. British journal of clinical pharmacology 1(4): 301–6</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Non-randomised observational study</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">de Vries, M., van Rijckevorsel, D. C. M., Vissers, K. C. P. et al. (2016) Tetrahydrocannabinol Does Not Reduce Pain in Patients with Chronic Abdominal Pain in a Phase 2 Placebo-controlled Study. Clinical gastroenterology and hepatology</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Deng, Yunkun, Luo, Lei, Hu, Yuhuai et al. (2016) Clinical practice guidelines for the management of neuropathic pain: a systematic review. BMC anesthesiology 16: 12</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Deshpande, Amol, Mailis-Gagnon, Angela, Zoheiry, Nivan et al. (2015) Efficacy and adverse effects of medical marijuana for chronic noncancer pain: Systematic review of randomized controlled trials. Canadian family physician Medecin de famille canadien 61(8): e372–81</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Felix, Elizabeth Roy (2014) Chronic neuropathic pain in SCI: evaluation and treatment. Physical medicine and rehabilitation clinics of North America 25(3): 545–viii</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fitzcharles, M. A., Baerwald, C., Ablin, J. et al. (2016) Efficacy, tolerability and safety of cannabinoids in chronic pain associated with rheumatic diseases (fibromyalgia syndrome, back pain, osteoarthritis, rheumatoid arthritis): A systematic review of randomized controlled trials. Schmerz (Berlin, Germany) 30(1): 47–61</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fitzcharles, Mary-Ann, Ste-Marie, Peter A., Hauser, Winfried et al. (2016) Efficacy, Tolerability, and Safety of Cannabinoid Treatments in the Rheumatic Diseases: A Systematic Review of Randomized Controlled Trials. Arthritis care & research 68(5): 681–8</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Guy, G., Gover, J., Rogerson, M. et al. (2010) Positive data in sativex phase IIb trial: Support advancing into phase III development in cancer pain. Revista de la Sociedad Espanola del Dolor 17(4): 219–221</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Letter (non-peer reviewed information)</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Haroutiunian, Simon, Rosen, Gila, Shouval, Rivka et al. (2008) Open-label, add-on study of tetrahydrocannabinol for chronic nonmalignant pain. Journal of pain & palliative care pharmacotherapy 22(3): 213–7</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Non-randomised observational study</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hauser, W., Fitzcharles, M. A., Radbruch, L. et al. (2018) Cannabinoids in pain management and palliative medicine - An overview of systematic reviews and prospective observational studies. Deutsches Arzteblatt International 115(9): 143</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hauser, W.; Petzke, F.; Fitzcharles, M. A. (2018) Efficacy, tolerability and safety of cannabis-based medicines for chronic pain management - An overview of systematic reviews. European journal of pain (London, England) 22(3): 455–470</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hauser, Winfried, Fitzcharles, Mary-Ann, Radbruch, Lukas et al. (2017) Cannabinoids in Pain Management and Palliative Medicine. Deutsches Arzteblatt international 114(38): 627–634</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hill, Kevin P. (2015) Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems: A Clinical Review. JAMA 313(24): 2474–83</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hill, Kevin P., Palastro, Matthew D., Johnson, Brian et al. (2017) Cannabis and Pain: A Clinical Review. Cannabis and cannabinoid research 2(1): 96–104</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hoggart, B., Ratcliffe, S., Ehler, E. et al. (2015) A multicentre, open-label, follow-on study to assess the long-term maintenance of effect, tolerance and safety of THC/CBD oromucosal spray in the management of neuropathic pain. Journal of neurology 262(1): 27–40</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Chronic pain study where placebo is not the comparator</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Holdcroft, A., Smith, M., Jacklin, A. et al. (1997) Pain relief with oral cannabinoids in familial Mediterranean fever. Anaesthesia 52(5): 483–6</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Holdcroft, A., Smith, M., Smith, B. et al. (1997) Clinical trial experience with cannabinoids. Pharmaceutical sciences 3(11): 546–550</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Holdcroft, Anita, Maze, Mervyn, Dore, Caroline et al. (2006) A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management. Anesthesiology 104(5): 1040–6</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Non-randomised observational study</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Houze, Berengere; El-Khatib, Hejar; Arbour, Caroline (2017) Efficacy, tolerability, and safety of non-pharmacological therapies for chronic pain: An umbrella review on various CAM approaches. Progress in neuro-psychopharmacology & biological psychiatry 79(ptb): 192–205</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hunter, D., Oldfield, G., Tich, N. et al. (2018) Synthetic transdermal cannabidiol for the treatment of knee pain due to osteoarthritis. Osteoarthritis and cartilage. Conference: 2018 osteoarthritis research society international, OARSI world congress. United Kingdom 26(supplement1): 26</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Iskedjian, Michael, Bereza, Basil, Gordon, Allan et al. (2007) Meta-analysis of cannabis-based treatments for neuropathic and multiple sclerosis-related pain. Current medical research and opinion 23(1): 17–24</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Issa, Mohammed A., Narang, Sanjeet, Jamison, Robert N. et al. (2014) The subjective psychoactive effects of oral dronabinol studied in a randomized, controlled crossover clinical trial for pain. The Clinical journal of pain 30(6): 472–8</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Iversen, L. (2001) Cannabinoids in pain management. Few well controlled trials of cannabis exist for systemic review. BMJ (Clinical research ed.) 323(7323): 1250–1</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Letter (non-peer reviewed information)</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Jensen, Troels S.; Madsen, Caspar S.; Finnerup, Nanna B. (2009) Pharmacology and treatment of neuropathic pains. Current opinion in neurology 22(5): 467–74</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Jochimsen, P. R., Lawton, R. L., VerSteeg, K. et al. (1978) Effect of benzopyranoperidine, a DELTA-9-THC congener, on pain. Clinical Pharmacology and Therapeutics 24(2): 223–227</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Study is on a synthetic cannabinoid not covered under the definition of cannabis-based products for medicinal use: It is not a cannabinol derivative and does not contain cannabis nor cannabis resin. Therefore, this is a Schedule 1 drug</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Kantor, T. G. and Hopper, M. (1981) A study of levonantradol, a cannabinol derivative, for analgesia in post-operative pain. Pain 10(suppl1): 37</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Karst, Matthias, Salim, Kahlid, Burstein, Sumner et al. (2003) Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA 290(13): 1757–62</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Study is on a synthetic cannabinoid not covered under the definition of cannabis-based products for medicinal use: It is not a cannabinol derivative and does not contain cannabis nor cannabis resin. Therefore, this is a Schedule 1 drug</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Lee, Gemayel, Grovey, Brittany, Furnish, Tim et al. (2018) Medical Cannabis for Neuropathic Pain. Current pain and headache reports 22(1): 8</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Lynch, M. E. and Ware, Mark A. (2015) Cannabinoids for the Treatment of Chronic Non-Cancer Pain: An Updated Systematic Review of Randomized Controlled Trials. Journal of neuroimmune pharmacology: the official journal of the Society on NeuroImmune Pharmacology 10(2): 293–301</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Lynch, Mary E. and Campbell, Fiona (2011) Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. British journal of clinical pharmacology 72(5): 735–44</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Martin-Sanchez, Eva, Furukawa, Toshiaki A., Taylor, Julian et al. (2009) Systematic review and meta-analysis of cannabis treatment for chronic pain. Pain medicine (Malden, Mass.) 10(8): 1353–68</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Mehta, Swati, McIntyre, Amanda, Janzen, Shannon et al. (2016) Systematic Review of Pharmacologic Treatments of Pain After Spinal Cord Injury: An Update. Archives of physical medicine and rehabilitation 97(8): 1381–1391.e1</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Meng, Howard, Johnston, Bradley, Englesakis, Marina et al. (2017) Selective Cannabinoids for Chronic Neuropathic Pain: A Systematic Review and Meta-analysis. Anesthesia and analgesia 125(5): 1638–1652</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Mucke, Martin, Phillips, Tudor, Radbruch, Lukas et al. (2018) Cannabis-based medicines for chronic neuropathic pain in adults. The Cochrane database of systematic reviews 3: cd012182</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Mucke, Martin, Weier, Megan, Carter, Christopher et al. (2018) Systematic review and meta-analysis of cannabinoids in palliative medicine. Journal of cachexia, sarcopenia and muscle 9(2): 220–234</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Narang, Sanjeet, Gibson, Daniel, Wasan, Ajay D. et al. (2008) Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. The journal of pain: official journal of the American Pain Society 9(3): 254–64</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Narang, Sanjeet, Wasan, Ajay D., Ross, Edgar L. et al. (2008) Patients with chronic pain on opioid therapy taking dronabinol: incidence of false negatives using radioimmunoassay. Journal of opioid management 4(1): 21–6</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nickel, J. Curtis (2018) Medical marijuana for urologic chronic pelvic pain. Canadian Urological Association journal = Journal de l’Association des urologues du Canada 12(6suppl3): S181–S183</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Notcutt, William, Price, Mario, Miller, Roy et al. (2004) Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 ‘N of 1’ studies. Anaesthesia 59(5): 440–52</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Results are presented in a narrative format. Essential information is missing, such as before and after comparisons and statistical variance</td></tr><tr><td headers="hd_h_ch2.appj.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><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Study at high risk of selection and reporting bias</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Noyes, R., Jr., Brunk, S. F., Avery, D. A. et al. (1975) The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clinical pharmacology and therapeutics 18(1): 84–9</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Noyes, R., Jr., Brunk, S. F., Baram, D. A. et al. (1975) Analgesic effect of delta-9-tetrahydrocannabinol. Journal of clinical pharmacology 15(23): 139–43</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nugent, Shannon M., Morasco, Benjamin J., O’Neil, Maya E. et al. (2017) The Effects of Cannabis Among Adults With Chronic Pain and an Overview of General Harms: A Systematic Review. Annals of internal medicine 167(5): 319–331</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nurmikko, T. J., Serpell, M. G., Hoggart, B. et al. (2005) A multi-centre, double-blind, randomized, controlled trial of oro-mucosal cannabis based medicine in the treatment of neuropathic pain characterized by allodynia. Neurology 64(suppl1): a374abstractnopo6119</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nurmikko, T. J., Serpell, M. G., Hoggart, B. et al. (2005) A multi-centre, double-blind, randomized, placebo-controlled trial of oro-mucosal cannabis-bsed medicine in the treatment of neuropathic pain characterized by allodynia. Neurology 64(suppl1): a374</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Pini, Luigi Alberto, Guerzoni, Simona, Cainazzo, Maria Michela et al. (2012) Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial. The journal of headache and pain 13(8): 677–84</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Headaches and/or orofacial pain</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Pinsger, M. (2012) Benefit of an Add-On-Treatment with a synthetic cannabinomimeticum on patients with chronic back pain-a randomized controlled trial. European spine journal. 21(11): 2366</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Pinsger, M., Schimetta, W., Volc, D. et al. (2006) Benefits of an add-on treatment with the synthetic cannabinomimetic nabilone on patients with chronic pain--a randomized controlled trial. Wiener klinische wochenschrift 118(1112): 327–335</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rintala, Diana H., Fiess, Richard Neil, Tan, Gabriel et al. (2010) Effect of dronabinol on central neuropathic pain after spinal cord injury: a pilot study. American journal of physical medicine & rehabilitation 89(10): 840–8</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Chronic pain study where placebo is not the comparator</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Riva, N., Mora, G., Soraru, G. et al. (2016) The CANALS study: a randomized, double-blind, placebo-controlled, multicentre study to assess the safety and efficacy on spasticity symptoms of a Cannabis Sativa extract in motor neuron disease patients. European journal of neurology 23(suppls2): 46abstractno01213</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Riva, N., Mora, G., Soraru, G. et al. (2016) The canals study: a randomized, double-blind, placebo-controlled, multicentre study to assess the safety and efficacyon spasticity symptoms of a cannabis sativa extract in motor neuron disease patients. Amyotrophic lateral sclerosis & frontotemporal degeneration 17(suppl1): 44abstractnoc62</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rocco, Matias and Rada, Gabriel (2018) Are cannabinoids effective for fibromyalgia? Son los cannabinoides un tratamiento efectivo para la fibromialgia? 18(1): e7154</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rog, David J.; Nurmikko, Turo J.; Young, Carolyn A. (2007) Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial. Clinical therapeutics 29(9): 2068–79</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Chronic pain study where placebo is not the comparator</p>
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<p>
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<i>[This is an open-label extension of Rog 2005, which has been included.]</i>
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</p>
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</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Russo, E. (2003) Cannabis and Cannabis based medicine extracts: Additional results. Journal of Cannabis Therapeutics 3(4): 153–161</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Russo, Ethan B. (2008) Cannabinoids in the management of difficult to treat pain. Therapeutics and clinical risk management 4(1): 245–59</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Salim, Kahlid, Schneider, Udo, Burstein, Sumner et al. (2005) Pain measurements and side effect profile of the novel cannabinoid ajulemic acid. Neuropharmacology 48(8): 1164–71</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Study is on a synthetic cannabinoid not covered under the definition of cannabis-based products for medicinal use: It is not a cannabinol derivative and does not contain cannabis nor cannabis resin. Therefore, this is a Schedule 1 drug</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Selvarajah, Dinesh, Gandhi, Rajiv, Emery, Celia J. et al. (2010) Randomized placebo-controlled double-blind clinical trial of cannabis-based medicinal product (Sativex) in painful diabetic neuropathy: depression is a major confounding factor. Diabetes care 33(1): 128–30</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>Study did not report the number of participants in each arm</p>
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<p>
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<i>[No details as to how many of the 30 patients were randomised to each arm. Six patients withdrew from the study. However, there is no information as to which arms they withdrew from.]</i>
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</p>
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</td></tr><tr><td headers="hd_h_ch2.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 openlabel trial in patients with spasticity due to multiple sclerosis. Journal of neurology 260(1): 285–95</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Snedecor, Sonya J., Sudharshan, Lavanya, Cappelleri, Joseph C. et al. (2013) Systematic review and comparison of pharmacologic therapies for neuropathic pain associated with spinal cord injury. Journal of pain research 6: 539–47</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Snedecor, Sonya J., Sudharshan, Lavanya, Cappelleri, Joseph C. et al. (2014) Systematic review and meta-analysis of pharmacological therapies for painful diabetic peripheral neuropathy. Pain practice: the official journal of World Institute of Pain 14(2): 167–84</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Sohler, Nancy L., Starrels, Joanna L., Khalid, Laila et al. (2018) Cannabis Use is Associated with Lower Odds of Prescription Opioid Analgesic Use Among HIV-Infected Individuals with Chronic Pain. Substance use & misuse 53(10): 1602–1607</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Wrong intervention. This is about illegal use of cannabis</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Staquet, M.; Gantt, C.; Machin, D. (1978) Effect of a nitrogen analog of tetrahydrocannabinol on cancer pain. Clinical Pharmacology and Therapeutics 23(4): 397–401</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Study is on a synthetic cannabinoid not covered under the definition of cannabis-based products for medicinal use: It is not a cannabinol derivative and does not contain cannabis nor cannabis resin. Therefore, this is a Schedule 1 drug</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Stockings, Emily, Campbell, Gabrielle, Hall, Wayne D. et al. (2018) Cannabis and cannabinoids for the treatment of people with chronic noncancer pain conditions: a systematic review and meta-analysis of controlled and observational studies. Pain 159(10): 1932–1954</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Svendsen, K. B.; Jensen, T. S.; Bach, F. W. (2005) Effect of the synthetic cannabinoid dronabinol on central pain in patients with multiple sclerosis--secondary publication. Ugeskrift for laeger 167(2531): 2772–2774</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Tateo, Sydney (2017) State of the evidence: Cannabinoids and cancer pain-A systematic review. Journal of the American Association of Nurse Practitioners 29(2): 94–103</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Toth, Cory, Mawani, Shefina, Brady, Shauna et al. (2012) An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain. Pain 153(10): 2073–82</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Treatment phase is not randomised - only the withdrawal phase is</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Tsang, Corey C. and Giudice, Mirella G. (2016) Nabilone for the Management of Pain. Pharmacotherapy 36(3): 273–86</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Turcott, J., Guillen-Nunez, M. D. R., Flores, D. et al. (2018) The Effect of Nabilone on Appetite, Nutritional Status, and Quality of Life in Lung Cancer Patients: a Randomized, Double-Blind Clinical Trial. Journal of thoracic oncology. Conference: IASLC 19th world conference on lung cancer. Canada 13(10supplement): S360–S361</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Turcott, Jenny G., Del Rocio Guillen Nunez, Maria, Flores-Estrada, Diana et al. (2018) The effect of nabilone on appetite, nutritional status, and quality of life in lung cancer patients: a randomized, double-blind clinical trial. Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer 26(9): 3029–3038</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Turcotte, D. A., Gomori, A. J., Esfahani, F. E. et al. (2011) Randomized, double-blinded, placebo-controlled study evaluating the efficacy and safety of nabilone adjunctive to gabapentin in managing multiple sclerosis-induced neuropathic pain. European journal of pain supplements. 5(1): 240–241</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Turcotte, D. A., Namaka, M. P., Gomori, A. J. et al. (2011) A randomized, double-blinded, placebo-controlled study evaluating the efficacy and safety of nabilone as an adjunctive to gabapentin in managing multiple sclerosis-induced neuropathic pain: an interim analysis. Pain research & management 15(2): 99</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Turcotte, D., Chateau, D., Doupe, M. et al. (2011) A randomised, double-blinded, placebocontrolled study evaluating the efficacy and safety of nabilone as an adjunctive to gabapentin in managing multiple sclerosisinduced neuropathic pain. Multiple sclerosis. 17(10suppl1): S475–S476</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Turcotte, Dana, Doupe, Malcolm, Torabi, Mahmoud et al. (2015) Nabilone as an adjunctive to gabapentin for multiple sclerosis-induced neuropathic pain: a randomized controlled trial. Pain medicine (Malden, Mass.) 16(1): 149–59</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Inadequate reporting of data: We cannot use data in graphs. Some data for the nabilone arm is given but not for the placebo arm.</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Turcotte, D., Doupe, M., Torabi, M. et al. (2013) A randomized, double-blinded, placebocontrolled study evaluating efficacy and tolerability of nabilone as an adjunctive to gabapentin in the management of multiple sclerosis-induced neuropathic pain. Multiple sclerosis. 19(11suppl1): 112</td><td headers="hd_h_ch2.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_ch2.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_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">van den Beuken-van Everdingen, Marieke H. J., de Graeff, Alexander, Jongen, Joost L. M. et al. (2017) Pharmacological Treatment of Pain in Cancer Patients: The Role of Adjuvant Analgesics, a Systematic Review. Pain practice: the official journal of World Institute of Pain 17(3): 409–419</td><td headers="hd_h_ch2.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_ch2.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_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>One arm follow-up study</p>
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<p><i>[Follow-up from</i>
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<a class="bibr" href="#ch2.appl.ref18" rid="ch2.appl.ref18">Wade 2004</a><i>]</i></p>
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</td></tr><tr><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary publication of existing studies</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Wade, Derick T., Robson, Philip, House, Heather et al. (2003) A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clinical rehabilitation 17(1): 21–9</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Walitt B, Klose P, Fitzcharles MA, Phillips T, Häuser W. Cannabinoids for fibromyalgia. Cochrane Database Syst Rev. 2016 Jul 18;7:CD011694</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Wallace, Mark S., Marcotte, Thomas D., Umlauf, Anya et al. (2015) Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy. The journal of pain: official journal of the American Pain Society 16(7): 616–27</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Smoked cannabis</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Ware, Mark A., Fitzcharles, Mary-Ann, Joseph, Lawrence et al. (2010) The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial. Anesthesia and analgesia 110(2): 604–10</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Chronic pain study where placebo is not the comparator</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Ware, Mark A., Wang, Tongtong, Shapiro, Stan et al. (2015) Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS). The journal of pain: official journal of the American Pain Society 16(12): 1233–1242</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Smoked cannabis</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Whiting, Penny F., Wolff, Robert F., Deshpande, Sohan et al. (2015) Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA 313(24): 2456–73</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Wilsey, Barth, Marcotte, Thomas D., Deutsch, Reena et al. (2016) An Exploratory Human Laboratory Experiment Evaluating Vaporized Cannabis in the Treatment of Neuropathic Pain From Spinal Cord Injury and Disease. The journal of pain: official journal of the American Pain Society 17(9): 982–1000</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Wilsey, Barth, Marcotte, Thomas, Deutsch, Reena et al. (2013) Low-dose vaporized cannabis significantly improves neuropathic pain. The journal of pain: official journal of the American Pain Society 14(2): 136–48</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Wirrell, E., Devinsky, O., Patel, A. et al. (2017) Cannabidiol (CBD) Significantly Reduces Drop and Total Seizure Frequency in Lennox Gastaut Syndrome (LGS): results of a Dose Ranging, Multicenter, Randomized, Double Blind, Placebo Controlled Trial (GWPCARE3). Annals of neurology 82(s21): S279–S280, Abstract no: 22</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Wissel, J., Entner, T., Muller, J. et al. (2004) Nabilone reduces spasticity related pain: a double-blind placebo-controlled cross-over trial. Neurologie und rehabilitation 10(4): 187–216</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Wu, G. Q. (1992) Pain-relief effect of tramadol HCL capsule for moderate and severe cancer pain. Zhonghua zhong liu za zhi [chinese journal of oncology] 14(3): 219–221</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Yassin, Mustafa; Oron, Amir; Robinson, Dror (2018) Effect of adding medical cannabis to analgesic treatment in patients with low back pain related to fibromyalgia: an observational cross-over single centre study. Clinical and experimental rheumatology</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Non-randomised observational study</td></tr><tr><td headers="hd_h_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Zajicek, John, Ball, Susan, Wright, David et al. (2013) Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial. The Lancet. Neurology 12(9): 857–865</td><td headers="hd_h_ch2.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_ch2.appj.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Zalai, D., Chung, S. A., Hussain, N. et al. (2015) Does cannabinoid really improve sleep? Testing the sleep effects of nabilone in chronic pain patients: a placebo-controlled, randomized, pilot study. Psychotherapy and psychosomatics. 84: 81</td><td headers="hd_h_ch2.appj.tab1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Conference abstract</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch2appktab1"><div id="ch2.appk.tab1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appk.tab1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appk.tab1_lrgtbl__"><table><tbody><tr><th id="hd_b_ch2.appk.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PICO</th><td headers="hd_b_ch2.appk.tab1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p><b>Population:</b> Adults with fibromyalgia or persistent treatment-resistant neuropathic pain being managed by a pain specialist using standard treatment</p>
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<p><b>Intervention</b>: CBD (either as a pure product or containing traces of THC)</p>
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<p><b>Comparator:</b> usual care as defined by the researchers</p>
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<p><b>Outcomes</b> should be measured at 6 months follow-up
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<ul id="ch2.l39"><li id="ch2.lt318" class="half_rhythm"><div>Cost effectiveness</div></li><li id="ch2.lt319" class="half_rhythm"><div>Participant reported pain relief of 30% or greater</div></li><li id="ch2.lt320" class="half_rhythm"><div>Participant reported pain relief of 50% or greater (to assist the economic analysis)</div></li><li id="ch2.lt321" class="half_rhythm"><div>Reduction in analgesics required</div></li><li id="ch2.lt322" class="half_rhythm"><div>Change in pain intensity using Numerical Rating Scale’, or Visual Analogue Scale’</div></li><li id="ch2.lt323" class="half_rhythm"><div>A validated pain measurement tool</div></li><li id="ch2.lt324" class="half_rhythm"><div>Participant/Patient/Subject Global Impression of Change (PGIC or SGIG) scale</div></li><li id="ch2.lt325" class="half_rhythm"><div>Quality of life score using SF-36 or EQ-5D.</div></li><li id="ch2.lt326" class="half_rhythm"><div>Mood</div></li><li id="ch2.lt327" class="half_rhythm"><div>Serious adverse events</div></li><li id="ch2.lt328" class="half_rhythm"><div>Adverse events including but not limited to: respiratory depression, 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="ch2.lt329" class="half_rhythm"><div>Withdrawals due to adverse events</div></li><li id="ch2.lt330" class="half_rhythm"><div>Complications due to adverse events</div></li><li id="ch2.lt331" class="half_rhythm"><div>Substance abuse due to the use of cannabis-based medicinal product.</div></li><li id="ch2.lt332" class="half_rhythm"><div>Misuse/diversion</div></li><li id="ch2.lt333" 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="ch2.l40"><li id="ch2.lt334" class="half_rhythm"><div>Contraindications as listed in exclusion criteria</div></li></ul>
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Monitoring requirements, treatment durations, reviewing and stopping criteria, including how should treatment be withdrawn stopped as discussed in the methods of individual RCTs</p>
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</td></tr><tr><th id="hd_b_ch2.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_ch2.appk.tab1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">No RCTs were identified which compare CBD with standard treatment to standard treatment for fibromyalgia or for persistent treatment-resistant neuropathic pain.</td></tr><tr><th id="hd_b_ch2.appk.tab1_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Study design</th><td headers="hd_b_ch2.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_ch2.appk.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Other comments</th><td headers="hd_b_ch2.appk.tab1_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Study should be adequately powered and have an adequate follow up period (minimum of 6 months)</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobch2appktab2"><div id="ch2.appk.tab2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK577083/table/ch2.appk.tab2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ch2.appk.tab2_lrgtbl__"><table><tbody><tr><th id="hd_b_ch2.appk.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PICO</th><td headers="hd_b_ch2.appk.tab2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p><b>Population:</b> Children with intractable cancer-related pain (intractable cancer-related pain was defined by the committee as cancer-related pain which does not respond to multiple interventions including non-pharmacological and drug therapies sufficiently to enable a reasonable quality of life).</p>
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<p><b>Intervention:</b> Cannabis-based medicinal product (CBMP) as an adjunct to standard care (standard care is defined as tertiary specialist pain management). CBP is defined as:
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<ol id="ch2.l42"><li id="ch2.lt336" 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="ch2.l43"><li id="ch2.lt337" 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="ch2.lt338" class="half_rhythm"><div>is produced for medicinal use in humans; and</div></li><li id="ch2.lt339" class="half_rhythm"><div>is a medicinal product, or</div></li><li id="ch2.lt340" 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="ch2.lt341" 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="ch2.lt342" class="half_rhythm"><div>Licensed products Sativex and nabilone</div></li><li id="ch2.lt343" class="half_rhythm"><div>Plant-derived cannabinoids such as pure cannabidiol</div></li></ol>
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<b>Comparator:</b> Standard care (tertiary specialist pain management)</p>
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<p><b>Outcomes:</b>
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<ul id="ch2.l44"><li id="ch2.lt344" class="half_rhythm"><div>Participant reported pain relief of 30% or greater</div></li><li id="ch2.lt345" class="half_rhythm"><div>Participant reported pain relief of 50% or greater (to assist the economic analysis)</div></li><li id="ch2.lt346" class="half_rhythm"><div>Reduction in analgesics required</div></li><li id="ch2.lt347" class="half_rhythm"><div>Change in pain intensity using Numerical Rating Scale’, or Visual Analogue Scale’</div></li><li id="ch2.lt348" class="half_rhythm"><div>A validated pain measurement tool</div></li><li id="ch2.lt349" class="half_rhythm"><div>Participant/Patient/Subject Global Impression of Change (PGIC or SGIG) scale</div></li><li id="ch2.lt350" class="half_rhythm"><div>Quality of life score using SF-36 or EQ-5D.</div></li><li id="ch2.lt351" class="half_rhythm"><div>Serious adverse events</div></li><li id="ch2.lt352" 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="ch2.lt353" class="half_rhythm"><div>Withdrawals due to adverse events</div></li><li id="ch2.lt354" class="half_rhythm"><div>Complications due to adverse events</div></li><li id="ch2.lt355" class="half_rhythm"><div>Substance abuse due to the use of cannabis-based medicinal product.</div></li><li id="ch2.lt356" class="half_rhythm"><div>Misuse/diversion</div></li><li id="ch2.lt357" 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="ch2.l45"><li id="ch2.lt358" class="half_rhythm"><div>Contraindications as listed in exclusion criteria</div></li></ul>
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Monitoring requirements, treatment durations, reviewing and stopping criteria, including how should treatment be withdrawn stopped as discussed in the methods of individual RCTs</p>
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</td></tr><tr><th id="hd_b_ch2.appk.tab2_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Current evidence base</th><td headers="hd_b_ch2.appk.tab2_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">No RCTs were identified which compare CBD with standard treatment to standard treatment for children with cancer-related pain and pain associated with specific conditions.</td></tr><tr><th id="hd_b_ch2.appk.tab2_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Study design</th><td headers="hd_b_ch2.appk.tab2_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_ch2.appk.tab2_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Other comments</th><td headers="hd_b_ch2.appk.tab2_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Study should be adequately powered and have an adequate follow up period.</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></div></div>
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