Evidence review: Optimum prescribing strategies or interventions delivered alongside prescribing

1. Optimum prescribing strategies

1.1. Review question: What are the optimum prescribing strategies or interventions delivered alongside prescribing, to limit the risk of dependence or withdrawal symptoms?

1.1.1. Introduction

It is not possible to predict which individuals will develop dependence on prescribed medicines or who will experience withdrawal symptoms if the medicine is reduced and stopped. Prescribers also vary in their confidence to manage these issues in clinical practice, often depending on previous experience to guide their actions. There may, however, be general strategies which could be applied when prescribing medicines associated with increased risk of dependence and withdrawal. Approaches to ensure safe use of medicines, especially when extended periods of use are necessary or the medicine needs to be stopped, will be considered for this review.

1.1.2. Summary of the protocol

For full details see the review protocol in Appendix A.

Table 1

PICO characteristics of review question.

1.1.3. Methods and process

This evidence review was developed using the methods and processes described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A and the methods document.

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

1.1.4. Effectiveness evidence

This guideline and this review question relate to the stage in the treatment pathway after a decision has been made to prescribe one of the relevant medicines. This review question looks at the evidence for what the best prescribing strategy is in terms of reducing the risk of or preventing dependence or withdrawal symptoms. This is highlighted in the aims and interventions of the review protocol. Determining which is the most effective treatment for the underlying condition was outside the scope of this guideline. Therefore, this review did not include efficacy and safety studies, unless the aim of the study was also to assess whether one of the prescribing strategies reduced the risk of dependence. Some studies were identified in the literature assessing 2 different prescribing strategies and then a subsequent withdrawal (with the withdrawal schedule being the same in both arms of the study), and reports withdrawal symptoms within the outcomes. These studies did not necessarily have an aim of reducing dependence. However, such studies were included, as they are involving a withdrawal stage, and therefore are more than just efficacy studies. Antidepressants are not considered to be dependence forming, but can cause withdrawal symptoms on withdrawal. The committee agreed if any studies were identified that did report dependence for antidepressants, they would be included.

1.1.4.1. Included studies

Ten studies were included in the review;^{36, 47, 52, 74, 76, 90, 92, 98, 105, 108} these are summarised by drug class in Table 2 to Table 5 below. Evidence from these studies is summarised in the clinical evidence summaries below (Table 8 to Table 18).

Evidence was identified in people prescribed opioids (n=4^{36, 52, 90, 98}), gabapentinoids (n=2^{47, 74}), Z-drugs (n=1¹⁰⁵) and antidepressants (n=3^{76, 92, 108}). No evidence was identified in people prescribed benzodiazepines.

Prescribing strategies or interventions used to reduce the risk of dependence or withdrawal symptoms included: different dosage regimens (gabapentinoids, n=2; antidepressants, n=2; Z-drugs, n=1),^{47, 74, 76, 92, 105} providing patient or physician information and education (opioids, n=1),⁹⁸ adding an extra drug to the prescription (opioids, n=1),³⁶ varying the rate of upward titration (escalating versus stable dose, opioids, n=1),⁹⁰ the use of mindfulness alongside the prescription (opioids, n=1),⁵² and class comparison (antidepressants, n=1).¹⁰⁸

Three studies assessed the effectiveness of a prescribing strategy or intervention on the risk of dependence.^{52, 90, 98} All of these studies were in people taking opioids. For the studies assessing dependence as the outcome, and the effect of a prescribing strategy or intervention on the risk of dependence, it was noted as important that the population did not have dependence at baseline. Therefore, the protocol stated that ideally the population should be initiating the prescribed medicines, or if currently taking it, the majority (at least 80%) shown not to have behaviours related to dependence at baseline. As all of these studies included participants who were already receiving the medication at baseline, the exclusion criteria was checked to ensure that people with behaviours related to dependence were excluded (this is noted in the summary of included studies listed below, see Table 2).

When agreeing the protocol, the committee acknowledged that dependence might not be commonly reported as an outcome, as it is difficult to measure. Therefore, any definition of dependence as described by the study authors was accepted, this could include measures indicating problems with dependence, such as early refill requests, shopping behaviour, or measures of medicine misuse

The seven other studies included in the review were studies assessing the effectiveness of a prescribing strategy or intervention on the risk of withdrawal symptoms: opioids;³⁶ gabapentinoids;^{47, 74} antidepressants^{76, 92, 108} and Z-drugs.¹⁰⁵

See also the study selection flow chart in Appendix C, study evidence tables in Appendix D, forest plots in Appendix E and GRADE tables in Appendix F.

1.1.4.2. Excluded studies

One Cochrane review was identified as potentially relevant to this review.⁵ The aim of the Cochrane review was to determine the effect of interventions to optimise overall prescribing for older people living in care homes, rather than reducing dependence or withdrawal symptoms. The population of the Cochrane review was also not limited to people being prescribed one of the five medicines associated with dependence or withdrawal symptoms in the current review protocol. Therefore, this review was not relevant to include.

See the excluded studies list in Appendix J.

1.1.5. Summary of studies included in the effectiveness evidence

1.1.5.1. Opioids

Table 2

Summary of studies included in the evidence review: opioids.

1.1.5.2. Gabapentinoids

Table 3

Summary of studies included in the evidence review: gabapentinoids.

1.1.5.3. Z-drugs

Table 4

Summary of studies included in the evidence review: Z-drugs.

1.1.5.4. Antidepressants

Table 5

Summary of studies included in the evidence review: antidepressants.

See Appendix D for full evidence tables.

1.1.6. Summary of the effectiveness evidence

1.1.6.1. Opioids

Table 6

Clinical evidence summary: Risk of Withdrawal Symptoms: Morphine plus Ondansetron vs Morphine plus placebo.

Table 7

Clinical evidence summary: Risk of Dependence: MORE vs support group.

Table 8

Clinical evidence summary: Risk of Dependence: Escalating vs stable dose.

Table 9

Clinical evidence summary: Risk of Dependence: Physician education vs physician patient information (opioids).

Table 10

Clinical evidence summary: Risk of Dependence: Physician education vs usual care.

Table 11

Clinical evidence summary: Risk of Dependence: Physician patient information and education vs physician patient information.

Table 12

Clinical evidence summary: Risk of Dependence: Physician patient information and education vs physician education.

Table 13

Clinical evidence summary: Risk of Dependence: Physician patient information vs usual care.

Table 14

Clinical evidence summary: Risk of Dependence: Physician patient information and education vs usual care.

1.1.6.2. Gabapentinoids

Table 15

Clinical evidence summary: high vs low dose short-term treatment (gabapentinoids).

Table 16

Clinical evidence summary: High vs low dose (long-term) gabapentinoids.

1.1.6.3. Z-drugs

Table 17

Clinical evidence summary: 20mg zolpidem vs 10mg zolpidem.

1.1.6.4. Antidepressants

Table 18

Clinical evidence summary: 6mg doxepin vs 3mg doxepin (tricyclic antidepressants).

Table 19

Clinical evidence summary: 20mg vortioxetine vs 10mg vortioxetine (other antidepressants).

Table 20

Clinical evidence summary: 10mg vortioxetine vs 5mg vortioxetine (other antidepressants).

Table 21

Clinical evidence summary: 20mg vortioxetine vs 5mg vortioxetine (other antidepressants).

Table 22

Clinical evidence summary: Sertraline vs Venlafaxine (SSRI / other antidepressants).

See Appendix F for full GRADE tables.

1.1.7. Economic evidence

1.1.7.1. Included studies

No health economic studies were included.

1.1.7.2. Excluded studies

No relevant health economic studies were excluded due to assessment of limited applicability or methodological limitations.

See also the health economic study selection flow chart in Appendix G.

1.1.8. Summary of included economic evidence

None.

1.1.9. Economic model

This area was not prioritised for new cost-effectiveness analysis.

1.1.10. Evidence statements

1.1.10.1. Economic

• No relevant economic evaluations were identified.

1.1.11. The committee's discussion and interpretation of the evidence

1.1.11.1. The outcomes that matter most

Dependence

This review aimed to assess the effectiveness of different prescribing strategies (such as the initial prescribing dose or duration), or interventions delivered alongside prescribing, to reduce the risk of the person developing dependence on the prescribed medicine. Therefore, dependence was agreed as a critical outcome. When agreeing the protocol, the committee acknowledged that dependence might not be commonly reported as an outcome, as it is difficult to measure. Therefore, any definition as defined by the study authors was accepted, which could also include measures indicating problems with dependence or addiction, such as early refill requests, shopping behaviour, or measures of medicine misuse.

The medicines of interest also included antidepressants, which are not considered to be dependence forming, unlike the other included medicines. However, any studies reporting dependence on antidepressants were reported, if identified.

Withdrawal

Antidepressants are known to cause withdrawal symptoms, therefore the committee were also interested in the effectiveness of the prescribing strategies or interventions on withdrawal symptoms, as a critical outcome. The committee acknowledged that this would also be influenced by other factors such as the withdrawal strategy, as well as the risk from the initial prescribing strategy.

The other critical outcomes for this review were mortality and health related quality of life. Important outcomes for this review were: use of illicit drugs or alcohol as a replacement to prescribed drugs, non-fatal overdose, patient satisfaction, self-harm or harm to others and symptoms for which the medication was originally prescribed.

Evidence was identified in people prescribed opioids, gabapentinoids, Z-drugs and antidepressants. No evidence was identified in people prescribed benzodiazepines.

Opioids

Dependence was reported as opioid medication discontinuation for non-compliance, opioid misuse (on the current opioid misuse measure score, COMM), uncoordinated opioid use and a diagnosis of opioid abuse. Evidence was also available on withdrawal symptoms in people prescribed and withdrawing from opioids plus ondansetron versus opioids plus placebo. None of the other protocol outcomes were reported.

Gabapentinoids

The only outcome reported was withdrawal symptoms in people prescribed and withdrawing from a higher versus a lower dose.

Z-drugs

Withdrawal symptoms and mortality were reported in people prescribed and withdrawing from a higher versus a lower dose. None of the other protocol outcomes were reported.

Antidepressants

The only outcome reported was withdrawal symptoms in people prescribed and withdrawing from either a higher versus a lower dose, or from sertraline versus venlafaxine.

1.1.11.2. The quality of the evidence

Overall, there was a lack of evidence across all drug classes, with a limited number of prescribing strategies or interventions identified in the literature, and only 1 or 2 outcomes reported for each comparison.

Opioids

The quality of evidence for all of the comparisons and outcomes for opioids were of very low or low quality due to risk of bias and imprecision. The main reason for high or very high risk of bias was due to incomplete outcome reporting (a high number of people who dropped out), along with some comparisons and outcomes also being rated as high risk of bias for selection bias or blinding.

Gabapentinoids

The quality of evidence for a higher versus lower dose, when given for short-term treatment before withdrawal, was of moderate quality for withdrawal symptoms assessed using the physician withdrawal checklist (PWC). The evidence was very low quality for a number of withdrawal symptoms when assessed with the Discontinuation- Emergent Signs and Symptoms checklist (DESS). This was due to evidence being downgraded for risk of bias for all outcomes, and additionally downgraded for imprecision for the DESS withdrawal symptom outcomes.

For a higher versus lower dose, long term before withdrawal, all of the withdrawal symptoms outcomes were downgraded for both risk of bias and imprecision, and were of low or very low quality. The main reason for high or very high risk of bias was due to selection bias, along with some comparisons and outcomes also being rated as high risk of bias for incomplete outcome reporting.

Z-drugs

The quality of evidence for the comparison of 20mg or 10mg zolpidem, with subsequent withdrawal, was of moderate quality for the occurrence of withdrawal symptoms, due to risk of bias. For mortality, the evidence was of very low quality due to risk of bias and imprecision. The main reason for high or very high risk of bias was due to selection bias, along with some outcomes also being rated as high risk of bias for blinding and outcome reporting.

Antidepressants

The quality of evidence for the comparison of 20mg, 10mg, or 5mg vortioxetine was of low quality, due to risk of bias and imprecision for the occurrence of withdrawal symptoms. For the comparison of sertraline versus venlafaxine, a number of withdrawal symptom measures were reported, with the quality of the evidence being low or very low quality, due to risk of bias and imprecision. The quality of evidence for the comparison of 6mg or 3mg doxepin was of very low quality, due to risk of bias and imprecision for withdrawal symptoms. The main reason for high or very high risk of bias was due to selection bias, along with some comparisons and outcomes also being rated as high risk of bias for incomplete outcome reporting or blinding.

1.1.11.3. Benefits and harms

Opioids

The committee acknowledged that all the studies reported problems associated with dependence, but that these were signs of misuse or abuse rather than dependence per se. They noted that people can be dependent on medicines without showing any problems of dependence such as misuse. Therefore, the committee interpreted this evidence with caution.

One study compared morphine plus ondansetron versus morphine plus placebo. The outcomes reported were withdrawal symptoms after a naloxone-induced withdrawal. Therefore, this study differed from the others in that it was an experimentally induced withdrawal. The committee agreed that it was not usual practice in the UK for ondansetron to be prescribed alongside opioids, and that this study was probably testing the hypothesis that 5HT-3 receptor antagonists (such as ondansetron) may help decrease withdrawal symptoms. There was no clinical difference demonstrated between the groups in terms of withdrawal symptoms when assessed with the objective opioid withdrawal scale. There was, however, a clinical benefit of placebo for withdrawal symptoms when assessed with the subjective opioid withdrawal scale. From the available evidence, the committee found no reason to recommend the use of ondansetron alongside prescribing, to reduce the risk of subsequent withdrawal symptoms.

One study compared MORE (a mindfulness-based intervention) versus the support group. There was no clinical difference in terms of dependence when assessed by the study as opioid misuse (COMM score). This intervention consisted of group mindfulness sessions over 8 weeks. The committee noted the active control condition of the support group in this study which also received 8 weekly group sessions, covering similar themes to the MORE intervention group. The committee agreed that it was likely the control group were receiving benefit from this support group and this may contribute to the lack of difference in effect seen, when compared to the mindfulness intervention in preventing opioid misuse. This was the only study providing evidence for a psychological intervention alongside prescribing. The committee agreed that this was insufficient evidence to inform a recommendation for psychological interventions to be offered alongside prescribing to limit the risk of dependence. However, the committee discussed the importance of providing the person with support and information at the time of prescribing. From committee experience, this is important in setting expectations with the person about what the medicine can and cannot do, but also can help prevent problems with dependence later down the line.

One study compared escalating versus stable dose. Escalating dose was associated with a clinical benefit in terms of dependence, when assessed by ‘opioid medication discontinuation for non-compliance’. The committee discussed that this was counter-intuitive if the assumption is that the escalating dose group end up on higher doses, as from the committee’s experience, higher doses tend to lead to more problems with dependence. The data from the study suggested that the final morphine equivalent doses only differed by around 10mg between groups at the end of the study, which the committee agreed was not a clinically meaningful difference in dose, and therefore cast doubt on the reliability of comparisons between these two groups. The committee also noted that it would depend on when dose escalations occurred, during the treatment period, and by how much. Starting at a lower dose and slowly increasing the dose may be better than starting on a dose that is too high for the person. One explanation for the benefit of the escalating dose group is about the control the person has over the medicine. If a person has more control over their dose, then they may feel more comfortable staying at a lower dose, as they know the option to increase is available. The committee also noted that increasing opioid doses too fast can have a cumulative effect and cause respiratory depression. Therefore, in addition to the considerations around the best prescribing strategy to reduce the risk of dependence, there may be considerations within condition-specific guidance around the most efficacious doses that reduce the chance of side effects or adverse effects.

One study compared interventions aimed at the physician responsible for prescribing. The interventions were, providing the physician with patient-specific information, providing the physician with links to education materials, providing the physician with both of these, or usual care. For the majority of these when compared to each other, there was no clinical difference between the groups in terms of development of dependence as assessed by ‘uncoordinated opioid use’ or ‘diagnosis of opioid abuse’. The exception was when providing the physician with both educational materials and patient-specific information, versus usual care. For this comparison there was potentially a clinical benefit from the physician intervention on the subsequent diagnosis of opioid abuse. The committee questioned what the aim of the interventions was, and whether the study was aiming to reduce overall prescribing or influence prescribing behaviour, but that this was not necessarily an intervention to give alongside prescribing intended to limit the individual’s risk of dependence. The committee noted they did not have enough evidence to make a recommendation on education for prescribers. However, the committee agreed that it is important that healthcare professionals prescribe within the limits of their competence and expertise, and that the GMC has guidance on good practice in prescribing which highlights this point.

No specific recommendations were made on the basis of the evidence for opioids.

Gabapentinoids

Two studies compared lower (150–300mg/day) versus higher dose (450–600mg/day) pregabalin, for both short-term (6 weeks flexible dose followed by 12 weeks fixed dose) or longer-term treatment (6 weeks flexible dose followed by 24 weeks fixed dose), both followed by a 1-week taper period.

For the short-term treatment study, there was a clinical benefit of the lower dose for withdrawal symptoms when assessed by the number of people with anxiety on the DESS checklist and the number of people with dizziness on the DESS checklist. There was no clinical difference for the other withdrawal symptoms outcomes including the PWC score, the number of people with symptoms on the DESS checklist, the number of people with rebound anxiety, or the number of people with headache, insomnia or nausea on the DESS checklist.

For the evidence of longer-term treatment, there was a clinical benefit of the lower dose for withdrawal symptoms when assessed by the number of people with symptoms on the DESS checklist and the number of people with rebound anxiety. However, there was no clinical difference for the other withdrawal symptoms outcomes including the PWC score, or the number of people with headache, insomnia or anxiety on the DESS checklist. The committee agreed this suggests that lower doses could result in a lower risk of withdrawal symptoms and agreed this reflected their experience of risk of both dependence and withdrawal with gabapentinoids. The committee noted that, as with other medicines considered in this review, withdrawal symptoms will be influenced by factors other than the initial prescribing strategy alone, and this evidence should be interpreted with caution. See discussion below for the recommendation on prescribing low doses.

Z-drugs

One study compared different doses of zolpidem (20mg and 10mg) given for 3 weeks followed by a subsequent withdrawal. There was no clinical difference between groups for withdrawal symptoms. However, it was noted that the study only reported narratively the number of people with ‘no withdrawal symptoms’, which was no one in either group. Indicating that all the participants in both groups experienced at least one withdrawal symptom, but conclusions could not be drawn on whether one group experienced more or less than the other. There was a clinical benefit of the group receiving 10mg of zolpidem for mortality, due to one death from pneumonia (post-treatment) in the 20mg group. The committee agreed they could not draw any firm conclusions on the use of different Z-drug doses from this study and no recommendations were made from this evidence.

Antidepressants

Three antidepressant studies reported withdrawal symptoms from antidepressants, each was a different comparison and reported a different measure of withdrawal symptom occurrence or severity (for example, total DESS score, BWSQ, rebound insomnia, and the antidepressant discontinuation scale) and therefore these could not be pooled. The committee noted that the antidepressant discontinuation scale was not validated, but that other withdrawal symptom outcomes were available for the relevant comparison. One compared different doses of vortioxetine (20mg, 10mg and 5mg) given for 8 weeks followed by a subsequent 2-week withdrawal period. One compared doxepin 6mg versus 3mg, given for 5 weeks followed by an abrupt withdrawal. Finally, one study compared sertraline with venlafaxine, given for 8 weeks followed by a 2-week taper period. There was no clinical difference in withdrawal symptoms in any of these included studies or comparisons, with one exception; a clinical benefit of sertraline for the number of people experiencing no or minimal discontinuation symptoms as assessed using investigator global assessment when compared to withdrawal from venlafaxine.

The committee noted that in each of these studies antidepressants were prescribed for a relatively short time period which did not reflect clinical practice where antidepressants would be given for much longer before being withdrawn. Therefore, it was thought likely that the withdrawal symptoms measured in these studies could underestimate occurrence in practice. The committee also acknowledged that other factors would influence withdrawal symptoms, not only the initial prescribing strategy. In particular, the withdrawal or dose reduction strategy would influence the risk of withdrawal symptoms. The committee agreed the withdrawal strategies used in the studies were not reflective of clinical practice, as antidepressants were either withdrawn abruptly or over a short 2-week period. Therefore, the committee did not base any recommendations on the evidence from withdrawal symptoms outcomes alone.

Considerations across all medicine classes

The committee agreed that it was difficult to base recommendations on the available evidence due to the limited evidence base and the concerns in interpretation. Furthermore, all dependence outcomes were reported by the studies as misuse or abuse outcomes. Therefore, it was difficult to determine which prescribing strategies or interventions may be effective in limiting the risk of dependence. They also noted that the majority of the studies reporting these outcomes of misuse are from the US where there are different prescribing practices and so the evidence was not necessarily generalisable to the UK setting.

For withdrawal symptoms, the committee also discussed that, at the stage of initial prescribing, the focus is more likely to be on the efficacy of the particular medicine and prescribing strategy, for the given indication. At this stage, the committee agreed it is important to also consider the risk of dependence of that prescribing strategy, but that withdrawal symptoms may be less impacted by the initial prescribing strategy, because if the medicine is reduced and withdrawn safely, this will decrease the risk of withdrawal symptoms. However, it was also noted from committee experience, that prescribing strategies that have a lower risk of dependence (such as prescribing at a lower dose for shorter periods) may also result in less problems with withdrawal. There was also an indication from some of the evidence that prescribing with lower doses was associated with a benefit on withdrawal symptoms outcomes upon subsequent withdrawal.

There was no evidence identified in the literature on interventions such as educational or support interventions that could be given to the person alongside prescribing, to limit the risks of dependence. The committee agreed that one of the most important aspects in terms of safe prescribing and avoiding future problems with dependence, is to give the person information and support before prescribing, in order to structure expectations. Therefore, the committee made recommendations on the information that should be given before starting treatment, including a management plan that should be given to the person prior to starting treatment. This was based both on the experience and consensus opinion of the committee and supported by evidence review A, the Patient Information and Support chapter of this guideline. For more detail, see the section on Patient Information and Support.

The committee agreed that although the evidence was limited, there was some indication from the evidence on gabapentinoids that prescribing at a lower dose may reduce the risk of withdrawal symptoms, albeit with the caveats of the limitations in this evidence as described above. Evidence was not available for the effect of prescribed dose on subsequent dependence to the medicine. However, there was some evidence from review E, the Risk Factors evidence review for this guideline demonstrating that higher opioid doses may increase the risk of problems associated with dependence. The committee agreed that this was consistent with their clinical experience that a person should be prescribed the lowest effective dose in order to reduce the risk of developing dependence. This would involve starting at the lowest dose likely to be safe and effective, and having a period of titration and observation to find the person’s lowest effective dose. The committee agreed (by consensus) that there was no reason that this recommendation should not apply to all the medicine classes.

No evidence was identified in the literature on comparisons of different prescribing durations. From their clinical experience, the committee agreed that longer duration of use of these medicines is more likely to result in dependence. The committee discussed that some people may be on these medicines longer than they need to be. There was also evidence from review E, the Risk Factors chapter of this guideline, that long-term opioid therapy is a risk factor for dependence and abuse related behaviours to opioids (see section on Risk Factors), and that being on a higher daily dose long-term increased the risk further. Based on this evidence and the committee’s consensus, it was agreed that a recommendation should be made for regular reviews, to ensure that the benefits of the medicine continue to outweigh the potential harms, to avoid medicines being used for longer than they are needed and in order to avoid risks of dependence from long-term use. The committee agreed based on consensus that it was important to take particular care during dose adjustments and not to automatically increase dose due to lack of response. They noted that although pharmacological tolerance is a property of the medicines considered, if a person has an initially favourable response which then diminishes, it is rarely helpful to increase the dose to try to restore the clinical benefit. They considered such an approach increases the risk of harms, and the loss of benefit is rarely due to pharmacological tolerance, but due to other factors.

It was highlighted that for some people long-term use at safe doses can be appropriate if they are beneficial. The committee agreed the trade-off between the risks associated with problematic use or dependence and the clinical benefit the person derives from the medication should determine prescribing decisions and it may be clinically appropriate for medicines to continue being prescribed for as long as they continue to be helpful. It was also noted that within the content of the management plan, regular reviews should pick up when it might be an appropriate time to stop a medicine. Discussions about the continued effectiveness of the medicine should be initiated at the point of initial prescribing and again at each encounter. This should be captured within the management plan. The point was raised that people may assume their prescriber will tell them when a medicine is no longer needed and may not necessarily know themselves. The information given along with the management plan may give people more awareness of this.

In addition, it was noted that someone should not be given multiple repeat prescriptions or be given a long duration of prescription without review, as this could lead to people remaining on medicines longer than necessary. There was also some qualitative evidence within the Patient Information and Support chapter (Evidence review A) showing that health care professionals emphasised the importance of setting short-term timeframes for the prescription of benzodiazepines. The committee discussed that when there are concerns around a person’s risk of dependence, it would be best practice to give shorter prescriptions. In addition, a shorter duration of prescription may also allow for an early assessment of whether the medicine is effective. However, the committee agreed it wasn’t possible to recommend a minimum length as it would vary according to medicine and condition being treated, therefore, the committee recommended that the duration of each prescription should be given for a duration reflecting the plan for review. Some of the medicines of interest are controlled drugs and the committee discussed that it is also important to highlight that the length of each prescription should be in line with relevant legislation.

1.1.11.4. Cost effectiveness and resource use

No economic evidence was found for this question.

The committee decided to make recommendations reflecting best practice when prescribing medicines and emphasised the need for determining the lowest effective dose to minimise the risk of dependence and harms. Higher doses at initial prescription was found in the clinical review to be related to increased withdrawal symptoms for gabapentinoids. This was supported by evidence in the risk factors review, demonstrating dose to be a risk factor for problems associated with dependence.

The committee noted that there is currently heterogeneity in prescribing strategies across different Trusts and these recommendations should encourage prescribers to adopt best practice. Longer consultations or additional follow-up may be needed to allow for a full discussion of treatments and treatment options when starting or reviewing a medicine. However, encouraging effective discussions, at the time of prescriptions, about risk and benefits could reduce unnecessary prescribing for people who could potentially experience harms, dependence or withdrawal symptoms in the future. This, in turn, should reduce costs to the NHS and ultimately improve its efficiency.

1.1.11.5. Other factors the committee took into account

The committee strongly agreed that every effort should be made to reach a shared decision with the person, however there are instances when agreement cannot be reached, and the healthcare professional believes the prescribing is particularly unsafe and is not in the person’s best interest. The committee noted that the prescriber has a professional obligation to not continue something which is unsafe. It was agreed that guidance should be in line with advice on ‘handling patient requests for medicines you don’t think will benefit them’ in the General Medical Council guidance: good practice in prescribing and managing medicines and devices. The reasons for the decision should be explained to the person and documented, and the person should be offered a second opinion.

The committee discussed situations that can occur in clinical practice, such as prescribing at the suggestion of another health care professional, taking over care for or becoming the prescriber of a person already taking a medicine. The committee agreed that the new prescriber should decide if the current medicine and dose are in the best interest of the person. For this decision to be made, it is essential that the health care professional has sufficient knowledge of the person’s health and personal circumstances. This is in line with good practice in prescribing guidance set out by the GMC. Even in cases where continued prescribing is deemed not to be in the person’s best interest, it would not be appropriate to abruptly withdraw the medicine, but rather that careful withdrawal would be advised in line with the recommendations in section 1.5 of this guideline: Withdrawing Medicines associated with dependence and withdrawal symptoms. There were concerns around the anxiety a person could feel if a healthcare professional takes over their prescribing and decides that the medicine should be stopped. To avoid this anxiety, it is important when prescribing is inherited that the person is seen promptly, and the information provided when starting treatment is reiterated to help establish the new therapeutic relationship and employ the principles of shared decision making. It was highlighted that there would be additional considerations if a person was going into prison, and therefore their care was being transferred to a new prescriber.

The committee emphasised the importance of continuity of care when prescribing recommendations are made in different settings, for example in secondary care with the recommendation to be prescribed in primary care. To facilitate this, they agreed that it is important for prescribers to provide clear information on the management plan and how to follow up. They also agreed that the person should be informed that this is only a recommendation to their primary care prescriber, as their primary care provider may wish to make a decision about whether the prescribed medicine is the best option for the person, potentially based on more in-depth information about the patient from a primary care perspective. In some situations, a medicine may be prescribed in secondary care to be reviewed in primary care. In these cases, it should be explained to the person that the medicine will be reviewed in primary care and may not be prescribed long term. Where primary care prescribers do not agree that a prescription recommended by a specialist is appropriate for prescription in primary care, then this should be discussed with the specialist to agree how the prescribing will be managed. They should involve the person in these discussions and ensure they are made aware if prescribing needs to be delayed while discussions continue.

The committee discussed that ensuring one person has overall responsibility for the prescribing could be difficult in a fast-flowing environment when people don’t always see the same GP or healthcare professional each time. In cases when the prescriber is unable to review the person, continuity of care is extremely important and there should be a consistent line of communication. The management plan should also be clearly documented in the person’s medical record, setting out aims and directions that everyone can follow as part of a multidisciplinary team. They noted that pharmacists are likely to play a key role in leading prescribing and can help ensure continuity of care in medicines reviews. It was noted that this is discussed in recommendations for structured medicines reviews in the NICE Medicines Optimisation guideline and so the committee agreed to cross refer to this section of that guideline.

The committee discussed that take home naloxone was commonly used in people with known current or history or substance misuse and discussed whether this might be a strategy that could be used when prescribing opioids to help prevent problems associated with dependence and withdrawal. However, it was noted that there is no evidence that this is an effective strategy for dependence on prescribed medicines, and although it is a strategy that is beginning to be used in the US, there is much more cross over in the US setting of people with prescription drug dependence and substance misuse problems. Therefore, this is likely to be a context-dependent strategy that is less likely to be relevant in the UK setting. The committee therefore agreed not to include a research recommendation on this topic.

1.1.12. Recommendations supported by this evidence review

This evidence review supports recommendations 1.2.7, 1.3.4, 1.3.5, 1.3.7, 1.3.8, 1.3.9, 1.3.10, 1.3.11, 1.3.12, 1.3.13 and 1.3.14. No research recommendations were made from this evidence review. Other evidence supporting these recommendations can be found in the evidence reviews on E Risk Factors for Dependence or Withdrawal; F Monitoring.

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Appendices