Current Practice Examples Review of the Evidence on Dependence, Short Term Discontinuation and Longer Term Withdrawal Symptoms Associated with Prescribed Medicines

National Guideline Centre

Current practice examples Review of the evidence on dependence, short term discontinuation and longer term withdrawal symptoms associated with prescribed medicines

Rapid Evidence Assessment Methods, evidence and summary May 2019

Serena Carville, Kate Ashmore, Agnès Cuyàs, Nicole Downes, Lina Gulhane, Clare Jones, Eleanor Priestnall, Sharangini Rajesh, Eleanor Samarasekera and Maria Smyth

Developed by the National Guideline Centre

Current practice examples

Contents

Current practice examples

Project team:

Serena Carville, Associate Director, Project lead

Kate Ashmore, Project manager to December 2018

Agnès Cyàs, Information Specialist.

Nicole Downes, Systematic reviewer.

Lina Gulhane, Head of Information Specialists.

Clare Jones, Senior Systematic reviewer.

Eleanor Priestnall, Project manager from January 2019.

Sharangini Rajesh, Senior Systematic reviewer.

Eleanor Samarasekera, Senior Systematic reviewer.

Maria Smyth, Senior Systematic reviewer.

Declarations of interest:

We declare the following conflicts of interest: KA; no conflicts of interest, SC; no conflicts of interest, AC; no conflicts of interest, Nicole Downes; no conflicts of interest, Lina Gulhane, CJ; no conflicts of interest, EP; no conflicts of interest, SR; no conflicts of interest, ES; no conflicts of interest and MS; no conflicts of interest. All authors were employees of the Royal College of Physicians at the time of the project.

Acknowledgements:

The development of this rapid evidence assessment was greatly assisted by Jill Cobb, Kirsten Elliott, Kate Kelley, Elizabeth Pearton, Joseph Runicles and Beth Shaw.

Executive summary Contents 1 Executive summary ...... 5 1.1 Objectives ...... 5 1.2 Methods ...... 5 1.3 Findings ...... 5 1.4 Conclusion ...... 6 2 Introduction ...... 7 2.1 What this evidence assessment will cover ...... 7 2.2 Review questions to be addressed ...... 7 3 Methodology ...... 8 3.1 Searching for evidence ...... 8 3.1.1 Call for evidence ...... 9 3.2 Identifying and analysing evidence ...... 9 3.2.1 Type of studies ...... 10 3.3 Methods of combining studies ...... 10 3.4 Appraising the quality of evidence ...... 10 4 Review question and findings ...... 12 4.1 Available evidence ...... 12 4.1.1 Main literature search ...... 12 4.1.2 Call for evidence ...... 13 4.1.3 Grey literature ...... 15 4.2 Evidence summary ...... 18 5 Conclusions ...... 22 6 References ...... 23 7 Appendices ...... 88 Appendix A: Review protocols ...... 88 Appendix B: Study selection ...... 90 Appendix C: Search strategies ...... 93 Appendix D: Evidence tables ...... 112 Appendix E: Risk of bias ...... 125 Appendix F: Unpublished data submitted ...... 131 Appendix G: Excluded studies ...... 138 Appendix H: List of medicines to be included ...... 187

Executive summary 1 Executive summary

1.1 Objectives

The Parliamentary Under Secretary of State for Public Health and Primary Care has commissioned Public Health England (PHE) to conduct a public health focussed review of the evidence on dependence, and the short term discontinuation or longer term withdrawal symptoms associated with prescribed medicines. A rapid evidence assessment was subsequently commissioned focussing on 5 key areas reported in 5 associated papers. This report focusses on a review of current examples of services providing withdrawal support and the effectiveness and cost-effectiveness of the health/social service delivery models that prevent or treat dependence and the short term discontinuation or longer term withdrawal symptoms.

1.2 Methods

We conducted searches of the Cochrane Library, Epistemonikos, Database of Promoting Health Effectiveness Reviews, Health Evidence, Medline, Epub Ahead of Print, In-Process & Other Non- Indexed Citations and Daily, Embase, PsycINFO, Health Technology appraisals, Trials Register of Promoting Health Interventions and Applied Social Sciences Index & Abstracts for systematic reviews, RCTs and non-randomised studies of dependence, short term discontinuation or longer term withdrawal symptoms from the following prescribed medicines: opioids for chronic pain (excluding end of life /palliative care/cancer pain), benzodiazepines, Z-drugs, gabapentin and pregabalin (excluding epilepsy treatment), and antidepressants. Searches were limited to the last 10 years to capture the most recent literature in the area.

To supplement the searches of peer reviewed articles, searches of grey literature were undertaken in the King’s fund library and the National Institute for Health Research Journals Library. A call for evidence was put out, asking stakeholders to submit evidence informing current examples of services in this field, focussing on the outcomes of interest as specified within the review protocol to assess the effectiveness and cost effectiveness of such services. A month was allowed for information to be submitted.

Records identified in the search and from call for evidence submissions were assessed for relevance to the review protocol. Information from included studies was extracted into evidence tables and studies were assessed for risk of bias using the Institute of Health Economics (IHE) Quality Appraisal of Case Series Studies Checklist. As full analysis of the data that was identified was not possible, a narrative summary of the results is presented within this report together with the risk of bias rating.

1.3 Findings

No relevant studies were identified from the database search of peer reviewed publications. Of 651 records identified in the grey literature search, 1 was subsequently included. One hundred and twenty five records were submitted via the call for evidence. Three of these were directly relevant to this question and included. This led to a total of 4 publications, describing a total of seven services, included within the review. Three of the included services were specific to opioid use. The remaining four covered a mixture of prescription drugs including benzodiazepines, z-drugs and antidepressants. Due to the variation in interventions and services reported, each was described separately in this report. None provided a comparison of services to inform the effectiveness or cost effectiveness. However, 6 out of 7 of services described reported the percentage of people who began withdrawal of prescribed medications of interest, ceased taking them in total or if there was a reduction in prescribing of these medications.

Executive summary

1.4 Conclusion

Although published evaluations of effectiveness of current services are limited, those described within this report identify initiatives from within the UK and beyond that are delivering such services. From submissions that had information in the public domain and provided information that could be included, some common themes were identified. All of the UK services described involved some degree of GP or primary care involvement, which ranged from services developed and based within primary care to community-based services run by non-clinicians who intended to communicate and work with the NHS. In addition, many of the services offered both a helpline or telephone support in addition to other support such as counselling or support groups. Individualised plans and programmes were a focus.

The limited number of reports of services, and detail on those services, coupled with the limited availability of published reports or evaluations, demonstrates a need for developers and users of services to evaluate them and publish their findings. Increased publication of service evaluations would help inform most effective configurations and consequently future provision of services.

Introduction 2 Introduction

2.1 What this evidence assessment will cover The Parliamentary Under Secretary of State for Public Health and Primary Care has commissioned Public Health England (PHE) to conduct a public health focussed review of the evidence on dependence, and the short term discontinuation or longer term withdrawal symptoms associated with prescribed medicines. Within scope of the review will be commonly prescribed medicines for adults who have chronic pain (excluding end of life /palliative care/cancer pain), anxiety, insomnia or depression.

The Review of the evidence on dependence, and the short term discontinuation and longer term withdrawal symptoms associated with prescribed medicines aims to answer the following three questionsa:

1. What is the scale and distribution of dependence, and the short term discontinuation or longer term withdrawal symptoms from prescribed benzodiazepines, z-drugs, gabapentinoids, opioid pain medicines and antidepressants?b 2. What are the factors that may contribute to the risk of dependence, and the short term discontinuation and longer term withdrawal symptoms? 3. How can dependence, and the short term discontinuation and longer term withdrawal symptoms be effectively prevented and treated?

The literature review was commissioned externally by PHE via an open tender process which started in June 2018. The specification for the literature review was drafted by the PHE project team and commented on by the expert reference group. The contract started in August 2018 and the work finished in February 2019. There were 9 bids in total; written bids were assessed by a panel, and 3 bidders were invited to a second stage interview/meeting. The National Guideline Centre (NGC) won the contract based on their skills, experience in undertaking this kind of review and understanding of the potentially contentious nature of the topic.

PHE worked closely with NGC formally in monitoring meetings, ensuring the work progressed, answering queries relating to the specification, or utilising PHE clinical advisers.

2.2 Review questions to be addressed

This report focusses on the evidence of existing examples of services to prevent or treat dependence, short term discontinuation and longer term withdrawal.

The review question was developed using a PICO framework (population, intervention, comparison and outcome) for intervention reviews.

This use of a framework guided the literature searching process, critical appraisal and synthesis of evidence. The review questions were agreed by PHE and the questions and protocols were reviewed and commented on by the expert reference group.

a The initial review commission sought the answers to three broad questions. During the development of the rapid evidence assessment (REA) methodology the broader questions were refined and the evidence was subsequently sought to answer five focussed research questions. Hereafter in this report we refer to the five review questions. b Prevalence and distribution will be covered in a separate data analysis exercise. However sociodemographic characteristics of patient groups disproportionately affected by prescribed medicine dependence/discontinuation and withdrawal is relevant to the REA.

Methodology 3 Methodology

3.1 Searching for evidence

Literature searches were undertaken to identify all published clinical evidence relevant to the review questions. The approach of running one larger search to cover all review questions was adopted, because it was more comprehensive and inclusive and avoided any overlaps.

The standard approach of applying a PICO structure would have resulted in excessive results. Instead, a systematic review and citation-led searching was used in preference to a more traditional database-led PICO approach. The traditional approach resulted in the retrieval of an unmanageable number of references for example, Medline alone retrieved in excess of 28,000 references.

This approach to finding the evidence is consistent with the requirements of NICE’s (2014) methods manual.

Step 1: A search of existing systematic reviews on dependence, discontinuation, and prescribed medicines was undertaken on the following databases: • Cochrane Database of Systematic Reviews (The Cochrane Library) • Epistemonikos • Database of Promoting Health Effectiveness Reviews (DoPHER) • Health Evidence

Step 2: Relevant systematic reviews were ordered to check for inclusion, and bibliographies of relevant reviews identified during step 1 were checked and ordered as required.

Step 3: Databases were then searched to identify more recent evidence which would not have been incorporated in existing reviews due to publication dates. Searches were composed using relevant medical subject headings specific to individual databases, free-text terms and where appropriate study-type filters were applied. Where possible, searches were restricted to papers published in English. Studies published in languages other than English were not reviewed.

Date parameters were applied from 2008 to the date the search was run. Applying a 10-year publication date limit to the search ensured the inclusion of only the most up to date evidence. The limit was chosen based on the upward trend in the prescribing of most classes of medicines and the fact that the larger proportion of the literature on prescribed medicines has been published in the last decade. All searches were completed from 19th September to 3rd October 2018. No papers published after these dates were considered.

Database searches were conducted in: • Medline & Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily (OVID) • Embase (OVID) • Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library -Wiley) • PsycINFO (Ebsco) • Health Technology appraisals (Centre for Reviews and Dissemination) • Trials Register of Promoting Health Interventions (TRoPHI) • Applied Social Sciences Index & Abstracts (ASSIA)

Step 4: In addition to the main searches, for this question, grey literature was searched in: • King’s fund library • National Institute for Health Research Journals Library

Methodology

Step 5: Six key papers covering the 5 questions were identified from the main search above for preliminary citation searching. Citation searching was undertaken using Scopus. After examining these results it was decided we did not need to undertake further Scopus searches.

Search strategies were quality assured by checking reference lists of highly relevant studies to ensure that relevant studies were picked up by the searches, and analysing search strategies in other systematic reviews. Searches strategies were also checked by a second information specialist using PRESS: Peer Review of Electronic Search Strategies before being run.

The questions, search strategies for the databases, study types and exclusions filters applied and the years covered can be found in appendix C.

The titles and abstracts of records retrieved by the searches were sifted for relevance by two independent reviewers. Discrepancies were resolved by a third party. Potentially significant publications were obtained in full text. These were assessed against the inclusion criteria as set out in the protocol.

3.1.1 Call for evidence

Due to the lack of relevant evidence to inform this question from preliminary scoping searches, it was decided a priori that a call for evidence would be conducted to invite stakeholders (relevant organisations or individuals with expertise or experience in the field) to submit research data or reports.

This call requested the following information which would inform the review question in section 4 below: • Information published between 2008 and 2018. • Unpublished information related to research carried out between 2008 and 2018, including any ongoing research. • Reports which summarise/collate patient experiences for example, organisational reports or internal evaluations of projects or services (the views, experiences and opinions of individual professionals, researchers, commentators or patients were not included).

Particular interest was expressed in the outcomes detailed in table 1.

The call was active for 4 weeks from 26th September - 23rd October 2018. Information submitted after that date was not included.

3.2 Identifying and analysing evidence

The inclusion and exclusion of studies was based on the criteria defined in the review protocol, which can be found in appendix A. Protocols were registered on PROSPERO prior to data extraction commencing. Excluded studies (excluded at the full text stage) with the reasons for their exclusion, are listed in appendix G.

The key population inclusion criterion was: • Adults (18 years and over) • Dependence, and the short term discontinuation or longer term withdrawal symptoms associated with the prescribed medicines: Benzodiazepines, Z drugs, GABA-ergic medication, opioid pain medications, antidepressants and combinations of these medicines. (Full list of drugs provided in appendix H). • Prescribing in the community, and on discharge from secondary care.

The key population exclusion criterion was:

Methodology

• People aged under 18 years • Over-the-counter medicines • Medicines prescribed/dispensed in prisons • Medicines prescribed for cancer pain/ palliative care/end of life patients • Gabapentinoids prescribed for epilepsy • Antipsychotic and stimulant medicines • Prescribed medicines to treat drug misuse disorders • The views, experiences and opinions of individual professionals, researchers, commentators or patients. • Non-NHS prescribed medicines.

Main database literature search

Letters, editorials, comment articles, unpublished studies and studies not in English were excluded. Systematic reviews were assessed for inclusion, if not relevant to include, references were checked for relevance to the review question and ordered if deemed potentially relevant.

Grey literature and call for evidence

All submissions and grey literature references were assessed for relevance to the review question, and collated by publication status. Submissions not included in the call for evidence but deemed relevant to other questions for inclusion in the rapid evidence assessment were ordered and considered for inclusion in the relevant review.

3.2.1 Type of studies

Systematic reviews, randomised trials and non-randomised studies were included in the evidence reviews as appropriate. Grey literature and policy reports were also included from the grey literature search and call for evidence submissions, where relevant to the review protocol. Please refer to the review protocols in appendix A for full details on the study design of studies selected for each review question.

3.3 Methods of combining studies

Data from non-randomised studies can usually not be combined due to differences in confounding factors adjusted for, or if not adjusted, heterogeneity in the populations. Therefore data from each study will be reported and assessed individually per study.

3.4 Appraising the quality of evidence

All data extracted from the included studies was in a narrative format and quality assessment at the outcome level could not be performed. Therefore, a risk of bias assessment was performed at the study level using the checklist described in Table 3 below.

Due to the fact that all included studies were non-comparative and did not provide data in a form that could be analysed, information reported by each study was extracted narratively into data extraction tables.

The lack of analysable data meant that forest plots could not be generated for this review and quality assessment at the outcome level using GRADE could not be performed. To ensure quality assessment was incorporated into this review, risk of bias at the study level was performed using the Institute of

Methodology

Health Economics (IHE) Quality Appraisal of Case Series Studies Checklist. These are reported in appendix E.

In the absence of any analysis and graphical representation of the data, narrative summaries were produced to describe the main information obtained for this review and are presented in section 4.1 below, with a conclusion based on the findings presented in section 5.

Review question and findings 4 Review question and findings

What are the current existing examples of services providing withdrawal support and what is the effectiveness and cost-effectiveness of the health/social service delivery models that prevent or treat dependence and the short term discontinuation or longer term withdrawal symptoms from the following prescribed medicines: opioids for chronic pain (excluding end of life/palliative care/cancer pain), benzodiazepines, Z-drugs, gabapentin and pregabalin (excluding epilepsy treatment), and antidepressants? (In England, as well as health service delivery models in other countries that might inform provision in England).

For full details see review protocol in appendix A.

Table 1: PICO characteristics of review question Population • Adults using prescription medicines associated with dependence and withdrawal (opioids for chronic pain (excluding end of life /palliative care/cancer pain), benzodiazepines, Z-drugs, gabapentin and pregabalin (excluding epilepsy treatment), and antidepressants). • Staff delivering services. Intervention(s) • Health / social service delivery models that prevent or treat dependence and the short term discontinuation or longer term withdrawal symptoms from prescribed medicines e.g. o Dedicated services o Dedicated sessions o ‘Addiction’ specialist services o Primary care support o Specialist services within or in liaison with primary care/shared care model o Online support services. Comparison(s) Compared to each other or usual care (as defined by studies). Non-comparative evidence will be considered if no comparative evidence is available. Outcomes Primary outcomes • Reduction/cessation in prescribed drug use • Successful withdrawal • Cost effectiveness • Use of healthcare resources • Health related quality of life • Patient / staff satisfaction • Social outcomes e.g. employment, relationships, parenting • Reduction in disability Study design • Systematic review • RCT – including cluster randomised • Observational studies including non-randomised studies • Grey literature / policy reports

4.1 Available evidence

4.1.1 Main literature search

No studies relevant to the review question protocol were identified from the main literature search of articles published in peer reviewed journals.

Review question and findings

4.1.2 Call for evidence

Submissions were received from 30 separate organisations or individuals, with 125 reports or references of publications. Of those that were considered to be relevant to this review question, 7 were unpublished reports and therefore, while outcomes were available, full quality assessment and inclusion in the analysis could not be undertaken. Details of these relevant, but unpublished data are described in section 4.1.2.1 below and in Appendix F:.

Three relevant publications obtained from the call for evidence have subsequently been included - a summary is given in table 2 below - which also provides details of 1 study identified and included from the grey literature search. Two of those included from the call for evidence are posters presented at a conference, therefore limited detail was available, but where possible this has been included and reported.

The main reasons studies or reports were excluded were that they were relevant to other review questions included in this project, but not part of the call. In these cases the studies were transferred for consideration in the other questions as appropriate (see associated reports). Additionally, many articles submitted were published prior to 2008.

In addition to the included studies, further submissions provided descriptions of programmes of interest which were in the public domain, but no evaluation or outcomes were available at present that could be analysed within the report of effectiveness of the service. These are excluded from the analysis but are listed and briefly described below as examples of programmes, services or research available and in progress: • British Medical Association (2017) Chronic pain: supporting safer prescribing of analgesics. London: British Medical Association. A briefing paper highlighting some of the key issues surrounding the use of analgesics in the management of patients with chronic pain; setting out a range of recommendations for governments, policy makers and healthcare professionals, with the aim of supporting the safer prescribing of these medicines. Whilst it provides an introduction to the current state of the evidence in this area, it is not intended to provide a systematic review of the evidence or act as a clinical guide. A comprehensive resource to support the clinical use of opioids – Opioids Aware – has also recently been developed and is discussed within this report. • The Faculty of Pain Medicine’s resource ‘Opioids aware’ https://www.rcoa.ac.uk/faculty-of-pain- medicine/opioids-aware. A resource written and collated by healthcare professionals with the support of stakeholder policy groups to provide information to support a safe and effective prescribing decision for opioids. This is an online resource which covers a number of aspects including; o best professional practice, o understanding pain and medicines for pain, o clinical use of opioids, o a structured approach to opioid prescribing, o opioids and addiction, and o information for patients. • Centre for Effective Practice Opioid Tapering Template https://thewellhealth.ca/opioidtaperingtool A tool developed in Ontario, Canada designed to assist family physicians and primary care nurse practitioners on developing tapering plans with their patients and adjusting those plans as their patients’ needs change due to pain, function and withdrawal symptoms. It is a template that can be freely downloaded from the website. The tool is divided into five sections to guide providers through the opioid tapering process:

Review question and findings

o Important considerations for opioid tapering. o How to taper, reduce or discontinue. o Withdrawal symptoms & management. o Tapering plan; and o Follow-up tapering visits. • I-WOTCH: Improving the Wellbeing of People with Opioid Treated Chronic Pain (I-WOTCH). https://warwick.ac.uk/fac/sci/med/research/ctu/trials/iwotch/health/ An ongoing randomised controlled trial with the Warwick Clinical Trials Unit to test the effectiveness and cost effectiveness of a multicomponent self-management intervention targeting withdrawal of strong opioids in comparison to best usual care (that is, the control intervention) for people living with persistent pain. • NHS Gloucestershire Living Well with Pain Programme. https://www.gloucestershireccg.nhs.uk/your-health/health-topic/pain/ The aim of the programme is "Making Gloucestershire the best place to live with persistent pain and to protect patients from the harms of pain treatments." The programme addresses challenges in managing pain generally and prescribing specifically. ‘Upstream’ and ‘downstream’ approaches are used. Upstream interventions promote a shared understanding of the complexity of persistent pain. Downstream initiatives focus on support and management for patients who remain on high dose opioids, often in combination with other psychoactive drugs, many of whom have failed to make progress with specialist support. Other elements include development of a joint formulary and promotion of the key concept of “first do no harm:” Offering multidisciplinary assessment for complex patients and follow-up of these patients with their GP. Running training sessions for primary care staff in the community and masterclasses for healthcare professionals, exploring conversations in pain management and using themes from transactional analysis to recognise prescribers’ own behaviours and feelings in consultations that often lead to poor prescribing decisions. Implementing a risk mitigation programme to ensure that all patients taking high dose opioids and those taking multiple opioids or opioids in combination with other medicines, particularly gabapentinoids, antidepressants and benzodiazepines are identified and reviewed in primary care to optimise their prescriptions and reduce exposure to harm. • South Gloucestershire opioid analgesics dependency pilot project: http://www.southglos.gov.uk/health-and-social-care/staying-healthy/drugs-and-alcohol/drug- information-and-treatment/opioid-analgesics-dependency-oad-pilot-project/ The pilot project aims to address the misuse of prescribed medications. It is seeking to establish how to work more effectively alongside GPs in primary care settings. The pilot has been commissioned to be delivered by Developing Health & Independence (DHI), in conjunction with Battle Against Tranquillisers (BAT) between July 2016 and June 2018. The effectiveness of the Pilot Project will be evaluated by NIHR CLAHRC West. (Evaluation not available at time of development of this rapid evidence assessment). • REDUCE Programme Work Stream 4: REviewing long term anti-DEpressant Use by Careful monitoring in Everyday practice. Randomised controlled trial http://www.isrctn.com/ISRCTN15036829 The REDUCE (REviewing long term antiDepressant Use by Careful monitoring in Everyday practice) study aims to identify safe, effective, and cost-effective ways of helping patients taking long-term antidepressants taper off and stop treatment, when appropriate. This study in particular, part of the REDUCE programme, aims to determine the feasibility of a randomised controlled trial of online (Internet) interventions to support practitioners and guide patients on coming off antidepressants. The aim is to assess the acceptability of the Internet interventions, recruitment of practitioners and patients, and acceptability of planned outcome measures.

Review question and findings

4.1.2.1 Unpublished data submitted/email communication only (see Appendix F:) • East Sussex Better Together (ESBT) Project Group Dependence Forming Medication Service • Bristol and District Tranquiliser Project - Annual report 2017-18 • Sheffield CCG controlled drug monitoring programme • Society for an Addiction Free Existence (SAFE) • South Yorkshire & Bassetlaw Controlled Drugs Lead Group Targeted controlled drug monitoring programme • NHS Brighton and Hove CCG - Prescribing Incentive SchemeCamden and Islington NHS Foundation Trust - Audit feedback cycle on reducing hypnotics and anxiolytic prescribing using 2 different approaches in 2 different practices in the North Camden locality.

4.1.3 Grey literature

A search of the grey literature identified 1 report of a prescription monitoring programme that was relevant to include for this question. Details are included in table 2 below.

See also the study selection flow chart in appendix B, study evidence tables in appendix D and excluded studies list in appendix G.

Review question and findings and question Review Currentpractice examples

Table 2: Summary of studies included in the review Study Intervention and comparison Population Outcomes Comments Barth 2017(1) Educational intervention to Physicians who serve military Staff satisfaction (issues Intervention aim: to improve safe improve physician use of members and veterans experienced with intervention opioid prescribing practices and prescription monitoring and barriers to prevent prescription opioid misuse programme (academic detailing) USA implementation) among this high-risk population

Non-comparative study Theoretical and modelling phases of intervention development are described and preliminary evidence of feasibility and acceptability only

Dann 2018(2) Patient self-care programme to be People taking opioids for Reduction/cessation in Conference poster using in primary care to enact chronic pain (n = not reported) prescribed drug use change in opiate prescribing. (percentage ceasing opioid use, Only assessment of effectiveness of UK percentage significantly programme is % ceasing or 16 Compares people stopping opioids reducing opioid use, effect on significantly reducing opioids – other following intervention and those long-term opioid prescriptions) results look at when people do who don’t successfully cease taking opioids Health-related quality of life compared to those who don’t. (quality of life, level of activity, level of anxiety)

Guy 2018(3) • Prescribed Medication Support People experiencing prescribed • Drugs covered by each Description of 4 services Service - North Wales NHS drug dependence service Also includes criteria for referral, key (PMSS) • Costs and outcomes features and feedback from clients. • Bristol and District Tranquiliser UK (outcomes vary according to Project (BTP) service) • The Bridge Project Addiction to Medicines Programme • Mind in Camden’s Recovery Experience Sleeping Tablets and

Review question and findings and question Review Currentpractice exa © Royal © College of Physicians 2019 Study Intervention and comparison Population Outcomes Comments Tranquilisers Service (REST) Scott 2018(4) • SUPPORT (service in primary People with chronic non-cancer • Reduction/cessation in Conference poster care to help patients pain treatment with long-term prescribed drug use (average understand relationship with opioids (n=34) prescribed opioid dose, No description of the service opioids and develop alternative proportion reducing/ceasing

pain management strategies) UK opioids at follow-up, Current mples • Non-comparative Opioid Misuse Measure

scale)

• Health-related quality of life (health, wellbeing and quality of life measures)

• Patient/staff satisfaction (positive/negative experiences of the service)

Current practice examples

Review question and findings

4.2 Evidence summary

All of the information extracted from the 4 included publications in this review was in a form that could not be analysed, and the major findings are reported narratively below. Please see clinical evidence tables in Appendix D for full details of the information extracted.

Opioid reduction/withdrawal services within the UK:

Two conference posters were included in the review(2, 4). One(2) described an existing opiate reduction service that had been developed within 1 primary care practice and the other(4) described a pilot intervention performed across 2 GP practices that aimed to help patients understand their relationship with opioids and develop non-drug-based methods of managing pain. Due to them being conference abstracts, information concerning the components of the services was very limited and reporting of the outcomes was brief.

Both reported that a proportion of service users were able to completely cease opioids or reduce their dose; 1(2) reported that 28% participants were able to cease use of opioids and 70% significantly reduced dose over a 2 month period, while the other(4) indicated that 15/34 (44%) service users reduced their dose of opioids over an unreported period of time, including 3 that ceased use completely (9%).

One study(2) also reported that becoming opiate aware as a practice had led to a reduction in the initiation of long-term opioid prescriptions, and that comparing those off opiates with those on high- dose opiates identified a higher quality of life (significant), lower anxiety (non-significant) and higher activity level (non-significant) in those off opiates.

One study(4) additionally reported that improvements in Current Opioid Misuse Measure (COMM) scale score, Brief Pain Inventory (BPI) severity and interference, Warwick-Edinburgh mental wellbeing scale and TOP quality of life scores (overall, physical and psychological), and a worsened percentage pain relief score, were observed at follow-up compared with baseline, with the length of follow-up being unclear. This study also reported on the positive and negative experiences of the service by its users, details of which can be found in the clinical evidence tables in Appendix D.

Both of these studies were rated as being at a high risk of bias. Primary limitations included the fact that very limited information was provided about the services, the time period outcomes were measured over was short or was not reported and that they are non-comparative reports, and therefore robust conclusions of their effectiveness cannot be made without a comparator group.

Mixed drug reduction/withdrawal services within the UK:

A document produced by the All Party Parliamentary Group for Prescribed Drug Dependence(3), which describes 4 existing UK services for prescription medication withdrawal, was also included in this review. This evidence was considered to be at a high risk of bias, with primary limitations being outcomes only being available for relatively short follow-up periods (6-12 months) or small numbers of participants over a longer period of time (therefore small sample sizes which cannot reliably inform generalisable conclusions), the population of those covered by each service not being well- described and the non-comparative nature of the reports. Details of each individual service included in this document are described below and in clinical evidence tables in Appendix D. Please note that each service described within this document was extracted into its own individual data extraction table for clarity and is labelled accordingly.

Prescription Medication Support Service: This is a service in Wales that covers benzodiazepines and Z-drugs, antidepressants, pain killers (within prescribed limits) and other drugs (not specified). The key features of this service are that it involves medication therapists/nurses that are based directly

Review question and findings within GP surgeries and collaborate with pharmacists and GPs to contact client groups directly. Education and training are provided through workshops and talks, and personalised programmes for patients are developed following assessment. Support is available for patients in the form of monthly in-person follow-up with telephone support available in between. The key information reported for this service was as follows:

• Reduction/cessation in prescribed drug use: of 329 people using the service between April and September of 2018, 62% were reducing prescribed medications and 33% had ceased taking them. • Cost outcomes: service covers a population of 701,000 across 6 counties, with a cost per annum of £179,000, a cost per population head of £0.26 per year and a cost per person helped of £272 per year.

The main limitations of the information reported for this service were that reduction/cessation outcomes were only available over a 6 month period and that the service covers over the counter pain killers, which were specified as an exclusion criterion for this project (see review protocol in Appendix A), as well as other, unspecified drugs.

Bristol and District Tranquiliser Project (BTP): This is a service in England that covers benzodiazepines and Z-drugs, antidepressants and antipsychotics (on GP request only). It does not work with pain killers. The key features of this service are that it consists of a helpline that supports the Bristol community and rest of the UK, with additional services available for Bristol residents only, where necessary, including weekly support groups and counselling. Non-Bristol residents can continue to use the helpline for support. The services are delivered by people with personal experience of prescribed drug dependence and prescriber permission is required before clients are given the opportunity to establish stabilising/tapering plans via the service. The key information reported for this service was as follows:

• Reduction/cessation in prescribed drug use: of 285 people helped in 2017/18, 83% commenced withdrawal. However, there is no mention of the proportion that successfully completed withdrawal. • Cost outcomes: Service covers a Bristol population of 450,000, with an annual expenditure of £91,200, a cost per head of £0.20 per year and a cost per person helped of £320 per year.

The main limitations of the information reported for this service were that reduction/cessation outcomes were only available over a 1 year time period, it was unclear whether the costs reported factor in those helped UK-wide via the helpline and it covers antipsychotics, which were specified as an exclusion criterion for this project (see review protocol in Appendix A).

The Bridge – Addiction to Medicines Programme: This is a service in England that covers benzodiazepines and Z-drugs, and opioids (pain killers). It does not work with antidepressants. The key features of this service are that it is delivered by a charity that wins funding/contracts to deliver services and works with GPs to identify patients for proactive contact. Meetings are arranged with Bridge contact workers, where assessments are performed and a support plan is designed. Support for tapering and prescription adjustments is provided by GPs, and follow-up Bridge meetings with tailored individual support are arranged. Telephone support is also available. The key information reported for this service was as follows:

• Reduction/cessation in prescribed drug use: of 364 people that were helped in the September 2016/17 time period, there were 43.3% successful completions for benzodiazepines and 47.4% successful completions for opioids. However, it is unclear what ‘successful completion’ refers to and whether this indicates successful reduction or cessation.

Review question and findings

• Cost outcomes: service covers a population of 532,000, with an annual expenditure of £98,000, a cost per population head of £0.18 per year and a cost per person helped of £269 per year.

The main limitations of the information reported for this service were that reduction/cessation outcomes were only available over a 1 year time period and it is unclear how ‘successful completion’ was defined.

Recovery Experience Sleeping Tablets and Tranquilisers (REST) – Mind in Camden: This is a service in England that covers benzodiazepines and Z-drugs only. The key features of this service are that it is run by non-clinicians in a community setting, though they state an intention and ability to work with the NHS. The manager of the service and service users undertake networking and provide education in the area (no further details provided in the report). The main aim of the service is to stabilise use of these prescribed drugs before reducing or withdrawing. Support available ranges from advice via a helpline, one-to-one tapering advice to counselling referral with tapering support (no description of what type of support provided in the report). It was noted that there is a 2-3 month wait for this component of the service. In addition, weekly peer support groups and monthly family support groups are available, and other help can be provided such as accompanying users of the service to GP appointments or assisting with benefits and housing. The key information reported for this service was as follows:

• Reduction/cessation in prescribed drug use: of 194 people that received counselling support over the last 8 years (as of March 2018), 4% stabilised their dose, 51% lowered their dose, 29% withdrew completely, 6% had no change in dose, 1% were on a higher dose and the outcome of the service was unclear/not applicable for 21% of service users. However, the length of follow-up for each individual is unclear. • Cost outcomes: service covers a population of 215,667, with 130 people helped annually through the helpline and counselling services combined. The service cost per annum was reported to be £49,000, with a cost per head of population of £0.22 per year and a cost per person helped of £376 per year.

The main limitations of the information reported for this service were that outcomes were only given for those that used the counselling service (outcomes for the helpline not included) and a relatively low number of people used the counselling support considering it was over an 8 year period.

Improving the use of prescription drug monitoring programmes:

One study(1) reported information on a pilot intervention in the USA that assessed the use of an academic detailing intervention to improve the use of a prescription drug monitoring programme by primary care physicians. This involved interactive sessions between academic detailers and primary care physicians on using and registering with the monitoring database. However, the study only reports preliminary findings regarding the feasibility and acceptability of the intervention by primary care physicians. The key information reported for this pilot intervention was as follows:

• Issues occurred concerning the delivery of the academic detailing sessions, with 8% of primary care physicians not able to complete the real-time experience with the prescription drug monitoring database during the allocated time, which was a key component of the session. Reasons for this included time constraints and issues logging into the database. • Physicians also reported on potential barriers to using the database in practice – 43/75 reported at least 1 potential barrier, including time constraints, the database not being user friendly and it requiring practice to remember how to run the reports.

The main limitations of this pilot intervention were that it was performed in the USA, it is unclear how relevant this type of intervention is to the UK setting and there are no outcomes concerning the effect on prescribing or patient use of prescription drugs. This study was considered to be at a high

Review question and findings risk of bias. Despite this, the study was included due to it matching the protocol for this review and having outcomes that could be considered to reflect ‘staff satisfaction’, which is listed in the protocol in Appendix A as a relevant outcome. If a similar service/intervention was considered in the UK, it potentially gives some insight into the potential barriers or issues that could arise in designing and delivering it, but this is extremely limited and would need to be built upon.

Conclusions 5 Conclusions

All of the studies identified that reported on reduction in dose/cessation of prescribed drugs indicate that a certain proportion of service users did benefit from the services in terms of reducing dose or ceasing use completely(2-4). However, the proportion benefitting varied across individual services, the time period over which data was collected was short or data were collected from a small number of participants relative to the population served, and there was a very limited description of the service and components of the service in some cases. These factors mean that it is difficult to determine the effectiveness of these services over a longer period of time, for example details of the proportion that may relapse at a later date are not available, and limited descriptions of some of the services make it difficult to identify key components of services that may work well. These issues, amongst others specific to each individual study, resulted in all included studies being considered to be at a high risk of bias, and the non-comparative nature of all of the studies meant that differences between those using a service and those not using a service or using an alternative service could not be compared. The limitations in the evidence mean it is not possible to make any firm conclusions on the effectiveness of current practice examples within the UK, and the studies included give only limited insight into existing UK services for prescribed medication dependence in terms of patient outcomes and the cost of these services.

Despite these limitations , some key themes within existing UK services were identified. All of the UK services/interventions described involved some degree of GP/primary care involvement, which ranged from services developed and based within primary care to community-based services run by non-clinicians who intended to communicate and work with the NHS. In addition, many of the services identified offer both helpline/telephone support in addition to further services such as counselling/support groups. Individualised plans and programmes were a focus of these services. Most of those identified are small services in terms of the number of staff involved and cover local areas. In terms of costs, the 4 services reported by 1 study(3) indicate that the costs per head of the population ranged from £0.18 to £0.26 per year and that the cost per person helped ranged from £269 to £376 per year between the services; the costs of introducing similar services across different local populations are likely to vary depending on available resources, prevalence of drug dependence and population size.

In conclusion, the evidence identified for this review is too limited to make conclusions in terms of effectiveness of UK current practice examples, though key features that were common to the existing UK services included in this review were a degree of GP/primary care involvement and the combination of a helpline service with further support in the form of counselling sessions and/or support groups, and a focus on individualised support plans. The limited number of reports of services, and detail on those services, coupled with the limited availability of published reports or evaluations, demonstrates a need for developers and users of services to evaluate them and publish their findings. Increased publication of service evaluations would help inform most effective configurations and consequently future provision of services.

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References

Appendices 7 Appendices Appendix A: Review protocols

Table 3: Review protocol: Examples of services (PROSPERO Registration: CRD42018111357) What are the current existing examples of services providing withdrawal support and what is the effectiveness and cost-effectiveness of the health/social service delivery models that prevent or treat dependence and the short term discontinuation or longer term withdrawal symptoms from the following prescribed medicines: opioids for chronic pain (excluding end of life /palliative care/cancer pain), benzodiazepines, Z-drugs, gabapentin and pregabalin (excluding epilepsy treatment), and antidepressants? (In England, as well as health service delivery models in other countries that might inform Review question provision in England). Objectives To identify, and evaluate the effectiveness and cost effectiveness of existing examples of English health / social service delivery models, and those from other countries that might inform provision in England, for prevention and treatment of dependence, discontinuation and withdrawal symptoms. Review population Adults using prescription medicines associated with dependence and withdrawal (opioids for chronic pain (excluding end of life /palliative care/cancer pain), benzodiazepines, Z-drugs, gabapentin and pregabalin (excluding epilepsy treatment), and antidepressants). Staff delivering services. Major age categories e.g. Adults ≥ 18 years adults Interventions and Health / social service delivery models that prevent or treat dependence and comparators: the short term discontinuation or longer term withdrawal symptoms from generic/class; prescribed medicines e.g. specific/drug Dedicated services Dedicated sessions ‘Addiction’ specialist services Primary care support Specialist services within or in liaison with primary care/shared care model Online support services.

Compared to each other or usual care (as defined by studies). Non-comparative evidence will be considered if no comparative evidence is available. Outcomes Primary outcomes Reduction/cessation in prescribed drug use Successful withdrawal Cost effectiveness Use of healthcare resources Health related quality of life Patient / staff satisfaction Social outcomes e.g. employment, relationships, parenting Reduction in disability Study design Systematic review RCT – including cluster randomised Observational studies including non-randomised studies

Appendices

What are the current existing examples of services providing withdrawal support and what is the effectiveness and cost-effectiveness of the health/social service delivery models that prevent or treat dependence and the short term discontinuation or longer term withdrawal symptoms from the following prescribed medicines: opioids for chronic pain (excluding end of life /palliative care/cancer pain), benzodiazepines, Z-drugs, gabapentin and pregabalin (excluding epilepsy treatment), and antidepressants? (In England, as well as health service delivery models in other countries that might inform Review question provision in England). Grey literature / policy reports.

If a high quality systematic review is identified that matches the protocol, analysis will be incorporated, otherwise relevant systematic reviews will be used for citation searching. Unit of randomisation Service Other exclusions Non-NHS prescribed medicines Medicines prescribed for end of life / palliative care / cancer pain. Over-the-counter medicines. Medicines dispensed/prescribed in prisons. Gabapentinoids prescribed for epilepsy. Antipsychotic and stimulant medicines. Medicines to treat drug misuse disorders.

The views, experiences and opinions of individual professionals, researchers, commentators or patients. Review strategy If a high quality systematic review is identified that matches the protocol, analysis will be incorporated, otherwise relevant systematic reviews will be used for citation searching.

Call for evidence: A call for evidence will be conducted alongside the systematic review. Reports which summarise / collate individual experiences will be considered here e.g. organisational reports or internal evaluations of projects or services).

Appendices Appendix B: Study selection

Figure 1: Flow chart of study selection for the literature search

Records identified through database Additional records identified through searching, n=39087 other sources, n=249

Records screened, n=39336

Records excluded, n=38269 (113 requested but unobtainable) Full-text papers assessed for eligibility, n=1067

Papers included in review Papers excluded from full text sift, • Harms n=30 n=990 • Risk factors n=17 • Interventions n=28 Reasons for exclusion: see appendix G • Patients’ experience n=2 (10 additional identified from call for evidence, leading to 12 total) • Current practice n=0 (3 included identified from call for evidence, 1 from grey literature, leading to 4 total)

NB. One search was carried out to cover all 5 questions, therefore the PRISMA flowchart covers all 5. The final box of included studies details the number relevant to each question.

Appendices

Figure 2: Flow chart of study selection for the grey literature search

Records submitted via call for evidence, n=651

Records excluded, n=648 (Personal communications)

Full-text papers assessed for eligibility, n=3

Papers included in review Papers excluded from full text sift, n=2 • Patients’ experience n=0 (10 additional identified from Reasons for exclusion: see appendix G call for evidence, leading to 12 total) • Current practice n=1 (3 included identified from call for evidence, leading to 4 total)

Appendices

Figure 3: Flow chart of study selection for the call for evidence

Records submitted via call for evidence, n=125

Records excluded, n=5 (Personal communications)

Full-text papers assessed for eligibility, n=120

Papers included in review Papers excluded from full text sift, • Patients’ experience n=10 n=106 (2 additional paper from literature searches leading to Reasons for exclusion: see appendix G a total of 12) • Current practice n=3 (1 from grey literature, leading to 4 total)

Submissions that were relevant for the questions on harms, risk factors or interventions, are included in the ‘additional records identified through other sources’ in the diagram for the literature search and therefore appear in the excluded records section for the call for evidence.

Appendices Appendix C: Search strategies

Systematic literature search:

The literature searches for these reviews are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual 2014, updated 2017 https://www.nice.org.uk/guidance/pmg20/resources/developing-nice-guidelines-the-manual-pdf- 72286708700869;

1. What are the harms associated with dependence, and the short term discontinuation and longer term withdrawal symptoms from the following prescribed medicines: opioids for chronic pain (excluding end of life /palliative care/cancer pain), benzodiazepines, Z-drugs, gabapentin and pregabalin (excluding epilepsy treatment), and antidepressants? 2. What are the factors that contribute to the risk of harms associated with dependence and the short term discontinuation or longer term withdrawal symptoms from the following prescribed medicines: opioids for chronic pain (excluding end of life /palliative care/cancer pain), benzodiazepines, Z-drugs, gabapentin and pregabalin (excluding epilepsy treatment), and antidepressants? 3. What are the most effective and cost effective approaches to the prevention and treatment of dependence and the short term discontinuation or longer term withdrawal symptoms from the following prescribed medicines: opioids for chronic pain (excluding end of life /palliative care/cancer pain), benzodiazepines, Z-drugs, gabapentin and pregabalin (excluding epilepsy treatment), and antidepressants? 4. What is the current evidence about patients’ own experiences of the harms caused by prescribed medicines specifically relating to dependence and the short term discontinuation or longer term withdrawal symptoms from the following prescribed medicines: opioids for chronic pain (excluding end of life /palliative care/cancer pain), benzodiazepines, Z-drugs, gabapentin and pregabalin (excluding epilepsy treatment), and antidepressants and experiences of accessing and engaging in treatment? 5. What are the current existing examples of services providing withdrawal support and what is the effectiveness and cost-effectiveness of the health/social service delivery models that prevent or treat dependence and the short term discontinuation or longer term withdrawal symptoms from the following prescribed medicines: opioids for chronic pain (excluding end of life/palliative care/cancer pain), benzodiazepines, Z-drugs, gabapentin and pregabalin (excluding epilepsy treatment), and antidepressants? (In England, as well as health service delivery models in other countries that might inform provision in England).

For more detailed information, please see the Methodology Review.

Appendices

C.1 Databases date parameters and filters used

C.1.1 Step 1: Existing systematic reviews

Database Dates searched Search filter used Cochrane Database of Systematic All years to Issue 9 of 12, None Reviews (The Cochrane Library - September 2018 Wiley)

Epistemonikos All years to 24 September 2018 Systematic review studies

Database of promoting health All years to 19 September 2018 None effectiveness reviews (DoPHER)

HealthEvidence All years to 19 September 2018 None

Cochrane Library (Wiley) search terms #1. MeSH descriptor: [Substance-Related Disorders] explode all trees #2. MeSH descriptor: [Substance Withdrawal Syndrome] explode all trees #3. MeSH descriptor: [Inappropriate Prescribing] explode all trees #4. MeSH descriptor: [Medical Overuse] explode all trees #5. MeSH descriptor: [Deprescriptions] explode all trees #6. (abstinen* or abstain* or cessat* or detox* or discontinu* or reduc* or stop* or taper* or withdraw* or substitut* or depend* or addict* or abuse* or abusing or chronic or long* term or longterm or short* term or short term or misus* or overus* or deprescrib*):ti,ab #7. (over* near/3 use* or using or utlisat* or utilizat*) near/3 (prescription* or prescrib* or drug* or medicine* or medication* or pharm*):ti,ab #8. inappropriate near/3 (prescription or prescrib*):ti,ab #9. (OR #1-#8) #10. MeSH descriptor: [Narcotics] explode all trees #11. MeSH descriptor: [Analgesics, Opioid] explode all trees #12. (analgesic* near/3 opioid* or narcotic near/3 agent*):ti,ab #13. MeSH descriptor: [Buprenorphine] explode all trees #14. MeSH descriptor: [Codeine] explode all trees #15. MeSH descriptor: [Dextromoramide] explode all trees #16. MeSH descriptor: [Heroin] explode all trees #17. MeSH descriptor: [Fentanyl] explode all trees #18. MeSH descriptor: [Hydromorphone] explode all trees #19. MeSH descriptor: [Meptazinol] explode all trees #20. MeSH descriptor: [Methadone] explode all trees #21. MeSH descriptor: [Morphine] explode all trees #22. MeSH descriptor: [Oxycodone] explode all trees

Appendices

#23. MeSH descriptor: [Opium] explode all trees #24. MeSH descriptor: [Pentazocine] explode all trees #25. MeSH descriptor: [Meperidine] explode all trees #26. MeSH descriptor: [Tramadol] explode all trees #27. (buprenorphine* or codeine* or dextromoramide* or diamorphine* or dihydrocodeine* or dipipanone* or fentanyl or hydromorphone* or meptazinol or methadone* or morphine* or oxycodone or papaveretum or pentazocine or pethidine or tapentadol or tramadol or heroin):ti,ab #28. (z drug* or z hypnotic* or non-benzodiazepin* or nonbenzodiazepin* or zaleplon or zopiclone or zolpidem):ti,ab #29. (generation near/3 hypnotic*):ti,ab #30. MeSH descriptor: [Benzodiazepines] explode all trees #31. (benzodiazepin* or bzd or flurazepam or loprazolam or lormetazepam or nitrazepam or temazepam or diazepam or chlordiazepoxide or lorazepam or oxazepam):ti,ab #32. MeSH descriptor: [Pregabalin] explode all trees #33. (gabapentin* or pregabalin*):ti,ab #34. MeSH descriptor: [Antidepressive Agents] explode all trees #35. (antidepress* or anti depress* or thymoanaleptic* or thymoleptic* or MAOI* or "monoamine oxidase inhibit*" or RIMA* or tricyclic* or SSRI* or SNRI* or SNORI*):ti,ab #36. MeSH descriptor: [Amitriptyline] explode all trees #37. MeSH descriptor: [Amoxapine] explode all trees #38. MeSH descriptor: [Clomipramine] explode all trees #39. MeSH descriptor: [Dothiepin] explode all trees #40. MeSH descriptor: [Doxepin] explode all trees #41. MeSH descriptor: [Imipramine] explode all trees #42. MeSH descriptor: [Lofepramine] explode all trees #43. MeSH descriptor: [Maprotiline] explode all trees #44. MeSH descriptor: [Mianserin] explode all trees #45. MeSH descriptor: [Nortriptyline] explode all trees #46. MeSH descriptor: [Protriptyline] explode all trees #47. MeSH descriptor: [Trazodone] explode all trees #48. MeSH descriptor: [Trimipramine] explode all trees #49. MeSH descriptor: [Isocarboxazid] explode all trees #50. MeSH descriptor: [Moclobemide] explode all trees #51. MeSH descriptor: [Phenelzine] explode all trees #52. MeSH descriptor: [Tranylcypromine] explode all trees #53. MeSH descriptor: [Citalopram] explode all trees #54. MeSH descriptor: [Fluoxetine] explode all trees #55. MeSH descriptor: [Fluvoxamine] explode all trees #56. MeSH descriptor: [Paroxetine] explode all trees #57. MeSH descriptor: [Sertraline] explode all trees #58. MeSH descriptor: [5-Hydroxytryptophan] explode all trees #59. MeSH descriptor: [Duloxetine Hydrochloride] explode all trees #60. MeSH descriptor: [Flupenthixol] explode all trees #61. MeSH descriptor: [Tryptophan] explode all trees #62. MeSH descriptor: [Venlafaxine Hydrochloride] explode all trees

Appendices

#63. (amitriptyline or amoxapine or clomipramine or dosulepin or doxepin or imipramine or lofepramine or maprotiline or mianserin or nortriptyline or protriptyline or trazodone or trimipramine or isocarboxazid or moclobemide or phenelzine or tranylcypromine or citalopram or escitalopram or fluoxetine or fluvoxamine or paroxetine or sertraline or agomelatine or duloxetine or flupentixol or mirtazapine or nefazodone or oxitriptan or reboxetine or tryptophan or venlafaxine or vortioxetine):ti,ab #64. (OR #10-#63) #65. #9 and #64

Epistemonikos search terms 1. "substance-related disorders" OR "substance withdrawal syndrome" OR "inappropriate prescribing" OR "medical overuse" OR "deprescriptions" OR "abstinen*" or "abstain*" or "cessat*" or "detox*" or "discontinu*" or "reduc*" or "stop*" or "taper*" or "withdraw*" or "substitut*" or "depend*" or "addict*" or "abuse*" or "abusing" or "chronic" or "long* term" or "longterm" or "short* term" or "short term" or "misus*" or "overus*" OR "deprescrib*" OR "inappropriate prescription" 2. "buprenorphine*" or "codeine*" or "dextromoramide*" or "diamorphine*" or "dihydrocodeine*" or "dipipanone*" or "fentanyl" or "hydromorphone*" or "meptazinol" or "methadone*" or "morphine*" or "oxycodone" or "papaveretum" or "pentazocine" or "pethidine" or "tapentadol" or "tramadol" or "heroin" OR "z drug*" or "z hypnotic*" or "nonbenzodiazepin*" or "nonbenzodiazepin*" or "zaleplon" or "zopiclone" or "zolpidem" OR "generation hypnotic" OR "benzodiazepin*" or "bzd" or "flurazepam" or "loprazolam" or "lormetazepam" or "nitrazepam" or "temazepam" or "diazepam" or "chlordiazepoxide" or "lorazepam" or "oxazepam" OR "gabapentin*" or "pregabalin*" OR "antidepress*" or "anti depress*" or "thymoanaleptic*" or "thymoleptic*" or "MAOI*" or "monoamine oxidase inhibit*" or "RIMA*" or "tricyclic*" or "SSRI*" or "SNRI*" or "SNORI*" OR "amitriptyline" or "amoxapine" or "clomipramine" or "dosulepin" or "doxepin" or "imipramine" or "lofepramine" or "maprotiline" or "mianserin" or "nortriptyline" or "protriptyline" or "trazodone" or "trimipramine" or "isocarboxazid" or "moclobemide" or "phenelzine" or "tranylcypromine" or "citalopram" or "escitalopram" or "fluoxetine" or "fluvoxamine" or "paroxetine" or "sertraline" or "agomelatine" or "duloxetine" or "flupentixol" or "mirtazapine" or "nefazodone" or "oxitriptan" or "reboxetine" or "tryptophan" or "venlafaxine" or "vortioxetine" 3. (title:("substance-related disorders" OR "substance withdrawal syndrome" OR "inappropriate prescribing" OR "medical overuse" OR "deprescriptions" OR "abstinen*" OR "abstain*" OR "cessat*" OR "detox*" OR "discontinu*" OR "reduc*" OR "stop*" OR "taper*" OR "withdraw*" OR "substitut*" OR "depend*" OR "addict*" OR "abuse*" OR "abusing" OR "chronic" OR "long* term" OR "longterm" OR "short* term" OR "short term" OR "misus*" OR "overus*" OR "deprescrib*" OR "inappropriate prescription") OR abstract:("substance-related disorders" OR "substance withdrawal syndrome" OR "inappropriate prescribing" OR "medical overuse" OR "deprescriptions" OR "abstinen*" OR "abstain*" OR "cessat*" OR "detox*" OR "discontinu*" OR "reduc*" OR "stop*" OR "taper*" OR "withdraw*" OR "substitut*" OR "depend*" OR "addict*" OR "abuse*" OR "abusing" OR "chronic" OR "long* term" OR "longterm" OR "short* term" OR "short term" OR "misus*" OR "overus*" OR "deprescrib*" OR "inappropriate prescription")) AND (title:("buprenorphine*" OR "codeine*" OR "dextromoramide*" OR "diamorphine*" OR "dihydrocodeine*" OR "dipipanone*" OR "fentanyl" OR "hydromorphone*" OR "meptazinol" OR "methadone*" OR "morphine*" OR "oxycodone" OR "papaveretum" OR "pentazocine" OR "pethidine" OR "tapentadol" OR "tramadol" OR "heroin" OR "z drug*" OR "z hypnotic*" OR "non-benzodiazepin*" OR "nonbenzodiazepin*" OR "zaleplon" OR "zopiclone" OR "zolpidem" OR "generation hypnotic" OR "benzodiazepin*" OR "bzd" OR "flurazepam" OR "loprazolam" OR "lormetazepam" OR "nitrazepam" OR "temazepam" OR "diazepam" OR "chlordiazepoxide" OR "lorazepam" OR "oxazepam" OR "gabapentin*" OR "pregabalin*" OR "antidepress*" OR "anti depress*" OR "thymoanaleptic*" OR "thymoleptic*" OR "MAOI*" OR "monoamine oxidase inhibit*" OR "RIMA*" OR "tricyclic*" OR "SSRI*" OR "SNRI*" OR "SNORI*" OR "amitriptyline" OR "amoxapine" OR "clomipramine" OR "dosulepin" OR "doxepin" OR "imipramine" OR "lofepramine" OR "maprotiline" OR

Appendices

"mianserin" OR "nortriptyline" OR "protriptyline" OR "trazodone" OR "trimipramine" OR "isocarboxazid" OR "moclobemide" OR "phenelzine" OR "tranylcypromine" OR "citalopram" OR "escitalopram" OR "fluoxetine" OR "fluvoxamine" OR "paroxetine" OR "sertraline" OR "agomelatine" OR "duloxetine" OR "flupentixol" OR "mirtazapine" OR "nefazodone" OR "oxitriptan" OR "reboxetine" OR "tryptophan" OR "venlafaxine" OR "vortioxetine") OR abstract:("buprenorphine*" OR "codeine*" OR "dextromoramide*" OR "diamorphine*" OR "dihydrocodeine*" OR "dipipanone*" OR "fentanyl" OR "hydromorphone*" OR "meptazinol" OR "methadone*" OR "morphine*" OR "oxycodone" OR "papaveretum" OR "pentazocine" OR "pethidine" OR "tapentadol" OR "tramadol" OR "heroin" OR "z drug*" OR "z hypnotic*" OR "non-benzodiazepin*" OR "nonbenzodiazepin*" OR "zaleplon" OR "zopiclone" OR "zolpidem" OR "generation hypnotic" OR "benzodiazepin*" OR "bzd" OR "flurazepam" OR "loprazolam" OR "lormetazepam" OR "nitrazepam" OR "temazepam" OR "diazepam" OR "chlordiazepoxide" OR "lorazepam" OR "oxazepam" OR "gabapentin*" OR "pregabalin*" OR "antidepress*" OR "anti depress*" OR "thymoanaleptic*" OR "thymoleptic*" OR "MAOI*" OR "monoamine oxidase inhibit*" OR "RIMA*" OR "tricyclic*" OR "SSRI*" OR "SNRI*" OR "SNORI*" OR "amitriptyline" OR "amoxapine" OR "clomipramine" OR "dosulepin" OR "doxepin" OR "imipramine" OR "lofepramine" OR "maprotiline" OR "mianserin" OR "nortriptyline" OR "protriptyline" OR "trazodone" OR "trimipramine" OR "isocarboxazid" OR "moclobemide" OR "phenelzine" OR "tranylcypromine" OR "citalopram" OR "escitalopram" OR "fluoxetine" OR "fluvoxamine" OR "paroxetine" OR "sertraline" OR "agomelatine" OR "duloxetine" OR "flupentixol" OR "mirtazapine" OR "nefazodone" OR "oxitriptan" OR "reboxetine" OR "tryptophan" OR "venlafaxine" OR "vortioxetine")) 4. Limit 3 to systematic reviews

Database of promoting health effectiveness reviews (DoPHER) search terms 1. Freetext (All but Authors): "substance-related disorders" OR "substance withdrawal syndrome" OR "inappropriate prescribing" OR "medical overuse" OR "deprescriptions" OR "abstinen*" or "abstain*" or "cessat*" or "detox*" or "discontinu*" or "reduc*" or "stop*" or "taper*" or "withdraw*" or "substitut*" or "depend*" or "addict*" or "abuse*" or "abusing" or "chronic" or "long* term" or "longterm" or "short* term" or "short term" or "misus*" or "overus*" OR "deprescrib*" 2. Freetext (All but Authors): "over*" near "use*" near "prescri*" 3. Freetext (All but Authors):"inappropriate" near "prescri*" 4. 1 or 2 or 3 5. Freetext (All but Authors): "buprenorphine*" or "codeine*" or "dextromoramide*" or "diamorphine*" or "dihydrocodeine*" or "dipipanone*" or "fentanyl" or "hydromorphone*" or "meptazinol" or "methadone*" or "morphine*" or "oxycodone" or "papaveretum" or "pentazocine" or "pethidine" or "tapentadol" or "tramadol" or "heroin" 6. Freetext (All but Authors): "z drug*" or "z hypnotic*" or "non-benzodiazepin*" or "nonbenzodiazepin*" or "zaleplon" or "zopiclone" or "zolpidem" 7. Freetext (All but Authors): "generation" near "hypnotic" 8. Freetext (All but Authors): "benzodiazepin*" or "bzd" or "flurazepam" or "loprazolam" or "lormetazepam" or "nitrazepam" or "temazepam" or "diazepam" or "chlordiazepoxide" or "lorazepam" or "oxazepam" 9. Freetext (All but Authors): "gabapentin*" or "pregabalin*" 10. Freetext (All but Authors): "antidepress*" or "anti depress*" or "thymoanaleptic*" or "thymoleptic*" or "MAOI*" or "monoamine oxidase inhibit*" or "RIMA*" or "tricyclic*" or "SSRI*" or "SNRI*" or "SNORI*" 11. Freetext (All but Authors): "amitriptyline" or "amoxapine" or "clomipramine" or "dosulepin" or "doxepin" or "imipramine" or "lofepramine" or "maprotiline" or "mianserin" or "nortriptyline" or "protriptyline" or "trazodone" or "trimipramine" or "isocarboxazid" or "moclobemide" or "phenelzine" or "tranylcypromine" or "citalopram" or "escitalopram" or "fluoxetine" or

Appendices

"fluvoxamine" or "paroxetine" or "sertraline" or "agomelatine" or "duloxetine" or "flupentixol" or "mirtazapine" or "nefazodone" or "oxitriptan" or "reboxetine" or "tryptophan" or "venlafaxine" or "vortioxetine" 12. 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 13. 4 AND 12

HealthEvidence search terms 1. [((substance-related disorders or substance withdrawal syndrome or inappropriate prescribing OR medical overuse OR deprescriptions or abstinen* or abstain* or cessat* or detox* or discontinu* or reduc* or stop* or taper* or withdraw* or substitut* or depend* or addict* or abuse* or abusing or chronic or long* term or longterm or short* term or short term or misus* or overus* or deprescrib*)) AND ((narcotics or analgesics or buprenorphine* or codeine* or dextromoramide* or diamorphine* or dihydrocodeine* or dipipanone* or fentanyl or hydromorphone* or meptazinol or methadone* or morphine* or oxycodone or papaveretum or pentazocine or pethidine or tapentadol or tramadol or heroin or z drug* or z hypnotic* or non-benzodiazepin* or nonbenzodiazepin* or zaleplon or zopiclone or zolpidem or benzodiazepin* or bzd or flurazepam or loprazolam or lormetazepam or nitrazepam or temazepam or diazepam or chlordiazepoxide or lorazepam or oxazepam or gabapentin* or pregabalin* or antidepress* or anti depress* or thymoanaleptic* or thymoleptic* or MAOI* or "monoamine oxidase inhibit*" or RIMA* or tricyclic* or SSRI* or SNRI* or SNORI*or amitriptyline or amoxapine or clomipramine or dosulepin or doxepin or imipramine or lofepramine or maprotiline or mianserin or nortriptyline or protriptyline or trazodone or trimipramine or isocarboxazid or moclobemide or phenelzine or tranylcypromine or citalopram or escitalopram or fluoxetine or fluvoxamine or paroxetine or sertraline or agomelatine or duloxetine or flupentixol or mirtazapine or nefazodone or oxitriptan or reboxetine or tryptophan or venlafaxine or vortioxetine))]

C.1.2 Step 2: Recent evidence

Database Dates searched Search filter used Medline (OVID) 1st January 2008 – 3 October 2018 Exclusions Randomised controlled trials Systematic review studies

Embase (OVID) 1st January 2008 – 3 October 2018 Exclusions Randomised controlled trials Systematic review studies

Cochrane Central Register of 1st January 2008 to Issue 8 of 12, None Controlled Trials (CENTRAL) (The August 2018 Cochrane Library -Wiley)

PsycINFO (ProQuest) 1st January 2008 – 3 October 2018 Exclusions Randomised controlled trials Systematic review studies

Health Technology Appraisals 1st January 2008 – 3 October 2018 None

Appendices

Database Dates searched Search filter used (Centre for Reviews and Dissemination) Trials Register of Promoting All years to 3 October 2018 None Health Interventions (TRoPHI)

ASSIA (Proquest) 1st January 2008 – 3 October 2018 None

Medline (Ovid) search terms 1. exp substance-related disorders/ 2. exp substance withdrawal syndrome/ 3. exp inappropriate prescribing/ 4. exp medical overuse/ 5. exp deprescriptions/ 6. (abstinen* or abstain* or cessat* or detox* or discontinu* or reduc* or stop* or taper* or withdraw* or substitut* or depend* or addict* or abuse* or abusing or chronic or long* term or longterm or short* term or short term or misus* or overus* or deprescrib*).ti,ab. 7. (over* adj3 (use* or using or utlisat* or utilizat*) adj3 (prescription* or prescrib* or drug* or medicine* or medication* or pharm*)).ti,ab. 8. (inappropriate adj3 (prescription or prescrib*)).ti,ab. 9. or/1-8 10. letter/ 11. editorial/ 12. news/ 13. exp historical article/ 14. anecdotes as topic/ 15. comment/ 16. case report/ 17. (letter or comment*).ti. 18. or/10-17 19. randomized controlled trial/ or random*.ti,ab. 20. 18 not 19 21. animals/ not humans/ 22. exp animals, laboratory/ 23. exp animal experimentation/ 24. exp models, animal/ 25. exp rodentia/ 26. (rat or rats or mouse or mice).ti. 27. or/20-26 28. 9 not 27 29. limit 28 to English language 30. exp narcotics/ 31. exp analgesics, opioid/ 32. (analgesic* adj3 (opioid* or narcotic) adj3 agent*).ti,ab.

Appendices

33. exp buprenorphine/ 34. exp codeine/ 35. exp dextromoramide/ 36. exp heroin/ 37. exp fentanyl/ 38. exp hydromorphone/ 39. exp meptazinol/ 40. exp methadone/ 41. exp morphine/ 42. exp oxycodone/ 43. exp opium/ 44. exp pentazocine/ 45. exp meperidine/ 46. exp tramadol/ 47. (buprenorphine* or codeine* or dextromoramide* or diamorphine* or dihydrocodeine* or dipipanone* or fentanyl or hydromorphone* or meptazinol or methadone* or morphine* or oxycodone or papaveretum or pentazocine or pethidine or tapentadol or tramadol or heroin).ti,ab. 48. (z drug* or z hypnotic* or non-benzodiazepin* or nonbenzodiazepin* or zaleplon or zopiclone or zolpidem).ti,ab. 49. (generation adj3 hypnotic*).ti,ab. 50. exp benzodiazepines/ 51. (benzodiazepin* or bzd or flurazepam or loprazolam or lormetazepam or nitrazepam or temazepam or diazepam or chlordiazepoxide or lorazepam or oxazepam).ti,ab. 52. exp pregabalin/ 53. (gabapentin* or pregabalin*).ti,ab. 54. exp antidepressive agents/ 55. (antidepress* or anti depress* or thymoanaleptic* or thymoleptic* or maoi* or "monoamine oxidase inhibit*" or rima* or tricyclic* or ssri* or snri* or snori*).ti,ab. 56. exp amitriptyline/ 57. exp amoxapine/ 58. exp clomipramine/ 59. exp dothiepin/ 60. exp doxepin/ 61. exp imipramine/ 62. exp lofepramine/ 63. exp maprotiline/ 64. exp mianserin/ 65. exp nortriptyline/ 66. exp protriptyline/ 67. exp trazodone/ 68. exp trimipramine/ 69. exp isocarboxazid/ 70. exp moclobemide/ 71. exp phenelzine/ 72. exp tranylcypromine/

Appendices

73. exp citalopram/ 74. exp fluoxetine/ 75. exp fluvoxamine/ 76. exp paroxetine/ 77. exp sertraline/ 78. exp 5-hydroxytryptophan/ 79. exp duloxetine hydrochloride/ 80. exp flupenthixol/ 81. exp tryptophan/ 82. exp venlafaxine hydrochloride/ 83. (amitriptyline or amoxapine or clomipramine or dosulepin or doxepin or imipramine or lofepramine or maprotiline or mianserin or nortriptyline or protriptyline or trazodone or trimipramine or isocarboxazid or moclobemide or phenelzine or tranylcypromine or citalopram or escitalopram or fluoxetine or fluvoxamine or paroxetine or sertraline or agomelatine or duloxetine or flupentixol or mirtazapine or nefazodone or oxitriptan or reboxetine or tryptophan or venlafaxine or vortioxetine).ti,ab. 84. or/30-83 85. 29 and 84 86. randomized controlled trial.pt. 87. controlled clinical trial.pt. 88. randomi#ed.ab. 89. placebo.ab. 90. randomly.ab. 91. clinical trials as topic.sh. 92. trial.ti. 93. or/86-92 94. meta-analysis/ 95. meta-analysis as topic/ 96. (meta analy* or metanaly* or metaanaly* or meta regression).ti,ab. 97. ((systematic* or evidence*) adj2 (review* or overview*)).ti,ab. 98. (reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab. 99. (search strategy or search criteria or systematic search or study selection or data extraction).ab. 100. (search* adj4 literature).ab. 101. (medline or pubmed or cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinahl or science citation index or bids or cancerlit).ab. 102. cochrane.jw. 103. ((multiple treatment* or indirect or mixed) adj2 comparison*).ti,ab. 104. or/94-103 105. 85 and (93 or 104)

Embase (Ovid) search terms 1. *drug dependence/ 2. *withdrawal syndrome/ or *alcohol withdrawal syndrome/ or *neonatal abstinence syndrome/ 3. *inappropriate prescribing/

Appendices

4. *deprescription/ 5. (abstinen* or abstain* or cessat* or detox* or discontinu* or reduc* or stop* or taper* or withdraw* or substitut* or depend* or addict* or abuse* or abusing or chronic or long* term or longterm or short* term or short term or misus* or overus* or deprescrib*).ti,ab. 6. (over* adj3 (use* or using or utlisat* or utilizat*) adj3 (prescription* or prescrib* or drug* or medicine* or medication* or pharm*)).ti,ab. 7. (inappropriate adj3 (prescription or prescrib*)).ti,ab. 8. or/1-7 9. letter.pt. or letter/ 10. note.pt. 11. editorial.pt. 12. case report/ or case study/ 13. (letter or comment*).ti. 14. or/9-13 15. randomized controlled trial/ or random*.ti,ab. 16. 14 not 15 17. animal/ not human/ 18. nonhuman/ 19. exp Animal Experiment/ 20. exp Experimental Animal/ 21. animal model/ 22. exp Rodent/ 23. (rat or rats or mouse or mice).ti. 24. or/16-23 25. 8 not 24 26. limit 25 to English language 27. *narcotic agent/ 28. *narcotic analgesic agent/ 29. (analgesic* adj3 (opioid* or narcotic) adj3 agent*).ti,ab. 30. *buprenorphine/ 31. *codeine/ 32. *dextromoramide/ 33. *diamorphine/ 34. *fentanyl/ 35. *hydromorphone/ 36. *meptazinol/ 37. *methadone/ 38. *morphine/ 39. *oxycodone/ 40. *opiate/ 41. *pentazocine/ 42. *pethidine/ 43. *tramadol/ 44. (buprenorphine* or codeine* or dextromoramide* or diamorphine* or dihydrocodeine* or dipipanone* or fentanyl or hydromorphone* or meptazinol or methadone* or morphine* or oxycodone or papaveretum or pentazocine or pethidine or tapentadol or tramadol or

Appendices

heroin).ti,ab. 45. (z drug* or z hypnotic* or non-benzodiazepin* or nonbenzodiazepin* or zaleplon or zopiclone or zolpidem).ti,ab. 46. (generation adj3 hypnotic*).ti,ab. 47. *benzodiazepine derivative/ 48. (benzodiazepin* or bzd or flurazepam or loprazolam or lormetazepam or nitrazepam or temazepam or diazepam or chlordiazepoxide or lorazepam or oxazepam).ti,ab. 49. *pregabalin/ 50. (gabapentin* or pregabalin*).ti,ab. 51. *antidepressant agent/ 52. (antidepress* or anti depress* or thymoanaleptic* or thymoleptic* or MAOI* or "monoamine oxidase inhibit*" or RIMA* or tricyclic* or SSRI* or SNRI* or SNORI*).ti,ab. 53. *amitriptyline/ 54. *amoxapine/ 55. *clomipramine/ 56. *dosulepin/ 57. *doxepin/ 58. *imipramine/ 59. *lofepramine/ 60. *maprotiline/ 61. *mianserin/ 62. *nortriptyline/ 63. *protriptyline/ 64. *trazodone/ 65. *trimipramine/ 66. *isocarboxazid/ 67. *moclobemide/ 68. *phenelzine/ 69. *tranylcypromine/ 70. *citalopram/ 71. *fluoxetine/ 72. *fluvoxamine/ 73. *paroxetine/ 74. *sertraline/ 75. *5 hydroxytryptophan/ 76. *duloxetine/ 77. *flupentixol/ 78. *tryptophan/ 79. *venlafaxine/ 80. (amitriptyline or amoxapine or clomipramine or dosulepin or doxepin or imipramine or lofepramine or maprotiline or mianserin or nortriptyline or protriptyline or trazodone or trimipramine or isocarboxazid or moclobemide or phenelzine or tranylcypromine or citalopram or escitalopram or fluoxetine or fluvoxamine or paroxetine or sertraline or agomelatine or duloxetine or flupentixol or mirtazapine or nefazodone or oxitriptan or reboxetine or tryptophan or venlafaxine or vortioxetine).ti,ab. 81. or/27-80 82. 26 and 81

Appendices

83. random*.ti,ab. 84. factorial*.ti,ab. 85. (crossover* or cross over*).ti,ab. 86. ((doubl* or singl*) adj blind*).ti,ab. 87. (assign* or allocat* or volunteer* or placebo*).ti,ab. 88. crossover procedure/ 89. single blind procedure/ 90. randomized controlled trial/ 91. double blind procedure/ 92. or/83-91 93. systematic review/ 94. Meta-Analysis/ 95. (meta analy* or metanaly* or metaanaly* or meta regression).ti,ab. 96. ((systematic* or evidence*) adj2 (review* or overview*)).ti,ab. 97. (reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab. 98. (search strategy or search criteria or systematic search or study selection or data extraction).ab. 99. (search* adj4 literature).ab. 100. (medline or pubmed or cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinahl or science citation index or bids or cancerlit).ab. 101. cochrane.jw. 102. ((multiple treatment* or indirect or mixed) adj2 comparison*).ti,ab. 103. or/93-102 104. 82 and (92 or 103)

Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library -Wiley) search terms #1. MeSH descriptor: [Substance-Related Disorders] explode all trees #2. MeSH descriptor: [Substance Withdrawal Syndrome] explode all trees #3. MeSH descriptor: [Inappropriate Prescribing] explode all trees #4. MeSH descriptor: [Medical Overuse] explode all trees #5. MeSH descriptor: [Deprescriptions] explode all trees #6. (abstinen* or abstain* or cessat* or detox* or discontinu* or reduc* or stop* or taper* or withdraw* or substitut* or depend* or addict* or abuse* or abusing or chronic or long* term or longterm or short* term or short term or misus* or overus* or deprescrib*):ti,ab #7. (over* near/3 use* or using or utlisat* or utilizat*) near/3 (prescription* or prescrib* or drug* or medicine* or medication* or pharm*):ti,ab #8. inappropriate near/3 (prescription or prescrib*):ti,ab #9. (OR #1-#8) #10. MeSH descriptor: [Narcotics] explode all trees #11. MeSH descriptor: [Analgesics, Opioid] explode all trees #12. (analgesic* near/3 opioid* or narcotic near/3 agent*):ti,ab #13. MeSH descriptor: [Buprenorphine] explode all trees #14. MeSH descriptor: [Codeine] explode all trees #15. MeSH descriptor: [Dextromoramide] explode all trees #16. MeSH descriptor: [Heroin] explode all trees

Appendices

#17. MeSH descriptor: [Fentanyl] explode all trees #18. MeSH descriptor: [Hydromorphone] explode all trees #19. MeSH descriptor: [Meptazinol] explode all trees #20. MeSH descriptor: [Methadone] explode all trees #21. MeSH descriptor: [Morphine] explode all trees #22. MeSH descriptor: [Oxycodone] explode all trees #23. MeSH descriptor: [Opium] explode all trees #24. MeSH descriptor: [Pentazocine] explode all trees #25. MeSH descriptor: [Meperidine] explode all trees #26. MeSH descriptor: [Tramadol] explode all trees #27. (buprenorphine* or codeine* or dextromoramide* or diamorphine* or dihydrocodeine* or dipipanone* or fentanyl or hydromorphone* or meptazinol or methadone* or morphine* or oxycodone or papaveretum or pentazocine or pethidine or tapentadol or tramadol or heroin):ti,ab #28. (z drug* or z hypnotic* or non-benzodiazepin* or nonbenzodiazepin* or zaleplon or zopiclone or zolpidem):ti,ab #29. (generation near/3 hypnotic*):ti,ab #30. MeSH descriptor: [Benzodiazepines] explode all trees #31. (benzodiazepin* or bzd or flurazepam or loprazolam or lormetazepam or nitrazepam or temazepam or diazepam or chlordiazepoxide or lorazepam or oxazepam):ti,ab #32. MeSH descriptor: [Pregabalin] explode all trees #33. (gabapentin* or pregabalin*):ti,ab #34. MeSH descriptor: [Antidepressive Agents] explode all trees #35. (antidepress* or anti depress* or thymoanaleptic* or thymoleptic* or MAOI* or "monoamine oxidase inhibit*" or RIMA* or tricyclic* or SSRI* or SNRI* or SNORI*):ti,ab #36. MeSH descriptor: [Amitriptyline] explode all trees #37. MeSH descriptor: [Amoxapine] explode all trees #38. MeSH descriptor: [Clomipramine] explode all trees #39. MeSH descriptor: [Dothiepin] explode all trees #40. MeSH descriptor: [Doxepin] explode all trees #41. MeSH descriptor: [Imipramine] explode all trees #42. MeSH descriptor: [Lofepramine] explode all trees #43. MeSH descriptor: [Maprotiline] explode all trees #44. MeSH descriptor: [Mianserin] explode all trees #45. MeSH descriptor: [Nortriptyline] explode all trees #46. MeSH descriptor: [Protriptyline] explode all trees #47. MeSH descriptor: [Trazodone] explode all trees #48. MeSH descriptor: [Trimipramine] explode all trees #49. MeSH descriptor: [Isocarboxazid] explode all trees #50. MeSH descriptor: [Moclobemide] explode all trees #51. MeSH descriptor: [Phenelzine] explode all trees #52. MeSH descriptor: [Tranylcypromine] explode all trees #53. MeSH descriptor: [Citalopram] explode all trees #54. MeSH descriptor: [Fluoxetine] explode all trees #55. MeSH descriptor: [Fluvoxamine] explode all trees #56. MeSH descriptor: [Paroxetine] explode all trees

Appendices

#57. MeSH descriptor: [Sertraline] explode all trees #58. MeSH descriptor: [5-Hydroxytryptophan] explode all trees #59. MeSH descriptor: [Duloxetine Hydrochloride] explode all trees #60. MeSH descriptor: [Flupenthixol] explode all trees #61. MeSH descriptor: [Tryptophan] explode all trees #62. MeSH descriptor: [Venlafaxine Hydrochloride] explode all trees #63. (amitriptyline or amoxapine or clomipramine or dosulepin or doxepin or imipramine or lofepramine or maprotiline or mianserin or nortriptyline or protriptyline or trazodone or trimipramine or isocarboxazid or moclobemide or phenelzine or tranylcypromine or citalopram or escitalopram or fluoxetine or fluvoxamine or paroxetine or sertraline or agomelatine or duloxetine or flupentixol or mirtazapine or nefazodone or oxitriptan or reboxetine or tryptophan or venlafaxine or vortioxetine):ti,ab #64. (OR #10-#63) #65. #9 and #64

PsycINFO (ProQuest) search terms 1. (((((MAINSUBJECT.EXACT("Drug Withdrawal") OR MAINSUBJECT.EXACT("Substance Use Disorder")) OR ti,ab(abstinen* OR abstain* OR cessat* OR detox* OR discontinu* OR reduc* OR stop* OR taper* OR withdraw* OR substitut* OR depend* OR addict* OR abuse* OR abusing OR chronic OR long* term OR longterm OR short* term OR short term OR misus* OR overus* OR deprescrib*) OR ti,ab(over* NEAR/3 (use* OR using OR utlisat* OR utilizat*) NEAR/3 (prescription* OR prescrib* OR drug* OR medicine* OR medication* OR pharm*)) OR ti,ab(inappropriate NEAR/3 (prescription OR prescrib*))) AND ((MAINSUBJECT.EXACT.EXPLODE("Analgesic Drugs") OR MAINSUBJECT.EXACT.EXPLODE("Narcotic Drugs")) OR ti,ab(analgesic* NEAR/3 (opioid* OR narcotic) NEAR/3 agent*) OR (MAINSUBJECT.EXACT.EXPLODE("Buprenorphine") OR MAINSUBJECT.EXACT.EXPLODE("Heroin") OR MAINSUBJECT.EXACT.EXPLODE("Methadone") OR MAINSUBJECT.EXACT.EXPLODE("Pentazocine") OR MAINSUBJECT.EXACT.EXPLODE("Morphine") OR MAINSUBJECT.EXACT.EXPLODE("Tramadol") OR MAINSUBJECT.EXACT.EXPLODE("Codeine") OR MAINSUBJECT.EXACT.EXPLODE("Fentanyl") OR MAINSUBJECT.EXACT.EXPLODE("Meperidine")) OR ti,ab(buprenorphine* OR codeine* OR dextromoramide* OR diamorphine* OR dihydrocodeine* OR dipipanone* OR fentanyl OR hydromorphone* OR meptazinol OR methadone* OR morphine* OR oxycodone OR papaveretum OR pentazocine OR pethidine OR tapentadol OR tramadol OR heroin) OR ti,ab(z drug* OR z hypnotic* OR non-benzodiazepin* OR nonbenzodiazepin* OR zaleplon OR zopiclone OR zolpidem) OR ti,ab(generation NEAR/3 hypnotic*) OR MAINSUBJECT.EXACT.EXPLODE("Benzodiazepines") OR ti,ab(benzodiazepin* OR bzd OR flurazepam OR loprazolam OR lormetazepam OR nitrazepam OR temazepam OR diazepam OR chlordiazepoxide OR lorazepam OR oxazepam) OR (MAINSUBJECT.EXACT.EXPLODE("Pregabalin") OR MAINSUBJECT.EXACT.EXPLODE("Gabapentin")) OR ti,ab(gabapentin* OR pregabalin*) OR MAINSUBJECT.EXACT.EXPLODE("Antidepressant Drugs") OR ti,ab(antidepress* OR anti depress* OR thymoanaleptic* OR thymoleptic* OR MAOI* OR "monoamine oxidase inhibit*" OR RIMA* OR tricyclic* OR SSRI* OR SNRI* OR SNORI*) OR (MAINSUBJECT.EXACT.EXPLODE("Doxepin") OR MAINSUBJECT.EXACT.EXPLODE("Tranylcypromine") OR MAINSUBJECT.EXACT.EXPLODE("Sertraline") OR MAINSUBJECT.EXACT.EXPLODE("Isocarboxazid") OR MAINSUBJECT.EXACT.EXPLODE("Tryptophan") OR MAINSUBJECT.EXACT.EXPLODE("Fluoxetine") OR MAINSUBJECT.EXACT.EXPLODE("Hydroxytryptophan (5-)") OR MAINSUBJECT.EXACT.EXPLODE("Nortriptyline") OR MAINSUBJECT.EXACT.EXPLODE("Citalopram") OR

Appendices

MAINSUBJECT.EXACT.EXPLODE("Phenelzine") OR MAINSUBJECT.EXACT.EXPLODE("Imipramine") OR MAINSUBJECT.EXACT.EXPLODE("Mianserin") OR MAINSUBJECT.EXACT.EXPLODE("Paroxetine") OR MAINSUBJECT.EXACT.EXPLODE("Moclobemide") OR MAINSUBJECT.EXACT.EXPLODE("Amitriptyline") OR MAINSUBJECT.EXACT.EXPLODE("Maprotiline") OR MAINSUBJECT.EXACT.EXPLODE("Trazodone") OR MAINSUBJECT.EXACT.EXPLODE("Fluvoxamine") OR MAINSUBJECT.EXACT.EXPLODE("Chlorimipramine")) OR ti,ab(amitriptyline OR amoxapine OR clomipramine OR dosulepin OR doxepin OR imipramine OR lofepramine OR maprotiline OR mianserin OR nortriptyline OR protriptyline OR trazodone OR trimipramine OR isocarboxazid OR moclobemide OR phenelzine OR tranylcypromine OR citalopram OR escitalopram OR fluoxetine OR fluvoxamine OR paroxetine OR sertraline OR agomelatine OR duloxetine OR flupentixol OR mirtazapine OR nefazodone OR oxitriptan OR reboxetine OR tryptophan OR venlafaxine OR vortioxetine))) AND ((su.exact.explode("clinical trials") OR ti,ab((clinical OR control*) NEAR/3 trial*) OR ti,ab((singl* OR doubl* OR trebl* OR tripl*) NEAR/5 (blind* OR mask*)) OR ti,ab(volunteer* OR control-group OR controls) OR su.exact("placebo") OR ti,ab(placebo*)) OR (((SU.EXACT("Literature Review") OR RTYPE(review) OR ti(review) OR me(literature review)) AND (ti,ab(systematic OR evidence OR methodol* OR quantitative*))) OR (SU.EXACT("Meta Analysis") OR ti,ab(meta-analys* OR metanalys* OR metaanalys* OR meta analys*) OR ti,ab((systematic OR evidence* OR methodol* OR quantitative*) NEAR/3 (review* OR overview*)) OR ti,ab((pool* OR combined OR combining) NEAR/2 (data OR trials OR studies OR results)) OR RTYPE(systematic OR meta*) OR ME(meta analysis OR systematic review))))) NOT (su.exact.explode("rodents") OR su.exact.explode("mice") OR (su.exact("animals") NOT (su.exact("human males") OR su.exact("human females"))) OR ti(rat OR rats OR mouse OR mice))) AND (la.exact("English"))

Health Technology appraisals (HTA) (Centre for Reviews and Disseminations) search terms 1. MeSH DESCRIPTOR Substance-Related Disorders EXPLODE ALL TREES 2. (MeSH descriptor Substance Withdrawal Syndrome explode all trees) 3. (MeSH descriptor Inappropriate Prescribing explode all trees) 4. (MeSH descriptor Medical Overuse explode all trees) 5. (MeSH descriptor Deprescriptions explode all trees) 6. ((abstinen* or abstain* or cessat* or detox* or discontinu* or reduc* or stop* or taper* or withdraw* or substitut* or depend* or addict* or abuse* or abusing or chronic or long* term or longterm or short* term or short term or misus* or overus* or deprescrib*)) 7. ((over* adj3 (use* or using or utlisat* or utilizat*) adj3 (prescription* or prescrib* or drug* or medicine* or medication* or pharm*))) 8. ((inappropriate adj3 (prescription or prescrib*))) 9. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 10. (MeSH descriptor Narcotics explode all trees) 11. (MeSH descriptor: [Analgesics, Opioid] explode all trees) 12. ((analgesic* adj3 (opioid* or narcotic) adj3 agent*)) 13. (MeSH descriptor: [Buprenorphine] explode all trees) 14. (MeSH descriptor: [Codeine] explode all trees) 15. (MeSH descriptor: [Dextromoramide] explode all trees) 16. (MeSH descriptor: [Heroin] explode all trees) 17. (MeSH descriptor: [Fentanyl] explode all trees) 18. (MeSH descriptor: [Hydromorphone] explode all trees)

Appendices

19. (MeSH descriptor: [Meptazinol] explode all trees) 20. (MeSH descriptor: [Methadone] explode all trees) 21. (MeSH descriptor: [Morphine] explode all trees) 22. (MeSH descriptor: [Oxycodone] explode all trees) 23. (MeSH descriptor: [Opium] explode all trees) 24. (MeSH descriptor: [Pentazocine] explode all trees) 25. (MeSH descriptor: [Meperidine] explode all trees) 26. (MeSH descriptor: [Tramadol] explode all trees) 27. (buprenorphine* or codeine* or dextromoramide* or diamorphine* or dihydrocodeine* or dipipanone* or fentanyl or hydromorphone* or meptazinol or methadone* or morphine* or oxycodone or papaveretum or pentazocine or pethidine or tapentadol or tramadol or heroin) 28. (z drug* or z hypnotic* or non-benzodiazepin* or nonbenzodiazepin* or zaleplon or zopiclone or zolpidem) 29. (generation adj3 hypnotic*) 30. (MeSH descriptor: [Benzodiazepines] explode all trees) 31. (benzodiazepin* or bzd or flurazepam or loprazolam or lormetazepam or nitrazepam or temazepam or diazepam or chlordiazepoxide or lorazepam or oxazepam) 32. (MeSH descriptor: [Pregabalin] explode all trees) 33. (gabapentin* or pregabalin*) 34. (MeSH descriptor: [Antidepressive Agents] explode all trees) 35. (antidepress* or anti depress* or thymoanaleptic* or thymoleptic* or MAOI* or "monoamine oxidase inhibit*" or RIMA* or tricyclic* or SSRI* or SNRI* or SNORI*) 36. (MeSH descriptor: [Amitriptyline] explode all trees) 37. (MeSH descriptor: [Amoxapine] explode all trees) 38. (MeSH descriptor: [Clomipramine] explode all trees) 39. (MeSH descriptor: [Dothiepin] explode all trees) 40. (MeSH descriptor: [Doxepin] explode all trees) 41. (MeSH descriptor: [Imipramine] explode all trees) 42. (MeSH descriptor: [Lofepramine] explode all trees) 43. (MeSH descriptor: [Maprotiline] explode all trees) 44. (MeSH descriptor: [Mianserin] explode all trees) 45. (MeSH descriptor: [Nortriptyline] explode all trees) 46. (MeSH descriptor: [Protriptyline] explode all trees) 47. (MeSH descriptor: [Trazodone] explode all trees) 48. (MeSH descriptor: [Trimipramine] explode all trees) 49. (MeSH descriptor: [Isocarboxazid] explode all trees) 50. (MeSH descriptor: [Moclobemide] explode all trees) 51. (MeSH descriptor: [Phenelzine] explode all trees) 52. (MeSH descriptor: [Tranylcypromine] explode all trees) 53. (MeSH descriptor: [Citalopram] explode all trees) 54. (MeSH descriptor: [Fluoxetine] explode all trees) 55. (MeSH descriptor: [Fluvoxamine] explode all trees) 56. (MeSH descriptor: [Paroxetine] explode all trees)

Appendices

57. (MeSH descriptor: [Sertraline] explode all trees) 58. (MeSH descriptor: [5-Hydroxytryptophan] explode all trees) 59. (MeSH descriptor: [Duloxetine Hydrochloride] explode all trees) 60. (MeSH descriptor: [Flupenthixol] explode all trees) 61. (MeSH descriptor: [Tryptophan] explode all trees) 62. (MeSH descriptor: [Venlafaxine Hydrochloride] explode all trees) 63. (amitriptyline or amoxapine or clomipramine or dosulepin or doxepin or imipramine or lofepramine or maprotiline or mianserin or nortriptyline or protriptyline or trazodone or trimipramine or isocarboxazid or moclobemide or phenelzine or tranylcypromine or citalopram or escitalopram or fluoxetine or fluvoxamine or paroxetine or sertraline or agomelatine or duloxetine or flupentixol or mirtazapine or nefazodone or oxitriptan or reboxetine or tryptophan or venlafaxine or vortioxetine) 64. #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48 OR #49 OR #50 OR #51 OR #52 OR #53 OR #54 OR #55 OR #56 OR #57 OR #58 OR #59 OR #60 OR #61 OR #62 OR #63 65. #9 AND #64

Trials Register of Promoting Health Interventions (TRoPHI) search terms 1. Freetext (All but Authors): "substance-related disorders" OR "substance withdrawal syndrome" OR "inappropriate prescribing" OR "medical overuse" OR "deprescriptions" OR "abstinen*" or "abstain*" or "cessat*" or "detox*" or "discontinu*" or "reduc*" or "stop*" or "taper*" or "withdraw*" or "substitut*" or "depend*" or "addict*" or "abuse*" or "abusing" or "chronic" or "long* term" or "longterm" or "short* term" or "short term" or "misus*" or "overus*" OR "deprescrib*" 2. Freetext (All but Authors): "over*" near "use*" near "prescri*" 3. Freetext (All but Authors): "inappropriate" near "prescri*" 4. 1 OR 2 OR 3 5. Freetext (All but Authors): "buprenorphine*" or "codeine*" or "dextromoramide*" or "diamorphine*" or "dihydrocodeine*" or "dipipanone*" or "fentanyl" or "hydromorphone*" or "meptazinol" or "methadone*" or "morphine*" or "oxycodone" or "papaveretum" or "pentazocine" or "pethidine" or "tapentadol" or "tramadol" or "heroin" 6. Freetext (All but Authors): "z drug*" or "z hypnotic*" or "non-benzodiazepin*" or "nonbenzodiazepin*" or "zaleplon" or "zopiclone" or "zolpidem" 7. Freetext (All but Authors): "generation" near "hypnotic" 8. Freetext (All but Authors): "benzodiazepin*" or "bzd" or "flurazepam" or "loprazolam" or "lormetazepam" or "nitrazepam" or "temazepam" or "diazepam" or "chlordiazepoxide" or "lorazepam" or "oxazepam" 9. Freetext (All but Authors): "gabapentin*" or "pregabalin*" 10. Freetext (All but Authors): "antidepress*" or "anti depress*" or "thymoanaleptic*" or "thymoleptic*" or "MAOI*" or "monoamine oxidase inhibit*" or "RIMA*" or "tricyclic*" or "SSRI*" or "SNRI*" or "SNORI*" 11. Freetext (All but Authors): "amitriptyline" or "amoxapine" or "clomipramine" or "dosulepin" or "doxepin" or "imipramine" or "lofepramine" or "maprotiline" or "mianserin" or "nortriptyline" or "protriptyline" or "trazodone" or "trimipramine" or "isocarboxazid" or "moclobemide" or "phenelzine" or "tranylcypromine" or "citalopram" or "escitalopram" or "fluoxetine" or "fluvoxamine" or "paroxetine" or "sertraline" or "agomelatine" or "duloxetine" or "flupentixol" or "mirtazapine" or "nefazodone" or "oxitriptan" or "reboxetine" or "tryptophan" or "venlafaxine" or "vortioxetine"

Appendices

12. 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 13. 4 AND 12

ASSIA (Proquest) search terms 1. ((MAINSUBJECT.EXACT.EXPLODE("Substance abuse disorders") OR ti,ab(abstinen* OR abstain* OR cessat* OR detox* OR discontinu* OR reduc* OR stop* OR taper* OR withdraw* OR substitut* OR depend* OR addict* OR abuse* OR abusing OR chronic OR long* term OR longterm OR short* term OR short term OR misus* OR overus* OR deprescrib*) OR ti,ab(over* NEAR/3 (use* OR using OR utlisat* OR utilizat*) NEAR/3 (prescription* OR prescrib* OR drug* OR medicine* OR medication* OR pharm*)) OR ti,ab(inappropriate NEAR/3 (prescription OR prescrib*))) AND ((MAINSUBJECT.EXACT.EXPLODE("Analgesics") OR MAINSUBJECT.EXACT.EXPLODE("Narcotics")) OR ti,ab(analgesic* NEAR/3 (opioid* or narcotic) NEAR/3 agent*) OR (MAINSUBJECT.EXACT.EXPLODE("Methadone") OR MAINSUBJECT.EXACT.EXPLODE("Heroin") OR MAINSUBJECT.EXACT.EXPLODE("Buprenorphine") OR MAINSUBJECT.EXACT.EXPLODE("Codeine") OR MAINSUBJECT.EXACT.EXPLODE("Hydromorphone") OR MAINSUBJECT.EXACT.EXPLODE("Tramadol") OR MAINSUBJECT.EXACT.EXPLODE("Morphine") OR MAINSUBJECT.EXACT.EXPLODE("Opium")) OR ti,ab(buprenorphine* or codeine* or dextromoramide* or diamorphine* or dihydrocodeine* or dipipanone* or fentanyl or hydromorphone* or meptazinol or methadone* or morphine* or oxycodone or papaveretum or pentazocine or pethidine or tapentadol or tramadol or heroin) OR ti,ab(z drug* or z hypnotic* or non-benzodiazepin* or nonbenzodiazepin* or zaleplon or zopiclone or zolpidem) OR ti,ab(generation NEAR/3 hypnotic*) OR MAINSUBJECT.EXACT.EXPLODE("Benzodiazepines") OR ti,ab(benzodiazepin* OR bzd OR flurazepam OR loprazolam OR lormetazepam OR nitrazepam OR temazepam OR diazepam OR chlordiazepoxide OR lorazepam OR oxazepam) OR MAINSUBJECT.EXACT.EXPLODE("Gabapentin") OR ti,ab(gabapentin* or pregabalin*) OR MAINSUBJECT.EXACT.EXPLODE("Antidepressant drugs") OR ti,ab(antidepress* or anti depress* or thymoanaleptic* or thymoleptic* or MAOI* or "monoamine oxidase inhibit*" or RIMA* or tricyclic* or SSRI* or SNRI* or SNORI*) OR (MAINSUBJECT.EXACT.EXPLODE("Imipramine") OR MAINSUBJECT.EXACT.EXPLODE("Amitriptyline") OR MAINSUBJECT.EXACT.EXPLODE("Clomipramine") OR MAINSUBJECT.EXACT.EXPLODE("Moclobemide") OR MAINSUBJECT.EXACT.EXPLODE("Sertraline") OR MAINSUBJECT.EXACT.EXPLODE("Paroxetine") OR MAINSUBJECT.EXACT.EXPLODE("Venlafaxine") OR MAINSUBJECT.EXACT.EXPLODE("Fluoxetine") OR MAINSUBJECT.EXACT.EXPLODE("Citalopram") OR MAINSUBJECT.EXACT.EXPLODE("Tryptophan")) OR ti,ab(amitriptyline OR amoxapine OR clomipramine OR dosulepin OR doxepin OR imipramine OR lofepramine OR maprotiline OR mianserin OR nortriptyline OR protriptyline OR trazodone OR trimipramine OR isocarboxazid OR moclobemide OR phenelzine OR tranylcypromine OR citalopram OR escitalopram OR fluoxetine OR fluvoxamine OR paroxetine OR sertraline OR agomelatine OR duloxetine OR flupentixol OR mirtazapine OR nefazodone OR oxitriptan OR reboxetine OR tryptophan OR venlafaxine OR vortioxetine))) AND (la.exact("English"))

C.1.3 Step 3: Grey literature

Database Dates searched Search filter used King’s Fund Library All years to 11 November 2018 None National Institute for Health All years to 29 November 2018 None Research Journals Library

Appendices

King’s Fund Library search terms 1. Prescription drug* on Annual report, journal article, journal supplement, electronic journal, King's funs publication, web publication, journal, statistical publication, web site 2. Drug* withdrawal on Annual report, journal article, journal supplement, electronic journal, King's funs publication, web publication, journal, statistical publication, web site 3. Drug* Dependency on Annual report, journal article, journal supplement, electronic journal, King's funs publication, web publication, journal, statistical publication, web site 4. Drug* dependent on Annual report, journal article, journal supplement, electronic journal, King's funs publication, web publication, journal, statistical publication, web site 5. Drug* harm on Annual report, journal article, journal supplement, electronic journal, King's funs publication, web publication, journal, statistical publication, web site

National Institute for Health Research Journals Library search terms 1. Prescription drugs 2. Prescription harm 3. Prescription misuse

C.1.4 Step 4: Citation searching Database Dates searched Search filter used Scopus 6 key references None

Scopus

The following papers were used for citation searching:

1. Siegfried Kasper, Celso Iglesias-García, Edward Schweizer, Jacquelyn Wilson, Sarah DuBrava, Rita Prieto, Verne W. Pitman and Lloyd Knapp. Pregabalin long-term treatment and assessment of discontinuation in patients with generalized anxiety disorder. International Journal of Neuropsychopharmacology (2014), 17, 685–695.

2. Cook B, Creedon T, Wang Y, Lu C, Carson N, Jules P et al. Examining racial/ethnic differences in patterns of benzodiazepine prescription and misuse. Drug and Alcohol Dependence. 2018; 187:29.

3. Zahradnik A, Otto C, Crackau B, Löhrmann I, Bischof G, John U, Rumpf HJ (2009). Randomized controlled trial of a brief intervention for problematic prescription drug use in non-treatment-seeking patients. Addiction. Jan;104(1):109-17. doi: 10.1111/j.1360-0443.2008.02421.x.

4. Tannenbaum et al. 2014 Reduction of inappropriate benzodiazepine prescriptions among older adults through direct patient education: the EMPOWER cluster randomized trial. JAMA Intern Med. 2014;174(6):890-898. doi:10.1001/jamainternmed.2014.949.

5. Davies 2018: Antidepressant withdrawal: a survey of patients' experience by the All-Party Parliamentary Group for Prescribed Drug Dependence

6. Guy 2018: The Patient Voice: an analysis of personal accounts of prescribed drug dependence and withdrawal submitted to persons in Scotland and Wales.

Evidence tables Evidence Currentpractice examples

© Royal © College of Physicians 2019 Appendix D: Evidence tables Study Barth 2017(1) Study type Observational (non-comparative), pilot intervention Number of studies (number of participants) 1 (n=93) Countries and setting Conducted in South Carolina, USA; Primary care physicians.

Duration of study Unclear. Inclusion criteria Primary care physicians. Exclusion criteria Not reported.

Recruitment/selection of patients Study website developed to facilitate recruitment and enrolment. Age, gender and ethnicity Age – mean (SD): Not reported. Gender (M:F): 46/47.. Ethnicity:. Black non-Hispanic, 20%; White non-Hispanic, 63.8%; Other non-Hispanic, 16.2%; Hispanic any race, 9.7%; Not reported, 4.3%. Setting: Veterans administration, 52.7%; Community clinic, 47.3%.

112 Years of medical practice: Under 5, 16.1%; 5-10, 16.1%; 11-20, 26.9%; >20, 40.9%.

Area of practice: General/internal/family, 93.6%; Other (oncologists not eligible), 6.4%. Registered PMP user prior to visit: Yes, 46.2%; No, 52.8%. Number of patients under treatment for chronic, non-cancer pain: ≥40, 60.2%; <40, 39.8%. Extra comments Development of the intervention: Developed by closely following the Medical Research Council complex intervention framework. Development involved theoretical and modelling phases: Theoretical phase – identification of evidence that an educational intervention may have the desired effect. Formal literature review of educational interventions for practicing physicians and chronic pain guideline was performed with an expert panel. It was agreed that Academic Detailing (AD)would be further evaluated as an educational outreach intervention , as it was felt to be the optimal intervention to improve prescriber’s effective use of prescription drug monitoring program (PMP) data. Key messages for the AD intervention were agreed upon by a team consisting of physicians, pharmacists, trained academic detailers and psychologists, and each of the key messages were reviewed to delineate the best standard of care recommendations for each key message. Modelling phase – Delineation of component parts of the educational intervention and how active components of the package may relate to final outcomes. Phase I included a focus group with prescribers serving military and non-military patients, interactive workshop sessions between detailers and physician consultants, development of educational

Evidence tables Evidence Currentpractice examples © Royal © College of Physicians 2019 Study Barth 2017(1) materials to support and reinforce the key messages of the intervention, and live testing of the AD intervention. Paper describes theoretical and modelling phases of the AD intervention development and preliminary evidence of feasibility and acceptability is provided.

Indirectness of population Serious indirectness? Opioid prescribing in general – not limited to those drugs specified on list. Interventions & comparators (n=) Intervention 1: Development of an educational intervention to increase physician use of safe opioid prescribing practices. AD involves face-to-face, interactive education of prescribers by trained health care professionals. Key messages agreed upon for the intervention were: Share a patient provider agreement; optimise patient treatment using a multidimensional pain rating scale; and screen for appropriate opioid use, including accessing PMP data. Following the modelling phase of development, the following 5 component parts of the AD were identified: Patient-provider agreement: one patient-centred, carbon-copied agreement that included patient education and

informed consent was developed and modified based on feedback from four prescribers Validated pain scale: All validated pain rating scales for primary care were reviewed and the PEG scale, a 3-item scale of Brief Pain Inventory, was agreed upon. This consists of one intensity item and two interference items which are scored 0-10. Facilitated PMP registration: Protocol for facilitated PMP registration developed. Allowed time required for 113 registration to be reduced from 2 weeks to 2 days.

Visit protocol: Face-to-face meetings between the detailer and physicians to assist with safe and evidence-based opioid prescribing and supporting patient care decisions balancing risks and benefits of opioids in chronic pain. Incentive: AD visit would contribute to required hours and enrolled physicians could earn up to 2 credits towards Continuing Medical Education through the University of South Carolina School of Medicine – Palmetto health CME Organisation. AD visit content and training: Included brief introduction, rapport building and use of open-ended questions to assess physician’s interest in each key message and possible barriers to change in practice and prescribing. Interactive techniques were used to address key messages and detailers facilitated the completion of the PMP registration for each physician during the visit. Provided opportunity to log in to PMP with practical example and detailers explained the appropriate use of the information on the patient record. Allowed for on-site training in generating and interpreting PMP reports. During live tests, detailers assessed learner’s needs, engaged in problem-solving learning activities, tested clinical support tools/materials and allowed learners to learn by navigating the PMP. Potential barriers to implementing intervention were noted and addressed.

Funding Funding by National Institute on Drug Abuse. RESULTS AND RISK OF BIAS FOR COMPARISON:

Protocol outcome 1: Staff satisfaction -Actual outcome: Narrative information concerning issues experienced with the intervention and potential barriers.

Issues with logging onto PMP database and gaining ‘real-time’ experience with this skill during the AD sessions: 7/86 (8%) did not complete practicing with the PMP database which was a critical component of the education – reasons for this included problems opening the PMP account (3/86) and time constraints and discussion of other key messages (4/86). Of those that could not complete this due to time constraints, one was because two physicians were being trained simultaneously and there was only sufficient time for one to log in and practice.

Physician-reported barriers to using the PMP or implementing aspects of three key messages:

PMP use: no barriers, 32/75; time constraints, 19/75; remembering to run/how to run reports (practice required), 11/75; concerns about data (accuracy, interpretation, consequences, need data from border state), 10/75; difficult to use/not user friendly, 6/75; concern about incorporating into workflow, 5/75; computer/connection issues, 2/75; liability concerns, 2/75; other (don’t write controlled substances, switching to new vendor, want/have delegate, unsure how to document), 6/75.

Other key messages: no barriers, 35/71; time constraints, 16/71; concern for push-back from patients using this approach, 6/71; issues locating electronic health 114 records, 3/71; concern for liability issues with patient-provider agreement, 1/71; unclassified, 4/71.

Note that only n=87 AD visits were performed – remaining 6 applicants either completed application after pharmacist visitor had travelled to a distant location and could not return to that location, or submitted application too late for a PMP account to be opened prior to an AD visit. Data available for n=86 visits, with one set of documentation missing. Risk of bias: NA.

Study Dann 2018(2) Study type Poster – conference proceeding. Non-comparative report of prescription opioid reduction service developed within one UK practice. Number of studies (number of participants) 1 (number of participants not specified). Countries and setting Conducted in UK; Setting, one primary care practice. Duration of study Unclear Inclusion criteria People taking opioids for chronic pain.

Evidence tables Evidence Currentpractice examples © Royal © College of Physicians 2019 Study Dann 2018(2) Exclusion criteria Not reported. Recruitment/selection of patients Not reported. Age, gender and ethnicity Age – mean (SD): Not reported. Gender (M:F): Not reported.. Ethnicity: Not reported..

Extra comments Very limited information concerning the methods. Indirectness of population No indirectness? Prescription opioids in general rather than limited to those on the list provided. Is within an NHS setting though so no indirectness?

Interventions & comparators (n=) Intervention 1: Funding secured from clinical commissioning group for a general practitioner, clinical pharmacist and full-time substance motivational health care worker to develop an opiate reduction service. As a result simple interventions which could be used in primary care setting were developed. Evidence-based stratified approach developed to identify and engage patients on high-risk prescriptions by using a motivational interviewing process consisting of 1-3 min interventions that could be incorporated into day to day primary care consultations. A 12-step approach termed a clinical pain tool-kit (self-care steps) also developed. Does not specify how these tools were used in the study to assess the outcomes reported. Funding Funding provided by the relevant clinical commissioning group. 115 RESULTS AND RISK OF BIAS FOR COMPARISON:

Protocol outcome 1: Reduction/cessation in prescribed drug use -Actual outcome: Cessation of opiates in those engaged with the study’s opiate work in a 2 month period, reported as percentage only – reported narratively. Cessation achieved in 28% of participants. Risk of bias: NA. Protocol outcome 2: Reduction/cessation in prescribed drug use -Actual outcome: Significant reduction in opiate use in those engaged with the study’s opiate work in a 2 month period, reported as percentage only – reported narratively. Significant reduction achieved in 70% of participants. Does not specify what degree of reduction was considered to be significant in this study. Risk of bias: NA. Protocol outcome 3: Reduction/cessation in prescribed drug use -Actual outcome: Long-term opiate prescriptions, narrative report. Study states that becoming an opiate-aware practice resulted in reductions in the initiation of long- term opiate prescriptions. No indication of over what time period this was observed or the degree of this reduction. Risk of bias: NA. Protocol outcome 4: Health-related quality of life -Actual outcome: Quality of life, narrative report. Scale, 1-10. Higher score = better quality of life. No details of the measure of quality of life used or the components that made up this scale. Quality of life was higher off opiates (cessation, n=20) compared with on high-dose opiates (n=20) – P=0.005 (significant).

Evidence tables Evidence Currentpract © Royal © College of Physicians 2019 Study Dann 2018(2) Risk of bias: NA. Protocol outcome 5: Health-related quality of life -Actual outcome: Level of activity, narrative report. Scale, 1-10. Higher score = higher level of activity. No details of how this was measured. Activity level was higher off

ice examples opiates (cessation, n=20) compared with on high-dose opiates (n=20) – P=0.050 (significant). Risk of bias: NA. Protocol outcome 6: Health-related quality of life -Actual outcome: Level of anxiety, narrative report. Scale, 1-10. Higher score = higher level of anxiety. No details of how this was measured. Anxiety level was lower off opiates (cessation, n=20) compared with on high-dose opiates (n=20) – P=0.86 (not significant). Risk of bias: NA.

Study Guy 2018(3) – Prescribed Medication Support Service (PMSS), Wales Study type Description of existing service in Wales for the support of prescribed medication withdrawal. Number of studies (number of participants) 1 (n=329 used service between April and September of 2018) 116 Countries and setting Conducted in UK; Setting, service supporting prescribed medication withdrawal.

Duration of study Not reported – gives outcomes for 6 month period between April and September of 2018 Inclusion criteria Criteria for referral to the service: Patients must have been taking medicines within prescribing limits otherwise PMSS would work with the substance misuse team. Exclusion criteria Those taking medicines outside of prescribing limits. Recruitment/selection of patients Those using this service between April and September of 2018. Age, gender and ethnicity Age – mean (SD): Not reported. Gender (M:F): Not reported.. Ethnicity: Not reported.. Extra comments Information on this service sourced by All Party Parliament Group for Prescribed Drug Dependence through combination of personal visits, telephone calls and desk research.

Drugs covered by the service and % of referrals in last 6 months: benzodiazepines and Z-drugs, 57.9%; antidepressants, 2%; pain killers (within prescribed limits) including over the counter, 39.5%); other, 0.7%. Indirectness of population Serious indirectness? Not limited to prescription medications the project is focused (e.g. Over the counter pain medications also included). Interventions & comparators Intervention 1: Dedicated services - Prescribed Medication Support Service (PMSS), Wales (n=329 used service between April and September 2018).

Evidence tables Evidence Currentpractice examples © Royal © College of Phy Study Guy 2018(3) – Prescribed Medication Support Service (PMSS), Wales

Key features of the service: Prescribed medication therapists (nurses/counsellors) based in GP surgeries have established strong relationships with doctors, practice nurses and pharmacists over 20 years. Collaboration with pharmacists and GPs to identify and contact certain client groups (e.g. Pregnant women taking particular drugs, elderly patients that have suffered a fall and patients that are being prescribed drugs beyond

sicians 2019 guideline recommendations). Patients may also be referred by secondary care or other services such as social workers.

Prescribed medication therapists provide education and training by running workshops and talks, and attending practice meetings Personalised programmes for patients developed following assessments by prescribed medication therapists

Monthly face-to-face follow-up personalized review appointments for tapering and withdrawal and telephone support available between meetings Detailed clinical service model available in original document. Funding Not reported. The report that provided details of this service was produced by the All Party Parliamentary Group for

117 Prescribed Drug Dependence. RESULTS AND RISK OF BIAS FOR COMPARISON:

Protocol outcome 1: Cost effectiveness -Actual outcome: Narrative report of costs mentioned within the document. Service covers a population of 701,000 across six counties. Cost per annum, £179,000. Cost per population head, £0.26 a year. Cost per person helped, £272. These costs were scaled up to the level of the mid-2017 population of England (~56 m) – suggested that similar service in England may have an annual cost of £14 m per annum. This was calculated by using the annual per capita expenditure of the service in Wales across the population of the counties served (£0.26) and multiplying this by English population. It was assumed that no economies of scale emerge. Potential savings to NHS will be on order of £1.5m if the following is assumed: prescriptions are monthly (on average), ‘reducers’ will (on average) cut use by half and ‘quitters’ by 100%, and that costs of antidepressants are roughly the same as other psychiatric medicines. Therefore net annual cost of programme estimated ~12.5 m. This figure may be further reduced by potential reductions in GP appointments, costs related to treatment of falls in the elderly, costs related to children born with problems related to prescribed drug dependence and other societal benefits (e.g. Reduced mental health disability payments). Risk of bias: NA.

Protocol outcome 2: Reduction/cessation in prescribed drug use. -Actual outcome: Narrative report of those ceasing reducing prescribed medications. Of 329 people (n=260 new referrals) using the service between April and September of 2018, 62% were reducing prescribed medications and 33% ceased taking prescribed medications. Does not separate proportions out for each drug type and will also include over the counter drugs. Scaled up to the level of the mid-2017 population of England (~56 m) – suggested that similar service in England has the

Evidence tables Evidence Currentpractice examples © Royal © College of Physicians 2019 Study Guy 2018(3) – Prescribed Medication Support Service (PMSS), Wales potential to help a total of ~50000 people annually to reduce or stop their intake of prescribed psychiatric drugs. Risk of bias: NA.

Study Guy 2018(3) – Bristol and District Tranquiliser Project (BTP) Study type Description of existing service for the support of prescribed medication withdrawal. Number of studies (number of participants) 1 (n=285 used service in 2017/18)

Countries and setting Conducted in UK; Setting, service supporting prescribed medication withdrawal. Duration of study Not reported – gives outcomes for 2017/18 time period. Inclusion criteria Those referred via any source to the service, primarily self-referral.

Exclusion criteria Not reported. Recruitment/selection of patients Those referred to the service in 2017/18 time period. Age, gender and ethnicity Age – mean (SD): Not reported. Gender (M:F): Not reported.. Ethnicity: Not reported..

118 Extra comments Information on this service sourced by All Party Parliament Group for Prescribed Drug Dependence through

combination of personal visits, telephone calls and desk research.

Drugs covered by the service and % of activity associated with each: benzodiazepines and Z-drugs (66% of its activity); antidepressants (33% of its activity); antipsychotics (1% of its activity – on GP request only). Does not work with pain killers. Indirectness of population No indirectness? Includes antipsychotics which are excluded, however only upon GP request and very small proportion (1%) of its work associated with this class of drugs. Interventions & comparators Intervention 1: Dedicated services - Bristol and District Tranquiliser Project (n=285 used service in 2017/18).

Key features of the service: Helpline supports people primarily from Bristol but also the rest of the UK: Open 10-15.30, Mon-Thurs Two weekly support groups and face-to-face counselling available to Bristol residents Services offered by people with personal experience of prescribed drug dependence Funding by Bristol CCG (£66K) with additional grant (£11K) from Helping Older People Scheme combined with smaller fundraising activities

Evidence tables Evidence Currentpractice examples © Royal © College of Physicians 2019 Study Guy 2018(3) – Bristol and District Tranquiliser Project (BTP) Education and GP practice visits undertaken but have reduced due to resource constraints Requires prescriber permission before opportunity to talk through withdrawal and establish stabilizing/tapering plan Prescriber can provide support for tapering and adjust prescriptions Bristol residents offered access to group or 1-2-1 counselling and non-Bristol residents offered continued helpline support. Prescriber can be alerted if client regarded to be anxious/suicidal Detailed clinical service model available in original document. Funding Not reported. The report that provided details of this service was produced by the All Party Parliamentary Group for Prescribed Drug Dependence. RESULTS AND RISK OF BIAS FOR COMPARISON:

Protocol outcome 1: Cost effectiveness -Actual outcome: Narrative report of costs mentioned for 2017/18 within the document. Annual expenditure, £91200. Cost per person helped, £320 pa. Population of Bristol, 450000 – cost per head = £0.20. Involved 2 FTE counsellors, 2 peer support group workers and 1 FTE admin.

119 Risk of bias: NA.

Protocol outcome 2: Reduction/cessation in prescribed drug use. -Actual outcome: Proportion of clients commencing withdrawal. Of 285 clients that were helped in 2017/18, 251 were via the helpline and 34 through face-to-face appointments (12 in groups, 22 1-2-1). Of these clients, 83% commenced withdrawal. No mention of the proportion that successfully completed withdrawal as a result of this.

Risk of bias: NA.

Study Guy 2018(3) – The Bridge Addiction to Medicines Programme Study type Description of existing service for the support of prescribed medication withdrawal. Number of studies (number of participants) 1 (n=364 used service in Sept 16/17) Countries and setting Conducted in UK; Setting, service supporting prescribed medication withdrawal. Duration of study Not reported – gives outcomes for Sept 16/17 time period. Inclusion criteria Those referred to the service during Sept 16/17 time period within Bradford Metropolitan District area.

Evidence tables Evidence Currentpractice examples © Royal © College of Physicians 2019 Study Guy 2018(3) – The Bridge Addiction to Medicines Programme Exclusion criteria Not reported. Recruitment/selection of patients Those referred to the service during Sept 16/17 time period. Age, gender and ethnicity Age – mean (SD): Not reported. Gender (M:F): Not reported.. Ethnicity: Not reported..

Extra comments Information on this service sourced by All Party Parliament Group for Prescribed Drug Dependence through combination of personal visits, telephone calls and desk research.

Drugs covered by the service: benzodiazepines and Z-drugs; opioids (pain killers). Antidepressants not covered by this service. Indirectness of population No indirectness? Does not specify the types of each class of drugs included, but within an NHS setting so all drugs likely to be on the inclusion list?

Interventions & comparators Intervention 1: Specialist services within or in liaison with primary care/shared care model - The Bridge Addiction to Medicines Programme (n=364 used service in Sept 16/17 time period).

Key features of the service:

120 - Service works with GPs to identify patients for proactive contact/outreach – 93% of referrals are from GPs. - Those with palliative care, nursing home residents and severe and enduring mental health issues excluded. Patients that are ill at the time of contact will be re-contacted at a later date. Those with epilepsy diagnoses are referred back to GP for a review. - Covers Bradford Metropolitan District area. - Charity that wins funding/contracts to deliver services - Since 2017 the Bridge is a subcontractor on super contract for substance misuse services run by Change Grow Live – same provider that will take over REST service in April 2019 -Involves one FTE with a focus on benzodiazepines and one with a focus on opioids -Meeting with Bridge Programme worker involves assessment and design of agreed support plan -Support for tapering and prescription adjustments provided by GP -Follow-up Bridge meetings with patient involving tailored individual support and telephone support also available - Detailed clinical service model available in original document. Funding Not reported. The report that provided details of this service was produced by the All Party Parliamentary Group for Prescribed Drug Dependence. RESULTS AND RISK OF BIAS FOR COMPARISON:

Evidence tables Evidence Currentpractice examples © Royal © College of Physicians 2019 Study Guy 2018(3) – The Bridge Addiction to Medicines Programme

Protocol outcome 1: Cost-effectiveness -Actual outcome: Narrative report of costs mentioned for Sept 16/17 within the document. Population of Bradford Metropolitan District, 532000. Annual expenditure,

£98000. Cost per population head, £0.18 per year. Cost per person helped, £269. Risk of bias: NA. Protocol outcome 2: Reduction/cessation in prescribed drug use. -Actual outcome: Proportion of successful completions for each drug type – unclear whether this refers to cessation of the drug or reduction of dose. Benzodiazepines,

43.3%; Opioids, 47.4%. Risk of bias: NA.

Study Guy 2018(3) – Recovery Experience Sleeping Tablets and Tranquilisers (REST), Mind in Camden Study type Description of existing service for the support of prescribed medication withdrawal. Number of studies (number of participants) 1 (n=194 received counselling over 8 years, n=130 per year helped with helpline and/or counselling)

121 Countries and setting Conducted in UK; Setting, service supporting prescribed medication withdrawal.

Duration of study Not reported – gives outcomes for those that received counselling over an 8 year period. Inclusion criteria Those referred to the service up until March 2018; users of benzodiazepines or Z-drugs (as prescribed, recreational or chaotic use). Exclusion criteria Users of drugs other than benzodiazepines or Z-drugs. Recruitment/selection of patients Those matching criteria for referral up until March 2018. Age, gender and ethnicity Age – mean (SD): Not reported. Gender (M:F): Not reported.. Ethnicity: Not reported.. Extra comments Information on this service sourced by All Party Parliament Group for Prescribed Drug Dependence through combination of personal visits, telephone calls and desk research.

Drugs covered by the service: benzodiazepines and Z-drugs only. Indirectness of population Serious indirectness: Includes recreational use of benzodiazepines and/or Z-drugs – not limited to prescription use. Unclear if drugs had to have been prescribed before this recreational use was initiated or those initially obtaining illicitly included in this section. Interventions & comparators Intervention 1: Dedicated services - Recovery Experience Sleeping Tablets and Tranquilisers (REST), Mind in Camden (n=130 helped per year through helpline and counselling)

Evidence tables Evidence Currentpractice examples © Royal © College of Physicians 2019 Study Guy 2018(3) – Recovery Experience Sleeping Tablets and Tranquilisers (REST), Mind in Camden

Key features of the service: - Has been running for 30 years and is run by non-clinicians in a community setting, although state ability and intention to work with the NHS - Manager and service users network and provide education in the area -Initial goal is to stabilize use of benzodiazepines and/or Z-drugs before reducing/withdrawing -Referrals to service may be via prescriber, self-referral or other services (e.g. MIND Camden, homeless projects, etc.) - Support offered ranges from general support/tapering advice via helpline to counselling or support groups - Counselling + tapering support involves 12 sessions, 2x person-centred counsellors, 2-3 month wait for this service -Peer group support once per week provide encouragement and support while reducing isolation and stigma -Family support group once per month for encouragement and support -Other help can be provided (e.g. Accompanying to GP, benefits, housing, employment, etc.). - Detailed clinical service model available in original document. Funding Not reported. The report that provided details of this service was produced by the All Party Parliamentary Group for 122 Prescribed Drug Dependence.

RESULTS AND RISK OF BIAS FOR COMPARISON:

Protocol outcome 1: Cost effectiveness. -Actual outcome: Narrative report of costs as of March 2018 reported in the document. Population of Camden and Islington, 215667. Helps 130 people per year through helpline and counselling. Service cost per annum, £49000. Cost per person helped, £376. Cost per head of population, £0.22. Risk of bias: NA. Protocol outcome 2: Reduction/cessation in prescribed drug use. -Actual outcome: Narrative report of outcomes in those that received counselling over an 8 year period (n=194 clients): Stabilised, 4%; lower dose, 51%; higher dose, 1%; complete withdrawal, 29%; no change, 6%; not known or applicable, 21%. Risk of bias: NA.

Study Scott 2018(4) Study type Conference poster – mixed methods evaluation of pilot SUPPORT service in primary care Number of studies (number of participants) 1 (n=34)

Evidence t Evidence Currentpractice examples © Royal © College of Physicians 2019 Study Scott 2018(4) Countries and setting Conducted in UK, Setting; primary care service.

Duration of study Not reported. ables Inclusion criteria Patients with chronic non-cancer pain treated with long-term opioids.

Exclusion criteria Not reported. Recruitment/selection of patients Unclear. Age, gender and ethnicity Age – mean (SD): 51 (10) years. Gender (M:F): 12/22.. Ethnicity: Not reported. Extra comments Quantitative data and semi-structured interviews used in evaluation of this study. Indirectness of population No indirectness? Does not list the prescription opioids included but within NHS setting so likely to all be included on the list? Interventions & comparators (n=) Intervention 1: Specialist services within or in liaison with primary care/shared care model. SUPPORT study designed to assess feasibility of implementing a service in primary care for patients with chronic non-cancer pain and treated with long-term opioids. Aimed to help patients in two GP practices understand their relationship with opioids and develop alternative, non-drug-based pain management strategies. Delivered by two project workers on an

123 individually tailored one-to-one basis and informed by shared care model.

Funding Funded and supported by NHS, National Institute for Health Research. RESULTS AND RISK OF BIAS FOR COMPARISON:

Protocol outcome 1: Reduction/cessation in prescribed drug use. -Actual outcome: Reduction in opioid dose at follow-up, narratively extracted. Average prescribed opioid dose (median and IQR) was significantly reduced at follow-up compared to baseline (P<0.001). At follow-up, 15/34 service users had reduced their dose (including 3 that ceased completely), 19/34 remained on the same dose and none had increased. Unclear what the length of follow-up was. Data available for all of those that enrolled for this outcome. Semi-structured interviews in 18 service users, performed either face-to-face or by telephone, indicated that service users modified their opioid use in several ways, including changing medication type and form (e.g. Pain patches), not using opioids for breakout pain, using medication less frequently and spreading the dose out over the day. Interviews were audio- recorded, transcribed verbatim, anonymised and analysed thematically. Risk of bias: NA. Protocol outcome 2: Reduction/cessation in prescribed drug use. -Actual outcome: Current Opioid Misuse Measure (COMM) scale. Score ≥9 indicates opioid misuse. At follow-up, 15/22 (68%) classified as misusing compared to 24/28 (86%) at baseline. Length of follow-up unclear. Definition of misuse unclear. Data not obtained for all enrolled participants for this outcome as indicated by denominators. Risk of bias: NA.

yal yal College of Physicians 2019 Protocol outcome 3: Health-related quality of life -Actual outcome: Health, wellbeing and quality of life. Extracted narratively. At follow-up, service users had on average improved on most health, wellbeing and quality of life outcome scales. Values not given and significance not indicated. Improvements observed for COMM scale score, BPI severity, BPI interference, Warwick-

Edinburgh mental wellbeing scale, TOP overall quality of life, TOP physical and TOP psychological. BPI % pain relief worsened at follow-up compared with baseline on average. Semi-structured interviews in 18 service users, performed either face-to-face or by telephone, identified a range of contributors to these improvements, including self-kindness, starting new hobbies and volunteering, which had positive effects on well-being, feelings of self-worth and distraction from pain symptoms. Interviews were audio-recorded, transcribed verbatim, anonymised and analysed thematically.

Risk of bias: NA. Protocol outcome 4: Patient/staff satisfaction -Actual outcome: Experiences of the service. Extracted narratively. Several service users described having an improved understanding of pain, what opioids do and their effectiveness in chronic pain. Positive experiences of the service reported were as follows: tailored to individual needs; time to discuss pain management; alternative to

traditional medical model of pain management; relationship with project worker. Negative experiences of the service reported were as follows: delays in accessing community-based services; insufficient GP support and communication; slow pace of progress; negative psychological effects. Unclear whether positive/negative experiences of the service were reported by service users only or also included experiences of GPs and project workers that were interviewed by semi-structured interviews. Interviews were audio-recorded, transcribed verbatim, anonymised and analysed thematically.

124 Risk of bias: NA.

Table 3: Study limitations [Institute of Health Economics (IHE). Quality Appraisal of Case Series Studies Checklist] Competing Intervention interests and Study and co- Outcome Statistical Results and sources of Overall Risk Study Study objective Study design population intervention measure analysis conclusions support of Biasa

Barth Objective Prospective Majority of Intervention Relevant No statistical Follow-up Sources of High 2017(1) clearly stated pilot study. relevant and its outcome analysis was unclear – support for the Non- physician delivery well measures performed potentially study were comparative. characteristics described. were based on the recorded reported but

were Seemed to be established a nature of the during competing Data collected described. dependent priori. outcomes intervention interests were in >1 centre on each reported. sessions. not reported session and Suitable Eligibility Outcome 125 criteria were adapted as assessors based on Participation deemed nature of by physicians not clearly were not stated. appropriate blinded to outcomes was voluntary depending on which and not based the needs of intervention. concern on provider Some individual experience

characteristic physicians had physicians. with the such as prior intervention. prescribing experience

patterns. with the Additional Website prescription interventions Losses to facilitated drug were not follow- recruitment. monitoring reported. up/missing programme outcome that the data intervention reported. was aiming to improve the Unclear how use of and the results

Riskof bias Currentpractice examples © Royal © College of Physicians 2019 Competing Intervention interests and Study and co- Outcome Statistical Results and sources of Overall Risk Study Study objective Study design population intervention measure analysis conclusions support of Biasa others did not. support some of the conclusions made in the abstract of the study. Dann Brief aim of Unclear No information Components Outcome Statistical Unclear Sources of High 2018(2) study stated but whether was provided on of measures not analysis whether support and

is vague. performed characteristic intervention reported a performed follow-up competing prospectively. of patients – briefly priori. was was of a interests were conference mentioned appropriate suitable not reported. Data collected poster. but Unclear where duration – 2 insufficient applicable. months may 126 from a single whether practice. Eligibility detail outcomes not be long provided. enough for criteria not assessors Additional some Unclear reported. blinded to interventions patients to whether the were not see an effect patients were Unclear intervention reported. that was of the recruited whether intervention. consecutively. patients were received. If

at a similar measured point in the subjectively Losses to disease/conditi then not follow-up not on. blinded. clearly reported. Unclear whether Estimates of outcomes variability measured provided but using not in a appropriate format that

events not Unclear reported. whether Results outcome vaguely measures support were made conclusions before and made but after the insufficient intervention. detail

127 provided to back up strong conclusion that has been made. Guy 2018(3) Objective Retrospective Characteristics Intervention/ Outcome No statistical Reports Sources of High clearly review of four of patients components measures not analysis was costs/ support for reported. existing using each of each established a performed outcomes study and services in the service not well service priori – due to the over a 1 year competing UK. reported. described differed for nature of the period in interests not well with each service data that was most of the reported. Outcomes/cos Eligibility detailed, and reported reported. included ts for those criteria not visual service information services, using each described in models that was which may be service during much detail. included. available. sufficient to give idea of a particular time period Additional Unclear how how these

disease/conditi clients using on. Outcomes services over not this time

measured period. (Small before and sample size after to infer interventions conclusions /services. from). 128

Losses to follow-up were not reported.

Adverse events/ negative experiences of services not reported. Only positive feedback statements from clients included. Scott Objective Prospective Limited Components Outcome Statistical Length of Sources of High

Riskof bias Currentpractice examples © Royal © College of Physicians 2019 Competing Intervention interests and Study and co- Outcome Statistical Results and sources of Overall Risk Study Study objective Study design population intervention measure analysis conclusions support of Biasa 2018(4) clearly pilot study information of the measures analysis follow-up support reported. concerning intervention/ mentioned a performed unclear reported but Data collected characteristic service not priori in the was not competing at >1 centre of patients described. methods appropriate Losses to interests. included in the section of where follow-up not study – only Additional conference applicable. reported. Unclear age and sex poster. whether interventions

patients were were not Adverse recruited Eligibility described. Outcome events consecutively. criteria not assessors not partially described blinded to reported – intervention reports received –

129 Unclear negative whether patients self- experiences patients reported of the entered study many of service. these at a similar point in the outcomes and were Conclusions disease/conditi made were on aware of the intervention. supported by the results,

however Appropriate based on objective/sub small number jective of measures participants used to (low sample assess size to infer outcomes conclusions from). Outcome

130

Unpublished data submitted data Unpublished Currentpractice examples © Royal © College of Physicians 2019 Appendix F: Unpublished data submitted

Table 4: Descriptions of services and outcomes, reported as per the submissions Name Brief description Summary Outcomes East Sussex Better Together (ESBT) Pilot scheme aiming to address the high levels of Following an initiation period the Pilot has reduced the cost of Project Group Dependence Forming prescribing of opiates and other dependence forming prescribed medications by £17,427 per annum over the past three Medication Service medications. Patients have been engaged by the multi- months (May-July 2018). Extrapolating this over a 12 month

disciplinary team and provided with holistic, person- period there is a potential reduction in cost of £ 69,708 per centred interventions. Interventions have used annum. motivational interviewing, mindfulness, TENS machines To date the service has assisted 44 patients to cease prescribing of and other psychosocial support to augment specialist 54 opiate medications. 19 other patients are reducing/detoxing

prescribing support from a GP and practice pharmacist. from opiates. Data relating to well-being (Quality of Life, Level of Activity, Level of Pain, Level of Anxiety, and Quality of Sleep) indicates a positive effect in all five areas, and indicates substantial improvements in

131 quality of life (+19%) for those engaged with the service. Further

data collection is required. Bristol and District Tranquiliser Objectives Key outcomes: Project - Annual report 2017-18 1. To assist those involuntarily addicted to (a) General benzodiazepines to understand and cope with their • Over the past 12 months 251 clients were helped by helpline, addiction, to plan and make a safe withdrawal where 22 at the Project, 6 at the Knowle group, and 6 at the appropriate and to lead normal lives without recourse Southmead group, a total of 285. to any psychotropic medication. • 207 of those in touch by helpline commenced withdrawal 2. To help those taking other prescribed psychotropic (85%), as did 17 of those at the Project (77%) and all 12 of medication to come off this medication where those in the outreach groups (100%). In all 236 out of 285 appropriate. clients commenced withdrawal (83%). 4. To inform, advise and support the families and friends • Of the 34 clients seen face to face, 11 were referred by their of those affected. GP, one was referred by Southmead Hospital and the 5. To inform and advise those professionally involved in remainder were self-referred. the problems of prescribed psychotropic medication • There were a total of 191 new clients during the year. addiction. (b) Medication Services provided • 91 clients came off benzodiazepines completely

Unpublished data submitted data Unpublished Currentpractice examples © Royal © College of Physicians 2019 Name Brief description Summary Outcomes 1. One-to-one prescribed drugs counselling especially for • 54 clients came off antidepressants those new to the Project and those undergoing • 6 clients came off Zopiclone particular difficulty. • 125 clients came off all their medication. 2. Withdrawal groups at the Project led by counsellors (c) Gender and Age but with a strong user involvement. • Of the 251 helpline clients 167 were female and 84 male 3. Outreach withdrawal groups in Knowle and Southmead. • Of the 34 clients seen face to face 17 were female and 17 male.

4. Drop-in availability at the Project for those in particular need. 5. A help-line open 4 days a week. 6. A programme of visits, talks, workshops, seminars,

etc., for doctors and other professionals within the Bristol area. Sheffield CCG controlled drug Controlled drug (CD) monitoring is undertaken in Sheffield Investigating all Fentanyl in Sheffield has created 61 additional monitoring programme to support NHS England’s (NHSE) statutory obligation to monitoring investigations out of a total of 191 across Quarter 2 132 monitor the usage of CD’s across each locality. Monitoring 17/18 and Quarter 3 17/18. This translates into a small 15.5%

aims to support prescribers in their clinical practice and increase in monitoring work load per quarter. not deter or delay them from prescribing important 100% of investigation requests were returned, with 9 significant medicines clinically required by patients. clinical interventions identified, correlating as 14.7% interventions Any prescribing of unusual items, quantities or strengths made overall. The interventions included 6 dose reductions, dose which fall outside of the tolerance levels set by the consolidation and better management of prescriptions which Controlled Drugs Accountable Officer (CDAO) are reduced the likelihood of possible misuse/abuse. Savings highlighted for investigation by the medicines generated at this point total in excess of £1380 per year, with management team (MMT) at the clinical commissioning further savings being realised as dose reductions take place. group (CCG). In order to capture any possible inappropriate use of prescribed Fentanyl, Sheffield CCG was supported by the CDAO in a decision to decrease their tolerance of all immediate release Fentanyl products to zero. Society for an Addiction Free In the field of substance addiction, we work with two None provided Existence (SAFE) quite separate but effective programmes, each of which we normally apply to different forms of addiction:

Unpublished data submitted data Unpublished Currentpractice examples © Royal © College of Physicians 2019 Name Brief description Summary Outcomes A majority of addicts dependent on the main illicit drugs (and including legal alcohol, methadone and Subutex) can be recovered on a 13 week residential self-help addiction recovery training programme, at our delivery partner's established South of England charity based and C.Q.C. registered recovery training centre.

However, addiction to the main medical drugs, including the benzodiazepines, the "C" drugs, "Z" drugs, opiates, and others we find are most often best dealt with via a Small-Dose Step-Down Withdrawal Management

Procedure, taking from 6 to 9 months to attain lasting relaxed abstinence - depending on the drug(s) involved and individual patient circumstances.

133 In both cases we expect 69+% of individuals entering either programme to attain lasting relaxed abstinence.

The reason this is not 100% is simply because half a century of experience has proven beyond doubt that 25 to 30% of all substance addicts are "Resistive Cases" who are not easy to recognise. i.e. Addicts who have no personal intention whatsoever to quit their habit. South Yorkshire & Bassetlaw Controlled drug (CD) monitoring is undertaken in Sheffield Work Load Controlled Drugs Lead Group to support NHS England’s (NHSE) statutory obligation to Investigating all Fentanyl in Sheffield has created 61 additional Targeted controlled drug monitoring monitor the usage of CD’s across each locality. Monitoring monitoring investigations out of a total of 191 across Quarter 2 programme aims to support prescribers in their clinical practice and 17/18 and Quarter 3 17/18. This translates into a small 15.5% not deter or delay them from prescribing important increase in monitoring work load per quarter. The extra workload medicines clinically required by patients. is felt to be warranted due to improvements in patient safety and Any prescribing of unusual items, quantities or strengths outcomes as well as being a very cost effective use of time. which fall outside of the tolerance levels set by the Controlled Drugs Accountable Officer (CDAO) are Interventions highlighted for investigation by the medicines 100% of investigation requests were returned, with 9 significant management team (MMT) at the clinical commissioning clinical interventions identified, correlating as 14.7% interventions

Unpublished data submitted data Unpublished Currentpractice examples © Royal © College of Physicians 2019 Name Brief description Summary Outcomes group (CCG). made overall (see table below). The interventions included In order to capture any possible inappropriate use of 6 dose reductions, dose consolidation and better management of prescribed Fentanyl, Sheffield CCG was supported by the prescriptions which reduced the likelihood of possible CDAO in a decision to decrease their tolerance of all misuse/abuse. Savings generated at this point total in excess of immediate release Fentanyl products to zero. £1380 per year, with further savings being realised as dose In effect, this meant that all prescriptions for these items reductions take place. would be investigated for appropriateness of prescribing,

and the prescriber asked to assure NHSE by providing A targeted drug monitoring programme for opioids is also information relating to the prescribing occurrence - such underway. as the indication, drug, duration, dose, and monitoring arrangements. NHS Brighton and Hove CCG - The Prescribing Incentive Scheme (PIS) has been in place Not yet reported Prescribing Incentive Scheme to encourage high quality cost-effective prescribing in areas of priority within the CCG. Target areas

134 • Routine review of High Cost Primary Care Items

(HCPCI) and Specials prescribing • Medicines optimisation of anticoagulation for atrial fibrillation • Review of inappropriate prescribing of antibiotics in primary care • Reduction of inappropriate initiations of pregabalin for chronic pain: To ensure that the following recently approved guidelines are being implemented by prescribers and agencies in the area of appropriate pregabalin prescribing in chronic pain: o BHCCG Chronic Non-Malignant Pain Prescribing Guidelines o BHCCG Pregabalin Prescribing Guideline • High Dose opioids in chronic non-malignant pain: Facilitate MMT led baseline review on practice

Unpublished data submitted data Unpublished Currentpractice examples © Royal © College of Physicians 2019 Name Brief description Summary Outcomes prescribing of high dose opioids* for chronic nonmalignant pain (ideally remotely if agreed), which will be passed on to the practice** for review. GP to review identified patients that require intervention and reduce dose to <120mg morphine (or equivalent) as per local non-malignant chronic pain guidelines. Record on the ‘Strong Opioid

Reduction - Summary & Data Collection Form’.

**anonymised data will be passed to the MMT in order to identify areas for improvement and learning across the city. • Prescription management • Reducing benzodiazepine and Z-drug prescribing: Individualised Practice Prescribing Target will be based on a move towards a 20% reduction in

135 ADQ/STAR PU [from January – March 2017 level] or <

the national average January – March 2017 (2.11 ADQ/STAR PU), whichever is higher. In order to help practices to achieve this, the CCG has worked with SPfT to produce a letter for surgeries to send to the consultants within the Trust. This letter queries the ongoing need and clinical appropriateness for primary care to continue to supply a prescription for benzodiazepines if a patients BZD was initiated by SPfT. Camden and Islington NHS Service designed to address the pressing need in general Practice A: Foundation Trust - Audit feedback practice of assisting people on long term prescriptions of 115 users of these drugs were identified, 10 were excluded for cycle on reducing hypnotics and benzodiazepine and Z drugs to reduce and/or stop the being intermittent users. 16 declined to participate and 61 did not anxiolytic prescribing using two intake of these drugs. Benzodiazepine and Z long term respond. A further 2 did not attend, leaving 26 participants (12 different approaches in two different drug users in one practice were invited using a letter to benzodiazepine users and 14 Z-drug users. practices in the North Camden attend a focussed hypnotic and anxiolytic clinic run in the locality. practice. Final outcome – BZD/Z drug use Those so identified were invited to attend the clinic where Stopped Reduced Undergoing No

U Currentpractice examples

© Royal © College of Physicians 2019 Name Brief description Summary Outcomes submitted data npublished an initial clinical assessment was conducted by the GP and use of drug use of drug drug detox change the nurse. On completion of this detailed assessment, a in use management plan was devised for each patient specific to BZD 3 (25%) 2 (17%) 5 (41%) 2 (17%) their needs. This included a structured drug reduction (N=12) schedule of benzodiazepines and/or Z drugs. The key principle was to facilitate a slow reduction of the drug Z drug 6 (42%) 2 (14%) 5 (35%) 1 (14%) which could be as little as 2.5mg reduction of diazepam (N=14) (or its equivalent) per week to a more rapid reduction

schedule of as much as 20-30mg reduction of diazepam or Both 9(35%) 4(15%) 10(38%) 3(12%) its equivalent per week depending on the ability and drugs motivation of the person to stop their use of the drug. Practice B:

There was also a structured management plan for other associated health problems that could impact on their 68 long term users of these drugs were identified (31 were intake of hypnotics and anxiolytics. This included the benzodiazepine users, 31 were Z drug users and 6 were users of treatment of: mood disorders and other associated both drugs). Of these, 1 was excluded as they were intermittent psychological problems; physical problems such as rather than long term users. 136 musculoskeletal disorders; pain management and any Uptake of the service: Of the remaining 67 people, 16 declined the

other relevant medical issues that contributed to their invitation and there was no response from 28 people, 3 initially anxiety symptoms or poor sleep patterns. accepted the invitation but then declined to attend the clinic and the remaining 36 agreed to be seen but only 34 (51%) attended From a review of practice A services were revised for the clinic, 16 were benzodiazepine users and 17 were Z drug users practice B: The service was set up in a similar manner as and 1 was a user of both. at Practice A but the users of BZD and/or Z drugs identified on the computer search of the clinical records Stopped Reduced Undergoing No were invited to an overall review of all the drugs use of drug use of drug drug detox change prescribed to them as repeat prescription at the time in use when they were due a review of their repeat medication with a particular focus on the hypnotics and anxiolytics. BZD 6 (33%) 4 (22%) 5 (28%) 3 (17%) (N=17) Z drug 6 (37.5%) 4(25%) 2 (12.5%) 4 25(%) (N=17) Both 12 (35.5%) 8 (23.5%) 7 (20.5%) 7 (20.5%) drugs

Un Currentpractice examples

Name Brief description Summary Outcomes submitted data published

Comparisons of the two services models Audit standard Practice A Practice B set Attendance 10% 28/105 36/67 (53.7%) (24.7%) PHQ > 8 9 10

GAD > 10 17 9.5 Insomnia 10 15 14

Severity > Cessation 25% 22/26 (88.5%) 27/36 (75%) of drug use

(a) Greyed text is reported as part of the programme, however not directly relevant to the focus of this review

137

Current practice examples

Excluded studies

Appendix G: Excluded studies

The excluded studies list includes details of studies excluded from all 5 questions after consideration for each.

Where population / study design / intervention etc. are listed as ‘wrong’, this is in reference to the review protocol for this rapid evidence assessment (appendix A) – i.e. not the population (or other element) of interest for this review, for example a study of harms from heroin use, or opioids obtained by illicit means, would be listed as wrong population. Where a study is excluded based on study design alone applies to the review question it was deemed most appropriate for, as the types of study design differ per protocols. ‘No relevant outcomes’ also refers to outcomes specified in the review protocol for this rapid evidence assessment.

Full literature search Study Exclusion reason Abrahms 1979(5) Published prior to 2008. Wrong population. Illicit drug use – heroin. Adi 2007(6) Wrong population. Illicit opioid use and not for chronic pain. Not prescribed opioids and also already detoxified. Aguiluz, 2018 (7) Wrong study type. Narrative review. Ahmadi, 2002 (8) Wrong population. Not prescription drug use – OUD. Ahmadi, 2003(9) Published prior to 2008. Ahmadi, 2003(10) Published prior to 2008. Ahmadi, 2018 Wrong population. No mention of prescription drug use, includes people with Opiate (11) Use Disorder – therefore likely all illicit drug use. Ahmadi, 2018, Wrong population. No mention of the dependence being on prescription opioids or (12) for chronic pain. Ahmed 2008 (13) No relevant outcomes. Alford, 2013 (14) Wrong study design. Narrative review / case study. Ali, 2017 (15) Wrong population. Non-medical/illicit use of prescription opioids - without a prescription or for euphoria. Alter 2017 (16) Wrong population. Surgical patients (not chronic pain). Altman, 2010 (17) Study design. Literature review. Amanti, 2018 (18) Wrong study type / not relevant to review questions. Development of a guideline, not assessment of the guideline being used in practice. Amarasuriya, Systematic review with different protocol to this review. Risk of mortality with long- 2012 (19) term benzodiazepine use. Amato 2013(20) Wrong population. Illicit opioid use and not for chronic pain. Amato 2011(21) Wrong population. Illicit opioid use. Not prescribed opioids for chronic pain. Amato 2011(22) Wrong population. Illicit opioid use. Not prescribed opioids for chronic pain. Amiri, 2014 (23) Wrong population. No mention of prescription opioids. Population of study is unclear, only references to opioids are illicit. Anonymous, 2009 Wrong study type / not relevant to review question. WHO guidelines, not assessment (24) of their effectiveness. Anonymous, 2014 Not relevant to review questions. Review of clinical evidence and guidelines for (25) gabapentin, only mention of dependence is re. NICE guideline consensus recommendation. Anonymous, 2015 Wrong outcomes. Policy report looking at safety and efficacy, not dependence, (26) discontinuation or withdrawal.

Excluded studies

Study Exclusion reason Anonymous, 2016 Wrong population / study type. Rapid response report. No mention of prescription (27) opioids, assume illicit use. Ansseau, Published prior to 2008. 1993(28) Apelt, 2013 (29) Wrong population. Not prescription drug use – OUD. Argoff 2014(30) Quality of systematic review inadequate. No quality assessment, no details of protocol Asaad, 2011 (31) Wrong population. Illicit opioids users - majority heroin with small proportion tramadol. Ashrafioun, 2016 Wrong population. Illicit use. (32) Ashton, 1990 (33) Published prior to 2008. Baandrup Wrong population. Majority of participants taking BZDs not mentioned on our drugs 2017(34) list - only 24% using oxazepam which is on list. Outcomes not given separately for those drugs on the list. Baandrup Wrong population. Majority of participants (>50%) taking a medication not included in 2016(35) the scope for this review. Outcomes not reported separately for those drugs that are on the pre-specified list. Baandrup Wrong population. Majority of participants (>50%) taking a medication not included in 2016(36) the scope for this review. Outcomes not reported separately for those drugs that are on the pre-specified list. Baandrup, 2016 Not relevant to review questions. Focus is whether melatonin restores circadian (37) rhythm in this group. Baandrup Wrong population. Includes studies beyond the scope of this review and illicit use. 2018(38) Bachhuber, 2016 Wrong population. Looks at whether introduction of pain management programmes (39) is associated with BZD misuse emergency department admissions. Mixed illicit and prescription misuse, unable to separate for analysis. Back 2011(40) Wrong population. Many were not introduced to the drug as a prescription from a doctor. Many using recreationally. Back, 2011 (41) Wrong population. Mainly illicit drug use. Does include prescription methadone, but results for illicit methadone and prescription are reported pooled. Bagra, 2018, (42) Wrong population. Majority using illicit opioids (heroin). Baewert, 2012 Wrong population. Not prescription drug use. (43) Bagoien 2013(44) Wrong population. Majority illicit drugs/alcohol. Only included BZDs that were not used as prescribed by physician. Baker 2005 (45) Wrong population. Illicit drug use – amphetamines. Baldacchino, 2012 Wrong population. Illicit drug use – heroin or methadone. (46) Baldacchino, 2016 Systematic review with different protocol. (47) Baldacchino, 2016 Study design and population. Only reporting on design and feasibility. (48) Baldini, 2012 (49) Systematic review – quality assessment and methods inadequate. Baldwin, 2015 Wrong outcomes. Safety and efficacy not harms. Literature review of safety of (50) pregabalin. References checked re dependence / withdrawal. Ballard, 2013 (51) Wrong study design. Correction due to omitted text from original article. Balodimos, 2015 Wrong population. Heroin users.

Excluded studies

Study Exclusion reason (52) Banta-green 2018 Wrong population. Mostly heroin users. (53) Banta-Green, Wrong population. Outcomes not relevant to review question. Although some people 2010 (54) may be dependent, this can't be clearly determined from the paper. Quantitative analysis of more qualitative data, relates to side effects. Barry, 2013 (55) Wrong population. Unclear if any are dependent on prescription opioids. Barry, 2016 (56) No relevant outcomes. Bartholomaeus Not relevant to review questions. Evaluates tamper resistant properties of two 2012(57) extended release drugs - chemical testing on the drugs. Bartoli, 2015 (58) No relevant outcomes. Reports side effects from use, not harms from dependence. Baser, 2014 (59) Not relevant to review questions. Determining prevalence and costs of prescription opioid dependence in US veterans. Bashir, 1994(60) Published prior to 2008. Bassiony, 2018 Wrong population. Substance Use Disorder. Some taking tramadol, but appears to not (61) be prescribed. Bassiony, 2018, Wrong population. Includes people obtaining tramadol without prescription and using (62) for conditions other than chronic pain. Bautista, 2017 Wrong population / Not relevant to review question. Looks an analysis of reasons for (63) increase in dose, not dependence, discontinuation or withdrawal. Baxley 2018 (64) Wrong population. 97% reported heroin as opioid of choice. Beaudoin, 2016 Not relevant to review questions. Assessing ability of this instrument to identify those (65) misusing/abusing prescription opioids. Not individual factors that may lead to dependence/harms of dependence or methods of treatment. Beaudoin, 2016 Systematic review – Definition of misuse unclear – references screened and relevant (66) studies ordered. Becka 2004(67) Article not in English Becker 2005(68) Wrong intervention. Intervention is to assess provider satisfaction of treatment in offices. Unclear if correct population as for treatment of opioids dependency but cause and if still prescribed unknown Becker, 2008 (69) Wrong population. Illicit drug use - non medical use. Becker, 2013 (70) Not relevant to review questions. Review of tools for patient reporting of safety, efficacy or harms. Belaise, 2014 (71) Wrong study type. Letter to editor reporting case studies. Belknap 2008 (72) Wrong population. Hospitalised surgical patients, no dependency/withdrawal outcomes. Bell 2008 (73) Wrong population. Illicit drug use. Belleville 2008 Wrong study design - unadjusted data. (74) Beneitez, 2017 Wrong population. No mention of prescription drug use. (75) Bentzley 2015(76) Systematic review – inadequate methodology and quality assessment. Bergman Wrong population - not all using drugs of dependence. Focus is treating the adverse 2018(77) event of the antipsychotic drugs. Berna, 2015 (78) Systematic review – different protocol. Inadequate risk of bias and quality assessment. Focus is to develop recommendations, no analysis of outcomes. Beswick, 2003 Wrong population. Illicit drug use. (79)

Excluded studies

Study Exclusion reason Bet, 2013 (80) No relevant outcomes. Adverse events rather than withdrawal and dependence harms. Bickel, 2008 (81) Wrong population. Illicit drug use. Bigal, 2009 (82) Wrong study design – literature review. Biondi, 2010 (83) Wrong study type / not relevant to review question. Abstract on safety and tolerability, not harms. Bisaga, 2014 (84) Wrong population. Includes a mix of heroin dependent and prescription opioid dependent - but people excluded if they were still being prescribed opioids for pain or illness. Only 18% included were dependent on prescription opioids. Bishop, 2018 (85) Wrong population. Users had been taking methadone and switched to buprenorphine (illicit drug use, not mention of prescription use). Black 2012(86) Wrong study type. Abstract. Bleckwenn, 2016 Not relevant to review questions. Focus is misuse of substitution medications for illicit (87) drug use. Blom, 2007 (88) No relevant outcomes. Blondell 2008 (89) Wrong population. Illicit drug use. Blondell 2010(90) Wrong population. Majority of patients taking hydrocodone - not on pre-specified drug list. Blondi, 2010 (91) Order cancelled - article not in English. Bobes 2012 (92) Wrong study design (higher quality evidence available). Bockting 2018 Wrong intervention/study aim. Aim of the study is preventing relapse of depression (93) with no mention of dependence. Bogetto, 2002 Published prior to 2008. (94) Bohnert 2011(95) Wrong study design (case control study). Bohnert 2016 (96) Wrong population. Non-medical use of prescription opioids. Bonar, 2014 (97) Wrong population. Non-prescription opioid use. Bondi, 2018, (98) Wrong population. Includes those using illicit opioids. No mention of prescription opioids. Bourgeois, 2014 Wrong study design (higher quality evidence available). (99) Bowman, 2013 Wrong study design. Narrative review of strategies. (100) Boyuan, 2014 Wrong population. Heroin dependence. (101) Braden, 2009 Wrong population / not relevant to review questions. Looks at trends in long term (102) opioid use based on whether used for depression or not. Not people who are dependent. Brady, 2017 (103) Wrong population. Not on prescription opioids as looking at abuse of drugs. Branstetter 2008 Wrong population. Illicit drug use. (104) Breen 2003(105) Wrong intervention / population. Methadone being used in this scenario to treat drug misuse disorder. Brigham, 2004 Order cancelled - conference abstract. (106) Broderick, 2009 Wrong study type. Editorial. (107) Brown, 2010 Wrong population. Mainly heroin use - unclear if people were non-prescription opioid

Excluded studies

Study Exclusion reason (108) users who then occasionally use prescription opioids, or a mix initially. Brown, 2011 Not relevant to review questions. Looking at one cohort and selecting risk categories (109) and checking urine for drug use. Checking to see if investigators following guidelines for risk selection and changing risk according to urine results. Brown, 2014 Wrong population. Excludes people who need to take opioids for chronic pain. (110) Brown, 2017 No relevant outcomes. (111) Bruehl, 2015 Not relevant to review questions. Prevalence of benzodiazepine use. (112) Brummett, 2017 Wrong population. Opioid use post-surgery not chronic pain. (113) Bucher Bartelson, No relevant outcomes. 2017 (114) Bujold, 2012 Not relevant to review questions. Development and implementation of a guideline to (115) reduce drug diversion. Butler 2013(116) Not relevant to review questions. Focuses on non-medical use/abuse of prescription opioids - e.g. abuse by tampering. Butler, 2011 (117) Not relevant to review questions. Risk of abuse of different drug preparations, not risk of dependence etc. Butler, 2018 (118) Not relevant to review questions. Looks at prescription-adjusted rates of abuse, but not risk factors for abuse. Buttram, 2014 Wrong population - opioids not said to be prescribed for chronic pain. Very specific (119) population - MSM, but does report risk of prescription opioid abuse. Buynak, 2015 Wrong study design. Open label extension - non-comparative. Better quality evidence (120) available for this question. Not comparative – includes people who previously received tapentadol, oxycodone or placebo, but when all are given tapentadol. Results are reported according to prior treatment group. Cadth, 2012 (121) Not relevant to review question / no relevant outcomes. Cadth, 2013 (122) Not relevant to review question / wrong study type. List of references only. Cadth, 2014 (123) Not relevant to review question / wrong study type - reference list. Compares safety of two preparations of the same treatment. Cadth, 2014 (124) No relevant outcomes. Cadth, 2015 (125) Systematic review - inadequate quality assessment. Review - strategies for BZD discontinuation. Cadth, 2015 (126) Systematic review - inadequate quality assessment. Cadth, 2015 (127) Systematic review - inadequate quality assessment. Calcaterra, 2018, Wrong population. Includes those given opioids for cancer and acute pain. (128) Caldentey, 2008 Order cancelled - not in English. (129) Campbell, 2017 Wrong population / not relevant to review population. Looks at risks of aberrant drug (130) related behaviour (diverting drugs to family members / receiving from family members) not risk of becoming dependent. Candiotti, 2010 Wrong study design. Literature review, not systematic. (131) Canham 2014 Non-UK study (excluded from patients experience question). (132) Canan, 2017 (133) Wrong population / not relevant to review question. Review of algorithms to detect

Excluded studies

Study Exclusion reason non-medical opioid use. Cardinali Published prior to 2008. 2002(134) Cardinali 2016 Systematic review – inadequate methodology. (135) Carroll 2006(136) Wrong population. Alcohol or illicit drug use within last 28 days as inclusion criterion. Casati, 2012 (137) Not relevant to review questions. More focus on prevalence. Cassano Published prior to 2008. 1996(138) Cassidy 2014(139) Wrong population. Adults assessed for substance abuse problems, not clear whether abuse was a result of becoming dependent on prescription opioid. Cepeda, 2013 Wrong study design - comparing 2 different opioids. (140) Chabal 1997(141) Published prior to 2008. Chan 2011 (142) Wrong study design (narrative description). Chan, 2018 (143) No relevant outcomes. Chand, 2013 Wrong population. No indication that abuse began after dependence on prescription (144) opioids. Chaparro Not relevant to review questions. Not approaches to prevent or treat dependence, 2013(145) but the effectiveness of opioids for chronic pain. Chaparro Not relevant to review questions. Not approaches to prevent or treat dependence, 2014(146) but the effectiveness of opioids for chronic pain Chatterjee, 2018 Wrong population. Homelessness and opioid use disorder. (147) Chattopadhyay Wrong study design. Case report and literature review. 2016 (148) Chavoustie, 2017, Wrong study design. Literature review. (149) Cheatle, 2013 Wrong study design. (150) Chen 2013(151) Wrong population. Illicit drug use. Cheon, 2016 No relevant outcomes. Just reports on effectiveness. (152) Cheung, 2014 Not relevant to review questions. Systematic review of existing guidelines, not an (153) assessment of those guidelines being implemented. Chopra, 2009 Wrong population. Abuse of cocaine and opioids, likely to have been obtained illicitly (154) without prescription. Intravenous and intranasal routes of administration. Chou, 2009 (155) Systematic review and guideline – analysis not reported. Quality assessment reported insufficiently. References checked re risk factors. Chou, 2015 (156) Systematic review. Risk of bias and quality assessment inadequate. Christensen, 2014 Wrong population. Not prescription opioid use, may contain some prescription opioid (157) users, but not reported separately, or a percentage of population. Cialdella Published prior to 2008. 2001(158) Cicero 2007(159) Wrong population. People using opioids to get high. Cicero 2008(160) Wrong population. Includes those using prescription opioids to get high - abuse rather than dependence. Also includes large proportion obtaining illicitly from sources other than doctors.

Excluded studies

Study Exclusion reason Cicero 2012(161) Wrong population. Those abusing oxycodone (using it to get high through alternative administration routes, e.g. nasal). Cicero, 2017 (162) Wrong intervention. Not interested in illicit use or comparison with illicit use. Cicero, 2017 (163) Systematic review - different protocol. Screened for relevant references. No relevant papers identified - studies on prescription opioid misusers. Clancy 2013 (164) No relevant outcomes. Clark, 2008 (165) Wrong study design. Narrative review only. Clemans-Cope, Wrong population. Not prescription drug use. 2017 (166) Cochran, 2015 Wrong population. Only 21.7% opioid abusers (not stated whether prescription use or (167) other). Cock, 2018 (168) Wrong population. Codeine dependent misusers. Unclear if prescribed or over the counter. People using supratherapeutic doses. Colquhoun, 2013 Order cancelled - not available, inspection of abstract appears to be illicit use. (169) Colson, 2012 Wrong study type. Narrative review only. (170) Cooper, 2018 No relevant outcomes. No qualitative outcomes (patient experience question). (171) Conermann, 2014 Not relevant to review questions. Comparing methods of compliance monitoring. (172) Conrardy, 2016 Not relevant to review questions. Patient views on whether the drugs are addictive or (173) not, rather than their experiences of harms. Cornish, 2010 Wrong population. Not prescription drugs. (174) Correa, 2015 Not relevant to review questions. Sleep apnoea association, not harm from (175) dependence. Cossmann, 2016 No relevant outcomes. Describes numbers and demographics of patients with opioid (176) addiction but not patient views. Courtney von, Wrong population. Not prescription drug use. 2017 (177) Couvee 2002(178) Published prior to 2008. Couvee 2002(179) Published prior to 2008. Couvee 2002(180) Published prior to 2008. Coviello, 2010 Wrong population. Opioid dependent offenders. (181) Coyle, 2018 (182) No relevant outcomes. Cragg, 2017 (183) Wrong study type. Systematic review protocol. Crawford- Not relevant to review question / wrong study type. Summary of study reported Faucher, 2011 elsewhere, just looking at efficacy of escitalopram for hot flushes. (184) Creac, 2011 (185) Wrong population. Medication overuse headache - only 1 participant used opioids, other drugs used not relevant to protocol. Crits-Christoph, Wrong population. Appears to be illicit use; opioid dependence, no mention of 2016 (186) prescription. Croissant, 2008 Wrong study design (higher quality evidence available). (187) Crowe 2017 (188) Systematic review with different protocol.

Excluded studies

Study Exclusion reason Culberson, 2011 No relevant outcomes. (189) Cunningham, Wrong population. Some people were dependent on opioid analgesics, but unclear if 2011 (190) that was due to prescription. Majority illicit drugs. Da Costa Wrong intervention/comparison. Not approaches to prevent or treat dependence, but 2014(191) the effectiveness of opioids for chronic pain. D’Agostino, 2017 Wrong population. Assumed illicit as online comment from chatrooms; actual (192) comments not included just themes. Dakwar2015 Wrong interventions. Discontinuation of medication used to treat opioid dependency. (193) Daniell, 2008 No relevant outcomes. Potential harms of medication rather than dependence (194) outcomes. Daniulaityte 2012 Wrong population. Misusers of various drugs. Not necessarily prescribed. (195) Daniulaityte Published prior to 2008. 2006(196) Darker 2015(197) Wrong population. Harmful benzodiazepine use, abuse or dependence in opiate dependent and non-dependent groups. Darnall, 2012 Not relevant to review question. Review of risks and consequences. (198) Dart, 2012 (199) Wrong study design (higher quality evidence available). Davies 2018(200) Systematic review. Inadequate methodology – no risk of bias or quality assessment. Davis 2016(201) Wrong population. Various drugs of abuse not listed in this review protocol. Davis 2017(202) Wrong population. Illicit drug use. Davis, 2018 (203) Wrong population. 'Substance use disorder'. Day 2005(204) Wrong population. Not prescribed opioids for chronic pain (illicit use). De, 2008 (205) Wrong population. Heroin dependence only. De Fulio Wrong population. Use of heroin at least 21 of last 30 days as inclusion criterion. 2012(206) Degenhardt 2010 Wrong population. Heroin as well as opioid addicts (unclear if prescription opioids). (207) Degenhardt Wrong population. Illicit drug use. 2015(208) De Gier, 2011 No relevant outcomes. Looks at determinants of successful discontinuation, not risk (209) factors for the harms. Dehghani-Arani, Wrong population. Illicit drug use. 2013 (210) Delcher, 2017 Wrong study type. Dissertation only. (211) Del Rio 1997(212) Wrong population. Illicit drug use. De Maeyer, 2010 Systematic review- screened for relevant references. Most studies on heroin users (213) and some were studies on opiate dependent individuals but did not meet our protocol criteria (participants who were dependent on illicit opioids drugs in receipt of substitute medication; non-UK studies) De Maricourt, Wrong study design (higher quality evidence available). 2016 (214) Demidenko, 2017 Wrong study design. (215)

Excluded studies

Study Exclusion reason Dengler, 2016 Order cancelled - conference abstract (216) Dennis, 2014 Wrong population. Illicit drug use. (217) de Oliveira, Wrong intervention/comparison. Not approaches to prevent or treat dependence, but 2016(218) the effectiveness of opioids for chronic pain. Derry 2016(219) Wrong intervention/comparison. Not approaches to prevent or treat dependence, but the effectiveness of opioids for chronic pain. Dhawan, 2015 Wrong population. Illicit drug use (primarily heroin). (220) Di Costanzo Order cancelled. Not available in English. 1992(221) Diener, 2018 Wrong population. Review of medication overuse headache, including prevalence. (222) Relates to drugs outside of our scope, some opioid use, but for acute pain not chronic. Dijkstra 2008 Wrong population. Illicit drug use. (223) Dijkstra, 2010 Wrong population. Not prescription drug use. (224) Doolittle 2011 Wrong population. Illicit drug use. (225) D'Onofrio Wrong population. Non-medical use of prescription opioids - those requiring opioids 2015(226) for a pain condition were excluded. D'Onofrio, 2017 Wrong population. Participants were excluded if opioids were needed for pain. (227) Donohue, 2018 Wrong study design (higher quality evidence available). (228) Dou 2018 (229) Systematic review - inadequate methodology. Dowell, 2016 Wrong study type / not relevant to review question. Guideline on prescribing opioids, (230) no assessment of the effect of the guideline. Dunn 2010(231) Wrong population / outcomes. Overdoses not always the result of dependence - includes accidental ingestion and suicide attempts. Not all drugs used on pre-specified list. Dunn 2011(232) Systematic review – inadequate methodology. No risk of bias or quality assessment. Dunn 2015(233) Wrong population. Using prescription opioids illicitly - without a valid prescription. Dunn, 2017 (234) Order cancelled - erratum/corrections Dunn, 2017 (235) Wrong population. Primarily heroin users. Dreyer, 2015 Not relevant to UK context. (236) Dutra 2008(237) Wrong population - illicit drug use Dzialdowski, 1998 Wrong population. Illicit drug use. (238) Eccleston, Systematic review – inadequate methodology. No quality assessment undertaken. 2017(239) Edlund, Published prior to 2008. 2007(240) Edlund, Wrong outcomes. Does not compare any relevant outcomes between different 2010(241) interventions/risk factors - gives incidence of chronic opioid use in certain subsets of patients but does not indicate dependence.

Excluded studies

Study Exclusion reason Edlund, 2010 Not relevant to review questions. Looks at reasons for heavy opioid use, e.g. higher (242) doses, particularly related to insurance status (US based). Ehrich, 2015 (243) Not relevant to review questions. Looks at opioids as a treatment alternative to antidepressants. Doesn’t report about dependence etc. Eibl, 2017 (244) Wrong population. Not prescription drug use. Eilender Systematic review – Inadequate methodology. No quality assessment, no data or 2016(245) analysis that can be reused. El-Aneed 2009 Wrong population. Abusers/diversion of prescriptions. (246) Elefritz, 2016 Wrong population. ‘Critically ill’ including people with cancer pain. (247) El-Hadidy, 2015 Wrong population. Illicit drug use. (248) Els 2017(249) Wrong intervention/comparison. Not approaches to prevent or treat dependence, but the effectiveness of opioids for chronic pain. Elsesser Published prior to 2008. 1996(250) Enriquez-Puga, Wrong population. Aim of intervention was actually to increase prescribing of 2009 (251) particular antidepressants. Espostito 2009 No relevant outcomes. Prevalence of benzodiazepine use. (252) Evans, 2014 (253) Not related to review questions. Review of misuse and abuse of prescription antidepressants. Not reporting harms. Everitt 2018(254) Wrong intervention/comparison. Not approaches to prevent or treat dependence, but the effectiveness of antidepressants for insomnia. Everly 2011(255) Wrong population. Illicit opioids - use of heroin at least 21 of the last 30 days as an inclusion criterion. Facey 2016 (256) Not a review question. 16 cases of patients received naloxone but were deemed to not follow guidelines for use. Faggiano Wrong population - illicit opioid use 2003(257) Fareed, 2012 Wrong study design (higher quality evidence available). (258) Fatseas, 2018 Order cancelled - not available. Inspection of the abstract suggests not relevant to (259) review questions. Fava, 2018 (260) Systematic review – inadequate reporting of risk of bias. No quality assessment. Different inclusion criteria. Fava, 2015 (261) Systematic review – inadequate reporting of risk of bias. No quality assessment. Different inclusion criteria. Fava, 2011 (262) Not relevant to review question. Feelemyer, 2014 Wrong population - illicit drug use. (263) Feingold, 2017 No relevant outcomes. Factors associated with problematic use of prescription (264) opioids, not risk of dependence. Fenton, 2016 Wrong study type. PhD thesis. (265) Fergusson, 2008 Wrong population. Childhood abuse links to mental health issues including substance (266) dependence (likely illicit). Ferguson, Wrong study design. Non-comparative, so only include if no better data.

Excluded studies

Study Exclusion reason 2012(267) Fernandes Published prior to 2008. 2002(268) Ferri, 2013(269) Wrong population. Not prescribed opioids for chronic pain (illicit use). Fibbi, 2012 (270) Wrong population. Includes substantial proportion under age of 18. Also includes proportion who may not have been prescribed prescription opioids initially prior to misusing. Fiellin, 2008 (271) Wrong population. Mix of prescription and heroin addicts, results not reported separately. Fiellin, 2014(272) Wrong population. Patients dependent on prescription opioids but those taking prescription opioids for a pain condition were excluded. Fine, 2010 (273) Wrong study design. Non-comparative cohort. Better quality evidence available for opioids for this question (Harms). Finkelman, 2017 Order cancelled - not available. Inspection of abstract suggests not relevant to review (274) questions. Finley, 2017 (275) Wong study type. Qualitative review of prescription drug monitoring programmes. Fischer 2013 No relevant outcomes. Risk factors for non-medical prescription opioid use defined as (276) pain relief pills without a prescription or a doctor telling them to take them. Fishbain 2011 Wrong study design, risk factors and outcomes. (277) Fishbain, 2012 Wrong population. Not all relating to prescribed opioid use. (278) Fister, 2010 (279) Wrong study type. Summary of articles to read in other journals. Fixsen, 2016 (280) Wrong study design. Personal account. Fixsen, 2017 (281) Wrong population. No distinction made between prescribed and illicit use. Fluyau 2018(282) Wrong study type. Literature review, not systematic. Frandsen, 2014 No relevant outcomes. Potential harms of medication rather than (283) dependence/withdrawal. Franklin Wrong study design (higher quality evidence available). 2012(284) Frauger, 2009 Wrong intervention. Drug not included in protocol. (285) Fredheim 2008 No relevant outcomes. (286) Freire 2011 (287) No relevant outcomes. Harm of dependency/withdrawal not discussed. Only that benzodiazepines known to have problems with dependency and should be second choice. Freire 2011 (288) No relevant outcomes. Freynhagen Wrong study type. Qualitative review of pregabalin as a treatment for withdrawal. 2016(289) Fullagar 2009 Wrong study design. Article not a study. (290) Furukawa Wrong intervention/comparison. Not approaches to prevent or treat dependence, but 2001(291) the effectiveness of opioids for chronic pain. Gafoor 2018 (292) Not relevant to review question. Looks at relationship between antidepressant prescribing and weight gain. Gahr 2013 (293) Wrong comparison. Cases of withdrawal and discontinuation phenomena from different studies placed in cohorts and compared. Systematic review - did not reference included studies.

Excluded studies

Study Exclusion reason Gaiennie 2018 Wrong study design (higher evidence available) (294) Garcia-Guix, 2018 Wrong study type / wrong population. Guest editorial on psychiatric comorbidities in (295) people with substance use disorder (illicit use). Garg 2013 (296) Wrong study design (higher quality evidence available). Garland, 2013 Not relevant to review question / no relevant outcomes. Not risk factors. (297) Garland, 2014 Not relevant to review questions. Reanalysis of another study of two withdrawal (298) interventions looking at patterns in outcomes. Garland, 2014 Not relevant to review questions. Looks at the effectiveness of the intervention on (299) pain and function, not related to dependence etc. Garland, 2014 Wrong risk factors. (300) Garland, 2015 Not relevant to review questions. Focus is on reward processing. (301) Garland, 2017 Wrong population. Opioid users but not dependent. (302) Gaughwin Wrong population. Illicit opioid users on methadone programmes. 1998(303) Gerardin, 2014 Wrong population. No relevant outcomes - just used questionnaire to work out (304) numbers they considered dependent; no harms reported. Gerra, 2002(305) Published prior to 2008. Ghaemi, 2010 Wrong population. Shows that no benefit to continue on antidepressants once (306) stabilised from episode. Ghalehney, 2018 Wrong population. Illicit drug use. (307) Ghitza, 2016 Wrong population – not specific to prescription drug use. Narrative review only. (308) Gibiino 2013 Wrong population. No harms associated with dependence/withdrawal just 8 weeks (309) adverse events from drug. Gibson, 2016 Non-UK study (excluded from patients experience question). (310) Gibson, 2017 No relevant outcomes. Study reports development of a benzodiazepine prescribing (311) support tool and reviews in how many previous prescriptions the tool had been adhered to the tool. Gilbert, Published prior to 2008. 1993(312) Gillaizeau, Not relevant to review question. Not relating to drugs on protocol. Review of 2013(313) computerised advice on drug dose to improve prescribing. Gilson, 2012 (314) Wrong study design (higher quality evidence available). GlaxoSmithKline, Cancelled - clinical trial webpage. 1992 (315) GlaxoSmithKline, Cancelled - clinical trial webpage. 1993 (316) GlaxoSmithKline, Cancelled - clinical trial webpage. 1994 (317) GlaxoSmithKline, Cancelled - clinical trial webpage. 1994 (318) GlaxoSmithKline, Cancelled - clinical trial webpage.

Excluded studies

Study Exclusion reason 1994 (319) GlaxoSmithKline, Cancelled - clinical trial webpage. 1994 (320) GlaxoSmithKline, Cancelled - clinical trial webpage. 1995 (321) GlaxoSmithKline, Cancelled - clinical trial webpage. 1996 (322) GlaxoSmithKline, Cancelled - clinical trial webpage. 1999 (323) GlaxoSmithKline, Cancelled - clinical trial webpage 2001 (324) Godfrey, 2008 No relevant effectiveness outcomes. Cost analysis of an intervention trialpublished in (325) 2006. Costs are based on 2005 prices. Costs have not been included as these are uninformative without corresponding effectiveness data. Gonzalez, 2015 Wrong population. Opioid prescription drugs but not with a prescription necessarily - (326) using intra-nasally and also includes those dependent on heroin. Goldstein Wrong population. Illicit drug use. 1973(327) Gomes 2011(328) Wrong population/outcomes. Includes those under 18 years of age. Unclear if deaths due to dependence issue - includes those where death was accidental or due to suicide. Gomes 2017(329) Wrong outcome - not to do with dependence. Case-control study. Looks at co- prescription of gabapentin and opioids and opioid overdose. Not sure it's relevant to the outcome we want? Gorgels 2005 Wrong study design (higher quality evidence available). (330) Gorgels, 2007 No relevant outcomes. Looks at rates of prescribing other drugs when people stop (331) taking BZDs. Gorgels, 2008 No relevant outcomes. Looks at practice visits before and after discontinuation. (332) Gould, 2014 (333) Systematic review. Majority of included studies prior to 2008, others checked for inclusion. Gowing Wrong population. Not prescribed opioids for chronic pain (illicit use). 2016(334) Gowing Wrong population. Not prescribed opioids for chronic pain (illicit use). 2017(335) Gowing, 2009 Wrong population. Systematic review, mainly including illicit drug dependence. (336) Gowing Wrong population. Not prescribed opioids for chronic pain (illicit use). 2010(337) Gowing Wrong population. Not prescribed opioids for chronic pain (majority illicit use). 2017(338) Graham, 2008 Not relevant to review questions. Focus on accidental drug deaths. (339) Green, 2011 (340) Not relevant to review question. Trialling people for intrathecal opioids. Green 2015 (341) No relevant outcomes. Systematic review of prescription monitoring programmes web based materials content. Green, 2017 (342) Not relevant to review question. Epidemiological review. Griesbach, 2015 Not relevant to review question. Programme to improve safety of prescribing - no

Excluded studies

Study Exclusion reason (343) focus on dependence withdrawal etc. Mainly drugs outside of our protocol. Griffin, 2014 Wrong study type: unadjusted data and no clear risk factors. (344) Griffin, 2015 Not relevant to review questions. Looks at quality of life in opioid dependent people (345) compared to those who aren't dependent. Griffin, 2016 Not relevant to review questions. Study describes link between pain and relapse to (346) opioid use. Not risk factor for dependence. Griffin, 2018 Wrong study type. Dissertation thesis. (347) Griswold, 2013 Cancelled - thesis not open access. (348) Gryczynski, 2014 No relevant outcomes. Patients’ reasons for stopping BZD treatment (from (349) questionnaire not views on harms. GSK 2002(350) Citation only. Guaiana, 2016 Systematic review with different protocol. Not relevant to any of our review questions (351) looks at link with PTSD, varies whether people had PTSD at baseline or not. Gudin, 2018, Wrong study design (higher quality evidence available). (352) Guina, 2015 (353) Not relevant to review question. Review of efficacy of benzodiazepines - does include a section on discontinuation / withdrawal but references prior to 2008. Gunderson, 2015 Wrong population. Illicit drug use. (354) Gunderson, 2016 Wrong population. Illicit drug use. (355) Guo 2018 (356) Wrong population. Illicit drug use. Hadjistavropoulos No relevant outcomes. Dependence only mentioned once in vague comment reported , 2014 (357) from a nurse. Hadley 2012(358) Wrong population. Majority using a BZD not on the pre-specified list. Haegerich, 2014 Wrong study design. Narrative review with limited information/data given. (359) Hajak 2003(360) Wrong study design. Review of case reports only. Hajak, 2015 (361) Wrong study design (higher quality evidence available). Hale, 2015 (362) Wrong study design (higher quality evidence available). Hall, 2016 (363) Wrong population. Opioid use, no mention of prescription. Hamann, 2007 No relevant outcomes / not relevant to review question. Doesn't report harms, just (364) that there were no cases of withdrawal. Hammig 2014 Wrong population. Illicit drug use. (365) Hansen, 2011 Wrong study type, wrong population. Very specific population - interviews these (366) people / give questionnaires to determine aberrant use of prescription opioids, but does not report on risks of misusing prescription opioids or harms etc. Hantouche, 1998 Cancelled - article not in English (367) Hantouche Published prior to 2008 1998(368) Harrison-Read, Published prior to 2008. 1996(369) Hartung 2018 Wrong study design – higher quality evidence available.

Excluded studies

Study Exclusion reason (370) Hartung, 2010 Not relevant to review question. Looks at change in prescribing practice of not giving (371) free-prescription samples and effect it has on prescribing. Covers all drugs, not specific to those on our protocol or to dependence etc. Hartung, 2014 Wrong population. Not prescription drug use. (372) Hartzler, 2010 Wrong population. Methadone maintained. (373) Hassan, 2017 No relevant outcomes. Study looked at whether people with PTSD were more likely to (374) have opioid use disorder (no mention of prescription) than non PTSD. Hatcher, 2018 Unclear population. No mention of prescription - appears to be illicit use. (375) Hawk, 2018 (376) Wrong population. Illicit drug use. Hay, 2008 (377) Not relevant to review questions. Reports relapse of bulimia in people discontinuing antidepressants when taking those as a treatment for bulimia. Systematic review and only identifies one RCT that they state is not directly relevant. Not dependence, withdrawal or discontinuation harms. Hay, 2009 (378) No relevant outcomes. Study compared levels of hyperalgesia in people taking opioids for chronic pain vs. methadone maintained people and healthy controls. Hay, 2010 (379) Not relevant to review questions. Reports relapse of bulimia in people discontinuing antidepressants when taking those as a treatment for bulimia. Systematic review and only identifies one RCT that they state is not directly relevant. Not dependence, withdrawal or discontinuation harms. Helm, 2008 (380) Wrong population. Review, no mention of prescription drugs. Focus on illicit use. Hengartner 2018 Wrong study design. Letter. (381) Henriksen, 2016 Wrong population. Illicit drug use. (382) Hesse 2007(383) Review withdrawn from publication. Published prior to 2008. Heser, 2018 (384) No relevant outcomes / not relevant to review questions. Dementia not harm of dependency/withdrawal but long term association with drug. Heslin, 2011 (385) Wrong population / not relevant to review question. Opioid misusers withdrawing from treatment (no mention of prescription opioids - likely to be illicit), looking at correlates with quality of life. Hewitt, 2015 Cancelled - thesis not open access. (386) Hill, 2012 (387) Wrong intervention. Quantitative questionnaire; programme aimed to reduce drug overdose deaths rather than treat dependence. Hillhouse, 2009 Cancelled - conference abstract. (388) Hillhouse, 2012 Cancelled - conference abstract. (389) Hindmarch, 2000 Published prior to 2008 (390) Hitzeman, 2010 Not relevant to review questions. Clinical opinion about prescribing opioids for people (391) with osteoarthritis. Hojsted, 2013 Not relevant to review questions. Assessing presence of various addictive behaviours (392) in different groups of patients - those with/without chronic pain treated with/without opioids.

Excluded studies

Study Exclusion reason Holbrook, 2013 Wrong population. Not prescription drug use. (393) Holland, 1995 Wrong study design. Letter. (394) Holliday2017 Not relevant to review questions. Study to assess whether training would mean fewer (395) prescriptions. Horspool 2008 Systematic review with different protocol. Buprenorphine reducing regime for (396) withdrawal from illicit use or detox following methadone maintenance. Houtsmuller, Wrong population. All heroin users. 1998 (397) Howard, 2016 Wrong population. Illicit drug use. (398) Howe, 2012 (399) Not relevant to review question / wrong population. Looks at people who have desire to stop taking opioids, but survey is closed questions on opioids. Not people's views of harms. Also not necessarily people dependent. Hser 2011(400) Wrong population. Illicit drug users. Hser, 2016 (401) Wrong population. Not prescription drug use. Hser, 2017 (402) Wrong population. Illicit drug use. Hsu, 2004 (403) Cancelled - conference abstract. Hu, 2018 (404) Wrong population. Illicit drug use. Huang, 2002 Cancelled - article not in English. (405) Hunt 2013(406) Wrong population. Substance misuse - not prescription drug use and majority not drugs listed in our protocol. Hussain, 2015 Wrong population. No mention of prescription drugs, appears to be illicit opioid use (407) (including heroin). Hussain, 2017 Cancelled - conference abstract. (408) Iafrati, 2015 (409) Wrong population. Drug addiction, type not specified Iannone, 2013 Not relevant to review questions. Looks at effect of antidepressants on cognitive (410) function. Ilgen 2011(411) Wrong population. Includes those taking non-opioid pain medications and also those with abuse of various substances (not limited to prescription opioids). Inciardi 2009 Wrong population. Abusers of prescription opioids. Not all obtaining legitimately from (412) prescribers. Imani, 2015 (413) Wrong population. Illicit drug use. Isaka, 2009 (414) Cancelled - article not in English Ives 2006(415) Wrong outcomes and pre-2008. Misuse is not limited to dependence/withdrawal symptoms - includes those involved in diversion of drugs, use of illicit stimulants, prescription forgery, etc. Iwanicki, 2016 Not relevant to review question. Looks at rates of abuse and diversion, not harms. (416) Iyer, 2008 (417) Systematic review – inadequate methodology (including no risk of bias or quality assessment). Jackman, 2008 Wrong study type / not relevant to review question. Narrative review on approaches (418) to chronic non-malignant pain. Jacob, 2015 (419) Wrong population / not relevant to review question. People's attitudes towards antidepressants - whether taking them or not. Not people dependent / withdrawing

Excluded studies

Study Exclusion reason from them. Jacobsen, 2015 Wrong study type. Non-comparative open label extension - better quality evidence (420) available for this question. Jain, 2017 (421) Wrong study type / not relevant to review question. Abstract for a workshop about substance misuse. James, 1975 (422) No relevant outcomes. Efficacy outcomes only. Jamison Wrong study design for prognostic review. 2010(423) Jamison Wrong study design. Literature review. 2011(424) Jamison, 2016 Not relevant to review questions. Attitudes of practitioners prescribing opioids. Not (425) risk factors or an intervention. Jarvis, 2018 (426) Wrong population. Not prescription drug use. Jean-Bart, 2017 No relevant outcomes. Study looked at whether certain prescription medications (427) were associated with falls (adverse events of the medication), no indication of length of medication use or dependence Jiang, 2017 (428) No relevant outcomes. Adverse events for drug treatment and not due to withdrawal or dependency. Joffe, 2011 (429) Wrong study type. Abstract. Jo‐Hanna, 2018 Wrong population. Assumed illicit drug use as no mention of prescription. (430) Johnson Wrong population. Mixture of illicit and prescribed use. Diversion included. 2014(431) Jones, 1994 (432) Cancelled - conference abstract. Jones, 2012 (433) Wrong population. Systematic review of buprenorphine for illicit drug use. Julius, 2017 (434) Cancelled - conference abstract. Kahan, 2011 (435) Wrong study type / not relevant to review protocol. Summary of guidelines for safe prescribing, not assessment of the guideline. Kahan, 2011 (436) Wrong study type / not relevant to review protocol. Summary of guidelines for safe prescribing, not assessment of the guideline. Kahler, 2017 Wrong study design (higher quality evidence available). (437) Kamara, 1998 Wrong population. Mixed drugs outside of the protocol. (438) Karow 2011 (439) Wrong population. Heroin addicted patients. Kasteenpohja, Wrong study type / not relevant to review protocol. Questionnaire on treatment 2015 (440) received for depressive disorders. Kasteenpohja, Wrong study type / wrong population / not relevant to review questions. 2016 (441) Questionnaire on treatment received for anxiety disorders. Katz, 2009 (442) Wrong population. Illicit use (heroin). Kavukcu, 2015 No relevant outcomes. (443) Kawai 2017(444) Wrong study design. Non-comparative, so only include if no better data. Kawasaki Wrong population. Prescription drug abuse (no indication that it started from 2012(445) prescribed use). Some patients were also on methadone maintenance therapy and had previous benzo withdrawal treatment. Keast, 2015 (446) Wrong study type. Narrative review of policies. Keast, 2018 (447) Wrong study design (higher quality evidence available).

Excluded studies

Study Exclusion reason Kelly, 2012 (448) Wrong population. Illicit drug use. Kelly 2014(449) Wrong population. Majority non-opioid substances. 20% that were opioid substance abusers not necessarily prescription opioid abusers. Kendall, 2010 Systematic review with different protocol. Cognitive effects of opioids, no (450) dependence outcomes. Kendrick, 2015 Wrong study type. Editorial. (451) Kern 2014 (452) Wrong study design. Case report and literature review. Khalifa 2010(453) Wrong population. Substance misuse - not prescription drug use and majority not drugs listed in our protocol. Khatami Wrong population. Almost all illicit drug use (intervention group 100% heroin). 1982(454) Kheirabadi 2018 Wrong population. Not necessarily prescription opioid dependent. No mention of (455) prescription and includes those smoking opioids. Kidorf 2013(456) Wrong population. Likely to be illicit opioids as all in methadone programme - is not clear but no mention of any being prescription opioid dependent. Kiepek, 2012 Wrong study type. Narrative review only. (457) King 2009(458) Wrong population. Illicit drug users. King, 2014 (459) Wrong population. No mention of prescription drug use, appears to be illicit use. Kitajima 2012 Wrong study design (higher quality evidence available). (460) Klein, 1994 (461) Published prior to 2008. Klemperer Wrong study design and population (drugs mentioned not on protocol (also tobacco 2015(462) and alcohol)). Knisely, 2008 No relevant outcomes. Study tested the sensitivity and specificity of an abuse (463) assessment tool in abusers and not abusers. Kondoni, 2017 Wrong population. Appears to be illicit use (methadone). (464) Kornowski Published prior to 2008. 2002(465) Kouvonen, 2016 Not relevant to review question. Looking at whether antidepressant use increases (466) injuries at work. Kovitwanichkano Wrong study design. Descriptive article. nt, 2018 (467) Kripke 2012(468) Wrong population. Not dependent. Krupitsky, 2011 Wrong population. Not prescription drug use, predominantly heroin. (469) Krauskopf 2017 Wrong study design. Not a clinical study, no outcomes. (470) Krupitsky, 2012 Wrong population. Illicit drug use – heroin. (471) Krupitsky, 2013 Wrong population. Illicit drug use – heroin. (472) Krupitsky, 2014 Cancelled - not in English. (473) Krupitsky, 2015 Cancelled - not in English. (474)

Excluded studies

Study Exclusion reason Krupitsky, 2016 Cancelled - not in English. (475) Krupitsky, 2016 Wrong population. Illicit drug use – heroin. (476) Krupitsky, 2017 Wrong population. Illicit drug use – heroin. (477) Kua, 2014 (478) Cancelled - erratum/corrections. Kumar, 2004 Wrong population / Published prior to 2008. Not prescription drug use. (479) Kunoe, 2010 Wrong population - illicit drug use. (480) Kunz, 2012 (481) Wrong study design (higher quality evidence available). Kuperwasser, Cancelled - conference abstract. 2009 (482) Kurita, 2018 (483) No relevant outcomes. Unclear if people are dependent on opioids, but have been prescribed them for >6 months. Kurokawa, 2011 Wrong population. People who abused BZD; no mention of prescription. (484) Kuyken, 2008 Wrong intervention. Aim of the paper is preventing relapse of depression with no (485) mention of dependence. Kuyken, 2015 Wrong intervention. Aim of the paper is preventing relapse of depression with no (486) mention of dependence. LaBelle, 2016 Wrong population. Not prescription drug addiction. (487) Lader, 1987(488) Published prior to 2008. Lader, 1993(489) Published prior to 2008. Ladewig, 1998 Cancelled - article not in English. (490) Lander, 2015 Wrong population. Not limited to prescription opioids - includes illicit opioids. (491) Landreat, 2010 Wrong study design: Prediction factors are part of the outcome measure; and Wrong (492) population: at least 33% taking non-listed drugs. Lankford 2011 Not relevant to review questions. Narrative review. (493) Lanier, 2012 (494) Wrong study design: unadjusted data. Risk factors from death for prescription opioids. Lanzillotta 2018 Wrong population. Review of postoperative opioid use. (495) Larney 2014 (496) Systematic review with different protocol. Focus on illicit use. LaRowe, 2018 Wrong population: only 57% were prescribed opioids. (497) Lasser, 2016 (498) Wrong study type. Protocol of a multicomponent intervention trial. Lauer, 1976 (499) No relevant outcomes. Efficacy outcomes only. Lavie, 2009 (500) Wong population. Assumed illicit drug use as no mention of prescription. Leas, 2010 (501) Cancelled - not available. Inspection of abstract suggests not relevant to review questions. Lecrubier Published prior to 2008. 2005(502)

Excluded studies

Study Exclusion reason Lee, 2016 (503) Not relevant to review questions. The effect of music on pain. Leonard, 2008 Not relevant to review questions. About opioid induced hyperalgesia, not dependence (504) / withdrawal etc. Leslie, 2015 (505) Wrong study design (higher quality evidence available). Levitt, 2005 (506) Cancelled - clinical trial webpage. Li, 2012 (507) Cancelled - thesis not open access. Li, 2017 (508) Cancelled - article not in English. Liebschutz 2018 No relevant outcomes/ not relevant to review questions. Focus on communication (509) strategies to avoid aberrant drug behaviour. Lin, 2016 (510) Wrong study type / not relevant to review questions. Trial protocol for opioids to reduce pain. Ling, 2013 (511) Wrong population. 57-62% heroin users in each group, the rest are prescription opioid users but no indication that abuse is a result of dependence on opioids prescribed for pain. Ling, 2012 (512) No relevant outcomes. No harms associated with withdrawal/dependency. Short term - 5 days. Ling 1996(513) Wrong population. All illicit drug use (heroin, cocaine, crack). Lintzeris, 2013 Wrong population; wrong comparison. Opioid dependence, no mention of (514) prescription; wrong comparison drug formulation. Liu, 2009 (515) Wrong population / study type. All heroin users. Llorca, 2009 (516) Wrong study design. Abstract. Lobmaier Wrong population. Alcohol dependence and illicit drug use. 2011(517) Lobmaier Wrong population. Substance misuse - not prescription drug use and includes drugs 2008(518) not listed in our protocol. Lofwall, 2016 Wrong population. Non-medical use of prescription drug use and heroin. (519) Lopez-Peig Wrong study design (higher quality evidence available). 2012(520) López-Torres, Wrong study type. Protocol only. 2013 (521) Lu, 2009 (522) Wrong study design. Literature review, not systematic. Lucas, 2010 (523) Wrong population. People taking medical cannabis. Lucas, 2016 (524) Wrong population. Cannabis users. Lucas, 2017 (525) No relevant outcomes. Lum 2011(526) Wrong outcomes. Does not report experiences of harms/treatment of dependence. Misuse not specifically for prevention of opioid withdrawal - includes diversion, for euphoria, etc. Addiction defined as physical dependence and loss of control over use. Lovejoy, 2017 Wrong study design. Not match any of the review questions. Population comparing (527) those with substance use disorders. Ma, 2008 (528) No relevant outcomes. No withdrawal symptoms occurred. Mackie, 2017 Wrong population / and outcomes. People with substance misuse disorder (80% (529) heroin) and alcohol misuse. Looking at prevalence of restless leg syndrome. Madden, 2011 Wrong comparison, population. Does not fit any of the questions, wrong population. (530) Maddux Wrong population. Illicit drug use. 1997(531)

Excluded studies

Study Exclusion reason Main, 2016 (532) Systematic review with different protocol. Not prescription opioid use. Mammen, 2009 Wrong study design / population. Not prescription opioid use. (533) Mannelli, 2013 Wrong population / not relevant. Effect of smoking on detoxification / not (534) prescription opioids. Mannelli, 2014 Wrong population. Not prescription drug use - use of opioids for chronic pain was (535) excluded. Mannelli, 2018 Wrong population. Not prescription opioid use. (536) Manning, 2012 Wrong population. (537) Manubay, 2015 Not relevant to review question / no relevant outcomes. Looks at differences (538) between sexes in opioid misuse, not risk factors. Marcovitz, 2016 Wrong population / no relevant outcomes. Only 16.7% prescription opioid use, looks (539) at predictors for dropping out of treatment programme. Maree, 2016 Systematic review with different protocol - not all prescription use, or relevant to (540) review question. Mariani Wrong population. Not all were prescription BZDs/opioids mixture of those obtained 2016(541) via prescriptions and those from elsewhere. Marschall, 2016 No relevant outcomes. (542) Martel, 2014 Wrong study design: correlations only. (543) Martin, 2015 Wrong study design. Protocol for an RCT on an intervention for reducing (544) inappropriate prescribing (D-PRESCRIBE trial) Martin, 2017 No relevant outcomes. (545) Martin, 2017 No relevant outcomes. (546) Martin, 2018 Wrong population. Illicit use (methadone). (547) Martinez, 2014 No relevant outcomes. Survey of GPs ability to correctly diagnose neuropathic pain (548) and prescribe appropriate medication. Maslej, 2017 Order cancelled - Looks at side effects of antidepressants in people with CVD (549) compared to those without and shows harms lower in that group (mortality & CV events, not dependence etc.). Mastropietro Not relevant to review questions. Looks at tamper resistant formulations. 2013 (550) Matthias, 2018 No relevant outcomes. Patients' experiences of opioid use but no dependency or (551) withdrawal experiences reported. Mattick Wrong population. Not prescribed opioids for chronic pain (majority illicit use). 2014(552) Mattick Wrong population. Not prescribed opioids for chronic pain (majority illicit use). 2009(553) Mattila, 1998 Published prior to 2008. (554) Matusow, 2018 No relevant outcomes. (555) Mauger, 2014 Systematic review with different protocol. Inadequate methodology. Includes non-

Excluded studies

Study Exclusion reason (556) prescription opioid use. Maughan, 2016 Not relevant to review questions. Looks at effects of social prescribing. (557) Mayet, 2014 Wrong population. Mainly includes illicit drug dependence. (558) Mbaba, 2018 Wrong population. Illicit use (primarily heroin). (559) McAdam-Marx, Wrong population. Not limited to prescription opioid abuse/dependence. Includes 2010 (560) those under 18 years. Cannot distinguish between those with prescription opioid dependence and illicit dependence - as stated by study in limitations, McAuley, 2012 Wrong population/intervention. Intervention aimed to reduce overdose among (561) injecting drug users. McCabe, 2009 Wrong population. Not prescription use. (562) McCarthy, 2015 Wrong population. Opioid not included on pre-specified drug list. (563) McDermott, 2015 Not relevant to review questions. Looks at whether initial response is a predictor of (564) overall response. McDonald Wrong population. Not prescribed opioids for chronic pain (majority illicit use). 2016(565) McHugh, 2013 Wrong population - opioids but not currently prescribed for chronic pain (those with (566) chronic pain requiring ongoing management were excluded). McHugh, 2014 Wrong population - opioids but not currently prescribed for chronic pain (those with (567) chronic pain requiring ongoing management were excluded). McMahon, 2011 Not relevant to review questions. Primarily concerns the efficacy of various (568) medications in premature ejaculation treatment. McNicol Wrong intervention/comparison. Not approaches to prevent or treat dependence, but 2013(569) the effectiveness of opioids for chronic pain. Meade, 2010 Wrong population. Half sample used heroin and the rest opioids (not mention if (570) prescription). Mechcatie, 2018 Wrong study type. Letter. (571) Merchant, 2015 Wrong population. Prescription opioids 24%; rest where illicit. (572) Merrill 2012(573) Wrong study design. Survey. Michael, 2018 Not relevant to review questions. Looks at opioid prescribing intensity in the (574) emergency department. Michna 2004(575) Wrong study design: unadjusted data. Middleton, 2014 Wrong study design. Descriptive review of mechanisms of tolerance. Descriptive (576) review of biochemical mechanisms of a certain form of tolerance. No relevant outcomes. Midmer, Published prior to 2008. 2006(577) Minegishi, 2018 Wrong study type. Protocol only. (578) Minozzi Wrong population. Not prescribed opioids for chronic pain (majority illicit use). 2013(579) Minozzi, 2013 Wrong population. Includes studies performed on those with acute pain or cancer (580) pain.

Excluded studies

Study Exclusion reason Minozzi Wrong population. Not prescribed opioids for chronic pain (illicit use). 2011(581) Miotto, 2012 Wrong population. Illicit use - mainly heroin. (582) Miranda, 2018 Wrong population. 68% heroin dependent, 31% used prescription opiates, 33% (583) buprenorphine/naloxone, 9% methadone. Mitchell, 2002 Cancelled - conference abstract. (584) Mol, 2007(585) Published prior to 2008. Mogri, 2014 (586) Not relevant to review questions. Sleep apnoea in people with chronic pain. Mohlman, 2016 Wrong population. No mention of prescription drug use. (587) Moisset, 2016 Cancelled - not available in English. (588) Mokri, 2016 (589) Wrong population. Illicit opioids - no mention of prescription opioids and only all taking either heroin or opium as primary drug. Mol 2006(590) No relevant outcomes. Does not give outcomes for the different interventions - compares craving between those quitting, still using or using intermittently - not relevant Molfenter, 2017 Wrong study design. Protocol. (591) Moller, 1992 Cancelled - article not in English. (592) Momper Wrong population. Not solely people taking oxytocin and mostly illicit use. 2011(593) Montgomery, Wrong study design. Unclear if is a systematic review - methods described 2009 (594) insufficiently. No quality assessment mentioned. Moore, 2012 Wrong study design (higher quality evidence available). (595) Moore, 2014 Wrong population. Predominantly heroin users. (596) Moore, 2016 Wrong population. Patients dependent on prescription opioids but those taking (597) prescription opioids for a pain condition were excluded. Morasco No relevant outcomes. 2008(294) Morasco, 2013 Not relevant to review protocol. Stratifies into risk groups, then analyses factors in (598) those groups to determine association with risk. Making assumption the risk stratification is accurate… Morgan, 2018 Wrong population. Does not specify this was in a prescription opioid population - (599) likely to be illicit or at least a mixture. Morley, 2017 Not relevant question. Survey of predictors of misuse; use of illicit drugs associated (600) with greater odds of misuse. Morris 2014 (601) Wrong outcome and population. Morton, Published prior to 2008. 1995(602) Moselhy 2010 Wrong population – heroin users. (603) Moselhy, 2012 Wrong population - illicit drug use. (604)

Excluded studies

Study Exclusion reason Moy, 2011 (605) Review –different protocol. Search only up to 2007. Mugunthan, 2013 Cancelled - erratum/corrections. (606) Munshi Wrong study design. Abstract. 2013(607) Murphy, 2016 Wrong study design. Narrative review only. (608) Murphy, 2017 No relevant outcomes. Aim was to reduce unnecessary use of the emergency (609) department - not related to opioid dependence etc. directly – opioid misuse. Mutlu, 2015 (610) Wrong population. Illicit use – heroin. Mysels, 2011 Wrong population. Illicit use - heroin. (611) Nadpara, 2018 No relevant outcomes. Risk factors for overdose. (612) Nalamachu, 2011 Wrong study design. Combined analysis of 3 studies. Checked individually for (613) relevance. Naliboff No relevant outcomes. Study design useful but although it mentions the amount that 2011(614) were discontinued from the trial due to opiate misuse, this outcome is combined with those not complying with clinic protocol so can’t be analysed. Nardi 2010(615) Wrong study design - case series. Narayan 2011 Wrong study design. Systematic review that included case reports all published prior (616) to 2008. Nathan, Published prior to 2008. 1986(617) National No relevant outcomes. Audit of local services, no outcome data. Treatment Agency 2011 (618) Naumann, 2018 Wrong study design - PhD dissertation. (619) Nct, 1999 (620) Cancelled - clinical trial webpage. Nct, 1999 (621) Cancelled - clinical trial webpage. Nct, 1999 (622) Cancelled - clinical trial webpage. Nct, 1999 (623) Cancelled - clinical trial webpage. Nct, 1999 (624) Cancelled - clinical trial webpage. Nct, 1999 (625) Cancelled - clinical trial webpage. Nct, 1999 (626) Cancelled - clinical trial webpage. Nct, 2002 (627) Cancelled - clinical trial webpage. Nct, 2005 (628) Cancelled - clinical trial webpage. Nct, 2005 (629) Cancelled - clinical trial webpage. Nct, 2005 (630) Cancelled - clinical trial webpage. Nct, 2005 (631) Cancelled - clinical trial webpage. Nct, 2005 (632) Cancelled - clinical trial webpage. Nct, 2005 (633) Cancelled - clinical trial webpage. Nct, 2005 (634) Cancelled - clinical trial webpage. Nct, 2005 (635) Cancelled - clinical trial webpage. Nct, 2005 (636) Cancelled - clinical trial webpage.

Excluded studies

Study Exclusion reason Nct, 2005 (637) Cancelled - clinical trial webpage. Nct, 2006 (638) Cancelled - clinical trial webpage. Nct, 2006 (639) Cancelled - clinical trial webpage. Nct, 2006 (640) Cancelled - clinical trial webpage. Nct, 2006 (641) Cancelled - clinical trial webpage. Nct, 2006 (642) Cancelled - clinical trial webpage. Nct, 2007 (643) Cancelled - clinical trial webpage. Nct, 2007 (644) Cancelled - clinical trial webpage.. Nct, 2007 (645) Cancelled - clinical trial webpage. Nct, 2007 (646) Cancelled - clinical trial webpage. Nct, 2008 (647) Cancelled - clinical trial webpage. Nct, 2008 (648) Cancelled - clinical trial webpage. Nct, 2008 (649) Cancelled - clinical trial webpage. Nct, 2008 (650) Cancelled - clinical trial webpage. Nct, 2008 (651) Cancelled - clinical trial webpage. Nct, 2009 (652) Cancelled - clinical trial webpage. Nct, 2009 (653) Cancelled - clinical trial webpage. Nct, 2009 (654) Cancelled - clinical trial webpage. Nct, 2009 (655) Cancelled - clinical trial webpage. Nct, 2009 (656) Cancelled - clinical trial webpage. Nct, 2009 (657) Cancelled - clinical trial webpage. Nct, 2010 (658) Cancelled - clinical trial webpage. Nct, 2010 (659) Cancelled - clinical trial webpage. Nct, 2010 (660) Cancelled - clinical trial webpage. Nct, 2010 (661) Cancelled - clinical trial webpage. Nct, 2010 (662) Cancelled - clinical trial webpage. Nct, 2011 (663) Cancelled - clinical trial webpage. Nct, 2011 (664) Cancelled - clinical trial webpage. Nct, 2011 (665) Cancelled - clinical trial webpage. Nct, 2012 (666) Cancelled - clinical trial webpage. Nct, 2012 (667) Cancelled - clinical trial webpage. Nct, 2012 (668) Cancelled - clinical trial webpage. Nct, 2012 (669) Cancelled - clinical trial webpage. Nct, 2013 (670) Cancelled - clinical trial webpage. Nct, 2013 (671) Cancelled - clinical trial webpage. Nct, 2013 (672) Cancelled - clinical trial webpage. Nct, 2013 (673) Cancelled - clinical trial webpage. Nct, 2014 (674) Cancelled - clinical trial webpage. Nct, 2014 (675) Cancelled - clinical trial webpage. Nct, 2017 (676) Cancelled - clinical trial webpage. Nelson, 2009 Not relevant to review questions. Literature review only. (677) Neumann Wrong population - majority hydrocodone abusers – not on pre-specified drug list. 2013(678)

Excluded studies

Study Exclusion reason Neven, 2016 Wrong population. People visiting emergency department frequently with pain. (679) Nielsen, 2012 Not relevant to review questions. Analyses definitions of dependence and withdrawal. (680) Nielsen, 2012 Systematic review. Inadequate quality. No mention of quality assessment of included (681) studies. Outcomes reported insufficiently - Just mentions the symptoms doesn’t specify number of patients that experienced each. Nielsen, 2013 Not relevant to review questions. Comparing heroin to opioid prescription users. (682) Nielsen, 2014 Not relevant to review questions. Looks at characteristics associated with dependence (683) this is reporting on difficult induction of treatment for dependence. Nielsen, 2015 Not relevant to review questions. Comparing heroin to opioid prescription users. (684) Nielsen 2016(685) Wrong population. Does not specify dependence is of prescribed drugs. Background text implies it is illicit use. Nielsen, 2016 No relevant outcomes. (686) Nielsen, 2018 Wrong intervention (intraoperative ketamine). (687) Nielsen 2018(688) Systematic review. Inadequate methodology. No protocol, GRADE done but not by outcome, no data that can be analysed or reused. Nihr, 2016 (689) Wrong study type / wrong population. Report of opioid dependence treatment, looks to be mainly illicit opioids. Nikulina, 2016 Not relevant review question. Patient vs prescriber reported of aberrant medication (690) taking. Nilsen, 2010 (691) Wrong study design. Case series. Noble, 2008 (692) Systematic review. Inadequate methodology. All studies were pre2008. Noble 2010(693) No relevant outcomes. Does not report on harms of addiction just the risk of addiction in this group Noller, 2018 (694) Wrong population. Not prescription drug use. Nordfjærn, 2013 Wrong study design: risk of harms from benzodiazepine use (not dependence) (695) compared with those not using benzodiazepines. Norman, 2016 Wrong study type. Collates information to inform best practice, but concludes further (696) research is needed. Study aim to review best practices. Focus on codeine - not necessarily prescribed, also includes OTC use. Based in Canada. Northrup, 2015 Wrong population. Not prescription drug use. (697) Nosyk, 2011 (698) Wrong population. Assumed illicit drug uses as no mention of prescription. Nosyk, 2015 (699) Wrong population. Mixture of prescription opioid and heroin. Those abusing/dependent on prescription opioids not necessarily obtaining them originally for chronic pain from doctor. Majority heroin dependent. Those with prescription opioid-dependence not necessarily prescribed them - not mentioned. Could have obtained illicitly without prescription. Novak, 2009 (700) Wrong population. Non-medical use of prescription analgesics (also aim of study not directly relevant - link to pain). Nuesch, 2009 Wrong study type. 'Cochrane highlight' - similar an abstract. Just one comment on (701) withdrawal symptoms after fentanyl treatment. Nunes, 2018 Wrong population. Opioid use disorder (not prescription) (702)

Excluded studies

Study Exclusion reason Nurminen, 2014 Wrong study design (higher quality evidence available). (703) O'Connor Wrong study design / not relevant to review questions. Factor analysis to develop a 2008(704) tool. O'Connor, 2012 Wrong study design (higher quality evidence available). (705) Ogawa, 2010 Cancelled - article not in English. (706) Ogle, 2013 (707) Wrong study type. Guidance based on a literature review of guidelines. Oliva, 2017(708) Wrong population. Not limited to those receiving opioids for chronic pain - also includes cancer pain and may include acute pain. Also, outcomes are overdose and suicide attempts but not explicitly related to dependence in these patients. O'Mullan, 2015 No relevant outcomes. Qualitative study on women’s experiences of sexual side (709) effects of long-term SSRIs. Onyett Stephen, Published prior to 2008. 1988(710) Osmun, 2011 Wrong population. Not risk factors for dependence etc. just difference between a (711) group using oxycodone and a group not using it. Ostini, 2011 (712) Wrong population. People included on any drugs - ordered papers where used one of our drugs. Otto, 1993(713) Published prior to 2008. Otto 2010(714) Wrong population. Drugs not on our list (mainly clonazepam and some alprazolam) Oulis 2009(715) Wrong study design. Case report of one patient. Oulis, 2010 (716) Wrong study design / not relevant to review questions. Descriptive review of pregabalin. Pade, 2012 (717) Wrong population. Opioid abuse, prescription and illicit, no clear link with initial prescribed use. Page, 2018 (718) Wrong study design (higher quality evidence available). Page, 2018 (719) Wrong study type. Protocol only. Pani 2010(720) Wrong intervention. About treating depression not dependence. Pani 2013(721) Wrong population. Not prescription drug dependence. Paolucci, 2017 Wrong population. Doesn't state what the overused drug is - possible could be drugs (722) not included in our protocol. Papaleontiou, Systematic review – not relevant to this protocol. Focus on efficacy, safety and abuse 2010 (723) potential. Papazisis, 2010 Cancelled - conference abstract (724) Paquin 2014 (725) Wrong comparison. Unclear if comparative studies from review - treatment types were not compared. Pardo, 2017 (726) Wrong study design (higher quality evidence available). Park 2010 (727) Wrong population. Includes those with cancer pain. Parker, 2018 Wrong population. Opioid misuse (heroin or illicit use of prescription drugs). (728) Parr, 2009 (729) Wrong population. Unclear if users in all studies obtained BZDs through prescription or whether they were using illicitly/recreationally. SR was also not a Cochrane SR. Parr, 2011 (730) Wrong study design (higher quality evidence available). Parran, 2010 Wrong population. Illicit drug use - 88% heroin users. (731)

Excluded studies

Study Exclusion reason Passik, 2006(732) Published prior to 2008. Passik, 2008 (733) Wrong study type / not relevant to review question. Review of tools to assess opioid addiction. Passik, 2009 (734) Wrong study type. Narrative review only. Passik, 2011 (735) Wrong study design: Unadjusted data. Passik, 2014 (736) No relevant outcomes. Doesn't inform the harms. Pat- Published prior to 2008. Horenczyk,1998(7 37) Patrick 2014(738) Wrong population. Illicit prescription opioid abusers. Paulozzi Wrong population. Not specifically opioids for chronic pain - could include deaths 2006(739) from adverse short term events, misuse/abuse etc. Paulozzi, 2012 Wrong population: mixed licit and illicit use, wrong study design - not prognostic (740) factors. Pauly, 2018 (741) Wrong population: not all using prescription opioids and unclear if opioids were prescribed. Peckham, 2018 Exclude: wrong study design - overuse as risk factor rather than outcome. (742) Peirce, 2012 (743) No relevant outcomes. Study compared rates of doctor/pharmacy shopping in cases of drug related deaths and controls. Peles, 2008(744) Published prior to 2008. Penninga, 2016 Wrong study type / not relevant to review population. Looks at adverse events (745) reported from a treatment for intoxication, not efficacy of that treatment Perahia, 2008 Wrong study design. 2 RCTs combined but not systematically. Studies prior to 2008. (746) Pergolizzi, 2018 Wrong study type / not relevant to review population. Review of abuse-deterrent (747) opioids. Pergolizzi, Wrong study design - literature review. 2012(748) Pietrasanta 2011 Wrong population. Illicit use - mostly methadone maintenance. (749) Pikovsky, 2018 Cancelled - not available. Inspection of the abstract suggests illicit use. (750) Pilkonis, 2017 Not relevant to review questions. Development of an 'item bank' to measure (751) prescription medication abuse. Pilowsky, 2011 Wrong population. Alcohol use disorder. (752) Pimlott, Published prior to 2008. 2003(753) Pink 2012(754) Wrong study design. Assesses opinions/practicality of method for assessing problematic prescription drug use and discusses how this method was altered following feedback. Pohjanoksa 2009 No relevant outcomes. No discussion of harms of withdrawal or dependency. (755) Pollack 2008(756) No relevant outcomes. Wrong intervention. Pollmann, 2015 Wrong study design. Review about the use of these drugs in community dwelling (757) adults. Polsky, 2010 Wrong population. Mainly illicit drug use (41% heroin, 8% mixed, 26% opiate

Excluded studies

Study Exclusion reason (758) analgesics, but don't know if these were on prescription. Popovici, 2018 Wrong population. Population not limited to those with opioids for chronic pain. Also (759) talks about nonmedical use of prescription opioids being those obtaining without a prescription/using for euphoria, which is not relevant to the reviews. Posadzki Wrong population. Not prescribed opioids for chronic pain (illicit use); other groups 2016(760) not listed in the protocol (e.g. alcohol-dependence). Posadzki, 2016 Wrong study design. Overview of systematic reviews. (761) Potter, 2010 (762) Wrong population. Illicit drug use. Potter, 2015 (763) Wrong study design (higher quality evidence available). Pottie, 2018 (764) Systematic review using GRADE but results are reported narratively as recommendations. No extractable outcome data. Prakash, 2016 Wrong population. Opioid dependent but no mention of prescription. (765) Prendergast Wrong population. Illicit drug use - aim is to reduce HIV risk 2001(766) Priddy, 2018 Wrong study design: correlations only. (767) Prommer, 2017 Wrong study type. Guideline - not assessment of its use. (768) Puangkot 2011 Not relevant to review questions. Prevalence data only of use. (769) Public Health No relevant outcomes. Guidelines for prevention, no outcome data. England, 2013 (770). Puustinen, 2014 Wrong study design (higher quality evidence available). (771) Quagliato, 2018 Systematic review with different protocol. (772) Raheem, 2017 Not relevant to review question. Treatment of an opioid side effect. (773) Rahimi‐Movaghar Wrong population. Not prescribed opioids for chronic pain (illicit use). 2013(774) Raisch, 2012 Wrong population. Appears to be illicit opioid use - mentions possibility of extending (775) treatment to prescription opioids in the future. Raknes, 2017 Not relevant to review population / wrong population. Looks at effect of low dose (776) naltrexone on opioid consumption - but not in people dependent on opioids. Raoof, 2008 (777) Not relevant to review questions. Views and awareness of benzodiazepines. Raphael, 2013 No relevant outcomes. Aim isn't to reduce use of morphine, but to show that long (778) term use is effective and reducing dose increases pain and number dropping out. Raskin, 2014 No relevant outcomes. No harms associated with dependence/withdrawal just 6 (779) weeks AE from drug. Rathlev, 2016 Wrong population. Not prescription drug use – OUD. (780) Reece, 2010 (781) Wrong population. Illicit opioid users – heroin. Reece, 2009 (782) Wrong population. Does not mention prescription addiction so presumed illicit. Reeve, 2017 (783) Systematic review – inadequate reporting of risk of bias. No quality assessment. Reid, 2002 (784) Published prior to 2008.

Excluded studies

Study Exclusion reason Reifler 2012(785) Wrong population. Illicit abuse/misuse of prescription opioids - using for non-medical purposes to get high. Reimer, 2016 Wrong study type / not relevant to review question. Impact of misuse and diversion. (786) Reisman 2009 Wrong study design (higher quality evidence available). (787) Rickels, 1999(788) Published prior to 2008. Rigg, 2010 (789) Wrong population. Included participants predominantly obtaining and using initially in illicit ways - without prescription from doctor or using by improper methods Rikala, 2011 (790) Wrong population. Looks at factors associated with persistent use of psychotropic drugs. Not necessarily dependence. Ringwalt, 2014 Not relevant to review questions. Looks at which specialists prescribe opioids the (791) most - but cannot assume this as a risk factor. Ristanovic, 2009 No relevant outcomes. Treatment is for cataplexy, reports whether that increased (792) when initially withdrew. Comparison of number of cataplexy events between groups. Robinson, 2015 No relevant outcomes. Views on opioids, not experiences of harms of dependence (793) etc. Roehrs, 2012 Not relevant to review question. At months 1, 4 and 12 there was a 7 day withdrawal (794) period where placebo replaced the active intervention - study assesses this phase. Not assessing discontinuation or withdrawal, or demonstrating harms. Rojo-Mota, 2017 Wrong population / study type. ‘Substance addiction' not prescription. (795) Romach, Published prior to 2008. 1998(796) Romach, Published prior to 2008. 2000(797) Roman 2009 Wrong study design. Not a clinical study, no outcomes. (798) Rosenblum Wrong study design (higher quality evidence available). 2012(799) Rosenthal, 2013 Wrong population. Illicit use - excluded if taking opioids for chronic pain. (800) Rounsaville Wrong population. Illicit opiate use. 1983(801) Roussin, 2013 Wrong population. Non-prescription codeine use or antihistamines. (802) Roux, 2013 (803) Wrong population. Mix of prescription and illicit drug use - higher percentage of prescription though. Non-comparative, so only include if no better data. Rudolf, 2018 Wrong population. Illicit drug use. (804) Ruetsch, 2014 Wrong study design. Review of another included study. (805) Ruetsch, 2012 Wrong population. No mention of prescription drugs so assume illicit use. (806) Ruetsch, 2010 Wrong population. Illicit drug use. (807) Sabzghabaee, Wrong population. Inappropriate use of naltrexone', no indication that abuse began 2012 (808) after dependence on prescription opioids. Safer, 2017 (809) No relevant outcomes. Only mentions relapse rate as main outcome - brief mentions

Excluded studies

Study Exclusion reason of withdrawal symptoms but insufficient detail. Compares five different maintenance methodologies for antidepressant treatment - assessing rate of relapse, not dependence/withdrawal. Saleh, 2014 (810) Wrong population. Appears to be illicit use. Saleh, 2014 (811) Not relevant to review question. Predictors of successful withdrawal, not predictors of harms. Salehi, 2015 (812) Wrong population. Illicit use. People on a methadone maintenance programme. Salminen, 2009 No relevant outcomes. Falls only. Other papers reporting on this study with relevant (813) outcomes are included. Sanchez, 2017 Wrong population. Illicit drug use. (814) Saul, 1989(815) Published prior to 2008. Saulle 2017(816) Wrong population. Not prescribed opioids for chronic pain (illicit use). Saunders 2015 Wrong study design (higher quality evidence available). (817) Saxon, 2018 (818) Wrong population. Population not specifically prescription opioid dependence - likely to include those dependent on illicit drugs. Saxon 2013(819) Wrong population. Includes those using and dependent on illicit opioids - Not limited to prescription opioids. Saxon, 2010 (820) No relevant outcomes. States no reports of misuse or abuse; but not what harms these are individually. Schaffer 2010 No relevant outcomes. (821) Schepis, 2018 Wrong study design: t-stat and p-value only. (822) Scherbaum Wrong population. Illicit drug use. 2005(823) Schieffer, Published prior to 2008. 2005(824) Schifano Wrong population. Not prescribed medicines, abuse of prescribed medicines. 2018(825) Schroeder, 2018 Wrong population. Only mentions heroin in study - illicit users. (826) Schuman-Olivier, Not relevant to review question. Looks at factors linked to retention in substance use 2014 (827) disorder treatment programmes. Schuman-Olivier, Wrong population. Mixture of heroin & prescription opioid use 27% only used 2014 (828) prescription opioids. Schwarzer, 2015 No relevant outcomes. Apnoea adverse event of drug not harm of (829) withdrawal/dependency. Schweizer, Published prior to 2008. 1995(830) Schweizer Published prior to 2008. 1990(831) Seay, 2017 (832) No relevant outcomes. Segal, 2017 (833) Not relevant to review question. Not looking at dependence etc. Sekhon, 2013 Not relevant review question. (834) Setnik, 2013 (835) Wrong intervention. Prevention as crushed pill releases naltrexone that stops morphine working effectively.

Excluded studies

Study Exclusion reason Setnik, 2015 (836) Wrong study design (higher quality evidence available). Setnik, 2017 (837) Wrong study design. Comparison of methodology and results of 2 studies. Shigemura No relevant outcomes. Not specifically related to withdrawal or dependency. 2007(838) Shokrzadeh, 2017 Cancelled - article not in English. (839) Shorey, 2017 Wrong population. Mostly alcohol substance abuse. (840) Siassi, 1975 (841) No relevant outcomes. No patients showed any evidence of psychological or physical withdrawal symptoms 1 week post treatment. Sigmon, 2009 Wrong study design (higher quality evidence available). (842) Sigmon 2013(843) Wrong population. People using prescription opioids illicitly - those prescribed them for pain were excluded. Simon, 2013 (844) Wrong study design. 2 RCTs combined but not systematically. Simonsen, 2016 Systematic review with different protocol. Animal studies. (845) Sinnemaki, 2013 Not relevant to review protocol. Not specific to drug dependence etc. (846) Slofstra, 2017 Wrong study design. Protocol and methodology. (847) Sirdifield, 2017 Not relevant to review protocol. Review of qualitative studies - remit broader than (848) our protocol. Smith, 2010 (849) Wrong study design (higher quality evidence available). Socias, 2018 (850) Wrong study design. Design and rationale only. Soeffing, 2009 Wrong population. Illicit use. Mainly heroin. (851) Sohler, 2010 Wrong population. 15% prescribed opioids rest are illicit. (852) Sokol, 2018 (853) Wrong population. Opioid use disorder - not prescription opioids. Soldatos, Published prior to 2008. 1999(854) Soyka, 2011 (855) Cancelled - article not in English. Spiegel, Published prior to 2008. 1994(856) Spiller 2009 (857) Not relevant to review questions. Stannard Wrong intervention. About treating pain not dependence. 2016(858) Stanton Wrong population. Illicit drug abuse or addiction. 1997(859) Starrels, 2010 Wrong outcomes. Drug misuse including diversion etc. (860) Steele, 2012 (861) Wrong population. Illicit drug use. Stein, 2015 (862) Wrong population. Does not mention opioids being prescribed to the patients in the prescription opioid group. Assume may have obtained illicitly as comparing with heroin. Compares life concerns of prescription opioid and heroin users. Stein, 2008 (863) No relevant outcomes. Wrong population. Illicit use. Stewart, 2007 Published prior to 2008.

Excluded studies

Study Exclusion reason (864) Strain, 2011 (865) Wrong population. Heroin dependence only. Strang, 2017 Wrong population. Illicit drug use. (866) Strick, 2014 (867) No relevant outcomes. Effectiveness and tolerability outcomes only. Su 2018(868) Wrong population / study design (higher quality evidence available). Methadone being used in this scenario to treat opioid withdrawal syndrome. Subodh, 2017 Wrong population. (869) Subramaniam, Wrong population. Assumed to be illicit use due to mention of injection and no 2017 (870) mention of prescription throughout study. Sullivan No relevant outcomes. No qualitative outcomes (patient experience question). 2010(871) Sullivan, 2017 Wrong population. Illicit use. Excluded people with opioids prescribed for chronic (872) pain. Sun, 2016 (873) Wrong population. Opioid-naïve surgical patients. Syed, 2013 (874) Wrong population. Illicit use. Mainly heroin. Syed, 2018 (875) Wrong population. Surgical patients; opioids not prescribed for chronic pain. Sylvestre, 2012 No relevant outcomes. Harms of the drugs rather than discontinuation. (876) Szczypa Wrong study design. Abstract only. 2009(877) Tavakolian, 2016 Wrong population. No mention of prescription, appears to be illicit use ('opium' used (878) as a buzz word in the intervention). Tetrault, 2012 Wrong population. (879) Thakral, 2018 Wrong study design (higher quality evidence available). (880) Thorlund, 2016 Systematic review with different protocol. Not relevant to review question. (881) Tint, 2009 (882) Cancelled - erratum/corrections. Tkacz 2012 (883) Not relevant to review question. Comparison of demographic data between prescription and street opioid use. Tkacz, 2012 (884) Wrong population. Appears to be illicit use. Tofighi, 2017 Wrong population, intervention. Under half opioid addicts of whom 39% was heroin. (885) Tompkins, 2009 Wrong population. Illicit drug use. (886) Tompkins, 2014 Wrong population. Illicit use – heroin. (887) Tonks, 2008 (888) Wrong study design. Summary. Tonks, 2010 (889) Wrong study design. Summary. Tonks, 2010 (890) Wrong study design. Summary. Tonks, 2011 (891) Wrong study design. Summary. Tourian 201(892) Wrong study design. Non-comparative, so only include if no better data. Tournebize Wrong intervention. Looks at adherence to risk reduction only, not what effect that 2016(893) has on opioid dependence etc.

Excluded studies

Study Exclusion reason Townsend, 2008 Wrong study design (higher quality evidence available). (894) Tribl, 2013 (895) Not relevant to review questions. Systematic review does not directly address any of the review questions. Trivedi, 2010 No relevant outcomes. No discontinuation/withdrawal related outcomes reported. (896) Turk, 2008 (897) Systematic review. Inadequate methodology. Included studies pre-2008. Tyrer, 1981(898) Published prior to 2008. Tyrer, 1996(899) Published prior to 2008. Udelman, Published prior to 2008. 1990(900) Uebelacker, 2015 No relevant outcomes. (901) Urton 2017 (902) Wrong study design (higher quality evidence available). Uzun, 2010 (903) Study design. Review of literature- descriptive only. Vaapio, 2015 No relevant outcomes. Patients divided in to those who withdrew, those who reduced (904) and non-users and reported symptoms for each group. Vankova, 2014 Wrong population. Not on prescription drugs. (905) Veal, 2017 (906) Wrong study design. Letter. Veiraiah, 2012 Wrong population. Majority heroin users and others not specified as prescription (907) opioids. Velert Vila, 2012 Cancelled - article not in English. (908) Vicens 2006(909) Pre-2008 study. Vicens, 2011 Wrong study design. Study protocol. (910) Victorri 2011 Not relevant to review question. Over use due to abuse/misuse or lack of (911) effectiveness etc. Victorri-Vigneau Published prior to 2008. 2007(912) Vittengl, 2017 Weren't able to order, but abstract provided clarifying it's a letter to editor. (913) Vo, 2018 (914) Cancelled - not available. Inspection of the abstract suggests illicit use. Voderholzer Published pre-2008. Population isn’t a group of patients receiving the drugs for a 2001(915) condition - healthy males. Vogel, 2011 (916) Wrong outcome: prolonged BZD use and wrong population: not all using BZD on prescription. Vogel, 2017 (917) Wrong study design. Commentary. Von Korff, 2017 Wrong study design (higher quality evidence available). (918) Voon, 2017 (919) Wrong study design / population / not relevant to review question. Include substance use generally as well as prescription opioids. Main focus is on prevalence. Voris John, 1989 Published prior to 2008. (920) Vorma, 2002(921) Published prior to 2008. Vorma 2010(922) Wrong population. Illicit users - those with medical illnesses were excluded. No mention of prescriptions.

Excluded studies

Study Exclusion reason Vosburg Wrong population. Healthy individuals abusing prescription opioids via nasal route. 2012(923) Vosburg Wrong study design. No relevant outcomes. 2018(924) Voshaar Wrong outcomes. Identifies predictors of successful BZD discontinuation in patients - 2006(925) not factors associated with dependence or their harms. Vowles, 2015 Systematic review – different protocol. Only gives rates of behaviours and does not (926) mention factors. Gives rates of abuse/misuse across different studies and compares among different types of study design etc. Voyer, 2010 (927) No relevant outcomes. Number that self-diagnosed themselves as dependent. No harms. Wakeland, 2013 Wrong study design. Report of simulated model. (928) Walsh, 2017 (929) Wrong population. Illicit use - chronic pain requiring opioid therapy was an exclusion criterion. Wang, 2010 (930) Wrong population. Mix of illicit and prescription users - predominantly heroin. Wang, 2011 (931) No relevant outcomes - pain sensitivity. Three groups: low back pain with and without opioid therapy, and healthy controls with neither pain nor opioids. Wang, 2015 (932) Wrong study design. Case control study. Watson, 2010 Wrong outcomes. Mainly refers to efficacy/adverse events of taking opioids. (933) Mentions withdrawal but only whether or not they experienced withdrawal symptoms if missing doses, and not assessing factors contributing to this or the harms. Weber, 2010 Wrong study design. Literature review. (934) Webster Pre-2008 study. 2005(935) Webster, 2010 Intervention. Testing new formulation of drug to see if tamper proof. Assessing long (936) term safety of a formation that is less prone to abuse when crushed in the population of chronic pain. Webster, 2015 Wrong intervention. (937) Webster, 2016 Wrong population –illicit use. (938) Webster, 2016 Not relevant to review questions. Looking to see whether withdrawal reaction can be (939) initiated. Weiss 2011(940) Wrong population. Not all participants were prescribed for pain. May include some that obtained them illicitly. Only 40% had chronic pain diagnosis at time of entry. Weiss 2010(941) Wrong population. Includes some that were not prescribed them for chronic pain - obtaining them illicitly. Weiss, 2009 (942) Wrong population. Mix of drug/alcohol dependence (prescription not mentioned). Weiss, 2014 (943) Wrong outcomes. Although chronic pain population mentioned separately, only mentions reasons for initiating opioid intake (not harms or factors contributing to dependence). Weiss, 2015 (944) Wrong population. Not limited to those being prescribed prescription opioids for chronic pain. Includes those may have obtained illicitly and not had them prescribed. Weiss, 2017 (945) Wrong population. Only 42% of the participants had chronic pain - reviews are only concerned with opioids for chronic pain. Welsh, 2018 (946) Wrong study design. Literature review rather than systematic review.

Excluded studies

Study Exclusion reason Westanmo 2015 Wrong study design (higher quality evidence available). (947) Westbury, 2011 Wrong outcomes. Paper focuses on success of reducing antipsychotic/BZD due to risk (948) of falls etc. in elderly nursing homes. No mention of dependence throughout. Whitehead 2018 Summary of review. Cochrane systematic review it refers to (Eccleston) already (949) included. Whiteside, 2017 Wrong population. Includes various prescription drugs (e.g. Stimulants which are not (950) included in our review). Not limited to those initially prescribed the drugs legitimately - includes some illicitly obtained. Wightman Wrong population. Mostly heroin users or recreational opioid users. 2012(951) Willems, 2013 Wrong outcomes. Assessing whether dose of BZD increases over time in incident and (952) prevalent prescription users of BZD - not describing harms or factors contributing to harms of dependence. Wilsey 2009(953) Wrong outcomes. Assessing effects of short vs. long term opioids in patients at high risk of abusing prescription opioids for chronic pain - outcomes are effects of taking the drug rather than harms of dependence/withdrawal. Wilson, 2015 Wrong study design. Literature review. (954) Wittchen, 2011 Cancelled - article not in English. (955) Wobrock, 2008 Systematic review with different protocol. Looks at comorbid substance use disorder (956) and schizophrenia. Wobrock, 2009 Wrong intervention. Looks at comorbid substance use disorder and schizophrenia. (957) Wong 2014 (958) Wrong study design. Case cross-over study looking at adverse events. Woody 2008(959) Wrong population. Predominantly illicit users of opioids with no mention of prescription opioids. Also substantial proportion under 18 years. Woody 1983(960) Wrong population. Illicit opiate use. Worley, 2015 Not relevant to review questions. Looks at predictors of favourable or poor treatment (961) outcome (treatment for opioid dependence) in chronic pain subpopulation. Worley, 2015 Wrong population. Includes those obtaining illicitly (without prior prescription) and (962) legitimately from doctors etc. Worley, 2017 Not relevant to review questions. Predictors of response to treatment, not risk of (963) harms. Wright 2015(964) Systematic review. No quality assessment. References checked and relevant studies ordered. Wu, 2011 (965) Not relevant to review questions. Looks at how ceasing BZDs may lead to improvements in risk of dementia - not necessarily harms of BZD dependence. Xiang, 2007 (966) Wrong study design and population. Compares long term use with no use so not all are using the prescribed medicine. Xie, 2014 (967) Wrong population. Patients prescribed opioids (or not prescribed them) for various conditions, not limited to chronic non-cancer pain (also includes cancer pain). Xue, 2012 (968) Wrong study design. Protocol only. Yang 2013(969) Wrong population. Opioid for premature ejaculation not chronic pain. Yang, 2006 (970) Cancelled - article not in English. Yarbrough, 2018 Wrong study design (higher quality evidence available). (971) Yasui-Furukori, Wrong study design. Non-comparative cohort. Separates participants into those with

Excluded studies

Study Exclusion reason 2016 (972) and without discontinuation syndrome, but only reports results for those with the syndrome. Yen, 2015 (973) Wrong study design: correlation only. Yeo, 2017 (974) Systematic review with different protocol. Not relevant to review question. Yeung, 2017 (975) Wrong study design. Study protocol. Yovell, 2016 (976) No relevant outcomes. Effectiveness outcomes only. Zacny 2009(977) Wrong population and no relevant outcomes. Zacny 2003(978) Wrong population. Performed in people that were healthy and not receiving oxycodone for a medical reason. Measures effects of the drugs rather than harms of dependence/withdrawal. Zacny 2003(979) Wrong population. Performed in people that were healthy and not receiving the drugs for a medical reason. Measures effects of the drugs rather than harms of dependence/withdrawal. Zacny 2008(980) Wrong population. Performed in people that were healthy and not receiving the drugs for a medical reason. Measures effects of the drugs rather than harms of dependence/withdrawal. Zahradnik Wrong study design for Q2. Includes opioids, anxiolytics, hypnotics, sedatives and 2009(981) caffeine -reports some separately. May include some abusing PDs rather than dependent on (see discussion section) Zajecka, 1998 Published pre2008. (982) Zarghami, 2012 Wrong population. Not prescription use. (983) Zedler, 2014 (984) Wrong outcomes. Serious opioid-induced respiratory depression or overdose not related to opioid dependence, discontinuation or withdrawal. Zedler, 2015 (985) Wrong outcomes. Serious opioid-induced respiratory depression or overdose not related to opioid dependence, discontinuation or withdrawal. Zgierska, 2016 Not relevant to review question. Although suggests could help reduce opioid use - (986) opioids were allowed during the study. Zgierska, 2016 Not relevant to review question. Looking at effectiveness of an alternative (987) intervention, but in people taking opioids Zhang, 2013 (988) Cancelled - article not in English. Zheng 2008(989) Wrong intervention. Aim to reduce opioid use by replacing with acupuncture in people who aren't addicted, rather than preventing addiction. Ziaaddini, 2012 Wrong population. Illicit use – opium (990) Ziedonis, 2009 Cancelled - not available. Inspection of abstract suggests illicit drug use and alcohol (991) dependence. Zippel-Schultz, Cancelled - not available. Inspection of abstract suggests illicit drug use. 2016 (992) Zisook, 2011 No relevant outcomes (993) Zullich, 1992(994) Published prior to 2008. Zullig, 2018 (995) Wrong population. Illicit drug use – opioid use disorder.

Call for evidence exclusion list Submission Exclusion reason

Excluded studies

Submission Exclusion reason Research Gate profile: Publications relevant to protocol considered in separate questions https://www.researchgate.net/sci entific- contributions/38113940_Heather _Ashton Godfrey, Heather, Bowie, Brodie, Cost analysis of a pre-2008 trial. Costs are based on 2006 figures, prior Parrott, Ashton & McAvoy (2008) to date cut-off. Randomised controlled trial of two brief interventions against long-term benzodiazepine use: Cost-effectiveness. Addiction Research and Theory, 16 (4), 309- 317 Sheffield CCG Controlled Drug Email communication only, unpublished. Included in report for Monitoring of fentanyl information only. South Yorkshire & Bassetlaw Email communication only, unpublished. Included in report for Controlled Drugs Lead Group information only. Targeted Controlled Drug Monitoring Programme Society for an Addiction Free Email communication only, unpublished. Included in report for Existence (SAFE) information only.

Davies, J., Read, J. (2018). A Not applicable to call for evidence questions, considered for inclusion in systematic review into the relevant question. incidence, severity and duration of antidepressant withdrawal effects: Are guidelines evidence- based? Addictive Behaviours. Fava, G., Benasi, G., Lucente, M., Not applicable to call for evidence questions, considered for inclusion in Offidani, E., Cosci, F., & Guidi, J. relevant question. (2018). Withdrawal symptoms after Serotonin-Noradrenaline Reuptake Inhibitor discontinuation: Systematic review. Psychotherapy and Psychosomatics, 87, 195–203. G. A. Fava, A., Gatti, C., Belaise, J. Not applicable to call for evidence questions, considered for inclusion in Guidi, E. Offidani . Withdrawal relevant question. symptoms after selective serotonin reuptake inhibitors discontinuation: a systematic review. Psychother Psychosom 84 (2015) pp. 72–81. Gibson, L., Cartwright, C., Read, J. Not directly relevant to call for evidence review questions. Focus of the (2014). Patient-centred review is experience of using the medications, not experience of harms. perspectives on antidepressant use: A narrative review. International Journal of Mental Health, 43, 81-99 C. Belaise A., Gatti V.A., Not applicable to call for evidence questions, considered for inclusion in Chouinard G., Chouinard (2014) relevant question Persistent post-withdrawal disorders induced by paroxetine,

Excluded studies

Submission Exclusion reason a selective serotonin reuptake inhibitor, and treated with specific cognitive behavioral therapy. Psychotherapy and Psychosomatics, 83 (2014) pp. 247–248. D. W. Black, R., Wesner, J. Gabel. Published prior to date cut-off The abrupt discontinuation of fluvoxamine in patients with panic disorder. Journal of Clinical Psychiatry. 54 (4) (1993) pp. 146- 9. Directly relevant study: K. Black, Not directly relevant to review questions C., Shea, S., Dursun, S., Kutcher. Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria, Revue de Psychiatrie et de Neuroscience, 25 (3) (2000) pp. 256-260 F. Bogetto, S. Bellino, R.B. Revello, Not applicable to call for evidence questions, considered for inclusion in l. Patria. Discontinuation relevant question syndrome in dysthymic patients treated with selective serotonin reuptake inhibitors: a clinical investigation. CNS Drugs,16 (4) (2002) pp. 273-83. Bogner, H., Cahill, E., Focus not directly relevant to call for evidence review protocol. Views Frauenhoffer, C. et al. (2009). on the medications, not on the harms. Older primary care patient views regarding antidepressants: a mixed methods approach. Journal of Mental Health, 18, 57-64. Cartwright, C., Gibson, K., Read, Non-UK based study (not included in question 4) J., Cowan, O., Dehar, T. (2016). Long term antidepressant use: Patients’ perspectives of benefits and adverse effects. Patient Preference and Adherence, 10, 1401-1407. G. Fava, M. Bernardi, E. Tomba, Published prior to date cut-off C., Rafanelli. Effects of gradual discontinuation of selective serotonin reuptake inhibitors in panic disorder with agoraphobia. Int J Neuropsychopharmacol. 10(6) (2007) pp. 835-8. Gibson, K., Cartwright, C., Read, J. Non-UK based study (not included in question 4) (2016). ‘In my life antidepressants have been….’ : A qualitative analysis of users’ diverse experiences of antidepressants. BMC Psychiatry, 16, 135.

Excluded studies

Submission Exclusion reason Givens, J., Datto, C., Ruckdeschel, Published prior to date cut-off K. et al. (2006). Older patients' aversion to antidepressants. Journal of General Internal Medicine, 21, 146-151. Groot, P., Van Os, J. (2018) Not applicable to call for evidence questions, considered for inclusion in Antidepressant tapering strips to relevant question help people come off medication more safely. Psychosis: Psychological, Social & Integrative Approaches, 10, 142-145. Hoencamp, E., Stevens, A., Published prior to date cut-off Haffmans, J. (2002). Patients' attitudes toward antidepressants. Psychiatric Services, 53, 1180- 1181. Montgomery, S., Nil, R., Durr-Pal, Published prior to date cut-off N., Loft, H., & Boulenger, J. (2005). A 24-week randomized, double- blind, placebo-controlled study of escitalopram for the prevention of generalized social anxiety disorder. Journal of Clinical Psychiatry, 66, 1270– 1278. Moore, M., Yuen, H., Dunn, N. et Not directly relevant to review questions - looks at prescribing patterns al. (2009). Explaining the rise in and reasons antidepressant prescribing: A descriptive study using the general practice research database. British Medical Journal, 339, b3999 V. Naryan, P. H. Haddad. Not applicable to call for evidence questions, considered for inclusion in Antidepressant discontinuation relevant question manic states: a critical review of the literature and suggested diagnostic criteria, Journal of Psychopharmacology 25 (3) (2011) pp. 306-313 Nielsen, M., Hansen, E. & Not applicable to call for evidence questions, considered for inclusion in Gøtzsche, P. (2012). What is the relevant question difference between dependence and withdrawal reactions? A comparison of benzodiazepines and selective serotonin re-uptake inhibitors. Addiction, 107, 900- 908. S. Oehrberg P.E., Christiansen K., Published prior to date cut-off Behnke A.L., Borup B., Severin J., Soegaard H., Calberg R., Judge J.K., Ohrstrom P.M, Manniche PM. Paroxetine in the treatment of panic disorder. A randomised, double-blind, placebo-controlled

Excluded studies

Submission Exclusion reason study. British Journal of Psychiatry 167 (1995) pp. 374-9. J. Price, P. Waller, S. Wood, A. Published prior to date cut-off MacKay. A comparison of the post-marketing safety of four selective serotonin re-uptake inhibitors including the investigation of symptoms occurring on withdrawal. British Journal of Clinical Pharmacology 42, (1996) pp. 757-63. Read, J., Cartwright, C., Gibson, K. Non-UK based study (not included for question 4) (2018). How many of 1,829 antidepressant users report withdrawal symptoms or addiction? International Journal of Mental Health Nursing. doi.org/10.1111/inm.12488 Read, J., Cartwright, C., Gibson, K. Non-UK based study (not included for question 4) (2014). Adverse emotional and interpersonal effects reported by 1,829 New Zealanders while taking antidepressants. Psychiatry Research 216, 67-73. Read, J., Williams, J. (2018). Non-UK based study (not included for question 4) Adverse effects of antidepressants reported by a large international cohort: Emotional blunting, suicidality, and withdrawal effects. Current Drug Safety, 13, 176-186. J.F., Rosenbaum, M.,Fava, S.L., Published prior to date cut-off Hoog, R.C., Ascroft, W.B., Krebs Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry 44 (1998) pp. 77-87. Royal College of Psychiatrists. Report unavailable at link and could not be sourced (2012). Coming Off Antidepressants. London: RCP. www.rcpsych.ac.uk/healthadvice/ treatmentswellbeing/antidepress ants/comingoffantidepressants.as px Sir, R.F., D’Souza, s. Uguz, T. Published prior to date cut-off George, S., Vahip, M. Hopwood, A.J. Martin, W. Lam, T., Burt Randomized trial of sertraline versus venlafaxine XR in major depression: efficacy and discontinuation symptoms. Journal of Clinical Psychiatry, 66

Excluded studies

Submission Exclusion reason (2005) pp. 1312–1320. Stone, J., Durrance, D., Wojcik, W. Published prior to date cut-off et al. (2004). What do medical outpatients attending a neurology clinic think about antidepressants? Journal of Psuchosomatic Research, 56, 293- 295. A. Tint, P.M. Haddad, I.M., Not applicable to call for evidence questions, considered for inclusion in Anderson. The effect of rate of relevant question antidepressant tapering on the incidence of discontinuation symptoms: a randomised study. J Psychopharmacol. 22 (3) (2008) pp.330-2. Tonks, A. (2002). Withdrawal Published prior to date cut-off from paroxetine can be severe, warns FDA. British Medical Journal, 324(7332), 260. Van Schaik, D., Klijnb, A., van Published prior to date cut-off Hout, H. et al. (2004). Patients’ preferences in the treatment of depressive disorder in primary care. General Hospital Psychiatry, 26, 184-189. N. Yasui-Furukori, K., Hashimoto, Not applicable to call for evidence questions, considered for inclusion in S., Tsuchimine, T., Tomita, N., relevant question Sugawara, M., Ishioka, K., Nakamura Characteristics of Escitalopram Discontinuation Syndrome: A Preliminary Study. Clin Neuropharmacol.39(3) (2016) pp. 125-7. J. Zajecka, J., Fawcett, J., Published prior to date cut-off Amsterdam, F., Quitkin, F., Reimherr, J., Rosenbaum, D., Michelson, C., Beasley. Safety of abrupt discontinuation of fluoxetine: a randomized, placebo-controlled study. J Clin Psychopharmacol.18(3) (1998) pp. 193-7. Hartdegan, M, Gibson, K, Not directly relevant to review questions Cartwright, C, Read, J. (2017). Stressful events and circumstances reported by patients prior to being prescribed antidepressants. New Zealand Medical Journal, 130, 45-53. Gibson, K., Cartwright, C., Read, J. Not directly relevant to review questions (2016). Conflict in men’s experiences with antidepressants. American Journal of Men’s Health. doi:

Excluded studies

Submission Exclusion reason 10.1177/1557988316637645 Read, J., Gibson, K., Cartwright, C. Not directly relevant to review questions (2016). Do GPs and psychiatrists recommend alternatives when prescribing anti-depressants? Psychiatry Research, 246, 838- 840. Read, J., Gibson, K., Cartwright, C. Not directly relevant to review questions (2016). Are older people prescribed anti-depressants for longer and at lower levels of depression? Australasian Journal of Ageing, 35, 193-197. Cartwright, C., Gibson, K., Read, J. Not directly relevant to review questions (2018). Personal agency in women’s recovery from depression: The impact of antidepressants and women’s personal efforts. Clinical Psychologist, 22, 72-82. Read, J., Gibson, K., Cartwright, Not directly relevant to review questions C., Shiels, C., Dowrick, C., Gabbay, M. (2015). Understanding the non-pharmacological correlates of self-reported efficacy of antidepressants. Acta Psychiatrica Scandinavica 131, 434-445. Read, J., Gibson, K., Cartwright, Not directly relevant to review questions C., Shiels, C., Magliano, L. (2015). Beliefs of people taking antidepressants about the causes of their own depression. Journal of Affective Disorders, 174, 150- 156. I-WOTCH: Improving the No evaluation available, link included for information only as an Wellbeing of People with Opioid example of research in progress (Question 5) Treated Chronic Pain (I-WOTCH) An ongoing randomised controlled trial. https://warwick.ac.uk/fac/sci/me d/research/ctu/trials/iwotch/heal th/ CADTH rapid response report: Not directly relevant to call for evidence review protocols. summary of abstracts Strategies for the Reduction or Discontinuation of Opioids: Guidelines https://www.cadth.ca/sites/defau lt/files/pdf/htis/2017/RB1078%20 - %20Opioid%20Tapering%20Final. pdf Frank, Lovejoy, Becker, Morasco, References considered for inclusion in relevant questions

Excluded studies

Submission Exclusion reason Koenig, Hoffecker, Dichinger, Dobscha & Krebs (2017) Patient Outcomes in Dose Reduction or Discontinuation of Long-Term Opioid Therapy: A Systematic Review. Annals of Internal Medicine 167 (3): 181-191. Berna, Kulich & Rathmell (2015) Not applicable to call for evidence questions, considered for inclusion in Tapering Long-term Opioid relevant question Therapy in Chronic Noncancer Pain: Evidence and Recommendations for Everyday Practice. Mayo Clin Proc 90 (6): 828-842. Eccleston, Fisher, Thomas, Hearn, Not applicable to call for evidence questions, considered for inclusion in Derry, Stannard, Knaggs & Moore relevant question (2017) Interventions for the reduction of prescribed opioid use in chronic non‐cancer pain. Cochrane Database of Systematic Reviews, Issue 11. Art. No.: CD010323. DOI: 10.1002/14651858.CD010323.pu b3. Centre for Effective Practice No evaluation available, included for information only as an example Opioid Tapering Template that could inform UK practice. https://thewellhealth.ca/opioidta peringtool http://nationalpaincentre.mcmas Not directly relevant to review questions ter.ca/guidelines.html Taylor D, Stewart S, Connolly A. Published prior to date cut-off Antidepressant withdrawal symptoms – Telephone calls to a national helpline. Journal of Affective Disorders 2006; 95: 129- 133. Ferguson, J. M. (2001). SSRI Not applicable to call for evidence questions, considered for inclusion in antidepressant medications: relevant question Adverse effects and tolerability. Prim Care Companion J Clin Psychiatry, 3(1), 22–27. Kendrick, T. (2015). Long-term Not applicable to call for evidence questions, considered for inclusion in antidepressant treatment: Time relevant question for a review? Prescriber, 26(19), 7–8 5th October. Gafoor, R., Booth, H. P., & Not applicable to call for evidence questions, considered for inclusion in Gulliford, M. C. (2018). relevant question Antidepressant utilisation and incidence of weight gain during 10 years' follow-up: Population based cohort study. BMJ, 361k1951.

Excluded studies

Submission Exclusion reason Hengartner, M. P., Angst, J., & Not applicable to call for evidence questions, considered for inclusion in Rössler, W. (2018). relevant question Antidepressant use respectively relates to a poorer long-term outcome of depression: Results from a prospective community cohort study over 30 years. Psychotherapy and Psychosomatics, 87, 181–183. Vittengl, J. R. Not applicable to call for evidence questions, considered for inclusion in (2017). Poorer long-term relevant question outcomes among persons with major depressive disorder treated with medication. Psychotherapy and psychosomatics, 86, 302–304. Maslej, M. M., Bolker, B. M., Not applicable to call for evidence questions, considered for inclusion in Russell, M. J., Eaton, K., relevant question Durisko, Z., Hollon, S. D., Andrews, P. W. (2017). The mortality and myocardial effects of antidepressants are moderated by pre-existing cardiovascular disease: A meta-analysis. Psychotherapy and Psychosomatics, 86, 268–282. Richardson, K., Fox, C., Maidment, Not applicable to call for evidence questions, considered for inclusion in I., Steel, N., Loke, T. K., Arthur, A., relevant question Savva, G. M. (2018). Anticholinergic drugs and risk of dementia: Case-control study. BMJ, 361, k1315. Simonsen, A. L., Danborg, P. B., & Not applicable to call for evidence questions, considered for inclusion in Gøtzsche, P. C. (2016). Persistent relevant question sexual dysfunction after early exposure to SSRIs: Systematic review of animal studies. The International Journal Of Risk & Safety In Medicine, 28(1), 1-12. doi:10.3233/JRS-160668 Claire Cartwright, Kerry Gibson, Not applicable to call for evidence questions, considered for inclusion in John Read, Ondria Cowan, Tamsin relevant question Dehar, 2016. Long-term antidepressant use: patient perspectives of benefits and adverse effects. Patient Preference and Adherence, July 2016. Read, J., Spada, M., Kolubinksi, D., Unpublished at present. No outcomes directly relevant to the call for & Frederick, B., (2018), A evidence review protocols.

Excluded studies

Submission Exclusion reason summary of evidence for withdrawal and what works psychotherapeutically the Ashton Manual available on Published prior to date cut-off this link: https://www.benzo.org.uk/manu al/index.htm British Medical Association (2017) No outcomes directly relevant to the call for evidence review protocols. Chronic pain: supporting safer prescribing of analgesics. London: British Medical Association BMA: Supporting individuals No outcomes relevant to review question - relevant report from this affected by prescribed drugs work included in question 4. associated with dependence and withdrawal www.bma.org.uk/collective- voice/policy-and-research/public- and-population- health/prescribed-drugs- dependence-and-withdrawal East Sussex Better Together Email communication, unpublished report/service evaluation. Included (ESBT) Project Group Dependence in report for information only Forming Medication Service Annual report: Bristol Email communication, unpublished annual report . Included in report Tranquilliser Project for information only. NHS England Midlands and East No outcomes directly relevant to the call for evidence review protocols, (East) & PresQIPP audit of unpublished patients on high dose medications, looking at indications, monitoring and poly pharmacy. Brighton & Hove CCG Prescribing Email communication, unpublished report. Included in report for Incentive Scheme information only. Read, J. (2009) Psychiatric drugs: Book. Not directly relevant to review question, service user key issue and service user perspectives not gained from qualitative research. perspectives, London, Mind and Palgrave Macmillan. Anonymised first person Unpublished information only, not possible to include within question 4 experiences from Mind stakeholders and service users of antidepressants Mordecai L, Reynolds C, Not directly relevant to review questions Donaldson LJ, de C Williams AC. Patterns of regional variation of opioid prescribing in primary care in England: a retrospective observational study. British Journal of General Practice. 2018. Wright E, Zarnegar R, Hermansen Not directly relevant to review questions I, McGavin D. A clinical evaluation of a community-based rehabilitation and social intervention programme for

Excluded studies

Submission Exclusion reason patients with chronic pain with associated multi-morbidity. J Pain Manag. 2017;10(2):149-59. Sandhu H, Underwood M, Furlan Not applicable to call for evidence questions, considered for inclusion in A, Noyes J, Eldabe S. What relevant question interventions are effective to taper opioids in patients with chronic pain? BMJ. 2018;362. Gomes T, Juurlink DN, Antoniou T, Not applicable to call for evidence questions, considered for inclusion in Mamdani MM, Paterson JM, van relevant question den Brink W. Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study. PLoS medicine. 2017;14(10):e1002396. Opioids Aware: A resource for Listed in report as example resource, no evaluation available patients and healthcare professionals to support prescribing of opioid medicines for pain, Faculty of Pain Medicine & PHE https://www.rcoa.ac.uk/faculty- of-pain-medicine/opioids-aware Audit feedback cycle on reducing Email communication, unpublished report/service evaluation. Included hypnotics and anxiolytic in report for information only. prescribing using two different approaches in two different practices in the North Camden locality

Napp Pharmaceuticals Ltd Email communication, unpublished position statement. References position statement checked for relevance for inclusion. Grünenthal Ltd position Email communication, unpublished position statement. References statement checked for relevance for inclusion. Walton Centre Pain Management No information directly relevant to the review outcomes Programme (PMP), Liverpool The Walton Centre Pain Management Programme (PMP) is a leading pain management service in the UK and delivers a variety of pain management support options incorporating a number of different models/approaches for opioid reduction. https://www.thewaltoncentre.nh s.uk/uploadedfiles/PMP%20Patie nt%20Resources/PMP%20Booklet %202017.pdf Opioid analgesics dependency Listed in report as an example pilot project in progress, no evaluation (OAD) pilot project, South available at present Gloucestershire http://www.southglos.gov.uk/hea lth-and-social-care/staying-

Excluded studies

Submission Exclusion reason healthy/drugs-and-alcohol/drug- information-and- treatment/opioid-analgesics- dependency-oad-pilot-project/ Wild JE et al. Long-term safety Not applicable to call for evidence questions, considered for inclusion in and tolerability of tapentadol relevant question extended release for the management of chronic low back pain or osteoarthritis pain. Pain Practice, 2010;10(5):416-427. Vosburg SK et al. Assessment of Not applicable to call for evidence questions, considered for inclusion in tapentadol API abuse liability with relevant question the Researched Abuse, Diversion and Addiction-Related Surveillance System. J Pain, 2018;19:439-453. Strick V. Management of severe Not applicable to call for evidence questions, considered for inclusion in chronic pain with tapentadol relevant question prolonged release – long-term data from pain specialists. Curr Med Res Opin, 2014;30:2085– 2092. Hale M et al. Tolerability of Not applicable to call for evidence questions, considered for inclusion in tapentadol immediate release in relevant question patients with lower back pain or osteoarthritis of the hip or knee over 90 days: A randomized, double-blind study. Curr Med Res Opin, 2009;25(5):1095-1104. Dart RC et al. Assessment of the Not applicable to call for evidence questions, considered for inclusion in abuse of tapentadol immediate relevant question release: The first 24 months. J Opioid Man, 2012;8:395-402. Buynak R et al. Long-term safety Not applicable to call for evidence questions, considered for inclusion in and efficacy of tapentadol relevant question extended release following up to 2 years of treatment in patients with moderate to severe, chronic pain: results of an open-label extension trial. Clin Ther, 2015;37:2420-2438. Cepeda MS et al. Comparison of Not applicable to call for evidence questions, considered for inclusion in the risks of opioid abuse or relevant question dependence between tapentadol and oxycodone: Results from a cohort study. J Pain, 2013;14:1227-1241. Dart RC et al. Diversion and illicit Not applicable to call for evidence questions, considered for inclusion in sale of extended release relevant question tapentadol in the United States. Pain Medicine, 2016;17(8):1490- 1496. Cepeda MS et al. Comparison of Not applicable to call for evidence questions, considered for inclusion in opioid doctor shopping for relevant question

Excluded studies

Submission Exclusion reason tapentadol and oxycodone: A cohort study. J Pain, 2013;14:158- 164. Maund E et al. Barriers and Systematic review – screened for relevant references. Two studies from facilitators to discontinuing this review have been included in the review. antidepressant use: a systematic review and thematic synthesis. Journal of Affective Disorders 2018;245:38-62. https://doi.org/10.1016/j.jad.201 8.10.107 Bowers H et al. How can we help No outcomes directly relevant to the call for evidence review protocols. people discontinue long-term antidepressants? Views of health professionals in UK primary care. Submitted to Journal of Affective Disorders Maund E et al. Managing Not directly relevant to call for evidence questions. antidepressant discontinuation: a systematic review. Submitted to Annals of Family Medicine REDUCE Programme Work Stream Listed in report as an example RCT in progress, no evaluation available 4: REviewing long term anti- at present DEpressant Use by Careful monitoring in Everyday practice. Randomised controlled trial http://www.isrctn.com/ISRCTN15 036829 NHS Gloucestershire CCG Listed in report example of an existing programme, no evaluation initiative. Living Well with pain available. programme Mars, Heron, Kessler, Davies, Not directly relevant to review questions Martin, Thomas & Gunnell (2016) Influences on antidepressant prescribing trends in the UK: 1995-2011. Social Psychiatry and Psychiatric Epidemiology. 52. 10.1007/s00127-016-1306-4. Roland & Guthrie (2016) Quality Not directly relevant to review questions and Outcomes Frameword: what have we learnt? BMJ 354 https://www.bmj.com/content/3 54/bmj.i4060.full.print Kendrick, Stuart, Newell, Not applicable to call for evidence questions, considered for inclusion in Geraghty & Moore (2015) J Affect relevant question Disord 1 (186) 171-177 DSM III and MUS Not directly relevant to review questions https://ajp.psychiatryonline.org/d oi/pdf/10.1176/appi.ajp.2013.130 50589 https://www.degruyter.com/dow nloadpdf/j/rjim.2015.53.issue- 1/rjim-2015-0003/rjim-2015- 0003.pdf

List of medicines to be included

Submission Exclusion reason http://www.utupub.fi/bitstream/ handle/10024/42500/D825.pdf;js essionid=46BA85E199115CA9B21 4A7057DA591DA?sequence=1 Lucire & Crotty (2011) Not applicable to call for evidence questions, considered for inclusion in Antidepressant-induced akathisia- relevant question related homicides associated with diminishing mutations in metabolizing genes of the CYP450 family. Pharmgenomics Pers Med. 4; 65-81 Johnson, MacDonald, Atkinson, Not applicable to call for evidence questions, considered for inclusion in Buchanan, Downes & Dougall relevant question (2012) Reviewing long-term antidepressants can reduce drug burden: a prospective observational cohort study. Br J Gen Pract 62 (604) e773-e779 Bosman, Huijbregts, Verhaak, Not applicable to call for evidence questions, considered for inclusion in Ruhe, Marwijk, van Balkon & relevant question Batelaan (2016) Long-term antidepressant use: a qualitative study on perspectives of patients and GPs in primary care. Br J Gen Pract; 66 (651): e708-e719 Sowińska A, Czachowski S. (2018) Not applicable to call for evidence questions, considered for inclusion in Patients' experiences of living relevant question with medically unexplained symptoms (MUS): a qualitative study. BMC Fam Pract. 2018;19(1):23. doi:10.1186/s12875-018-0709-6 Buckley Nicholas A, Dawson Not applicable to call for evidence questions, considered for inclusion in Andrew H, Isbister Geoffrey K. relevant question (2014) Serotonin syndrome BMJ; 348 :g1626 Keks N, Hope J, Keogh S. (2016) Not applicable to call for evidence questions, considered for inclusion in Switching and stopping relevant question antidepressants. Aust Prescr; 39(3):76-83.

Appendix H: List of medicines to be included

This list refers to codes from BNF version 68. Drug class (for this analysis) BNF chapter Drugs included Opioids 4.7.2 Buprenorphine Codeine* Dextromoramide Diamorphine

List of medicines to be included

Drug class (for this analysis) BNF chapter Drugs included Dihydrocodeine** Dipipanone (including with cyclizine) Fentanyl Hydromorphone Meptazinol Methadone Morphine (including with cyclizine) Oxycodone (including with naloxone) Papaveretum Pentazocine Pentazocine Pethidine Tapentadol Tramadol (including with paracetamol) 4.7.1 Codeine with paracetamol = co-codamol* Dihydrocodeine with paracetamol = co-dydramol** Z-drugs 4.1.1 Zaleplon Zopiclone Zolpidem Benzodiazepines 4.1.1 (insomnia) Flurazepam Loprazolam Lormetazepam Nitrazepam Temazepam 4.1.2 (anxiety) Diazepam Chlordiazepoxide Lorazepam Oxazepam Gabapentinoids 4.7.3 Gabapentin 4.8.1 Pregabalin Antidepressants 4.3.1 (Tricyclics) Amitriptyline (including with perphenazine) Amoxapine Clomipramine

Dosulepin

Doxepin

Imipramine

Lofepramine Maprotiline Mianserin Nortriptyline

Protriptyline

List of medicines to be included

Drug class (for this analysis) BNF chapter Drugs included Trazodone Antidepressants Trimipramine (continued) 4.3.2 (MAOIs) Isocarboxazid Moclobemide Phenelzine Tranylcypromine 4.3.3 (SSRIs) Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline 4.3.4 (Other Agomelatine antidepressants) Duloxetine Flupentixol Mirtazapine Nefazodone Oxitriptan Reboxetine Tryptophan Venlafaxine Vortioxetine

* Although they are captured within different BNF chapters, codeine and co-codamol will be regarded as a single drug when considering co-prescribing within the opioid class.

** Although they are captured within different BNF chapters, dihydrocodeine and co-dydramol will be regarded as a single drug when considering co-prescribing within the opioid class.

List of medicines to be included