National Guideline Centre . Harms of dependence, withdrawal or discontinuation syndrome Review of the evidence on harms associated with dependence, and the short term discontinuation and longer term withdrawal symptoms from prescribed medicines. Rapid Evidence Assessment Methods, evidence and summary 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 Harms Contents 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. Copyright © Royal College of Physicians 2019 © Royal College of Physicians 2019 Harms Executive summary Contents 1 Executive summary ............................................................................................................... 6 1.1 Objectives .............................................................................................................................. 6 1.2 Methods ................................................................................................................................ 6 1.3 Findings ................................................................................................................................. 6 1.4 Conclusion ............................................................................................................................. 6 2 Introduction ......................................................................................................................... 8 2.1 Review question to be addressed ......................................................................................... 8 3 Methodology ........................................................................................................................ 9 3.1 Searching for evidence .......................................................................................................... 9 3.2 Identifying and analysing evidence ..................................................................................... 10 3.2.1 Inclusion and exclusion criteria .............................................................................. 10 3.2.2 Type of studies ....................................................................................................... 11 3.3 Methods of combining clinical studies................................................................................ 11 3.3.2 Heterogeneity ........................................................................................................ 12 3.4 Appraising the quality of evidence by outcomes ................................................................ 12 3.4.1 Risk of bias .............................................................................................................. 13 3.4.2 Indirectness ............................................................................................................ 14 3.4.3 Inconsistency .......................................................................................................... 14 3.4.4 Imprecision ............................................................................................................. 15 3.4.5 Overall grading of the quality of clinical evidence ................................................. 16 4 Review question and findings ............................................................................................... 18 4.1 Available evidence .............................................................................................................. 18 4.1.1 Summary of included studies ................................................................................. 19 4.1.2 Short term versus long term opioid use ................................................................. 28 4.1.3 Short versus long term drug withdrawal ............................................................... 28 4.2 Evidence summary .............................................................................................................. 31 4.2.1 Harms of dependency on a medication ................................................................. 31 4.2.2 Harms/ side effects from stopping these medications over a short time frame ... 32 4.2.3 Short term versus long term opioid use ................................................................. 43 4.2.4 Short term versus long term drug withdrawal ....................................................... 44 4.3 Narrative findings ................................................................................................................ 52 4.3.1 Opioids ................................................................................................................... 52 4.3.2 Z drugs .................................................................................................................... 52 4.3.3 Antidepressants...................................................................................................... 52 5 Conclusions ......................................................................................................................... 56 6 References .......................................................................................................................... 58 © Royal College of Physicians 2019 4 Harms Executive summary 7 Appendices ........................................................................................................................ 126 Appendix A: Review protocols .................................................................................................... 126 Appendix B: Study selection ........................................................................................................ 128 Appendix C: Search strategies ..................................................................................................... 129 Appendix D: Forest plots ............................................................................................................. 148 Appendix E: Evidence tables ....................................................................................................... 172 Appendix F: GRADE tables .......................................................................................................... 251 Appendix G: Excluded studies ..................................................................................................... 272 Appendix H: List of medicines to be included ............................................................................. 310 © Royal College of Physicians 2019 5 Harms 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 the evidence on harms associated with dependence, and the short term discontinuation and longer term withdrawal symptoms from prescribed medicines. 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. A systematic review was undertaken for all evidence relevant to the review protocol that assessed harms for the specified drug classes. Data were extracted into evidence tables from the included studies. Risk of bias assessment of individual studies was undertaken according to the Cochrane risk of bias tool for randomised and non-randomised studies as appropriate and quality of the evidence was assessed using the GRADE approach. When