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Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies

BMJ 2017; 357 doi: (Published 26 April 2017) Cite this as: BMJ 2017;357:j1550
  1. Luis Sordo, assistant professor and research fellow1 2 3,
  2. Gregorio Barrio, research associate4,
  3. Maria J Bravo, research associate1 2,
  4. B Iciar Indave, doctoral candidate1 2,
  5. Louisa Degenhardt, Scientia professor and principal research fellow5 6,
  6. Lucas Wiessing, principal scientist7,
  7. Marica Ferri, head of department7,
  8. Roberto Pastor-Barriuso, research associate1 2
  1. 1National Centre for Epidemiology, Carlos III Institute of Health, Madrid, Spain
  2. 2Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
  3. 3Department of Preventive Medicine and Public Health, Faculty of Medicine, Complutense University, Madrid, Spain
  4. 4National School of Public Health, Carlos III Institute of Health, 28029 Madrid, Spain
  5. 5National Drug and Alcohol Research Centre, University of New South Wales, Sidney, Australia
  6. 6Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia
  7. 7Sector Best Practices, Knowledge Exchange and Economic Issues, European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), Lisbon, Portugal
  1. Correspondence to: G Barrio gbarrio{at}
  • Accepted 17 March 2017


Objective To compare the risk for all cause and overdose mortality in people with opioid dependence during and after substitution treatment with methadone or buprenorphine and to characterise trends in risk of mortality after initiation and cessation of treatment.

Design Systematic review and meta-analysis.

Data sources Medline, Embase, PsycINFO, and LILACS to September 2016.

Study selection Prospective or retrospective cohort studies in people with opioid dependence that reported deaths from all causes or overdose during follow-up periods in and out of opioid substitution treatment with methadone or buprenorphine.

Data extraction and synthesis Two independent reviewers performed data extraction and assessed study quality. Mortality rates in and out of treatment were jointly combined across methadone or buprenorphine cohorts by using multivariate random effects meta-analysis.

Results There were 19 eligible cohorts, following 122 885 people treated with methadone over 1.3-13.9 years and 15 831 people treated with buprenorphine over 1.1-4.5 years. Pooled all cause mortality rates were 11.3 and 36.1 per 1000 person years in and out of methadone treatment (unadjusted out-to-in rate ratio 3.20, 95% confidence interval 2.65 to 3.86) and reduced to 4.3 and 9.5 in and out of buprenorphine treatment (2.20, 1.34 to 3.61). In pooled trend analysis, all cause mortality dropped sharply over the first four weeks of methadone treatment and decreased gradually two weeks after leaving treatment. All cause mortality remained stable during induction and remaining time on buprenorphine treatment. Overdose mortality evolved similarly, with pooled overdose mortality rates of 2.6 and 12.7 per 1000 person years in and out of methadone treatment (unadjusted out-to-in rate ratio 4.80, 2.90 to 7.96) and 1.4 and 4.6 in and out of buprenorphine treatment.

Conclusions Retention in methadone and buprenorphine treatment is associated with substantial reductions in the risk for all cause and overdose mortality in people dependent on opioids. The induction phase onto methadone treatment and the time immediately after leaving treatment with both drugs are periods of particularly increased mortality risk, which should be dealt with by both public health and clinical strategies to mitigate such risk. These findings are potentially important, but further research must be conducted to properly account for potential confounding and selection bias in comparisons of mortality risk between opioid substitution treatments, as well as throughout periods in and out of each treatment.


  • Contributors: LS, GB, MJB, BII, MF, and RP-B were involved in the conception and design of the review. LS, GB, and BII developed the search strategy and performed study selection. LS and RP-B extracted data from included studies. LS, GB, and RP-B were involved in the data analysis. LS, GB, MJB, LD, LW, MF, and RP-B were involved in the interpretation and discussion of results. LS, GB, MJB, and RP-B drafted the manuscript, and BII, LD, LW, and MF contributed to the drafting of the review. All authors approved the final version of the article. RP-B is the guarantor.

  • Funding: This work was partially supported by the ISCIII Network on Addictive Disorders (Networks for Cooperative Research in Health from the Carlos III Institute of Health) (grant No RD16/0017/0013 and RD12/0028/0018) and by the EMCDDA in the context of the activities related to identification, promotion, and monitor of best practices.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: LD has received grants from Reckitt Benckiser/Indivior and grants from Mundipharma outside the submitted work. No further support from any organisation for the submitted work; no other financial relationships with any organisation that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not required.

  • Transparency: The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been disclosed.

  • Data sharing: No additional data available.

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