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Original Investigation
June 2, 2021

Association of Opioid Agonist Treatment With All-Cause Mortality and Specific Causes of Death Among People With Opioid Dependence: A Systematic Review and Meta-analysis

Author Affiliations
  • 1National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Sydney, Australia
  • 2Population Health Sciences, University of Bristol, Bristol, United Kingdom
  • 3Kirby Institute, University of New South Wales, Sydney, Sydney, Australia
  • 4University of the Sunshine Coast, Sunshine Coast, Queensland, Australia
  • 5Consortium for Biomedical Research in Epidemiology and Public Health, Madrid, Spain
  • 6Department of Preventive Medicine and Public Health, Faculty of Medicine, Complutense University, Madrid, Spain
  • 7Clinical Research Unit for Anxiety and Depression, St Vincent's Hospital, Sydney, New South Wales, Australia
  • 8School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
  • 9University Department of General Medicine, University of Toulouse, Faculty of Medicine, Toulouse, France
  • 10Inserm UMR1027, University of Toulouse III, Faculty of Medicine, Toulouse, France
  • 11The School of Population & Global Health, The University of Western Australia, Perth, Australia
  • 12Department of Internal Medicine, Germans Trias i Pujol-IGTP University Hospital, Autonomous University of Barcelona, Barcelona, Spain
  • 13British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
  • 14Faculty of Health Sciences, Simon Fraser University, Vancouver, British Columbia, Canada
  • 15Epidemiological Monitoring Center on Addiction, Azienda Unità Sanitaria Locale Bologna, Mental Health Dipartimento Salute Mentale – Dipendenze Patologiche, Bologna, Italy
  • 16Italian Society on Addiction, Milan, Italy
JAMA Psychiatry. 2021;78(9):979-993. doi:10.1001/jamapsychiatry.2021.0976
Key Points

Question  Is opioid agonist treatment (OAT) associated with risk of overall and cause-specific mortality among people with opioid dependence?

Findings  In this systematic review and meta-analysis, risk of all-cause, overdose, suicide, alcohol-related, cancer, and cardiovascular-related mortality was significantly lower for people with opioid dependence during OAT.

Meaning  These findings suggest that increasing access to OAT and retention in treatment are critical for reducing rates of preventable mortality among people with opioid dependence.


Importance  Mortality among people with opioid dependence is higher than that of the general population. Opioid agonist treatment (OAT) is an effective treatment for opioid dependence; however, there has not yet been a systematic review on the relationship between OAT and specific causes of mortality.

Objective  To estimate the association of time receiving OAT with mortality.

Data Sources  The Embase, MEDLINE, and PsycINFO databases were searched through February 18, 2020, including clinical trial registries and previous Cochrane reviews.

Study Selection  All observational studies that collected data on all-cause or cause-specific mortality among people with opioid dependence while receiving and not receiving OAT were included. Randomized clinical trials (RCTs) were also included.

Data Extraction and Synthesis  This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Data on study, participant, and treatment characteristics were extracted; person-years, all-cause mortality, and cause-specific mortality were calculated. Crude mortality rates and rate ratios (RRs) were pooled using random-effects meta-analyses.

Main Outcomes and Measures  Overall all-cause and cause-specific mortality both by setting and by participant characteristics. Methadone and buprenorphine OAT were evaluated specifically.

Results  Fifteen RCTs including 3852 participants and 36 primary cohort studies including 749 634 participants were analyzed. Among the cohort studies, the rate of all-cause mortality during OAT was more than half of the rate seen during time out of OAT (RR, 0.47; 95% CI, 0.42-0.53). This association was consistent regardless of patient sex, age, geographic location, HIV status, and hepatitis C virus status and whether drugs were taken through injection. Associations were not different for methadone (RR, 0.47; 95% CI, 0.41-0.54) vs buprenorphine (RR, 0.34; 95% CI, 0.26-0.45). There was lower risk of suicide (RR, 0.48; 95% CI, 0.37-0.61), cancer (RR, 0.72; 95% CI, 0.52-0.98), drug-related (RR, 0.41; 95% CI, 0.33-0.52), alcohol-related (RR, 0.59; 95% CI, 0.49-0.72), and cardiovascular-related (RR, 0.69; 95% CI, 0.60-0.79) mortality during OAT. In the first 4 weeks of methadone treatment, rates of all-cause mortality and drug-related poisoning were almost double the rates during the remainder of OAT (RR, 2.01; 95% CI, 1.55-5.09) but not for buprenorphine (RR, 0.58; 95% CI, 0.18-1.85). All-cause mortality was 6 times higher in the 4 weeks after OAT cessation (RR, 6.01; 95% CI, 4.32-8.36), remaining double the rate for the remainder of time not receiving OAT (RR, 1.81; 95% CI, 1.50-2.18). Opioid agonist treatment was associated with a lower risk of mortality during incarceration (RR, 0.06; 95% CI, 0.01-0.46) and after release from incarceration (RR, 0.09; 95% CI, 0.02-0.56).

Conclusions and Relevance  This systematic review and meta-analysis found that OAT was associated with lower rates of mortality. However, access to OAT remains limited, and coverage of OAT remains low. Work to improve access globally may have important population-level benefits.

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