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Meta-Analysis
. 2021 Sep 1;78(9):979-993.
doi: 10.1001/jamapsychiatry.2021.0976.

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

Thomas Santo Jr  1 , Brodie Clark  1 , Matt Hickman  2 , Jason Grebely  3 , Gabrielle Campbell  1   4 , Luis Sordo  5   6 , Aileen Chen  1   7 , Lucy Thi Tran  1 , Chrianna Bharat  1 , Prianka Padmanathan  2 , Grainne Cousins  8 , Julie Dupouy  9   10 , Erin Kelty  11 , Roberto Muga  12 , Bohdan Nosyk  13   14 , Jeong Min  13 , Raimondo Pavarin  15   16 , Michael Farrell  1 , Louisa Degenhardt  1
Affiliations
Meta-Analysis

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

Thomas Santo Jr et al. JAMA Psychiatry. .

Erratum in

  • Error in Abstract.
    [No authors listed] [No authors listed] JAMA Psychiatry. 2021 Sep 1;78(9):1044. doi: 10.1001/jamapsychiatry.2021.1754. JAMA Psychiatry. 2021. PMID: 34190969 Free PMC article. No abstract available.
  • Error in Abstract.
    [No authors listed] [No authors listed] JAMA Psychiatry. 2022 May 1;79(5):516. doi: 10.1001/jamapsychiatry.2022.0357. JAMA Psychiatry. 2022. PMID: 35293962 Free PMC article. No abstract available.
  • Errors in Results and Tables.
    [No authors listed] [No authors listed] JAMA Psychiatry. 2023 Sep 1;80(9):972. doi: 10.1001/jamapsychiatry.2023.2537. JAMA Psychiatry. 2023. PMID: 37466992 Free PMC article. No abstract available.

Abstract

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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Conflict of interest statement

Conflict of Interest Disclosures: Mr Santo reported receiving the Australian Government Research Training Program Fee Offset scholarship and Australian Federal Government Department of Health Grants National Centre Core Funding during the conduct of the study. Dr Hickman reported receiving grants from National Institute for Health Research & Medical Research Council for analysis of the data set included in this review during the conduct of the study and speaker honoraria from Merck Sharp & Dohme and Gilead in the past 3 years outside the submitted work. Dr Grebely reported receiving grants from AbbVie, Cepheid, Gilead Sciences, Hologic, Indivior, and Merck, and personal fees from AbbVie, Cepheid, Gilead Sciences, and Merck outside the submitted work. Dr Campbell reported receiving grants from Indivior and National Health and Medical Research Council Early Career Fellowship during the conduct of the study. Dr Bharat reported receiving the National Drug and Alcohol Research Centre and University of New South Wales Scientia PhD Scholarships outside the submitted work. Dr Dupouy reported being a member of a working group for and writing a recommendation on the proper use of prescribed opioid analgesics for the French High Authority of Health. Dr Farrell reported receiving grants from the Australian Federal Government Department of Health National Centre Core Funding, an united grant from Indivior to evaluate new opioid medications in Australia, and grants from Seqirus United to evaluate new opioid medications in Australia outside the submitted work. Dr Degenhardt reported receiving grants from National Health and Medical Research Council Fellowship, project funding and grants from the National Institutes of Health Project funding, grants from Indivior United to evaluate new opioid medications in Australia, and grants from Seqirus United to evaluate new opioid medications in Australia outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. Studies on the Association of Opioid Agonist Treatment (OAT) With All-Cause Mortality From Randomized Clinical Trials and Cohort Studies by Administration of Buprenorphine or Methadone
Weights are from random-effects analysis.
See this image and copyright information in PMC

Comment in

References

    1. Irvine MA, Kuo M, Buxton JA, et al. . Modelling the combined impact of interventions in averting deaths during a synthetic-opioid overdose epidemic. Addiction. 2019;114(9):1602-1613. doi:10.1111/add.14664 - DOI - PMC - PubMed
    1. Degenhardt L, Grebely J, Stone J, et al. . Global patterns of opioid use and dependence: harms to populations, interventions, and future action. Lancet. 2019;394(10208):1560-1579. doi:10.1016/S0140-6736(19)32229-9 - DOI - PMC - PubMed
    1. Wen LS, Sadeghi NB. The opioid crisis and the 2020 US election: crossroads for a national epidemic. Lancet. 2020;396(10259):1316-1318. doi:10.1016/S0140-6736(20)32113-9 - DOI - PMC - PubMed
    1. Brignone E, George DR, Sinoway L, et al. . Trends in the diagnosis of diseases of despair in the United States, 2009-2018: a retrospective cohort study. BMJ Open. 2020;10(10):e037679. doi:10.1136/bmjopen-2020-037679 - DOI - PMC - PubMed
    1. Larney S, Tran LT, Leung J, et al. . All-cause and cause-specific mortality among people using extramedical opioids: a systematic review and meta-analysis. JAMA Psychiatry. 2020;77(5):493-502. doi:10.1001/jamapsychiatry.2019.4170 - DOI - PMC - PubMed

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