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Cited by 1,816Opioid Use Disorder TreatmentSubstance Abuse Treatment and OutcomesHIV, Drug Use, Sexual Risk

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

Open access
Sordo, Luis, Barrio, Gregorio, Bravo, Maria J, Indave, B Iciar, Degenhardt, Louisa, Wiessing, Lucas, Ferri, Marica, Pastor-Barriuso, Roberto·2017·BMJ
DOI 10.1136/bmj.j1550PMC PMC5421454
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Abstract

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.

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Fig 1 Selection process of cohort studies on mortality among people receiving opioid substitution treatment
Fig 1 Selection process of cohort studies on mortality among people receiving opioid substitution treatmentCC BY-NC · PubMed Central
Fig 2 All cause mortality rates in and out of opioid substitution treatment with methadone or buprenorphine and overall pooled all cause mortality rates, 1974-2016. Area of each square is proportional to study weight in meta-analysis. Horizontal lines represent exact 95% confidence intervals based on Poisson distribution. Diamonds represent pooled all cause mortality rates during periods in and out of treatment across all methadone or buprenorphine cohorts estimated from bivariate random effects meta-analysis on log transformed rates in both treatment periods
Fig 2 All cause mortality rates in and out of opioid substitution treatment with methadone or buprenorphine and overall pooled all cause mortality rates, 1974-2016. Area of each square is proportional to study weight in meta-analysis. Horizontal lines represent exact 95% confidence intervals based on Poisson distribution. Diamonds represent pooled all cause mortality rates during periods in and out of treatment across all methadone or buprenorphine cohorts estimated from bivariate random effects meta-analysis on log transformed rates in both treatment periodsCC BY-NC · PubMed Central
Fig 3 Overdose mortality rates in and out of opioid substitution treatment with methadone or buprenorphine and overall pooled overdose mortality rates, 1974-2016. Area of each square is proportional to study weight in meta-analysis. Horizontal lines represent exact 95% confidence intervals based on Poisson distribution. Diamonds represent pooled overdose mortality rates during periods in and out of treatment across all methadone cohorts estimated from bivariate random effects meta-analysis on log transformed rates in both treatment periods
Fig 3 Overdose mortality rates in and out of opioid substitution treatment with methadone or buprenorphine and overall pooled overdose mortality rates, 1974-2016. Area of each square is proportional to study weight in meta-analysis. Horizontal lines represent exact 95% confidence intervals based on Poisson distribution. Diamonds represent pooled overdose mortality rates during periods in and out of treatment across all methadone cohorts estimated from bivariate random effects meta-analysis on log transformed rates in both treatment periodsCC BY-NC · PubMed Central
Fig 4 All cause mortality rates by time interval in and out of opioid substitution treatment with methadone or buprenorphine and pooled all cause mortality rates, 2009-16. Mortality data were disaggregated into first four weeks and remaining follow-up in and out of treatment in all cohort studies except Degenhardt et al,6 which reported mortality before and after two weeks of treatment initiation and cessation. High risk cohort of Nosyk et al36 (injectors positive for HIV receiving highly active antiretroviral therapy) was excluded from meta-analysis. Area of each square is proportional to study weight in meta-analysis. Horizontal lines represent exact 95% confidence intervals based on Poisson distribution. Diamonds represent pooled all cause mortality rates before and after four weeks in and out of treatment across methadone or buprenorphine cohorts estimated from multivariate random effects meta-analysis on log transformed rates in four time-by-treatment intervals
Fig 4 All cause mortality rates by time interval in and out of opioid substitution treatment with methadone or buprenorphine and pooled all cause mortality rates, 2009-16. Mortality data were disaggregated into first four weeks and remaining follow-up in and out of treatment in all cohort studies except Degenhardt et al,6 which reported mortality before and after two weeks of treatment initiation and cessation. High risk cohort of Nosyk et al36 (injectors positive for HIV receiving highly active antiretroviral therapy) was excluded from meta-analysis. Area of each square is proportional to study weight in meta-analysis. Horizontal lines represent exact 95% confidence intervals based on Poisson distribution. Diamonds represent pooled all cause mortality rates before and after four weeks in and out of treatment across methadone or buprenorphine cohorts estimated from multivariate random effects meta-analysis on log transformed rates in four time-by-treatment intervalsCC BY-NC · PubMed Central
Fig 5 All cause mortality rates by time since treatment initiation and cessation in methadone cohorts and pooled all cause mortality risk trends, 2009-16. High risk cohort of Nosyk et al36 (injectors positive for HIV receiving highly active antiretroviral therapy) was excluded from meta-regression. Area of each circle is proportional to weight of each time interval in meta-regression. Pooled trends in all cause mortality risk (solid lines) and their 95% confidence intervals (shaded regions) over time in and out of methadone treatment were estimated from bivariate random effects meta-regression of log transformed rates on quadratic linear spline function of log time with knot at four weeks
Fig 5 All cause mortality rates by time since treatment initiation and cessation in methadone cohorts and pooled all cause mortality risk trends, 2009-16. High risk cohort of Nosyk et al36 (injectors positive for HIV receiving highly active antiretroviral therapy) was excluded from meta-regression. Area of each circle is proportional to weight of each time interval in meta-regression. Pooled trends in all cause mortality risk (solid lines) and their 95% confidence intervals (shaded regions) over time in and out of methadone treatment were estimated from bivariate random effects meta-regression of log transformed rates on quadratic linear spline function of log time with knot at four weeksCC BY-NC · PubMed Central
Fig 6 Overdose mortality rates by time interval in and out of opioid substitution treatment with methadone or buprenorphine and pooled overdose mortality rates, 2002-16. Mortality data were disaggregated into first four weeks and remaining follow-up in and out of treatment in all cohort studies except Buster et al,7 which reported mortality before and after two weeks of treatment initiation and cessation. Area of each square is proportional to study weight in meta-analysis. Horizontal lines represent exact 95% confidence intervals based on Poisson distribution. Diamonds represent pooled overdose mortality rates before and after four weeks in and out of treatment across methadone cohorts estimated from multivariate random-effects meta-analysis on log transformed rates in four time-by-treatment intervals
Fig 6 Overdose mortality rates by time interval in and out of opioid substitution treatment with methadone or buprenorphine and pooled overdose mortality rates, 2002-16. Mortality data were disaggregated into first four weeks and remaining follow-up in and out of treatment in all cohort studies except Buster et al,7 which reported mortality before and after two weeks of treatment initiation and cessation. Area of each square is proportional to study weight in meta-analysis. Horizontal lines represent exact 95% confidence intervals based on Poisson distribution. Diamonds represent pooled overdose mortality rates before and after four weeks in and out of treatment across methadone cohorts estimated from multivariate random-effects meta-analysis on log transformed rates in four time-by-treatment intervalsCC BY-NC · PubMed Central

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  1. [15]Degenhardt L, Calabria B, Nelson P, et al, and Global Burden of Disease Mental Disorders and Illicit Drug Use Expert group. Methodology used in a systematic review of evidence on the prevalence of amphetamine use and dependence. 2009. Sydney, National Drug and Alcohol Research Centre, University of NSW. Illicit drugs discussion paper No.13.

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Metadata

Authors
Sordo, L., Barrio, G., Bravo, M. J., Indave, B. I., Degenhardt, L., Wiessing, L., Ferri, M., & Pastor-Barriuso, R.
Affiliations
  • Universidad Complutense de Madrid (ES)
  • Instituto de Salud Carlos III (ES)
  • The University of Melbourne (AU)
  • European Monitoring Centre for Drugs and Drug Addiction (PT)
Corresponding author
Barrio, Gregorio
ORCID
Venue
BMJ
Publisher
BMJ
Published
2017-04-26
Volume
357
Pages
j1550
ISSN
  • 1756-1833 (ISSN-L)
  • 0959-8138
DOI
10.1136/bmj.j1550
PMC
PMC5421454
OpenAlex
W2608446001
Cited by
1,816
References
76
Citations by year
2026: 156 · 2025: 194 · 2024: 201 · 2023: 239 · 2022: 228 · 2021: 261 · 2020: 213 · 2019: 187 · 2018: 99 · 2017: 32
FWCI
23.58
Type
journal article
Language
en
Open access
Licence
Locations
  • BMJ (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc)
  • HighWire Press Open Archive (submittedVersion)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
  • Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
  • Health Sciences › Medicine › Epidemiology › HIV, Drug Use, Sexual Risk
Keywords
opioid substitution therapy, methadone, buprenorphine, opioid use disorder, all-cause mortality, drug overdose deaths, treatment retention, treatment discontinuation, harm reduction, opioid antagonists
MeSH terms
Buprenorphine, Humans, Methadone, Opioid-Related Disorders, Narcotics, Risk, Opiate Substitution Treatment, Drug Overdose

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