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

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.

Fig 1 Selection process of cohort studies on mortality among people receiving opioid substitution treatment

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 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 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, which reported mortality before and after two weeks of treatment initiation and cessation. High risk cohort of Nosyk et al (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 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 al (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 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, 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