The impact of opioid agonist treatment delivered in different settings on all-cause mortality and specific causes of death: A systematic review and meta-analysis

Thomas Santo Jr , Matt Hickman, Prianka Padmanathan, Louisa Degenhardt, et al.

Research output: Contribution to journalArticle (Academic Journal)peer-review


Importance: Mortality among people with opioid dependence is higher than the general population and a global health burden. 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 impact of time in OAT on all-cause and cause-specific mortality. We also examine risk during time periods of treatment, by setting (community and incarceration) and by participant characteristics.

Data Sources: We searched Embase, MEDLINE, and PsycINFO through January 2020; 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 in and out-of-OAT were included. Randomised controlled trials (RCTs) were also included.

Data Extraction and Synthesis: We followed GATHER, PRISMA, and MOOSE guidelines. Data on study, participant and treatment characteristics were extracted; person-years, and all-cause and cause-specific mortality. Crude mortality rates and rate ratios (RRs) were pooled using random-effects meta-analyses.

Main Outcomes: All-cause and cause-specific mortality, overall; by methadone, buprenorphine; setting, and time-period.

Results: 15 eligible RCTs, N=3,852 participants; 36 primary cohort studies, N=749,634. Cohort studies found all-cause mortality during OAT more than halved compared to time out-of-OAT (RR=0.47; 95%CI 0.42-0.53). This relationship was consistent by gender, age, location, HIV, or HCV status, and people who inject. Associations were not different for methadone (RR=0.47; 95%CI 0.41-0.54) versus buprenorphine (RR=0.34; 95%CI 0.26-0.45). There was lower risk of drug-related, suicide, alcohol-related, cancer, and cardiovascular mortality during OAT. In the first four weeks of methadone, all-cause mortality and drug-related poisoning was almost double that in the remainder of OAT (not so for buprenorphine). It was six-times higher in the four weeks following OAT cessation, remaining double the rate for the remainder of time out-of-OAT. OAT is strongly associated with a lower risk fo mortality when incarcerated and after release from incarceration, particularly suicide and overdose.

Discussion: OAT is associated with a reduction in multiple causes of death. Nonetheless, access remains limited, and coverage too low. Work to improve access globally is likely to have important population-level benefits.
Original languageEnglish
JournalJAMA Psychiatry
Publication statusAccepted/In press - 1 Apr 2021

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