Risk of opioid-related mortality associated with buprenorphine versus methadone: A systematic review of observational studies

IntroductionBuprenorphine and methadone are effective treatments of opioid use disorder (OUD) and can reduce drug-related mortality. While observational studies have compared head-to-head buprenorphine and methadone, this evidence has not been previously synthesized. Our study aims to systematically review the available evidence on the comparative effectiveness of buprenorphine and methadone in people with OUD, thereby rigorously assessing the methodological quality of individual studies. MethodsWe searched Medline, Embase, PsycINFO, and Web of Science for all relevant articles published between 1978 and April 8, 2023. Observational studies directly comparing the risk of drug-related mortality between buprenorphine and methadone among people with OUD were eligible. We assessed the overall risk of bias using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool. ResultsOur systematic review included seven studies. There was mixed evidence of comparative mortality risk, with heterogeneity across study region, time, and treatment status (on treatment vs. discontinued). Three studies reported no difference, and four reported findings in favour of buprenorphine. Based on ROBINS-I, three studies had a moderate risk of bias, two had a severe risk, and two had a critical risk. Major sources of biases were residual confounding and selection bias along with presence of prevalent user bias, informative censoring, and left truncation. ConclusionsDue to methodological limitations of the observational studies, generalizability of their findings remains unknown. Therefore, to provide a more accurate comparative safety profile for these two medications, further observational studies with methodological rigour are warranted.