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

Introduction Buprenorphine 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. Methods We 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. Results Our 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. Conclusions Due 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. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Protocols ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript.