Myanca Rodrigues, Brittany B Dennis, Behnam Sadeghirad, Anna Oprea, Mikail Malik, Leen N Naji, Alannah McEvoy, Devon Malhotra, Sameer Parpia, Lehana Thabane, Zainab Samaan
ObjectiveTo assess the comparative benefits and harms of opioid substitution and antagonist therapies (OSATs) for opioid use disorder (OUD) using a network meta-analysis (NMA) of randomized controlled trials (RCTs).Data SourcesMedline, EMBASE, PubMed, PsycINFO, Web of Science, Cochrane Library, Cochrane Clinical Trials Registry, and the National Institutes of Health Clinical Trials Registry were searched through 10 August 2025, for trials assessing the effectiveness or safety of any OSAT for people with OUD.Data Extraction and SynthesisPairs of reviewers independently screened studies, extracted data, and assessed risk of bias. Frequentist random-effects NMAs were conducted, and certainty of evidence for treatment effects was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach.Main Outcomes and MeasuresTreatment retention (people remaining in follow-up at study end), opioid abstinence (during follow-up), criminal activity, all-cause mortality, and overdose-related death.ResultsWe included 103 RCTs assessing 13 interventions across 26,624 people with OUD. Compared with placebo, moderate-certainty evidence demonstrated that heroin was most effective for treatment retention (Odds Ratio [OR] = 31.47; 95% confidence interval [CI] = 12.29,80.58). Heroin + methadone (OR = 8.00; 95% CI = 3.21,19.93) and high-dose methadone (HMET) (OR = 6.94; 95% CI = 3.76, 12.82) also ranked highly (moderate certainty). High- and low-dose buprenorphine (moderate certainty) and HMET (low certainty), improved abstinence as measured by urine drug screens. No intervention reduced criminal activity (moderate certainty), all-cause mortality (low certainty), or overdose-related death.Conclusions and RelevanceHeroin-assisted therapy, alone or with methadone, and HMET were most effective for treatment retention. Buprenorphine and HMET improved abstinence, although certainty was lower. Evidence for mortality, overdose, and other patient-important outcomes remains limited. Heroin-assisted therapy exclusively enrolled people with heroin dependence and should not be initiated in those without prior use. Larger trials directly comparing methadone, buprenorphine, and heroin-assisted therapy, and enrolling patients with fentanyl use, are needed in the evolving toxic drug supply.PROSPERO RegistrationCRD42013006507.