IntroductionSeveral pharmacotherapeutic interventions are available for maintenance treatment for opioid-related disorders. However, previous meta-analyses have been limited to pairwise comparisons of these interventions, and their efficacy relative to all others remains unclear. Our objective was to unify findings from different healthcare practices and generate evidence to strengthen clinical treatment protocols for the most widely prescribed medications for opioid-use disorders.MethodsWe searched Medline, EMBASE, PsycINFO, CENTRAL, and ClinicalTrials.gov for all relevant randomized controlled trials (RCT) from database inception to February 12, 2022. Primary outcome was treatment retention, and secondary outcome was opioid use measured by urinalysis. We calculated risk ratios (RR) and 95% credible interval (CrI) using Bayesian network meta-analysis (NMA) for available evidence. We assessed the credibility of the NMA using the Confidence in Network Meta-Analysis tool.ResultsSeventy-nine RCTs met the inclusion criteria. Due to heterogeneity in measuring opioid use and reporting format between studies, we conducted NMA only for treatment retention. Methadone was the highest ranked intervention (Surface Under the Cumulative Ranking [SUCRA] = 0.901) in the network with control being the lowest (SUCRA = 0.000). Methadone was superior to buprenorphine for treatment retention (RR = 1.22; 95% CrI = 1.06–1.40) and buprenorphine superior to naltrexone (RR = 1.39; 95% CrI = 1.10–1.80). However, due to a limited number of high-quality trials, confidence in the network estimates of other treatment pairs involving naltrexone and slow-release oral morphine (SROM) remains low.ConclusionAll treatments had higher retention than the non-pharmacotherapeutic control group. However, additional high-quality RCTs are needed to estimate more accurately the extent of efficacy of naltrexone and SROM relative to other medications. For pharmacotherapies with established efficacy profiles, assessment of their long-term comparative effectiveness may be warranted.Trial RegistrationThis systematic review has been registered with PROSPERO (https://www.crd.york.ac.uk/prospero) (identifierCRD42021256212).