Extended-release naltrexone versus buprenorphine-naloxone for opioid use disorder: a systematic review and meta-analysis of randomized controlled trials

Background: Extended-release naltrexone (XR-NTX) and buprenorphine-naloxone (BUP-NLX) are approved for opioid use disorder (OUD), but their comparative efficacy and safety are unclear.Objectives: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing XR-NTX and BUP-NLX.Methods: PubMed, Embase, and Cochrane were searched from inception to July 2025. Main efficacy outcomes were treatment initiation, retention, time to relapse, number of relapses, opioid-positive urine samples, and self-reported opioid use days. Odds ratios (OR), mean differences (MD), and hazard ratios (HR) with 95% confidence intervals (CI) were calculated. Heterogeneity was assessed with I2 and evidence certainty rated with GRADE.Results: Five RCTs comprising 1,043 patients (68.2% male; XR-NTX, n = 512; BUP-NLX, n = 531) were included. Treatment initiation was lower with XR-NTX (OR 0.27; 95% CI 0.12–0.64; p = .003; I2 = 67.6%). There were no differences in treatment retention (OR 0.85; 95% CI 0.65–1.11; p = .25; I2 = 0%). XR-NTX was associated with a significantly lower proportion of opioid-positive urine samples (OR 0.52; 95% CI 0.38–0.73; p < .001; I2 = 0%). There were no differences in relapse (OR 0.60; 95% CI 0.21–1.73; p = .35; I2 = 89.9%), opioid use days in 30 days (MD − 0.99; 95% CI − 3.62 to 1.64; p = .46; I2 = 63.8%), or adverse events.Conclusion: XR-NTX and BUP-NLX did not differ across most outcomes, though initiation was lower with XR-NTX and evidence certainty was very low to moderate. With neither clearly superior, initiating either treatment may matter most.