Importance Emergency departments (EDs) serve patients at high risk for overdose. There is increasing interest in peer-delivered ED interventions for substance use but little rigorous research on their effectiveness. Objective To examine the effectiveness of an initiative (Relay) operated by the New York City Health Department that dispatches trained peer wellness advocates (WAs) to support ED patients after a nonfatal opioid overdose. Design, Setting, and Participants This randomized clinical trial compared Relay and site-directed care (SDC) at 4 EDs in New York, New York. Adult patients presenting after opioid-involved overdose were enrolled from October 6, 2020, to June 30, 2022, with 12 months of outcome follow-up. Statistical analysis was performed from November 4, 2024, to May 6, 2025. Intervention ED workers (generally physicians) called the Relay hotline for patients presenting after a suspected opioid-involved overdose. WAs met patients in the ED to provide peer support and brief overdose risk reduction education. WAs attempted to contact patients for 90 days to provide ongoing support, education, and referrals using a harm reduction framework. Main Outcomes and Measures Opioid-related adverse events (any opioid-involved overdose fatal or nonfatal or any other substance use–related ED visit) in the 12 months after enrollment were identified using health care administrative data plus self-report. Results Among a total of 253 participants randomized, 127 were randomized to the Relay arm and 126 to the SDC arm. A total of 247 participants, 125 in the Relay arm and 122 in the SDC arm (190 76.9% men; 80 32.4% Black, 126 51.0% Hispanic or Latinx, 76 30.8% White, and 91 other race 36.8%), were included in the intention-to-treat analyses. No statistically significant differences between arms were observed for the primary outcome (mean SD opioid-related adverse events, 3.29 4.52 in the Relay arm and 4.10 9.36 in the SDC arm; rate ratio, 1.02; 95% CI, 0.72-1.45; P = .90). By 12 months after enrollment, 24 participants (9.7%) had died (17 70.8% due to overdose). Relay participants reported high satisfaction with the ED intervention. Conclusions and Relevance This randomized clinical trial examining the impact of an ED peer navigator intervention on subsequent opioid-related adverse events did not find significant outcome differences for Relay vs SDC participants. These findings highlight the importance of intervening to save lives in this high-risk population and suggest potential refinements to future ED peer intervention research. Trial Registration ClinicalTrials.gov Identifier: NCT04317053
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