Naloxone and Clinical Outcomes in Suspected Opioid-Associated Out-of-Hospital Cardiac Arrests

Importance: Although US opioid overdose deaths have recently declined, mortality remains higher than before the COVID-19 pandemic, and the role of naloxone in opioid-associated out-of-hospital cardiac arrest (OA-OHCA) remains uncertain. The American Heart Association has identified a critical evidence gap regarding the role of naloxone in resuscitation care. Objective: To assess the association between naloxone administered by emergency medical services (EMS) clinicians and outcomes in patients with suspected OA-OHCA. Design, Setting, and Participants: This retrospective cohort study of adults (aged ≥18 years) with EMS-treated OHCA used data from the California Resuscitation Outcomes Consortium from January 1, 2021, to December 31, 2022. The primary cohort was patients with OA-OHCA, identified using the Naloxone Cardiac Arrest Decision Instrument (NACARDI) as age younger than 50 years and unwitnessed cardiac arrest. Additional analyses were conducted in patients with EMS-presumed drug-related OHCA and all patients with OHCA. Data were analyzed between November 2024 and July 2025. Exposure: Naloxone administration during EMS resuscitation. Main Outcomes and Measures: The primary outcome was survival to hospital discharge. Secondary outcomes were favorable neurologic outcome and return of spontaneous circulation (ROSC). Inverse probability weighted regression was used to estimate naloxone treatment effects as absolute risk differences (ARDs). Results: Among 3811 patients meeting NACARDI criteria (median patient age, 37 years [IQR, 30-43 years]; 2792 [73.3%] male), 1251 (32.8%) received naloxone and 2560 (67.2%) did not. Survival to hospital discharge occurred in 101 patients (8.1%) who received naloxone vs 112 (4.4%) who did not. Favorable neurologic outcome occurred in 92 (7.4%) vs 84 (3.3%) and sustained ROSC in 177 (14.1%) vs 245 (9.6%), respectively. After adjustment for patient, OHCA incident, and agency-level factors, naloxone was associated with improved survival to hospital discharge (ARD, 2.75 percentage points [pp]; 95% CI, 1.25 to 4.26 pp), favorable neurologic outcome (ARD, 3.18 pp; 95% CI, 1.79 to 4.57 pp), and sustained ROSC (ARD, 3.27 pp; 95% CI, 1.11 to 5.43 pp). In sensitivity analyses of patients who received epinephrine, naloxone was not associated with improved survival to hospital discharge (adjusted ARD, 0.31 pp; 95% CI, -0.09 to 1.58 pp) or the other clinical outcomes. Conclusions and Relevance: In this cohort study, among patients with suspected OA-OHCA, EMS-administered naloxone was associated with improved survival and neurologic status and sustained ROSC. These findings support the need for a randomized trial to assess the effects of naloxone in opioid-associated cardiac arrest.