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.

Question: Is naloxone administered by emergency medical services (EMS) clinicians associated with improved outcomes in patients with suspected opioid-associated out-of-hospital cardiac arrest (OA-OHCA)?

Findings: In this cohort study of 3811 patients with suspected OA-OHCA, naloxone was associated with higher rates of survival to hospital discharge, return of spontaneous circulation, and favorable neurologic outcome. Risk differences were larger among patients who had EMS-presumed drug-related cardiac arrest and were attenuated among patients who received epinephrine.

Meaning: The findings suggest naloxone administration during EMS resuscitation was associated with improved outcomes in patients with suspected OA-OHCA, supporting the need to assess effects of naloxone in opioid-associated cardiac arrest.