Question: What factors are associated with an increased risk for opioid overdose after the initial opioid prescription to a previously opioid-naive individual?

Findings: In this cohort study of 236 921 individuals who received a first opioid prescription, 667 experienced an incident opioid overdose. Patient risk factors included being aged 75 years or older, being male, receiving Medicaid or Medicare Advantage coverage, having a comorbid substance use disorder or depression, and having medical comorbidities. Prescription-related risk factors included an initial prescription of oxycodone or tramadol, concurrent use of benzodiazepines, and filling opioid prescriptions from 3 or more pharmacies.

Meaning: Findings from this study suggest that several patient- and prescription-related risk factors are associated with opioid overdose; prescribers, researchers, policy makers, and insurers can apply this information to guide opioid counseling and monitoring, develop clinical decision-making tools, and provide additional opioid prevention and treatment resources to individuals who are at greatest risk for opioid overdose.