Naltrexone as Pre-exposure Prophylaxis for Unintentional Opioid Overdose in Stimulant Use Disorder: A Case Report

Stimulant-involved overdose deaths have increased sharply in the United States, largely driven by adulteration of the stimulant drug supply with fentanyl and other high-potency synthetic opioids. Individuals with stimulant use disorder (StUD) who do not intentionally use opioids remain at elevated risk for unintentional opioid overdose. Pharmacologic strategies for overdose prevention in this population remain limited.

We describe a 32-year-old woman with severe stimulant use disorder who smoked crack cocaine and denied intentional opioid use but experienced 2 nonfatal opioid overdoses attributed to fentanyl-adulterated cocaine. After emergency department treatment with naloxone, we initiated daily oral naltrexone off-label as a harm-reduction strategy to reduce the risk of future opioid overdose. The patient tolerated naltrexone well after brief nausea and reported consistent adherence without reduction in stimulant effects or cravings. She continued daily cocaine use but experienced no further opioid overdoses during 5 months of follow-up.

This case highlights the potential role of naltrexone as pre-exposure prophylaxis (PrEP) for unintentional opioid overdoses. Framing naltrexone use around unintentional opioid overdose prevention may enhance acceptability and adherence in patients not seeking a decrease or cessation of stimulant use. This strategy does not prevent non-opioid-involved stimulant deaths and should complement, not replace, naloxone distribution and other first-line overdose prevention measures.

Oral naltrexone may represent a novel harm-reduction intervention to mitigate opioid-related morbidity and mortality in the setting of an increasingly adulterated stimulant supply. Further research is needed to evaluate efficacy and implementation.