J Clin Pharmacol

How does the nalmefene auto-injector compare to intranasal naloxone in fentanyl overdose?

August 19, 2025

Intramuscular (IM) nalmefene may be a more effective alternative to intranasal (IN) naloxone, especially in high-potency opioid overdoses like fentanyl. Its auto-injector format could offer practical advantages in emergency and community settings, potentially improving outcomes in opioid overdose reversal.

Study details: A randomized, 4-period, 2-treatment crossover study enrolled 24 healthy, opioid-experienced adults to compare IM nalmefene 1.5 mg (auto-injector, rapid-onset formulation) vs. IN naloxone 4 mg for reversal of opioid-induced respiratory depression. Fentanyl infusions targeted a 50% reduction in minute ventilation (MV), with reversal agents administered under steady-state opioid agonism. Primary endpoints included change in MV, pharmacokinetics, and safety.

Results: IM nalmefene demonstrated superior reversal at 5 minutes post-administration, increasing MV by 4.59 L/min vs. 1.99 L/min for naloxone (p<.0001). Superiority persisted at 10, 15, 20, and 30 minutes; non-inferiority was shown at 2.5 and 90 minutes. Nalmefene produced a faster onset and higher peak antagonist concentrations (5–10 min) compared with naloxone (20–30 min). Time to reversal at all thresholds (25%–100%) was consistently shorter with nalmefene. Both agents were well tolerated, with no serious adverse events.

Source:

Cipriano A, et al. (2025, August 12). J Clin Pharmacol. Reversal of Fentanyl-Induced Respiratory Depression in Healthy Subjects by Intramuscular Nalmefene Administered by Auto-Injector Versus Intranasal Naloxone. https://pubmed.ncbi.nlm.nih.gov/40796531/