Time Course of Reversal of Fentanyl-Induced Respiratory Depression in Healthy Subjects by Intramuscular Nalmefene and Intramuscular and Intranasal Naloxone

The increase in opioid overdose deaths, particularly involving potent, long-acting synthetic opioids, has led to calls for stronger, longer-acting opioid-overdose-reversal agents. Using an opioid-induced respiratory depression model, we investigated the onset and time course of action of naloxone and a long-acting opioid antagonist, nalmefene, in reversing the effects of an ongoing intravenous fentanyl infusion over a period of up to 100 min. Healthy, moderately experienced opioid users received intramuscular (IM) nalmefene 1 mg, IM naloxone 2 mg, or intranasal (IN) naloxone 4 mg after fentanyl-induced respiratory depression was established based on reduction in respiratory minute volume (MV). Each participant received each opioid antagonist twice per a randomized crossover schedule. Reversal of respiratory depression, pharmacokinetics, and safety were investigated. Participants showed rapid increases in plasma opioid antagonist concentrations, and meaningful reversal of depressed MV tended to occur earlier with IM nalmefene and IM naloxone than with IN naloxone. Compared to naloxone, nalmefene provided extended exposure, and mean MV was maintained at a higher level. All participants experienced treatment-related adverse events, but none were severe, serious, or led to study drug discontinuation. This study provides evidence that IM nalmefene 1 mg achieves reversal of fentanyl-induced respiratory depression similar to or better than that achieved with standard-of-care naloxone treatments. No new safety concerns were raised for IM nalmefene at the tested dose. The pharmacokinetic and pharmacodynamic properties of IM nalmefene position it as an important treatment option in opioid overdose reversal, particularly given the increasing prevalence of overdoses involving potent, long-acting synthetic opioids.