Reversal of Fentanyl-Induced Respiratory Depression in Healthy Subjects by Intramuscular Nalmefene Administered by Auto-Injector Versus Intranasal Naloxone.

As illegally made fentanyl and congeners continue to drive overdose deaths in the US, experts have called for stronger and longer-lasting antagonists. A randomized, 4-period, 2-treatment crossover replicate-design study in healthy moderately-experienced opioid users (n = 24) evaluated the reversal of opioid-induced respiratory depression (OIRD) by intramuscular (IM) nalmefene 1.5 mg administered by auto-injector delivering a formulation developed for faster onset, compared to intranasal (IN) naloxone 4 mg. Fentanyl infusions were administered to induce a 50% reduction in minute ventilation (MV). Reversal of OIRD, pharmacokinetics, and safety were investigated under steady-state fentanyl agonism. For the primary endpoint, nalmefene demonstrated superiority at 5 min with an MV increase of 4.59 L/min, more than twice the 1.99 L/min increase for naloxone (p < .0001). Nalmefene superiority was also demonstrated at 10, 15, 20, and 30 min, while non-inferiority was demonstrated at 2.5 and 90 min. The time-course of mean antagonist concentrations correlated with increases in mean MV, peaking at approximately 5-10 min following nalmefene compared to 20-30 min following naloxone. Decreases in transcutaneous CO₂ (TCO₂) followed a similar time-course with a slight delay. At each threshold of percent reversal (25%-100%), nalmefene consistently showed a faster time to onset than naloxone. Both antagonist treatments were tolerated with no serious adverse events. This study shows that nalmefene 1.5 mg IM administered by auto-injector achieved a faster onset, higher magnitude, and longer duration of reversal of OIRD compared to naloxone 4 mg IN and represents another option for the treatment of opioid overdose.