Intranasal naloxone reverses opioid-induced respiratory depression in opioid-naive and daily users within 2 to 17 minutes

BACKGROUND: Since current opioid overdose deaths occur mainly from potent synthetic opioids with high affinity for the opioid receptor, such as fentanyl and carfentanil, it is important to determine the efficacy of naloxone, particularly the intranasal formulation, in reversing opioid-induced respiratory depression. This study evaluated effectiveness of 4 mg intranasal naloxone (Narcan; Adapt Pharma Inc., USA) in reversing moderate respiratory depression induced by fentanyl and sufentanil in opioid-naive individuals and self-reported daily opioid users. Sufentanil was compared to fentanyl because of its higher affinity for the opioid receptor. METHODS: In this prospective, crossover trial, 12 opioid-naive individuals and 18 daily opioid users (morphine milligram equivalent, 291; range, 60 to 2,250 mg/day) received continuous fentanyl or sufentanil infusions, titrated to achieve 30 to 40% reduction in minute ventilation ( ). Participants were administered Narcan during steady-state respiratory depression. Primary endpoints included time to reversal of diminished and elevated end-tidal carbon dioxide concentration (pCO 2 ). RESULTS: Narcan restored within 2 to 4 min across all participants but showed delayed reversal of end-tidal pCO 2 (11 to 17 min), with pCO 2 recovery during sufentanil exposure in just 8 opioid-naive individuals and 10 daily opioid users. Hysteresis analysis showed for reversal onset/offset times (blood-effect-site equilibration half-lifes) of 0 to 1 min and for end-tidal pCO 2 2 to 11 min. Because of withdrawal symptoms, 7 of 18 daily opioid users participated once in the study. Study limitations included continuous opioid infusions that do not occur in real-world overdose settings. CONCLUSIONS: A single Narcan dose reversed moderate fentanyl- and sufentanil-induced respiratory depression, although effectiveness varied by endpoint and opioid receptor affinity. Rapid recovery suggests clinical utility of intranasal naloxone, but delayed and sometimes incomplete recovery of end-tidal pCO 2 , particularly during exposure to the high-affinity opioid sufentanil, indicates reversal inefficacy and persistence of respiratory instability. Further studies are needed to address optimal naloxone doses and alternative formulations to address high-dose potent opioid threats.