Intranasal naloxone reversal of opioid-induced respiratory depression in opioid-naïve individuals and self-reported daily opioid users

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®) in reversing moderate respiratory depression induced by fentanyl and sufentanil, in opioid-naïve individuals and self-reported daily opioid users. Sufentanil was compared to fentanyl because of its higher affinity for the opioid receptor than fentanyl.

METHODS: In this prospective, crossover trial, 12 opioid-naïve individuals and 18 daily opioid users (morphine milligram equivalent of 291 (range 60-2250 mg/day) received continuous fentanyl or sufentanil infusions, titrated to achieve 30-40% reduction in ventilation (V̇E). Participants were administered Narcan® during steady-state respiratory depression. Primary endpoints included time to reversal of diminished V̇E and elevated end-tidal carbon dioxide concentration (pCO2).

RESULTS: Narcan® restored V̇E within 2-4 min across all participants but showed delayed reversal of end-tidal pCO2 (11-17 min), with pCO2 recovery during sufentanil exposure in just 8 opioid-naïve individuals and 10 daily opioid users. Hysteresis analysis showed for V̇E-reversal onset/offset time (blood-effect-site equilibration half-life) of 0-1 min and end-tidal pCO2 2-11 min. Because of withdrawal symptoms, seven of eighteen daily opioid users participated once in the study. Study limitations included continuous opioid infusions that do not occur in real-world overdose settings.

CONCLUSION: A single Narcan® dose reversed moderate fentanyl- and sufentanil-induced respiratory depression, though effectiveness varied by endpoint and opioid receptor affinity. Rapid V̇E-recovery suggests clinical utility of intranasal naloxone, but delayed and sometimes incomplete recovery of end-tidal pCO2, particularly during exposure to the high-affinity opioid sufentanil, indicating 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.