A comparison of intramuscular (Zimhi) and intranasal naloxone (Narcan) in reversal of fentanyl-induced apnea: a randomized, crossover, open-label trial

Maarten A. Lemmen, Monique Velzen, Elise Y. Sarton, Albert Dahan (), Marieke Niesters and Rutger M. Schrier ()
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Maarten A. Lemmen: Leiden University Medical Center
Monique Velzen: Leiden University Medical Center
Elise Y. Sarton: Amsterdam University Medical Center
Albert Dahan: MediD Consultancy Group
Marieke Niesters: Leiden University Medical Center
Rutger M. Schrier: Leiden University Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: Abstract Severe opioid-induced respiratory depression (OIRD) can be treated with intranasal (IN) or intramuscular (IM) naloxone. It is relevant to compare their efficacy and determine the optimal strategy to restore breathing following OIRD. In this open label, crossover, one-on-one randomized trial, conducted in a research unit of an academic medical center, we compared the required number of IM (5 mg/0.5 mL) versus IN (4 mg/0.1 mL) naloxone doses following 10 µg/kg intravenous fentanyl-induced apnea in opioid-naïve participants and participants who chronically use an opioid. After 2 min of apnea, IM or IN naloxone was given at 2 min intervals until return of adequate ventilation. The primary outcome was the number of naloxone doses needed to achieve full reversal of breathing. If necessary, rescue intravenous naloxone was administered. Eighteen opioid-naïve participants were randomized, 16 analyzed. The required median IM naloxone doses were 1.5 (IQR 1-2) versus 2 (1-3) for IN naloxone (p = 0.0002); one participant required rescue naloxone. No serious adverse events occurred. Similarly, in participants who chronically used an opioid, IM was more effective than IN naloxone. In these participants, adverse effects included muscle rigidity in the IN treated participants and mild to moderate withdrawal irrespective of treatment. Here we show the superiority of IM over IN naloxone in the number of doses required for full reversal of breathing following opioid-induced apnea. While the trial shows superiority for IM naloxone with products used in the community, we relate our findings to the higher naloxone plasma concentrations after IM naloxone compared to IN naloxone. The study was registered at https://doi.org/10.1186/ISRCTN21068708 .

Date: 2025
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DOI: 10.1038/s41467-025-59932-7

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