Publications
A comparison of intramuscular (Zimhi) and intranasal naloxone (Narcan) in reversal of fentanyl-induced apnea: a randomized, crossover, open-label trial
Authors: Maarten A. van Lemmen 1, Monique van Velzen 1, Elise Y. Sarton 2, Albert Dahan 3, 4, 5, 6, Marieke Niesters 1, 5, 6, Rutger M. van der Schrier 1
Affiliations:
- Department of Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands
- Department of Anesthesiology, Amsterdam University Medical Center, Amsterdam, the Netherlands
- MediD Consultancy Group, Amsterdam, the Netherlands
- Outcomes Research Consortium, Houston, TX, USA
- Centre for Human Drug Research, Leiden, the Netherlands
- Painless Foundation, Leiden, the Netherlands
Journal: Nature Communications - May 2025, Volume 16, Article no. 4659 (DOI: 10.1038/s41467-025-59932-7)
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Field & Applications:
- Medical
- Treatment evaluation
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.
In conclusion, in this small and descriptive study, we compared the efficacy of IM versus IN naloxone following high-dose fentanyl-induced apnea. The study was performed in 16 healthy volunteers. Additionally, we conducted an exploratory adjunct study in 6 participants who chronically use opioids. In healthy volunteers, we observed greater efficacy in reversal of apnea after IM compared to IN naloxone with the need for lesser IM doses and no need for rescue naloxone. The decreased IN naloxone efficacy was replicated in the small set of participants who use opioids on a daily basis. While our results are relevant, further larger studies are required, particularly in participants who chronically use opioids, focusing not only on respiration but also on muscle rigidity and withdrawal symptoms.