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

Summary

In a randomized crossover trial in volunteers, intramuscular naloxone (5 mg) required fewer doses than intranasal naloxone (4 mg) to reverse fentanyl-induced apnea, with no serious adverse events. Findings were consistent in opioid-naïve and chronic opioid users, supporting IM delivery for rapid reversal.

Key Findings

• IM naloxone (5 mg) required fewer doses than IN naloxone (4 mg) to reverse fentanyl-induced apnea (median 1.5 vs 2 doses; p=0.0002) in opioid-naïve participants.
• Efficacy superiority of IM over IN naloxone was also observed in chronic opioid users.
• No serious adverse events occurred; mild-to-moderate withdrawal and muscle rigidity were observed, with rigidity more frequent after IN.
• Rescue IV naloxone was rarely needed (1 participant).

Clinical Implications

Overdose response programs and EMS protocols should consider prioritizing IM naloxone for rapid reversal of opioid-induced apnea, while future work evaluates optimized IN formulations/doses. Training and kits may need updating to ensure timely IM access in community settings.

Limitations

• Open-label design and controlled research-unit setting may limit generalizability to out-of-hospital overdoses
• Sample size is modest, and the exact number in the chronic user cohort is not specified in the abstract

Future Directions

Pragmatic EMS and community-based trials comparing IM vs optimized IN dosing, pharmacokinetic-pharmacodynamic modeling across body types and substances, and implementation studies assessing time-to-ventilation and survival outcomes.