Intranasal Naloxone Repeat Dosing Strategies and Fentanyl Overdose: A Simulation-Based Randomized Clinical Trial.

Area of Science:

• Pharmacology
• Emergency Medicine
• Toxicology

Background:

• Standard intranasal naloxone dosing protocols are being questioned due to the rise of illicitly manufactured fentanyl.
• Fentanyl and its derivatives present unique challenges in overdose reversal.

Purpose of the Study:

• To compare plasma concentrations of naloxone across different intranasal naloxone repeat dosing strategies.
• To estimate the impact of these strategies on simulated fentanyl overdoses.

Main Methods:

• A crossover randomized clinical trial involving healthy participants.
• Comparison of three intranasal naloxone dosing regimens: 1 dose at 0, 2.5, 5, and 7.5 minutes; 2 doses at 0 and 2.5 minutes; and 1 dose at 0 and 2.5 minutes (reference).
• Pharmacokinetic analysis of naloxone plasma concentrations and pharmacodynamic modeling for simulated fentanyl overdose.

Main Results:

• Administering 1 dose at 0, 2.5, 5, and 7.5 minutes significantly increased naloxone plasma concentration at 10 minutes compared to 1 dose at 0 and 2.5 minutes.
• Administering 2 doses at 0 and 2.5 minutes significantly increased naloxone plasma concentration at 4.5 minutes compared to the reference.
• Simulated fentanyl overdose showed a trend towards reduced brain hypoxia time with the 2-dose strategy.

Conclusions:

• Repeated intranasal naloxone dosing strategies, particularly four doses or two doses, can significantly increase naloxone plasma concentrations.
• These findings suggest potential improvements in reversing fentanyl overdoses with adjusted dosing.
• Further community-based research is necessary to establish optimal naloxone dosing for fentanyl-related emergencies.