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

Abstract

Importance: Questions have emerged as to whether standard intranasal naloxone dosing recommendations (ie, 1 dose with readministration every 2-3 minutes if needed) are adequate in the era of illicitly manufactured fentanyl and its derivatives (hereinafter, fentanyl).

Objective: To compare naloxone plasma concentrations between different intranasal naloxone repeat dosing strategies and to estimate their effect on fentanyl overdose.

Design, setting, and participants: This unblinded crossover randomized clinical trial was conducted with healthy participants in a clinical pharmacology unit (Spaulding Clinical Research, West Bend, Wisconsin) in March 2021. Inclusion criteria included age 18 to 55 years, nonsmoking status, and negative test results for the presence of alcohol or drugs of abuse. Data analysis was performed from October 2021 to May 2023.

Intervention: Naloxone administered as 1 dose (4 mg/0.1 mL) at 0, 2.5, 5, and 7.5 minutes (test), 2 doses at 0 and 2.5 minutes (test), and 1 dose at 0 and 2.5 minutes (reference).

Main outcomes and measures: The primary outcome was the first prespecified time with higher naloxone plasma concentration. The secondary outcome was estimated brain hypoxia time following simulated fentanyl overdoses using a physiologic pharmacokinetic-pharmacodynamic model. Naloxone concentrations were compared using paired tests at 3 prespecified times across the 3 groups, and simulation results were summarized using descriptive statistics.

Results: This study included 21 participants, and 18 (86%) completed the trial. The median participant age was 34 years (IQR, 27-50 years), and slightly more than half of participants were men (11 [52%]). Compared with 1 naloxone dose at 0 and 2.5 minutes, 1 dose at 0, 2.5, 5, and 7.5 minutes significantly increased naloxone plasma concentration at 10 minutes (7.95 vs 4.42 ng/mL; geometric mean ratio, 1.95 [1-sided 97.8% CI, 1.28-∞]), whereas 2 doses at 0 and 2.5 minutes significantly increased the plasma concentration at 4.5 minutes (2.24 vs 1.23 ng/mL; geometric mean ratio, 1.98 [1-sided 97.8% CI, 1.03-∞]). No drug-related serious adverse events were reported. The median brain hypoxia time after a simulated fentanyl 2.97-mg intravenous bolus was 4.5 minutes (IQR, 2.1-∞ minutes) with 1 naloxone dose at 0 and 2.5 minutes, 4.5 minutes (IQR, 2.1-∞ minutes) with 1 naloxone dose at 0, 2.5, 5, and 7.5 minutes, and 3.7 minutes (IQR, 1.5-∞ minutes) with 2 naloxone doses at 0 and 2.5 minutes.

Conclusions and relevance: In this clinical trial with healthy participants, compared with 1 intranasal naloxone dose administered at 0 and 2.5 minutes, 1 dose at 0, 2.5, 5, and 7.5 minutes significantly increased naloxone plasma concentration at 10 minutes, whereas 2 doses at 0 and 2.5 minutes significantly increased naloxone plasma concentration at 4.5 minutes. Additional research is needed to determine optimal naloxone dosing in the community setting.

Trial registration: ClinicalTrials.gov Identifier: NCT04764630.

Figure 1.. Participant Flow Diagram, Study Design, and Physiologic Pharmacokinetic-Pharmacodynamic Model

A, Study flow diagram. B, Clinical trial design. C, Physiologic pharmacokinetic-pharmacodynamic model and overdose simulation methods. IV indicates intravenous. ^aSix participants did not meet the inclusion or exclusion criteria due to abnormal medical history, laboratory results, or physical examination findings. ^bParticipants were not needed as replacements. ^cOne participant replaced a participant who dropped out on the first day in the first cohort. ^dSorg et al.

Figure 2.. Naloxone Plasma Concentration and Comparisons Between Treatment Groups

A, Individual participant observed data and box-and-whisker plot summaries for naloxone plasma concentration. The line through each box represents the median. The lower and upper borders of the box represent the 25th and 75th percentiles, respectively. The whisker extends from the box border to the last observation within 1.5 times the IQR. B, Naloxone plasma concentration. Error bars represent 2-sided 95% CIs. C, Comparison of naloxone plasma concentration between dosing strategies. Error bars represent 1-sided 97.8% CIs. The prespecified times for comparison of 1 dose at 0, 2.5, 5, and 7.5 minutes vs 1 dose at 0 and 2.5 minutes were 10, 12.5, and 15 minutes. The prespecified times for comparison of 2 doses at 0 and 2.5 minutes vs 1 dose at 0 and 2.5 minutes were 4.5, 7, and 10 minutes. eTable 3 in Supplement 2 contains the number of participant samples included at each time for each dosing group.

Figure 3.. Model-Estimated Effects of Naloxone on Fentanyl and Carfentanil Overdoses

A to D, Simulations of the effect of fentanyl and carfentanil overdoses on ventilation (A), arterial oxygen saturation (B), brain oxygen partial pressure (C), and cardiac output (D) for the typical patient. Each graph begins with the time of fentanyl or carfentanil administration. The first dose of intranasal naloxone 4 mg was administered 1 minute after ventilation decreased below 40% of baseline (ie, first naloxone dose at 0 minutes in each graph). With no naloxone, the simulated typical patient experienced cardiac arrest (diamonds in D). In A, the dotted black line is 40% of baseline ventilation. In C, the dotted black line is brain oxygen partial pressure of 20 mm Hg, which was used as an end point in this study. eFigure 1 in Supplement 2 contains similar graphs for the other physiologic outcomes. IV indicates intravenous.

Figure 4.. Simulated Intranasal vs Intravenous Naloxone and Model-Estimated Fentanyl Overdose Outcomes

A and B, Simulated naloxone plasma concentrations after intranasal (IN) or intravenous (IV) administration where each dose was administered at 0 minutes (A) or with repeat dosing every 2.5 minutes (B). C, Model-estimated percentage of simulated patients experiencing cardiac arrest following fentanyl overdoses with different naloxone dosing. The first naloxone dose was administered 1 minute after ventilation decreased below 40% of baseline. The intravenous naloxone escalating dosing protocol was as described by Boyer (intravenous naloxone 0.04 mg at 0 minutes, 0.5 mg at 2.5 minutes, 2 mg at 5 minutes, and 4 mg at 7.5 minutes) and is provided for comparative purposes. The intravenous simulations use the model from Papathanasiou et al. The points and error bars represent the median and IQR of cardiac arrest percentage. eFigure 2 in Supplement 2 contains a similar graph for carfentanil overdoses. NA indicates not applicable.