Intranasal Naloxone Repeat Dosing Strategies and Fentanyl Overdose

Abstract

ImportanceQuestions 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).ObjectiveTo compare naloxone plasma concentrations between different intranasal naloxone repeat dosing strategies and to estimate their effect on fentanyl overdose.Design, Setting, and ParticipantsThis 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.InterventionNaloxone 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 MeasuresThe 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.ResultsThis 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 RelevanceIn 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 RegistrationClinicalTrials.gov Identifier: NCT04764630

Comparison of intranasal naloxone and intranasal nalmefene in a translational model assessing the impact of synthetic opioid overdose on respiratory depression and cardiac arrest

“…The simulation results for IN naloxone were consistent with recent data by Strauss et al. ( 19 ) who used the same translational model as in the present work despite different data used for their IN naloxone pharmacokinetic model. In their simulations, Strauss et al.…”

“…For example, multiple reports used to support the position that naloxone doses have not increased attempted to standardize IN, IV, and IM naloxone dosing as “naloxone IV equivalents” based on bioavailability ( 36 – 38 ). While the attempt to standardize naloxone dosing based on plasma exposure is understandable, it does not account for differences in early plasma concentrations across routes of administration ( 18 , 19 , 40 ), which is essential for the successful reversal of a synthetic opioid overdose ( 11 , 18 , 19 ). These reports may also introduce a significant reporting bias, with reported EMS rescue rates of ≥99% ( 38 , 41 ) which underestimate opioid overdose deaths reported in the SUDORS database.…”

“…Strauss et al. ( 19 ) reported that even a brief (3–10 min) delay in administration of IN naloxone could result in a dramatic loss in the effectiveness of IN naloxone. Also, while fentanyl remains the predominant synthetic found in DEA seizures ( 11 ), the illicit drug supply varies over time and by region.…”

“…Furthermore, the higher plasma naloxone concentrations which may be needed to reverse a synthetic opioid overdose also carries an increased risk of precipitated withdrawal. Ironically, multiple doses of IN naloxone administered using a standard regimen (i.e., a dose administered every 2–5 minutes if there is no response) increases the risk of sustained precipitated withdrawal without conferring significant therapeutic advantage compared to a single IN dose ( 19 ).…”

“…( 18 ) was developed to predict the extent of respiratory depression and incidence of cardiac arrest triggered by a synthetic opioid overdose in the absence of antagonist treatment and following administration of IM naloxone. This model was recently implemented to evaluate the efficacy of IN naloxone given as single or multiple doses ( 19 ).…”