Intranasal Naloxone Repeat Dosing Strategies and Fentanyl Overdose
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Published:2024-01-23
Issue:1
Volume:7
Page:e2351839
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ISSN:2574-3805
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Container-title:JAMA Network Open
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language:en
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Short-container-title:JAMA Netw Open
Author:
Strauss David G.1, Li Zhihua1, Chaturbedi Anik1, Chakravartula Shilpa1, Samieegohar Mohammadreza1, Mann John1, Nallani Srikanth C.2, Prentice Kristin13, Shah Aanchal13, Burkhart Keith1, Boston Jennifer4, Fu Yu-Hui Ann5, Dahan Albert6, Zineh Issam7, Florian Jeffry A.1
Affiliation:
1. Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 2. Division of Neuropsychiatric Pharmacology, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration. Silver Spring, Maryland 3. Booz Allen Hamilton, McLean, Virginia 4. Spaulding Clinical Research, West Bend, Wisconsin 5. KCAS Bioanalytical Services, Olathe, Kansas 6. Department of Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands 7. Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
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
Publisher
American Medical Association (AMA)
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