Evaluating the rate of reversal of fentanyl-induced respiratory depression using a novel long-acting naloxone nanoparticle, cNLX-NP

Saadyah E Averick; Andrew J Kassick; Daihyun Song; Borui Zhang; Jennifer Vigliaturo; Diego Luengas; Pedro Silva-Ortiz; Marco Pravetoni; Michael D Raleigh

doi:10.3389/fpsyt.2024.1366186

Evaluating the rate of reversal of fentanyl-induced respiratory depression using a novel long-acting naloxone nanoparticle, cNLX-NP

Front Psychiatry. 2024 Mar 14:15:1366186. doi: 10.3389/fpsyt.2024.1366186. eCollection 2024.

Authors

Affiliations

¹ Neuroscience Disruptive Research Lab, Allegheny Health Network Research Institute, Allegheny General Hospital, Pittsburgh, PA, United States.
² Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN, United States.
³ Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, United States.
⁴ Center for Medication Development for Substance Use Disorders, University of Washington, Seattle, WA, United States.
⁵ Garvey Institute for Brain Health Solutions, University of Washington, Seattle, WA, United States.

Abstract

Introduction: Fentanyl and fentanyl analogs (F/FA) have become increasingly common adulterants in counterfeit prescription pills and illicit street drug mixtures due to their ease of synthesis and exceedingly high potency. The ongoing epidemic of fatal overdoses fueled by F/FA continues to highlight the need for longer-acting therapies than naloxone (NLX), the current gold-standard for reversing opioid overdoses, which shows limited efficacy to prevent renarcotization associated with F/FA toxicity. A novel opioid reversal agent based on covalent naloxone nanoparticles (cNLX-NP) has been shown to blunt fentanyl-induced respiratory depression out to 48 hr, demonstrating its potential therapeutic utility. The purpose of this study was to characterize how rapidly cNLX-NP reverses fentanyl-induced respiratory effects as well as the duration of its protective effects.

Methods: Sprague Dawley male rats (n=6/group) were tested on an oximeter for baseline percent arterial oxygen saturation (%SaO₂) challenged with 0.1 mg/kg SC fentanyl and 15 min later given 10 mg/kg IM doses of NLX, nalmefene (NLMF), or cNLX-NP and continuously monitored via oximetry for 10 minutes. One week later the experiment was repeated using a 1:1 mixture of NLX:cNLX-NP as the reversal agent in the rats that previously received NLX alone.

Results: While both NLX and NLMF rapidly reversed %SaO₂ to baseline within 1 min, rats that received cNLX-NP did not return to >90% SaO₂ levels until 9 min after administration. Similarly, heart and breath rates returned to baseline within 1 min of treatment with NLX and NLMF but did not return to baseline until 10 minutes after cNLX-NP administration. In contrast, NLX:cNLX-NP reversed all fentanyl-induced respiratory depressive effects within one minute.

Discussion: While cNLX-NP alone may not sufficiently reverse F/FA overdose in a timely manner, mixing free NLX with cNLX-NP can provide a mechanism to both rapidly reverse fentanyl-related effects and maintain extended protection against synthetic opioid toxicity. These data support further development of cNLX-NP as a fast-acting and long-lasting antidote to treat F/FA-induced respiratory depression and overdose, and potentially prevent renarcotization in humans.

Keywords: antagonist; antidote; fentanyl; opioid use disorder; reversal agent; substance use disorder; synthetic opioids.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Institutes of Health National Institute on Drug Abuse Grant R21DA050565. NMR measurements and instrumentation were accessed through CMU, which was partially supported by the NSF (CHE-0130903 and CHE-1039870).