# Repurposing L-NAC to prevent fentanyl-induced respiratory depression

> **NIH NIH R21** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $201,250

## Abstract

Abstract
This R21 proposal, “Repurposing L-NAC to prevent fentanyl-induced respiratory depression” seeks to expand
on our evidence that a bolus intravenous injection of the clinically-approved drug, N-acetyl-L-cysteine (L-NAC),
reverses the profound respiratory depression elicited by infusion of fentanyl in rats. The clinical effectiveness of
opioid analgesics such as fentanyl are compromised by their adverse actions on breathing and arterial blood-
gas (ABG) chemistry. Opioid-induced respiratory depression (OIRD) can be reversed by opioid receptor (OR)
antagonists but these antagonists also reverse opioid-induced analgesia We are reporting on the efficacies of
L- and D-thiolesters such as D-cysteine ethyl ester (D-CYSee) to reverse OIRD while preserving analgesia and
our current NIDA funding is allowing us to examine the efficacy of D-CYSee as a reversal agent against
fentanyl and analogues in rats (PI: Stephen Lewis, NIH/NIDA U01DA051373: Optimization of Novel Thiolesters
as a Therapeutic Strategy for Combating Opioid Overdoses and Abuse) and goats (PI: Matt Hodges, NIH/NIDA
1RF1DA050571: Reversing opioid-induced hypoxemia with thiol-based drugs without compromising analgesia
in goats). N-acetyl-L-cysteine (L-NAC), which readily enters central peripheral and cells upon systemic/oral
administration, has many beneficial effects in humans/experimental animals and is approved for human use for
numerous conditions. There are no reports that L-NAC overcomes OIRD although it is evident that L-NAC (a)
provides reducing equivalents to cells, (b) increases intracellular concentrations of L-cysteine/ L-glutathione,
and (c) exerts numerous other intracellular actions via multiple enzymatic pathways. We have begun studying
the ability of our thiol compounds to overcome the OIRD elicited by continuous intravenous infusion of fentanyl
in rats. Such infusions are used widely in adult/pediatric patients but their ability to provide pain relief is greatly
compromised by their ability to depress respiration. This project will expand upon our findings that intravenous
injection of L-NAC elicits an immediate and sustained reversal of the deleterious adverse effects of continuous
fentanyl infusion on breathing and ABG chemistry in anaesthetized rats whereas it did not affect the analgesic
effects of the opioid. It appears that continuous infusion of fentanyl somehow sets up a scenario that allows for
L-NAC to modulate intracellular signaling cascades that mediate fentanyl-induced OIRD but not analgesia. Our
findings raise the possibility that L-NAC could be readily evaluated for potential reversal of OIRD elicited by the
infusion of fentanyl in human subjects. The Specific AIMS of this project are: AIM 1 – determine the efficacy of
bolus injections of L-NAC to countermand fentanyl-induced OIRD: This will establish how effectively L-NAC
reverses the deleterious effects of fentanyl infusion on breathing and ABG (but not analgesia) at early (e.g., 5
min) and prolonged ...

## Key facts

- **NIH application ID:** 10912705
- **Project number:** 5R21DA058086-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** stephen john lewis
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $201,250
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10912705

## Citation

> US National Institutes of Health, RePORTER application 10912705, Repurposing L-NAC to prevent fentanyl-induced respiratory depression (5R21DA058086-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10912705. Licensed CC0.

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