# Restoring The Mechanical Properties of the Respiratory System as a Treatment of Fentanyl Overdose-Induced Hypoventilation using Kappa Agonists

> **NIH NIH R21** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2022 · $202,950

## Abstract

ABSTRACT
Mu-opioid agonist overdose is associated with immediate and prolonged tetanic and rhythmic contractions of the
inspiratory and expiratory muscles that impede respiratory movements for hours. This effect, referred to as opioid
induced chest wall rigidity, is a critical mechanism contributing to the lethality of opioid-induced hypoventilation.
Mu-opioid-induced muscle “rigidity” is produced by neurons in the locus coeruleus and can be suppressed by
kappa-opioid receptor agonists, but not by current ventilatory stimulants. The objective of our proposal is to
demonstrate, following an overdose by the mu-opioid receptor agonist fentanyl, that kappa-opioid receptor
agonists 1- restore the alteration of passive respiratory mechanics and suppress the hypermetabolism produced
by fentanyl induced muscle rigidity, 2- prevent a fatal outcome in unsedated rats. We will test nalfurafine, the
only commercially available kappa agonist, and show that it counteracts the ventilatory effects of a fentanyl
overdose. If efficacy is demonstrated in rodents, we will pursue these efficacy studies in non-anesthetized large
mammal models and will test intravenous as well as intranasal route. Our ultimate goal is to obtain FDA approval
for nalfurafine as a treatment of mu-opioid receptor agonist-induced hypoventilation, treatment that could be
used in indications ranging from mass casualty to individual victims of opioid intoxication.

## Key facts

- **NIH application ID:** 10410611
- **Project number:** 1R21DA053551-01A1
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Philippe A Haouzi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $202,950
- **Award type:** 1
- **Project period:** 2022-04-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10410611

## Citation

> US National Institutes of Health, RePORTER application 10410611, Restoring The Mechanical Properties of the Respiratory System as a Treatment of Fentanyl Overdose-Induced Hypoventilation using Kappa Agonists (1R21DA053551-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10410611. Licensed CC0.

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