# Potentiation of fentanyl-induced respiratory depression by alcohol is not fully reversed by naloxone

## TL;DR

Combining fentanyl and alcohol causes severe breathing problems that naloxone cannot fully reverse, increasing overdose risk.

## Contribution

The study reveals that naloxone is ineffective at fully reversing apnea caused by fentanyl and alcohol co-use.

## Key findings

- Fentanyl plus alcohol caused 42% and 33% mortality in female and male rats, respectively.
- Naloxone did not reverse apneic pauses caused by fentanyl+alcohol.
- Alcohol-dependent rats showed increased sensitivity to apnea from fentanyl+alcohol.

## Abstract

The high frequency of opioid overdose deaths often involves co-use of alcohol, which is reported in approximately 30% of fentanyl fatalities. Both substances depress respiratory function, and their combined effects can be lethal. The present study investigated physiological parameters of respiratory-depressant effects of fentanyl when coadministered with alcohol and their sensitivity to naloxone reversal using whole-body plethysmography in male and female Long-Evans rats. Administration of a high, sedative-like dose of alcohol alone or fentanyl alone resulted in no mortality, but fentanyl plus alcohol led to mortality rates of 42% and 33% in females and males, respectively. The fentanyl+alcohol combination reduced minute ventilation and increased apneic pauses compared with either drug alone. Lower, binge-like alcohol doses when combined with fentanyl also amplified respiratory depression. Pretreatment with naloxone did not fully restore normal respiration. Naloxone administered after fentanyl+alcohol transiently reversed the decrease in minute ventilation but did not reverse apneic pauses. Fentanyl-dependent rats were partially tolerant to fentanyl- and fentanyl+alcohol–induced respiratory depression, but alcohol-dependent rats exhibited sensitization to alcohol- and fentanyl+alcohol–induced apnea. These findings highlight physiological parameters of severe respiratory risks with fentanyl+alcohol co-use, which are inadequately reversed by naloxone, underscoring the need for targeted strategies to manage opioid+alcohol overdoses.

Overdoses resulting from the combination of fentanyl and alcohol lead to severe apnea that is not fully rescued by naloxone.