Potentiation of fentanyl-induced respiratory depression by alcohol is not fully reversed by naloxone
Emma V. Frye, Lyndsay E. Hastings, Aniah N. Matthews, Adriana Gregory-Flores, Janaina C.M. Vendruscolo, Lindsay A. Kryszak, Shelley N. Jackson, Aidan J. Hampson, Nora D. Volkow, Leandro F. Vendruscolo, Renata C.N. Marchette, George F. Koob
Emma V. Frye, Lyndsay E. Hastings, Aniah N. Matthews, Adriana Gregory-Flores, Janaina C.M. Vendruscolo, Lindsay A. Kryszak, Shelley N. Jackson, Aidan J. Hampson, Nora D. Volkow, Leandro F. Vendruscolo, Renata C.N. Marchette, George F. Koob
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Research Article Neuroscience Public Health

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

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.

Authors

Emma V. Frye, Lyndsay E. Hastings, Aniah N. Matthews, Adriana Gregory-Flores, Janaina C.M. Vendruscolo, Lindsay A. Kryszak, Shelley N. Jackson, Aidan J. Hampson, Nora D. Volkow, Leandro F. Vendruscolo, Renata C.N. Marchette, George F. Koob

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Figure 1

Effects of 25 μg/kg fentanyl and 1.18 g/kg alcohol alone and combined on minute ventilation and apneic pauses.

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Effects of 25 μg/kg fentanyl and 1.18 g/kg alcohol alone and combined on...
Rats received i.v. infusions of sterile water (5 mL/kg), fentanyl (25 μg/kg, 5 mL/kg), alcohol (1.18 g/kg, 30% vol/vol, 5 mL/kg), or a fentanyl+alcohol combination (25 μg/kg and 1.18 g/kg, respectively, 5 mL/kg) in a within-subjects Latin square design with each test separated by 1 week. (A) Timeline of each test. (B) Mortality for each drug. Data from the 12 rats that completed the experiment are shown in C–F. (C) Alcohol and fentanyl, alone and combined, decreased minute ventilation in a time-dependent manner. (D) Alcohol and fentanyl alone and combined increased apneic pauses in a time-dependent manner. The data are expressed as the mean ± SEM and were analyzed by 2-way RM-ANOVA followed by Duncan’s post hoc test. Filled symbols are different from water. fCombination different from fentanyl; ecombination different from alcohol (P < 0.05). (E) AUC of the first 15 min after infusion for minute ventilation. (F) AUC of the first 15 min after infusion for apneic pauses. The data are expressed as the mean ± SEM and were analyzed by 2-way RM-ANOVA followed by Šidák’s post hoc test when appropriate. Main effect of treatment: vP < 0.05, compared with water; eP < 0.05, compared with alcohol. n = 7 females, 5 males. (G) Representative raw plethysmography traces.