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
View: Text | PDF
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

×

Figure 8

Effects of 25 μg/kg fentanyl and 0.59 g/kg alcohol on arterial partial pressure gasometry and serum and brain fentanyl and alcohol levels.

Options: View larger image (or click on image) Download as PowerPoint
Effects of 25 μg/kg fentanyl and 0.59 g/kg alcohol on arterial partial p...
Rats received i.v. infusions of sterile water (2.5 mL/kg), fentanyl (25 μg/kg, 2.5 mL/kg), alcohol (30% vol/vol, 0.59 g/kg, 2.5 mL/kg), and fentanyl+alcohol (25 μg/kg + 0.59 g/kg, 2.5 mL/kg). Arterial blood was collected 5 min after the infusion, and trunk blood and brains were collected 10 min after infusion. (A–L) Effect of water, fentanyl, alcohol, and fentanyl+alcohol on partial pressure of oxygen (pO2) (A), partial pressure of carbon dioxide (pCO2) (B), hydrogen ion concentration (pH) (C), oxygen saturation (SO2) (D), alcohol concentration in blood (E), fentanyl concentration in blood (F), alcohol concentration in blood in nondependent and dependent rats (G), fentanyl concentration in blood nondependent and dependent rats (H), alcohol concentration in brain (I), fentanyl concentration in brain (J), alcohol concentration in brain in nondependent and dependent rats (K), and fentanyl concentration in brain in nondependent and dependent rats (L). The data are expressed as the mean ± SEM and were analyzed by 1-way ANOVA followed by Šidák’s post hoc test. **P < 0.01, ****P < 0.0001. n = 10 males, 9 females.