Dose- and time-dependent physiological effects of fentanyl in adult goats.

Abstract

Osverdoses (ODs) involving the synthetic opioid fentanyl annually contribute to thousands of deaths in the United States and are largely attributed to opioid-induced respiratory depression (OIRD). However, fentanyl OD negatively affect several aspects of cardiorespiratory function, including respiratory muscle rigidity and pulmonary gas exchange. Here, we tested the hypothesis that high doses of intravenous fentanyl (50-750 µg/kg) cause unique, time- and dose-dependent changes in physiologic functions and behaviors consistent with OIRD, muscle rigidity, impaired gas exchange, and acute withdrawal in a large animal model (adult female goats; n = 12). Within the first 15 min after injection, intravenous fentanyl dose-dependently reduced minute ventilation (V̇i; P < 0.0001), breathing frequency (Fb; P < 0.0001), swallowing (P < 0.001), and [Formula: see text] (P < 0.0001) but increased tidal volume (Vt; P = 0.0029), [Formula: see text] (P < 0.0001), the alveolar-arterial O₂ gradient (A-a; P = 0.0024), and respiratory pump and airway muscle electromyographic (EMG) activity. Thereafter (30-90 min postfentanyl), swallowing and [Formula: see text] remained reduced, whereas the A-a O₂ gradient and muscle EMG activity remained increased. Beginning 90 min postfentanyl, overall movement (cumulative vector magnitude, g; P < 0.0001) and the total behavioral response (sum of withdrawal behaviors; P < 0.001) were dose-dependently increased for 4 h. Thus, high-dose fentanyl caused significant and transient OIRD, sustained respiratory muscle activation, impaired gas exchange, and dose-dependent acute withdrawal-like behaviors. We conclude that fentanyl elicits dose- and time-dependent impairments of vital physiologic systems in adult goats similar to those reported in humans, suggesting that the goat is a unique and valuable model for translational hypothesis testing for future novel countermeasure development in vivo.NEW & NOTEWORTHY Here, we defined the time course of integrated physiologic effects of high doses of fentanyl in adult goats. High-dose fentanyl caused hypoventilation and sustained increases in tonic respiratory-related chest wall and airway muscle activity, increased the alveolar-to-arterial O₂ gradient, and caused dose-dependent increases in acute withdrawal-like behaviors. These data suggest that the integrated physiologic responses to fentanyl in adult goats closely resemble those in humans.