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

Overdoses (ODs) involving the synthetic opioid fentanyl annually contribute to thousands of deaths in the U.S. 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 IV 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 minutes after injection, IV fentanyl dose-dependently reduced minute ventilation (V̇ I ; P<0.0001), breathing frequency (F B : P<0.0001), swallowing ( P<0.001), and PaO 2 ( P<0.0001) but increased tidal volume (V T ; P=0.0029), PaCO 2 (P<0.0001), the alveolar-arterial O 2 gradient (P=0.0024) and respiratory pump and airway muscle EMG activity. Thereafter (30-90 minutes post-fentanyl) swallowing and PaO 2 remained reduced while the A-a O 2 gradient and muscle EMG activity remained increased. Beginning 90 minutes post-fentanyl, overall movement (cumulative vector magnitude (g); P<0.0001) and total behavioral response (sum of withdrawal behaviors; P<0.001) were dose-dependently increased for 4 hours. Thus, high dose fentanyl caused significant and transient OIRD but sustained respiratory muscle activation, impaired gas exchange and caused 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 the goat is a unique, and valuable model for translational hypothesis testing for future novel countermeasure development in vivo.