Characterizing enhanced physiologic dysfunction during “fentanyl+” situations in adult female goats

Opioids such as fentanyl are addictive and at high doses compromise multiple physiologic functions including breathing leading to life-threatening hypoxemia and death. Opioid-involved overdose deaths (ODs), driven primarily by fentanyl, are currently thought to arise from the extreme inhibitory effects on brain centers that control breathing, leading to Opioid-induced Respiratory Depression (OIRD). However, fentanyl also impairs the respiratory system via alveolar-capillary gas exchange (increased A-a O 2 gradient), causes upper airway (UAW) dysfunction, and increases chest wall rigidity via the synchronous activation of normally reciprocal respiratory muscles. In addition, opioid-involved ODs from fentanyl alone are less common than those that include 1 or more additional drugs (~75% of opioid-involved ODs; fentanyl+) such as the non-opioid sedative xylazine (α2-adrenergic receptor agonist). The opioid receptor antagonist Narcan (naloxone; NAL) is a highly effective “rescue” agent for severe OIRD but has a short half-life and may not be as effective during fentanyl+ situations. To date, few studies have systematically tested whether fentanyl in combination with xylazine has more severe physiological effects than fentanyl alone. Given this, we hypothesize that combinations of fentanyl and xylazine will elicit enhanced physiologic dysfunction and hypoventilation-induced hypoxemia more than fentanyl alone. Adult female goats (n=4) were surgically instrumented with electromyographic (EMG) wires in upper airway and respiratory pump muscles and the carotid arteries were relocated subcutaneously for arterial blood sampling via catheters. Goats were allowed 2 weeks for recovery before the onset of studies and all injections were made via jugular catheter. Following a 30-minute control period, we injected saline (vehicle) or fentanyl alone (50 µg/kg; IV) or co-administration of Xylazine (0.01 µg/kg; IV) + fentanyl (50 µg/kg; IV) and measured physiologic effects for 60 min thereafter. Fentanyl alone (50 µg/kg; IV) lead to a transient reduction in breathing frequency (F B ) (~25% reduction from baseline), but a sustained increase in tidal volume (V T ) and total ventilation (V E ) over the duration of the study. Combinations of xylazine (0.01 µg/kg; IV) and fentanyl (50 µg/kg; IV) reduced both F B (40% from baseline) and V E (60% from baseline), with sustained reduction persisting ≥ 15min post-injection. Arterial oxygen (PaO 2 ) decreased substantially (40 mmHg), and arterial CO 2 (PaCO 2 ) increased to as high as 50mmHg. This preliminary data suggests that fentanyl in combination with xylazine further exacerbates the life-threatening effects on ventilation when compared to fentanyl alone. Funded by NIH DA050571 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.