Xylazine/fentanyl combinations cause severe and long-lasting respiratory suppression resistant to naloxone reversal

Ultrapotent synthetic opioids such as fentanyl are highly addictive and at high doses can cause life-threatening cardiorespiratory depression, hypoxemia and death. Fentanyl is the primary driver of the high rates of opioid-involved overdose (OD) deaths (~80K/year in US) through at least three mechanisms: 1) its extreme inhibitory effects on brain centers controlling breathing (Opioid-induced Respiratory Depression; OIRD), 2) reductions in Alveolar-arterial oxygen exchange (increased A-a O 2 gradient), and 3) increased chest wall rigidity and upper airway dysfunction via tonic muscle activation (Wooden Chest Syndrome; WCS). However, opioid-involved OD deaths from fentanyl alone are less common than those that include additional drugs. Among the fastest growing are opioid-involved OD deaths from fentanyl combined with the α2 receptor agonists xylazine or medetomidine. Here we tested in adult female goats (n=5) the hypothesis that fentanyl/xylazine combinations have greater than additive (supra-additive) physiological effects compared to fentanyl alone which are resistant to µ-opioid receptor (MOR) antagonism (naloxone; NAL). IV fentanyl (50-150 µg/kg) caused transient (~10 min) reduction in ventilation (-20%) and modest hypoventilation (PaCO 2 ; +5 mmHg) and hypoxemia (PaO 2 ; -18 mmHg) with a sustained (>90 min) increase in tonic respiratory muscle activation (consistent with WCS) and an increased A-a O 2 gradient (+20 mmHg). Xylazine alone (10-20 µg/kg; IV) also reduced ventilation (-20%) for 30-45 min but did not alter arterial blood gases and had no effect on respiratory muscle activity or the A-a O 2 gradient. However, xylazine/fentanyl combinations had a more severe and long-lasting respiratory suppression (-50% for ~45 min), increasing PaCO 2 by +12 mmHg, reducing PaO 2 by 40 mmHg and increasing the A-a O 2 gradient by ~40 mmHg. In addition, cardiorespiratory coupling (measured by the respiratory sinus arrhythmia (RSA) amplitude) was not appreciably affected with high dose fentanyl or xylazine alone, but xylazine/fentanyl combinations increased the RSA amplitude >2-fold. Finally, IV NAL only briefly (~5 min) reversed the severe breathing suppression during xylazine/fentanyl combinations even after giving twice standard doses (6-12 µg/kg). While IV administration of the α2 receptor antagonist atipamezole (20 µg/kg) increased ventilation, the goats developed severe tachycardia and hypertension and showed adverse behavioral responses. Thus, these preliminary data support the hypothesis that xylazine/fentanyl combinations elicit a supra-additive and lasting cardiorespiratory suppression greater than that predicted from each drug alone, and that the enhanced cardiorespiratory suppression appears resistant to reversal by NAL. This abstract was presented at the American Physiology Summit 2026 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.