Co-administration of naloxone and atipamezole to simultaneously reverse the acute effects of fentanyl and xylazine in rats

The veterinary α2 agonist anaesthetic xylazine is an increasingly common fentanyl adulterant which complicates overdose reversal of these co-intoxicants with a unique toxidrome featuring enhanced sedation and respiratory depression with cardiovascular, endocrine, and thermoregulatory impairment. This preclinical trial tested atipamezole as a naloxone adjunct in male Sprague Dawley rats to improve fentanyl–xylazine reversal. After determining a fentanyl–xylazine dose which produced profound sedation persisting after naloxone administration, escalating doses of α2 antagonist atipamezole were tested in combination with naloxone in reducing effects of direct clinical concern including sedation, bradycardia, hyperglycemia, and hypothermia. Afterward, the intervention was tested in fentanyl–xylazine–methamphetamine co-intoxication currently seen in illicit drug exposures to evaluate effects on the major clinical concern of methamphetamine-induced agitation using locomotor activity as a surrogate measure. Skin condition and blood counts were also evaluated. Co-administered naloxone-atipamezole most potently reversed fentanyl–xylazine-induced sedation, completely reversed xylazine-induced bradycardia and hyperglycemia at the highest dose, incompletely reversed xylazine-induced hypothermia, but did not attenuate weight loss, injection site proximal lesion formation, or minor peripheral blood composition alterations. The highest tested atipamezole dose significantly prolonged methamphetamine-induced locomotion, while the intermediate dose did not. These data provide support for use of naloxone-atipamezole in acute opioid-xylazine intoxication.