ENA-001 Reverses Xylazine/Fentanyl Combination-Induced Respiratory Depression in Rats: A Qualitative Pilot Study

Xylazine exacerbates the respiratory depression induced by fentanyl. Because xylazine is a non-opioid, it is resistant to reversal by opioid receptor antagonists such as naloxone (e.g., Narcan^®), thereby complicating attempts at treatment of fentanyl overdose. Antagonists of large-conductance potassium BK (big potassium) channels (BK_Ca) in the carotid bodies reverse drug-induced hypoxia (decreased pO₂) and hypercapnia (increased pCO₂). In animals and human volunteers, the selective BK antagonist ENA-001 reverses the respiratory depression induced by opioids and non-opioids, i.e., it is an "agnostic" respiratory reversal agent. Given the seriousness of xylazine plus fentanyl combination (XFC) overdose, the present pilot study in rats was designed to evaluate the potential of a single intravenous bolus of ENA-001 to mitigate the acute respiratory depression induced by a prior intravenous bolus infusion of an XFC. XFC-induced respiratory depression was manifested as a decrease in pO₂ and an increase in pCO₂. ENA-001, but not the vehicle, rapidly reversed these XFC-induced changes. Based on the results of this pilot study, the "agnostic" nature of ENA-001 respiratory stimulation appears to extend to XFC-induced overdose. Given the urgent clinical need, additional study seems warranted.