Intramuscular ENA-001 Combined With Low-Dose Naloxone Versus Intranasal Naloxone for Reduction of Cardiac Arrest Rate in a Simulated Fentanyl-Xylazine Overdose

Overdose fatalities are commonly caused by fentanyl combined with non-opioid depressants such as xylazine.We performed in silico modeling to evaluate the ability of an opioid-receptor-agnostic respiratory stimulant, the BK Ca -blocker ENA-001, combined with low-dose naloxone, both administered intramuscularly (IM) versus intranasally (IN) naloxone, to reduce hypoxia and ischemic cardiac arrest.We additionally simulated fentanyl/propofol as a secondary model of polysubstance overdose.We extended a published pharmacokinetic/pharmacodynamic model describing the effects of fentanyl on ventilatory control with blood-gas kinetics and their reversal by naloxone by including opioid-receptor-independent components: respiratory depression from either xylazine or propofol, and respiratory stimulation by ENA-001.We simulated no rescue, 4 mg IN naloxone, and 120 mg IM ENA-001 + 0.3 mg IM naloxone, following an overdose with 0.2 mg fentanyl combined with either 12 mg xylazine (primary endpoint) or 64 mg propofol (secondary endpoint).Treatments were administered as a single dose or as three consecutive doses at twominute intervals.Outcomes were PO 2 nadir, duration of PO 2 < 50 mmHg, apnea duration, and cardiac arrest rate.In fentanyl/xylazine overdose, cardiac arrest rate decreased from 74% (no rescue) to 50% (three consecutive doses of IN naloxone) and 36% (three consecutive doses of IM ENA-001/naloxone; p < 0.001 versus IN naloxone and no rescue).The combined treatment resulted in higher PO 2 levels, shorter hypoxia and apnea duration (p < 0.001).Similar findings were observed following single-dose reversal and in simulated fentanyl/propofol overdose.In simulated mixed opioid/non-opioid overdose, combining an IM opioid-receptor-independent respiratory stimulant with low-dose naloxone resulted in lower cardiac arrest rates than 4 mg IN naloxone alone.These findings support further studies on ENA-001 combined with naloxone as a rescue strategy for polysubstance overdose where naloxone will cause incomplete reversal.These findings are model-derived and hypothesis-generating.