Reversal of a synthetic opioid overdose: Insights from a validated translational model.

Synthetic opioids are linked to >90 % of opioid overdose deaths in the United States. A FDA's validated translational model of synthetic opioid overdose, expanded to include intranasal reversal agents, was used to compare the effectiveness of FDA-approved intranasal naloxone (4 mg) and intranasal nalmefene (3 mg nalmefene hydrochloride, 2.7 mg base). In the absence of intervention, simulations using various intravenous doses of fentanyl and carfentanil predicted an incidence of cardiac arrest ranging from 18 % to 90 % in chronic opioid users and from 40 % to 96 % in opioid naïve subjects. Across dosing scenarios, intranasal nalmefene produced large and clinically meaningful reductions in the incidence of cardiac arrest compared to intranasal naloxone; the greatest differences in effectiveness were manifested at the higher doses of synthetic opioids. In the original publication describing FDA's model, the reversal agent was administered 1 min after ventilation was reduced to 40 % of baseline. Introducing further delays in intervention reduced the effectiveness of both reversal agents. Simulations showed intranasal nalmefene reduced the incidence of cardiac arrest compared to intranasal naloxone when intervention was delayed 2.5-3 min; delays ≥7.5 min abolished the effectiveness of both agents. The model was also used to predict the duration of brain hypoxia following a synthetic opioid overdose in a typical chronic opioid user. Across those simulations, intranasal nalmefene was generally more effective than intranasal naloxone in reducing brain hypoxia duration. These findings illustrate both the relative effectiveness of nalmefene and naloxone in reversing a synthetic opioid overdose and the importance of rapid intervention.