A Non‐Human Primate Model of Carfentanil Overdose: Preventing Renarcotization with Superior Countermeasures

Abstract

We established a physiological and overt intoxication model using African green monkeys (Chlorocebus aethiops sabeus) and a high dose of injected carfentanil. Intoxication is rapid and rescue is typically required within 10 minutes. Naloxone, administered at a 10 mg human‐equivalent dose (HED; 0.355 mg/kg), is immediately effective but is limited by its short duration of action. Specifically, animals typically return to a state of severe respiratory depression within about 2.5 hours, necessitating further medical intervention. Therefore, we studied two novel medical countermeasures: nalmefene and CS‐1131. Nalmefene is a mu‐opioid antagonist with high affinity and a much longer duration of action, but little is known about its efficacy against carfentanil. Therefore, we covered a range of doses from 3‐30 mg estimated HED (based upon allometric scaling) through both the intramuscular and intranasal routes. CS‐1131 is a novel opioid scavenger (created by Clear Scientific, LLC) capable of binding carfentanil stoichiometrically, inactivating the synthetic opioid, and then eliminating the scavenger‐opioid complex through renal excretion. Results show that both countermeasures were superior to naloxone alone and exhibited dose‐dependent efficacy. This research provides strong proof‐of‐concept and sets the stage for additional studies of longer‐lasting opioid antagonists administered through various routes, and for the further development, characterization, and refinement of novel opioid scavenger molecules. This non‐human primate model can be utilized to study potent synthetic opioids, new analogues, and other novel countermeasures in a way that yields predictive results to support human clinical trials.