Daily methocinnamox treatment dose-dependently attenuates fentanyl self-administration in rhesus monkeys

Abstract

Opioid use disorder and opioid overdose continue to be significant public health challenges despite the availability of effective treatments. Methocinnamox (MCAM) is a novel, long-acting opioid receptor antagonist that might be an effective treatment for opioid use disorder (i.e., preventing relapse and overdose). In nonhuman primates, MCAM selectively blocks the positive reinforcing effects of mu opioid receptor agonists, including heroin, fentanyl, and its ultra-potent analogs (e.g., carfentanil) with a single administration of MCAM being effective for up to two weeks. Because treatment of opioid use disorder would involve repeated administration of a medication, MCAM was studied in rhesus monkeys (3 males and 2 females) responding under a fixed-ratio self-administration procedure for a range of doses of fentanyl (0.000032-0.1 mg/kg/infusion). The fentanyl self-administration dose-effect curve was determined before and during treatment with progressively increasing daily doses of MCAM (0.001-0.1 mg/kg) given subcutaneously 1 h before the session. MCAM dose-dependently shifted the fentanyl dose-effect curve rightward and then, at larger doses, downward. The largest treatment dose of MCAM (0.1 mg/kg/day) shifted the curve more than 120-fold rightward with monkeys receiving doses much larger than the likely lethal dose of fentanyl with no adverse effect or observable change in behavior. This study demonstrates that MCAM reliably and dose-dependently decreases fentanyl self-administration and prevents opioid overdose, with no evidence of adverse effects over a broad dose range, further supporting the potential therapeutic utility of this novel antagonist.

Keywords: Daily treatment; Fentanyl; Methocinnamox; Nonhuman primates; Opioid use disorder; Self-administration.