It is estimated that more than 932,000 people in the United States have died of an opioid overdose since 1999 (CDC, 2021). Many factors contribute to this ongoing public health crisis including the fact that existing treatments for opioid use disorder (OUD; methadone, buprenorphine, and naltrexone) are not widely available, ineffective in some patients, or plagued by poor patient compliance. Being opioid receptor agonists, buprenorphine and methadone have abuse liability and potentially fatal effects (Jones et al., 2012). In the case of the opioid receptor antagonist naltrexone, poor patient compliance coupled with the need for frequent/daily administration could be a significant hindrance to treatment success (Minozzi et al., 2011), although a sustained-release formulation of naltrexone (Vivitrol®) might mitigate some of these shortcomings. Methocinnamox (MCAM) is a long lasting μ-opioid receptor antagonist and potential novel treatment for OUD. A single administration of MCAM antagonizes the positive-reinforcing and ventilatory depressant effects of opioid receptor agonists including fentanyl and its ultra-potent analogs, for 2 weeks or longer (Maguire et al., 2020). Collectively, studies in nonhuman species suggest that MCAM could provide long-lasting protection from the abuse-related and toxic effects of opioids in patients. Such a long duration of action would also require less frequent administration, which could improve patient compliance.

While MCAM provides long-term protection from the adverse effects of opioids, it can also block potential therapeutic effects, including antinociception (Gerak et al., 2019). Given the continuing, if reduced, use of μ-opioid receptor agonists to treat moderate to severe pain, the long duration of action of MCAM might necessitate the use of nonopioid drugs for pain management in MCAM-treated patients. This study aimed to characterize the effects of alternative strategies for pain management under conditions of long term μ-opioid receptor antagonism by a single administration of MCAM. Hypersensitivity to mechanical stimulation was induced via intraplantar (i.pl.) administration of complete Freund’s adjuvant (CFA). To determine the selectivity of drug effects on CFA-evoked hypersensitivity. The same drugs were studied using the rotarod apparatus to test for possible impairments in motor performance.