Methocinnamox (MCAM) Reverses and Provides Extended Protection from Fentanyl‐Induced Respiratory Depression in Awake Unrestrained Rats

Abstract

Opioid use disorder affects over 2 million Americans with an increasing number of deaths due to overdose from the synthetic opioid fentanyl and its analogs. Opioid toxicity is due, in large part, to the suppression of respiratory function. The FDA‐approved opioid receptor antagonist naloxone (e.g. Narcan®) is used currently to reverse opioid‐induced respiratory depression; however, its short duration of action limits its clinical utility. Many abused opioids have a duration of action longer than naloxone and reemergence of respiratory depression is common after rescue with naloxone. Methocinnamox (MCAM) is a selective, pseudoirreversible mu opioid receptor antagonist with a long duration of action that may reverse and provide long‐term protection from the respiratory‐depressant effects of fentanyl. Previous research has shown that MCAM reverses and prevents the respiratory‐depressant effects of heroin in nonhuman primates. However, the effects of MCAM on opioid agonist‐induced respiratory depression has not been examined in other species. Moreover, its effectiveness in antagonizing the respiratory depressant effects of intravenous (i.v.) opioids, including fentanyl, has not been examined. This study compared the ability of naloxone and MCAM to reverse and protect from fentanyl‐induced respiratory depression in rats. On different occasions, male Sprague‐Dawley rats (N = 8) received 0.01, 0.032, 0.056, 0.1, or 0.178 mg/kg fentanyl i.v. and ventilatory parameters were recorded using a whole‐body plethysmograph. Fentanyl decreased respiration in a dose‐ and time‐dependent manner. Compared with respiration under control conditions, these doses of fentanyl decreased minute volume by 20–65% with 0.178 mg/kg of fentanyl producing the largest and longest decrease in minute volume. Within 1 minute after i.v. administration, naloxone (10 mg/kg) and MCAM (10 mg/kg) reversed fully the respiratory depressant effects (minute volume) of 0.178 mg/kg fentanyl. The day after antagonist administration, MCAM, but not naloxone, attenuated fully the respiratory depressant effects of 0.178 mg/kg fentanyl. This study extends to another species (rats), another route of administration (i.v.), and another mu opioid receptor agonist (fentanyl) the ability of MCAM to reverse and provide extended protection from the respiratory depressant effects of opioids. Prolonged antagonism by MCAM may provide a useful treatment option for the current opioid crisis, including toxicity from fentanyl and related highly potent analogs.Support or Funding InformationSupported by NIH (R01DA005018 and R01DA048417) and the Welch Foundation (AQ‐0039).