Alternative reinforcers enhance the effects of opioid antagonists, but not agonists, on oxycodone choice self-administration in nonhuman primates

Clinical reports suggest that the most effective strategies for managing opioid use disorder comprise a comprehensive treatment program of both pharmacological and non-pharmacological approaches. However, the conditions under which these combinations are most effective are not well characterized. This study examined whether the presence of an alternative reinforcer could alter the efficacy of FDA-approved opioid antagonist or agonist medications, as well as the non-opioid flumazenil, in decreasing oxycodone choice self-administration in nonhuman primates. Adult squirrel monkeys (n=7; 4 females) responded under concurrent second-order FR3(FR5:S);TO45s schedules of reinforcement for intravenous oxycodone (0.1mg/kg) or saline on one lever and 30% sweetened condensed milk or water on the other. Doses of naltrexone (0.00032-1.0mg/kg), nalbuphine (0.32-10mg/kg), buprenorphine (0.0032-0.032mg/kg), methadone (0.32-1.0mg/kg), or flumazenil (1-3.2mg/kg) were administered intramuscularly prior to oxycodone self-administration sessions that occurred with either milk or water as the alternative. Naltrexone, a m-opioid receptor antagonist, was >30-fold more potent when milk was available compared to water and abolished oxycodone intake (injections/session) while concomitantly increasing milk deliveries at the highest dose tested. Pretreatment with the low efficacy m-agonist nalbuphine was most effective in the presence of milk compared to water, decreasing oxycodone preference to <50% of control values. The higher efficacy m-agonists, methadone and buprenorphine, and the benzodiazepine antagonist flumazenil, did not appreciably alter the reinforcing potency of oxycodone under either condition. These results suggest that antagonist medications used in combination with alternative reinforcers may be an effective strategy to curtail opioid abuse-related behaviors.