Preference for an opioid/benzodiazepine mixture over an opioid alone using a concurrent choice procedure in rhesus monkeys

Increased abuse of opioids is contributing to an escalation in overdose deaths. Benzodiazepines are frequently abused with opioids, possibly because they increase the potency and/or effectiveness of opioids to produce reinforcing effects. This study used a concurrent-choice procedure to determine whether monkeys would choose to self-administer a mixture of the opioid remifentanil and the benzodiazepine midazolam over remifentanil alone. Initially, three monkeys could respond on one lever for saline and on a second lever for either remifentanil alone or midazolam alone. Thereafter, monkeys chose between a dose of remifentanil (0.32 μg/kg/infusion) that did not change and a dose of remifentanil that varied across sessions; for some sessions, midazolam was combined with varying doses of remifentanil. All monkeys received more infusions of remifentanil (0.0032-0.32 μg/kg/infusion) than saline, whereas only two monkeys responded more for midazolam than for saline. When 0.32 μg/kg/infusion remifentanil was available on one lever and a dose of remifentanil that varied across sessions (0.1-1 μg/kg/infusion) was available on the other lever, monkeys chose the larger dose. Combining 3.2 μg/kg/infusion midazolam with 0.32 μg/kg/infusion remifentanil increased responding for the mixture over 0.32 μg/kg/infusion remifentanil alone, although monkeys chose remifentanil alone over mixtures containing smaller doses of remifentanil. When 10 μg/kg/infusion midazolam was combined with 0.1 μg/kg/infusion remifentanil, monkeys chose the mixture over 0.32 μg/kg/infusion remifentanil alone. Thus, monkeys prefer some opioid/benzodiazepine mixtures to larger doses of the opioid alone, suggesting that opioid/benzodiazepine coabuse might be due to increased potency (and possibly effectiveness) of opioids to produce reinforcing effects.