• Peter F Weed, Charles P France, and Lisa R Gerak.
• Departments of Pharmacology (P.F.W., C.P.F., L.R.G.) and Psychiatry (C.P.F.), and the Addiction Research, Treatment & Training Center of Excellence (P.F.W., C.P.F, L.R.G.), University of Texas Health Science Center at San Antonio, San Antonio, Texas.
• J. Pharmacol. Exp. Ther. 2017 Jul 1; 362 (1): 59-66.

AbstractIncreased 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.Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

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