Studies on benzodiazepines and opioids administered alone and in combination in rhesus monkeys: ventilation and drug discrimination

Abstract

 Benzodiazepines and opioids are co-administered recreationally as well as clinically; in the current study, the ventilatory-depressant and discriminative stimulus effects of several benzodiazepines and opioids were examined alone and in combination in order to evaluate any interaction between agonists from these pharmacological classes. The benzodiazepines alprazolam, diazepam, flunitrazepam, lorazepam, midazolam and triazolam and the opioids morphine and fentanyl decreased ventilation (V_E) in monkeys breathing either air or 5% CO₂ in air, although decreases in ventilation produced by opioids were greater in magnitude than decreases produced by benzodiazepines. Flumazenil antagonized the ventilatory-depressant effects of flunitrazepam and triazolam and not those of fentanyl; naltrexone antagonized the ventilatory-depressant effects of fentanyl and not those of flunitrazepam or triazolam. Interactions between the ventilatory-depressant effects of agonists from the two classes were less than additive. In monkeys receiving 3.2 mg/kg per day of morphine and discriminating 0.01 mg/kg naltrexone, neither flunitrazepam nor triazolam substituted for naltrexone; in morphine-deprived monkeys, morphine, and not flunitrazepam or triazolam, reversed naltrexone-lever responding. Moreover, benzodiazepines did not modify the discriminative stimulus effects of naltrexone in morphine-treated monkeys or of morphine in morphine-deprived monkeys. In contrast to studies showing synergism between benzodiazepines and opioids, the current study suggests that, under some conditions, combinations of these drugs can be administered without enhancing the ventilatory-depressant effects of either class of drugs or the discriminative stimulus effects of opioids.