Drug discrimination in human postaddicts: agonist-antagonist opioids

To assess the stimulus properties of opioid mixed agonist-antagonist drugs in humans, postaddict volunteers were trained in a three-choice drug discrimination procedure to discriminate among the effects of i.m. given saline (4 ml), hydromorphone (3 mg/70 kg) and pentazocine (45 mg/70 kg). Subjects earned monetary reinforcement by correctly identifying the training drugs by letter code. Other subjective, behavioral and physiological measures were also collected. After training, subjects were tested for their ability to discriminate between the three drugs; generalization curves for the training drugs and three mixed agonist-antagonist test drugs (butorphanol, nalbuphine and buprenorphine) were then determined. In generalization testing both hydromorphone and pentazocine produced dose-related increases in drug-appropriate responses and in characteristic subjective effects measures. Butorphanol produced dose-related increases in identifications as pentazocine and in those subjective effect measures increased by pentazocine. Nalbuphine was not consistently identified as either pentazocine or hydromorphone and produced relatively flat dose-response functions on most of the subjective effect measures. At the three highest doses tested buprenorphine was identified in 50% of trials as hydromorphone and in 50% of trials as pentazocine in the discrimination measures and increased subjective effect scales which were characteristic of both hydromorphone and pentazocine. The results are most consistent with butorphanol having the stimulus properties of a kappa agonist and both nalbuphine and buprenorphine having the stimulus properties of partial mu agonists although the profiles of observed drug effects were complicated and not entirely consistent with a simple mu/kappa opioid receptor model.