Assessment of opioid partial agonist activity with a three-choice hydromorphone dose-discrimination procedure

The discriminative stimulus and subjective effects of opioid mixed agonist- antagonists were assessed in volunteer nondependent heroin users trained in a three-choice drug discrimination procedure to discriminate among the eff ects of i.m. administration of 2 ml of saline, 1 mg of hydromorphone, and 4 mg of hydromorphone (a morphine-like mu agonist). Other subjective, behavi oral, and physiological measures were concurrently collected. The discrimin ation was readily learned by six of the eight subjects. After training, gen eralization curves were determined for the following i.m. drug conditions: hydromorphone (0.375-4.0 mg), pentazocine (7.5-60 mg), butorphanol (0.75-6 mg), nalbuphine (3-24 mg), and buprenorphine (0.075-0.6 mg), All five of th e test drugs were discriminated significantly or showed trends toward being discriminated as hydromorphone 1 mg-like at one or more dose levels. Hydro morphone showed an inverted U-shaped dose-effect function on the hydromorph one 1 mg-like discrimination. Subjective effect measures produced clearer d ifferentiation among the test drugs than did drug discrimination performanc e. The present results differ from those of a previous study that observed a close relationship between the results of the discrimination measure and subjective effect measures. The previous study used similar methods and tes t drugs but different training drugs (e.g., 3 mg of hydromorphone versus 6 mg of butorphanol versus saline), It appears that both the sensitivity of d rug discrimination performance to between-drug differences and the relation ship between discriminative and subjective effects depends upon the specifi c discrimination that is trained (e.g., two-choice or three-choice), The pr esent high dose-low dose-saline discrimination procedure appears useful for assessing partial agonist activity. The present data are consistent with p artial agonist activity for pentazocine, butorphanol, nalbuphine, and bupre norphine.