APPLICANT'S ABSTRACT: The subjective and physiological effects of opiates, both full mu and mixed agonist-antagonists, have been well-documented in both physically- dependent addicts and post-opiate addicts, through abuse liability testing. This methodology employs testing a range of doses in a crossover double-blind trial, using standardized assessment techniques, and placebo and positive controls. This rigorous testing of opiates has not been done in non-drug abusers. There are several important reasons why such testing should be done. First, abuse liability testing in abusers errs on the side of producing "false positives" when attempting to predict abuse liability of opiates in the general population. Abuse liability of opiates should certainly be done first in opiate abusers because these are the people most at risk for abusing the drugs, but subsequent testing in other populations (e.g., non-drug abusers) gives a more comprehensive picture of the abuse liability of an opiate. Second, the effects of a drug can be altered by a person's past drug history and the studies we have proposed, using a similar methodology to that used in abuse liability testing of opiates in abusers, should enable us to 1) determine the effects of opiates in the absence of an extensive drug history and 2) compare and contrast our findings to those obtained with opiate abusers. Third, abuse liability also is concerned with liability of abuse - that is, what are the behavioral toxic effects of using the drug? We intend to scrutinize this aspect of possible adverse consequences of opiate use with a variety of psychomotor and cognitive tests. All of these studies will be conducted in a laboratory setting in our anesthesiology department which will promote subject safety and well- being. In Experiments 1 and 2, we will continue with a series of studies in which we are examining the effects of full mu agonists by testing oral and intramuscular codeine.In Experiment 3, we propose to systematically replicate those studies we have already completed, in which we will be able to determine within the same individual the effects of different mu opiate agonists. In Experiments 4-6, we will test mixed agonist-antagonists; these drugs have been examined intensively in drug abusers but, again, much less intensively in a non- drug abusing population. In Experiment 7, we will systematically replicate these studies, testing the different mixed agonist- antagonists within the same individual.Finally, in Experiments 8 and 9, we will examine the effects of different opiates in the context of pain - virtually no studies in humans have examined the effects of opiates in the presence vs. the absence of pain to determine what modulating influence this stressor may have on drug effects.
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