This application proposes to study the antagonist properties of opioid mixed agonist-antagonists, using a precipitated withdrawal procedure. Precipitated withdrawal is a syndrome of signs and symptoms produced by the administration of an antagonist to a subject who has received a prior dose of an agonist. Precipitated withdrawal can be contrasted to spontaneous withdrawal, the syndrome produced by cessation of agonist administration. While the two syndromes share qualitative features, precipitated withdrawal can be studied under the controlled conditions of the laboratory, and is a safe, reliable, and sensitive method for studying the antagonist properties of mixed agonist-antagonists. There are two reasons why the study of these properties is valuable: It is useful in the development of agonist-antagonists as treatment agents for opioid dependence, and it provides information about the pharmacologic effects of opioids in humans. There are six studies proposed in this application. The first study will investigate the pharmacologic effects of the novel opioid tramadol, using a standard precipitated withdrawal procedure developed at our laboratory. This procedure has been used in prior studies of other mixed agonist- antagonists, and the characterization of tramadol will complement these other investigations, allowing conclusions to be drawn across this set of methodologically-constant studies. The next two studies systematically examine the parameters which can influence the degree of precipitated withdrawal, and the profile of the withdrawal syndrome, in methadone-maintained volunteers. These studies will provide valuable data on the characteristics of precipitated withdrawal under different experimental conditions, and will also be useful in designing further studies for the development of new medications for the treatment of opioid dependence. The last three studies follow-up results from three of the prior related studies, and will determine if butorphanol, dezocine, or pentazocine, can be administered to hydromorphone-dependent volunteers and not precipitate withdrawal, and whether they can administered to hydromorphone-dependent volunteers and not precipitate withdrawal, and whether they can suppress spontaneous withdrawal. This will be done by varying the time interval between agonist (hydromorphone) administration and test-drug administration. This integrated set of six studies will accomplish the two goals of this proposal. The results from these studies will also be useful in the development of new medications for the treatment of opioid dependence, and these precipitated withdrawal studies will enhance our knowledge of he pharmacologic effects of opioids.
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