Until recently, little attention had been paid to characterizing behavioral effects of opioids in normal volunteers (i.e., volunteers with no history of drug or alcohol dependence) using the rigorous testing methodologies that had been employed in the studies with abusers. For the past three years, we have employed an abuse liability/behavioral toxicology testing methodology to examine the effects of a number of different opioids that are typically given to patients for postoperative pain. This application will have four series of studies that are logical continuations of studies from the previous grant period. In the first series of studies, we will focus on opioids that are typically given to patients who are recovering from outpatient surgery. These patients might be at home or at work, engaging in different activities that may or may not be adversely affected by the opioids. It is vitally important to understand the behavioral toxicology of these opioids, yet rigorous toxicology studies (employing multiple measures of behavior and examining a range of doses that might be used by patients) have not been conducted to date. Therefore, we plan to continue our opioid characterization studies in normal volunteers, focusing on four oral drugs commonly used in outpatient settings: hydrocodone, oxycodone, propoxyphene, and tramadol. In the second series of studies, we will follow up on a study from the previous granting period in which some of morphine's subjective effects were attenuated by a painful stimulus. In four studies, we will use a cumulative dosing procedure recently developed in our laboratory to examine the degree to which a painful stimulus modulates the subjective and psychomotor effects of morphine, meperidine, butorphanol and nalbuphine. We will study different opioids at different doses and at different levels of painful stimulation in order to better understand how pain, which frequently accompanies opioid administration in patients, modulates behavioral effects of opioids. In the third series of studies, we will again follow up on a previous study from our laboratory in which we demonstrated that a painful stimulus modulated the reinforcing effects of an opioid, fentanyl. We propose to utilize a patient controlled analgesia (PCA) methodology to examine the degree to which four different opioids- morphine, meperidine, nalbuphine and butorphanol- maintain self-administration, and the degree to which self-administration is modulated by a painful stimulus. In the fourth series of studies, the effects of psychomotor stimulants alone and in combination with an opioid will be examined. Psychomotor stimulants are often given as adjuncts to opioids in patients suffering from chronic malignant pain to offset the sedating and impairing effects of high-dose opioid therapy. We will study buprenorphine in combination with three psychomotor stimulants- d-amphetamine, methylphenidate, and pemoline- to determine the relative pharmacodynamic profiles and which combination(s) produces the most analgesia with the least degree of troublesome side effects (including marked sedation and psychomotor/cognitive impairment).
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