EXCEED THE SPACE PROVIDED. This is a competitive renewal proposal to continuea successful series of studies examiningthe pharmacological effects of opioids utilizing the human laboratory. Daring this grant's first funding period, studies tested the abuse liability of opioids such as baprenorphine, dezocine, and pentazocine, contributing to a series of investigations of the pharmacological characteristics of mixed agonist-antagonistopioids in human volunteers. In the current funding period, studies have determined the abuse liability of sublingualbuprenorphine/naloxonein opioid dependent subjects, the relative antagonist effects of parenteral doses of buprenorphine/naloxonein opioid dependent subjects, the abuse potential of sublingual buprenorphine/naloxcne in non-dependent opioid abusers, and the blockade efficacy of different buprenorphine/naloxone dose levels. These studies have provided important data useful in both understanding the pharmacological effects of this combination of medications,and also have been informativein the clinical development of buprenorphine/naloxone for the treatment of opioid dependence. The current application proposes a further set of studies investigating the effects of buprenorphineand buprenorphine/naloxone in the human laboratory. While it is hoped that Food and Drug Administration (FDA) approval of buprenorphine/naloxonefor use in the treatment of opioid dependence is imminent, optimal parameters for use of this medication under a variety of circumstances hav; not been systematically studied. Results from human laboratory studies can aid in the development of recommendations regarding dosing, expected outcomes, and safety. In addition,results from such studies have high scientific interest, as. they demonstrate pharmacological effects of these medications under different controlled experimental conditions. The proposed set of studies will address the followingfive questions: (1) What is the parenteral abuse potential of buprenorphine/naloxone in non-dependent opioid abusers? (2) How does the abuse potential of parenteral buprenorphine/naloxone vary as a function of maintenancelevel of sublingualbuprenorphine/naloxone? (3) How do the relative agonist and antagonist effects of bupreriorphine/naloxone vary as a function of dose in subjects transitioning from methadone ro buprenorphine/naloxone? (4) How does the blockade efficacy of buprenorphine/naloxone vary as a function of dependence level, and the time interval since last active dose? (5) How do the agonist and antagonist effects of buprenorphine and antagonist effects of naloxone vary as a function of level of physical dependence? Results from these controlled human laboratory studies will provide information that is clinically informative and useful whentreating patients with buprenorphine/naloxone, and also will be scientifically valuablein understanding the pharmacological effects of opioids and combinations of opioid compounds in humans. PERFORMANCE SITE ========================================Section End===========================================
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