The major objectives of this proposal are to better understand the theoretical and practical aspects of the clinical pharmacology of opioid analgesics in humans. This knowledge will facilitate the development of scientifically based guidelines for the use of these drugs in pain management. We have developed analgesic assay methods for assessing pain and opioid side effects, specific and sensitive analytical methods to quantitate opioids and their metabolites in biofluids and techniques of PK-PD analysis that relate drug concentration to opioid effects. We will now extend this approach and apply PK-PD analysis to the elucidation of morphine pharmacology, the improved administration of common (e.g. oral) and novel (transdermal) opioid therapies and investigation of tolerance and cross-tolerance. We also plan to study the steady-state concentrations of morphine and its metabolites in children as well as adults with hepatic and renal dysfunction as well as adverse effects. This information will provide quantitative data to substantiate or refute clinical dosing guidelines and will provide information about effect of age on drug disposition.