Dr. Maywin Liu, Assistant Professor of Anesthesia at the University of Pennsylvania Medical Center, is applying for a Mentored Patient-Oriented Research Career Development Grant. Dr. Liu is committed to an academic career in clinical research, examining the mechanisms and adverse effects of opioids. This proposal will allow Dr. Liu to expand from her previous training in experimental pain research to clinically-based research to become an independent, funded academic investigator. Pain affects up to 80 percent of cancer patients. Many patients can obtain adequate relief with the proper use of opioids, however, opioid-related adverse effects often substantially limit pain therapy. Side effects of opioids are difficult to treat as the same receptors responsible for production of analgesia are believed to be responsible for producing the side effects. Constipation is the most common opioid-induced side effect occurring in up to 85 percent of patients. Constipation appears to be chiefly a peripheral effect arising from stimulation of the opioid receptors of the gastrointestinal tract. In our first study, we will evaluate the efficacy of methyl-naltrexone, a peripherally-selective opioid antagonist, for the treatment of opioid-induced constipation in cancer patients. In a double-blind, placebo-controlled, randomized trial, subjects will receive either placebo or active drug for 3 weeks after baseline data is obtained. Efficacy will be assessed using changes in bowel frequency, oral-cecal transit time, and constipation-related symptoms. Constipation has objective, i.e., bowel frequency, and subjective components, e.g., abdominal pain, difficulty passing stool. Although difficult to measure, constipation-related symptoms are usually the primary concern to patients. Assessing for both bowel frequency and subjective symptoms will result in a more appropriate measurement scale. No scale combining both the clinical signs and subjective symptoms of constipation currently exists. As a result, we have developed the Constipation Measurement Scale (CMS) to assess both the symptoms and clinical signs. In this proposal, we will test the reliability, validity, and responsiveness of the CMS. Using a case-control design, patients who respond "yes" to the question "are you constipated?" and age-matched controls who answer "no" will be asked to complete the CMS daily for one week. Total scores of the CMS and subscores of each part will be correlated to the screening question to assess validity. Comparison of daily response will assess the reliability. Patients who are constipated will be treated with lactulose and asked to continue the daily CMS during this time. Pre- and post-treatment scores will be compared to assess for responsiveness of the scale. These studies will serve as a foundation for future studies examining the role of adverse effects of treatment on pain control. In addition, the mechanisms of opioid adverse effects and analgesia will be further explored with the use of methyl-naltrexone, e.g., contribution of peripheral opioid receptors to analgesia and peripheral vs. central mechanisms of other side effects. The methodologic techniques and research skills developed through formal training and conducting the clinical trials will serve as a foundation for pursuing related research questions as Dr. Liu matures into a fully independent academic clinical investigator. In addition, the study will provide important information about the appropriate treatment of opioid-induced constipation which will have an immediate relevance to the care of the cancer patient.