Methylnaltrexone (MNTX) is a peripheral opioid receptor antagonist that has been shown to reverse the peripheral effects of opioids without affecting analgesia or precipitating withdrawal in opioid treated normal subjects and chronic methadone users. Constipation is partially mediated by peripheral opioid action and may be a target for this drug, especially in cancer patients with advanced disease, for whom opioid-induced constipation (OIC) is a common and debilitating problem. The activity of MNTX in this population was evaluated in a double-blind, dose finding study. Hospice patients with OIC unrelieved by standard laxatives (defined as constipation distress score of>3 on a 5 point scale and no laxation for>48 hrs. were randomized to one of four MNTX doses (1 mg, 5 mg, 12.5 mg, or 20 mg), which were administered subcutaneously (SC) every other day for three doses. Laxation, symptoms of withdrawal, pain and side effects were monitored after each dose. Following this double-blind period, patients could continue on open label MNTX beginning at 5 mg and titrating to laxation effect for a 3 week period. 33 patients were accrued. The results indicate that doses]/5 mg induced laxation in about 60% of patients in a median time of about 1 hour. No withdrawal or increased pain was seen. The most common adverse events were abdominal cramping and flatulence. These symptoms were transient and interpreted as part of the normal physiological process of laxation. Thus, methylnaltrexone appears to be highly active in reversing opioid-induced constipation in an end-of-life population and is well tolerated. A large multi-center, placebo-controlled phase III trial is currently underway to further assess methylnaltrexone.