¹Committee on Clinical Pharmacology and the Department of Anesthesia and Critical Care, University of Chicago, Chicago, Ill.

Correspondence: Chun-Su Yuan, MD, PhD, Department of Anesthesia and Critical Care, Pritzker School of Medicine, University of Chicago, 5841 S. Maryland Ave., MC 4028, Chicago, IL 60637. E-mail: cyuan@midway.uchicago.edu

^*Supported in part by The Rice Foundation (Skokie, Ill.); Clinical Practice Enhancement & Anesthesia Research Foundation (Chicago, Ill.); grant T32-GM07019-18 from the National Institutes of Health Clinical Therapeutics Training; and grant M01 RR00055 from the U.S. Public Health Service General Clinical Research Center.

The commercial rights for methylnaltrexone are held in part by the University of Chicago. None of the investigators in this study is currently entitled to receive any royalties or payments. The Department of Anesthesia and Critical Care and the University of Chicago may benefit financially if this compound is commercialized. Methylnaltrexone has received Orphan Drug Status from the U.S. Food and Drug Administration for the treatment of chronic opioid-induced constipation in advanced malignant conditions.

Received 10 September 1996; Accepted 31 October 1996.

Abstract

Methylnaltrexone is a quaternary opioid antagonist with limited ability to cross the blood-brain barrier that has the potential to antagonize the peripherally mediated gastrointestinal effects of opioids. In recent trials in human volunteers, we demonstrated that intravenous methylnaltrexone prevented morphine-induced changes in gastroin-testinal motility and transit, without affecting analgesia. In this study, 14 healthy volunteers were first given three ascending oral doses of methylnaltrexone to obtain safety and tolerance data (phase A study). In phase B, these subjects were then given single-blind oral placebo and intravenous placebo, followed by randomized, double-blind oral placebo and intravenous morphine (0.05 mg/kg) or oral methylnaltrexone (19.2 mg/kg, an established highest and safe dose based on previous administrations of two smaller doses of 0.64 mg/kg and 6.4 mg/kg in phase A) and intravenous morphine (0.05 mg/kg). Oral-cecal transit time was assessed by the pulmonary hydrogen measurement technique after lactulose ingestion. Morphine significantly increased oral-cecal transit time from 114.6 37.0 minutes (mean SD) to 158.6 50.2 minutes (p < 0.001). Oral methylnaltrexone (19.2 mg/kg) completely prevented morphine-induced increase in oral-cecal transit time (110.4 45.0 minutes; not significant compared with baseline; p < 0.005 compared with morphine alone). These sessions were then followed by single-blind evaluations of descending doses of methylnaltrexone. We observed that 6.4 mg/kg oral methylnaltrexone significantly attenuated the morphine-induced delay in oral-cecal transit time (p < 0.005 compared with morphine alone), and a dose-dependent response was obtained. There was no correlation between oral methylnaltrexone effects on the transit time and the drug plasma concentration, suggesting direct preferential luminal effects of oral methylnaltrexone. Oral methylnaltrexone may have a clinical value in the prevention and treatment of constipation induced by long-term opioid use.