Effects of enteric-coated methylnaltrexone in preventing opioid-induced delay in oral-cecal transit time

Background: Methylnaltrexone is the first peripheral opioid receptor antago nist. It has the potential to prevent or reverse the peripherally mediated gastrointestinal effects of opioids, In previous human volunteer trials, me demonstrated that oral uncoated methylnaltrexone prevented morphine-induce d delay in gastrointestinal transit time. Methods: This trial consisted of two studies: a pilot study and a controlle d study The lactulose hydrogen breath test was used to measure the oral-cec al transit time. Results: In the pilot study with three subjects, an oral dose of 6.4 mg/kg enteric-coated methylnaltrexone effectively reversed the effects of morphin e, producing transit times shorter than baseline levels. Subsequently, in t he controlled study with another nine subjects, the transit time increased after intravenous morphine administration in all nine subjects, and the low er dose (3.2 mg/kg) of enteric-coated methylnaltrexone completely prevented the morphine-induced change in oral-cecal transit time in all nine subject s. Morphine significantly increased oral-cecal transit time from baseline l evel of 96.7 +/- 54.1 minutes (mean +/- SD) to 155.0 +/- 53.6 minutes (P = .014). After enteric-coated methylnaltrexone and morphine, the transit time returned to the baseline level (93.3 +/- 56.0 minutes; P = .55 compared wi th placebo), Plasma concentrations after 6.4 mg/kg and 3.2 mg/kg enteric-co ated methylnaltrexone were substantially lower compared with those after 6. 4 mg/kg of the uncoated formulation. Conclusion: Our results suggest that there is a prevailing direct and local luminal effect of enteric-coated methylnaltrexone and that the enteric-coa ted formulation exerts its gut pharmacologic actions more efficiently than the uncoated formulation.