Effects of intravenous methylnaltrexone on opioid-induced gut motility andtransit time changes in subjects receiving chronic methadone therapy: a pilot study

In this preliminary study, we evaluated the effects of methylnaltrexone, a peripheral opioid-receptor antagonist, on chronic opioid-induced gut motili ty and transit changes in four subjects with chronic methadone-induced cons tipation. Subjects participated in this single blind, placebo controlled st udy for up to 8 days. We gave placebo the first day; for the remainder of t he study, we gave intravenous methylnaltrexone (0.05-0.45 mg/kg) twice dail y. During the study period, we recorded oral-cecal transit time and opioid withdrawal symptoms, as well as laxation response based on the frequency an d consistency of the stools. Subjects 1 and 2 who were administered methyln altrexone 0.45 mg/kg, a dose previously administered in normal volunteers, showed immediate positive laxation. Subject 2, after positive laxation resp onse, had severe abdominal cramping, but showed no opioid systemic signs of withdrawal. The subject was discontinued due to the cramping. In Subjects 3 and 4, we reduced the methylnaltrexone dose to 0.05-0.15 mg/kg. The latte r two subjects also had an immediate laxation response during and after int ravenous medication without significant side effects. The stool frequency o f these four subjects increased from 1-2 times per week before the study to approximately 1.5 stool per day during the treatment period. Oral-cecal tr ansit times of Subjects 1, 3, and 4 were reduced from 150, 150 and 150 min (after placebo) to 90, 60 and 60 min (with methylnaltrexone), respectively. Our preliminary results demonstrate that low dose intravenous methylnaltre xone effectively reversed chronic methadone-induced constipation and delay in gut transit time. Thus, we anticipate that cancer patients receiving chr onic opioids may also have increased sensitivity to methylnaltrexone, and t hat low dose methylnaltrexone may have clinical utility in managing opioid- induced constipation in chronic-pain patients. (C) 1999 International Assoc iation for the Study of Pain. published by Elsevier Science B.V.