METHYLNALTREXONE CHANGES GUT MOTILITY AND TRANSIT TIME IN CHRONIC METHADONE-MAINTAINED SUBJECTS*

Abstract

S404 Constipation is the most common side effect of opioids and can be a severe problem in patients with chronic opioid pain therapy. [1] Methylnaltrexone (MNTX), a peripheral opioid receptor antagonist, offers the therapeutic potential of decreasing the side effects of opioids in the gut while preserving analgesia. [2] As a paradigm for cancer patients receiving chronic opioid therapy, we evaluated the effects of intravenous MNTX on subjects receiving chronic methadone therapy. METHODS: All protocols were approved by the IRB. In Study 1, the lactulose hydrogen breath test [3] was used to assess gastrointestinal transit time in 9 males and 10 females (mean age +/- SD 37.2 +/- 8.0 yr) who were chronically receiving methadone. Results of oral-cecal transit times were compared with results obtained from a previous study in healthy volunteers. Wilcoxon matched pairs signed rank test was used for statistical comparison. In Study 2, 4 subjects (2 males and 2 females) with opioid-induced constipation from chronic methadone therapy received placebo on day 1 and iv MNTX (0.05-0.45 mg/kg) twice daily for the rest of the week in a single-blind protocol. Oral-cecal transit time was recorded as well as laxation response based on the frequency and consistency of stools during the study period. Pharmacokinetic data were collected and analyzed. RESULTS: Constipation was experienced by 58% of our subjects. Mean oral-cecal transit time without MNTX was 159 +/- 49.2 min, significantly longer than the transit time in our previous study of volunteers (105 +/- 32 min, P < 0.01). These results suggest that chronic opioid use does not induce tolerance in the gut. In the second study, 2 subjects who received MNTX 0.45 mg/kg (a dose previously used in volunteers) showed immediate positive laxation with infusion. Of these, 1 subject had severe abdominal cramping but showed no other signs of systematic withdrawal such as lacrimation, diaphoresis, mydriasis, or hallucinations. In the remaining 2 subjects, MNTX was reduced to 0.05-0.15 mg/kg. They also had immediate laxation with mild abdominal cramping during and after medication. Stool frequency increased from 2-3 times/week before the study to 1.785 times/day during the treatment period. Gut transit times were reduced from 150 min (baseline) 5o 60 min for each subject by the end of the study. CONCLUSION: Tolerance to opioids does not appear to extend to gastrointestinal motility and transit. Low-dose MNTX transit time in chronic methadone subjects. Low-dose MNTX effectively reversed opioid-induced constipation and delay in gut transit time in chronic methadone subjects. We expect that cancer patients receiving opioids chronically also will have increased sensitivity to MNTX. Low-dose MNTX may have clinical utility in managing opioid-induced constipation. Supported in part by the IARS; Clinical Practice Enhancement & Anesthesia Research Foundation; grant M01 RR00055 from the U.S. Public Health Service General Clinical Research Center