Oral Methylnaltrexone for Opioid-Induced Constipation

To the Editor: Constipation is a common adverse effect of opioid pain medication used to treat cancer patients.¹ Conventional therapy may not provide sufficient relief of constipation, which can be severe enough to limit opioid use or dose.² We previously reported that intravenous methylnaltrexone (N-methylnaltrexone bromide; Mallinckrodt Specialty Chemicals, St Louis, Mo), the first quaternary ammonium opioid receptor antagonist that does not cross the blood-brain barrier in humans, reversed chronic opioid-induced constipation in patients in a methadone maintenance program.³ However, oral medication is a safer and more convenient way to deliver the drug. In this study, we evaluated the efficacy of oral methylnaltrexone for patients receiving long-term methadone therapy.

With approval from the University of Chicago Institutional Review Board, 12 constipated adults (≤2 stools per week) undergoing methadone treatment were enrolled. Their mean (SD [range]) daily methadone dosage was 73.3 (16.2 [41-100]) mg. On day 1 at 9 AM, patients ingested a placebo capsule and 10 g of lactulose (Solvay Pharmaceuticals, Marietta, Ga) to assess oral-cecal transit time using the hydrogen breath test.⁴ On day 2 at 9 AM, patients again received lactulose and a capsule containing methylnaltrexone. Increasing oral methylnaltrexone dosages (0.3, 1.0, and 3.0 mg/kg, respectively) were given to patients in 3 groups (4 patients per group). Patients were single-blinded to the treatment they received. Laxation response (or bowel movement) and potential opioid withdrawal symptoms were recorded, and blood samples were collected.

None of the 12 patients showed laxation response to placebo on day 1. On the second day, 3 of 4 patients had a bowel movement a mean (SD [range]) of 18.0 (8.7 [8-24]) hours after receiving 0.3 mg/kg of methylnaltrexone. All patients in the 1.0 mg/kg and 3.0 mg/kg groups had bowel movements at a mean (SD [range]) of 12.3 (8.7 [3-24]) and 5.2 (4.5 [1.2-10]) hours, respectively, after receiving the oral compound. Most patients reported very mild abdominal cramping after oral methylnaltrexone, which they described as similar to a defecation sensation without discomfort. Bowel movements, in most cases, were loose and large in quantity. There were no symptoms of opioid withdrawal in any patient, and no adverse effects were reported. Dose-related reduction of oral-cecal transit times is shown in Figure 1. Oral methylnaltrexone has a significant dose-response effect using the Spearman rank correlation coefficient test (P = .04) and linear regression (P = .03). Eight patients had undetectable plasma methylnaltrexone levels. Mean (SD [range]) peak plasma level for the other 4 patients (1 from the 1.0 mg/kg group and 3 from the 3.0 mg/kg group) was 17.8 (6.6 [10-26]) ng/mL.

Tertiary opioid antagonists, such as naloxone, cross the blood-brain barrier and reverse both the pain-relieving benefits and the adverse effects of opiates. Although oral naloxone may relieve opioid-induced constipation, the therapeutic index is very narrow,⁵ and naloxone may induce opioid withdrawal symptoms. Many patients receiving opioid pain medications face a difficult choice between burdensome adverse effects or ineffective analgesia. Methylnaltrexone may allow for more aggressive use of opioid analgesics with fewer adverse effects. The low methylnaltrexone plasma levels observed in our study suggest that this charged compound acts directly in the gut. Oral methylnaltrexone has potential clinical utility in managing opioid-induced constipation with minimal adverse effects.