Thomas, J., Karver, S., Cooney, G.A., Chamberlain, B.H., Watt, C.K., Slatkin, N.E., . . . Israel, R.J. (2008). Methylnaltrexone for opioid-induced constipation in advanced illness. New England Journal of Medicine, 358, 2332-2343.

To examine the safety and efficacy of subcutaneous methylnaltrexone for treating opioid-induced constipation in patients with advanced illness.

Patients were randomly assigned to receive either methylnaltrexone 0.15 mg/kg or placebo subcutaneously every other day for two weeks. Patients were permitted to continue their baseline laxatives and could use rescue laxatives. By day 8, the study drug dose (methylnaltrexone or placebo) could be doubled if patients had fewer than three rescue-free bowel movements. Patients in both groups who completed the two-week study were eligible to enter an open-label extension phase. During the extension trial, methylnaltrexone 0.15 mg/kg was offered as needed every 24 hours for up to three months. Subsequent doses could be increased to 0.3 mg/kg if there was no defecation.

• The study reported on a sample of 134 patients aged 18 years or older.
• Median age was 72 years (range 34-93) in the methylnaltrexone group and 70 years (range 39-98) in the placebo group.
• The sample comprised 27 men (43%) and 36 women (57%) in the methylnaltrexone group, and 31 men (44%) and 40 women (56%) in the placebo group.
• Patients had advanced illness, such as terminal cancer or other end-stage diseases with a life expectancy of at least one month, as well as opioid-induced constipation. 
• Patients were receiving a median opioid dose of 100 mg of oral morphine equivalent. 
• More than 50% of study participants had a diagnosis of terminal cancer.

• Multi-site
• 27 U.S. and Canadian nursing homes, palliative care centers, and hospice centers

The study has clinical applicability for the end-of-life and palliative phases of care.

This was a two-week, double-blind, randomized, placebo-controlled phase III study with a subsequent three-month, open-label extension phase.

• Global Clinical Impression of Change (GCIC)
• National Cancer Institute common toxicity criteria (CTC), version 2.0
• Numeric pain rating scale (0 = no pain and 10 = worst pain possible)
• Modified Himmelsbach Withdrawal Scale

Efficacy Analysis: Double-Blind Phase

• Forty-eight percent of patients in the methylnaltrexone group, as compared with 15% of patients in the placebo group, had rescue-free laxation within four hours of receiving the first dose (p < 0.001 for all comparisons).
• Sixty-eight percent of patients in the methylnaltrexone group, as compared with 45% of patients in the placebo group, had three or more rescue-free laxations per week (p = 0.009).
• The median time to laxation after the first dose was 6.3 hours in the methylnaltrexone group and 48 hours in the placebo group (p < 0.001).

Pain Scores and Opioid Withdrawal

• Both groups had stable scores on the Modified Himmelsbach Withdrawal Scale and no change in pain scores. 

Adverse Events

• Similar percentages of patients in both groups had at least one adverse event (AE), of which abdominal pain and flatulence were the most common.
• Most AEs were rated by investigators as being mild or moderate. 

Open-Label Extension

• Eighty-nine patients entered the open-label extension phase.
• Response rates to methylnaltrexone were consistent during the extension.

Methylnaltrexone as administered in this study was effective in inducing laxation in patients with advanced illness and opioid-induced constipation, without compromising analgesia or triggering withdrawal symptoms.

Calculations showed that a total of 130 patients (65 in each group) would allow detection of a difference of 30% to 35% in the proportion of patients having a laxation response. However, only 106 patients (52 in the methylnaltrexone group and 54 in the placebo group) completed the study.

Subcutaneous methylnaltrexone seems effective in treating constipation in patients with advanced illness and opioid-induced constipation without compromising analgesia or causing withdrawal symptoms. In this study, more than 50% of patients had a diagnosis of cancer; therefore, conclusions can likely be extended to patients with cancer. In addition, patients in this study were receiving a median opioid dose of approximately 100 mg of oral morphine equivalent. Many patients with cancer receive a larger dose; therefore, further study with increased doses of morphine equivalent is warranted.