Methylnaltrexone Has No Significant CNS Activity in Patients with Chronic Nonmalignant Pain and Opioid-Induced Constipation

BALTIMORE, Md.—Subcutaneous methylnaltrexone does not affect pain intensity or analgesic use in patients with chronic nonmalignant pain and opioid-induced constipation.

In a double-blind, randomized study, patients taking opioids daily for chronic nonmalignant pain received methylnaltrexone 12 mg once daily, methylnaltrexone 12 mg every other day, or placebo for 4 weeks, Arnold J. Weil, MD, of Non-Surgical Orthopedics, Atlanta, Ga., and colleagues reported. Use of routine laxatives was not permitted; however, rescue laxatives were allowed, if needed, after 3 days without laxation.

Patients were included if they had chronic pain due to a nonmalignant underlying condition for at least 2 months and were taking a daily dose of ≥50 mg oral morphine equivalents for ≥2 weeks. Opioid-induced constipation during screening was defined as ≤2 rescue-free bowel movements per week associated with at least one of the following: hard or lumpy stools, straining during bowel movements, or sensation of incomplete evacuation after bowel movement.

Excluded were patients with a history of chronic constipation prior to opioid therapy; a diagnosis of bowel obstruction, fecal incontinence, rectal prolapse, or other significant gastrointestinal disorder; <5 year history of malignancy prior to screening; history of inflammatory bowel disease, irritable bowel syndrome, or megacolon within the previous 6 months, or history of unexplained rectal bleeding; and previous exposure to subcutaneous methylnaltrexone.

Using an 11-point Pain Intensity Scale (scale 0-10), pain intensity was measured at baseline and on study days 14 and 28. Opioid use was measured in daily oral morphine equivalents.

A total of 460 patients were randomized and received at least one dose of study medication; 388 completed the study, 122 in the methylnaltrexone once daily dose group, 120 in the methylnaltrexone every other day dose group, and 146 in the placebo group. Mean age was similar among the treatment groups: 48.0 years in the methylnaltrexone once daily group, 48.6 years in the methylnaltrexone every other day dose group; and 49.7 years in the placebo group. Approximately two thirds of the patients in each group were female and most were white. Back pain was the primary pain condition in each group; others included cervical/neck pain, fibromyalgia, osteoarthritis, and low extremity/hip pain.

Compared with baseline, no treatment differences were observed in pain-scale changes. At day 14, mean pain scores were 6.2 for the methylnaltrexone 12 mg/day dose, 6.1 for alternate-day dosing, and 6.2 for placebo; at day 28, the adjusted mean scores were 6.1, 5.9, and 6.3, respectively. Adjusted mean changes in pain scores from baseline were similar in all treatment groups: at day 14, those changes were -0.1, -0.1, and 0; at day 28, they were -0.2, -0.3, and -0.1. No significant differences in median daily opioid use were found during the double-blind period for either treatment group compared with placebo.

These results suggest absence of significant methylnaltrexone activity in the central nervous system, the investigators reported at the American Pain Society's 29th Annual Scientific Meeting.