An oral formulation of methylnaltrexone met the primary and key secondary end points in a study that examined its effectiveness in relieving constipation related to opioid use for noncancer-related pain. The findings were presented here at Digestive Disease Week 2012.
Opioid use for chronic noncancer-related pain can be complicated by dose-limiting opioid-induced constipation (OIC). Subcutaneous methylnaltrexone is a peripherally acting selective μ-opioid receptor antagonist approved for the treatment of OIC in patients with advanced illness around the world. This multicenter, phase 3, double-blind, placebo-controlled, parallel-group, dose-ranging study evaluated an oral formulation of the product.
"Oral methylnaltrexone daily significantly increased the proportion of rescue-free bowel movements [RFBMs] and decreased the time to first RFBM in a dose-dependent manner in patients with OIC," said John F. Peppin, MD, from the Pain Treatment Center in Lexington, Kentucky. "The efficacy of the oral formulation was comparable to subcutaneous injection."
The effectiveness of oral methylnaltrexone in this study was comparable to that reported in clinical studies of subcutaneous methylnaltrexone in subjects with chronic noncancer-related pain.
The researchers randomly assigned 804 individuals to placebo or to methylnaltrexone tablets 150 mg, 300 mg, or 450 mg for 12 weeks (daily for 4 weeks, followed by 8 weeks of as-needed dosing). Subjects had been taking at least 50 mg of oral morphine equivalents per day for at least one month for chronic noncancer-related pain and had a history of OIC.
The primary end point was the percentage of doses resulting in a RFBM within four hours of dosing during the 4-week daily dosing period. RFBM was defined as a bowel movement that occurs without laxative use in the previous 24 hours. Response was defined as at least three RFMBs per week, with an increase from baseline of at least one RFBM per week, during at least three of the first four weeks.
There were two key secondary end points: the proportion of subjects with at least three RFBMs per week and an increase of at least one RFBM per week from baseline for at least three of four weeks; and the change in weekly RFBMs from baseline during daily dosing.
Drug Increased Laxative-Free Bowel Movements
"In the intent-to-treat analysis, oral methylnaltrexone 300 mg and 450 mg significantly increased the percentage of doses resulting in any RFBM within 4 hours," Dr. Peppin reported. "This was true for the [daily dosing] period, which was the primary end point, and for the overall 12-week study period."
A RFBM occurred within 4 hours of dosing in 18.1% of the placebo group, 27.4 % of the methylnaltrexone 450 mg group (P < .0001), 24.6% of the 300 mg group (P = .0040), and 21.0% of the 150 mg group (P = .3078).
A key secondary end point — at least three RFBMs per week with an increase of at least one RFBM per week from baseline — was met with 300 mg and 450 mg daily. The percentage of subjects responding during the daily dosing period was 36.8% with placebo, 50.5% with methylnaltrexone 450 mg (P = .0083), 47.8% with 300 mg (P = .0321), and 41.3% with 150 mg (not statistically significant).
This translated into an 80% improvement in response with the 450 mg dose and a 55% improvement with 300 mg.
Mean change in weekly number of RFBMs from baseline, during the daily dosing period, was 1.7 with placebo, 2.4 with 450 mg (P = .0088), 2.4 with 300 mg (P = .0088), and 1.9 with 150 mg (not statistically significant).
These findings were maintained throughout the entire 12 weeks, including the daily dosing and as-needed phases, Dr. Peppin reported.
Analyses based on the primary end point demonstrated a linear dose-response for the two active doses (P < .0001) over 28 days of once-daily dosing.
Dr. Peppin discussed his own experience with the drug. "I have patients who literally want to go off opioids because their constipation is so bad. From my experience, patients respond well to this drug and there is quite a bit of satisfaction when it works, although it does not work in all patients."
The incidence of adverse events was similar in the methylnaltrexone and placebo groups, with the most common being abdominal pain (6.8% vs 6.0%), nausea (4.7% vs 5.5%), flatulence (4.0% vs 4.5%), and diarrhea (3.3% vs 2.0%). Serious adverse events were seen in 3% of the methylnaltrexone group and 4% of the placebo group; none were considered to be related to the study drug.
"There were no notable differences in clinical or laboratory results, vital signs, ECG findings, or use of concomitant medications," he said. In addition, "mean opioid withdrawal scores and pain scores did not demonstrate any clinically significant change from baseline."
Moderators of the late-breaking abstract session, Maria T. Abreu, MD, professor of medicine at the University of Miami School of Medicine in Florida, and Gianrico Farrugia, MD, from the Mayo Clinic in Rochester, Minnesota, told Medscape Medical News that the availability of an oral formulation of methylnaltrexone would be a big advantage for patients. "But it's extraordinarily expensive," Dr. Abreu pointed out, "at least the subcutaneous drug. It's something you only use once or twice."
Whether patients will use it regularly, as they did in this study, remains to be seen, she said.
Dr. Peppin reports consulting for Salix, which sponsored the study, and serving on the Salix advisory board. Dr. Abreu reports consulting for Takeda and Abbott. Dr. Farrugia has disclosed no relevant financial relationships.
Digestive Disease Week (DDW) 2012: Abstract 943a. Presented May 22, 2012.
Caroline Helwick • Medscape Medical News © 2012 WebMD, LLC