Drug relieves severe constipation from painkillers used for advanced cancer

Jan 18, 2000. One of the most troubling side-effects of effective cancer pain control is constipation. Methylnaltrexone is a a new drug designed to solve the problem of constipation caused by opium-based pain medications. According to a report from the University of Chicago Medical Center in the January 19, 2000 issue of JAMA, methylnaltrexone works rapidly, without interfering with pain relief, at low doses with no apparent side effects. The problem now is to get it to patients who need it.

More than 250,000 cancer patients a year take opioids, such as morphine, for pain relief. About half of those patients experience severe constipation. The discomfort can be so great that many patients choose to stop the drug and lose the pain relief to avoid the constipation.

This double-blind, placebo-controlled study, methylnaltrexone promptly reversed opioid-induced constipation. In more than 90 percent of patients, relief came within one minute of the first infusion.

"By preventing this debilitating but little-discussed problem, methylnaltrexone could substantially enhance the quality of the last months of life for terminal cancer patients and others who depend on opioid pain relievers," said the study's first author Chun-Su Yuan, M.D., Ph.D., assistant professor of anesthesia and critical care at the University of Chicago.

Push Needed to Get It to Market
"Our current challenge," notes his co-author Joseph Foss, M.D., assistant professor of anesthesia at the University of Chicago, "is to make this drug available to the patients who need it, so that they won't have to choose between inadequate pain relief and debilitating constipation."

Methylnaltrexone has been intensively studied, primarily at the University of Chicago, but with only limited support from the pharmaceutical industry.

"The costs of developing a new drug are substantial," Foss says. "With a medication designed for short-term use by a fairly small group of users -- fewer than 150,000 people -- manufacturers may fear it would be difficult to recoup that investment, but this drug is near the end of its development cycle and could potentially be brought to market quickly."

Methylnaltrexone was invented in 1979 by the late University of Chicago pharmacologist Leon Goldberg, who wanted to help a dying friend who suffered from morphine-induced constipation. Goldberg started with naltrexone, an established drug that completely blocks the effects of morphine. He altered the drug slightly by attaching a methyl group, which changed the charge of the molecule so that it could no longer cross the protective barrier that surrounds the brain.

Consequently, it did not interfere with morphine's effect on pain, which is centered in the brain, but it did block morphine's effects on gut motility, which are mediated by receptors in the peripheral gastrointestinal tract.

It worked like a charm for his dying friend, who shared the drug with several of his friends also suffering from cancer. Its initial success in this compassionate-use setting drew the notice of Goldberg's colleagues. After Goldberg's demise, they continued to develop the compound, testing it in animals, performing the initial human safety trials and a completing a series of pre-clinical studies in volunteers.

Tested On Addicts
In this JAMA study, rather than risk interrupting pain relief for patients with terminal cancer, the researchers focused on 22 volunteers who were enrolled in a methadone maintenance program for opioid addiction. All 22 suffered from opioid-induced constipation, which affects about 60 percent of long-term methadone users. The volunteers averaged 1.5 bowel movements a week.

Eleven of the 22 subjects received low doses of intravenous methylnaltrexone and 11 received a placebo. Ten of the 11 who received the drug had an immediate laxation response following the first infusion and all 11 responded to a second infusion on day two.

"By immediate response we mean you did not want to be between the subject and the bathroom," explains Foss.

All 11 reported rapid onset of mild to moderate abdominal cramping, which they described as being "similar to a defecation sensation, without discomfort." The cramping disappeared after a bowel movement. None of the subjects reported symptoms of opioid withdrawal, indicating that the drug, as expected, did not cross the blood-brain barrier and would not interfere with pain relief.

At the end of the study, all 11 who received methylnaltrexone reported that they were "satisfied" with their bowel-movement activity. Eight reported that they were "very satisfied."

None of the patients who received placebo had a laxation response, cramping, or a change in bowel movement frequency. Seven reported that they were "disappointed."

Because opioids slow down the entire digestive process, the researchers also measured oral-cecal transit time, how long it took for food to travel from the mouth to the cecum -- the chamber at the beginning of the large intestine.

Under the influence of methadone, the 22 subjects had an average transit time of more than two hours, about twice the normal speed. This interval did not change for those in the placebo group, but for the 11 subjects who received methylnaltrexone, oral-cecal transit time fell from an average of 132.3 minutes without the drug down to 54.5 minutes after treatment.

The next step, say the researchers, is to find a U.S. pharmaceutical company to support a phase-III clinical trial in patients with advanced cancer. One trial, using an oral preparation, is already underway in cancer patients receiving palliative care at St. Christopher's Hospice, outside London.

You may read the full report online in the January 19, 2000, issue of JAMA. The research was done at University of Chicago Medical Center and was supported by grants from the American Cancer Society, the International Anesthesia Research Society, the Clinical Practice Enhancement and Anesthesia Research Foundation and the U.S. Public Health Service. Drs. Michael Roizen, Jonathan Moss, Michael O'Connor, Theodore Karrison and Joachim Osinski, all of the University of Chicago, contributed to the study. Drs. Yuan, Foss, Moss, and Roizen hold patents related to methylnaltrexone.