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Key Words

Methylnaltrexone, opioid, constipation, palliative care. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)

Summary

Seriously ill patients in hospice or palliative care settings who were constipated because of their opioid-based pain medications were given a drug called methylnaltrexone. More than two-thirds achieved laxation (bowel movement) within 24 hours, about 90 percent of those in four hours.

Source

American Society of Clinical Oncology annual meeting, Orlando, Florida, May 17, 2005.

Background

Drugs given for pain are common in cancer treatment, especially in hospice settings where many patients are classified as having advanced medical illness and usually survive for less than six months. One common class of pain-killing drugs are the opioids, synthetic versions of opiate drugs like morphine and codeine. About half of the patients taking opiates or opioids develop constipation, where patients are unable to move their bowels. The pain can be so severe that patients are faced with choosing the pain of their disease or the pain of the opioid-induced constipation.

Methylnaltrexone (MNTX) has been in development since it was first synthesized in 1979 to offset the constipating effect of morphine, but it is not yet approved by the FDA for this use. By not crossing the blood-brain barrier, methylnaltrexone is thought to counter the constipating effects of opioids without reducing their effectiveness as pain relievers. Major questions remain about what dose is most effective and at what point, and how often, the drug should be given.

The Study

In this phase III trial, 154 patients at 16 hospice or palliative care sites with a life expectancy of less than six months who hadn’t had a bowel movement in 48 hours were randomly assigned to one of three groups. One group received a low dose (0.15 mg) of methylnaltrexone; a second group received a higher dose (0.30 mg); and the third group received a placebo. The study was double-blinded, meaning that neither the doctors or the patients knew who was receiving which treatment. The patients were evaluated for how long it took them to have a bowel movement (time to laxation), side effects, pain, and symptoms of opioid withdrawal.

The primary author was Jay Thomas, M.D. at the San Diego Hospice and Palliative Care in California. The study was sponsored by the drug’s manufacturer, Progenics Pharmaceuticals.

Results

The lower dose of methylnaltrexone worked in many more patients than the placebo. Four hours after treatment, 62 percent of the low-dose group had achieved laxation compared to 13 percent of the placebo group. The advantage held at the 24-hour mark (68 percent versus 33 percent). The higher dose was four percent less effective than the lower at both time points, but the median time to laxation was significantly quicker: 45 minutes as compared to 70 minutes for the lower dose.

The patients survived for a median of three weeks. No severe adverse events were linked to the drug, though there was predictable abdominal cramping and flatulence and also some nausea and dizziness. There were also no reports of opioid withdrawal, suggesting that the drug was not interfering with the pain-relieving aspect of the constipation-causing treatment.

Comments

Methylnaltrexone appears poised to be approved and marketed for sale, according to the study’s researchers. “There’s only good news here,” said Thomas, “as this drug is well tolerated and works in about 60 percent of patients in about an hour.”

The end-of-life population enrolled in this trial is “highly needy because they often experience tremendous suffering,” said Thomas. Whether methylnaltrexone can be adapted for oral use, rather than the shot given here, remains to be seen. Other studies are needed, he said, to fine-tune the dosage and to explore the drug’s use in other populations, such as non-elderly severely sick oncology patients and methadone users.

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