A new drug, methylnaltrexone, may improve opioid-induced constipation without interfering with pain control, according to researchers from the US (Journal of the American Medical Association 2000;283:367).
Professor Chun-Su Yuan (department of anaesthesia and critical care, University of Chicago) and colleagues undertook a study on 22 volunteers who were enrolled in a methadone maintenance programme for opioid addiction. (These subjects were chosen because the investigators did not wish to risk interrupting pain relief for patients with terminal cancer.) All of the volunteers suffered from opioid-induced constipation.
Intravenous methylnaltrexone was given daily for two days to 11 of the 22 volunteers, and the remaining 11 received placebo injections. The mean dose was 0.09mg/kg (range 0.01-0.37) on day one and 0.1mg/kg (0.01-0.37) on day two.
An immediate response (within one minute) to the first injection of the active drug was experienced by 10 of the 11 subjects and by all 11 after the second injection on day two. The patients in the placebo group reported no change in their bowel habit. All 11 volunteers in the "active" group reported mild-to-moderate abdominal cramping, which disappeared after a bowel movement. None experienced symptoms of opioid withdrawal.
"By preventing this debilitating but little-discussed problem, methylnaltrexone could substantially enhance the quality of the last months of life for terminal cancer patients," Professor Yuan says.
The authors explain that adding a methyl group to naltrexone changes the charge of the molecule and it is no longer able to cross the blood-brain barrier. This means that methylnaltrexone does not affect morphine's analgesic effects. However, it does affect gut motility by blocking morphine receptors in the gastrointestinal tract.
They hope that a pharmaceutical company will support phase III trials in patients with advanced cancer.
A trial using an oral form of methylnaltrexone is underway at St Christopher's hospice in Sydenham, Kent. Dr Nigel Sykes (head of medicine) told The Journal on January 18 that opioid-induced constipation was a major problem that was experienced by about 90 per cent of cancer sufferers admitted to a hospice. Of those, 40 per cent required either suppositories or enemas to manage their constipation.
"Many patients find that constipation is more of a problem than pain and stop taking their analgesia as a result," he said. For this reason, an effective oral treatment was needed, he explained.
Dr Sykes described the trial at St Christopher's as being placebo controlled, blinded and a dose-ranging study. In the active group, the dose of methylnaltrexone was linked to that of the patient's morphine dose, being either equal to, three times or 10 times the morphine dose. Patients were maintained on conventional laxatives throughout, in case they were in a placebo group, he said.
Both inpatients and home care patients with all types of cancer were being entered into the trial and, so far, two-thirds of the total number required had been recruited.