The researchers say the drug, ADL 8-2698, blocks the actions of morphine and other opioids in the intestines without inhibiting their ability to relieve pain. The finding is reported in this week’s New England Journal of Medicine. “Return of bowel function is one of the key indicators of recovery following surgery,” said principal investigator Andrea Kurz. M.D., an assistant professor and director of the Division of Clinical Research in the Department of Anesthesiology at Washington University School of Medicine, as well as associate director of the Outcomes Research ™ Institute, an international group of researchers. "One of the ways that we know a person is about ready to go home is that they pass gas, and that indicates their bowel function is returning to normal."
Drugs such as morphine and other opioids are very good at relieving post-operative pain, but they also act on opioid receptors in the gut, blocking normal GI function. Kurz found that ADL 8-2698 kept the opioids from affecting those receptors without blocking the beneficial pain-relieving actions of the drug in the brain.
The investigators studied 78 patients undergoing abdominal surgery — either colectomy or hysterectomy — and divided the patients into three groups of 26 each. One group received an inactive placebo. The second study group received a 1 mg dose of ADL 8-2698, and the third group got a 6 mg dose of the investigational drug. All three groups received identical-looking capsules two hours before surgery and again twice daily until they either had a full return of bowel function or were discharged from the hospital. Patients who received 6 mg of ADL 8-2698 reported no greater pain and did not receive more pain medication, but they did have much quicker recovery of bowel function. Those who received 1 mg of ADL 8-2698 had smaller, less significant improvements.
The median length of time before first flatus decreased from 70 hours in the placebo group to 49 hours in the group that got 6 mg doses of the drug. Time to first bowel movement declined from 111 hours to 70. And the time at which patients were deemed ready for discharge decreased from 91 hours in the placebo group to 68 hours in the 6 mg group.
"A big advantage of this drug is that it’s poorly absorbed," Kurz said. "It acts selectively on the periphery — the bowel in this case — without crossing into the bloodstream and subsequently into the brain. There are many drugs that antagonize opioids, but most of them also cross into the brain, too. That limits the analgesic effects of the opioids, and patients end up having pain."
Patients who received the 6 mg dose of the drug also had significant decreases in nausea and vomiting in the hours and days after surgery. And because patients who were given the drug were ready to go home sooner, it follows that the drug has the potential to lower health care costs. “We did not evaluate cost effectiveness in this particular study, but showing that most patients are discharged about a day earlier would suggest that the cost savings are substantial,” Kurz said. Kurz and colleagues continue to study the drug in abdominal surgery patients, hoping to fine-tune the dosage at which the drug will work most effectively. They also hope to study its actions in patients undergoing other types of surgery.
Akiko Taguchi, et. al., "Selective Postoperative Inhibition of Gastrointestinal Opioid Receptors," New England Journal of Medicine, vol. 345(13), 935-940, Sept. 27, 2001.
This research was supported by grants from the Adolor Corporation, the Joseph Drown Foundation, the Commonwealth of Kentucky Research Challenge Trust Fund and the National Institutes of Health.
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Journal
New England Journal of Medicine