Opioid Antagonists Can Control Opioid-Induced Constipation

BETHESDA, Md--How important is it to prevent opioid-induced constipation in patients taking opioids for cancer pain? "Some patients have said they would rather live with the pain than suffer with constipation," Joseph F. Foss, MD, assistant professor of anesthesia, University of Chicago, said at the First International Conference on Research in Palliative Care, held at the National Institutes of Health (NIH).

Opioid receptors in the gut are primarily responsible for the decreased intestinal motility in patients who are taking opioid analgesics, Dr. Foss said. For any person who is taking an opioid on a chronic basis, a prophylactic bowel regimen is important to prevent the anticipated constipatory effects.

Increased physical activity, adequate hydration, and adequate dietary fiber are routine recommendations for any patient with a complaint of constipation. However, Dr. Foss stressed, when opioids are prescribed, the physician should have an algorithmic approach to bowel management that includes laxatives, cathartics, stimulants, or mechanical interventions.

"Up to 80% of patients who receive opioids for chronic pain will require institution of some pharmacologic measure to prevent or treat opioid-induced constipation," he said.

Naloxone hydrochloride (Narcan and generics), an opioid antagonist that is used intravenously to reverse adverse effects of excessive opioid administration, has been used successfully given orally to manage opioid-induced constipation. When given via the oral route, naloxone has a very high first-pass hepatic metabolism. This route allows pharmacologic doses of naloxone to reach the opioid receptors in the bowel that cause constipation, without leading to significant plasma levels of the drug that would reverse any analgesic effects of the opioid.

In a small study, Dr. Foss said, oral naloxone doses that caused a laxative response ranged from 1 to 16 mg in patients who had been receiving opioids at a dose of 49 to 53 morphine-equivalent milligrams intramuscularly. Opioid withdrawal was seen in one patient at naloxone doses higher than 12 mg.

In a controlled study by N. P. Sykes [Palliative Medicine 10(2):135-144, 1996], patients received an oral naloxone dose of 0.5% to 80% of the daily morphine equivalent dose (1 to 20 mg of naloxone for 40 to 600 mg of oral morphine).

Higher naloxone doses (more than 10% of the total equivalent morphine dose) had a laxation response, in a dose-dependent manner. However, in those patients receiving naloxone at a rate more than 20% of the morphine dose, adverse effects occurred, ranging from abdominal colic attributed to laxation, to symptoms of opioid withdrawal syndrome in patients who received the highest naloxone percent doses.

Dr. Foss concluded that there is a relatively narrow therapeutic window for effective dosing of oral naloxone to manage opioid-related constipation. Nalbu-phine glucuronide, an agent with both opioid agonist and antagonist activity, also showed a narrow therapeutic window when similarly used to manage constipation, he said.

Dr. Foss has been studying a newer quaternary opioid antagonist, methyl-naltrexone, to selectively inhibit opioid receptor binding in the gut without producing systemic opioid antagonism. The methylated molecule has lower lipo-philicity, which results in less drug being absorbed across the GI mucosa.

In studies to date with normal volunteers and with people on methadone maintenance, methylnaltrexone has been shown to normalize delayed gastrointestinal transit stemming from opioids and to produce a rapid laxative effect without causing systemic opioid withdrawal, Dr. Foss commented.