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
"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
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.