Naloxegol reduces opioid-induced constipation in trials

Abuse of opioid analgesics is the nation's fastest growing drug problem. In 2012, physicians wrote more than 259 million prescriptions for opioids — the equivalent of one bottle for every adult in the United States. In the two highest prescribing states, the rate was 143 prescriptions per 100 people. According to data from the Centers for Disease Control and Prevention, many of these prescriptions are for three months or more, increasing the risk of abuse and addiction.

But opioids can have a negative effect on health, productivity and quality of life, even when prescribed and used appropriately; increasing use has led to a corresponding rise in opioid-induced constipation (OIC) and bowel dysfunction.

According to results of a 2009 survey published in Pain Medicine, 81 percent of 322 opioid-treated patients in the U.S. and Europe reported constipation, and 45 percent reported fewer than three bowel movements a week. One-third of patients had decreased or stopped their medication to relieve severe gastrointestinal symptoms.

In general, opioid-related side effects, which result from opioid binding at mu-opioid receptors in the enteric nervous system, are thought to affect around 41 percent of patients receiving the drugs for chronic noncancer pain. Decreased intestinal motility and secretion of water and electrolytes can develop within two or three days, although physiologic reactions increase with long-term use.

Michael Camilleri, M.D., a gastroenterologist at Mayo Clinic's campus in Rochester, Minnesota, was lead author of an international consensus statement on opioid-induced constipation. The multidisciplinary work group concluded that an unacceptable number of patients struggle with OIC because of barriers to proper diagnosis and treatment in clinical practice, including:

  • A lack of awareness among clinicians about the gastrointestinal side effects of opioids and opiates
  • Failure to ask patients about OIC or patient reluctance to discuss it
  • The failure of standard criteria for functional constipation to completely capture the full spectrum of opioid-induced constipation
  • Use of nonspecific constipation treatments, such as stool softeners, bulking agents, stimulants, lubricants and osmotic agents

The last point may well be the most actionable. In a 2011 review in The American Journal of Gastroenterology, Dr. Camilleri found that fewer than half of opiate-treated patients reported satisfactory results from traditional laxative therapy compared with 84 percent of controls.

One answer, he says, lies in new, peripherally restricted opioid receptor antagonists. Two of them, methylnaltrexone and alvimopan, are already approved by the Food and Drug Administration — methylnaltrexone for OIC in terminally ill patients and alvimopan to aid recovery of intestinal function after bowel resection surgery. Alvimopan is approved with a Risk Evaluation and Mitigation Strategy because it has been associated with increased cardiovascular events.

Drugs in development

Several similar drugs, which vary in their chemical structures and opioid receptor binding affinities, are in different stages of development. All aim to decrease gastrointestinal effects without affecting centrally mediated analgesia, but require thorough evaluation to ensure that higher doses don't cross the blood-brain barrier.

One orally administered, peripheral mu-opioid receptor antagonist that has performed well in two multicenter phase III clinical trials is naloxegol. According to research reported in the June 19, 2014, issue of the New England Journal of Medicine, patients randomized to receive 25 mg or 12.5 mg of naloxegol achieved response rates 10 to 15 percentage points higher than those receiving placebo.

In the first study, 29.4 percent of the placebo group, 40.8 percent of the 12.5 mg group and 44.4 percent of the 25 mg group were responders using endpoints required by the FDA and other regulatory agencies. For unknown reasons, the 12.5 mg dose wasn't associated with a higher response rate in the second study compared to placebo, although the 25 mg dose was.

Multiple secondary end points, such as time to first spontaneous bowel movement, number of weekly spontaneous bowel movements and constipation severity were also improved in patients taking naloxegol.

The most common adverse events — abdominal pain, diarrhea, nausea and vomiting — were more frequently observed with the 25 mg dose. Of particular importance, cardiovascular events were rare and no significant changes in opioid dose or pain scores occurred during the study, suggesting that naloxegol's effects were restricted to the periphery and the drug did not antagonize the pain-relieving properties of opioids.

"Some patients do not achieve satisfactory relief with this drug," Dr. Camilleri points out. "It's not 100 percent effective, but it appears to be superior to other laxatives, though direct comparisons with other, more easily available laxatives have not been reported. OIC is a very common problem, and there are specific things that can be done to help relieve it, including prescribing laxatives whenever we prescribe opiates."

Naloxegol is not yet approved by the FDA. The two opioid receptor antagonists that are approved are limited to use in specific populations. A third approved drug, lubiprostone, is a chloride channel agonist that induces intestinal secretion directly without antagonizing binding of opioids to their receptors. It is not effective in relieving constipation induced by methadone.

Dr. Camilleri notes, "I think it's important to bring to the attention of clinicians the opportunity to relieve OIC with possibly greater efficacy if naloxegol and similar drugs are approved for marketing in the future."

For more information

Bell TJ, et al. The prevalence, severity and impact of opioid-induced bowel dysfunction: Results of a US and European Patient Survey (PROBE 1). Pain Medicine. 2009;10:35.

Camilleri M. Opioid-induced constipation: Challenges and therapeutic opportunities. The American Journal of Gastroenterology. 2011;106:835.

Camilleri M, et al. Emerging treatments in neurogastroenterology: A multidisciplinary working group consensus statement on opioid-induced constipation. Neurogastroenterology & Motility. In press.

Chey WD, et al. Naloxegol for opioid-induced constipation in patients with noncancer pain. New England Journal of Medicine. 2014;370:2387.