Opioid-induced constipation – naloxegol

Published: 6-Jan-2014

About half of all patients taking opioids commonly experience constipation

Patients whose pain is being treated with opioid drugs commonly experience constipation. Global estimates put the number of patients affected in this way at up to 35 million, about half of all those taking opioids. Only around half of these find successful relief using treatments such as over-the-counter laxatives.

The problem arises because of the non-selective nature of the drugs, and the presence of opioid receptor types in multiple sites in the body. In this case, the problematic receptors are the mu-opioid receptors in the gut. If these are blocked by opioid painkillers, decreased fluid absorption and reduced motility in the lower gastrointestinal tract can lead to constipation.

Naloxegol was discovered by Nektar Therapeutics, licensed to AstraZeneca, and is being developed as a potential alternative treatment for opioid-induced constipation.1 It is a PEGylated form of naloxol, a human metabolite of Sankyo’s drug naloxone, which is used to counter the wider side-effects of opiate overdoses.

A double blind, placebo-controlled Phase II clinical trial has been carried out in 207 patients with opiate-induced constipation.2 Subjects had been on a stable opioid regimen of 30–1000mg/day of morphine equivalents for at least two weeks, and had fewer than three spontaneous bowel movements a week, with accompanying symptoms.

They were given 5, 25 or 50mg of naloxegol or placebo once a day in sequential cohorts, after a one-week placebo run-in, or placebo. Both higher doses gave a statistically significant increase in spontaneous bowel movements, which was maintained over four weeks. The drug was generally well tolerated, with most adverse events – mainly diarrhoea and nausea – being mild and transient at the lower doses, although they were more frequent and severe at the highest dose. There was no statistically significant increase in pain levels, opioid use, or centrally mediated opioid withdrawal symptoms.

Two prospective, double blind, randomised, placebo-controlled Phase III trials have also been carried out.3 In both, a similar population of subjects, with non-cancer pain, was given 12.5mg or 25mg oral doses of naloxegol or placebo once a day. In one of the trials, a statistically significant number of the 652 treated patients had an increase in spontaneous bowel movements of at least one per week. In the second, in 700 patients, this primary endpoint was achieved only at the higher dose. Again, there were no statistically significant changes from baseline in mean daily pain scores or opioid doses. It was generally well tolerated and safe, and the most common adverse events were gastrointestinal. The drug was submitted for FDA approval in November.


1. M.A. Eldon et al. 18th Ann. Clin. Meet. Amer. Acad. Pain Management, 2007 (27–30 September, Las Vegas), Poster 28

2. L. Webster et al. Pain 2013, 154, 1542

3. W.D. Chey et al. Dig. Dis. Week, 2013 (18–21 May, Orlando), Abst. 9002.

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