Most of the commonplace adverse effects associated with opioid analgesia, e.g., nausea, cognitive clouding, sedation, and pruritus, are transient. Constipation, unfortunately in addition to being one of the most common adverse effects of opioids, is also the most persistent. Mu receptors in the enteric nervous system (the colon has a brain, you say? Who knew!?) have a critical responsibility for controlling active propulsive activity of the colonic musculature: Activation of the mu receptorsuppresses propulsive activity. Since all traditional opioids possess potent mu receptor agonist activity, suppression of colonic propulsive activity is routinely seen during opioid treatment, and the bowel does not appear to develop much tolerance to this effect.
Naloxegol is an oral mu receptor antagonist pending FDA approval in the United States. Because it is only effective at peripheral opioid receptor sites (e.g., colon) and not at central mu receptor sites (i.e., the CNS), it should not induce opioid withdrawal or reduce the efficacy of opioid analgesia. Data published from two randomized, double-blind, placebo-controlled clinical trials support the efficacy and tolerability of naloxegol. By intention-to-treat analysis, naloxegol provided a statistically significant and clinically meaningful sustained increase in frequency of bowel movements over a 12-week opioid treatment period compared to placebo. The drug was well tolerated. Although there are other mu receptor antagonists on the market — one is parenteral and the other is indicated only for postoperative ileus — it would be nice to have an orally active agent for patients treated with chronic opioids.
Source: Chey WD, et al. N Engl J Med 2014;370:2387-2396.