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Opioid-Induced Constipation: New and Emerging Therapies—Update 2015

Approximately 50% of patients on opioid therapy will experience constipation. New and emerging therapies are targeting the root cause of opioid-induced constipation and providing real relief to patients.
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Severe chronic pain affects more than physical or mental function, it impacts quality of life and productivity, which “imposes a significant financial burden on affected individuals, as well as their families, their employers, their friends, their communities, and the nation as a whole.”1,2

Almost all patients requiring chronic opioid therapy develop side effects, the most common of which affect the gastrointestinal (GI) and central nervous systems (CNS).3,4 Although tolerance develops to many of the CNS side effects over time (ie, sedation), resolution of opioid-induced bowel dysfunction (OIBD), and more specifically opioid-induced constipation (OIC), does not occur with continued use.3

How prevalent is OIC? The numbers vary widely based on study design and patient populations. Based on an analysis of 16 clinical trials and observational studies, OIC has been reported to occur in 15% to 90% of patients.5 When these studies are qualified according to type of chronic pain, estimates from observational studies in the United States suggested that the prevalence of OIC in patients with non-cancer pain ranged between 40% and 50%.6

In addition to being a common side effect, OIC significantly affects a patient’s quality of life.7 A study of work productivity in patients on chronic opioid therapy found that OIC impacted productivity and activity levels. Specifically, the study found that patients reported 9% work time missed, 32% impairment while working (equivalent of 14 hours of lost productivity per week), and 38% activity impairment.8

To appreciate the impact OIC has on patients, the authors conducted an informal survey of their patients. Here are actual quotes about OIC from pain patients:

  • “I have to get off of my opioid pain medications because of my plumbing bills…I keep clogging the toilet.”
  • “I have had many surgeries and injuries in my life and nothing compares to the pain of severe constipation.”
  • “Coming to the emergency room for disimpaction was the most embarrassing experience in my life.”
  • “My constipation was so bad I thought I was going to die…actually, I wanted to die.”
  • “I’d much rather live with pain than the side effect of severe constipation.”
  • “I’d rather give birth again with no anesthesia than go through a bout of constipation from my medications.”

Additionally, participants in a recent OIC study commonly reported that their constipation interfered with the ability of their opioid medication to control pain, with 49% reporting moderate or complete interference, and 8% reporting that they changed how they used their opioid in order to have a bowel movement.9

Effect of Opioids on the GI Tract

Multiple mechanisms influence the occurrence of OIC. In fact, the very mechanisms that allow opioids to be effective pain medications are also involved in causing OIC. Opioid agonists mitigate pain by binding to opioid receptors that are located in the central and peripheral nervous systems. Mu-opioid receptors, and to a lesser extent kappa- and delta-opioid receptors, are located throughout the GI tract. Here opioids reduce contractility and tone leading to increased transit time.3

Specifically, they exert their effects in the neuronal plexi, located between the longitudinal and circular muscle layers (myenteric plexus) and within the submucosa (submucosal plexus),9 and indirectly through the central nervous system via intrathecal administration of opioids, decreasing GI motility and intestinal secretion.10

Passive absorption of fluids is increased and intestinal secretions are reduced in the GI tract with opioids due to increased frequency and strength of circular muscle contractions that cause non-propulsive contractions.3 Within the myenteric plexus, opioids stimulate relaxation of the longitudinal smooth-muscle layer, thus increasing tonicity in the circular smooth-muscle layer. The mechanism of this action is believed to occur through inhibition of acetylcholine release and inhibition of vasoactive intestinal peptide and nitric oxide release.

Ultimately, this results in an increase in segmental contraction, while peristaltic activity is decreased, inducing constipation. 6 Reduced propulsive contractions of longitudinal muscles also contributes to hard and dry stools.4 Rectal stool evacuation is decreased by an increased threshold for triggering of the anorectal reflex.3,11

Diagnosis of OIC

Opioids affect the entire gut, from the mouth to the anus, and OIBD refers to the constellation of GI effects.4 This includes gastroparesis, gastroesophageal reflux disease (GERD), and other GI-related disorders.12 Although no delineation for constipation has been universally accepted, various definitions of constipation exist and guidelines for initiating prescription therapies for OIC have been developed.3,11,13,14

According to the American College of Gastroenterology definition, constipation is defined as unsatisfactory defecation with infrequent bowel movements, difficult stool passage, or both.11,15 Functional constipation, as outlined by the Rome III criteria, requires 2 or more of the following symptoms to occur no less than 25% of the time in the past 12 weeks: straining with bowel movements, passing lumpy or hard stools; feeling of incomplete evacuation; feeling of anorectal obstruction; using manual maneuvers for facilitation of defecation; and having less than 3 bowel movements per week.16 Even though this definition is not restricted to opioid-induced constipation, the Rome III criteria is often used to describe this condition (Table 1).11,17

Treatment Options

There are a variety of non-pharmacologic treatments and over-the-counter options for management of constipation, including increasing dietary fiber intake, increasing fluid intake, and increasing physical activity.3 Exercise has been shown to improve functional constipation, however, there is inadequate evidence to support its use in OIC and pain patients are often limited in their tolerance for physical activity.3

Last updated on: December 8, 2015
First published on: December 1, 2015
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Medication Guide for Pain—A Short Primer for Primary Care