Combating Opioid-Induced Constipation: New and Emerging Therapies
Pain is a significant and prevalent public health problem that costs society approximately $560 to $635 billion annually, an amount equal to about $2,000.00 for every person living in the US.1 As a result of the number of individuals experiencing persistent pain, the National Institute of Health reported that approximately 200 million prescriptions for opioids were dispensed in 2013, a trend that has grown by more than 50% over the last 10 years, and by nearly 100% since 2000.2
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 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 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.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
Over-the-counter options for management of constipation include increasing dietary fiber intake, increasing fluid intake, and increasing physical activity.3 However, there is inadequate evidence to support the use of these interventions for OIC, and they often are ineffective, which necessitates use of laxatives.3 Stimulant laxatives are often used first-line due to their low cost and efficacy despite not correcting the underlying mechanism.3,13 Table 2 describes categories of anti-constipating agents.
Stimulant laxatives, including senna and bisacodyl, work by increasing muscle contractions. Patients, however, may develop tolerance and dependence to stimulant laxatives.3 Docusate, a surfactant stool softener, does not assist with muscle contractility but is non-habit forming.3 Bulk-forming laxatives, for example psyllium, may lead to increased abdominal pain and bowel obstruction.3 Lactulose and polyethylene glycol are osmotic laxatives that pull water into the GI tract and have evidence for use in OIC, but they do not target the actual OIC cause, and they may provoke electrolyte abnormalities.3,11,13,15 Unfortunately, patients may have inadequate symptom relief from OIC with these laxatives alone or combined.
It is not often in medicine that a pharmacological antidote exists to a drug treatment or adverse effect. Although newer select agents (ie, ion channel activators) have been approved for OIC, there is only one class of drug that targets the specific underlying cause of OIC—binding of opioids to the mu-receptors in the enteric nervous system. This new class, known as PAMORAs (Peripheral Acting Mu Opioid Receptor Antagonists), work by selectively inhibiting opioid receptors in the gut, thereby decreasing the constipating effects of opioids without affecting opioid-mediated analgesic effects within the central nervous system or precipitating withdrawal symptoms (Table 3).4,18