Opioid-induced Constipation: Causes and Treatments
The treatment of chronic pain, whether of cancer or noncancer origin, frequently involves the use of opioids. It has been estimated that up to 90% of patients with chronic pain receive opioids.1 Interestingly, in spite of being used for millenia, opioids have not seemed to garner the attention and investigation seen in other medication classes, until recently. The endogenous opioid system has only been elucidated within the last few decades (eg, the µ receptor being discovered in 1973).2 Much is currently known about the physiology, biochemistry, and action of opioids, both endogenous and exogenous, yet much has still to be discovered. For example, we are only beginning to understand and identify the many side effects of opioids. Constipation, nausea, emesis, pruritus, respiratory depression, and somnolence are well known. However, not so well known are effects on immune function, urinary retention, endocrinopathies, gastroesophageal reflux (GERD), gastroparesis, sleep apnea, cardiovascular system, osteoporosis, emotions, dentition, and renal function. This review is the first part of a series of articles that will focus on opioid-induced complications. For this review, we focus on bowel dysfunction (OIBD), and more specifically opioid-induced constipation (OIC).
Why it Occurs
The gastrointestinal (GI) tract has an extensive nervous network, which has been called the “second brain.”3 This endogenous opioid system controls many functions in our body (eg, immune, sexual, behavioral, as well as gut function). These neurons are found in the myenteric and submucosal plexus as well as other areas of the GI tract and supply nervous stimulation to all parts of the alimentary canal.4 Enteric neurons synthesize and release many neurotransmitters, but also endogenous opioids. These endogenous opioids are neuroactive and will bind to the three opioid receptors—µ, k, and to a lesser extent ∂—to affect bowel function, influencing both secretion and motility. Teleologically, these endogenous opioids will slow down an overactive gut in an attempt to maintain homeostatic gut function. However, they have shorter half-lives than exogenous opioids, performing their function and then being quickly metabolized (except endorphin).5,6
Since opioids affect the entire gut, from the mouth to the anus, the term OIBD has been coined.7 This includes constipation as well as gastroparesis, GERD, and other GI-related disorders.8 The incidence of OIC has been estimated from 40% to 90%.8,9 Neither OIBD nor OIC have been given universally accepted definitions—there are no Rome III criteria (or other accepted canonical criteria) for these disorders. There is also reason to believe the physiologic mechanisms of functional constipation (FC) and OIC may be distinctly different. However, the Rome III criteria for FC may be helpful for guidance in the diagnosis of OIC. Using the Rome III FC criteria, as well as those symptoms mentioned in the literature and used in clinical trials, a symptomatic approach to diagnosis can be constructed (see Table 1).8-12 Interestingly, in a study from Canada patients who were given opioids were prescribed laxatives and frequently acid suppressive therapy; therefore, it may be important to include GERD in the diagnosis as well.8,9,13
As mentioned, if we take the “symptom approach” to defining and diagnosing OIC, then FC and OIC are similar. A full history and physical examination is critically important.1 Other causes of constipation should obviously be evaluated, as well as a full psychological evaluation. The clinical history is the key: What was the patient’s previous bowel pattern prior to starting opioids? What is the current pattern now that the patient is taking opioids? These two questions will help diagnose as well as provide goals for treatment. A treatment goal of a daily bowel movement would not be appropriate in a patient whose normal bowel pattern is every 2 to 3 days. Once it is established that no other cause exists, that the constipation started after the opioids were initiated, then specific questions concerning bowel movements should be asked.
Treatment of Constipation
There does not seem to be a tolerance to the constipatory effects of opioids.8 Therefore, once diagnosed, patients may need to stay on laxatives for as long as the patient is on opioids. The use of prophylactic anti-constipatory agents is the current standard of care. These should be started in conjunction with the start of the opioid.14 Although there is little research data to support this intuitive approach, a few studies have been done. A recent study by Ishihara et al showed significant reduction in the incidence of constipation in patients receiving laxatives, including magnesium oxide, as premedication than in those without them (34% vs 55%, P<0.001).15 In 2010, Myotoku et al found that simultaneous prescribing of opioids and laxatives reduced the incidence of constipation as well.16
The available options for treating constipation include medications that have a variety of mechanisms17 (see Table 2).
Until recently, the treatment of OIC has been based on the treatment of FC. Since this is still the initial treatment approach, a short review of these treatments follows. Interestingly, lifestyle changes, exercise, and diet have little evidential support for treatment of FC. There are, however, other compelling reasons to suggest and implement exercise and dietary improvement. In addition, biofeedback has some supportive evidence, although it is rarely used probably due to insurance reimbursement issues.18
Although bulking agents are commonly used in the treatment of FC, there is a paucity of support for the efficacy of many of these treatments. For example, there is only one trial each for the support of methylcellulose and polycarbophil.19-20 Psyllium has been shown to have increased efficacy in three randomized controlled trials (RCTs).21-23 There are two studies using bran that show improvement in colonic transit time and consistency.24,25 The over-the-counter stool softener docusate was found to be inferior to psyllium in one study.21 However, polyethylene glycol has been shown beneficial over placebo in three well-designed trials.26-28 Lactulose has two RCTs showing superior evidence over placebo.29,30 No RCTs exist for sorbitol or magnesium hydroxide. Bisacodyl has a single RCT demonstrating efficacy and superiority over placebo.31 There are no studies on senna compared to placebo, but three studies compared it to other laxatives.32-34 Probiotics, in the treatment of FC, are without supportive evidence at this point in time.