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12 Articles in Volume 12, Issue #3
Alternative Medicine in Chronic Migraine: What Clinicians Need to Know
Classic Central Pain Syndromes: Review of Neurologic Causes of Pain
Effective Treatments for Neuropathic Pain
Electric Current and Local Anesthetic Combination Successfully Treats Pain Associated With Diabetic Neuropathy
HCG and Diabetic Neuropathy
Migraine Treatment From A to Z
Opioid-induced Constipation: Causes and Treatments
Pain Management of Diabetic Neuropathy
Partnering With Parents
PPM Editorial Board Discusses Mental Deterioration in Pain Patients
The Critical Necessity to Diagnose Pain That Is Centralized
Unique Use of Near-Infrared Light Source to Treat Pain

Opioid-induced Constipation: Causes and Treatments

Constipation is a well-recognized side effect of opioid use, yet its impact on patients’ quality of life remains underappreciated by many healthcare providers, leaving many patients undertreated.

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.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.”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

Diagnosis
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.

Therefore, even for the very common condition of FC there is a paucity of research support for current treatment regimens. Leung et al stated, “It is indeed surprising that as a common condition found in at least one quarter of patients, chronic constipation is treated in a wide variety of ways, with relatively little evidence-based data, especially regarding dietary fiber, fluids, and exercise.”35 The recommendations of their 2011 meta-analysis included 62 articles and suggests using bulk forming agents (psyllium or bran) with a stool softener or osmotic agent for FC. A bowel stimulant can be added next and finally the newer agents such as chloride channel activators or a 5-HT4 agonist can be tried.

Prostaglandins or prokinetic drugs change the way the intestine absorbs water and electrolytes, thus increasing the weight and frequency of stools while reducing transit time. Examples include metoclopramide (Reglan, others) and cisapride (Propulsid), which is currently only available under compassionate conditions. Lubiprostone (Amitiza) is a selective chloride channel activator that acts in the apical membrane of the gastrointestinal epithelium to enhance chloride-rich intestinal fluid secretion by intraluminal fluid collection in the gut.36 Lubiprostone has been shown in three RCTs to improve chronic constipation in the majority of individuals within 24 to 48 hours of initial dosing.37-39 It has been approved for the treatment of primary constipation in adults and is currently being studied in the setting of OIC.

Tegaserod (Zelnorm), a 5-HT4 partial agonist, causes stimulation of peristaltic reflex, colonic motility, colonic lumen secretion, and decreased visceral hypersensitivity.40 Due to cardiac problems in the clinical trials, however, the manufacturer voluntarily removed tegaserod from the market in 2008. It is now only available for cases that are life threatening or require hospitalization. Prucalopride (Resolor) is a highly selective 5-HT4 agonist and is currently under development.41

Other medications are being evaluated in the treatment of FC, which may see utility in the setting of OIC. Linaclotide, a novel, poorly absorbed guanylate cyclase agonist, is also under development for the treatment of chronic constipation.42 The mixed 5-HT4 receptor agonist/5-HT3 receptor antagonist renzapride, which has been shown to improve stool consistency and increase colonic transit time, has been tested only in patients with irritable bowel syndrome (IBS) and constipation.43 Other agents currently under investigation in FC include 5-HT4 agonists, such as norcisapride and mosapride, cannabinoid receptor antagonists (SR141716A), and neurotrophic factors.

Treatment of OIC
Because there is a dearth of data or meta-analysis for the management of OIC, the standard approach has been to use similar treatments as for FC, and to approach OIC in a symptoms fashion. Bulking agents should be avoided by convention. It is intuitively believed that bulking agents will worsen OIC secondary to the removal and absorption of water from the gut with further hardening of the stool, although this has never been studied systematically.44

Therefore, the treatment approach to OIC, once the diagnosis has been given, should start with a bowel stimulant and/or stool softener.45 If this approach fails, advance to polyethylene glycol or lactulose. If these are unsuccessful, advancing to an opioid antagonist would be appropriate. As mentioned previously, bowel stimulants and stool softeners should be started in conjunction with the opioid.14 As far as timing to treatment effect, this has not been established (ie, how long should they be on a specific agent before failure is admitted and the agent changed) (see Figure).

The above approach takes into account healthcare cost. However, if one were to approach OIC mechanistically, using an opioid antagonist as a first-line therapy seems very reasonable. Unfortunately, to date there has not been any pharmacoeconomic data to suggest the use of opioid antagonists are cost neutral or cost reductive (this would be most helpful data to have available).

Opioid Antagonists
Opioid antagonists have been used for OIC for a number of years with newer agents currently approved for marketing or in the process of development. Although not FDA approved for OIC, naloxone was the most common opioid antagonist described in the literature.46,47 Meissner et al developed a naloxone protocol for OIC in 2000, which this author has used in his in-patient practice.48 However, great care must be observed when using naloxone since it crosses the blood-brain barrier, which could cause an acute opioid abstinence syndrome, as well as reversal of analgesia—both unwanted consequences of any opioid antagonists in the setting of OIC.

When a methyl group is added to the opioid antagonist naltrexone, methylnaltrexone is formed. The molecule does not cross the blood-brain barrier, and does not induce acute opioid abstinence syndrome or cause loss of analgesia.49Methylnaltrexone’s mechanism of action (as with other opioid antagonists) in the treatment of OIC is specific to the opioid receptor in the gut wall (most specifically µ). The molecule binds to the opioid receptor with high affinity, greater than that of opioid agonists, displacing the exogenous opioid. However, it causes no receptor conformational change; therefore, no action and, in the case of OIC, no reduced colonic motility.49 The effect is to reverse the constipatory effects of exogenous opioids on gut motility and secretion. Methylnaltrexone (Relistor) is currently available in a subcutaneous formulation, although an oral product is currently under development. Some initial studies using the oral formulation have been encouraging.50

The clinical trials of subcutaneous methylnaltrexone used “real-world” patients—those with end-stage disease and fewer than 6 months to live.51,52 However, it is important to keep in mind that the current FDA indication does not include fewer than 6 months or life or a hospice admission. In a review of the studies done on methylnaltrexone in “advanced illness,” more than 70% of patients had efficacy in global clinical impression of change.52 In these studies no reversal of opioid analgesia or evidence of acute opioid abstinence syndrome were observed. Further, little difficulty was observed in the subcutaneous injection administration—by the patient or family member.51

Again, from a mechanistic perspective, it is logical to use a drug such as methylnaltrexone. When cost constraints are a concern, however, using the “symptom approach” to treatment also seems to be a logical alternative. Empirically, patients do respond to treatments that are generalized in their mechanism of action and not specific such as methylnaltrexone. However, for the patient who fails the FC approach to treatment, methylnaltrexone provides a new and effective next step in treatment.53

Although the only product indicated and marketed for OIC is methylnaltrexone, the market for treatments in OIC is expanding into a very contracted space. Many new opioid antagonists are in development. For example, NKTR-118, TD-1211, ADL-7445, and ADL-5945 (see Table 3).54-58 In addition, there are 63 studies listed on ClinicalTrials.gov (as of press time) engaged in clinical trials involving OIC.59 This may be good news for patients, as a multitude of options may allow for individual patient variations. There will, however, be continued financial constraints, which will reduce access.

Conclusion
Although OIBD is frequently ignored, it is done so at the patients’ disadvantage. “Constipation is a recognized side effect of opioid use; however, its impact and the wider condition of OIBD have been underestimated and underappreciated by healthcare professionals.”60 OIC can have a significant impact on patients taking opioids; for example, quality of life was significantly reduced in a 2011 Swiss study.61 Further, in this author’s clinical experience, patients with cancer who are treated with opioids may request that the opioids be stopped, as the cancer pain is less uncomfortable than the constipation. Therefore, it is critical that OIC (and OIBD) be routinely and fully evaluated, and commonly treated (Figure). This review outlines an approach that can easily be taken by primary care physicians as well as specialists.

Last updated on: May 1, 2012
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