Improving the Recognition and Diagnosis of Opioid-Induced Constipation in Clinical Practice

Introduction

The objective of this article is to provide family physicians with information on how to recognize and diagnose opioid-induced constipation (OIC) in their patients. This issue is of immediate importance to clinical practice for the following reasons: (1) primary care physicians are responsible for >40% of opioid prescriptions in the United States¹; (2) OIC is a common side effect of opioid therapy^2-7; (3) opioid use has been increasing steadily since 1999–2000^8-10 triggered by implementation of less restrictive laws governing the prescribing of opioids for noncancer pain, new pain management standards, and increasing awareness of the prevalence and negative effects of chronic noncancer pain^8,9,10 (if opioid use continues to rise, family physicians will encounter increasing numbers of cases of OIC); (4) OIC can cause psychological distress,¹¹ negatively affecting patient quality of life (QOL)^2,3,5,12 and work productivity¹²; and (5) OIC compromises pain management,^5,12,13 resulting in increased health care utilization and costs.^14,15

What family physicians should know about OIC

OIC is an under-recognized and undertreated condition. This may be because for over 20 years, OIC has been inconsistently defined in the literature or, in many cases, not defined at all.¹⁶ A systematic literature analysis of articles published between January 1993 and August 2013 in which OIC was directly associated with the primary clinical outcome or had a central role in the purpose (ie, clinical trials and Cochrane reviews, chronic or acute cancer and noncancer pain patients with OIC) found that of 47 articles that met the inclusion criteria for analysis, 31 did not define OIC, and the definitions contained in the remaining 16 articles varied widely.¹⁶ A consensus definition of OIC developed at a roundtable meeting by a panel of US and international experts in pain medicine, palliative care, gastroenterology, and neurobiology and intended for use across disciplines was recently published.¹⁷

Use of this definition in clinical practice may aid in the recognition and diagnosis of OIC.

It is important to realize that patients often will not disclose to their physician that they are having problems with constipation. A recently conducted multicenter international survey of 493 patients receiving daily opioid therapy for at least 4 weeks who self-reported OIC found that almost 40% of patients responded that they did not discuss their OIC with their physician.¹² Reasons why patients did not bring up OIC included having previously discussed the problem with their physician, concern that the discussion would lead to a change or reduction in pain medication, and embarrassment.¹² This illustrates the need to ask patients receiving opioid therapy if they are experiencing any side effects with their pain medication, including constipation, in addition to asking them about the adequacy of the pain control it is providing.

Some patients with OIC may experience psychological distress, which may manifest as depressive symptoms and anticipatory anxiety.¹¹ The effects of OIC on patient QOL can be considerable. In an international survey, more than half of the patients with OIC responded that OIC had a moderate to great impact on their QOL⁵; 24% of patients responded that OIC affected their daily activity and 19% responded that it affected work productivity.¹² Another study found that when compared with patients without OIC, the QOL (eg, worries and concerns, physical discomfort, psychosocial discomfort) of patients with OIC was significantly worsened²; a separate study demonstrated that this difference was present regardless of whether the patients had nonadvanced illness or advanced illness.³

Once diagnosed, OIC must be effectively treated. Studies have shown that patients will often try to balance their pain control with their constipation and may reduce or stop their opioid therapy to relieve their constipation.^2,5,6,12 In the previously mentioned international survey, 44% of patients responded that constipation moderately interfered with the ability of their opioid medication to control their pain, and only 19% responded that constipation did not interfere with their pain control at all.¹² Traditional methods used to treat constipation are not specific for OIC and have limited evidence of efficacy.^6,12 Targeted treatments that address the pathophysiologic mechanism of OIC have become available and have been demonstrated to increase the number of spontaneous bowel movements (SBMs) per week without compromising pain relief.^18-20 Therefore, it is important for family physicians to have an understanding of this common side effect of opioid therapy, to know how it is diagnosed, and to recognize when treatment for OIC is indicated.

Potential for OIC in patients encountered in the clinic

In addition to opioids, a wide range of commonly used prescription and nonprescription medications are associated with the side effect of constipation (Table 1),²¹ so it is important to review all the medications that a patient presenting with constipation may be taking. Opioids are recommended for their efficacy in relieving moderate to severe acute and chronic pain, including chronic cancer pain and chronic noncancer pain. Therefore, large populations of patients who are taking opioids for a variety of painful conditions are at risk of developing OIC.^6,22

The use (and misuse) of opioids is rising in the United States.^8-10 It follows that with the increasing use of opioids, more patients will be presenting with OIC. Some opioids are associated with a higher incidence of OIC than others. In one study, 67% of patients receiving morphine, 38% of patients receiving oxycodone, 34% of patients receiving codeine, and 32% of patients receiving hydrocodone had OIC.⁶ In contrast, OIC was reported in 21% of patients receiving propoxyphene and 17% of patients receiving tramadol or transdermal fentanyl.^6,23 Some patients receive multiple opioid medications and/or high doses of opioid medications and should be considered at high risk for OIC.⁶

Clinical presentation of OIC

It is important to understand that OIC is not the same as functional constipation. Typically, functional constipation has no known cause,²¹ whereas the mechanism of OIC is known to involve opioid actions at opioid receptors in the enteric nervous system.²⁴ Stimulation of enteric opioid receptors reduces the propulsive contractions of intestinal muscles, decreases intestinal fluid secretions, and increases fluid absorption. These pharmacologic effects result in impaired peristalsis, increased sphincter tone, delayed gastric emptying, and delayed oral-cecal transit.²⁴ OIC is part of a spectrum of opioid effects on the gastrointestinal tract that is known as “opioid-induced bowel dysfunction.”²⁵ Symptoms of opioid-induced bowel dysfunction in addition to constipation may include bloating, loss of appetite, flatulence, straining during defecation, pelvic discomfort, abdominal pain during defecation, epigastric discomfort, gastroesophageal reflux disease,² abdominal cramping, spasm, nausea, and vomiting.²⁵

Although a defecation frequency of <3 bowel movements (BMs) per week has often been used to define constipation²⁶ and is part of the Rome III criteria for functional constipation,²⁷ a normal BM frequency for one patient may not be normal for another, and the use of BM frequency without consideration of other features of bowel habits may result in misdiagnosis.²⁸ Figure 1 presents a flow chart that may be used for the diagnosis and treatment of patients presenting with symptoms of constipation. Key decision points include whether the patient is receiving therapy with drugs that cause constipation, and if so, whether the patient is receiving opioid therapy, and if the patient’s symptoms fit the consensus definition of OIC.

Considerations in elderly patients

Similar to the trend in the general population, the use of opioids is also increasing in individuals ≥65 years of age.²⁹ Gerontological guidelines recommend the use of opioids after acetaminophen for pain management in elderly patients owing to the risks associated with traditional nonsteroidal anti-inflammatory drugs (eg, gastrointestinal toxicity, exacerbation of renal failure, cardiovascular effects).^30,31 OIC is also common in elderly patients receiving opioids,^13,32 and it may be exacerbated owing to patient immobility, dehydration, and use of concomitant medications.³³ It is reported that elderly individuals take an average of 7 medications.³⁴ The effects of these other medications as well as disease processes must be considered.^33,34 In general, extra caution is warranted when prescribing opioids to elderly patients, as they often have age-related physiologic changes that affect drug distribution and elimination as well as declines in renal and hepatic function that affect drug metabolism and excretion.^34,35 In addition, existing comorbidities may contribute to an increased incidence of opioid-related adverse events.³⁴

In addition, poor adherence to opioid therapy is common among elderly patients.^13,34 One study of elderly patients in a primary care practice who initiated opioid therapy for chronic noncancer pain documented that 33% of patients took their medication only when they had severe pain. They did this for a variety of reasons, including fear of making their constipation worse.¹³

Overview of options for the management of OIC

Options to treat constipation include dietary modifications, lifestyle measures, and behavioral changes.^21,26,28 Dietary measures for the treatment of constipation may include increased fluid and fiber intake, whereas lifestyle measures may include increased physical activity and biofeedback bowel training.^36-38 However, it is important to note that diminished cognitive function and the presence of comorbidities (eg, chewing/swallowing disorders, chronic pain, debilitating medical conditions) may limit effectiveness or preclude the use of nonpharmacologic interventions in some patients.^36,37,39 Laxatives, available both over the counter and by prescription, are often used but they do not block or counteract opioid actions at gastrointestinal opioid receptors and have limited efficacy in OIC.¹² Moreover, the use of bulk-forming laxatives may not be appropriate in patients with OIC owing to the reduction in peristalsis by opioids and the potential worsening of abdominal pain and bowel obstruction by the laxative-increased bulk.³⁷ In addition, because the effectiveness of bulk-forming laxatives depends on sufficient fluid intake, which may not be possible in some patients (eg, those in palliative care settings),⁴⁰ the efficacy of these agents may be limited. Moreover, the efficacy of osmotic laxatives may be limited by an increased risk for aspiration of polyethylene glycol-balanced electrolyte solution in patients with certain medical conditions (eg, Parkinson disease, supranuclear palsy), and the efficacy of stimulant laxatives may be limited in elderly patients by an increased risk for hypokalemia.³⁶ Therefore, even though treatment guidelines recommend diverse nonpharmacological interventions in patients with OIC, it is important that health care providers recognize the complex nature of this condition to achieve optimal patient management.

Targeted prescription therapies that block opioid receptors (peripherally acting μ-opioid receptor antagonists [PAMORAs]) have been approved recently.^18,19 These agents are restricted to the periphery as a result of their structure or structural modifications, so they act specifically at peripheral locations including the enteric opioid receptors.^17,25 At recommended doses, the central nervous penetration of PAMORAs is expected to be negligible, limiting their potential to interfere with centrally mediated opioid analgesia.^{17-19,25,41,42} Available PAMORAs indicated for the treatment of OIC include subcutaneous methylnaltrexone (Relistor) for patients with chronic noncancer pain and patients with advanced illness receiving palliative care when response to laxative therapy is insufficient,¹⁸ and oral naloxegol (Movantik) for patients with chronic noncancer pain.¹⁹ In addition, the oral chloride channel activator lubiprostone (Amitiza), which increases fluid transport into the intestine to counteract the opioid antisecretory effect, is approved for the treatment of OIC in patients with chronic noncancer pain.²⁰ These agents are discussed in more detail in the Issue #2 of this e-newsletter series.

Summary

Opioid-induced constipation is a common side effect of opioid therapy that has been under-recognized and undertreated. With the continued increase in opioid use in the United States, along with the growth of the elderly population, more patients will develop OIC, and family physicians will encounter more patients with OIC. OIC negatively affects patient QOL, daily activity, work productivity, and psychological well-being. If not treated effectively, OIC may result in patients attempting to balance their pain relief against their constipation, by self-adjusting their opioid dose. OIC results from opioid actions at enteric opioid receptors. Although commonly prescribed for OIC, laxatives do not target the pathophysiologic mechanism of OIC and have limited efficacy. Specific, effective treatments for OIC, consisting of a subcutaneously administered PAMORA, an oral PAMORA, and an oral chloride channel activator, have been developed and have received US Food and Drug Administration approval. After recognizing the signs and symptoms of OIC to facilitate diagnosis, family physicians can initiate effective treatments in appropriate patients.

References

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Table 1. Nonopioid classes of agents that may cause constipation^17,21,26

Figure 1. Suggested pathway for the diagnosis and treatment of OIC.