Opioid-Induced Constipation: A Recent American Gastroenterological Association Guideline Focuses Attention on an Often Neglected Adverse Event

OCTOBER 30, 2019
Joseph Pergolizzi, MD, Senior Partner, Naples Anesthesia and Pain Associates, Inc.
Joseph Pergolizzi, MD

Joseph Pergolizzi, MD

An estimated 20% of adults in the United States experience chronic pain.1 With approximately one-quarter of US adult patients with severe activity-limiting non-cancer pain receiving an opioid prescription,2 there is an understandable (and well-publicized) increase in concern about opioid misuse and overdosing. Perhaps overlooked with respect to patients with legitimate, compelling indications for aggressive pain management is the impact of opioid-related adverse events, such as opioid-induced constipation (OIC).

It is, therefore, encouraging that the American Gastroenterological Association (AGA) has recognized the need for dedicated attention to the management of OIC and has released a guideline on its medical management.3 Opioid-induced constipation is estimated to occur in 40%–85% of patients taking opioids,4-6 and may be associated with impairment of health-related quality of life.7 In its most refractory manifestation, OIC may require invasive therapy such as manual disimpaction.8 Prompt diagnosis and intervention are thus essential.

The AGA guideline and the associated Clinical Decision Tool9,10 are not specifically directed toward an audience of pain-management specialists and are applicable across specialties. Moreover, the guideline considers OIC as a distinct entity specific to pain management that resembles constipation due to other causes in terms of symptoms3 but differs from it mechanistically.

Opioid-Induced Constipation Is a Distinct Entity Requiring Specific Treatment
Like other forms of constipation, the presence of OIC is characterized by symptoms of straining during defecation, lumpy or hard stools, a sensation of incomplete evacuation or anorectal obstruction, use of manual maneuvers to facilitate defecation, and having <3 stools weekly.11

However, OIC is a secondary constipation that arises only during opioid therapy, due to an opioid-specific mechanism, and may persist for the duration of opioid therapy.12 Opioids activate μ-opioid receptors throughout the body. In the central nervous system (CNS), activation of μ-opioid receptors is a primary mediator of opioid-induced analgesia,13,14 but in the gastrointestinal (GI) tract, this activation in the myenteric and submucosal plexuses and the ileal mucosa can decrease GI motility, increase fluid absorption from the stool, decrease GI secretion, and increase anal sphincter tone.13,14

Discussion of OIC as a distinct entity is an important undertaking because it introduces clinicians across a broad range of disciplines to the idea that standard therapies for constipation may help alleviate some symptoms of OIC, but do not address its underlying mechanisms.

Opioid-Specific Considerations
The AGA guideline suggests that for patients with confirmed OIC, it may be appropriate to consider an opioid dose reduction or rotation to a substitute opioid that is considered less constipating, such as a transdermal opioid (eg, fentanyl). Opioid-induced constipation can, however, occur even at low doses of opioids and may persist for the duration of opioid use,12,15,16 making it difficult to predict whether a switch or dose adjustment will alleviate OIC. Despite their inclusion, recommendations with respect to adjusting opioid therapy remain a secondary focus of the guideline. The primary focus of the guideline is a discussion of appropriate pharmacotherapy.

AGA-Recommended Treatments for Opioid-Induced Constipation – Laxatives
The AGA guideline gives a strong recommendation to conventional laxatives as first-line therapy for OIC.3 These agents work by drawing water into the intestine or water and lipids into the stool, lubricating the intestine to facilitate transit, or acting as a mild irritant to stimulate motility and prevent colonic water absorption.3 They do not target the underlying mechanism of OIC. The AGA recommendation is based primarily on clinical trial data showing that osmotic and stimulant laxatives improve the frequency of defecation and stool consistency compared with no treatment. The recommendation also considers the low cost and proven safety of laxatives.3

The AGA guideline recommends that the laxative treatment should include a combination of at least two different types of laxatives and that they be taken in a scheduled dosing regimen (not PRN)3 before determining if alternative treatment is needed. The AGA deems this to be an adequate trial of laxatives. If there is incomplete relief of OIC symptoms after this laxative therapy regimen, then the AGA guideline recommends use of other pharmacologic therapy.3 To effectively evaluate the response to laxative therapy, close communication and interaction between the clinician and patient is required. 

AGA-Recommended Treatments for Opioid-Induced Constipation – PAMORAs
If the patient is considered to have an inadequate response following an acceptable trial of conventional laxatives, the AGA then recommends utilization of a class of drugs that addresses the underlying mechanism of OIC. The guideline suggests escalation of pharmacotherapy to a peripherally acting μ-opioid receptor antagonist (PAMORA) drug.3 PAMORAs inhibit opioid-mediated μ-receptor agonism in the GI tract but have negligible CNS penetration, at the recommended dosage.3 Selectivity for peripheral μ-opioid receptors and negligible penetration across the blood-brain barrier mean that PAMORAs reduce the constipating effects of opioids while limiting the potential for interference with centrally mediated pain relief.

Communication Between Doctors and Patients is Key
Throughout the AGA guideline, the authors highlight important areas where communication between healthcare providers and patients is paramount. As in pain-management guidelines, the AGA guideline encourages providers to ensure that any opioid-treated patient has a legitimate indication for an opioid and is receiving the lowest possible dose. Every patient should have a clear understanding of the risks inherent with opioid therapy, including misuse and overdosing.3 In patients with confirmed or suspected OIC, providers should conduct a thorough medical history that includes a frank discussion of the patient’s diet, defecation patterns, and additional symptoms. Other causes of constipation should be considered and, if identified, be treated accordingly.3 It is also important that healthcare providers and patients have a clear discussion regarding the effectiveness of conventional laxatives to better inform the decision whether or not to consider alternative therapies.
While the importance of open provider–patient communication about opioid therapy generally and OIC specifically may seem obvious, research suggests that communication with respect to OIC is insufficient. In a 2016 study of 489 patients with OIC about two-thirds of patients who had visited their provider in the previous month (n=405) had discussed or been asked by the provider about OIC.17 The proportion of agreement between patients and providers about whether OIC was present was 61%.17 In contrast the average pain ratings of patients and providers were nearly identical suggesting there may be a higher level of provider–patient communication about pain than OIC.17

With the continuing therapeutic use of opioids guided by comprehensive opioid risk management plans, particularly in patients with chronic non-cancer pain,2 an increasingly diverse patient population may experience OIC and report it, not only to their gastroenterologist or pain specialist, but also to their primary care providers, internists, PAs, and NPs. All healthcare providers should have literacy in the management of opioid treatment and the adverse events that patients may experience. The new AGA guideline is an important step in disseminating vital information beyond the gastroenterologists’ and pain specialists’ offices and into general practice. The AGA’s recommendation of pharmacotherapeutic intervention for the medical management of OIC requires close and thorough communication between the clinician and patient to evaluate the effectiveness of the therapies.

For a summary of the AGA guideline and more information about a treatment option for OIC, click here.

For the full AGA guideline, click here.

Dr Joseph Pergolizzi, MD is an internationally renowned perioperative and pain specialist, well-versed in the multiplicity of issues confronting patients and caregivers in acute and chronic pain. He is currently a senior partner at Naples Anesthesia and Pain Associates, Inc. In clinical practice, he combines the latest medical advances and scientific breakthroughs with his profound professional compassion for patients facing painful, life-altering conditions. As a physician, inventor, research scientist and advocate for patients with pain, Dr Pergolizzi has leveraged his significant medical, regulatory and business expertise to build a strong track record of success within the healthcare industry.

Previously, Dr Pergolizzi served as Assistant Professor (adjunct) in the Department of Medicine at Johns Hopkins University School of Medicine, a committee member of the Food and Drug Administration’s Safe Use Initiative and as a Special Government Employee for the Veterans Health Administration. He is a member of various advisory boards and medical societies, as well as institutional committees, including Medical Errors Committee and Pharmacy and Therapeutics Committee. Dr Pergolizzi is the author of over 250 peer reviewed articles, abstracts, platform presentations and book chapters, and has been awarded the American Medical Association Physician Recognition Award with Commendation.

Sponsored by AstraZeneca and Daiichi Sankyo.

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