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PAINSCAN LITERATURE REVIEW
Issue 1, Volume 6
Opioid-Induced Constipation: Treatment Modalities
5 Articles in this Series
Introduction
Opioid Induced Constipation: A Book/Primer
A Review of Health-related Quality of Life, Patient Burden, Practical Clinical Considerations, and the Impact of Peripherally Acting μ-Opioid Receptor Antagonists
Systematic review with meta-analysis: efficacy and safety of treatments for opioid-induced constipation
Peripheral Opioid Receptor Antagonists for Opioid-Induced Constipation: A Primer on Pharmacokinetic Variabilities with a Focus on Drug Interactions
The Use of Peripheral μ-Opioid Receptor Antagonists (PAMORA) in the Management of Opioid-Induced Constipation: An Update on Their Efficacy and Safety

Opioid Induced Constipation: A Book/Primer

StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing
2020;Book/Primer:

Introduction

Opioid-induced constipation (OIC) accounts from over 40% to 60% in patients without cancer receiving opioids. Laxatives must be started at the same time as the opioid to prevent OIC. Once the disorder is established, treatment involves both pharmacological and nonpharmacological therapies. OIC may present immediately when a patient takes the opioid, or it may present gradually during opioid therapy. In association with constipation, patients may also develop other GI side effects like nausea, vomiting, bloat, abdominal pain, and straining. Many patients who develop constipation following opioids stop the drug therapy because they simply cannot tolerate the adverse effects on the GI tract. Once constipation to opioids has developed, the relief with treatment is slow and does not always result in optimal relief from constipation.

See commentary below

Commentary

Jeremiah Jeffers, MD
Dalton Fazekas, MD
This document’s goal is to provide a summary of what opioid-induced constipation (OIC) is in the form of a review. The primer-style publication provides a good basis for understanding and especially treating OIC. It is broken down into distinct categories to provide a framework to approach and understand OIC, and as with any publication, has its strengths and weaknesses. A summary follows.

The document starts off with a brief overview of OIC noting its common prevalence – 40 to 60% of non-cancer patients on chronic opioids, although some studies have found higher rates.1 The authors advocate for the use of pharmacologic and non-pharmacologic treatments to mitigate the effects of OIC, and concomitant prescription of laxatives when prescribing opioids. They also describe some of the mechanisms behind OIC, specifically highlighting inhibition of gastric emptying, peristalsis, pancreatic and biliary function, and the resultant delayed transport, digestion, and increased water absorption. Moreover, they note the increased sphincter tone resulting in impaired defecation reflex.

The pathophysiology of opioid activity on mu, delta, and kappa receptors is discussed in further detail. The authors state that opioid association with G-protein coupled receptors in the GI tract leads to increased production of adenylate cyclase and inhibition of calcium channels, and thereby decreased release of neurotransmitters. Although long-term use of opioids may lead to upregulation of adenylate cyclase, the effect of opioids is actually to inhibit adenylate cyclase, with resultant decrease in cyclic AMP. The authors claim that tolerance to opioids effects on the GI tract develops over time, although the sources cited do not back this.2-5

Typical features found by history and physical are discussed, as well as using the Rome IV criteria, and the Bristol Stool Scale in evaluating patients for OIC. Moreover, when evaluating patients for OIC, providers are encouraged to be observant for alarm symptoms of underlying GI malignancy which could be confused for OIC.

Treatment is discussed detail. Mitigation steps such as increasing fiber and fluid intake as well as physical exercise are routine recommendations for those prescribed opioids, and, as noted, physicians are encouraged to co-prescribe laxatives (except for bulk-forming agents) with opioids.

For those with refractory OIC, the authors note that methylnaltrexone bromide, a peripherally acting mu-opioid-receptor antagonist (PAMORA), has been found to be a superior agent as it allows patients to continue taking opioids without the risk of inducing withdrawals. Despite the positive effects of methylnaltrexone, it should not be used in those with peptic ulcer disease, diverticulosis, colon cancer, or obstruction. Other alternatives to traditional laxatives such as lubiprostone (a type-2 chloride channel agonist), naloxegol, naldemedine, and alvimopan (PAMORAs) may be considered as well. However, alvimopan specifically has only been approved for postoperative ileus at the time of this writing (January 2021).

The document emphasizes the importance of patient education regarding OIC, including increased fiber/fluid intake, exercise and taking minimal opioids while also taking laxatives. Specific education about what types of foods are high in fiber should be included when educating patients. The authors conclude their discussion by highlighting the importance of an interprofessional team of healthcare providers – all of whom play a key role in both monitoring and treating OIC and in providing patient education. They also advocate for using non-opioids as drugs of choice to manage pain in order to prevent OIC in the first place.

The document serves as a salient review of OIC. It is particularly geared toward identification and treatment and lacks some detail regarding pathophysiology and etiology. Below, some strengths and weaknesses are listed:

The claim that laxatives must be started at the same time as opioids in order to prevent OIC, while recommended, has not necessarily proven to be successful. Even when clinicians do co-prescribe laxatives, the results can be suboptimal: in one study. of concomitant laxative prescriptions, 54% of patients did not achieve the desired symptom relief 50% of the time.6,7

While the section on etiology provides a basic framework for understanding some of the mechanisms of OIC, it appears to be a vast oversimplification and fails to mention many of the associated mechanisms linked to OIC. Involved mechanisms which are not highlighted by the authors include but are not limited to: opioid effects on interstitial cells of cajal (ICC), activation of potassium channels and the subsequent hyperpolarization, increased sphincter tone of the biliary system, decreased small and large bowel propulsion, increased amplitude of non-propulsive contractions, decreased production of vasoactive intestinal peptide (VIP) and nitrous oxide (NO) as a result of mu-opioid receptor activation in descending neurons (which inhibits relations of forward adjacent segments during peristalsis), and the centrally mediated effects on autonomic output contributing to antitransit effects.8,9

In discussing the intracellular effects of opioid receptor agonism, there again is an oversimplification of the process. The document makes no mention of the effects on potassium channels and subsequent hyperpolarization of cell membranes. The article also fails to describe how inhibition of adenylate cyclase results in decreased cAMP. Instead, the article seems to insinuate that opioid agonism leads to increased adenylate cyclase, which inhibits neurotransmitter release.

The claim regarding tolerance of OIC/OBS developing over time is incorrect. In fact, the cited sources actually refute this and make a point to discuss how there seems to be no developed tolerance to OIC/OBS.4,10-12

The portion of the document discussing treatment is an especially strong attribute of this article. The authors go into detail and provide a comprehensive discussion of the options available for the management of OIC.

The authors also do an excellent job of emphasizing the importance of patient education and lifestyle/dietary changes which can improve or reduce the occurrence of OIC (such as exercise, increased fiber/fluid intake, limiting opioids to when absolutely necessary and taking concomitant laxatives).

Overall, this primer-style document provides clinicians with a solid background on when and how to prescribe opioids with an eye toward preventing opioid-induced constipation, with tools to monitor and treat OIC symptoms when they do present.

Next Article:
A Review of Health-related Quality of Life, Patient Burden, Practical Clinical Considerations, and the Impact of Peripherally Acting μ-Opioid Receptor Antagonists
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