Treatment of Opioid-Induced Constipation

Authors: Neel Mehta, Adam P. Laitman, Rowe B. Brookfield, Lucinda A. Harris

Abstract

Patients receiving opioid analgesics may experience constipation [ie, opioid-induced constipation (OIC)], require treatment to induce laxation, and may be at risk for gastrointestinal perforation, an uncommon but potentially life-threatening condition. Management of OIC includes treatment with over-the-counter laxatives and peripherally acting μ-opioid receptor antagonists (PAMORAs; methylnaltrexone, naloxegol, naldemedine). In patients receiving treatment for OIC, gastrointestinal perforation may result from the laxation process, causing disruption of the gastrointestinal lining that may already have compromised integrity. A PubMed literature review and a search of the US Food and Drug Administration Adverse Event Reporting System database identified several cases of gastrointestinal perforation (life-threatening or with mortality) across the range of agents administered for the treatment of OIC or other constipation types. Methylnaltrexone in the subcutaneous form was the first PAMORA approved for OIC. Its real-world use in the ∼6 years before the availability of another OIC-indicated PAMORA helped establish the adverse-event profile of the class, and experience has been gained in identifying and treating appropriate patient populations. Class labeling of PAMORAs includes a contraindication in patients with known or suspected gastrointestinal obstruction or increased risk of recurrent obstruction. Appropriate patient selection during laxation therapy for OIC, regardless of treatment plan, involves consideration of the overall risk versus benefit in patients at increased risk of perforation due to comorbid medical conditions, concurrent medications, or recent gastrointestinal procedures. After initiating treatment for OIC, clinicians should assess the effectiveness of laxation therapy and carefully monitor for signs of gastrointestinal perforation.

Gastrointestinal (GI) perforation is an uncommon but potentially life-threatening condition in which there is a loss of integrity in the GI lining and leakage of intraluminal contents into the otherwise sterile peritoneal cavity.^1^ A variety of situations may cause GI perforation, including bowel obstruction, infection, inflammation, malignancy, and trauma.^1^ In cases of bowel obstruction, distention of the GI lining results in decreased perfusion (ie, ischemia), leading to full-thickness necrosis (eg, pressure necrosis from fecal mass) and ensuing perforation of the lining.^2^ Medical conditions such as inflammatory bowel disease, malignancy, and peptic ulcer disease may cause erosive penetration through the GI lining.^2^ Mechanical penetration through the GI lining may result from external injury (ie, penetrating or blunt trauma), ingestion of a harmful object (eg, a sharp, pointed, and/or jagged foreign body), or medical instrumentation (eg, injury due to endoscope or cleansing enema device tip).^1–3^

Certain medications may increase the risk of GI perforation. Antivascular endothelial growth factor (anti-VEGF) therapies used to treat cancer (eg, bevacizumab, erlotinib, ramucirumab, sorafenib) have been associated with cases of GI perforation in patients with cancer.^4–9^ An increased risk of GI perforation has also been reported among patients with rheumatoid arthritis receiving biological disease-modifying antirheumatic drugs, with perforation occurring most frequently in the lower GI tract and the greatest risk reported with tocilizumab and tofacitinib, after controlling for potential confounding factors.^10–12^ Nonsteroidal anti-inflammatory drugs and systemic corticosteroids have been associated with increases in GI perforation risk among patients with rheumatoid arthritis^12,13^ and other conditions.^13–15^

In addition, intestinal perforation, including stercoral perforation, can occur in the setting of opioid-induced constipation (OIC), a common complication of opioid analgesics administered for the management of pain.^16–18^ Acute or chronic opioid exposure can alter the gut microbiota and/or GI barrier function, which can promote intestinal inflammation, infection risk, and GI permeability.^19–22^ In addition, OIC can be, but is not necessarily, chronic in all patients. Chronic constipation has been linked to cases of stercoral perforation, including spontaneous colonic perforation (ie, in the absence of disease, such as diverticulosis, malignancy, or injury).^22–25^ In these cases, fecal mass retention due to chronic constipation can result in GI lining ischemia, inflammation, and necrosis, which, in some cases, leads to colonic rupture (feculent perforation).^23^

Furthermore, GI perforation may be caused by asymmetric pressure within the colonic lumen, inducing hyperdilation of the GI lining and leading to idiopathic colonic perforation.^23^ Laxation-induced peristalsis among patients with OIC who likely already have compromised integrity of the GI lining has been associated with events of GI perforation.^26–28^ Therefore, there is a risk of GI perforation in patients who receive opioid administration for pain management, experience constipation-related adverse effects, and require treatment to induce laxation. Although a rare event, this narrative review discusses the role of laxation in GI perforation in patients with impaired integrity of the GI lining, identifies real-world data on perforation rates for medications that promote laxation, and highlights potential counseling points and strategies to reduce the risk of GI perforation in patients receiving treatment for OIC.

METHODS

A PubMed search of all available English-language articles through July 16, 2024, was conducted using the following search (“guideline” or “recommendation”); “intestinal perforation,” “methylnaltrexone,” “naloxegol,” “naldemedine,” “opioid-induced constipation,” “pathophysiology,” “prevalence,” “PAMORA,” “perforation,” “peripherally acting μ-opioid receptor antagonist,” “obstruction,” and “risk factors.” The US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database, which contains information on adverse event and medication error reports submitted to the FDA, was searched, with reports available through June 30, 2024. Data were gathered on all reports of perforation (predefined reaction diverticular perforation, gastric perforation, gastrointestinal perforation, intestinal perforation, large intestine perforation, ileal perforation, esophageal perforation, small intestinal perforation) associated with methylnaltrexone, naloxegol, naldemedine, lubiprostone, prucalopride, linaclotide, plecanatide, bisacodyl, and senna. Both generic and brand names were searched, and outcomes of life-threatening events or mortality were tabulated.

OPIOID-INDUCED CONSTIPATION

Data on the exact prevalence of OIC are lacking, and estimates vary widely depending on population (eg, cancer-related vs. noncancer-related pain, opioid-treated patients vs. the general population), definition employed, assessment methods/scales, opioids used, and trial study design.^29–34^ A study conducted in the United States and other countries estimated a prevalence of OIC among the general population of 2% to 3%.^35^ The prevalence of OIC among opioid-treated patients in the clinical setting is substantially higher, with estimates ranging from 51% to 87% for patients with cancer receiving opioids and 41% to 57% for patients receiving opioids for treatment of chronic noncancer pain.^16^

Various mechanisms contribute to the pathophysiology of OIC. The main opioid receptors (ie, μ, δ, and κ) are distributed throughout the GI tract, and μ-opioid receptors, predominantly expressed in the small intestine and proximal colon, are a key mediator of the analgesic action of endogenous and exogenous opioids.^36–38^ Activation of opioid receptors within the GI tract regulates a variety of functions, including motility and secretion.^36,38^ Opioid binding and activation of μ-opioid receptors in the GI tract lead to suppression of motility, increased colonic fluid absorption, stool hardening, and constipation.^16,37^ In addition, stimulation of opioid receptors can increase contraction of the internal anal sphincter, resulting in straining, hemorrhoids, and a sense of incomplete evacuation, which is also related to an opioid-induced increase in the threshold rectal volume required for minimal sensory perception.^16,37,39^ In severe cases, these adverse effects can result in colonic perforation.^16,18^

Over-the-counter (OTC) laxatives (eg, bisacodyl, senna) are generally recommended as first-line therapy for management of OIC in patients with or without cancer.^37,40^ Peripherally acting μ-opioid receptor antagonists (PAMORAs) are recommended for patients with or without cancer with OIC who have an inadequate response to laxative therapy.^37,40^ The subcutaneous formulation of the PAMORA methylnaltrexone is indicated for the treatment of OIC in adults with advanced illness or cancer pain who require opioid dosage escalation for palliative care.^41^ In addition, the oral PAMORAs (methylnaltrexone, naloxegol, naldemedine) and lubiprostone, a chloride channel activator, are indicated in the United States for the treatment of OIC in adults with chronic noncancer pain, including those with chronic pain related to prior cancer or its treatment who do not require frequent increases in their opioid dosage.^41–44^ Although off-label use of oral prucalopride for OIC has been considered, the American Gastroenterological Association makes no recommendations for the use of this agent due to insufficient evidence supporting efficacy.^37^ Linaclotide and plecanatide have also been considered but are not indicated for OIC.^34,45^

GASTROINTESTINAL PERFORATION DURING TREATMENT OF OIC

Cases of GI perforation have been reported across the spectrum of laxation agents used for the treatment of OIC. All agents of the PAMORA class indicated for the treatment of OIC (methylnaltrexone, naldemedine, and naloxegol) have a class warning and precaution statement in the US prescribing information about the risk of GI perforation.^41–43^ Prescribers are advised to consider the overall risk-benefit profile in patients with known or suspected lesions of the GI tract, monitor patients for severe, persistent, or worsening abdominal pain, and discontinue treatment if patients develop these symptoms.^41–43^ Although the exact mechanism is unknown, GI perforation after initiation of OIC treatment may result from the laxation (bowel movement) process causing disruption of the GI lining, which already has compromised integrity related to other pathologic processes.^27^

GI perforation associated with PAMORA administration for OIC is uncommon, but postmarketing cases have been reported for all agents in the class.^27,46–48^ Subcutaneous methylnaltrexone was the first PAMORA approved in the United States for OIC in adults (2008), and thus the GI perforation risk profile of the PAMORA class was best understood in relation to experience with this agent. Oral formulations of naloxegol, methylnaltrexone, and naldemedine were approved in 2014, 2016, and 2017, respectively. Lubiprostone, first marketed in 2006, was approved for the treatment of OIC in the United States in 2013.^44^

Previously published searches of the FAERS database identified 13 postmarketing cases of GI perforation associated with methylnaltrexone in patients with risk factors (eg, anatomic or pathologic abnormalities of the GI system, anti-VEGF use),^27,47^ and 4 cases of perforation associated with naloxegol use.^47^ In addition, a single-center retrospective review of 333 children and adults with peritoneal carcinomatosis receiving subcutaneous methylnaltrexone identified 1 patient with a GI perforation.^46^ For lubiprostone, a search of the FAERS database identified 2 reports of GI perforation.^47^ No studies published to date have directly compared rates of GI perforation between subcutaneous and oral PAMORAs.

A search of the FAERS database conducted by the authors confirmed reports of GI perforation (life-threatening or fatal) across a range of agents administered for the treatment of OIC or other forms of constipation (Fig. 1). The time frame of cases observed differed and depended on drug methylnaltrexone, 2008 to 2024; naloxegol, 2014 to 2024; and naldemedine, 2017 to 2024. Given that methylnaltrexone was the first PAMORA approved for OIC, its real-world use in the ∼6 years before the availability of another OIC-indicated PAMORA helped to establish the adverse event profile of the class. Health care providers learned, through methylnaltrexone use, about this new drug class for the treatment of OIC and gained experience in identifying and treating appropriate patient populations. During this ∼6-year window, subcutaneous methylnaltrexone was (and continues to be) indicated in the United States for the treatment of OIC in patients with advanced illness or cancer-related pain and noncancer pain,^41^ unlike other agents for OIC in the PAMORA class, which do not have an advanced illness indication and are, therefore, restricted to patients with chronic noncancer pain.^42,43^ In registration trials of subcutaneous methylnaltrexone for treatment of OIC in adults with advanced illness, 58%-85% of patients included in the studies had a primary cancer diagnosis.^49–51^ Therefore, the underlying advanced illness and the chronic use of opioids may have increased the risk of GI perforation in patients receiving methylnaltrexone to induce a bowel movement. Further, considering the association between certain cancer therapies and risk of GI perforation, these treatments may have contributed to postmarketing cases of GI perforations for this indication.^4–9^ The availability of oral PAMORA agents starting in 2014 for OIC in patients with chronic noncancer pain also likely shifted the use of subcutaneous methylnaltrexone to a population with a potentially higher risk of GI perforation in the setting of advanced illness and/or cancer-related pain. Since approval of naloxegol, oral methylnaltrexone, and naldemedine, the annual incidence of deaths or life-threatening events of GI perforation reported in FAERS has been relatively similar among the 3 PAMORA products.

Non-PAMORA agents have also been associated with cases of GI perforation. Lubiprostone was associated with 1 death and 2 life-threatening events related to GI perforation (time frame of cases, 2006 to 2022). Among OTC laxatives, bisacodyl tablets were associated with 1 report of death due to GI perforation in a patient with colon cancer (time frame of cases, 1989 to 2023), and 4 deaths due to GI perforation were reported in association with senna use (1998 to 2023). Of note, cases of GI perforation also have been reported for laxation products approved to treat other forms of constipation. For example, a case of GI perforation (diverticular) was reported with linaclotide treatment in a pooled analysis of clinical trials for irritable bowel syndrome with constipation and chronic idiopathic constipation,^52^ and 8 deaths and 2 life-threatening events of GI perforation (time frame of cases, 2013 to 2023) were identified in the FAERS database for linaclotide for the treatment of constipation.

CLINICAL CONSIDERATIONS IN OIC

Clinicians should obtain a detailed medical history from patients with suspected OIC to assess comorbid illnesses and regular medication use before starting treatment.^37^ Tools such as the Bristol Stool Form Scale^53^ and the Bowel Function Index^54^ can be used to help identify patients with OIC and monitor response to treatment.^34,37,40,55^ Ideally, symptoms of constipation should be assessed before starting opioid therapy to obtain a “baseline” and facilitate detection of OIC. Given that chronic opioid use can increase the risk of GI perforation,^15^ it is important to screen patients at increased risk, particularly those with diagnosed or suspected comorbid conditions that also may impair the structural integrity of the GI lining (Table 1). These medical conditions can increase the risk of GI perforation and although rare, the risk of GI perforation may increase due to the process of laxation in susceptible patients. This screening stage is an opportunity for counseling patients taking opioid analgesics who also have been prescribed laxative agents.

Over-the-counter laxatives are recommended as first-line therapy for OIC, followed by PAMORA monotherapy if patients show an inadequate response to first-line treatment.^34,37,40^ Due to the potential for GI perforation, PAMORAs are contraindicated in patients with known or suspected GI obstruction, and in patients at increased risk of recurrent obstruction.^41–43^ The effectiveness of any laxation therapy should be assessed as soon as possible, ideally within the first week after the start of OIC treatment. If PAMORA monotherapy does not appear to be effective, consideration of treatment with intestinal secretagogues also has been recommended,^34^ and other causative factors for constipation in the patient should be investigated. In addition, non-PAMORA agents, such as lubiprostone, are contraindicated in patients with known or suspected mechanical GI obstruction.^44^

Patients with GI obstruction may present with abdominal pain, nausea, and/or vomiting.^56,57^ Other hallmarks include abdominal distension and cessation of flatus and bowel movements.^56^ Though mild, vague symptoms, such as bloating and abdominal discomfort, may occur in patients with constipation, they can also point towards early obstruction.^56^ Evaluation of the patient with suspected obstruction includes patient history, physical examination (eg, evaluating for abdominal tenderness or rigidity), laboratory testing, and radiography (starting with an abdominal plain X-ray),^56,57^ with identified patients undergoing surgical consultation.^2^ Detailed assessment of intestinal obstruction is outside the scope of this review and has been described elsewhere.^56,57^

In patients receiving treatment for OIC, early recognition and prompt management of GI perforation are crucial to prevent morbidity and potential mortality.^2^ Patients should be counseled about clinical symptoms suggestive of GI perforation, such as the development of severe, persistent, or worsening abdominal pain. Further, OIC treatment should be discontinued, and it is recommended that the patient seek urgent care.^41–43^ As described above, perforation events are rare in patients with OIC and/or laxative use. However, there is an educational need to further understand the risk factors. Patients with OIC generally have more comorbidities than traditional patients with chronic idiopathic constipation. The presence of OIC and the use of any form of laxative can increase the risk for GI perforation, including in patients without preexisting constipation at the start of opioid analgesia. The clinical considerations discussed herein should be regarded as an opportunity for discussion and counseling for patients using opioid analgesics with or without concomitant OIC treatment.

CONCLUSIONS

Patients with OIC who require treatment to induce laxation are at risk for GI perforation. Although several cases of GI perforation were reported within the initial few years after the availability of subcutaneous methylnaltrexone, the first PAMORA to be approved for the treatment of OIC, limited cases of life-threatening or fatal events of GI perforation have been reported subsequently for oral and subcutaneous PAMORAs, with similar rates observed across those administered in the treatment of OIC. This decrease is likely related to improvements in patient selection and in risk-management strategies. However, appropriate selection of patients is critical to reduce the risk of GI perforation during laxation therapy for OIC. In patients considered at risk of GI obstruction or perforation due to comorbid medical conditions, concurrent medication use, and/or recent GI procedures, avoidance of pharmacologic laxation therapy may be merited. After initiating treatment for OIC, clinicians should assess the effectiveness of therapy across all laxation-inducing agents and carefully monitor patients for signs of GI perforation to optimize patient outcomes and limit treatment-related morbidity.