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Management of opioid-induced constipation.

SUMMARY

What's known

* Opioid-induced constipation is common and impairs function and quality of life.

* Preventive treatment is generally recommended.

* Although recommended in practice guidelines, the use of fiber, water, and laxatives has limited support from published clinical trials.

What's new

* All causes for constipation, including opioid analgesic use, should be investigated.

* The peripherally acting [mu]-opioid receptor antagonists methylnaltrexone and naloxegol and the locally acting chloride channel activator lubiprostone have been shown to be effective for many--but not all--patients with acceptable safety, and are FDA-approved for opioid-induced constipation.

INTRODUCTION

Opioid analgesics are commonly used to treat people with a wide variety of pain disorders, including severe acute pain and moderate to severe cancer and noncancer pain. (1) In 2012, 259 million prescriptions were written for opioids in the United States. (2) While opioids can provide effective pain relief for some patients, their use is not without limitations. Constipation is the most common adverse event, affecting an average of 41% of patients taking an oral opioid for up to 8 weeks. (3) Part of a broader constellation of symptoms called opioid-induced bowel dysfunction, opioid-induced constipation (OIC) is "a change when initiating opioid therapy from baseline bowel habits that is characterized by any of the following: reduced bowel movement frequency, development or worsening of straining to pass bowel movements, a sense of incomplete rectal evacuation, or harder stool consistency." (4) OIC can result in hemorrhoid formation, rectal pain and burning, bowel obstruction, bowel rupture, gastroesophageal reflux disease, and death. (5) Moreover, OIC causes significant patient distress, limits work productivity, and diminishes overall health-related quality of life. As a consequence, patients may reduce the dose of or stop taking the opioid. (4,6-8) One study reported that almost half of patients reported moderate to complete interference with pain management resulting from their constipation. (7)

The objectives of this article are to describe the clinical presentation of OIC, means to differentiate OIC from other causes of constipation, and evidence-based options for the treatment of OIC.

OPIOIDS AND THE GASTROINTESTINAL TRACT

The gastrointestinal (GI) effects of opioids arise from direct actions on the GI tract, and to a lesser degree indirect actions through the central nervous system, possibly by altering autonomic outflow. (5) The actions of opioids on the GI tract are mediated primarily via p receptors; centrally, opioids agonize 4 receptor subtypes: [mu], [delta], [kappa], and opioid receptor-like-1. (5)

The enteric nervous system within the gut has a dense concentration of neurons, which supply all layers of the alimentary canal and influence nearly every aspect of the digestive process. (9) Through interactions with enteric p-opioid receptors, p-opioid medications cause constipation by inhibiting enteric neuron function. (10) Specific effects include delaying gastric emptying, reducing bowel tone and contractility, and prolonging GI transit time. Opioids enhance fluid absorption by producing more frequent and stronger contractions of the circular muscles, while reducing longitudinal muscle propulsive contractions, leading to harder, drier stools. Difficulty in rectal evacuation stems from the ability of opioids to increase anal sphincter pressure and decrease reflex relaxation in response to rectal distention. (5,9-11) Although these effects of opioids may be useful for treating diarrhea, they often lead to constipation in the absence of diarrhea. OIC also can interfere with digestion and drug absorption. (9)

CLINICAL EVALUATION

Constipation may be due to one or more etiologies. Nonopioid causes of constipation may have existed prior to initiation of opioid therapy, but may not have been reported by the patient. Thus, investigating the cause should extend beyond the existing symptoms and common consequences of OIC to include other etiologies, such as irritable bowel syndrome, slow transit, or an evacuation disorder, or secondary causes, such as medications, neuropathic or myopathic disorders, and endocrinopathies. (12,13)

A complete medical history is essential to investigate nonopioid causes of constipation. In addition to medication (both prescription and nonprescription) use, the patient should be questioned about dietary and lifestyle habits. The history should also establish when symptoms of constipation first emerged and their timing relative to opioid initiation. (12) The Bristol Stool Form Scale is useful to categorize stool based on appearance. (14) Of the 7 types of stools, types 1 and 2 indicate constipation; 3 and 4 are ideal; and 5, 6, and 7 indicate diarrhea.

A physical examination that includes a digital rectal examination to assess relaxation of the anal sphincter and pelvic floor on straining should be performed as part of the assessment of pelvic floor dysfunction. Symptoms of pelvic floor dysfunction include excessive straining, prolonged time to defecate, need for digital evacuation, and persistent symptoms despite loose stools with laxatives. In addition to pelvic floor dysfunction, other situations in which further testing is warranted include unexplained weight loss, rectal bleeding, colorectal cancer, or constipation refractory to conventional treatment. Laboratory testing is useful to exclude metabolic disorders. (13)

MANAGEMENT

Several factors should be kept in mind when managing patients with OIC. First, tolerance to the constipating effects of opioids generally does not occur; thus, OIC may last as long as opioid therapy is continued. (5,10) For this reason, coupled with the high prevalence of OIC in patients taking an opioid, strong consideration should be given to beginning preventive therapy at the time opioid therapy is initiated, particularly for older adults or others with additional reasons for developing constipation. (1,3,15) Another factor to keep in mind when initiating opioid therapy is that constipation may occur at opioid doses lower than those required for analgesia. Thus, merely lowering the opioid dose may not be effective for managing OIC, while the analgesic benefit of the prescribed opioid may be lessened or lost. (13)

Patient preferences for symptom improvement should also be identified and treatment individualized. A survey of 513 patients with chronic pain who were experiencing OIC demonstrated 7 aspects of constipation that [greater than or equal to] 80% of patients would prefer to improve (TABLE). (8) Additionally, more than 70% of the patients surveyed indicated that it was very or extremely important that they have one additional bowel movement per week.

Initial management

The goal of initial management is to prevent OIC from the time opioid therapy is begun. A suggested algorithm developed by the authors is shown in the FIGURE. One approach is the empiric use of laxatives, fluids, and other options. (5) Another approach is to use an opioid associated with a lower rate of constipation. Among the opioids, transdermal fentanyl and tapentadol, a dual p-opioid receptor agonist and norepinephrine reuptake inhibitor approved for acute pain, have been shown to cause less impairment of bowel function. If the patient experiences constipation with one opioid, switching to another opioid may result in less severe constipation. This process of switching to another opioid, also called opioid rotation, is complicated by the need for utilizing equianalgesic doses and must take into account the possibility of tolerance to the current opioid.

Opioid selection

Some medical evidence suggests that specific opioids may be less constipating than others. (13,16) A randomized, open-label, 28-day crossover trial of 212 patients with noncancer pain showed significantly better pain relief with transdermal fentanyl than sustained-release oral morphine, while constipation occurred in fewer patients with fentanyl than with morphine (16% vs 22%). (17) Reduced bowel function, as confirmed by the bowel function questionnaire, was less common among users of transdermal fentanyl (29% fentanyl vs 48% morphine; P<.001). Similar results were observed in another randomized, open-label, 30-day crossover study involving 202 patients with cancer treated with transdermal fentanyl and sustained-release oral morphine. (18) Both provided similar pain relief, but significantly fewer patients treated with fentanyl experienced constipation (27.2% vs 44.5%, respectively; P<.001).

Several studies have demonstrated tapentadol to be less constipating than roughly equianalgesic doses of oxycodone immediate-release and sustained-release. (19-22) In patients with lower back pain or osteoarthritis, tapentadol consistently caused less impairment of bowel function than oxycodone, with scores for tapentadol similar to those for placebo over 90 days. (21) Compared with oxycodone, patients treated with tapentadol experienced significantly fewer days without a bowel movement, softer stools, less straining, less laxative use, and fewer abdominal, rectal, stool, and overall symptoms. (21)

Laxatives and lifestyle changes

A broad array of management options are available, yet only limited clinical trial data, particularly for OIC, support the use of conventional agents such as stool softeners, osmotic laxatives, and stimulant laxatives, as well as increased fluid and fiber intake and other lifestyle changes. (1,12,13,15,23) Nonetheless, current guidelines issued by pain specialists recommend initial treatment with bowel regimens that include these options, as they are perceived as often being effective. No specific recommendations are provided in the guidelines regarding the agents and doses to be used. (1,15)

Pharmacological therapy

An increasing number of opioid antagonists and other options are available for the treatment of OIC, generally supported by clinical trial evidence demonstrating their benefits and limitations for OIC.

One of the most widely used opioid antagonists, naloxone has been combined with the opioid agonists buprenorphine, oxycodone, and pentazocine to minimize the risk of abuse. The combination of naloxone and oxycodone has demonstrated beneficial effects on bowel function with no effect on analgesia. It was approved for severe pain in the United States in 2014, but is not yet commercially available. (24-27) Experience with buprenorphine/naloxone and pentazocine/naloxone for OIC is limited. None of the combination therapies are approved for OIC in the United States.

Peripherally acting p-opioid receptor antagonists

Medications that serve as competitive antagonists of peripheral [mu]-opioid receptors are an option for adjunctive therapy for OIC. These include methylnaltrexone, naloxegol, and alvimopan.

Methylnaltrexone

Methylnaltrexone was approved in 2008 by the US Food and Drug Administration (FDA) for the management of OIC in palliative care and has recently been approved for the treatment of OIC in adults with chronic noncancer pain. Laxation within 4 hours has been observed in 48% of patients with OIC in advanced illness after subcutaneous administration of a single dose of methylnaltrexone 0.15 mg/kg, compared with 15% for placebo. (28) Over the 2 weeks of treatment, rescue-free laxation within 24 hours of each of the 7 doses occurred in 55% to 66% of the methylnaltrexone group and 29% to 39% of the placebo group. Most adverse events involved the GI tract, with those occurring more commonly with methylnaltrexone (methylnaltrexone vs placebo): abdominal pain (17% vs 13%), flatulence (13% vs 7%), nausea (11% vs 7%), and diarrhea (6% vs 4%).

Similar benefits have been observed in patients with OIC and chronic noncancer pain. (29) Patients received methylnaltrexone 12 mg once daily or every other day (alternating with placebo) or placebo for 4 weeks. Within 4 hours of the first dose, 34.2% of patients in both methylnaltrexone groups had a rescue-free bowel movement compared with 9.9% of patients receiving placebo. Both methylnaltrexone groups had significantly shorter time to first rescue-free bowel movement and greater increase in number of weekly rescue-free bowel movements compared with placebo. Bristol Stool Form Scale scores and sensation of complete evacuation were significantly superior with methylnaltrexone once daily. Significantly greater improvement in patient-reported, constipation-specific quality of life was seen in both methylnaltrexone groups. Adverse events included abdominal pain, diarrhea, nausea, and hyperhidrosis.

Naloxegol

Naloxegol is a pegylated derivative of naloxone with increased oral bioavailability and peripheral selectivity, with negligible penetration of the blood-brain barrier. (30) Naloxegol was approved in 2014 by the US FDA for the treatment of OIC in adults with chronic noncancer pain. In 2 identically designed double-blind, parallel-group, phase 3 studies, outpatients with OIC who had been taking an oral opioid for noncancer pain at a stable daily dose of 30 to 1000 mg of morphine-equivalents for 4 weeks or longer were randomized to naloxegol 12.5 or 25 mg or placebo once daily for 12 weeks. (30) The primary endpoint was the 12-week response rate, ie, [greater than or equal to] 3 spontaneous bowel movements per week and an increase from baseline of [greater than or equal to] 1 spontaneous bowel movements for [greater than or equal to] 9 of 12 weeks and for [greater than or equal to] 3 of the final 4 weeks.

A significantly higher response rate compared with placebo was observed with naloxegol 25 mg in both studies and with naloxegol 12.5 mg in one study. (30) Other benefits observed with naloxegol compared with placebo included a reduction in the time to the first spontaneous bowel movement, increase in the mean number of days per week with one or more spontaneous bowel movements, and increase in the mean number of spontaneous bowel movements per week. Greater improvements in straining, stool consistency, and frequency of days with complete spontaneous bowel movements also were observed at the 25-mg dose in both studies and at the 12.5-mg dose in one of the 2 studies.

In both studies combined, an adverse event was observed in 54.6% and 65.2% of the padents receiving naloxegol 12.5 and 25 mg, respectively, and 53.2% of patients receiving placebo. Most adverse events involved the GI tract. A serious adverse event occurred in 5.7%, 3.4%, and 5.2% of patients in the naloxegol 12.5 mg, naloxegol 25 mg, and placebo groups, respectively, and was similar in type and frequency across the 3 groups. (30)

The long-term safety and tolerability of naloxegol 25 mg once daily were compared with investigator-chosen laxative treatment (usual care) in an open-label, 52-week study of 804 patients with noncancer pain and OIC. (31) Patients were taking an opioid at a dose of 30 to 1000 morphine-equivalents per day for [greater than or equal to] 4 weeks. An adverse event occurred in 81.8% of patients treated with naloxegol 25 mg and 72.2% of patients treated with usual care over the 52 weeks of the study. Treatment-emergent adverse events primarily involved the gastrointestinal tract and consisted of (naloxegol vs usual care) abdominal pain (17.8% vs 3.3%), diarrhea (12.9% vs 5.9%), nausea (9.4% vs 4.1%), back pain (9.0% vs 8.9%), headache (9.0% vs 4.8%), flatulence (6.9% vs 1.1%), arthralgia (6.2% vs 5.9%), nasopharyngitis (6.2% vs 5.6%), upper respiratory tract infection (5.8% vs 8.5%), bronchitis (5.6% vs 4.4%), vomiting (5.1% vs 5.6%), upper abdominal pain (5.1% vs 1.1%), sinusitis (4.3% vs 7.0%), and urinary tract infection (4.1% vs 8.1%).

A serious adverse event occurred in 9.6% of patients receiving naloxegol and 11.1% of patients receiving usual care. Two patients in each group experienced a major adverse cardiovascular event judged to be unrelated to study treatment. Two patients treated with naloxegol experienced symptoms of opioid withdrawal, both of which were attributed to a change in opioid dose.

Alvimopan

Alvimopan is another peripherally acting [mu]-opioid receptor antagonist. Although it is not approved for OIC, the efficacy and safety of alvimopan in patients with opioid-induced bowel dysfunction have been demonstrated in patients with noncancer pain in clinical trials lasting up to 6 weeks. (32,33) Alvimopan is for use in hospitals for up to 7 days to accelerate GI recovery after surgeries that include partial bowel resection with primary anastomosis. Long-term use of alvimopan is associated with an increased incidence of myocardial infarction. Accordingly, alvimopan is available only through a restricted program for short-term use. (34)

Chloride Channel Activator

Lubiprostone

Approved by the US FDA in 2013 for OIC, lubiprostone is a locally acting chloride channel activator that bypasses the antisecretory action of opioids and enhances chloride-rich intestinal fluid secretion. (35) As a consequence, lubiprostone softens stools and facilitates the passage of stool. This effect may be reduced in methadone-treated patients. (36)

In a phase 3 double-blind study, patients treated with stable doses of an opioid for chronic noncancer pain were randomized to lubiprostone 24 meg twice daily or placebo for 12 weeks. (35) The overall change from baseline to week 8 in the mean number of spontaneous bowel movements was significantly greater with lubiprostone than placebo (2.2 vs 1.6, respectively; P=.004). At week 12, the difference between the 2 groups was not significant due to the high dropout rates (lubiprostone [32.9%] and placebo [30.3%]). Significantly more patients treated with lubiprostone achieved a spontaneous bowel movement within 24 (P=.018) and 48 (P-.05) hours of the first dose. Compared with placebo, patients treated with lubiprostone showed significantly greater improvement in abdominal discomfort, straining, constipation severity, and stool consistency. An adverse event was experienced by 63.5% of patients receiving lubiprostone and 54.4% of patients receiving placebo. Nausea, diarrhea, and abdominal distention were the most frequently reported adverse events and were common reasons for treatment discontinuation.

Lubiprostone 24 meg twice daily has also been compared with sennosides once daily in patients (N=60) with self-reported constipation taking an opioid for pain control after orthopedic surgery. (37) After 7 days of treatment, the mean changes in bowel symptoms did not differ between the 2 groups, except for completeness of bowel movement and reduction of abdominal pain, both favoring sennosides. An adverse event was experienced by 45.2% of patients treated with lubiprostone and 41% of patients treated with sennosides. Gastrointestinal adverse events that were the most common (in the lubiprostone and sennosides groups, respectively) included the following: nausea (9.7% vs 17.2%), diarrhea (16.1% vs 6.9%), abdominal pain (25.8% vs 6.9%), abdominal cramping (19.4% vs 20.7%), and constipation (0% vs 3.4%).

SUMMARY

Constipation is a common complication of opioid therapy that contributes to substantial patient morbidity, decreased productivity, and opioid nonadherence. Other causes of constipation may occur concomitantly and should be investigated. Although evidence supporting their use is limited, the use of fiber, water, laxatives, and/or exercise is recommended in current guidelines as initial management. Peripherally acting p-opioid receptor antagonists are important treatment options, are well-tolerated, and improve many signs and symptoms of OIC in patients taking an opioid for chronic noncancer pain.

David A. Johnson, MD, MACG, FASGE, FACP, Professor of Medicine, Chief of Gastroenterology, Eastern Virginia Medical School, Norfolk, VA

Charles E. Argoff, MD, Professor of Neurology, Director, Comprehensive Pain Center, Albany Medical College, Albany, NY

DISCLOSURES

Dr. Johnson discloses that he is a consultant for Covidien pic, Ironwood Pharmaceuticals, Inc., Medscape (of WebMD LLC), and Pfizer Inc. He is a Board Member for CRH Medical Corporation.

Dr. Argoff discloses that he is on the advisory board and speakers' bureau for AstraZeneca.

SUPPORT

This article is sponsored by Primary Care Education Consortium and was supported by funding from AstraZeneca.

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TABLE
Aspects of opioid-induced constipation most ([greater than or equal to]
80%) patients would prefer to improve (8)

Aspect                                                   Participants
                                                         in
                                                         agreement (%)

Be able to have a bowel movement without pain            87.9
Be able to have a soft stool that is not loose or        87.1
  watery
Not experience rectal straining due to my constipation   83.4
Feel less bloated                                        83.0
Be more comfortable using my opioid                      82.1
  medication without fear of being constipated
Worry less about being able to have a bowel movement     80.5
Have less pain in my stomach area                        80.3

With kind permission from Springer Science+Business Media: Advances
in Therapy, Patient Preferences for Change in Symptoms Associated
with Opioid-Induced Constipation, volume 31,2014, page 1268,
Epstein RS, et al., Table 3.
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Title Annotation:Hot Topics in Primary Care
Author:Johnson, David A.; Argoff, Charles E.
Publication:Journal of Family Practice
Article Type:Disease/Disorder overview
Date:Dec 1, 2015
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