Medically Managing Opioid-Induced Constipation: A Primer

Zara Risoldi Cochrane, PharmD

Disclosures

September 20, 2019

Patients who require opioid analgesics to treat their pain often face the additional discomfort of constipation, which can alter or disrupt their therapy. Although estimates of the prevalence of opioid-induced constipation (OIC) vary widely, most experts agree that it occurs in up to half of patients treated with opioids.[1,2,3] Patients may be reluctant to discuss their bowel habits with healthcare providers, so pharmacists can play a role in identifying and managing OIC by proactively inquiring about the development of this adverse event.

Why It Occurs

Beyond just alleviating pain, opioids also stimulate mu-opioid receptors in the enteric nervous system, reducing gastric emptying and increasing intestinal water absorption and sphincter tone. These effects result in constipation that is unlikely to diminish with continued opioid treatment.

There is no consensus on whether the incidence of OIC varies by drug, and comparative data are limited. According to the American Academy of Pain Medicine, there is no difference in the rates of OIC seen with morphine, hydrocodone, and hydromorphone.[3] Transdermal opioids are less likely to constipate patients than oral formulations.[2,3] Higher and more frequent doses of opioids are probably associated with greater rates of OIC, although evidence is limited.

Additional risk factors for the development of OIC include advanced age and cancer-related pain.[1]

Taking the First Steps Toward Treating OIC

Nonpharmacologic measures are reasonable to recommend for prevention and initial treatment of OIC. These interventions include increased fluid and fiber intake, as well as moderate physical activity, although the latter may be challenging for patients with chronic pain.[2,3]

When appropriate, discourage the use of a bedpan, which is also associated with constipation.

It is also important to evaluate the patient's opioid regimen and consider adjunctive analgesic agents that may facilitate dosage reduction of the opioid.[1]

In cases where continued treatment with an opioid is necessary, traditional laxatives are considered first-line pharmacologic treatment for OIC.[3,4] Bisacodyl has been studied most often in clinical trials, but other stimulant laxatives (eg, senna) or osmotic laxatives (eg, polyethylene glycol) appear to be equally effective.[3] Osmotic laxatives cause less cramping than stimulants and are a reasonable choice for initial therapy.

Stool softeners do not increase gastrointestinal motility and may be less appropriate for the management of OIC; however, they are included in the current recommendations from the American Gastroenterological Association (AGA), as is mineral oil.[4]

Emerging Therapies

With less than half of patients experiencing adequate relief from traditional laxatives,[2] a number of agents have been developed and marketed specifically for the treatment of OIC in recent years.

These include the peripherally acting mu-opioid receptor antagonists (PAMORAs) methylnaltrexone, naldemedine, and naloxegol, as well as lubiprostone, a chloride channel activator. The off-label use of prucalopride, a serotonin 5-HT4 receptor agonist approved for the treatment of chronic idiopathic constipation, has also been investigated.[5]

Clinical practice guidelines support using PAMORAs, but not lubiprostone or prucalopride, in patients whose constipation is refractory to dietary changes and traditional laxatives. According to the AGA, naldemedine, naloxegol, or methylnaltrexone should be recommended over no treatment in patients with laxative-refractory OIC. There is insufficient evidence to support the use of lubiprostone or prucalopride at this time. The AGA also recognizes that the high cost of naldemedine, naloxegol, and methylnaltrexone may limit the use of these agents.[4]

The approval trials for all these agents compared them against placebo, which makes selection of a preferred agent difficult. Direct comparisons of the drugs used in the treatment of OIC would help to better stratify the options but are not currently available. However, low-quality evidence from a recent network meta-analysis suggests that methylnaltrexone may be most effective at improving the symptoms of OIC. In pooling data from 21 randomized controlled trials, investigators reported that lubiprostone, naloxegol, and oral methylnaltrexone were significantly less effective than subcutaneous methylnaltrexone at eliciting rescue-free bowel movements.[6,7] This was in agreement with a systematic review, which reported that methylnaltrexone has the most consistent body of evidence to support its use in OIC.[8]

Prolonged OIC can have a profound impact on a patient's quality of life, activities of daily living, and ability to maintain productivity at work.[3] Left untreated, constipation can lead to such complications as hemorrhoids, fecal impaction, or bowel obstruction. Therefore, the judicious use of lifestyle modifications, nonpharmacologic treatments, and drug therapy is needed to manage constipation in patients receiving chronic opioid therapy.

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