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Methylnaltrexone and opioid-induced constipation
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Opioid-induced constipation is a common adverse effect of narcotic pain relievers and can range in severity from slightly annoying to extremely distressful and potentially life-threatening. Tolerance to the constipating effects of opioids usually does not develop. Up to 90% of cancer patients receiving opioid therapy develop bowel dysfunction.
Opioid-induced constipation (OIC) is caused by complex interactions in the GI tract. Agonists at the mu-opiate receptors in the GI tract decrease the forward peristalsis, which reduces evacuation. In addition, there is an increase in segmental contractions. This leads to an increase in the absorption of fluids from the stool, leaving it harder and dryer. Opioids also decrease GI secretions and lengthen the gastric emptying time.
Patients with OIC may have other contributing causes to the constipation such as diabetes, hypercalcemia, bowel obstruction due to tumor mass, as well as other medications including anticholinergics, aluminum hydroxide, antiseritonergic agents, calcium channel blockers, muscle relaxants, anticonvulsants, phenothiazines and others. In addition, patients may also suffer from fatigue, weakness, immobility, poor intake of fluids and fiber-rich foods, all of which contribute to constipation.
Standard laxatives available for use in treating OIC are described in table 1. Standard laxative therapy relies heavily on agents that pull or trap water in the stool, making it softer, larger, and easier to pass, thus promoting evacuation. Although very useful in healthier people, fiber supplements are not recommended in debilitated patients. A large fluid intake is needed for efficacy, but most cancer patients cannot maintain this large fluid intake, which can then lead to intestinal impaction. Stools softeners and osmotic laxatives are very useful, but some of these agents can cause flatulence and bloating. The use of stimulant laxatives is often necessary in treating OIC, but can cause abdominal pain and cramping. Successful treatment of OIC often requires multiple medications with different mechanisms of action.
Many researchers have sought a method of blocking the peripheral action of opioid mu-agonists without blocking the central nervous system actions of opioid-mediated pain relief. Orally administered naloxone, a mu-receptor antagonist, has limited bioavailability due to a high first pass metabolism. Unfortunately, it does cross the blood-brain barrier and has the potential to reverse the central nervous system effects of opioids. Oral naloxone can be used to treat OIC if titrated carefully, although some patients may experience withdrawal symptoms and increased pain. Patients with the highest doses of narcotics would be at the highest risk of withdrawal with oral naloxone.
Alvimopan is mu-receptor antagonist that has poor oral bioavailability and is excluded from the blood-brain barrier because it contains a negative and a positive charge. Alvimopan (Entereg, Adolor) has been studied in OIC, but risks of cardiovascular adverse effects preclude its further use. It is available in a limited fashion for the treatment of postoperative ileus.
Methylnaltrexone is a positively charged quaternary ammonium derivative of naltrexone with increased polarity and reduced lipid solubility. This reduces the ability of this compound to cross the blood-brain barrier.
A group of researchers (N Engl J Med. 2008;358:2332-2343) studied subcutaneous methylnaltrexone in a group of 133 patients with chronic OIC unresponsive to standard laxative therapy. With an average age of 70 years, the study group had slightly more women than men and most of the patients had cancer, cardiovascular disease or COPD/emphysema. The patients were treated with an average of two classes of laxative medications, with a range of one to five drug classes. The two groups were being treated with comparable amounts of narcotics; the group randomized to methylnaltrexone had actually slightly larger amounts of opioids. The participants were treated with methylnaltrexone 0.15 mg/kg subcutaneously every other day for two weeks, or placebo.
The efficacy measures and results are shown in table 2.
Pain scores and withdrawal symptoms scores remained stable in both groups, pointing to the lack of central opioid blockade with methylnaltrexone. The majority of patients with a response to methylnaltrexone had that response within 30 to 60 minutes after the dose. Patients who did not have a response after the first three doses were unlikely to respond to additional doses. Unfortunately, methylnaltrexone treatment was successful in only roughly half of the patients. One explanation is that these patients were probably suffering from constipation with more than one etiology. Methylnaltrexone was well tolerated with only mild to moderate adverse effects, primarily of GI symptoms such as abdominal pain, flatulence and nausea.
Methylnaltrexone was recently approved by the FDA for the treatment of OIC. The recommended dose is 8 mg subcutaneously every other day for patients weighing 38 kg to 62 kg, and 12 mg for those weighing 62 kg to 114 kg. For patients with a CrCl <30 mL/min, the dose should be reduced by half. The most common adverse effects include abdominal pain, flatulence, nausea and dizziness.
Methylnaltrexone is moderately expensive and would not be appropriate for all patients, and not all patients would tolerate a subcutaneous medication for constipation. A maximally titrated laxative combination of a stimulant plus a stool softener or osmotic laxative should be used in all patients treated with opioid analgesics. Despite optimal laxative therapy, some patients have substantial, resistant bowel dysfunction. These patients may be candidates for therapy with methylnaltrexone.
One day at our hospital, a physician colleague of mine had just completed a phone call with patient who reported successful results from the newly recommended bowel regimen. The physician turned to me and pronounced, “Never underestimate the power of a good BM.”
Lisa Lohr, PharmD, BCPS, BCOP, is Clinical Pharmacist in Oncology and Bone Marrow Transplantation in the Department of Pharmacy Services at the University of Minnesota Medical Center and is a HemOnc Today Editorial Board member.
For more information:
- Klaschik E, Nauck F, Ostgathe C. Constipation – modern laxative therapy. Support Care Cancer. 2003; 11:679-685.
- Thomas J. Opioid-induced bowel dysfunction. J Pain Symptom Manage. 2008; 35;103-113.
- Thomas J, Karver S, Cooney GA, et al. Methynatrexone for opioid-induced constipation in advanced illness. N Engl J Med. 2008; 358:2332-2343.