Methylnaltrexone: A New Treatment for an Old Problem

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Thomas J, Karver S, Cooney GA, et al. (San Diego Hospice and Palliative Medicine, San Diego, California). Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med 2008;358:2332–2343.

The role of the peripherally acting μ-opioid receptor antagonist, methylnaltrexone, for treatment of opiate-induced constipation was recently evaluated by Thomas et al in a multicenter, Phase III randomized, placebo-controlled trial. The investigators studied 133 patients with terminal disease (terminal cancer or other end-stage disease) from 27 US and Canadian nursing homes, palliative care centers, or hospice sites. Eligible subjects had a life expectancy of >1 month, used opioid analgesics for >2 weeks, and required laxatives for ≥3 days before study entry. Opioid-induced constipation (OIC) was defined as ≤3 bowel movements during the preceding week and no “meaningful” bowel movement within the 24 hours before the first dose of study drug, or no “meaningful” bowel movement within 48 hours of first dose of study drug.

During the double-blind phase of the study, patients were randomly assigned to receive either methylnaltrexone 0.15 mg/kg or placebo subcutaneously every other day over 2 weeks. All study drug doses were given by study staff or trained caregivers. Patients were allowed to take their baseline and rescue laxatives through the double-blind treatment period but not within 4 hours of receiving a dose of study drug. Patients who completed the double-blind phase of the study were eligible to enter a 3-month, open-label extension trial. The co-primary endpoints for the double-blind phase of the study were defecation within 4 hours after the first dose of study drug and defecation within 4 hours after ≥2 of the initial 4 doses of study drug. Other parameters assessed included stool consistency, difficulty with defecation, use of concurrent medications, constipation-related distress, changes in bowel function, level of pain, symptoms of withdrawal, and presence of adverse events. Comparisons between groups were evaluated using an intention-to-treat analysis and χ² tests.

For the double-blind phase of the study, compared with the placebo group, patients receiving methylnaltrexone experienced (1) a higher rate of rescue-free defecation within 4 hours of receiving the first dose of study drug (48% vs 15%; P < .001); (2) a higher rate of rescue-free defecation within 4 hours after receiving ≥2 doses (52% vs 8%; P < .001); (3) a higher rate of having ≥3 rescue-free bowel movements per week (68% vs 45%; P = .009); (4) more rapid time to defecation (6.3 vs 48 hours; P < .001); (5) greater reduction in difficulty with defecation; and (6) greater reduction in constipation-related distress. The 2 groups did not differ in reported stool consistency, pain scores, or opioid withdrawal scores. Compared with placebo, patients receiving methlynatrexone were more likely to report abdominal pain (17% vs 13%), nausea (11% vs 7%), flatulence (13% vs 7%), dizziness (8% vs 3%), and increase in body temperature (8% vs 3%). Serious adverse events (SAEs) were reported in 17% and 28% of the methylnaltrexone and placebo groups, respectively. In the investigator's judgment, the majority of SAEs and all deaths that occurred during the study were related to progression of the patient's underlying disease process.

Eighty-two patients received ≥1 dose of methylnaltrexone during the open-label extension phase. The rates of rescue-free defecation for all doses were 45%–58%. In patients who had previously received placebo during the double-blind phase, response rates ranged between 48% and 52%. The most common adverse events reported during the extension trial were abdominal pain (30%), progression of neoplasm (24%), nausea (21%), and vomiting (20%).

The authors concluded that SQ methylnaltrexone rapidly stimulated defecation in patients with advanced medical illness and OIC without inhibiting centrally mediated analgesia or inducing opioid withdrawal.

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Comment 

Prescriptions for opioid analgesics have steadily increased in the United States and elsewhere in recent years, particularly for nonmalignant indications (Clin Gastroenterol Hepatol 2007;5:1126–1139). These drugs provide much-needed pain relief for patients in the postoperative setting as well as those with a variety of medical conditions. Unfortunately, the benefits of opioid analgesics are limited by potentially serious side effects including sedation, orthostatic hypotension, respiratory depression, urinary retention, and various gastrointestinal (GI) complications (Drug Saf 1992;7:200–213).

Constipation is the most common and bothersome side effect reported by patients regularly using opioids. In a recent population-based survey of 2055 individuals using opioids for non–cancer-related pain, 57% reported constipation that they associated with opioid therapy and 49% reported constipation in the past 4 weeks. One third of respondents reported that constipation was their most bothersome opioid-associated GI side effect (Aliment Pharmacol Ther 2008;27:1224–1232).

The increasing prevalence of opioid use and consequently, opioid-induced bowel dysfunction has prompted interest in identifying effective treatment options. Until now, the treatment of OIC has been viewed as an extension of constipation in general. Traditional therapies for constipation such as bulking agents, stool softeners, stimulant laxatives, and osmotic agents are commonly utilized, but there are currently no well-designed studies to support efficacy in this population. Although there is sound evidence to support the use of the osmotic agents lactulose and polyethylene glycol, the 5-HT4 receptor agonist tegaserod, and the chloride channel activator lubiprostone, for the treatment of occasional or chronic constipation, none of these agents has thus far been specifically investigated in patients with OIC (J Pain Symptom Manage 2008;35:103–113). Furthermore, tegaserod is no longer available in the United States or many other countries.

The use of these agents is predicated on the notion that the treatment of OIC should be the same as treatment of constipation in general. Of course, this may or may not be the case. There are 3 major opioid receptors in the human body: δ-opioid receptor, κ-opioid receptor, and μ-opioid receptor. These receptors overlap in their distribution and function throughout the central and enteric nervous systems, but maintain some selectivity for endogenous opioids. In contrast, exogenous opioids preferentially activate μ-opioid receptors. In the human GI tract, the μ-opioid receptor is primarily found in the myenteric and submucosal plexi of the small and large intestines (Neurogastroenterol Motil 2004;16[Suppl 2]:3–16). Both endogenous and exogenous opioids impair GI transit by altering neuronal excitability and inhibiting the release of acetylcholine and other neurotransmitters. Opioids have also been found to stimulate fluid and electrolyte absorption in the gut (Neurogastroenterol Motil 2004;16[Suppl 2]:17–28).

More specifically targeted therapies for OIC have included both systemic and peripherally acting opioid antagonists. Oral naloxone, a systemic opioid antagonist with low bioavailability owing to first-pass hepatic metabolism, has been studied for its theoretical accumulation in the bowel without systemic levels in the blood. Unfortunately, when this hypothesis was subjected to clinical testing, a significant number of patients reported symptoms of unpredictable systemic opioid withdrawal and increased pain (J Pain Symptom Manage 2002;23:48–53).

The desire to maintain analgesia without constipation has led to the investigation of peripherally acting opioid antagonists, such as methylnaltrexone and alvimopan. These agents selectively antagonize the peripheral μ-opioid receptor receptor, without diminishing opioid effects on the central nervous system.

Methylnaltrexone is a μ-opioid receptor–selective antagonist that is being studied for its role in OIC. Methylnaltrexone can be supplied in various formulations (oral, subcutaneous, and IV) and has been shown to reverse morphine-induced oral–cecal transit delay (Clin Pharmacol Ther 200;67:398–404). In 1 study of oral methylnaltrexone, 12 chronic methadone users received placebo on the first day and methylnaltrexone on the second day in 1 of 3 doses (0.3, 1, or 3 mg/kg). No patient had a bowel movement after receiving placebo, and 11 of 12 patients experienced defecation after receiving methylnaltrexone. Higher methylnaltrexone doses were associated with a more rapid time to defecation, and there were no reports of systemic opioid withdrawal (JAMA 2000;284:1383–1384). In a double-blind, randomized, placebo-controlled study of 22 chronic methadone users receiving placebo or escalating doses of IV methylnaltrexone, 10 of 11 patients receiving IV methylnaltrexone experienced immediate laxation after 1 session, and 11 of 11 patients had immediate laxation after a second session without evidence of systemic opioid withdrawal (JAMA 2000;283:367–372).

Given such encouraging results from smaller studies, it is intriguing to note that in the study by Thomas et al roughly half of patients achieved a bowel movement after receiving methylnaltrexone. This was clearly an improvement over placebo but by no means a silver bullet for OIC in this selected group of patients. These findings suggest that constipation in patients with advanced illness, unlike constipation in younger chronic methadone users, is multifactorial in etiology with contributions not only from the narcotic but also from diet, level of activity, other constipating medications, electrolyte abnormalities, and pelvic floor dysfunction. Furthermore, exogenous opioids may suppress intestinal transit through effects on opioid receptors in the central nervous system. This phenomenon has been previously described in animals, where sympathectomy and α-noradrenergic blockade have been shown to reverse the effects of morphine (Auton Neurosci 2002;100:27–31).

Whether peripherally acting opioid receptor antagonists have a role in the treatment of other disorders such as OIC in nonmalignant conditions, postoperative ileus, gastroparesis, chronic constipation, and constipation-predominant irritable bowel syndrome (IBS-C) remains to be seen. Several studies have demonstrated the efficacy of alvimopan in postoperative ileus including a Phase III trial by Delaney et al, in which patients with postoperative ileus receiving alvimopan experienced a reduction in time to GI recovery and hospital discharge (Dis Colon Rectum 2005;48:1114–1125). These data have led the US Food and Drug Administration (FDA) recently to approve alvimopan for use in postoperative ileus. The effects of peripheral opioid receptor antagonists on opioid-induced gastroparesis have been mixed. Unlike alvimopan, methylnaltrexone may reverse opioid-induced gastroparesis (Anesthesiology 1997;87:765–770). Peripherally acting opioid receptor antagonists may have a role in the treatment of functional GI disorders such as IBS-C or chronic constipation, particularly given evidence that endogenous opioids suppress intestinal motility when motor function is compromised (Neurogastroenterol Motil 2004;16[Suppl 2]:38–45). Whether this scientific observation will translate into clinical benefits for IBS-C or chronic constipation remains to be tested in appropriately designed clinical trials.

Based on the available data, methylnaltrexone seems to provide a promising new treatment for OIC. As is nearly always the case with new drugs, FDA approval should be viewed as the beginning and not the end of the process of understanding where methylnaltrexone fits into clinical practice. In the preceding paragraphs, we have discussed a number of areas in which this drug might prove useful. It is also exciting to consider the mechanistic studies that can now be conducted to better understand the role of peripheral endogenous opiates in the pathogenesis of selected disorders of GI motility and neurogastroenterology. Hopefully, peripheral opiate antagonists, by eliminating bothersome side effects without affecting analgesia, will improve the quality of life of patients with intractable pain rather than promote the irresponsible use of opiate analgesics.