New drugs: methylnaltrexone bromide, alvimopan, and rilonacept.

Agent for opioid-induced constipation Each year, an estimated 1.5 million Americans are treated with an opioid analgesic (e.g., morphine) on a continuous basis to relieve pain associated with incurable cancers, end-stage chronic obstructive pulmonary disease from emphysema, heart failure, and other advanced illnesses. The analgesic benefi ts of the opioids result from their action at receptors in the central nervous system (CNS). However, the opioids also act at opioid receptors in peripheral tissues such as the gastrointestinal tract, one of the consequences of which is that almost all patients who are treated with these analgesics on a continuous basis will experience constipation. To reduce the likelihood of constipation, the use of a bowel regimen (i.e., a laxative such as senna [e.g., Senokot] and a stool softener such as docusate [e.g., Colace]) is usually recommended for patients who are to be treated with an opioid analgesic on a continuous basis. For many patients, however, even the use of a bowel regimen is insuffi cient to prevent opioid-induced constipation, and patients experience symptoms and discomfort that add to those associated with the underlying disease. Methylnaltrexone bromide (Relistor—Progenics; Wyeth) is an opioid antagonist that is related to naltrexone (e.g., ReVia, Vivitrol) that has been used for treating opioid and alcohol dependence. The new drug is a quaternary amine that does not cross the blood– brain barrier, and it functions as a selective peripherally acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract. Therefore, it decreases the constipating action of opioid analgesics without reducing the centrally mediated analgesic effects. Methylnaltrexone is administered subcutaneously and is indicated for treating opioid-induced constipation in patients with advanced illness who are receiving palliative care, when the response to laxative therapy has not been suffi cient. Its unique mechanism of action provides a very useful alternative for patients in whom conventional laxatives have not been effective in preventing or treating constipation associated with the use of opioids. The effectiveness of methylnaltrexone was demonstrated in placebo-controlled studies. In a single-dose study, approximately 60% of the patients treated with the new drug experienced a laxative action within 4 hours following administration of the drug compared with 14% of those receiving placebo. In a study in which methylnaltrexone was administered every other day, those receiving the drug had a higher rate of laxation within 4 hours of the fi rst dose (48%) than placebo-treated patients (16%). Methylnaltrexonetreated patients also had signifi cantly higher rates of laxation within 4 hours after at least two of the fi rst four doses (52%) compared with placebo-treated patients (9%). In both studies, approximately one-third of the patients reported laxation within 30 minutes following administration of the drug. The use of methylnaltrexone in an orally administered formulation for treating opioid-induced constipation is currently being evaluated, as is an intravenously administered formulation in the treatment of postoperative ileus. The adverse events reported most frequently with the use of methylnaltrexone include abdominal pain (29%), fl atulence (13%), nausea (12%), dizziness (7%), and diarrhea (6%). If severe or persistent diarrhea occurs during treatment, the drug should be discontinued. There is no known risk of dependency with methylnaltrexone, and it is not a controlled substance. The use of the new agent is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. If a patient stops taking the opioid analgesic, the use of methylnaltrexone should also be discontinued. Methylnaltrexone is classifi ed in Pregnancy Category B and should be used during pregnancy only if the anticipated benefi t outweighs the risk to the fetus. Its effectiveness and safety in pediatric patients have not been evaluated. Following administration of methylnaltrexone, peak concentrations are usually achieved within 0.5 hour. It undergoes only limited metabolism, and approximately 85% of a dose is eliminated as unchanged drug. Approximately one-half of a dose is excreted in the urine and somewhat less in the feces. The dosage should be reduced in patients with severe renal impairment, but dosage adjustment is not necessary in patients with mild or moderate renal or hepatic impairment. The drug has not been evaluated in patients with severe hepatic impairment. Methylnaltrexone is administered subcutaneously in the upper arm, abdomen, or thigh. The usual frequency of administration is one dose every other day, as needed. No more than one dose should be administered in a 24-hour period. The recommended dose is 8 mg for patients weighing 38 to 61 kg (84– 135 lb) and 12 mg for patients weighing 62 to 114 kg (136–251 lb). For patients weighing less than 38 kg or more than 114 kg, a dosage of 0.15 mg/kg should be used. In patients with severe renal