DALLAS — Backed by two positive phase III randomized trials, methylnaltrexone is now under Food and Drug Administration review for treatment of opioid-induced constipation in patients with advanced illness.
The investigational drug, a quaternary derivative of naltrexone, offers significant advantages over conventional laxatives for this tough-to-treat condition, Dr. Jay Thomas said at the annual meeting of the Society of Hospital Medicine.
The response to subcutaneous methylnaltrexone is rapid, with most responders in the two double-blind, randomized, placebo-controlled phase III trials having a bowel movement within 1 hour of injection—and many within 30 minutes, Dr. Thomas said.
Moreover, as was shown in one of the phase III trials that included 134 patients, efficacy persists without tachyphylaxis when methylnaltrexone is administered every other day over a 2-week period, added Dr. Thomas, medical director of San Diego Hospice.
There is also interest in pursuing a second indication for methylnaltrexone in the future. The results of a phase II study presented at the hospitalist meeting indicated that methylnaltrexone—this time given intravenously—accelerated GI recovery and hospital discharge eligibility without affecting opioid analgesia in patients who underwent bowel resection, reported Dr. James Rathmell of Harvard Medical School, Boston.
Dr. Thomas, principal investigator in the two phase III trials that included a total of 288 frail hospice patients with opioid-induced constipation, said about 60% of methylnaltrexone-treated patients responded to the drug with a bowel movement within 4 hours, compared with 13%–15% who received a placebo injection. All participants had continued on their baseline laxative regimen.
In an interview, he said he sees two major advantages for methylnaltrexone: reduced pill burden, and the speed and smoothness of the drug's effect.
“Sometimes with these patients you have to titrate up the traditional laxatives such that the number of pills they're taking becomes a burden. And there can be an unpredictable response to them. For example, with an oral osmotic like magnesium citrate, sometimes the bowel movement can happen unpredictably—and in some cases explosively and uncontrollably,” he explained.
“The people in these studies who responded to methylnaltrexone did so within 30 minutes,” Dr. Thomas observed. “Let's say you want to go to the park with your grandkids. You can potentially do a subQ injection with methylnaltrexone and have a response within 30 minutes. If you need help from a caregiver, the caregiver can schedule [his or her] day. So it gives you some control back, especially for very sick advanced-illness patients, like hospice patients.
“Whereas if you do an oral medication,” he continued, “it may be hours before you have a response, and you don't know when that response is going to happen. If you're in the park with your grandkids, you may have a hard time dealing with it. Sometimes patients lose control and soil themselves.”
Methylnaltrexone reverses the slowing of GI transit caused by opioids. Importantly, there was no sign of central opioid withdrawal or loss of analgesic effect in the 2-week study.
The most common methylnaltrexone-related side effect was mild to moderate abdominal pain, of a magnitude that could be associated with a normal physiologic bowel movement, in 29% of patients. There was also an increase in flatulence and nausea and vomiting. No patients dropped out because of these adverse events, Dr. Thomas said.
In a separate presentation, Dr. Rathmell reported on 65 patients who received opioids after undergoing segmental colectomy by laparotomy who were randomized in a double-blind manner to methylnaltrexone or placebo starting within 90 minutes after completion of the operation.
Mean time to first bowel movement was 98 hours in the methylnaltrexone group, 20 hours faster than in controls. The methylnaltrexone group was eligible for hospital discharge in a mean of 116 hours, which was 33 hours sooner than controls.
Two patients in the methylnaltrexone group developed postoperative ileus, compared with five controls. These are clinically meaningful improvements, Dr. Rathmell noted.
Analgesic requirements and pain scores were similar in the two study arms. Nausea, vomiting, and abdominal pain were more frequent in the placebo arm.
All three clinical investigations were sponsored by Progenics Pharmaceuticals Inc.
With traditional oral laxatives, the number of pills can be a burden and the response can be unpredictable. DR. THOMAS
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