Methylnaltrexone Relieves Opioid-Induced Constipation Without Tachyphylaxis

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—and many within 30 minutes, he said.

Moreover, 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. The results of a phase II study presented at the 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 had a bowel movement within 4 hours, compared with 13%–15% who got a placebo.

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.”

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 in 29% of patients. There was also an increase in flatulence and nausea and vomiting. No patients dropped out because of these adverse events, he 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.

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, 33 hours sooner than controls. These are clinically meaningful improvements, Dr. Rathmell noted.

All three clinical trials were sponsored by Progenics Pharmaceuticals Inc.

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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—and many within 30 minutes, he said.

Moreover, 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. The results of a phase II study presented at the 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 had a bowel movement within 4 hours, compared with 13%–15% who got a placebo.

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.”

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 in 29% of patients. There was also an increase in flatulence and nausea and vomiting. No patients dropped out because of these adverse events, he 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.

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, 33 hours sooner than controls. These are clinically meaningful improvements, Dr. Rathmell noted.

All three clinical trials were sponsored by Progenics Pharmaceuticals Inc.

ELSEVIER GLOBAL MEDICAL NEWS

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—and many within 30 minutes, he said.

Moreover, 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. The results of a phase II study presented at the 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 had a bowel movement within 4 hours, compared with 13%–15% who got a placebo.

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.”

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 in 29% of patients. There was also an increase in flatulence and nausea and vomiting. No patients dropped out because of these adverse events, he 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.

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, 33 hours sooner than controls. These are clinically meaningful improvements, Dr. Rathmell noted.

All three clinical trials were sponsored by Progenics Pharmaceuticals Inc.

ELSEVIER GLOBAL MEDICAL NEWS