Methylnaltrexone Relieves Opioid-Induced Constipation

ORLANDO – Single injections of methylnaltrexone relieved opioid-induced constipation in 4 hours for 60% of hospice and palliative care patients in a randomized, placebo-controlled phase III trial.

The earliest responses occurred within 5 minutes, and most patients responded within 2 hours, investigator Jay Thomas, M.D., reported at the annual meeting of the American Society of Clinical Oncology. The patients in the trial had not had a bowel movement for at least 48 hours prior to treatment, despite being on a stable laxative regimen for at least 3 days.

Dr. Thomas, clinical medical director of the San Diego Hospice and Palliative Care Center, reported that the single-dose trial enrolled 154 patients with advanced medical disease from 16 hospices. Of the 154 patients, 123 (80%) had cancer. The population also included patients with pulmonary disorders (12) AIDS (8), amyotrophic lateral sclerosis (3), cardiovascular conditions (2), and other disorders (6).

“These patients were very sick and near the end of life,” Dr. Thomas said. Since most patients lived at home, visiting nurses trained family members to give the injections in place of an enema or other rescue regimen. If the study drug did not provide relief within 4 hours, rescue was permitted.

The trial randomized patients into three groups: 52 patients were given a placebo, 57 received 0.15 mg/kg of methylnaltrexone, and 55 received 0.30 mg of methylnaltrexone/kg. Median time to laxation was 70 minutes for the 0.15-mg dose, 45 minutes at 0.30 mg, and more than 1,440 minutes (24 hours) with placebo.

Dr. Thomas, an internist, said the difference in efficacy between the two methylnaltrexone doses was negligible. “With the higher dose, you didn't get more bang for your buck,” he said. “If anything, you got more side effects.”

Side effects were minimal, however. The two most common adverse events, abdominal cramping and flatulence, were associated with successful laxation. The next most common side effects were nausea and dizziness.

The trial's sponsor, Progenics Pharmaceuticals Inc. of Tarrytown, N.Y., has already started a second phase III study at 30 centers to assess repetitive doses in patients with chronic constipation due to opioid painkillers. The company hopes to apply for U.S. Food and Drug Administration approval by the end of the year, Robert J. Israel, M.D., medical affairs vice president, told this newspaper.

The late Leon Goldberg, a pharmacologist at the University of Chicago, synthesized methylnaltrexone 25 years ago to help a dying friend who suffered from morphine-induced constipation. A μ receptor antagonist, it does not cross the blood-brain barrier, and therefore can act on opioid-induced constipation without blocking the pain-killing effects of opioids.

Dr. Israel said Progenics obtained the rights to develop methylnaltrexone after he read a report on a randomized trial in which the experimental drug relieved constipation in methadone patients (JAMA 2000;283:367–72).

“The market was small for end of life, so a lot of [drug companies] look at that as not attractive,” Dr. Israel said. “We are a small company. That was not an obstacle for us.”

Enthusiastic physicians surrounded Dr. Thomas and Dr. Israel after the presentation. “The sooner it gets to market, the better,” said Lee Schwartzberg, M.D., research director of the West Clinic in Memphis, as others in the crowd suggested strategies for convincing insurance companies to provide reimbursement.

In a podium discussion of the presentation, Kathleen M. Foley, M.D., called methylnaltrexone “the palliative and pain world's answer to a targeted therapy.” Dr. Foley of Memorial Sloan-Kettering Cancer Center in New York said the investigators need to refine the dose in short-term vs. long-term opioid users, and to explore intravenous and oral delivery systems. She also suggested that methylnaltrexone might have a role in treating postoperative ileus.

Dr. Thomas predicted that drug makers would eventually be able to offer pills combining methylnaltrexone with opioid painkillers. “When someone takes OxyContin they would have methylnaltrexone in the pill, so they would never have the opioid-induced side effect of nausea, urinary retention, and constipation,” he said.

ORLANDO – Single injections of methylnaltrexone relieved opioid-induced constipation in 4 hours for 60% of hospice and palliative care patients in a randomized, placebo-controlled phase III trial.

The earliest responses occurred within 5 minutes, and most patients responded within 2 hours, investigator Jay Thomas, M.D., reported at the annual meeting of the American Society of Clinical Oncology. The patients in the trial had not had a bowel movement for at least 48 hours prior to treatment, despite being on a stable laxative regimen for at least 3 days.

Dr. Thomas, clinical medical director of the San Diego Hospice and Palliative Care Center, reported that the single-dose trial enrolled 154 patients with advanced medical disease from 16 hospices. Of the 154 patients, 123 (80%) had cancer. The population also included patients with pulmonary disorders (12) AIDS (8), amyotrophic lateral sclerosis (3), cardiovascular conditions (2), and other disorders (6).

“These patients were very sick and near the end of life,” Dr. Thomas said. Since most patients lived at home, visiting nurses trained family members to give the injections in place of an enema or other rescue regimen. If the study drug did not provide relief within 4 hours, rescue was permitted.

The trial randomized patients into three groups: 52 patients were given a placebo, 57 received 0.15 mg/kg of methylnaltrexone, and 55 received 0.30 mg of methylnaltrexone/kg. Median time to laxation was 70 minutes for the 0.15-mg dose, 45 minutes at 0.30 mg, and more than 1,440 minutes (24 hours) with placebo.

Dr. Thomas, an internist, said the difference in efficacy between the two methylnaltrexone doses was negligible. “With the higher dose, you didn't get more bang for your buck,” he said. “If anything, you got more side effects.”

Side effects were minimal, however. The two most common adverse events, abdominal cramping and flatulence, were associated with successful laxation. The next most common side effects were nausea and dizziness.

The trial's sponsor, Progenics Pharmaceuticals Inc. of Tarrytown, N.Y., has already started a second phase III study at 30 centers to assess repetitive doses in patients with chronic constipation due to opioid painkillers. The company hopes to apply for U.S. Food and Drug Administration approval by the end of the year, Robert J. Israel, M.D., medical affairs vice president, told this newspaper.

The late Leon Goldberg, a pharmacologist at the University of Chicago, synthesized methylnaltrexone 25 years ago to help a dying friend who suffered from morphine-induced constipation. A μ receptor antagonist, it does not cross the blood-brain barrier, and therefore can act on opioid-induced constipation without blocking the pain-killing effects of opioids.

Dr. Israel said Progenics obtained the rights to develop methylnaltrexone after he read a report on a randomized trial in which the experimental drug relieved constipation in methadone patients (JAMA 2000;283:367–72).

“The market was small for end of life, so a lot of [drug companies] look at that as not attractive,” Dr. Israel said. “We are a small company. That was not an obstacle for us.”

Enthusiastic physicians surrounded Dr. Thomas and Dr. Israel after the presentation. “The sooner it gets to market, the better,” said Lee Schwartzberg, M.D., research director of the West Clinic in Memphis, as others in the crowd suggested strategies for convincing insurance companies to provide reimbursement.

In a podium discussion of the presentation, Kathleen M. Foley, M.D., called methylnaltrexone “the palliative and pain world's answer to a targeted therapy.” Dr. Foley of Memorial Sloan-Kettering Cancer Center in New York said the investigators need to refine the dose in short-term vs. long-term opioid users, and to explore intravenous and oral delivery systems. She also suggested that methylnaltrexone might have a role in treating postoperative ileus.

Dr. Thomas predicted that drug makers would eventually be able to offer pills combining methylnaltrexone with opioid painkillers. “When someone takes OxyContin they would have methylnaltrexone in the pill, so they would never have the opioid-induced side effect of nausea, urinary retention, and constipation,” he said.

ORLANDO – Single injections of methylnaltrexone relieved opioid-induced constipation in 4 hours for 60% of hospice and palliative care patients in a randomized, placebo-controlled phase III trial.

The earliest responses occurred within 5 minutes, and most patients responded within 2 hours, investigator Jay Thomas, M.D., reported at the annual meeting of the American Society of Clinical Oncology. The patients in the trial had not had a bowel movement for at least 48 hours prior to treatment, despite being on a stable laxative regimen for at least 3 days.

Dr. Thomas, clinical medical director of the San Diego Hospice and Palliative Care Center, reported that the single-dose trial enrolled 154 patients with advanced medical disease from 16 hospices. Of the 154 patients, 123 (80%) had cancer. The population also included patients with pulmonary disorders (12) AIDS (8), amyotrophic lateral sclerosis (3), cardiovascular conditions (2), and other disorders (6).

“These patients were very sick and near the end of life,” Dr. Thomas said. Since most patients lived at home, visiting nurses trained family members to give the injections in place of an enema or other rescue regimen. If the study drug did not provide relief within 4 hours, rescue was permitted.

The trial randomized patients into three groups: 52 patients were given a placebo, 57 received 0.15 mg/kg of methylnaltrexone, and 55 received 0.30 mg of methylnaltrexone/kg. Median time to laxation was 70 minutes for the 0.15-mg dose, 45 minutes at 0.30 mg, and more than 1,440 minutes (24 hours) with placebo.

Dr. Thomas, an internist, said the difference in efficacy between the two methylnaltrexone doses was negligible. “With the higher dose, you didn't get more bang for your buck,” he said. “If anything, you got more side effects.”

Side effects were minimal, however. The two most common adverse events, abdominal cramping and flatulence, were associated with successful laxation. The next most common side effects were nausea and dizziness.

The trial's sponsor, Progenics Pharmaceuticals Inc. of Tarrytown, N.Y., has already started a second phase III study at 30 centers to assess repetitive doses in patients with chronic constipation due to opioid painkillers. The company hopes to apply for U.S. Food and Drug Administration approval by the end of the year, Robert J. Israel, M.D., medical affairs vice president, told this newspaper.

The late Leon Goldberg, a pharmacologist at the University of Chicago, synthesized methylnaltrexone 25 years ago to help a dying friend who suffered from morphine-induced constipation. A μ receptor antagonist, it does not cross the blood-brain barrier, and therefore can act on opioid-induced constipation without blocking the pain-killing effects of opioids.

Dr. Israel said Progenics obtained the rights to develop methylnaltrexone after he read a report on a randomized trial in which the experimental drug relieved constipation in methadone patients (JAMA 2000;283:367–72).

“The market was small for end of life, so a lot of [drug companies] look at that as not attractive,” Dr. Israel said. “We are a small company. That was not an obstacle for us.”

Enthusiastic physicians surrounded Dr. Thomas and Dr. Israel after the presentation. “The sooner it gets to market, the better,” said Lee Schwartzberg, M.D., research director of the West Clinic in Memphis, as others in the crowd suggested strategies for convincing insurance companies to provide reimbursement.

In a podium discussion of the presentation, Kathleen M. Foley, M.D., called methylnaltrexone “the palliative and pain world's answer to a targeted therapy.” Dr. Foley of Memorial Sloan-Kettering Cancer Center in New York said the investigators need to refine the dose in short-term vs. long-term opioid users, and to explore intravenous and oral delivery systems. She also suggested that methylnaltrexone might have a role in treating postoperative ileus.

Dr. Thomas predicted that drug makers would eventually be able to offer pills combining methylnaltrexone with opioid painkillers. “When someone takes OxyContin they would have methylnaltrexone in the pill, so they would never have the opioid-induced side effect of nausea, urinary retention, and constipation,” he said.