New treatment for cancer patients and constipation

New class of drugs featured

A new class of drugs, called peripheral-acting mu opioid receptor antagonists, offers cancer patients and other advanced illness patients relief from some of the debilitating side effects of opioid use.1

The first of this class to be approved is methylnaltrexone, which helps advanced illness patients who suffer from opioid-induced constipation (OIC).

Methylnaltrexone blocks the peripheral effects of opiates, especially those in the gastrointestinal tract, by selectively blocking peripheral mu opioid receptors.1 However, because it does not cross the blood brain barrier, it does not reverse the analgesia caused by opioids.

"It decreases the peripheral side effect of opiates without impacting the pain relief," says Jonathan Moss, MD, PhD, a professor and vice chair for research in the department of anesthesia and critical care at the University of Chicago in Chicago, IL.

"It's been an incredible benefit for these patients, who may often have to choose between opiates for relief of their cancer pain and having a bowel movement," Moss says. "About half will choose to forego pain relief so they can have the bowel movement."

Methylnaltrexone, given subcutaneously, is intended for use in cancer patients and other patients with advanced illness receiving palliative care when response to conventional laxatives has not been sufficient.

"Many of these patients only move their bowels once or twice a week despite all drugs, and they get very distended," Moss says. "It's not really a casual problem."

There has been a great deal of interest in the drug since it was approved by the FDA in April, 2008, as Relistor for the treatment of OIC in advanced illness patients receiving palliative care when response to laxative therapy has not been sufficient, he adds.

Many physicians are interested to see if its use can be extended to treat some of the other effects of opiates, Moss says.

Other peripheral side effects of opioids that have been studied experimentally include pruritis, nausea and vomiting, gastric emptying, and urinary retention, he adds.

"We tried to use the drug to distinguish between central and peripheral effects of opiates," he says. "We have some data showing it also may have use in intensive care units in terms of facilitating feeding of patients and gastric emptying, but these are not approved, indicated uses."

Also there are clinical trials underway to extend the drug's use to OIC in chronic pain, but this research is not yet complete, Moss says.

Another new drug in the same new class, alvimopan, to facilitate gut function after bowel surgery, was recently approved by the FDA, Moss says.

"Alvimopan, an oral drug, has been proven useful in facilitating gut recovery in the perioperative period, but to date has not been successful in trials for chronic pain or cancer pain," he says. "People have tried chewing gum and a lot of things, but aside from alvimopan there are no other approved therapies to facilitate gut function after surgery."

Unlike methylnaltrexone, alvimopan is actually contraindicated at its current dose in patients taking chronic opiates and requires enrollment in a Rise Evaluation and Mitigation Strategy (REMS) program.

How this little drug got to market

Methylnaltrexone's journey to reach market is somewhat unusual since the first investigators working on the product had personal investments of time and interest in finding a successful treatment for cancer patients to use.

Methylnaltrexone is an old drug developed decades ago. In 1978, Leon Goldberg, a University of Chicago chair on the Committee on Clinical Pharmacology, was asked by a colleague with metastatic prostate cancer for help in coping with morphine-induced constipation. The man had declined morphine because of the side effect of constipation.2

Goldberg studied methylnaltrexone as a possible peripheral antagonist, but died before he could complete his investigations.2

"Dr. Goldberg was a close, personal friend of mine, and I knew him before I came here," Moss says.

Other researchers at the University of Chicago decided to continue the research.

"We thought the idea was a very good one and elected to try to finish his work," Moss says. "We thought we could complete his mission of developing the drug successfully within a few years, but it took far longer."

The investigators worked on their own, taking the drug from conception to animal studies to human studies before licensing the drug to Progenics Pharmaceuticals Inc., a biopharmaceutical company located in Tarrytown, NY, says Moss, who has continued to use the drug in clinical and cellular research.

Progenics chose to develop the drug initially in patients with the greatest need, those with advanced illness receiving palliative care.

"Palliative care physicians are very protective of their patients, and doing trials that would pass ethical review required thoughtful deliberation," he explains. "It is very difficult to develop a new drug in the palliative care setting."

During the past decade, as the drug was being studied, it was made available to patients on a compassionate use basis, Moss says.

"The drug eases a tremendous burden," Moss says. "Within 15-20 minutes, patients usually start to move their bowels and sometimes pass three to four pounds of stool if they have not laxated in several days."

"Methylnaltrexone helps advanced illness patients to receive adequate analgesia and maintain GI function," Moss adds.

"My personal recommendation is that patients should start out with the recommended dose," he says. "Although patients reported some discomfort with the side effects, generally related to the return of bowel function, they almost all chose to continue Relistor."

Progenics partnered in producing methylnaltrexone with Wyeth Pharmaceuticals in December 2005.

Initial trials involve IV use, but investigators found that subcutaneous administration was very effective, Moss says.

"One thing we like about subcutaneous usage is the onset is reported to be 30 minutes in 30% of patients," Moss says. "Once injected, the drug works quickly and reliably, so nurses can time when patients will need help with defecation."

Also, there is an oral methylnaltrexone product currently in development, Moss adds.

References

  1. Moss J, Rosow CE. Development of peripheral opioid antagonists: New insights into opioid effects. Mayo Clin Proc 2008;83:1116-1130.
  2. Mutations in a molecule: The virtues of antagonism. Mayo Clin Proc 2008;83:1083-1086.