Laird Harrison

May 22, 2012

May 22, 2012 (Honolulu, Hawaii) — An experimental drug, CB-5945, reduced constipation in patients taking opioid drugs for chronic noncancer pain, new phase 2 trial results show.

The drug helped about half of those patients who took 0.25 mg twice a day and about a quarter of those who took 0.10 mg twice a day in the trial.

"We saw a very nice dose response," Lee M. Techner, DPM, vice president for clinical research at the drug's maker, Cubist Pharmaceuticals Inc, Lexington, Massachusetts, told Medscape Medical News.

The results were reported here at the American Pain Society (APS) 31st Annual Scientific Meeting. The study was funded by Cubist Pharmaceuticals; Cubist acquired Adolor Corporation, which was initially developing the drug, in October 2011.

Gut Motility

CB-5945, formerly called ADL5945, competes with opioids in binding to mu opioid receptors, which are believed to be responsible for affecting gut motility, Dr. Techner said. It also competes for delta opioid receptors, which might also play a role, he said.

Laxatives don't always work in patients with opioid-induced constipation and can cause their own adverse reactions, said Dr. Techner.

Currently the US Food and Drug Administration has approved only 1 mu opioid receptor antagonist for treatment of opioid constipation, methylnaltrexone (Relistor, Salix Pharmaceuticals).

Patients must take methylnaltrexone by injection, but CB-5945 is an oral formulation.

To test the experimental drug's effectiveness, Dr. Techner and his colleagues randomly assigned 45 patients to take a placebo twice per day, 43 to take 0.10 mg of CB-5945 twice per day, 56 to take 0.25 mg of CB-5945 twice per day, 45 to take CB-5945 once per day, and 41 to take the placebo once per day.

The patients were taking the morphine equivalent of 30 to 1284 mg per day and had been experiencing opioid-induced constipation for a mean of 3.4 years. Fifty-seven percent were taking the drugs for back pain.

The proportion of patients who reported increased spontaneous bowel movements ranged from 55.6% of patients who took 0.25 mg twice a day to 27.9% of those who took 0.10 mg twice a day and 25.6% of those who took the placebo twice per day.

The difference in the proportion of those responding between those receiving the 0.25-mg twice-daily dose and those taking the lower dose and placebo was statistically significant (P = .0052).

Of those who took the placebo once a day, 29.3% reported a response, compared with 42.5% of those who took 0.25 mg of the drug once per day.

The number of mean spontaneous weekly bowel movements increased from about 1 in each of the treatment groups to the following:

  • 2.42 for those receiving the once-daily placebo

  • 2.46 for those receiving the twice-daily placebo

  • 3.11 for those receiving the twice-daily low dose

  • 3.39 for those receiving the once-daily high dose, which was statistically significant (P = .0118)

  • 4.62 for those receiving the twice-daily high dose, which was statistically significant (P = .0003)

High Placebo Response

These numbers did not impress Edward Michna, MD, JD, an anesthesiologist at Brigham & Women's Hospital in Cambridge, Massachusetts, who was not involved in the study.

"It's a pretty high placebo response," he told Medscape Medical News. By contrast, 34.2% of patients responded to methylnaltrexone and 9.9% responded to a placebo in a similar study Dr. Michna and colleagues published in May 2011 in the Journal of Pain.

Dr. Michna said doctors at Brigham & Women's Hospital have not found much use for methylnaltrexone, and he thought the new drug would also appeal to only a small niche.

"It's hard for me to find patients who need this drug," he said. "We have over 1000 patients on chronic opioids and it's rare for our physicians to prescribe for constipation. Most don't have the problem or can get by on laxatives."

He speculated that patients who get constipation from opioids stop taking the opioids before it becomes necessary to treat this side effect.

Still, he imagined various categories of patients who might want to take advantage of CB-5945, including patients taking opioids for acute injury; patients with chronic diseases, such as osteoarthritis, who are getting opioids for the first time; or patients taking opioids in the perioperative period.

Even then, the market could be limited by the expense of the new drugs. At his center, patients usually can't get methylnaltrexone covered by insurance unless they have already shown no improvement with less expensive medication, he said.

In addition its oral formulation, Dr. Techner suggested that CB-5945 might appeal to more patients than methylnaltrexone because it takes effect more gradually, which he said could reduce adverse reactions.

In the CB-5945 study, the proportion of patients experiencing treatment-emergent adverse events ranged from 4% in the twice-daily 0.25-mg group to 15% in the once-daily 0.25-mg group and was also 15% in the once-daily placebo. "The safety profile was comparable to placebo," concluded Dr. Techner.

Dr. Michna responded that patients might favor different onset times. "Probably for some patients more gradual is better," he said. "Other patients might like having an immediate effect."

The drug is now entering phase 3 trials, said Dr. Techner.

The study was funded by Cubist Pharmaceuticals. Dr. Techna disclosed that he is employed by Cubist Pharmaceuticals, the maker of CB-5945. Dr. Michna disclosed that he has served as a consultant to Salix, the maker of methylnaltrexone.

American Pain Society (APS) 31st Annual Scientific Meeting. Abstract # 434. Presented May 17, 2012.

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