Nancy A. Melville

September 26, 2012

September 26, 2012 (Phoenix, Arizona) — Constipation drug lubiprostone (Amitiza, Sucampo Pharmaceuticals, Takeda Pharmaceuticals) shows efficacy and tolerability in treating opioid-induced constipation without affecting patients' analgesic response to the pain medications, according to research presented here at the American Academy of Pain Management (AAPM) 23rd Annual Meeting.

Lubiprostone has approval from the US Food and Drug Administration (FDA) for the treatment of chronic constipation and irritable bowel syndrome with constipation.

In an effort to evaluate its efficacy in the treatment of the common problem of constipation related to opioid use, researchers conducted a phase 3, placebo-controlled study of 439 patients with opioid bowel dysfunction.

The patients were evenly, randomly assigned to receive either lubiprostone 24 mcg or placebo twice daily for 12 weeks. Eligible participants had to have been receiving consistent treatment with a full-agonist opioid other than methadone for at least 30 days prior to screening and maintained throughout the study.

Criteria also included having reported an average of fewer than 3 spontaneous bowel movements (SBMs) per week.

The study's primary endpoint was overall SBM response rate, defined as having 3 or more SBMs per week for at least 9 weeks and at least 1 additional SBM over the mean baseline.

At the end of the 12-week treatment period, the results showed that significantly more patients taking lubiprostone were overall SBM responders compared with those receiving placebo (26.9% vs 18.6%, P = .035), and the median time to first SBM was also significantly reduced for patients in the lubiprostone group (24.3 vs 38.5 hours, P = .019).

In addition, a significantly higher proportion of lubiprostone patients reported their first SBM within 4, 8, 12, 24, and 48 hours of taking the first dose (P ≤ .022).

"Patients in the treatment group had a first SBM after treatment 14 hours sooner than those in the placebo group, so the rapid onset of action is another key differentiating factor with this drug," said coauthor Taryn R. Joswick, vice president of clinical development with Sucampo, in Bethesda, Maryland.

Importantly, there were no significant differences between the lubiprostone-treated and placebo groups in terms of opioid-related analgesia during treatment, assessed according to the Brief Pain Inventory–Short Form, and changes in morphine equivalent daily dose.

"We didn't see a difference between opioid dose adjustments between the 2 groups," Joswick said.

Lubiprostone is a locally acting chloride channel (ClC-2) activator that has a distinctive mechanism that counteracts the constipation associated with opioids without interfering with the opiates binding to their target receptors, Joswick explained.

"The unique aspect of this drug is it acts by a totally different route mechanism of action — selective chloride channel activation. Opiates can cause decreased electrolyte absorption in the gut, which thereby decreases intestinal fluid, but this drug can counteract that without any interaction with the opiate that is locally metabolized in the intestine."

The most common adverse events reported in the lubiprostone group compared with the placebo group were diarrhea (9.6% vs 1.4%), nausea (8.2% vs. 2.7%), and abdominal pain (5.5% vs 0.0%), and there were no serious adverse events.

Sucampo and Takeda Pharmaceuticals USA filed a supplemental New Drug Application with the FDA in July seeking approval for this new indication for lubiprostone in the treatment of opioid-induced constipation (OIC) among patients with chronic, noncancer pain; the application is currently under review.

"There are currently no approved drugs for OIC in patients with chronic noncancer pain in this market, so hopefully this will be the first drug of this type in the US for these patients," Joswick said.

Ongoing Struggle

According to pain specialist Srinivas R. Nalamachu, MD, codirector of the Pain Management Institute in Overland Park, Kansas, opioid-related constipation is an ongoing struggle for pain management patients, and an effective treatment to address the problem is needed.

"About 20% of patients on opioids develop constipation, and some of the traditional constipation medications don't work as well with these patients," he explained.

"That's because the problem is not from the gastrointestinal tract but from the central nervous system, so treating these patients is different from treating a traditional patient with constipation."

"We are looking forward to this type of drug, and I would say it could be a welcome addition," he said.

The study was supported by Sucampo Pharmaceuticals, Inc, and Takeda Pharmaceutical Company. Joswick is an employee of Sucampo. Dr. Nalamachu has disclosed no relevant financial relationships.

American Academy of Pain Management (AAPM) 23rd Annual Meeting. Poster abstract 10. Presented September 21, 2012.