Long-Term Efficacy With Lubiprostone in Opioid Constipation

Nancy A. Melville

September 09, 2013

LAS VEGAS — Constipation drug lubiprostone (Amitiza, Sucampo Pharmaceuticals, Takeda Pharmaceuticals) remains effective and well tolerated in the treatment of opioid-induced constipation (OIC) over the course of 9 months, a new analysis shows.

The locally acting chloride channel (CIC-2) activator, which previously had approval from the US Food and Drug Administration for the treatment of chronic constipation and irritable bowel syndrome with constipation, was approved in April for the indication of OIC, as reported by http://www.medscape.com/viewarticle/802953 Medscape Medical News.

It is the first oral medication to receive approval in the United States for the treatment of OIC in adult patients with chronic, noncancer pain.

The drug was previously demonstrated to effectively treat the constipation that commonly affects opioid users in two 12-week, placebo-controlled clinical trials, and the new extension study was conducted to evaluate the safety and efficacy of the treatment (24 μg twice daily) over an additional 9 months.

"Lubiprostone treatment was well tolerated and resulted in overall improvement in symptoms and signs of OIC in this 9-month, open-label study," the authors concluded.

These long-term results were presented here at PAINWeek.

9-Month Extension

The study population included 439 patients (59.9% female) who were initially enrolled in the 12-week studies. Inclusion criteria included treatment with a full opioid agonist for the duration of the study and OIC, defined as fewer than 3 spontaneous bowel movements (SBMs) per week during the screening period, in addition to hard stools, sensation of incomplete evacuation, or at least moderate straining.

During the 9-month extension study period, participants showed statistically significant improvements from baseline at monthly assessments, with SBM frequencies ranging from 4.9 to 5.3 per week, compared with an average of 1.4 per week at baseline (P < .001 vs baseline at all months).

Patients also reported improvements in factors including the average degree of straining, stool consistency, constipation severity, abnormal bloating and discomfort, and bowel habit irregularity (P < .001 at all treatment months).

Reliance on rescue medication declined significantly over the course of the study, from 33% at month 1 to 18.6% at month 9, and 24.6% of patients reported treatment-related adverse events. The most common adverse events were nausea (5.0%), diarrhea (4.6%), and flatulence (1.6%).

Only 2 of the nausea and 2 diarrhea cases were rated as severe.

While the findings suggest important benefits from lubiprostone, lead author Egilius L.H. Spierings, MD, PhD, asserted that clinicians prescribing patients opioids should take prophylactic action to prevent constipation before patients even get to the point of needing a prescription medication.

"I think it is rare that physicians provide patients with the proper instruction from the start," said Dr. Spierings, an associate clinical professor of neurology at Brigham and Women's Hospital in Boston, Massachusetts.

"The general mistake they make is to wait until the patient gets constipated and by then it is already more difficult to treat," he told Medscape Medical News. "So it's really important that you start with it right away and then you can discontinue if you need."

Dr. Spierings recommended stool softeners to begin with, but underscored the need to additionally monitor such patients.

"I give patients specific instructions as to what to get, how to dose it and what to do if things don't work," he said.

"In my experience, constipation can often be addressed with relatively simple means that are relatively cheap, and certainly before prescription medication is needed, which can be more expensive."

Not Ideal Treatment

Gastroenterologist Darren M. Brenner suggested that stool softeners in fact may not be the most ideal treatment for OIC.

"Opioids slow things down, drawing water out of the GI [gastrointestinal] tract and causing stool to harden," said Dr. Brenner, an assistant professor of medicine in gastroenterology, hepatology, and surgery at Northwestern University's Feinberg School of Medicine in Chicago, Illinois.

"A stimulant can be useful to jump-start the system, but in the same vein I am very much against stool softeners," he said.

"If you have hard impacted stool throughout the colon that is not moving and you use a medication that does not increase motility but just makes the stool softer, there is a potential for leakage. Patients may complain of fecal seepage or soiling and they will think they have diarrhea but what they're really doing is leaking around hard impacted stool."

Dr. Brenner said he supports the use of mu-opioid receptor agonists in a treatment regimen for OIC.

"Overall I feel the mu-opioid receptor agonists work better faster and the data is more robust. I use these agents in my treatment algorithm."

In initiating treatment, Dr. Brenner said that, instead of stool softeners, he prefers to start patients on osmotic laxatives.

"Specifically, polyethylene glycol 3350 — it is safe, effective, it's evidence-based, and it does not get out of the gastrointestinal tracts and patients don't have to worry about drug-to-drug interactions," he said.

"In addition, patients will not become tolerant to it or dependent on it."

The study was sponsored by Takeda Pharmaceuticals International Inc. and Sucampo PharmaAmericas, LLC. Dr. Spierings is a consultant for Sucampo Pharmaceuticals. Dr. Brenner is on the speaker's bureaus for Ironwood Pharmaceuticals Inc./Forest Laboratories, Inc. and Salix Pharmaceuticals, Inc. He is a consultant for Perrigo Co., and Salix Pharmaceuticals.

PAINWeek 2013. Abstract 43.

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