A peripherally acting oral μ-opioid receptor antagonist is superior to placebo in treating opioid-induced constipation (OIC) and doesn’t reduce the analgesic effect of opioids, a new phase 3 study shows.
If approved, the new drug, naldemedine (Shionogi Inc), will provide another option for physicians and patients to treat OIC, which is common in patients taking opioids, said lead researcher, Juan Camilo Arjona Ferreira, MD, senior vice president, clinical development, Shionogi Inc.
Dr Arjona presented the research at a poster session during the American Academy of Pain Medicine (AAPM) 2016 Annual Meeting.
Currently, he said, the most frequently used treatment for OIC is over-the-counter laxatives, but several drugs have recently been approved for this indication, including naloxegol (Movantik, AstraZeneca Pharmaceuticals), a peripherally acting opioid receptor antagonist, and methylnaltexone (Relistor, Salix Pharmaceuticals/Progenics Pharmaceuticals) subcutaneous injection.
This drug, now in development, doesn’t cross the blood-brain barrier but acts peripherally. This means that it doesn’t also reverse the effect of the opioid, said Dr Arjona.
“You can treat opioid-induced constipation without removing the analgesic effect of the opioid. So you still have the benefit of pain management, but you don’t have the constipation.”
Dr. Arjona believes that naldemedine has a better tolerability profile than anything currently available. “It solves the symptoms of constipation, improves the frequency of bowel movements, and also improves the consistency of stools.”
The multicenter, 12-week study included 545 patients with chronic noncancer pain receiving opioid therapy for 3 or more months and experiencing OIC. They were not using laxatives or were willing to give them up during the study.
These patients were randomly assigned to placebo or naldemedine (0.2 mg once daily).
Of the 273 patients in the naldemedine group, 47.6% were responders compared with 34.6% of the 272 patients in the placebo group, a difference of 13 percentage points (P = .002). A responder was defined as having at least 9 positive-response weeks (PRW) and 3 or more in the last 4 weeks of treatment. A PRW was a week with 3 or more spontaneous bowel movements, and an increase of at least 1 of these from baseline.
Those receiving naldemedine also did better than the placebo group on several secondary endpoints related to the change in frequency of spontaneous bowel movements, including those without straining and those accompanied by a feeling of complete evacuation.
The most common adverse effects associated with this drug are related to the gastrointestinal tract and include abdominal pain, diarrhea, and nausea, which are linked to the mechanism of action. These usually occur right after initiation of treatment and then get better, according to Dr Arjona.
In this study, abdominal pain occurred in 6.3% of patients taking naldemedine compared with 1.8% of those receiving placebo. Diarrhea was reported in 6.6% of the treatment group and 2.9% of the placebo group, while nausea occurred in 4.8% of the treatment and 2.6% of the placebo group.
The treatment was not associated with signs or symptoms of opioid withdrawal and did not affect the analgesic effect of opioids.
In addition to the current study, the company has a completed positive dose-finding study. It plans to submit a new drug application to the US Food and Drug Administration “within this quarter” said Dr Arjona.
For a comment on the study, Medscape Medical News approached Erin E Krebs, MD, associate professor of medicine, University of Minnesota, Minneapolis, who is a primary care physician with a research focus on chronic pain management.
Dr. Krebs said she doesn’t see the need for another constipation treatment for her patients.
“Constipation is common, and we have a lot of options for it, most of which have been around for decades. They’re cheap, they’re easy to use, and they work.”
There may be a need for such a new medication “in some super-specialized practices,” said Dr Krebs. “But at least in my practice, I haven’t seen a need for a specific product for opioid-induced constipation.”
Constipation is so “exceptionally” common among opioid users that Dr Krebs typically prescribes something to treat it — over-the-counter or otherwise — whenever she gives an opioid prescription to a patient.
American Academy of Pain Medicine (AAPM) 2016 Annual Meeting.