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In three placebo-controlled randomized studies, the drug increased the number of spontaneous bowel movements and improved stool consistency without inducing opioid withdrawal symptoms.
Naldemedine (Symproic) received FDA approval last year based on COMPOSE 1 and COMPOSE 2, which were published in Lancet Gastroenterology and Hepatology last year (2017 Aug 2[8]:555-64). James E. Wild, MD, of Upstate Clinical Research Associates, in Williamsville, N.Y., reported these in a poster presented at the annual PAINWeek.
The year-long COMPOSE 3 trial was not presented at the meeting, but appeared in the journal Pain (2018 May;5:987-94).
Opioids not only affect the central nervous system but also bind to mu-opioid receptors in the gut, decreasing intestinal motility. Naldemedine blocks these receptors from opioid binding but cannot cross the blood-brain barrier. Its peripheral action blocks gut opioid binding, side-stepping the motility problem without inducing any opioid withdrawal symptoms.
COMPOSE 1 (C1) and COMPOSE 2 (C2) comprised a total of 1,095 subjects with chronic, noncancer pain. They were randomized to either naldemedine 0.2 mg daily or placebo for 12 weeks.
Patients were a median of 53 years with a mean opioid use of 61 months. About 60% had a mean daily morphine equivalent of 30-100 mg, and 40% a mean dose of more than 100 mg. At baseline, they had a mean of one spontaneous bowel movement (BM) per week, with a mean of 0.4 deemed “complete.” All the BMs were accompanied by straining.
Response was defined as a patient who had at least three spontaneous BMs per week and an increase of at least one for that week, for at least 9 of the 12 treatment weeks and at least 3 of the last 4 weeks of the trial.
In both studies, the responder rate was significantly higher in the naldemedine group than in the placebo group (C1 48% vs. 34%; C2 53% vs. 33%). Those taking naldemedine had a mean of two more spontaneous BMs per week than did those taking placebo, and significantly more of those were accomplished without straining.
The most common treatment-emergent adverse effects were diarrhea (about 8% vs. 3%) and abdominal pain (about 6% vs. 1%).
Three patients in C1 experienced at least one event of opioid withdrawal (two taking the study drug and one taking placebo). There were no confirmed withdrawal events in C2, but seven patients (five taking the study drug and two taking placebo) experienced possible gastrointestinal withdrawal symptoms.
COMPOSE 3 demonstrated naldemedine’s lasting benefit in this population. It randomized 1,246 patients to 52 weeks of placebo or the 0.2 mg/day dose. Patient demographics were similar to the earlier COMPOSE studies.
The primary endpoint was treatment-emergent adverse events. Additional endpoints included opioid withdrawal, pain intensity, frequency of bowel movements, and constipation-related symptoms.
There was a significant and sustained increase from baseline in the frequency of bowel movements with naldemedine, increasing from about two to four each week. Constipation symptoms and quality of life scores both improved significantly, relative to placebo.
Again, the most common adverse event was diarrhea (11% naldemedine vs. 5% placebo). The drug was not associated with any opioid withdrawal symptoms, nor did it interfere with a patient’s pain control.