Naldemedine a potential treatment for opioid-induced constipation
A once-daily dose of naldemedine improved opioid-induced constipation in adults with chronic noncancer pain, according to results from the phase III COMPOSE-1 and COMPOSE-2* trials.
Patients (mean age 53 and 54 years in the COMPOSE-1 and COMPOSE-2 trials, respectively) on a stable opioid regimen for chronic noncancer pain (≥30 mg equivalent of oral morphine daily for ≥1 month prior to screening) and not using laxatives were randomized to receive oral naldemedine (0.2 mg, n=274 [COMPOSE-1] and n=277 [COMPOSE-2]) or placebo (n=273 [COMPOSE-1] and n=276 [COMPOSE-2]) once a day for 12 weeks.
The primary endpoint was the proportion of patients having ≥3 spontaneous bowel movements (SBMs) per week, with an increase of ≥1 SBM per week from baseline for ≥9 weeks and ≥3 of the last 4 weeks of the treatment period.
Compared with placebo, more patients on naldemedine met the primary endpoint in both the COMPOSE-1 (47.6 percent vs 34.6 percent, difference 13 percent, 95 percent confidence interval [CI], 4.8–21.3 percent; p=0.002) and COMPOSE-2 trials (52.5 percent vs 33.6 percent, difference 18.9 percent, 95 percent CI, 10.8–27.0 percent; p<0.0001). [Lancet Gastroenterol Hepatol 2017;doi:10.1016/S2468-1253(17)30105-X]
There was a greater increase in mean SBM frequency per week between baseline and the last 2 weeks of treatment in the naldemedine vs placebo groups in both trials (3.42 vs 2.12 in COMPOSE-1 and 3.56 vs 2.16 in COMPOSE-2; p<0.0001 for both trials).
Adverse event (AE) incidence was comparable between naldemedine and placebo in both COMPOSE-1 (49 percent vs 45 percent) and COMPOSE-2 (50 percent vs 48 percent).
Incidence of treatment-related AEs was higher among patients on naldemedine compared with placebo (22 percent vs 17 percent [COMPOSE-1] and 20 percent vs 11 percent [COMPOSE-2]), driven primarily by the higher incidence of gastrointestinal disorders in individuals on naldemedine compared with placebo (15 percent vs 7 percent [COMPOSE-1] and 16 percent vs 7 percent [COMPOSE-2]).
The most frequent AE among patients on naldemedine compared with placebo were diarrhoea (7 percent vs 3 percent [COMPOSE-1] and 9 percent vs 2 percent [COMPOSE-2]) and abdominal pain (6 percent vs 2 percent [COMPOSE-1] and 5 percent vs 1 percent [COMPOSE-2]). One patient on naldemedine in COMPOSE-1 and one patient on placebo in COMPOSE-2 had a major adverse cardiovascular event.
Study design prevented the researchers from determining if naldemedine was effective in treating both opioid-induced and opioid-exacerbated constipation, as well as whether naldemedine was superior to laxatives.
“Unlike many other opioid-related adverse effects, opioid-induced constipation does not subside over time,” said the researchers.
“Our data ... provide evidence that the use of a [peripherally acting µ-opioid receptor antagonist] for the treatment of opioid-induced constipation is a safe and effective therapeutic approach to reverse the most common and bothersome side effect of opioid use for patients with chronic noncancer pain,” they said.