Onset of action of naldemedine in the treatment of opioid-induced constipation in patients with chronic noncancer pain: results from 2 randomized, placebo-controlled, phase 3 trials

Abstract

Opioid-induced constipation (OIC) is a common side effect of chronic opioid therapy. Previously, naldemedine, a peripherally acting μ-opioid receptor antagonist demonstrated efficacy in the treatment of OIC. In this exploratory analysis, the onset of action of naldemedine was evaluated in 2 identically designed phase 3, randomized, placebo-controlled trials. Proportion of patients experiencing a spontaneous bowel movement (SBM) within 24 hours of treatment initiation, time from initial dose to first SBM and weekly SBM frequency were assessed. Naldemedine was associated with significant increases in the proportion of patients experiencing an SBM at 4, 8, 12, and 24 hours after the initial dose compared with placebo (all P < 0.0001). Within 24 hours in both studies, statistically significantly (P < 0.0001) more patients treated with naldemedine compared with placebo experienced an SBM (61.2% vs 28.3% and 56.5% vs 33.6%, respectively). Median times to first SBM were significantly shorter in the naldemedine group vs placebo (COMPOSE-1, 16.1 vs 46.7 hours; COMPOSE-2, 18.3 vs 45.9 hours; P < 0.0001). Naldemedine was also associated with significant increases in weekly SBM frequency vs placebo within 1 week (P < 0.001). Most common treatment-emergent adverse events were gastrointestinal-related (abdominal pain, diarrhea, and nausea). Treatment-emergent adverse events were reported most frequently on day 1, followed by a decrease from days 2 to 7. Naldemedine had a timely onset of effect, and gastrointestinal adverse events largely resolved within the first week. These findings should assist clinicians counseling patients with chronic noncancer pain on expectations when initiating naldemedine for OIC.

Trial registration: ClinicalTrials.gov NCT01965158 NCT01993940.

Conflict of interest statement

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Figures

Figure 1.

COMPOSE-1 and COMPOSE-2 study design.

Figure 2.

Patients with ≥1 spontaneous bowel movement after the first dose. *P < 0.0001; naldemedine vs placebo; Cochran–Mantel–Haenszel test adjusted by opioid dose stratum. SBM, spontaneous bowel movement.

Figure 3.

Patients with ≥1 complete spontaneous bowel movement after the first dose. *P < 0.0001; naldemedine vs placebo; Cochran–Mantel–Haenszel test adjusted by opioid dose stratum. CSBM, spontaneous bowel movement with a feeling of complete evacuation.

Figure 4.

Time to first spontaneous bowel movement. aKaplan–Meier analysis of time to first SBM was conducted in the intent-to-treat population, including patients who might have discontinued within 72 hours of the initial dose. SBM, spontaneous bowel movement.

Figure 5.

Change from baseline in frequency of spontaneous bowel movements per week (mixed-effect repeat-measures model with terms for treatment group, time, treatment-by-time as a fixed effect, and the opioid dose strata as a covariate). *Nominal P < 0.0001; †Nominal P = 0.0001; ‡Nominal P < 0.005. BL, baseline; LS, least squares; SBM, spontaneous bowel movement; SE, standard error.

Figure 6.

Incidence of spontaneous bowel movements and gastrointestinal treatment-emergent adverse events during study days 1 to 7. (A) COMPOSE-1. (B) COMPOSE-2. AE, adverse event; GI, gastrointestinal; SBM, spontaneous bowel movement.

Figure 7.

Number of patients reporting the 3 most common gastrointestinal treatment-emergent adverse events during study days 1 to 7. (A) Abdominal Pain. (B) Diarrhea. (C) Nausea. *Abdominal pain includes treatment-emergent adverse events of “abdominal pain,” “abdominal pain lower,” “abdominal pain upper,” and “abdominal discomfort.” C1, COMPOSE-1; C2, COMPOSE-2; Nald, naldemedine; Plac, placebo.