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Opioid-induced constipation (OIC) is a common side effect of chronic opioid therapy. Previously, naldemedine, a peripherally acting ì-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 versus 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 versus placebo within 1 week (P<0.001). Most common treatment-emergent adverse event (TEAE) were gastrointestinal-related (abdominal pain, diarrhea, and nausea). TEAEs were reported most frequently on day 1, followed by a decrease from days 2–7. Naldemedine had a timely onset of effect, and gastrointestinal AEs largely resolved within the first week. These findings should assist clinicians counseling patients with chronic noncancer pain on expectations when initiating naldemedine for OIC. ClinicalTrials.gov Registration: NCT01965158 and NCT01993940This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.