The long-term safety of naldemedine, a peripherally acting µ-opioid receptor antagonist, was evaluated in patients with opioid-induced constipation and chronic noncancer pain in a 52-week, randomized, double-blind, phase 3 study. Eligible adults who could be on a routine laxative regimen were randomized 1:1 to receive once-daily oral naldemedine 0.2 mg (n = 623) or placebo (n = 623). The primary endpoint was summary measures of treatment-emergent adverse events (AEs). Additional endpoints included opioid withdrawal on the Clinical Opiate Withdrawal Scale and the Subjective Opiate Withdrawal Scale, pain intensity on Numeric Rating Scale, frequency of bowel movements, and constipation-related symptoms and quality of life on the Patient Assessment of Constipation Symptoms and Patient Assessment of Constipation Quality of Life scales, respectively. Treatment-emergent AEs (naldemedine, 68.4% vs placebo, 72.1%; difference: −3.6% [95% confidence interval: −8.7 to 1.5]) and treatment-emergent AEs leading to study discontinuation (6.3% vs 5.8%; difference: 0.5% [−2.2 to 3.1)] were reported for similar proportions of patients. Diarrhea was reported more frequently with naldemedine (11.0%) vs placebo (5.3%; difference: 5.6% [2.6-8.6]). There were no meaningful differences between groups in opioid withdrawal or pain intensity. Sustained significant improvements in bowel movement frequency and overall constipation-related symptoms and quality of life were observed with naldemedine (P ≤ 0.0001 vs placebo at all time points). Naldemedine was generally well tolerated for 52 weeks and did not interfere with opioid-mediated analgesia or precipitate opioid withdrawal. Naldemedine significantly increased bowel movement frequency, improved symptomatic burden of opioid-induced constipation, and increased patients' quality of life vs placebo.
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Naldemedine treatment of opioid-induced constipation was well tolerated for 52 weeks, did not precipitate opioid withdrawal, and increased bowel movements and quality of life.
aScientific Affairs -- Neuroschences PRA Health Sciences, PRA Health Sciences, Salt Lake City, UT, USA
bMid America PolyClinic, Overland Park, KS, USA
cDepartment of Cardiovascular Sciences, Unit Anesthesiology and Algology, University of Leuven, Leuven Center for Algology and Pain Management, University Hospital Leuven, Catholic University of Leuven, Leuven, Belgium
dShionogi Inc, Florham Park, NJ, USA
Corresponding author. Address: Shionogi Inc, 300 Campus Dr, Florham Park, NJ 07930, USA. Tel.: +1 973-307-3886. E-mail address: firstname.lastname@example.org (T. Yamada).
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Received November 07, 2017
Received in revised form January 09, 2018
Accepted January 29, 2018