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.