Naldemedine is effective in the treatment of opioid-induced constipation in patients with chronic non-cancer pain who had a poor response to laxatives

Abstract

Background: Two studies demonstrated the efficacy and safety of naldemedine in adult patients with chronic non-cancer pain and opioid-induced constipation (OIC). However, no studies have compared the efficacy of peripherally acting µ-opioid receptor antagonists in patients with adequate and inadequate responses to prior OIC therapy with laxatives. This post hoc analysis of integrated data from the two previous studies compared the efficacy of naldemedine in patients who were unsuccessfully treated with laxatives [poor laxative responders (PLRs)] with those who either did not receive laxatives >30 days prior to screening or those who only received rescue laxative at or after screening (non-PLRs).

Methods: Patients with OIC were randomized to once-daily treatment with naldemedine 0.2 mg or placebo. The primary efficacy endpoint was the proportion of responders [⩾3 spontaneous bowel movements (SBMs)/week and an increase from baseline of ⩾1 SBM/week for ⩾9 weeks of the 12-week treatment period and ⩾3 weeks of the final 4 weeks of the 12-week treatment period]. Additional endpoints included change in SBM frequency, change in frequency of SBMs without straining, proportion of complete SBM (CSBM) responders, change in CSBM frequency, and time to first SBM. Treatment-emergent adverse events (TEAEs) were assessed.

Results: The analysis included 538 (317 PLRs, 221 non-PLRs) and 537 (311 PLRs, 226 non-PLRs) patients in the naldemedine and placebo arms, respectively. There were significantly more responders in the naldemedine PLR (46.4%; p < 0.0001) and non-PLR (54.3%; p = 0.0009) subgroups versus the placebo groups (30.2% and 38.9%, respectively). In both the PLR and non-PLR subgroups, naldemedine treatment was superior to placebo on all additional endpoints. Overall incidence of TEAEs in the PLR subgroups treated with naldemedine or placebo was similar.

Conclusion: This integrated analysis further supports the efficacy and tolerability of naldemedine in the treatment of OIC and demonstrates a consistent effect in both PLR and non-PLR subgroups.[ClinicalTrials.gov identifier: NCT01965158 and NCT01993940].

Keywords: antagonists; chronic pain/drug therapy; constipation; laxatives; opioid.

Conflict of interest statement

Conflict of interest statement: MH was a clinical trial investigator, consultant to Shionogi Inc. and received a stipend for review of the clinical study report. JW received a stipend from Shionogi Inc. for review of the clinical study report. T Yamada is an employee of Shionogi Inc. who may or may not own stock options. T Yokota is an employee of Shionogi & Co., Ltd. who may or may not own stock options. JT has provided scientific advice to Allergan, Kyowa Kirin, Shionogi, and Shire, has been a speaker for Allergan and Kyowa Kirin, and has received a research grant from Kyowa Kirin related to opioid-induced constipation. VA has received speaker and/or consultant fees from Allergan, Bayer, Falk, Ferring, Hexal, Kyowa Kirin, 4M-Medical, Sanofi, and Shionogi. AMD has no conflicts to declare.

© The Author(s), 2021.

Figures

Figure 1.

Study design. PLRs were defined as patients who were on laxative therapy prior to entering the study and who stopped its use within 30 days prior to screening. Non-PLRs were defined as patients who stopped laxatives >30 days prior to screening or who only received rescue laxative at or after screening. Non-PLR, non-poor laxative responder; OIC, opioid-induced constipation; PLR, poor laxative responder; QD, once daily; R, randomization.

Figure 2.

Spontaneous bowel movement responders in PLR and non-PLR subgroups by laxative response at baseline (primary endpoint). NAL, naldemedine; non-PLR, non-poor laxative responder; PLR, poor laxative responder. *p value calculated by Cochran–Mantel–Haenszel test.

Figure 3.

Change from baseline to each week in frequency of spontaneous bowel movements in (a) PLR and (b) non-PLR subgroups. LS, least-squares; NAL, naldemedine; non-PLR, non-poor laxative responder; PLR, poor laxative responder; SBM, spontaneous bowel movement; SE, standard error. *p ⩽ 0.0001 for naldemedine versus placebo.

Figure 4.

Change from baseline in frequency of spontaneous bowel movements without straining per week to the last 2 weeks of the treatment period in PLR and non-PLR subgroups by laxative response at baseline. ANCOVA, analysis of covariance; LS, least-squares; NAL, naldemedine; non-PLR, non-poor laxative responder; PLR, poor laxative responder; SBM, spontaneous bowel movement. *p value calculated by ANCOVA using the opioid dose strata as a covariate.

Figure 5.

Kaplan–Meier estimate of time to first spontaneous bowel movement in (a) PLR and (b) non-PLR subgroups and (c) in PLR/non-PLR subgroups treated with naldemedine. Vertical lines represent censored time. NAL, naldemedine; non-PLR, non-poor laxative responder; PLR, poor laxative responder; SBM, spontaneous bowel movement. *p value calculated by the generalized Wilcoxon test adjusted by study.