A randomized study of lubiprostone for opioid-induced constipation in patients with chronic noncancer pain

Abstract

Objective: To evaluate the efficacy and safety of oral lubiprostone for relieving symptoms of opioid-induced constipation (OIC) in patients with chronic noncancer pain.

Design: Prospective, randomized, double-blind, placebo-controlled trial.

Setting: Seventy-nine US and Canadian centers.

Subjects: Patients aged ≥ 18 years with OIC, defined as <3 spontaneous bowel movements (SBMs) per week.

Methods: Patients received lubiprostone 24 mcg or placebo twice daily for 12 weeks. The primary endpoint was change from baseline in SBM frequency at week 8.

Results: Among randomized patients (N=418; lubiprostone, N=210; placebo, N=208), most completed the study (lubiprostone, 67.1%; placebo, 69.7%). The safety and efficacy (intent-to-treat) populations included 414 (lubiprostone, N=208; placebo, N=206) and 413 (lubiprostone, N=209; placebo, N=204) patients, respectively. The mean (standard deviation) age was 50.4 (10.9) years; most patients were female (64.4%) and white (77.7%). Changes from baseline in SBM frequency rates were significantly higher at week 8 (P=0.005) and overall (P=0.004) in patients treated with lubiprostone compared with placebo. Pairwise comparisons showed significantly greater overall improvement for abdominal discomfort (P=0.047), straining (P<0.001), constipation severity (P=0.007), and stool consistency (P<0.001) with lubiprostone compared with placebo. Moreover, patients rated the effectiveness of lubiprostone as significantly (P<0.05) better than placebo for 11 of 12 weeks. The most common treatment-related adverse events (AEs) with lubiprostone and placebo were nausea (16.8% vs 5.8%, respectively), diarrhea (9.6% vs 2.9%), and abdominal distention (8.2% vs 2.4%). No lubiprostone-related serious AEs occurred.

Conclusion: Lubiprostone effectively relieved OIC and associated signs and symptoms and was well tolerated in patients with chronic noncancer pain (https://ichgcp.net/clinical-trials-registry/NCT00595946).

Keywords: Bowel Movement; ClC-2; Opioid; Opioid-Induced Constipation; Placebo-Controlled Trial; Prostone.

© 2014 The Authors. Pain Medicine published by Wiley Periodicals, Inc. on behalf of American Academy of Pain Medicine.

Figures

Figure 1

(A) Change from baseline in frequency of spontaneous bowel movements (SBMs) in patients treated with lubiprostone 24 mcg twice daily compared with placebo (intent-to-treat population). P values from van Elteren tests stratified by pooled center. (B) Percentage of patients with first SBM within 24 and 48 hours of initial dose of lubiprostone 24 mcg twice daily compared with placebo. P values are from χ2 tests. No imputation of missing data was performed.

Figure 2

Overall change from baseline in constipation-associated symptoms in patients treated with lubiprostone 24 mcg twice daily compared with placebo (intent-to-treat population). P values are from the van Elteren test. Hommel's stagewise rejective method was used to adjust P values for the following: *stool consistency, for straining; †straining, for stool consistency; ‡abdominal discomfort, for abdominal bloating; and §abdominal bloating, for abdominal discomfort. The scale ranged from 0 (very loose) to 4 (very hard; little balls) for stool consistency, from 0 (absent) to 4 (very severe) for severity of associated symptoms, and from 1 (very regular) to 7 (very irregular) for bowel habit regularity. No imputation of missing data was performed.

Figure 3

Overall effectiveness of lubiprostone 24 mcg twice daily compared with placebo in the intent-to-treat population. *P < 0.05 by van Elteren test stratified by pooled site. Missing data were imputed using the last observation carried forward (LOCF) method. Results from non-LOCF analysis were similar at almost all treatment weeks. The scale ranged from 0 (not at all effective) to 4 (extremely effective).