Abstract and Introduction
Abstract
Objectives: To assess the efficacy and safety of lubiprostone in adults with chronic constipation.
Methods: This multicenter, parallel-group, double-blind controlled trial enrolled 242 patients with constipation and randomized them to receive oral lubiprostone 24 mcg or placebo twice daily for 4 wk. The primary efficacy end point was the number of spontaneous bowel movements (SBMs; those occurring without use of constipation relieving medications) after 1 wk of double-blind treatment. Other evaluations included SBMs at weeks 2, 3, and 4; bowel movement (BM) characteristics (i.e., consistency and straining); constipation severity; abdominal bloating/discomfort; global treatment effectiveness ratings; and safety assessments.
Results: The 120 lubiprostone-treated patients reported a greater mean number of SBMs at week 1 compared with the 122 placebo-treated patients (5.69 vs 3.46, P = 0.0001), with a greater frequency of SBMs also reported at weeks 2, 3, and 4 (P ≤ 0.002). Within 24 h of the first dose of study drug, 56.7% of those given lubiprostone reported a SBM compared with 36.9% of those given placebo (P = 0.0024); within 48 h, 80% and 60.7% of these patients reported a SBM (P = 0.0013), respectively. Stool consistency, straining, and constipation severity, as well as patient-reported assessments of treatment effectiveness, were significantly improved with lubiprostone compared with placebo at all weeks (P ≤ 0.0003). The two most common treatment-related adverse events were nausea (31.7%) and headache (11.7%).
Conclusions: In patients with chronic constipation, treatment with lubiprostone produces a BM in the majority of individuals within 24-48 h of initial dosing and improves the frequency as well as other characteristics associated with BMs with short-term (i.e., 4 wk) treatment. The most commonly reported adverse event was mild to moderate nausea, which resulted in treatment discontinuation in 5% of treated patients.
Introduction
Constipation is a common gastrointestinal complaint, generally defined as infrequent or difficult passage of stool. It has been estimated that 12-19% of the overall population experiences chronic constipation; however, the actual occurrence may be higher as many individuals with constipation suffer without seeking professional care. Constipation is more often reported by females than males (estimated prevalence rate of 2.2:1) and by those over 65 yr of age. Those reporting constipation experience significant decrements in their quality of life, reduced productivity, and increased numbers of missed days of work/school.
Although in some instances constipation may be caused by mechanical obstruction, other cases may be associated with factors such as a diet low in soluble and insoluble fiber, inadequate exercise, medication use (in particular, opiate analgesics, anticholinergic antidepressants, and calcium channel blockers), bowel dysfunction, neuromuscular disorders, metabolic abnormalities, poor abdominal pressure, or muscular atony. Patients generally report constipation in terms of symptoms, such as straining and stool consistency, whereas physicians often define constipation in terms of frequency of bowel movements (BMs).
Regardless of etiology, the goals of constipation treatment are to improve patients' symptoms and restore normal bowel function. Until recently, treatment options for those with constipation were generally limited to lifestyle (i.e., exercise) and dietary changes such as increased fiber and fluid intake, with these still considered the first line of management. Unfortunately, many patients with constipation continue to experience infrequent BMs or unpleasant symptoms such as gas production from the increased fiber intake. These patients may benefit from the initiation of various laxatives (including bulking agents, osmotic and stimulant laxatives, and stool softeners) that have been approved for short-term treatment of constipation. However, results of two recently published systematic reviews of the literature reported primarily fair to poor evidence in support of the benefits of these agents in patients with chronic constipation. The osmotic laxatives polyethylene glycol (PEG) and lactulose were supported by good evidence of benefit, leading to the American College of Gastroenterology Task Force's conclusion that these agents are effective in improving stool frequency and consistency. The serotonin (5-HT4) agonist tegaserod, which augments the peristaltic reflex and promotes movement of stool through the colon for evacuation, has received considerable attention in the treatment of constipation.
Lubiprostone is a new agent indicated for the treatment of patients with chronic constipation. It is a member of a new class of compounds called prostones. Nonclinical studies demonstrated that lubiprostone exerts its effects on type-2 chloride channels (ClC-2), enhancing fluid secretion into the intestinal lumen. Furthermore, lubiprostone does not affect the cystic fibrosis transmembrane conductance regulator (a different chloride channel), overstimulation of which has been linked to severe diarrhea and other conditions that damage the surface epithelium. Previous studies in healthy volunteers and in patients with constipation have demonstrated the efficacy of lubiprostone in increasing BM frequency and in alleviating other symptoms of constipation. The objective of the present study was to assess the efficacy and safety of lubiprostone 24 mcg b.i.d. versus placebo in patients with chronic constipation.