- Top of page
- MATERIALS AND METHODS
Constipation is a very common gastrointestinal disorder.1–4 However, many patients who present with constipation have no obvious dietary, systemic or local structural causes for their symptoms, i.e. they have idiopathic or functional constipation.5
The treatment of chronic functional constipation is a challenge, as current treatments, such as dietary adjustments and laxatives, do not always improve patients' symptoms, particularly those with a long history of constipation. Increased dietary fibre and laxatives can result in significant bloating, flatulence and distension,6 or may be insufficient to improve the complaints of patients. There is therefore a need for more effective and better tolerated treatments that normalize bowel motility.
Functional constipation is often associated with impaired colonic motility. Moreover, in some patients with severe functional constipation, there is a decrease in the frequency and duration of high-amplitude propagating contractions (the human equivalent of giant migrating contractions),7 and an associated reduction in the number of mass movements.8 Delayed colonic transit can be measured adequately using radio-opaque markers. In such patients, a reasonable therapeutic approach would appear to be to stimulate intestinal motility.9
Prucalopride is a novel, highly selective, specific, serotonin4 (5-hydroxytryptamine4, 5-HT4) receptor agonist with enterokinetic properties.9–11 Stimulation of 5-HT4 receptors facilitates cholinergic and non-adrenergic, non-cholinergic excitatory neurotransmission,12 and this mechanism has been proposed to explain the enterokinetic properties of prucalopride.13 Pre-clinical studies have shown that prucalopride stimulates the peristaltic reflex14 and dose dependently enhances the occurrence of giant migrating contractions in the colon of a canine model,15 which suggest that it might be suitable for the treatment of disorders associated with dysmotility of the small or large bowel.
Studies with prucalopride in healthy volunteers showed that it increased stool frequency and improved stool consistency, and shortened the colonic transit time,10, 11 but did not alter anorectal function.11
The aim of this study was to evaluate the efficacy and tolerability of prucalopride (1 or 2 mg) on bowel function, gastrointestinal transit time and anorectal function in patients with chronic functional constipation.
- Top of page
- MATERIALS AND METHODS
The frequency of constipation in the population is not precisely known. Depending on the definition used, prevalence is reported to vary from 2% to 4% for infrequent stools and from 10% to 16% for excessive straining.21–23 In nursing homes, frequencies seem to be higher: up to 20%.24 Depending on the population studied and the definition used, it has been estimated that up to 15% of the normal population has symptoms associated with functional constipation, while 5–10% may experience outlet delay. However, the true prevalence may be even higher as many patients do not consult their doctors.23, 25, 26
The results of this double-blind, placebo-controlled, crossover study confirm the safety and efficacy of prucalopride (1 or 2 mg) in the treatment of chronic functional constipation. Because the study population was predominantly female and had a long history of not responding to laxatives or dietary counselling, it therefore reflected the normal population of patients with severe functional constipation.6
As it was not clear from previous studies in healthy volunteers, which had used doses of 1 and 2 mg,10, 11 whether the effects of prucalopride on colonic transit were dose dependent; both doses were evaluated in this study. In the first study,10 no dose dependence was found but, in the second,11 the effects of prucalopride on gastrointestinal motility were dose dependent, with the 2 mg dose having greater effects. A study in healthy volunteers has shown that prucalopride (single and once-daily dosing with 1–6 mg) has a well-characterized, predictable, dose-proportional, pharmacokinetic profile with rapid, oral absorption. Furthermore, prucalopride is not associated with food interactions as concomitant food intake had no significant effects on its oral bioavailability (> 90%).27, 28 Because prucalopride has a long elimination half-life, approximately 24 h, once-daily administration was used in our study.
Although both doses of prucalopride (1 and 2 mg) decreased the colonic transit time in our study, the differences were not statistically significant compared with placebo. However, despite randomization, the MCTT during placebo treatment for the prucalopride (2 mg) group was considerably longer than that for the prucalopride (1 mg) group, which may have affected the result with active treatment. In addition, because the transit studies were conducted during the second week of each treatment period, this may not have allowed sufficient time for prucalopride to show its full beneficial effects; most other published studies have involved at least 4 weeks of treatment.29–31 The additional analysis of all patients with two valid MCTT assessments (both prucalopride and placebo) resulted in an overall 24% reduction (14 h) with prucalopride (1 and 2 mg) compared with placebo (P=0.057). This is consistent with previous studies in patients with chronic constipation,29, 30 which demonstrated that 4 weeks of once-daily prucalopride (0.5–4 mg) improved colonic transit.
In our study, prucalopride (1 mg) resulted in significant improvements in the average weekly number of bowel movements (spontaneous complete, spontaneous and all), stool consistency, the need to strain at defecation and the urge to defecate compared with placebo. Significant changes were not seen with prucalopride (2 mg), but this may have been influenced by the relatively high frequency of bowel movements in this group of patients during placebo treatment.
Anorectal function (anal sphincter pressure, anorectal sensitivity and rectal compliance) was unaffected by prucalopride in the present study. Similar results have been found in studies in healthy volunteers.10, 11 However, another study in patients with chronic constipation showed that 4 weeks of prucalopride (1 mg) significantly enhanced several parameters (both of distension and electrical stimulation) of rectal visceral sensitivity compared with placebo.32
Prucalopride was generally well tolerated in our study. The majority of adverse events were mild to moderate in severity, and there were no clinically relevant changes in blood biochemistry, urinalysis, blood pressure, heart rate or electrocardiogram. The most common adverse event with prucalopride was transient headache, which was reported by 29% of the prucalopride patients compared with 17% receiving placebo. Other adverse events experienced by prucalopride patients were mainly gastrointestinal in nature (abdominal cramps, diarrhoea, nausea and flatulence) and reflected the colonic effects expected from a drug with enterokinetic properties.10, 11 The adverse event profile with prucalopride in our study was similar to that observed in previous studies in healthy volunteers9, 10, 33, 34 and in patients with chronic constipation.29–31
In conclusion, once-daily administration of prucalopride was safe and effective for the treatment of patients with chronic functional constipation. Prucalopride (1 mg) significantly improved stool frequency and consistency and reduced the need to strain at defecation. The results suggest that it may also decrease MCTT in these patients. Although improvements with prucalopride (2 mg) were not always statistically significant compared with placebo, this probably reflects the refractory nature of the long-standing constipation in this patient population. Because treatment with prucalopride was also generally well tolerated, it therefore has potential in the management of chronic constipation.