Review article: the role of serotonergic agents in the treatment of patients with primary chronic constipation

Abstract

SUMMARYChronic constipation is a highly prevalent disorder that is associated with significant direct and indirect costs and has substantial impact on patient quality of life. It is more common among women and non-white populations and is evenly distributed across adult age groups. Constipation is a heterogeneous disorder associated with multiple symptoms and aetiologies.Recent research has increased our understanding of the pathogenesis of this disorder and the central role of the neurotransmitter serotonin in mediating gastrointestinal motility, secretion and sensation. Abnormal serotonin signalling and reuptake appear to play central roles in the symptoms of a subset of patients with chronic constipation. This observation provides a rationale for the use of targeted serotonergic agents for the treatment of chronic constipation. As the role of serotonin in gastrointestinal function is further elucidated and additional candidate drugs are developed, it is likely that serotonergic agents will afford additional treatment options for patients with chronic constipation.This article provides a concise review of the evidence supporting a role for serotonin in the pathogenesis of chronic constipation and a summary of the currently available evidence supporting the use of serotonergic agents for this disorder. OVERVIEW OF CHRONIC CONSTIPATION DefinitionThere is no universally agreed upon definition for constipation. Traditionally, doctors have focused on decreased stool frequency, with most accepting a cut-off of fewer than three bowel movements per week as consistent with constipation. Patients, on the other hand, often use the term constipation to describe a variety of symptoms, including straining, bloating, quality of bowel movements (i.e. hardness of stool, ease/difficulty of passing a bowel movement) in addition to decreased stool frequency.

Serotonin and Its Role in Colonic Function and in Gastrointestinal Disorders

“…54,74 Prucalopride is a benzofuran-derived 5-HT 4 receptor agonist that stimulates stomach and ascending colonic emptying in healthy volunteers. 26,46 Randomized, double-blind, placebo-controlled studies have demonstrated an increase in the number of spontaneous bowel movements in response to prucalopride. 44,45,47,48 At present, drug development has been halted secondary to reports of cardiac arrhythmias and concerns regarding carcinogenicity in animal studies.…”

“…However, to avoid tachyphylaxis as a result of the rapidly desensitizing property of this receptor and the nausea and vomiting that typically occur in response to vagal afferent stimulation, it is likely that only partial agonists would be effective pharmacotherapeutic agents. The effects of the partial 5-HT 3 agonist MKC-733 have been tested in a gastric emptying assay, 26 but data are lacking with regard to colonic function and sensitivity. This medication is not currently FDA approved.…”

Prucalopride: the evidence for its use in the treatment of chronic constipation

“…It is postulated that this reduced serotonin activity may be associated with the motor and secretory abnormalities described in patients with slow transit constipation. These data make the 5-HT 4 receptor an attractive mechanistic target for agents that may be useful in the treatment of constipation (Cash & Chey 2005;Gershon & Tack 2007). …”

“…In patients with impaired colonic propulsive motor activity, a gastrointestinal prokinetic may be a better therapeutic approach (Cash & Chey 2005). Also, in patients with other types of chronic constipation, including those associated with dyssynergic defecation and pelvic floor dysfunction, it is reasonable to expect that the addition of a promotility agent to current standard treatment options may be useful.…”

“…In most cases however, some form of laxative treatment will be required, particularly in patients with pelvic floor dyssynergia and slow transit constipation (Chiarioni & Salandini 2005;Chiarioni et al 2006). The observation that abnormal serotonin signalling and reuptake appears to play a central role in the symptoms of a subset of patients with chronic constipation provides a rationale for the use of targeted serotonergic agents for the treatment of chronic constipation (Cash & Chey 2005;De Maeyer et al 2008). …”