Review Article: The Role of Serotonergic Agents in the Treatment of Patients With Primary Chronic Constipation

B.D. Cash; W.D. Chey

Disclosures

Aliment Pharmacol Ther. 2005;22(11):1047-1060. 

In This Article

Serotonergic Agents and Chronic Constipation

For a detailed assessment of the traditional therapies for constipation, the reader is directed elsewhere.[3,55,56] This review focuses on the evidence supporting a role for serotonergic agents in the treatment of patients with primary chronic constipation. The following discussion focuses on existing serotonergic agents either in use or in development and is organized according to the targeted serotonin receptor type(s) and action (agonist vs. antagonist) of the agent.

3 Receptor Agonists                

It is attractive to speculate that 5-HT3 receptor agonists may have prokinetic properties. Studies in healthy volunteers found that the selective 5-HT3 receptor agonist MKC-733 relaxed the proximal stomach and delayed liquid gastric emptying while it stimulated antroduodenal migrating motor complex activity and accelerated small bowel transit.[41] To date, no reports have been published on the effects of the 5-HT3 receptor agonists on colon function.

4
Receptor Agonists                

Identifying and characterizing the 5-HT4 receptors and uncovering their role in the GI tract have resulted in novel approaches to the pharmacological management of chronic constipation. 5-HT4 receptor agonists have demonstrated the ability to increase transit throughout the GI tract and to enhance chloride secretion, thus offering a potential treatment option for patients with chronic constipation. Three distinct chemical classes of agents have demonstrated 5-HT4 receptor agonist activity: indoles [e.g. tegaserod (first in class)], substituted benzamides [e.g. cisapride, mosapride, renzapride, prucalopride (first in class benzofuran)] and benzimidazolones.[57] Individual differences with respect to the degree and site of serotonergic activation in the gut and potential drug-drug interactions are likely based on these different chemical structures. To date the benzimidazolones, which have been shown to modulate chloride secretion, have primarily been evaluated as possible therapies for the pulmonary disease associated with cystic fibrosis.[58]

Prucalopride. In studies conducted in healthy volunteers, the full 5-HT4 receptor agonist prucalopride stimulated emptying of the stomach and the ascending colon and increased the rate of small and large bowel transit, potentially through the stimulation of high amplitude-propagating contractions and segmental contractions.[42]

In a randomized, double-blind, placebo-controlled clinical trial of patients with severe, disabling constipation, Coremans et al.[19] noted a non-statistically significant improvement in constipation in patients receiving prucalopride for 4 weeks compared with patients receiving placebo (37% vs. 19.2%; P > 0.05). In a report of two randomized, blinded studies enrolling more than 1200 patients, Johanson et al.[59] noted that among patients with severe constipation, relief of constipation [increase in the number of complete spontaneous bowel movements (CSBMs)] was seen in 29% of patients taking prucalopride and in 13% of patients receiving placebo (P < 0.003). The potential clinical relevance of this result becomes more apparent when the severity of the baseline constipation in this patient population (baseline median: 0 CSBM/week) is taken into consideration.

Additional studies have documented improvements in motility among chronically constipated patients treated with prucalopride[60,61] and beneficial effects on associated symptoms, such as straining. Emmanuel et al.[62] noted significant improvements in symptoms, upper gut transit and gut sensitivity in patients with slow- and normal-transit constipation and acceleration of whole gut transit time in patients with slow-transit constipation. Perhaps most important, these changes were also associated with an improved sense of well-being and quality of life.

Although few adverse effects were initially reported in association with prucalopride, its development was halted after reports of cardiac arrhythmias. These events have been hypothesized to result from its specific chemical structure (benzofuran) and not from its 5-HT4 receptor agonist activity.[63,64]

Tegaserod. Tegaserod, a selective 5-HT4 receptor agonist with no 5-HT3 receptor activity, is the first in a novel drug class called the aminoguanidine indoles. It is structurally distinct from cisapride and prucalopride. Based on the data from large, methodologically rigorous studies,[65,66] tegaserod was approved by the US Food and Drug Administration (FDA) in 2002 for the treatment of women with IBS-C. Subsequent to this approval, two large, randomized, placebo-controlled, double-blind clinical trials also demonstrated benefits of tegaserod in patients with chronic constipation.[67,68] Based on the results of these trials, the FDA, in August 2004, approved tegaserod for use in women and men <65 years who have chronic idiopathic constipation.

The first study (E2302) of tegaserod in chronic constipation, conducted in North and South America, included more than 1300 patients with at least a 6-month history of constipation, defined as fewer than 3 CSBMs/week with at least one additional constipation-related symptom (e.g. straining, incomplete evacuation, hard stools).[67] CSBM improvement was greater at 4 weeks (primary efficacy variable) in the tegaserod 2 and 6 mg b.d. treatment groups (41.4% and 43.2%, respectively; P < 0.0001) than in the placebo group (25.1%). This benefit was sustained throughout the 12-week study (40.3% and 44.8% vs. 26.9% for tegaserod 2 mg b.d., tegaserod 6 mg b.d., and placebo, respectively; P < 0.0001).

The second study (E2301), conducted in Europe, South Africa and Australia, confirmed the results of study E2302.[68] In study E2301,1200 patients were randomly assigned to receive either placebo or tegaserod at 2 mg or 6 mg b.d. During this trial 40.2% of those receiving tegaserod 6 mg b.d. (P < 0.0001), 35.6% of those receiving tegaserod 2 mg b.d. (P = 0.0059) and 26.7% of those receiving placebo reported an increase in weekly CSBMs. During the entire 12 weeks of treatment, the responder rate for CSBMs in the tegaserod 6 mg b.d. group (43.2%) was superior to that for placebo (30.6%; P < 0.0001).

Several comments are worthy of mention regarding the results of these trials. First, both were large, methodologically rigorous studies that adhered to the Rome II recommendations for the design of clinical trials in patients with functional GI disorders.[69] Because of the high quality of the study designs and the consistently positive results, two recent systematic reviews gave tegaserod a grade A recommendation for the treatment of patients with chronic constipation.[3,55] While acknowledging the strengths of these studies, it is also important to point out that these trials were designed to mimic clinical practice, where patients typically are treated empirically without detailed attempts to determine the aetiology of their constipation. As has already been mentioned, constipation is a condition of heterogeneous pathogenesis. As such, it should come as no surprise that tegaserod proved effective in only a subset of patients with chronic constipation. In fact, one could argue that the results of the trials suggest that serotonin plays an important role in 40-50% of the study populations. Further studies to better understand the subgroups of patients with chronic constipation who are most likely to respond to tegaserod are eagerly awaited.

Overall, tegaserod was well-tolerated in these studies. In trial E2302, the most common adverse effects, headache and nasopharyngitis, were similarly reported in the different patient groups. Diarrhoea was reported in 4.5% and 7.3% of patients in the tegaserod 2 mg b.d. and 6 mg b.d. groups, respectively, compared with 3.8% of patients receiving placebo.[67] In study E2301, the most frequent adverse effects were reported more often in the placebo group (headache: 13.7%; abdominal pain: 7.5%) than in either tegaserod group (headache: 11-12.3%; abdominal pain: 4.9-6.1%).[68] Reports of diarrhoea were more common in the tegaserod 2 mg b.d. (3.9%) and the tegaserod 6 mg b.d. (5.8%) groups than in the placebo (2.2%) group. This diarrhoea was typically transient (mean duration: 2 days), resulted in no cases of electrolyte imbalance, and necessitated study discontinuation in <1% of tegaserod-treated patients.[67,68] Although several investigators have reported that tegaserod results in improved quality of life and decreased healthcare resource utilization in patients with IBS-C,[70,71,72] similar analyses in patients with chronic constipation have not yet been reported.

Longer term use of tegaserod in patients with chronic constipation appears safe. In a 13-month, uncontrolled extension of study E2301 designed to assess the long-term safety and tolerability of tegaserod, 842 patients were observed for up to 16 months.[73] Patients who received tegaserod 2 mg b.d. (n = 279) or 6 mg b.d. (n = 281) during the initial 12-week study (E2301) remained on the same dose during the extension, and patients who received placebo during the initial 12-week study received tegaserod 6 mg b.d. during the extension (n = 273). Safety and tolerability were assessed through monitoring adverse effects and laboratory values. In all, 53.6% of patients completed the extension study. Adverse effect rates remained constant during the extension period. Proportions of patients experiencing adverse effects were similar in the tegaserod 2 (79.9%) and 6 mg b.d. (76.0%) groups after 16 months of treatment; headache and abdominal pain were the most commonly reported adverse effects in both groups. Diarrhoea, which was generally mild and transient, occurred at a slightly higher frequency in patients treated with tegaserod 6 mg b.d. (9.9%) than in those treated with 2 mg b.d. (8.1%).[73]

Coleski et al.[74,75] recently described a possible mechanism for tegaserod-associated diarrhoea through a study in which they compared the effects of a single 6-mg dose of tegaserod with 6 mg twice daily for 1 week on the factors that modulate colon propulsion - extended (gastrocolic) and local (peristaltic) reflexes, basal tone and phasic contractions - in 10 healthy adults using a catheter with three balloons in series.[74,75] A single dose of tegaserod was associated with increased tonic and phasic colon motor activity and augmentation of extended and local reflex activity. The increases in tonic and phasic colon motor activity observed with single-dose administration were significantly reduced when administration was increased to twice daily for 1 week. The single dose of tegaserod augmented experimentally induced peristalsis and a gastrocolonic response. With extended administration; however, changes to the ascending contraction component of the peristaltic reflex returned to baseline, whereas augmentation of the descending contraction component of the peristaltic reflex and the gastrocolonic reflex were preserved. The authors concluded that differential desensitization of segmental colonic propulsion may provide a plausible mechanism for the transient diarrhoea associated with tegaserod therapy.

There has been a great deal of concern surrounding a potential association between serotonergic agents and ischaemic colitis.[76] An association between possible ischaemic colitis and certain 5-HT3 receptor antagonists, including alosetron and cilansetron, has been reported.[43,77] To date, no cases have been reported of ischaemic colitis in patients treated with tegaserod as part of the IBS-C or chronic constipation clinical trials. A small number of possible ischaemic colitis cases have been reported during postmarketing surveillance, all of which were transient and led to no long-term sequelae. The event rate for possible ischaemic colitis in patients using tegaserod during postmarketing surveillance is estimated to be 7-8 per 100 000 patient-years of tegaserod use, a rate similar to that reported in the general population.[77] Importantly, recent epidemiological studies from several large health plans suggest that patients with IBS and possibly chronic constipation may be at higher risk for ischaemic colitis than healthy controls.[78,79,80] Regardless, the reported occurrences of possible ischaemic colitis have resulted in a change in the prescribing information for tegaserod, and ischaemic colitis is now listed as a 'precaution.' To date; however, no causal relationship has been established between any 5-HT4 receptor agonist and the development of ischaemic colitis. In the clinical development programmes for IBS-C and chronic constipation, tegaserod has not been associated with changes in cardiac conduction or the development of cardiac arrhythmias. Further, no clinically important drug-drug interactions involving tegaserod have been identified to date.

3
Receptor Antagonist/5-HT 4
Receptor Agonist                

Cisapride. Cisapride, a mixed 5-HT4 receptor agonist/5-HT3 receptor antagonist, was once widely used to treat upper GI disorders such as gastro-oesophageal reflux disease and gastroparesis. In several studies, cisapride has also been evaluated as a treatment for constipation.[81,82] In two placebo-controlled trials, both cisapride and placebo significantly increased stool frequency compared with baseline. In one trial, laxative consumption was significantly decreased in both groups,[81] whereas in the other trial, only cisapride significantly decreased laxative consumption.[81,82] In a double-blind, placebo-controlled trial (consisting of a 3-week run-in period, 12-week active phase and 4-week run-out period), cisapride, at a dose of 5 mg three times a day (t.d.s.) or 10 mg t.d.s., increased stool frequency by 70% compared with baseline (P < 0.002); placebo resulted in a 43% increase (P < 0.07). Between-group differences were not statistically significant. Use of cisapride, but not of placebo, decreased laxative use (statistical evaluation not performed). However, both the 5 and 10 mg t.d.s. doses of cisapride were significantly superior to placebo in improving bowel habits overall (including stool frequency, stool consistency, ease of defecation and laxative use, based on patient diary data; P < 0.05 vs. placebo).[83] Unfortunately, cisapride use is associated with infrequent cardiac arrhythmias that proved fatal in a number of patients. Although cisapride is no longer available in most of the world, the results of these studies provided evidence that 5-HT4 receptor agonists may be of benefit in patients with constipation. Attempts to develop a 'heart-safe' formulation of cisapride (norcisapride; ATI-7505) are in progress.

Mosapride Citrate. Mosapride citrate is a 5-HT4 receptor agonist used outside the United States largely as a therapy for gastro-oesophageal reflux disease and dyspepsia. In contrast to other substituted benzamides, mosapride citrate does not have dopamine D2 or potassium-channel antagonistic properties, but it does exert weak 5-HT3 receptor antagonist activity, and one of its major metabolites has been shown to be a 5-HT3 receptor antagonist.[84] Although conjectural, this feature may explain the observation that mosapride citrate more selectively stimulates the upper GI tract in animals.[85] Recent data; however, suggest that mosapride may also exert effects on colonic motility.[44,45] A recent open-label trial in 14 patients with Parkinson's disease and constipation reported improvements in stool frequency, colonic transit time and rectal contractile activity with mosapride 15 mg/day for 3 months.[44,45]

Renzapride. Renzapride, like cisapride and mosapride, is a substituted benzamide compound with combined 5-HT3 receptor antagonist/5-HT4 receptor agonist activities. Renzapride is under evaluation for the treatment of patients with IBS-C and IBS with alternating diarrhoea and constipation. Results of a dose-ranging study evaluating the pharmacodynamic effects of renzapride on GI transit and symptoms in patients with IBS-C were recently published.[46] In this study, 48 patients meeting the Rome II criteria for IBS-C were randomly assigned to renzapride at doses of 1 mg, 2 mg, or 4 mg or to placebo daily for 11-14 days after a 1-week observation period. Upper and lower GI tract transit evaluations and bowel habit diaries were measured before and during therapy for patients in each group. Plasma levels of renzapride were also measured for pharmacokinetic analysis. Renzapride did not alter gastric emptying or small bowel transit but did accelerate colonic transit and ascending colon emptying in a linear, dose-related fashion. Acceleration of colonic transit was associated with improvement in bowel function scores (stool form and ease of passage). However, the overall symptoms of IBS were not significantly improved with renzapride compared with placebo.[46,56] To date, no clinical trial results have been published evaluating the efficacy of renzapride for patients with chronic constipation.

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