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Summary

  1. Top of page
  2. Summary
  3. Overview of chronic constipation
  4. The brain–gut axis and the role of serotonin in gastrointestinal function
  5. Serotonergic agents and chronic constipation
  6. Conclusion
  7. Acknowledgements
  8. References

Chronic 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

  1. Top of page
  2. Summary
  3. Overview of chronic constipation
  4. The brain–gut axis and the role of serotonin in gastrointestinal function
  5. Serotonergic agents and chronic constipation
  6. Conclusion
  7. Acknowledgements
  8. References

Definition

There 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.1

To achieve a uniform definition to identify patients for clinical trials, an international group of experts created the Rome criteria for functional constipation (Table 1).2 In addition to decreased stool frequency, this definition acknowledges the diversity of symptoms reported by patients. The American College of Gastroenterology Chronic Constipation Task Force has proposed a description directed towards clinical practice, defining constipation as ‘a symptom-based disorder… characterized by infrequent defecation, difficult stool passage, or both.’ The Task Force defines chronic constipation as the presence of these symptoms for at least 3 months.3

Table 1.  Rome II criteria for functional constipation2
  1. * Loose stools are not present, and criteria for irritable bowel syndrome (IBS) are not met.

The presence of two or more of the following symptoms for at least 12 weeks (need not be consecutive) in the preceding 12 months*
 Straining in >25% of defecations
 Lumpy or hard stools in >25% of defecations
 Sensation of incomplete evacuation in >25% of defecations
 Sensation of anorectal obstruction/blockade in >25% of defecations
 Manual manoeuvres to facilitate >25% defecations (e.g. digital evacuation, support of the pelvic floor)
 Fewer than three defecations per week

Epidemiology and burden of illness

Constipation is one of the most commonly reported gastrointestinal (GI) disorders. A recent systematic review found that constipation affects between 2% and 28% of Americans, and most estimates place the prevalence between 12% and 19%.4 A recent analysis of the epidemiological features of constipation found that more than 45% of constipated patients have had symptoms for more than 5 years.5 Numerous studies report a higher prevalence of constipation in women than in men [median odds ratio (OR): 2.20; range: 1.10–3.77].4 The prevalence of constipation also appears to be higher among non-white than white populations (median OR: 1.41; range: 1.13–2.89).4 Although it is generally thought that the prevalence of constipation increases with age, large epidemiological studies have not uniformly endorsed this position.6

Constipation can significantly affect patient quality of life. In a Canadian-based study, participants with constipation (Rome II criteria or self-reported) scored significantly worse on all subscales of the Medical Outcomes Survey short-form 36 (SF-36) questionnaire, with the most notable decrements in the measures of role functioning, social functioning, vitality and general health.7 This study also demonstrated that decreased quality of life scores were predictive of greater use of healthcare resources.7 A study assessing GI-related health care use by 76 854 patients with constipation who were enrolled in the California Medicaid program revealed a total healthcare cost (including in-patient and out-patient doctor visits, emergency room visits and procedures) during a 15-month observation period of $18 891 007.8 It has been estimated that within the United States, constipation accounts for 2.5 million doctor visits, at least 100 000 referrals to gastroenterologists, and more than 38 000 in-patient hospitalizations per year.9, 10

Subgroups of primary constipation

When assessing a patient with constipation, it is important to keep in mind the many potential causes of this condition because treatment options can vary considerably depending upon the aetiology of a specific patient's constipation. For example, constipation can be attributed to secondary causes such as medications or metabolic, endocrine, or neurological disorders. In this case, addressing the cause should alleviate constipation. Primary (idiopathic) causes of constipation include normal-transit constipation, slow-transit constipation and dyssynergic defecation (outlet obstruction, pelvic floor dyssynergia).11, 12 Although this schema attempts to place patients with primary constipation into three distinct subgroups, studies have shown that there is significant overlap among the subgroups.13

In normal-transit constipation, affecting approximately 24–58% of chronically constipated patients,11, 13 stool traverses the colon at a normal rate; however, patients describe themselves as constipated and note associated symptoms such as abdominal pain, bloating, or straining. Many of these patients also fulfil the criteria for irritable bowel syndrome with constipation (IBS-C).14

In patients with slow-transit constipation, which affects approximately 13–47% of constipated patients,11, 13 the movement of faecal material through the GI tract, particularly the colon, is delayed.15Motility abnormalities, including absent early postprandial contractions, reduced high amplitude-propagating contractions and excessive uncoordinated low-amplitude distal contractions, have been identified in patients with slow-transit constipation.16, 17 The aetiology of these changes is unclear but may include enteric nervous system (ENS) or smooth muscle abnormalities. Microscopy of the ENS in patients with slow-transit constipation shows a range of abnormalities, including axonal vacuolation, loss of myenteric neurones, Schwann cell hyperplasia and non-specific plexus degeneration. Other abnormalities of potential physiological relevance to patients with slow-transit constipation include reduced numbers of colonic enterochromaffin (EC) cells, decreased interstitial cells of Cajal and autonomic dysfunction.1, 15, 18, 19 Using immunoreactivity techniques, El Salhy et al.18 have identified reduced numbers and function of EC cells in this group of patients. Reduced cell density and cell secretory index, a measure of secretory activity, indicate decreased enteroglucagon and serotonin activity, which the authors postulate may be associated with the motility and secretory abnormalities observed in patients with slow-transit constipation.18

Patients with dyssynergic defecation, variously termed outlet obstruction, pelvic floor dyssynergia, anismus, or obstructive defecation, have difficulty expelling, or are unable to expel, stool from the anorectum.17, 20 Structural (rectocele, intussusception, rectal prolapse), functional (puborectalis dyssynergia, anismus), or sensory abnormalities thought to cause dyssynergic defecation can be identified in approximately 25–59% of patients reporting chronic constipation.11, 13 Contrary to the case with the other subtypes of chronic constipation, the primary therapies for dyssynergic defecation are centred on behavioural and surgical therapies. Because of the overlap between subtypes, it is reasonable to consider promotility agents as adjunctive therapeutic approaches for patients with dyssynergic defecation who do not respond to standard therapy, although there is no evidence that promotility agents affect the pelvic floor abnormalities observed with dyssynergic defecation.

The brain–gut axis and the role of serotonin in gastrointestinal function

  1. Top of page
  2. Summary
  3. Overview of chronic constipation
  4. The brain–gut axis and the role of serotonin in gastrointestinal function
  5. Serotonergic agents and chronic constipation
  6. Conclusion
  7. Acknowledgements
  8. References

Brain–gut axis

The ENS regulates motor, secretory and sensory functions through an extensive neural network contained within the GI tract. It functions semiautonomously but is influenced by bidirectional communication with the central nervous system (CNS) through the autonomic nervous system. The ENS is composed of ‘intrinsic’ and ‘extrinsic’ neurones. Intrinsic pathways consist of primary afferent neurones (IPANs), which respond to physiological stimuli such as distension and inflammation and mediate motor and secretory reflexes. IPANs are located in the submucosal and myenteric plexuses and, along with interneurones and motor neurones, form integrated local circuits.21–24 Extrinsic pathways relay information to and from the CNS through the autonomic nervous system. Sympathetic neurones within spinal afferent and splanchnic pathways primarily convey sensory information to the CNS but also can exert inhibitory influence on the motor activities of the gut. Conversely, parasympathetic neurones located in vagal and sacral afferents facilitate communication from the CNS to the ENS and also exert a predominantly stimulatory motor influence to the gut (Figure 1). The aggregate of these neuronal pathways serves as the foundation of what is referred to as the brain–gut axis.25

image

Figure 1. Bidirectional brain–gut interactions. Originally published in Am J Health Syst Pharm 2005; 62: 700–11. © 2005, American Society of Health-System Pharmacists, Inc. All rights reserved (reprinted with permission; R0515). ENS, enteric nervous system; CNS, central nervous system; ANS, autonomic nervous system; IPANs, intrinsic primary afferent neurones.

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As in the CNS, molecular messengers are responsible for selective neuronal activation in the ENS. Numerous neurotransmitters and neuropeptides have been identified in the ENS, including calcitonin-gene receptor protein (CGRP), substance P, vasoactive intestinal peptide, nitric oxide, adenosine triphosphate, acetylcholine (ACh) and serotonin (5-HT). Of these, serotonin has been found to be most relevant to the neural pathways involved with motility, secretion and sensation within the GI tract, and significant physiological evidence demonstrates its effects on these functions.26

Serotonin and serotonin receptors

Serotonin is a prominent neurotransmitter and mucosal signalling molecule associated with a wide variety of physiological actions within the human body. Although widely distributed, virtually all plasma serotonin originates from EC cells located within the gut. In fact, more than 90% of the body's total serotonin content localizes to the GI tract.25It should come as no surprise then that serotonin plays an important role in a broad range of functions in the gut.26, 27 To date, 14 serotonin receptor subtypes have been identified. Of these, type 1 (5-HT1), type 2 (5-HT2), type 3 (5-HT3), type 4 (5-HT4) and type 7 (5-HT7) have been implicated in the function of the GI tract.21, 28 The greatest knowledge related to GI health and disease has been accumulated on the 5-HT3 and 5-HT4 receptor subtypes.21

The 5-HT3 receptors, which can be found in both the ENS and the CNS, are vital to GI motility, secretion and sensation. Stimulation of these ligand-gated ion-channels results in a fast inward current responsible for mediating a subset of fast excitatory postsynaptic potentials in the ENS (most are mediated by ACh).27 5-HT3 receptors have been localized to emetic pathways, providing an explanation for the antiemetic properties offered by 5-HT3 receptor antagonists such as ondansetron and granisetron. Peripherally, these receptors can be found on intrinsic and extrinsic neurones of the myenteric plexus. Blocking these receptors at this level with 5-HT3 receptor antagonists alters the colonic peristaltic reflex, decreases postprandial colonic motility,29, 30 delays colonic transit and alters colonic compliance.31 Another important role of 5-HT3 receptors is to transmit sensory information to primary spinal afferent nerves and higher CNS levels. Serotonin release from EC cells appears to stimulate 5-HT3 receptors on vagal afferents, potentially resulting in nausea and other non-painful gut sensations such as bloating and abdominal fullness. Antagonism of 5-HT3 receptors may thereby reduce symptoms associated with altered visceral sensation, as can be the case in patients with IBS.27, 32–34 With this as background, it makes intuitive sense that 5-HT3 receptor antagonists are most appropriate for patients with IBS whose primary bowel symptom is diarrhoea. Alternatively, it is conceivable that a 5-HT3 agonist might be of benefit to patients with IBS whose primary bowel symptom is constipation.

In contrast to 5-HT3 receptors, 5-HT4 receptors are G protein-coupled receptors found on smooth muscle cells, EC cells, myenteric plexus neurones and IPANs.21 Although they are not directly involved in initiating the peristaltic or secretory reflex, 5-HT4 receptors work in conjunction with other 5-HT receptors to augment peristalsis and secretion by mediating the release of other neurotransmitters directly involved in GI motility, such as ACh and CGRP. The peristaltic reflex is typically initiated in response to food or luminal distension, and serotonin release from EC cells is an initiating event in this process. Once released, serotonin stimulates 5-HT1P receptors on the presynaptic nerve endings of IPANs in the submucosal plexus. The signal from the 5-HT1P receptor is communicated to 5-HT4 receptors, which are located on the terminals of submucosal IPANs. Secondary messengers (ACh and CGRP) then activate a unique neuromuscular cascade in which excitatory neurotransmitters are released in an orad direction and inhibitory neurotransmitters are released caudally. These differing regional effects lead to coordinated proximal smooth muscle contraction and distal smooth muscle relaxation, resulting in effective peristalsis (Figure 2).21

image

Figure 2. The peristaltic reflex (adapted from Grider et al. Gastroenterology 1998; 115: 370, Baker Am J Health Syst pharm 2005; 67: 700 and Gershon J Clin Gastroenterol 2005; 39(4): S184). 5-HT, serotonin; ENS, enteric nervous system; CNS, central nervous system; CGRP, calcitonin gene-related peptide; Ach, acetylcholine; VIP, vasoactive intestinal peptide; NO, nitric oxide; NKA, neurokinin A; PACAP, pituitary adenylate cyclase-activating peptide; IPAN, intrinsic primary afferent neurone, ESN, extrinsic sensory neurone.

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In addition to promoting peristalsis, the effect of stimulation of colonic 5-HT4 receptors on other gut functions makes them an attractive mechanistic target for agents directed at treating constipation. These receptors also modulate stool fluid content through cyclic adenosine monophosphate-mediated release of chloride from colonocytes such that stimulation increases the water content of stool.35 There is also preliminary evidence that 5-HT4 receptor agonists can decrease visceral hypersensitivity.36–38 For example, tegaserod (a 5-HT4 receptor agonist) was able to (i) inhibit rectal distension-induced responses and limbic system c-Fos expression in rats with experimentally induced visceral hypersensitivity,36 (ii) decrease the firing rate of rectal sensory nerves after visceral distension in a cat model37 and (iii) inhibit the RIII reflex, a human model of visceral nociception, in humans,38 and it has been shown to reduce abdominal pain/discomfort in patients with IBS-C or chronic constipation.39 The postulated mechanisms for these effects include modulation of primary spinal afferent transmission or inhibition of descending bulbospinal pathways; however, the precise mechanism(s) remains to be clearly defined.40 Whether these emerging data using experimental models will translate into meaningful effects on pain in clinical practice remains to be determined.

In recent years, a number of serotonergic agents have been developed for use in patients with GI conditions (Table 2),39, 41–52 such as chemotherapy-induced, radiation-induced, and postsurgical nausea and vomiting, and with GI motility disorders. These agents, which function as selective 5-HT3 and 5-HT4 receptor antagonists and/or agonists, have markedly different actions, both physiologically and clinically.

Table 2.  Serotonergic agents and targeted GI conditions
AgentActionGI conditionStatus
  1. FDA, United States Food and Drug Administration; CNS, central nervous system; GI, gastrointestinal; IBS, irritable bowel syndrome; CINV, chemotherapy-induced nausea and vomiting; PONV, post-operative nausea and vomiting; RINV, radiation-induced nausea and vomiting; GERD, gastro-oesophageal reflux disease.

5-HT3 receptor antagonists
 MKC-73341 (substituted benzamide)Delays liquid gastric emptying in association with relaxation of the proximal stomach, stimulates fasting antroduodenal migrating motor complex activity and accelerates small intestinal transitNot yet determinedUnder investigation
5-HT4 receptor agonists
 Prucalopride42 (benzofuran derivative)Prokinetic: stimulates emptying of the stomach and the ascending colon and increases the rate of small and large bowel transit, potentially through the stimulation of high amplitude-propagating contractions and segmental contractionsIBS with constipationStudies on hold (concerns about intestinal carcinogenicity and potential cardiac events)
 Tegaserod39 (aminoguanidine indole)Prokinetic: stimulates 5-HT4 receptors, which are G protein-coupled receptors, and triggers release of additional neurotransmitters, including acetylcholine and calcitonin gene-related peptide, from sensory neurones leading to enhanced GI motility and intestinal secretion and to reduced visceral sensitivityIBS with constipation Chronic idiopathic constipationApproved by FDA for  women with IBS-C  men and women <65 with chronic idiopathic constipation
5-HT3 receptor antagonists (these agents are contraindicated in patients with constipation)
 Alosetron47 (methylimidazole analogue)Activates 5-HT3 receptors, which are ligand-gated cation-channels, resulting in neuronal depolarization that affects the regulation of visceral pain (reduces), colonic transit (slows) and small intestinal absorption (enhances)IBS with diarrhoeaApproved by FDA for women with severe IBS-D for whom treatment with conventional agents has failed under restricted conditions of use, which include a risk management programme, a prescribing programme and a revised indication (above)
 Cilansetron43 (methylimidazole analogue) IBS with diarrhoea‘Not-approvable’ action letter from FDA in March 2005 (more data needed)
 Ondansetron48 (aminoimidazole carboxamide)Antiemetic: centrally acting agents that prevent serotonin from initiating afferent transmission to the CNS through vagal and spinal sympathetic nerves; may also block serotonin stimulation at the chemoreceptor trigger zone and other CNS structuresCINV PONV RINVApproved by FDA for  CINV  PONV  RINV
 Granisetron49 (aminoimidazole carboxamide)Approved by FDA for  CINV  RINV
 Dolasetron50 (aminoimidazole carboxamide)Approved by FDA for  CINV  RINV
 Ramosetron51 (thiazole monofumarate)Not approved by FDA
 Palonosetron52 (isoquinoline)Approved by FDA for delayed emesis for patients receiving moderate emetogenic chemotherapy
5-HT3 receptor antagonist/5-HT4 receptor agonists
 Cisapride (substituted piperidyl benzamide derivative)Prokinetic with dual mechanism of action 5-HT3 receptor antagonist activity   Antiemetic activity   Accelerates gastric emptying in some species  5-HT3 receptor antagonist activity Prokinetic activity: enhances the release of acetylcholine from the postganglionic nerve endings of the myenteric plexus, resulting in increased motility in the GI tract by full agonist activity at 5-HT4 receptorsHeartburn/GERD Gastroparesis IBS with constipation ConstipationWithdrawn from market [arrhythmogenic potential (QT internal prolongation)] Available in the United States only through a limited-access programme developed by Janssen Pharmaceutica and the FDA
 Mosapride44, 45 (substituted benzamide)Prokinetic: facilitates acetylcholine release from enteric cholinergic neurones of the myenteric plexus through stimulation of 5-HT4 receptors, thereby increasing gastric emptying, stimulating gastric motor activity and increasing electrically evoked contractionsNon-ulcer dyspepsia Gastroparesis Gastric stasis Gastro-oesophageal reflux disease Constipation in Parkinson's diseaseNot approved by FDA
 Renzapride46 (substituted benzamide)Prokinetic: does not alter gastric emptying or small bowel transit but does accelerate colonic transit and ascending colon emptyingIBS with constipationUnder investigation (phase III trials)

Serotonin reuptake

As in the CNS, serotonin levels in the perineural spaces of the ENS are regulated by the serotonin reuptake transporter (SERT), a plasma membrane protein that deactivates and degrades serotonin and whose function has been likened to a serotonin ‘off’ switch.27 The presence of the SERT protein represents a physiological mechanism by which serotonin levels (and, thus, activity) are regulated. Abnormalities in SERT would be expected to result in disturbed GI motility. It has been suggested that impaired SERT activity (reduced uptake) could result in excessive serotonin-mediated receptor stimulation, manifesting clinically as diarrhoea. Eventually, as a result of excessive exposure, the sensitive G protein-coupled 5-HT4 receptors may undergo desensitization, resulting in constipation. Preliminary evidence from animals and humans appears to support this hypothesis. Mice devoid of the SERT gene have been observed to exhibit a cyclic diarrhoea-constipation sequence similar to that seen in a subset of patients with IBS and mixed bowel pattern.53 Crowell et al.40 and Coates et al.54 have demonstrated that patients with IBS-C, IBS with diarrhoea and ulcerative colitis all have reduced mucosal serotonin and SERT mRNA expression compared with controls. Similar studies in patients with chronic constipation are not yet available.

Serotonergic agents and chronic constipation

  1. Top of page
  2. Summary
  3. Overview of chronic constipation
  4. The brain–gut axis and the role of serotonin in gastrointestinal function
  5. Serotonergic agents and chronic constipation
  6. Conclusion
  7. Acknowledgements
  8. References

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.

5-HT3 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.

5-HT4 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 prucalopride60, 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,70–72 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.78–80 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.

Mixed 5-HT3 receptor antagonist/5-HT4 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.

Conclusion

  1. Top of page
  2. Summary
  3. Overview of chronic constipation
  4. The brain–gut axis and the role of serotonin in gastrointestinal function
  5. Serotonergic agents and chronic constipation
  6. Conclusion
  7. Acknowledgements
  8. References

Our understanding of the pathophysiology of chronic constipation continues to evolve. Serotonin appears to play an important role in a number of physiological functions relevant to the symptoms of chronic constipation. As a consequence, drugs that accentuate the effects of serotonin, such as the 5-HT4 receptor agonists, are attractive treatment candidates for patients with chronic constipation. Of the 5-HT4 agonists that have been developed, tegaserod has been shown to accelerate gut transit and to improve the symptoms of chronic constipation while it retains an attractive safety profile in recent large, methodologically rigorous clinical trials. Although the exact mechanisms for these benefits remain unclear, it appears that the promotility effect of tegaserod, rather than its prosecretory effects or its amelioration of heightened visceral sensation, are largely responsible for the clinical effects of this medication. Although clearly superior to placebo, tegaserod improves symptoms in only a subset of patients with chronic constipation. This suggests that serotonin plays a critical role in some, but not all, patients with chronic constipation. Though unproven, it may be that patients with subtle or overt pelvic floor dysfunction are less likely to respond to serotonergic agents than patients with normal or delayed colonic transit. The roles of other serotonergic agents, including the 5-HT3 agonists, the mixed 5-HT3 antagonists/5-HT4 agonists and agents that affect SERT, in the treatment of patients with chronic constipation remain to be determined.

Acknowledgements

  1. Top of page
  2. Summary
  3. Overview of chronic constipation
  4. The brain–gut axis and the role of serotonin in gastrointestinal function
  5. Serotonergic agents and chronic constipation
  6. Conclusion
  7. Acknowledgements
  8. References

The authors would like to acknowledge the editorial assistance of Maribeth Bogush PhD and Sophia Shumyatsky, PharmD, in the preparation of this manuscript. This work was supported by an educational grant from Novartis Pharmaceuticals. Drs Chey and Cash have served as consultants to and are members of the speakers bureau of Novartis Pharmaceuticals.

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  8. References
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