Alimentary Pharmacology & Therapeutics
Review Article: The Role of Serotonergic Agents in the Treatment of Patients With Primary Chronic Constipation
B.D. Cash; W.D. Chey
Aliment Pharmacol Ther. 2005;22(11):1047-1060.
Overview of Chronic Constipation
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]
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]
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.[15]Motility 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.
Aliment Pharmacol Ther. 2005;22(11):1047-1060. © 2005 Blackwell Publishing
Rome II Criteria for Functional Constipation [2]
Serotonergic Agents and Targeted GI Conditions
GI condition
5-HT3 receptor antagonists
MKC-733[41] (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 transit Not yet determined Under investigation
5-HT4 receptor agonists
Prucalopride[42] (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 contractions IBS with constipation Studies on hold (concerns about intestinal carcinogenicity and potential cardiac events)
Tegaserod[39] (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 sensitivity IBS with constipation Chronic idiopathic constipation Approved 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)
Alosetron[47] (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 diarrhoea Approved 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)
Cilansetron[43] (methylimidazole analogue) IBS with diarrhoea 'Not-approvable' action letter from FDA in March 2005 (more data needed)
Ondansetron[48] (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 structures CINV
PONV
RINV Approved by FDA for
CINV
Granisetron[49] (aminoimidazole carboxamide) Approved by FDA for
Dolasetron[50] (aminoimidazole carboxamide) Approved by FDA for
Ramosetron[51] (thiazole monofumarate) Not approved by FDA
Palonosetron[52] (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 Heartburn/GERD
IBS with constipation
Constipation Withdrawn 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
5-HT3 receptor antagonist activity
Antiemetic activity
Accelerates gastric emptying in some species
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 receptors
Mosapride[44,45] (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 contractions Non-ulcer dyspepsia
Gastric stasis
Constipation in Parkinson's disease Not approved by FDA
Renzapride[46] (substituted benzamide) Prokinetic: does not alter gastric emptying or small bowel transit but does accelerate colonic transit and ascending colon emptying IBS with constipation Under investigation (phase III trials)
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.
B.D. Cash* & W.D. Chey †
*Departments of Gastroenterology and Internal Medicine, Uniformed Services University of the Health Sciences, National Naval Medical Center, Bethesda, MD, USA; †Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
Disclosure: Drs Chey and Cash have served as consultants to and are members of the speakers bureau of Novartis Pharmaceuticals.
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