IBS – Review and What's New

Abstract and Introduction

Abstract

Irritable bowel syndrome (IBS) is a highly prevalent gastrointestinal motility disorder broadly characterized by abdominal pain/discomfort associated with altered bowel habits. The chronic and bothersome nature of IBS symptoms often negatively affects patient quality of life and activity level and places a substantial economic burden on patients and the healthcare system. Advances in research have led to a greater understanding of the underlying pathophysiology of IBS, particularly regarding the role serotonin plays in the gastrointestinal tract; the development of stepwise, symptom-based diagnostic strategies that allow for a diagnosis of IBS to be made without the need for extensive laboratory testing; and the development of treatment options targeting underlying pathophysiologic mechanisms that provide relief of the multiple symptoms associated with IBS. This review highlights recent advances in research and discusses how these findings can be applied to daily clinical practice.

Introduction

IBS – a complex, multifaceted condition broadly characterized by abdominal pain/discomfort associated with altered bowel habits – is among the most prevalent gastrointestinal (GI) motility disorders. Prevalence estimates for IBS range from 3% to 20%, with most estimates in North America ranging from 10% to 15%.[1–3] Women are affected by IBS more often than men (2:1 in the community setting and 3:1 to 4:1 in the tertiary care setting).[2] IBS-related symptoms are often chronic and bothersome, negatively affecting patient activities of daily living (eg, sleep, leisure time), social relationships, and productivity at work or school.[4–6] Patients with IBS typically score lower than population norms or those with other chronic GI and non-GI disorders on measures of quality of life.[7–10] IBS also puts a heavy economic burden on patients, employers, and the healthcare system, resulting in more than $10 billion in direct costs (eg, from office visits, medications) and $20 billion in indirect costs (eg, through work absenteeism and reduced productivity) each year.[11–14]

Advances in research during the past several decades have provided insight into the underlying pathophysiology of IBS, particularly the role of serotonin in the GI tract; the development of stepwise, symptom-based diagnostic strategies; and the development of targeted treatment options. This review discusses recent advances in research and explores how these findings can be applied in the clinical practice setting.

Readers are encouraged to respond to George Lundberg, MD, Editor of MedGenMed, for the editor's eye only or for possible publication via email: glundberg@medscape.net

Making a Positive Diagnosis of IBS

IBS is not associated with any definitive biochemical, structural, or serologic abnormalities that define its presence. The hallmark feature of IBS is abdominal pain or discomfort associated with altered bowel habits, and, often, the abdominal pain prompts patients to seek medical care. Because the symptoms of IBS are common to a number of other GI conditions, IBS was long considered a “diagnosis of exclusion,” leading to excessive testing of patients with characteristic symptoms. Fortunately, advances in research have led to the development of symptom-based approaches, aimed at standardizing IBS patient subgroups, and the development of consensus guidelines advocating a positive diagnosis of IBS based primarily on the pattern and nature of symptoms, without the need for excessive laboratory testing.[2,15]

In 1978, Manning and colleagues[16–18] proposed diagnostic criteria for IBS that were found to be reasonably sensitive and specific. More recently, an international group of experts in functional GI motility disorders convened to develop symptom-based criteria, known as the Rome criteria (Rome I,[19] Rome II,[15] and Rome III[20,21]), to better define and provide tools by which a positive diagnosis of these disorders could be made. The Rome I criteria for IBS were shown to be sensitive and specific.[22,23] The Rome II criteria, published in 1999,[15] were intended to simplify the more complex Rome I criteria by better defining the nonconsecutive, multisymptom nature of this disorder. Clinical studies validating the Rome II criteria are beginning to emerge.[24] Consensus has not yet been reached regarding which of the Rome criteria are more sensitive for identifying IBS patients in clinical practice[22,24,25] and which of the 2 more accurately estimates the prevalence of IBS.[17,26,27] A recent US population-based follow-up study found that the Rome II criteria were limited in capturing the fluctuating nature of IBS. Over a 2-year period, patients experienced symptoms episodically, including abdominal pain; the absence of pain at time of follow-up excluded many patients from meeting IBS criteria.[28] Overall, the Rome I and II criteria are considered useful for standardizing enrollment of patients into clinical trials. However, many clinicians believe that these criteria are too restrictive for use in clinical practice. The American College of Gastroenterology (ACG) Functional GI Disorders Task Force suggests using a broader definition of IBS: abdominal discomfort associated with altered bowel habits.[2] The Rome III working team met in the fall of 2004; updated criteria were published in April 2006. The principle difference between Rome III guidelines as compared with the Rome II criteria lies in the less restrictive timeframe for symptoms. Whereas the Rome II criteria require symptoms to be present for at least 12 weeks (not necessarily consecutive) in the past 12 months, the Rome III criteria require symptoms to originate for 6 months prior to diagnosis, and be currently active (ie, patient meets criteria) for 3 months. The categorization of IBS patients into the constipation, diarrhea, or mixed subtypes has also been revised (based on stool consistency).[20] It is hoped that the less restrictive symptom timeframe requirements of the Rome III guidelines will make them more clinically practical than the previous iterations.

The Rome III criteria, in conjunction with careful history-taking (medical, family, and medication) and thorough physical examination, can be applied as part of the stepwise, symptom-based approach to diagnosing IBS (Figure). The presence of alarm features (eg, rectal bleeding, history of colon cancer or inflammatory bowel disease) potentially indicative of organic disease necessitates further evaluation.[2]

Figure.

Symptom-based diagnostic algorithm for IBS.[29–31]

Until recently, the role of diagnostic testing in diagnosing IBS was a topic of continuing debate. Recent evidence indicates that when a patient meets the Rome criteria, and has no features suggestive of organic disease, the pretest probability of making an accurate diagnosis of IBS based primarily on symptoms is high. In a systematic review conducted by Cash and colleagues,[32] the pretest probability of inflammatory bowel disease, colorectal cancer, or infectious diarrhea was found to be less than 1% in patients meeting symptom-based criteria for IBS. Extensive diagnostic testing rarely identifies organic GI disease in these patients. However, one exception is celiac disease: the pretest probability of celiac disease in patients meeting symptom-based criteria for IBS was 10 times higher than that in the general population.[32] Recently, testing for celiac disease in patients with suspected IBS with diarrhea (IBS-D) has been shown to be most financially feasible in areas in which the prevalence of celiac disease is at least 8%.[33] These findings were supported by the evidence-based recommendation made by the ACG Functional GI Disorders Task Force, whereby they concluded that there is insufficient evidence to recommend the routine performance of diagnostic testing in patients who meet symptom-based criteria for IBS (eg, Manning, Rome I, Rome II) – therefore, supporting a symptom-based approach to making a positive diagnosis of IBS.[2]

The extent to which this guidance is implemented into clinical practice is based on clinical judgment and experience of the physicians. Most physicians agree that standard laboratory testing, such as complete cell blood count, chemistry panel, and erythrocyte sedimentation rate, should be performed in patients with symptoms of IBS. However, if these studies have been performed recently, after symptoms emerged, there is no need to repeat them. For a patient with IBS symptoms and no comorbid conditions, test results should all be within normal limits. Colonoscopy is generally not required in the absence of features indicative of organic disease (eg, family history of colon cancer), although it should be performed in individuals older than 50 years of age.[1] However, as mentioned previously, if the patient (regardless of age) underwent colonoscopy after the development of symptoms, a repeat test is not warranted. In addition to routine laboratory testing, thyroid function studies, ova and parasite examination, urinalysis, and breath tests for lactose intolerance may be considered. Globally, however, the value of diagnostic testing in IBS has not been established in patients who meet symptom-based criteria for IBS and who do not have symptoms indicative of organic disease; additional diagnostic testing does not increase the probability of detecting organic disease and does not alter the diagnosis of IBS once it is made.[32,34–36]

A symptom-based diagnosis of IBS is durable. In a longitudinal study in which 75 patients were reevaluated 10 to 13 years after an initial IBS diagnosis, all patients still met the diagnostic criteria for IBS (Manning, Rome I, Rome II) and few had received an alternative diagnosis during that period.[37] In other studies with follow-up periods ranging from 3 to 5 years, development of organic disease occurred in less than 7% of patients initially given a diagnosis of IBS using the symptom-based approach.[38]

Historically IBS was considered a diagnosis by exclusion and was viewed as a purely psychosomatic condition. Within the past 2 decades, however, symptom-based diagnostic criteria have been established that allow physicians to positively and confidently diagnose IBS.

The Science of IBS

Given the lack of definitive organic markers for IBS, the absence of a unifying hypothesis regarding its underlying pathophysiology is not surprising. Nevertheless, important advances in research made during the past 50 years have brought us closer than ever to understanding the numerous putative etiologic factors involved in this multifaceted disorder, including environmental factors, genetic links, previous infection, food intolerance, and abnormal serotonergic signaling in the GI tract.

Environmental Influences

Although a patient's psychological state may influence the way in which he or she presents, copes with illness, and responds to treatment, no evidence supports the theory that psychological disturbances are the cause of IBS.[39,40] The biopsychosocial model proposed by Engel takes into account the interplay between biologic, psychological, and social factors.[41] This model proposes that there is an underlying biologic predisposition for IBS that may be acted on by environmental factors and psychological stressors, which contribute to disease development, the patient's perception of illness, and impact on treatment outcomes.[42,43]

Studies evaluating the role of acute stress have shown that stress can result in release of stress-related hormones that affect colonic sensorimotor function (eg, corticotropin-releasing factor [CRF] and inflammatory mediators [eg, interleukin (IL)-1]), leading to inflammation and altering GI motility and sensation.[44] For example, CRF-1 receptors located in the central nervous system (CNS) and gut can affect colonic motility, epithelial water transport, and gut permeability.[45] Sagami and colleagues[46] determined that the peripheral administration of a nonselective corticotropin-releasing hormone (CRH) receptor antagonist improved GI motility, visceral perception, and negative mood in response to gut stimulation in patients with IBS. These findings suggest that CRH may play an important role in the pathophysiology of IBS.

Genetics

Studies with twins have shown that IBS is twice as prevalent in monozygotic twins as in dizygotic twins.[47–49] Limited research on familial aggregation has found that individuals who have a family member (other than a spouse) with a history of abdominal pain or bowel disorder have more than 2-fold increased odds of having IBS. It is likely that environmental influences may help explain this finding (eg, awareness of the symptom status of family members may make sufferers more open to discussing their symptoms and seeking help for the condition).[50] Preliminary findings also suggest that IBS may be associated with select gene polymorphisms, including those in IL-10, G-protein GNb3, alpha adrenoceptor, and serotonin reuptake transporter (SERT).[47,51–54] Despite these potential links, however, conclusive evidence for a genetic basis for IBS has not been established.

Postinfectious IBS

The presence of postinfectious (PI)-IBS, referring to the development of IBS symptoms – particularly abdominal pain and diarrhea – shortly after an enteric infection, is based on research from prospective studies in which IBS symptoms developed in 7% to 32% of patients after they recovered from bacterial gastroenteritis.[52,55,56] Specific risk factors for the development of PI-IBS have been identified, including younger age, female sex, presence of severe infectious gastroenteritis for a prolonged period, use of antibiotics to treat this infection, and presence of concomitant psychological disorders (eg, anxiety).[39,52,55,57] Difficulty in downregulating intestinal inflammation in the colonic mucosa has been suggested as a potential underlying mechanism in this condition.[52] Also suggested as a potential underlying mechanism is the presence of colonic changes shown in patients with PI-IBS compared with controls, including increased gut permeability, increased mucosal enterochromaffin cell production, and increased concentration of mast cells and T lymphocytes in the gut mucosa.[39,52,55,57] Despite considerable evidence linking IBS with an inflammatory etiology (perhaps triggered by enteric infection), in a controlled trial of patients with PI-IBS, anti-inflammatory treatment with prednisolone was not more effective than placebo in improving patient symptoms.[58] The true role of prior infection as a key factor in PI-IBS remains to be established.[59]

The use of probiotics (products containing live or attenuated bacteria that have a positive effect on the host) in alleviating symptoms in patients with PI-IBS is an area of recent focus.[60,61] The potential utility of probiotics in this setting stems from their antibacterial, antiviral, and immune-modulating properties; their ability to modify intestinal flora; and their potential to enhance intestinal mucus secretion or influence stool consistency or volume and gas handling.[60] The number of studies evaluating the efficacy of probiotic preparations in patients with IBS is limited but growing.[60–68] Because trials vary in study design, dose, and strain (Lactobacillus and Bifidobacteria alone or in combination; mixture of Lactobacillus, Bifidobacteria, and Streptococcus), direct comparison of results is challenging. Overall, some degree of IBS symptom improvement has been demonstrated in symptoms such as abdominal pain,[65,66] bloating,[63,66] gas,[66] and daily symptom scores.[62,65] O'Mahoney and colleagues[60] have recently demonstrated that results with the Bifidobacterium infantis strain are particularly promising. In a separate analysis, these investigators showed that the baseline characteristics of urgency and hard stool increased the odds ratio of response to this strain, whereas straining and alcohol consumption reduced the likelihood of response.[69,70] The ultimate place in therapy of probiotics in IBS remains to be elucidated.

Small Intestinal Bacterial Overgrowth

The presence of a higher than usual population of bacteria in the small intestine (leading to bacterial fermentation of poorly digestible starches and subsequent gas production) has been proposed as a potential etiologic factor in IBS.[71] Pimentel and colleagues have shown that, when measured by the lactose hydrogen breath test (LHBT), small intestinal bacterial overgrowth (SIBO) has been detected in 78% to 84% of patients with IBS.[71,72] However, the accuracy of the LHBT in testing for the presence of SIBO has been questioned.[73] Sensitivity of the LHBT for SIBO has been shown to be as low as 16.7%, and specificity approximately 70%.[74] Additionally, this test may suboptimally assess treatment response.[75] The glucose breath test has been shown to be a more reliable tool,[76] with a 75% sensitivity for SIBO[77] vs 39% with LHBT for the “double-peak” method of SIBO detection.[74] In a recently conducted retrospective study involving review of patient charts for the presence of gastrointestinal-related symptoms (including IBS) in patients who were referred for glucose hydrogen breath tests for SIBO, of 113 patients who met Rome II criteria for IBS, 11% tested positive for SIBO.[78] Thus, results demonstrated that IBS symptoms are often unrelated to the presence of SIBO. Despite the controversy regarding the contribution of SIBO to the underlying pathophysiology of IBS and its symptoms, short-term placebo-controlled clinical studies with select antibiotics, including neomycin and rifaximin, have demonstrated symptom improvement in IBS patients.[61,72,79] Antibiotics may therefore have potential utility in select subgroups of IBS patients in whom SIBO contributes to symptoms. However, the chronic nature of IBS symptoms often leads to the need for long-term treatment. Given the fact that long-term use of antibiotics is generally undesirable, the place of antibiotics in IBS therapy remains to be established.[73]

Food Intolerance

Food intolerance has been proposed as a potential cause of GI symptoms in some patients with IBS; however, this link is not well established. Although some patients associate onset of IBS symptoms with ingestion of particular foods, identification of a true food intolerance is challenging, and elimination diets are typically time-consuming and difficult to implement. Recent research involving exclusion of foods to which patients had immunoglobulin (Ig) G antibodies, which are associated with a more delayed response after antigen exposure than IgE antibodies, resulted in significantly better symptom improvement than in patients in the nonexclusion group.[80] Further research into the role of food intolerance in IBS is warranted.

Serotonin Signaling

Of the putative mechanisms underlying the pathophysiology of IBS, the strongest evidence points to the role of serotonin in the GI tract. The effect of serotonergic mechanisms in the manifestation of IBS symptoms has led to development of a new drug class for the treatment of IBS patients: the GI serotonergic agents.

Normal GI function relies on a properly functioning brain-gut axis, which involves the coordinated interplay of the GI musculature, the CNS, the autonomic nervous system, and the enteric nervous system (ENS). The ENS contains millions of neurons embedded in the wall of the digestive tract and functions, at least in part, independently of the CNS. The size, complexity, and independent function of the ENS has resulted in application of the terms “the second brain” and “the mini-brain.”[81] Impaired function or coordination of any of these systems, or the communication between these systems and the GI musculature, can lead to symptoms of dysmotility and altered sensory perception, which are characteristic of IBS and select other GI motility disorders.[82]

The neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) is a predominant signaling molecule in the ENS. Most (90% to 95%) of the body's serotonin is found in the gut, and smaller amounts are found in the brain (about 3%) and in platelets (about 2%).[83] In the GI tract, serotonin facilitates communication between the ENS and its effector systems (muscles, secretory endothelium, endocrine cells, and vasculature of the GI tract), thus playing a key role in normal GI tract functioning.[84] In addition, serotonin plays a role in the communication between the ENS and the CNS.

In the gut, serotonin is synthesized by and stored in the enterochromaffin cells, which are located within the mucosa of the intestinal wall. When material passes through the lumen and the mucosa is stimulated, enterochromaffin cells release serotonin, which then binds to its receptors (primarily 5-HT_1P receptors) on intrinsic primary afferent neurons, initiating peristalsis and secretion. Serotonin also binds to 5-HT₄ receptors on interneurons, which augments the transmission of signals to motor neurons, resulting in enhanced peristaltic activity. In transgenic mice lacking 5-HT₄ receptors, colonic motility is abnormally slow, confirming the role of these receptors in facilitating normal colonic motility.[85] By binding to 5-HT₃ receptors on efferent sensory innervations coming from the vagus and the spinal nerves, serotonin mediates signaling between the ENS and the CNS and, thus, modulates pain perception.

To regulate the signaling process, excess serotonin must be removed; this is accomplished by the SERT molecule expressed by intestinal epithelial cells.[86] Human studies have shown that defects in serotonin signaling contribute to the pathophysiology of IBS and, potentially, other GI motility disorders. In a recent study by Coates and colleagues,[87] biopsy specimens from patients with IBS showed significantly lower mucosal serotonin concentrations than those from healthy controls, potentially the result of lower mRNA levels for tryptophan hydroxylase (the rate-limiting enzyme in serotonin synthesis), which were also significantly lower in patients with inflammatory bowel disease.[87] There was no significant difference in the number of enterochromaffin cells or in the capacity of these cells to release serotonin under stimulated conditions. In another study, higher serotonin levels were observed in mucosal biopsy samples from patients with IBS with constipation (IBS-C) than in patients with IBS-D or in healthy volunteers.[88]

Serotonin levels may also be affected by altering the amount or function of SERT. The study by Coates and colleagues[87] showed a significant decrease in the level of SERT mRNA and SERT protein expressed in the intestinal epithelial cells of IBS patients compared with that of healthy volunteers. In another study,[89] SERT expression and binding capacity in platelets were decreased in women with IBS-D compared with expression and binding capacity in healthy controls. Furthermore, Chen and colleagues[90] showed that mice with a SERT gene deletion had altered colonic motility. It is interesting to note that the mice thrived in laboratory housing conditions, indicating that other transporters could compensate for the lack of SERT. Additional studies have focused on SERT polymorphisms. Yeo and colleagues[91] showed an association between patients with IBS-D and the homozygous short polymorphism of the SERT gene promoter. This mutation results in lower levels of SERT gene transcription and reduced amounts of SERT protein available for reuptake of serotonin. In addition, Camilleri and colleagues[92] showed a possible link between the long promoter polymorphism and patient response to therapy.

Thus, a substantially large body of work shows that normal gut physiology is predicated on the interplay between the GI musculature and the ENS, autonomic nervous system, and CNS. One of the central mediators of this complex interplay is the neurotransmitter serotonin. Impairment or imbalance in serotonergic signaling, which can affect GI motility, secretion, and visceral sensitivity, may be affected by defects or deficiencies in serotonin production, specific serotonin receptors, or proteins such as SERT. These changes can manifest in symptoms associated with IBS, including abdominal pain, altered bowel habits (constipation, diarrhea, or alternation between these 2 states), and bloating.

IBS Treatments

Traditional Treatment Options

The goal of IBS treatment is to provide relief of symptoms and improve overall well-being.[2] Traditional therapies for IBS can effectively treat single symptoms (Table 1), but their utility may be limited when patients have moderate-to-severe symptoms or when they have multiple symptoms. The multisymptom nature of IBS often leads patients to try numerous treatment methods to achieve a broad spectrum of symptom relief. Additionally, many of these agents are associated with adverse effects that may limit their routine use. Some of these adverse effects mimic IBS symptoms (eg, fiber may cause bloating, tricyclic antidepressants may cause constipation).[2]

Table 1.

Pharmacologic Therapies for IBS Primarily Target Single Symptoms

Drug Category	Examples	Therapeutic Rationale	Primary Target Symptoms	Tolerability Concerns
Traditional Therapies
Bulking agents[2]	Wheat bran, corn fiber, calcium polycarbophil, psyllium	Accelerate intestinal transit, add fluid to stool mass, and create gel-like matrix in stool	Constipation, diarrhea	May increase intestinal gas, bloating, and abdominal discomfort
Osmotic laxatives[137]	Magnesium hydroxide, sodium phosphate, lactulose, sorbitol solution	Poorly absorbed ions or sugars that cause an influx of fluid and electrolytes into the intestine	Constipation	Diarrhea, dehydration, electrolyte disorders
Stimulant laxatives[137]	Senna, bisacodyl, castor oil, aloe	Reduce water and electrolyte absorption by stimulating colonic neurons and irritating the colonic mucosa	Constipation	Dehydration, electrolyte disturbances, significant cramping, and diarrhea. Should be avoided
Antidiarrheal agents[2]	Loperamide	Delay intestinal transit and may enhance resting internal anal sphincter tone	Diarrhea	May cause constipation: should not be used in patients with IBS-C; use with caution in patients with alternating IBS symptoms
Antispasmodic agents[2]	Hyoscyamine, dicyclomine	Anticholinergic effects and decreased spontaneous activity of intestinal smooth muscle	Diarrhea, abdominal pain	Anticholinergic adverse effects at high doses (including urinary retention and constipation). Use with caution in patients with IBS-C
		Decreased fluid and electrolyte secretion
Antidepressants[2,138]	Desipramine, amitriptyline, trimipramine, doxepin, paroxetine, fluoxetine	Decreased gut sensitivity, decreasing experience of abdominal pain	Pain	Constipation, dry mouth, and dizziness are common adverse effects of TCAs
		Antianxiety and antidepressant effects		Diarrhea, nausea, nervousness, and fatigue are common adverse effects of SSRIs
Multiple-Symptom Relief
5-HT3 receptor antagonists (methylimidazole analogs)[102]	Alosetron	Reduce visceral sensitivity and colonic transit	Abdominal pain, diarrhea, urgency	Alosetron: Black box warning regarding serious consequences of constipation; ischemic colitis (reported during clinical trials and in postmarketing surveillance)
5-HT4 receptor agonists[111] (aminoguanidine indoles)	Tegaserod	Reduce visceral sensitivity and increase GI transit and intestinal secretion	Abdominal pain/discomfort, bloating, constipation	Diarrhea, ischemic colitis (reported in postmarketing surveillance)

IBS = irritable bowel syndrome; IBS-C = IBS with constipation; TCA = tricyclic antidepressant; SSRI = selective serotonin reuptake inhibitor.

Because of their ability to alter serotonin function in the CNS and possibly in the periphery, low-dose tricyclic antidepressants and selective serotonin reuptake inhibitors are sometimes used to treat patients with IBS. They are primarily effective in reducing the pain associated with this disorder and are used at doses well below those used for psychiatric indications such as depression.[2,3] Although evidence suggests that some patients with IBS may benefit from tricyclic antidepressants or selective serotonin reuptake inhibitor therapy, results of clinical studies show significant variability in the response and do not provide overwhelming support for their use, except perhaps in patients with comorbid psychiatric conditions and a lack of response to other therapies.[93,94]

Along with traditional pharmacologic therapies, additional measures such as patient education and behavioral therapy (eg, hypnosis, biofeedback, relaxation, cognitive therapy) are used in treating patients with IBS. Most studies use a combination of these techniques. Biofeedback is one example of a noninvasive, behavioral intervention that may help patients with IBS achieve symptom relief. In this approach, sensors are strategically placed at specific positions on patients, and a computer and video monitor are used to illustrate (via sounds or line graphs) body functions of which patients are normally not aware. This information can be used to help patients recognize and modify (eg, increase, decrease, coordinate) their physiologic responses to various stressful stimuli (eg, stress-related motility).[95,96] The value of biofeedback and other behavioral therapies cannot be discounted in the management strategy for IBS and should be considered in the overall treatment plan.[2] A recently reported systematic review of published trials of psychological treatments for IBS, including biofeedback, found an overall positive outcome for these interventions (odds ratio of treatment effect [50% reduction in symptoms] of 12 [95% CI, 5.56-25.96]); however, this study did not examine the comparative efficacy of one psychological treatment over another.[97] To maximize the likelihood of success with behavioral therapy, these techniques should be administered by a trained professional (eg, physician, physical or occupational therapist, nurse). The scarcity of such trained personnel often limits the utility of these approaches.[95,96]

US Food and Drug Administration-Approved Gastrointestinal Serotonergic Agents

As discussed previously, increased understanding of the role of serotonin in gut physiology has led to the development of drugs designed to modulate serotonin function in the GI tract. Serotonin affects GI motility, secretion, and visceral sensitivity – all of which are altered in patients with IBS. Drugs designed to target key serotonin receptors in the GI tract, including 5-HT₃ receptor antagonists (eg, alosetron for IBS-D) and 5-HT₄ receptor agonists (eg, tegaserod for IBS-C), effectively improve multiple symptoms of IBS. These agents have been tested in large, randomized, placebo-controlled trials and were found to be more effective than placebo in providing global relief of IBS symptoms. Alosetron and tegaserod received grade A recommendations (the highest possible) from the ACG Functional GI Disorders Task Force in its systematic review of treatments for IBS.[2]

Alosetron

Alosetron is a 5-HT₃ receptor antagonist originally approved by the US Food and Drug Administration (FDA) in 2000 for the treatment of women with IBS-D. In large, double-blind, placebo-controlled clinical trials, alosetron (1 mg twice daily) was significantly more effective than placebo in improving individual symptoms (eg, bowel urgency, abdominal pain) of IBS-D,[98,99] as well as in global symptom improvement (as measured using the IBS Global Improvement Scale).[100,101] The most frequently reported adverse effects during clinical trials, for alosetron and placebo, respectively, were constipation (29% vs 6%), abdominal pain/discomfort (7% vs 4%), and nausea (6% vs 5%).[102] Constipation generally occurred as single episodes during the first month of treatment and resolved either on its own or after an interruption in treatment.[102] Ischemic colitis and serious complications related to constipation were reported during the clinical trials and during postmarketing surveillance, prompting the withdrawal of the drug from the market less than a year after its introduction. Toward the end of 2002, however, alosetron was reintroduced with a restricted indication for women with severe IBS-D who have not responded to conventional therapy and in whom anatomic and biochemical abnormalities have been excluded.[102] Furthermore, the new prescribing label (revised again in February 2005) includes: (1) a black box warning regarding the risk for serious GI adverse effects, such as ischemic colitis; (2) a new starting dosage (0.5 mg twice daily); and (3) a requirement that physicians and patients subscribe to a risk-management program. The risk-management program was put into place to ensure that physicians and patients are aware of the potential for serious adverse effects and agree to follow steps to maximize the safe use of alosetron.

Recently, the long-term efficacy and safety profile of alosetron (1 mg twice daily) was shown in a 12-month randomized, double-blind, placebo-controlled trial in women with severe IBS-D.[103] In this trial, constipation occurred in 23% of patients taking alosetron and in 5% of those receiving placebo; however, no cases of ischemic colitis or serious constipation were documented.[103] Current clinical trials (phase 2) are aimed specifically at showing the efficacy and safety of alosetron in men with IBS-D.[104]

Tegaserod

Tegaserod is a selective 5-HT₄ receptor agonist approved by the FDA for the short-term treatment of women with IBS-C and for men and women younger than 65 years of age with chronic idiopathic constipation. In large, randomized, placebo-controlled clinical trials, tegaserod (6 mg twice daily) provided significantly greater global relief of IBS symptoms, as assessed using the Subject's Global Assessment of Relief, and relief of individual IBS-C symptoms (eg, stool consistency and frequency, abdominal pain and discomfort, bloating).[105–108] Treatment response was observed within the first week of therapy and continued for the 12-week duration of the trials. Additional studies, in which tegaserod was stopped until symptoms returned and then restarted, indicate that symptoms recur in most patients after tegaserod is withheld, and re-treatment yields response rates similar to those observed during initial treatment.[109–110]

The adverse effects occurring significantly more frequently in tegaserod-treated vs placebo-treated patients, respectively, in IBS clinical trials were headache (15% and 12%) and diarrhea (9% and 4%).[111] In most cases, diarrhea was mild, occurred as a single episode during the first week of therapy, and resolved with continued treatment. Discontinuation of the use of tegaserod as a result of diarrhea was low (1.6% vs 0% for those receiving placebo). Clinically significant diarrhea (resulting in hospital admission, hypovolemia, hypotension, and need for intravenous fluid) occurred in a minority (4 [0.04%] of 10,000) of patients in clinical trials.[111] A long-term, open-label safety study showed that tegaserod was safe and well tolerated in patients receiving 6 mg twice daily for up to 1 year.[112]

Emerging Treatments for IBS

The enhanced understanding of putative underlying mechanisms in IBS has led the way for the development of innovative drug classes. Numerous agents are in the drug development pipeline, including newer GI serotonergic agents, alpha₂-adrenergic agonists, kappa-opioid receptor agonists, chloride channel openers, 2,3 benzodiazepines, and guanylate cyclase-C agonists. A brief overview of the mechanism of action and potential place in IBS therapy of some of these novel agents appears and is summarized in Table 2.

Table 2.

Emerging Pharmacologic Classes for IBS

Drug Class	Examples	Mechanism of Action	Potential Utility/Place in Therapy	Limitations/Comments
Newer GI serotonergic agents	Cilansetron (5-HT3 receptor antagonist)[113–115]	Inhibits colonic motility and reduces visceral hypersensitivity	IBS-D	Constipation is a common adverse effect
				Cases of ischemic colitis have been reported (all resolved with complications) within several weeks
				Currently in phase e3 clinical trials. FDA approval was rejected in April 2005
	Renzapride (mixed 5-HT4 receptor agonists/5-HT3 receptor antagonist [benzamide derivative])[117–120]	Accelerates colonic transit and reduces visceral hypersensitivity	IBS-C	In phase 2 clinical trials, diarrhea and headache were frequently reported adverse effects
Alpha2-Adrenergic agonist	Clonidine[118-120,139]	Reduces colonic motor activity and pain sensitivity	IBS-D	Commonly reported adverse effects include somnolence and hypotension
kappa-Opioid receptor agonists	Asimadoline[122,123]	Reduces colonic sensation without affecting GI motility	Has been evaluated in a preliminary study in patients with IBS-C	Does not cross the blood-brain barrier (and is therefore unlikely to cause central side effects typical of opioid agonists, including constipation)
Chloride Channel Openers	Lubiprostone*[127,128]	Increases intestinal fluid secretion, thereby softening the stools, promoting bowel movement, and decreasing bloating and abdominal pain	IBS-C	In phase III clinical trials of patients with constipation, the most commonly reported adverse effects were headache, diarrhea, and nausea
				A phase III clinical trial in patients with IBS-C began in mid-2005
2,3 Benzodiazepines	Dextofisopam[131–133]	Decreases autonomic function by binding to 2,3 benzodiazepine receptors	IBS-C and IBS-A	In a Phase 2 clinical trial, abdominal pain occurred more frequently in the dextofisopam treatment group, whereas headache was more common in the placebo group
Guanylate cyclase-C agonist	MD-1100[134–136]	Act locally on intestinal epithelium to enhance secretion and motility and reduce visceral sensation.	IBS-C	Phase 1 study found MD-100 to be well tolerated. No systemic absorption was detected, and a decrease in stool consistency (assessed by the Bristol Stool Scale) was noted.	A Phase II study with patients with IBS-C is underway.
				A Phase II study with patients with IBS-C is underway.

GI = gastrointestinal; IBS = irritable bowel syndrome; IBS-C = IBS with constipation; IBS-D = IBS with diarrhea.

^*Recently FDA-approved for the treatment of patients with chronic idiopathic constipation.

Cilansetron is a 5-HT₃ receptor antagonist.[113–116] Similar to alosetron, cilansetron works by inhibiting colonic motility and reducing visceral hypersensitivity. This agent has been shown to be effective (in both male and female patients) in relieving abnormal bowel habits and abdominal pain in patients with IBS-D. Constipation is a common adverse effect. Cases of ischemic colitis have been reported, but all resolved (without complications) within several weeks. This agent received a nonapproval letter from the FDA in April of 2005.

Renzapride is a mixed 5-HT₄ receptor agonists/5-HT₃ receptor antagonist (benzamide derivative)[117–120] that works by accelerating colonic transit and reducing visceral hypersensitivity. Preliminary data demonstrate a beneficial effect of renzapride in improving symptoms of abdominal pain/discomfort, stool consistency, and stool frequency in patients with IBS-C; its utility in patients with alternating bowel habits (IBS-A) is less clear, however. In phase 2 clinical trials, diarrhea and headache were frequently reported adverse effects.[117–120]

Clonidine is an alpha₂-adrenergic agonist that works by reducing colonic motor activity and pain sensitivity. In a study conducted in patients with IBS-D, clonidine reduced bowel dysfunction and enhanced the proportion of patients achieving satisfactory relief of IBS, without altering gastrointestinal transit.[121] Commonly reported adverse effects, including somnolence and hypotension, may limit its usefulness on a chronic basis.

Asimadoline[122,123] is a kappa-opioid receptor agonist that exerts anti-nociceptive properties on the gut by reducing colonic sensation without affecting gastrointestinal motility. This agent does not cross the blood-brain barrier and therefore works in a peripheral manner (partially though blockage of gut sodium channels).[124,125] Its efficacy in reducing sensitivity to colonic distension (without altering compliance or tone) has been shown in a preliminary study in patients with IBS-C.[126]

Lubiprostone (a prostaglandin E1 derivative bicyclic fatty acid) acts as a chloride channel opener, increasing intestinal fluid secretion and thereby softening stools, promoting bowel movement, and decreasing bloating and abdominal pain.[127] In phase 3 clinical trials of patients with constipation, the most commonly reported adverse effects were headache, diarrhea, and nausea.[128] A phase 3 clinical trial in patients with IBS-C was initiated in mid-2005.[127]

Dextofisopam is classified as a 2,3 benzodiazepine. Unlike typical benzodiazepines, this agent does not bind to GABA receptors, but rather to 2,3 benzodiazepine receptors.[129,130] Although opioid neurotransmission and altered phosphorylation of proteins that affect signal transmission are among the proposed modes of action, the exact mechanism by which this drug class works continues to be evaluated.[129] The efficacy of dextofisopam in male and female patients with IBS-D or IBS-A was demonstrated in a randomized, placebo-controlled, phase 2b 12-week study. For the primary efficacy endpoint (overall IBS symptom relief), dextofisopam was more effective than placebo for both IBS subtypes. For the secondary endpoints of stool frequency and stool consistency, however, dextofisopam was more effective vs placebo in patients with IBS-D than those with IBS-A.[131–133] Abdominal pain occurred more frequently in the dextofisopam treatment groups, whereas headache occurred more often in the placebo groups.[131–133]

MD-1100 is an agonist of guanylate cyclase-C, a receptor located on intestinal cell surfaces. In preclinical studies, this compound has been shown to act locally on the intestinal epithelium to enhance secretion and motility and reduce visceral sensation. This agent is in early-stage development for the treatment of patients with IBS-C. Results from a double-blind, randomized, placebo-controlled, single-dose phase 1 study found MD-1100 to be well tolerated. No systemic absorption was detected, and a decrease in stool consistency (as assessed by the Bristol Stool Scale) was noted.[134,135] A multiple, ascending-dose phase 1 study is ongoing, and a phase II study with patients with IBS-C is under way.[135,136]

Conclusion

Advances in research over the past several decades have paved the way for an enhanced understanding of the underlying pathophysiology of IBS; development of standardized symptom-based approaches that can be implemented in making a positive diagnosis; and development of innovative treatment options that target multiple IBS symptoms. Although many unanswered questions remain, the progress is promising and it has equipped physicians better to efficiently diagnose IBS and choose from a growing armamentarium of treatment options.