Pathophysiology of irritable bowel syndrome

Authors Andrew B Chun, MD Arnold Wald, MD Section Editor Nicholas J Talley, MD, PhD Deputy Editor Peter A L Bonis, MD

Last literature review version 17.1: January 2009 | This topic last updated: April 22, 2008 (More)

INTRODUCTION Irritable bowel syndrome (IBS) is a gastrointestinal disorder characterized by chronic abdominal pain and altered bowel habits in the absence of any organic cause. It is the most commonly diagnosed gastrointestinal condition and comprises 25 to 50 percent of all referrals to gastroenterologists [1] . IBS also accounts for a significant number of visits to primary care physicians and is the second highest cause of absenteeism after the common cold [2] .

This topic review will summarize the current state of knowledge concerning the pathogenesis of IBS. The clinical manifestations, diagnosis, and therapy of this disorder are presented separately. (See "Clinical manifestations and diagnosis of irritable bowel syndrome" and see "Treatment of irritable bowel syndrome").

PATHOPHYSIOLOGY The pathophysiology of IBS remains uncertain. Hereditary and environmental factors are likely to have a role [3] . Many studies have reported abnormal gastrointestinal motility, visceral hypersensitivity, psychologic dysfunction, and emotional stress in patients with IBS. Despite intensive

investigations, the results have often been conflicting and no physiologic or psychologic abnormality has been found to be specific for this disorder.

Gastrointestinal motility The symptoms of IBS have traditionally focused attention on colonic motility. A number of different findings have been obtained: One study described 3 cpm (contractions per minute) in the unstimulated colon in patients with IBS compared to 6 cpm in controls [4] . Other reports, however, found basal motility to be increased in IBS, but these changes were also found in psychoneurotic patients without bowel symptoms [5] . The "gastro-colonic" response to test meals or sham feeding in patients with IBS results in prolonged rectosigmoid motor activity compared to normals [6] . Stress, anger, intravenous cholecystokinin, and colonic perfusion of deoxycholic acid also increase colonic motility in IBS, but these findings occur in control subjects as well.

These and other studies of motility in IBS have been plagued by inconsistent results and the wide range of normal findings. No predominant pattern of motor activity has emerged as a marker for IBS.

As in the colon, the results of small bowel motility in IBS have been inconsistent. Decreased fasting amplitude and cycle length of migrating motor complexes (MMC) and increased frequency of clustered contractions have been found [7] . These changes have also been demonstrated in patients without symptoms of IBS.

Some investigators have described a shortening of the fed motor pattern after meals [8] . However, other studies have not been able to reproduce this finding.

Visceral afferent hypersensitivity Perception in the gastrointestinal (GI) tract results from stimulation of various chemoreceptors and mechanoreceptors in the gut wall. These receptors transmit signals via afferent neural pathways to the dorsal horn of the spinal cord and ultimately to the brain. Several studies have focused on selective hypersensitization of visceral afferent nerves in the gut as a possible biologic marker for IBS. The following observations have been noted: Increased colonic sensitivity was strongly influenced by a psychological tendency to report pain and urgency rather than increased neurosensory sensitivity in a study involving balloon distension of the descending colon [9] . Rectal distension in patients with IBS increases cerebral cortical activity more than in controls [10] . Patients who complain of bloating and excess gas actually had volumes of gas in

the GI tract similar to asymptomatic controls but exhibit impaired handling of intestinal gas loads [11,12] . More recent studies demonstrate that the intestinal dysfunction in gas propulsion is magnified by relatively low intraluminal lipid loads, suggesting that patients with IBS exhibit hypersensitivity to a lipid induced modulating mechanism [13] . About one-half of patients with IBS (mainly those with constipation) have a measurable increase in abdominal girth associated with bloating, although this may not be related to the volume of intestinal gas [14] .

In addition, many patients with IBS have lower tolerance for rectal distension with a balloon than controls [15,16] . This possible increase in sensitivity appears to be specific for visceral afferents since patients with IBS have normal or even increased thresholds to somatic pain [17] . Repetitive stimulation of the sigmoid colon can induce visceral hyperalgesia in the rectum in patients with IBS, but not in controls [18] . This response occurs even in patients who do not initially exhibit afferent hypersensitivity. These observations have led to the hypothesis that sigmoid contractions that are naturally associated with stress and response to meals may induce transient visceral hyperalgesia in IBS. Visceral hyperalgesia in IBS is not specific to the colon but can be demonstrated at different sites in the gut [19] .

Visceral hyperalgesia is only found in a subset of patients with IBS. As an example, community based patients who report IBS symptoms, but do not seek medical attention, do not have visceral hyperalgesia [20] . This observation suggests that psychologic distress or chronic healthcare seeking behavior may contribute to the sensitization of visceral afferents in some patients.

Visceral hyperalgesia may not be a specific biological marker for IBS. It also occurs in the absence of bowel symptoms in patients with other chronic pain syndromes, including esophageal chest pain, angina pectoris with normal coronary arteries, and fibromyalgia [21] . (See appropriate topic reviews.)

It is still unclear whether visceral hyperalgesia is mediated by the local gastrointestinal nervous system, by central modulation from the brain, or some combination of the two. In one report, for example, control subjects had increased activity in the anterior cingulate cortex of the brain in response to rectal distension, whereas patients with IBS had increased activity in the left prefrontal cortex [22] . However, a subsequent study using functional MRI in a larger group of patients found normal patterns of regional cerebral activation in response to rectal distension but activity was much higher in IBS than controls [23] . These

observations support the theory that central nervous system processing of visceral afferent impulses may be important in IBS. Candidate mediators include serotonin, calcitonin gene-related peptide, substance P, bradykinin, tachykinins, and neurotrophins [24] . A study in humans suggested that the development and maintenance of visceral hypersensitivity may in part depend upon the N-methyl-Daspartate (NMDA) receptor [25] . The NMDA receptor is located on dorsal horn neurons of the spinal cord, which receive primary afferent input from the gastrointestinal organs.

Furthermore, psychologic factors have been hypothesized to account for all or part of the increased pain sensitivity exhibited by patients with IBS [26] . Selective attention to gastrointestinal sensation and disease attribution are thought to be the major contributing factors. In a longitudinal study of perceptual responses to rectal stimulation, patients with IBS normalized during repeated testing over 12 months although there were no changes in either symptoms or psychological profiles [27] . Thus, the conclusion that there is a purely biologic basis for visceral hyperalgesia in IBS may be premature.

Microscopic inflammation Detailed immunohistologic investigation has revealed mucosal immune system activation in a subset of patients with irritable bowel syndrome (mostly those with the diarrhea predominant type) [28,29] . Similar observations have been made in patients with presumed postinfectious IBS (see "Postinfectious" below), suggesting a possible common link. A study in which fullthickness jejunal biopsies were obtained in 10 patients with severe IBS found an increase in lymphocyte infiltration in the myenteric plexus in nine patients and neuron degeneration in six patients [30] . The extent to which these observations might contribute to the pathogenesis of IBS in the general population remains unclear as only a small number of patients have been studied, most of whom were derived from tertiary referral centers. Other studies have demonstrated a correlation between abdominal pain in IBS and the presence of activated mast cells in proximity to colonic nerves [31,32] .

Postinfectious The development of irritable bowel syndrome following infectious enteritis has been suspected clinically based upon a history of an acute diarrheal illness preceding the onset of irritable bowel symptoms in some patients. The term "postdysenteric bowel disturbance" has been proposed to describe this disorder [33] .

Few controlled studies have investigated this topic in detail, but persistent irritable bowel symptoms have been noted in approximately 10 to 30 percent of patients after acute bacterial infection [33-39] . A systematic review of eight studies estimated a prevalence of postinfectious IBS in 10 percent of patients with a history of bacterial gastroenteritis compared with about 1 percent of controls (odds ratio 7.3, 95% CI 4.7-11.1) [40] . Another systematic review found that risk factors included young age, prolonged fever, anxiety and depression [41] .

One of the largest prospective studies included a total of 2069 individuals who had been exposed to contaminated drinking water after heavy rainfall [36] . Pathogens included Escherichia coli O157:H7 and Campylobacter jejuni. There were 904 cases of self-reported gastroenteritis and several documented positive stool cultures including 27 cases of hemolytic uremic syndrome.

The outbreak spawned development of a prospective cohort study (known as the Walkerton Health Study) to evaluate long-term outcomes in affected individuals. During follow-up, significantly more individuals with self-reported gastroenteritis fulfilled the Rome I criteria for IBS compared with controls (28 versus 10 percent). The predominant symptom was diarrhea. Independent risk factors included younger age and female sex, and (during the outbreak) bloody stools, abdominal cramps, weight loss, and prolonged diarrhea.

Similar risk factors were noted in another study [33] . In this report, patients who had vomiting as part of their initial illness were less likely to develop persistent bowel symptoms. Although this study was potentially limited by several possible sources of bias (particularly recall bias), it at least suggests that a subset of patients may become more focused on bowel complaints following acute infection, and that bowel complaints in these patients can be a source of significant disability. Persistence of symptoms in these patients appears to be at least partly related to psychological factors [42] .

The cause of persistent or new bowel symptoms following acute infection is uncertain although several theories have been proposed: One possible explanation is suggested by the association of persistent symptoms with more severe acute illness. The severity of illness may reflect the degree to which the organism invades the mucosa [43] . In severe infection, disruption of mucosal nerves may lead to irritability [44] . Another possible explanation is the development of idiopathic bile acid malabsorption, which may respond to cholestyramine [45,46] . An increase in

enteroendocrine cells, T lymphocytes, and gut permeability has been demonstrated following acute Campylobacter enteritis. In one report, these changes persisted for more than one year [47] . Neither a reduction in enteroendocrine cells nor improvement in symptoms was observed in a controlled trial of prednisolone of patients with post-infectious IBS [48] . One study suggested that increased numbers of enterochromaffin cells and depression were independent predictors of developing post-infectious IBS [49] . Patients treated with antibiotics may develop diarrhea related to alteration in colonic flora. Some patients may have had previously occult inflammatory bowel disease, or may have developed inflammatory bowel disease following infection. Reduced disaccharidase activity with resulting malabsorption of dietary sugars has been observed following enteric infections [50] .

These observations need to be considered in the context of several biases that may be inherent in the studies described above. One potentially important observation is that patients with preexisting IBS may be more likely to present to their physician with bacterial gastroenteritis compared with those without IBS [51] . Thus, epidemiologic studies examining the rate of IBS following bacterial gastroenteritis may have overestimated the rate at which new symptoms develop. Furthermore, not all studies have detected an increase in IBS following acute infectious diarrhea [52] .

Alteration in fecal microflora The complex ecology of the fecal microflora has led to speculation as to whether perturbations in its composition could be associated with diseases including IBS. Emerging data suggest that the fecal micribiota in individuals with IBS differs from healthy controls [53] . Additional studies are needed to validate these observations and to understand whether they are pathophysiologically significant.

Psychosocial dysfunction Many patients with IBS who present to a tertiary referral center exhibit increased anxiety, depression, phobias, and somatization. These patients rarely meet criteria for a major psychiatric diagnosis. However, patients with IBS symptoms who do not seek medical attention are indistinguishable psychologically from healthy controls [54] . The implication of these observations is that psychiatric distress may influence the experience of IBS but does not cause the symptoms.

Patients with IBS are more likely than controls to have a history of physical or sexual abuse [55] and/or a learned pattern of illness behavior originating in

childhood. One study evaluating the association between IBS and abuse found that patients with IBS were more likely to express neuroticism than those without this disorder [56] . Neuroticism was associated with abuse during childhood and adulthood. The investigators hypothesized a causal pathway whereby abuse leads to the expression of neuroticism that in turn leads to IBS.

One unifying hypothesis concerning the role of stress and psychoneuroticism in IBS is based upon corticotropin releasing factor (CRF), a peptide released from the paraventricular nucleus and now considered to be a major mediator of the stress response [57] . Emerging data suggest that overactivity in the brain CRF and CRFreceptor signaling system contributes to anxiety disorders and depression [57] . Intravenous administration of CRF increases abdominal pain and colonic motility in IBS patients to a higher degree than normal controls. Similar findings have been observed in animal models. Furthermore, this response can be blunted by the administration of a CRF receptor antagonist with no effect on the hypothalamopituitary-adrenal axis [58] .

The relationship between learned behavior and genetics in IBS is still being elucidated. One study found that concordance rates for IBS were twice as high in monozygotic compared to dizygotic twins [3] . Having a parent with IBS was a greater independent predictor for IBS than having an affected twin.

Other possible mechanisms Several other factors that may mimic or exaggerate existing symptoms of IBS have been investigated, but none have been proven to have a role. These include: Carbohydrate malabsorption (such as lactose or fructose intolerance) Bile acid malabsorption Neurohumoral or neuroimmune stress responses Elevated levels of short chain fatty acids in the stool Bacterial overgrowth An increased concentration of intestinal serine proteases

INFORMATION FOR PATIENTS Educational materials on this topic are available for patients. (See "Patient information: Irritable bowel syndrome"). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES Everhart, JE, Renault, PF. Irritable bowel syndrome in office based practice in the United States. Gastroenterology 1991; 100:998. Schuster, MM. Diagnostic evaluation of the irritable bowel syndrome. Gastroenterol Clin North Am 1991; 20:269. Levy, RL, Jones, KR, Whitehead, WE, et al. Irritable bowel syndrome in twins: Heredity and social learning both contribute to etiology. Gastroenterology 2001; 121:799. Snape, WJ Jr, Carlson, GM, Cohen, S. Colonic myoelectric activity in the irritable bowel syndrome. Gastroenterology 1976; 70:326. Latimer, P, Sarna, S, Campbell, D, et al. Colonic motor and myoelectrical activity: A comparative study of normal subjects, psychoneurotic patients, and patients with irritable bowel syndrome. Gastroenterology 1981; 80:893. Jepsen, JM, Skoubo-Kristensen, E, Elsborg, L. Rectosigmoid motility response to sham feeding in irritable bowel syndrome: Evidence of a cephalic phase. Scand J Gastroenterol 1989; 24:53. Kellow, JE, Eckersley, GM, Jones, M. Enteric and central contributions to intestinal dysmotility in irritable bowel syndrome. Dig Dis Sci 1992; 37:168. Kellow, JE, Gill, RC, Wingate, DL. Prolonged ambulant recordings of small bowel motility demonstrate abnormalities in the irritable bowel syndrome. Gastroenterology 1990; 98:1208. Dorn, SD, Palsson, OS, Thiwan, SI, et al. Increased colonic pain sensitivity in irritable bowel syndrome is the result of an increased tendency to report pain rather than increased neurosensory sensitivity. Gut 2007; 56:1202. Lawal, A, Kern, M, Sidhu, H, et al. Novel evidence for hypersensitivity of visceral sensory neural circuitry in irritable bowel syndrome patients. Gastroenterology 2006; 130:26. Lasser, RB, Bond, JH, Levitt, MD. The role of intestinal gas in functional abdominal pain. N Engl J Med 1975; 293:524. Serra, J, Azpiroz, F, Malagelada, JR. Impaired transit and tolerance of intestinal gas in the irritable bowel syndrome. Gut 2001; 48:14. Serra, J, Salvioli, B, Azpiroz, F, Malagelada, JR. Lipid-induced intestinal gas retention in irritable bowel syndrome. Gastroenterology 2002; 123:700. Houghton, LA, Lea, R, Agrawal, A, et al. Relationship of abdominal bloating to distention in irritable bowel syndrome and effect of bowel habit. Gastroenterology 2006; 131:1003. Whitehead, WE, Holtkotter, B, Enck, P, et al. Tolerance for rectosigmoid distension in irritable bowel syndrome. Gastroenterology 1990; 98:1187. Bouin, M, Plourde, V, Boivin, M, et al. Rectal distention testing in patients with irritable bowel syndrome: Sensitivity, specificity, and predictive values of pain sensory thresholds. Gastroenterology 2002; 122:1771. Cook, IJ, van Eeden, A, Collins, SM. Patients with irritable bowel syndrome have greater pain tolerance than normal subjects. Gastroenterology 1987; 93:727. Munakata, J, Naliboff, B, Farzaneh, H, et al. Repetitive sigmoid stimulation induces rectal hyperalgesia in patients with irritable bowel syndrome. Gastroenterology 1997; 112:55. Trimble, KC, Farouk, R, Pryde, A, et al. Heightened visceral sensation in functional gastrointestinal disease is not sitespecific; Evidence for a generalized disorder of gut sensitivity. Dig Dis Sci 1995; 40:1607. Zighelboim, J, Talley, NJ, Phillips, SF, et al. Visceral perception in irritable bowel syndrome: Rectal and gastric responses to distension and serotonin type 3

antagonism. Dig Dis Sci 1995; 40:819. Chun, AB, Desautels, S, Slivka, A, et al. Visceral algesia in irritable bowel syndrome, fibromyalgia, and sphincter of oddi dysfunction, type III. Dig Dis Sci 1999; 44:631. Silverman, DH, Munakata, J, Ennes, H, et al. Regional cerebral activity in normal and pathological perception of visceral pain. Gastroenterology 1997; 112:64. Mertz, H, Morgan, V, Tanner, G, Pickens, D. Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention. Gastroenterology 2000; 118:842. Bueno, L, Fioramonti, J, Garcia-Villar, R. Pathobiology of visceral pain: Molecular mechanisms and therapeutic implications. III. Visceral afferent pathways: A source of new therapeutic targets for abdominal pain. Am J Physiol Gastrointest Liver Physiol 2000; 278:G670. Willert, RP, Woolf, CJ, Hobson, AR, et al. The development and maintenance of human visceral pain hypersensitivity is dependent on the N-MethylD-Aspartate Receptor. Gastroenterology 2004; 126:683. Whitehead, WE, Palsson, OS. Is rectal pain sensitivity a biological marker for irritable bowel syndrome: Psychological influences on pain perception. Gastroenterology 1998; 115:1263. Naliboff, BD, Berman, S, Suyenobu, B, et al. Longitudinal change in perceptual and brain activation response to visceral stimuli in irritable bowel syndrome patients. Gastroenterology 2006; 131:352. Chadwick, VS, Chen, W, Shu, D, et al. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology 2002; 122:1778. Liebregts, T, Adam, B, Bredack, C, et al. Immune activation in patients with irritable bowel syndrome. Gastroenterology 2007; 132:913. Tornblom, H, Lindberg, G, Nyberg, B, Veress, B. Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome. Gastroenterology 2002; 123:1972. Barbara, G, Stanghellini, V, De Giorgio, R, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 126:693. Guilarte, M, Santos, J, de Torres, I, et al. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut 2007; 56:203. Neal, KR, Hebden, J, Spiller, R. Prevalence of gastrointestinal symptoms six months after bacterial gastroenteritis and risk factors for development of the irritable bowel syndrome: Postal survey of patients. BMJ 1997; 314:779. Gwee, KA, Graham, JC, McKendrick, M, et al. Psychometric scores and persistence of irritable bowel after infectious diarrhoea. Lancet 1996; 347:150. McKendrick, MW, Read, NW. Irritable bowel syndrome-post salmonella infection. J infect 1994; 29:1. Marshall, JK, Thabane, M, Garg, AX, et al. Incidence and epidemiology of irritable bowel syndrome after a large waterborne outbreak of bacterial dysentery. Gastroenterology 2006; 131:445. Marshall, JK, Thabane, M, Borgaonkar, MR, James, C. Postinfectious irritable bowel syndrome after a foodborne outbreak of acute gastroenteritis attributed to a viral pathogen. Clin Gastroenterol Hepatol 2007; 5:457. Tornblom, H, Holmvall, P, Svenungsson, B, Lindberg, G. Gastrointestinal symptoms after infectious diarrhea: a five-year followup in a Swedish cohort of adults. Clin Gastroenterol Hepatol 2007; 5:461. Ruigomez, A, Garcia Rodriguez, LA, Panes, J. Risk of irritable bowel syndrome after an episode of bacterial gastroenteritis in general practice: influence of comorbidities. Clin Gastroenterol Hepatol 2007; 5:465. Halvorson, HA, Schlett, CD, Riddle, MS.

Postinfectious irritable bowel syndrome--a meta-analysis. Am J Gastroenterol 2006; 101:1894. Thabane, M, Kottachchi, DT, Marshall, JK. Systematic review and metaanalysis: The incidence and prognosis of post-infectious irritable bowel syndrome. Aliment Pharmacol Ther 2007; 26:535. Gwee, KA, Leong, YL, Graham, C, et al. The role of psychological and biological factors in postinfective gut dysfunction. Gut 1999; 44:400. Everest, PH, Goossens, H, Butzler, JP, et al. Differentiated Caco-2 cells as a model for enteric invasion by Campylobacter jejuni and E coli. J Med Microbiol 1992; 37:319. Swain, MG, Blennerhassett, PA, Collins, SM. Impaired sympathetic nerve function in the inflamed rat intestine. Gastroenterology 1991; 100:675. Niaz, Sk, Sandrasegaran, K, Renny, FH, Jones, BJ. Postinfective diarrhoea and bile acid malabsorption. J R Coll Physicians Lond 1997; 31:53. Sinha, L, Liston, R, Testa, HJ, Moriarty, KJ. Idiopathic bile acid malabsorption: qualitative and quantitative clinical features and response to cholestyramine. Aliment Pharmacol Ther 1998; 12:839. Spiller, RC, Jenkins, D, Thornley, JP, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut 2000; 47:804. Dunlop, SP, Jenkins, D, Neal, KR, et al. Randomized, double-blind, placebo-controlled trial of prednisolone in post-infectious irritable bowel syndrome. Aliment Pharmacol Ther 2003; 18:77. Dunlop, Sp, Jenkins, D, Neal, KR, Spiller, RC. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterology 2003; 125:1651. Muldoon, C, Maguire, P, Gleeson, F. Onset of sucrase-isomaltase deficiency in late adulthood. Am J Gastroenterol 1999; 94:2298. Parry, SD, Stansfield, R, Jelley, D, et al. Is irritable bowel syndrome more common in patients presenting with bacterial gastroenteritis? A community-based, case-control study. Am J Gastroenterol 2003; 98:327. Ilnyckyj, A, Balachandra, B, Elliott, L, et al. Post-traveler's diarrhea irritable bowel syndrome: a prospective study. Am J Gastroenterol 2003; 98:596. Kassinen, A, Krogius-Kurikka, L, Makivuokko, H, et al. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology 2007; 133:24. Whitehead, WE, Bosmajian, L, Zonderman, AB, et al. Symptoms of psychological distress associated with irritable bowel syndrome: Comparisons of community and medical clinic samples. Gastroenterology 1988; 95:709. Drossman, DA, Leserman, J, Nachman, G, et al. Sexual and physical abuse in women with functional or organic gastrointestinal disorders. Ann Intern Med 1990; 113:828. Talley, NJ, Boyce, PM, Jones, M. Is the association between irritable bowel syndrome and abuse explained by neuroticism? A population based study. Gut 1998; 42:47. Keck, ME, Holsboer, F. Hyperactivity of CRH neuronal circuits as a target for therapeutic interventions in affective disorders. Peptides 2001; 22:835. Sagami, Y, Shimada, Y, Tayama, J, et al. Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome. Gut 2004; 53:958.

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Clinical manifestations and diagnosis of irritable bowel syndrome

Authors Andrew B Chun, MD Arnold Wald, MD Section Editor J Thomas LaMont, MD Deputy Editor Peter A L Bonis, MD

Last literature review version 17.1: January 2009 | This topic last updated: February 4, 2009 (More)

INTRODUCTION Irritable bowel syndrome (IBS) is a gastrointestinal syndrome characterized by chronic abdominal pain and altered bowel habits in the absence of any organic cause. It is the most commonly diagnosed gastrointestinal condition. The prevalence of IBS in North America estimated from population-based studies is approximately 10 to 15 percent [1-6] . A population based study in Europe found an overall prevalence of 11.5 percent (a value similar to that noted in reports in the United States); however, the prevalence varied widely among countries [7] .

IBS affects men and women, young patients and the elderly. However, younger patients and women are more likely to be diagnosed with IBS. A systematic review estimated that there is an overall 2:1 female predominance in North America [3] .

Only about 15 percent of those affected actually seek medical attention [1,2,8-10] . Nevertheless, the absolute number of patients is still so large that IBS in its various forms comprises 25 to 50 percent of all referrals to gastroenterologists [11] . IBS also accounts for a significant number of visits to primary care physicians, and is the second highest cause of work absenteeism after the common cold [12] . IBS has been associated with increased health care costs, with some studies suggesting annual direct and indirect costs of up to $30 billion [13] .

This topic review will discuss the clinical manifestations and diagnosis of IBS. The pathophysiology and therapy of this disorder are presented separately. (See "Pathophysiology of irritable bowel syndrome" and see "Treatment of irritable bowel syndrome"). The AGA guideline for irritable bowel syndrome [14] , as well as other AGA guidelines, can be accessed through the AGA web site at http://www.gastro.org/wmspage.cfm?parm1=4453.

CLINICAL MANIFESTATIONS Patients with IBS can present with a wide array of symptoms which include both gastrointestinal and extraintestinal complaints. However, the symptom complex of chronic abdominal pain and altered bowel habits remains the nonspecific yet primary characteristic of IBS [15] .

Chronic abdominal pain Abdominal pain in IBS is usually described as a crampy sensation with variable intensity and periodic exacerbations. The pain is generally located in the lower abdomen, often on the left side; however, the location and character of the pain can vary widely [15,16] . The severity of the pain may range from mildly annoying to debilitating. Several factors, such as emotional stress and eating, may exacerbate the pain, while defecation often provides some relief.

Despite the variability of abdominal pain in IBS, some clinical features are clearly not compatible with the syndrome and should prompt an investigation for organic diseases. These include: Pain associated with anorexia, malnutrition, or weight loss. This constellation is extremely rare in IBS unless there is concurrent major psychologic illness. Pain that is progressive, awakens the patient from sleep, or prevents sleep. Such pain is not characteristic of IBS.

Altered bowel habits By definition, patients with IBS complain of altered bowel habits. However, since the range of normal bowel habits is quite broad, it is important to elicit a careful history of the volume, frequency, and consistency of the

patient's stools. The normal frequency of bowel movements is variable. In one study, for example, 99 percent of normal subjects reported between three bowel movements per day to three bowel movements per week [17] . Patients with IBS complain of diarrhea, constipation, alternating diarrhea and constipation, or normal bowel habits alternating with either diarrhea and/or constipation.

Diarrhea Diarrhea is usually characterized as frequent loose stools of small to moderate volume. Stools generally occur during waking hours, most often in the morning or after meals. Most bowel movements are preceded by lower abdominal cramps and urgency even to the point of fecal incontinence and may be followed by a feeling of incomplete evacuation.

Approximately one-half of all patients with IBS complain of mucus discharge with stools. Large volume diarrhea, bloody stools, nocturnal diarrhea, and greasy stools are not associated with IBS and suggest an organic disease. A subgroup of patients describe an acute viral or bacterial gastroenteritis which then leads to a subsequent disorder characteristic of diarrhea-predominant IBS, called post-infectious IBS. (See "Pathophysiology of irritable bowel syndrome").

Constipation Constipation may last from days to months, with interludes of diarrhea or normal bowel function. Stools are often hard and may be described as pellet shaped. Patients may also experience a sense of incomplete evacuation even when the rectum is empty. This can lead to straining with defecation, prolonged time on the toilet, and inappropriate use of enemas and laxatives.

Other gastrointestinal symptoms Upper gastrointestinal symptoms, including gastroesophageal reflux, dysphagia, early satiety, intermittent dyspepsia, nausea, and non-cardiac chest pain, are common in patients with IBS [15] . Patients with IBS also frequently complain of abdominal bloating and increased gas production in the form of flatulence or belching. (See "Pathophysiology of irritable bowel syndrome").

Extraintestinal symptoms Patients with IBS often complain of a broad range of non-gastrointestinal symptoms. These include impaired sexual function, dysmenorrhea, dyspareunia, and increased urinary frequency and urgency [18] . They are also more likely to have hypertension, reactive airway disease, and rheumatologic syndromes, including fibromyalgia [19,20] .

DIAGNOSTIC CRITERIA In the absence of a biologic disease marker, efforts have been made to standardize the diagnosis of IBS using symptom based criteria. This concept originated in 1978 when Manning, et al formulated a symptom complex suggestive of IBS (show table 1) [21] . These symptoms included relief of pain with bowel movements, looser and more frequent stools with onset of pain, passage of mucus, and a sense of incomplete emptying. A later report substantiated the usefulness of these symptoms in 361 outpatients: 81 had IBS, 101 had organic gastrointestinal disease, and 145 were controls [22] . The following results were noted: The likelihood of IBS was proportional to the number of Manning's criteria (show table 2). The sensitivity and specificity to discriminate IBS from organic gastrointestinal disease were 58 and 74 percent, respectively. The sensitivity and specificity to discriminate IBS from all patients without IBS were 42 and 85 percent, respectively.

In the above study, the predictive ability of the Manning criteria was reduced in the elderly, and in men; the latter observation has also been noted in other reports [22,23] . However, discordant data have also been reported. In one study, three of the core Manning criteria (loose stools, more frequent bowel movements with onset of pain, and pain relieved by defecation) equally applied to both genders; the other three criteria were not useful for making the diagnosis of IBS in any patient subgroups [24] .

In an effort to standardize clinical research protocols, an international working team published a consensus definition in 1992 called the Rome criteria, which was revised in 1999 and then again in 2005 [15] . IBS was defined as a functional group of discomfort or bowel disorders in which abdominal pain is associated with defecation or a change in bowel habit and with features of disordered defecation (show table 3). Supportive symptoms that are not part of the Rome III criteria include: abnormal stool frequency ( 3 bowel movements per week or >3 bowel movements per day); abnormal stool form (lumpy/hard or loose/watery), defecation straining, urgency, or a feeling of incomplete bowel movement, passing mucus and bloating. Four subtypes of IBS were also recognized: IBS with constipation (hard or lumpy stools 25 percent and loose (mushy) or watery stools <25 percent of bowel movements) IBS with diarrhea (loose (mushy) or water stools 25 percent and hard or lumpy stools <5 percent of bowel movements) Mixed IBS (hard or lumpy stools 25 percent and loose (mushy) or watery stools 25 percent of bowel movements Unsubtyped IBS (insufficient abnormality of stool consistency to meet the above subtypes).

The Rome criteria have been criticized for overemphasis on abdominal pain and failure to emphasize postprandial urgency, abdominal pain, and/or diarrhea [25] . As a result, some investigators continue to use the Manning criteria or a combination of both. Other criteria have also been proposed (such as the Kruis criteria) but are uncommonly used [26-28] .

A number of studies have assessed the accuracy of the Rome and Manning criteria in a variety of practice settings [27] . Although the overall sensitivity and specificity are high, results in individual studies have been variable, providing a rationale for ongoing studies that are attempting to further refine these criteria [29,30] . Furthermore, the predictive values of the criteria depend upon the prevalence of IBS and organic disease in the individual practice setting.

Considering the available data and the above limitations, a consensus statement issued by the American Gastroenterological Association recommends that the diagnosis of IBS should be based upon the identification of positive symptoms consistent with the condition (as summarized by the Rome criteria) and excluding in a cost-effective manner other conditions with similar clinical presentations. The AGA guideline for irritable bowel syndrome [14] , as well as other AGA guidelines, can be accessed through the AGA web site at http://www.gastro.org/wmspage.cfm? parm1=4453.

DIAGNOSTIC APPROACH Many physicians place great importance on the exclusion of organic causes of symptoms compatible with IBS. However, to avoid unnecessary and costly testing, the diagnosis of IBS can be made on the basis of classic symptoms in most patients. As discussed above, emphasis should be placed upon identifying a symptom complex compatible with IBS and then using prudent, albeit not exhaustive, diagnostic testing except in those patients with "alarm" or atypical symptoms or laboratory abnormalities such as anemia or electrolyte disturbances. The Rome and Manning criteria provide guidelines to identify patients with suspected IBS. A 2009 position statement issued by the American College of Gastroenterology (ACG) suggests specific forms of testing be guided by the clinical setting (show table 4) [3] .

The first step in diagnosis is a careful assessment of the patient's symptoms. A nonjudgmental series of open-ended questions helps to establish a caring physicianpatient relationship. A careful history may identify dietary factors and medications

that mimic or exacerbate symptoms of IBS. Examples include lactose [31] , sorbitol [32] , and magnesium containing antacids that may cause diarrhea, and medications such as anticholinergic drugs and calcium channel blockers that can cause constipation. (See "Lactose intolerance" and see "Etiology and evaluation of chronic constipation in adults").

Initial diagnostic studies Multiple diagnostic tests have been recommended for patients with IBS symptoms. However, as noted above, there is limited evidence supporting the routine performance of specific diagnostic testing in patients without alarm features and in those without diarrhea. Nevertheless, some amount of testing is usually performed. In patients who have symptoms suggestive of IBS based upon the Rome III criteria (show table 3) and no alarm symptoms or signs on the history and physical examination, a limited number of diagnostic studies can rule out organic illness in the majority of patients: Routine laboratory studies such as a complete blood count are normal in IBS. A normal C-reactive protein is useful in excluding an underlying inflammatory condition causing symptoms. In patients with diarrhea as the predominant symptom who have risk factors for a parasitic infection (such as recent foreign travel to a developing country), we suggest that three separate and fresh stools be examined for ova and parasites. (See "Approach to the adult with acute diarrhea in developed countries"). A 24-hour stool collection may sometimes be useful if osmotic or secretory diarrhea or malabsorption is suspected, since stool weight in excess of 300 g per day or increased fecal fat is unlikely in IBS [15] . (See "Clinical features and diagnosis of malabsorption"). As noted above, serum testing for celiac disease using IgA antibody to tissue transglutaminase (tTG) is recommended [33] . (See "Diagnosis of celiac disease"). Routine flexible sigmoidoscopy and biopsy have a low diagnostic yield and are not cost-effective in IBS, although they may help to reassure an anxious patient. We occasionally perform this procedure in younger patients with persistent diarrhea to exclude inflammatory bowel disease [34] . Others, including the American Gastroenterological Association Patient Care Committee, have recommended colonoscopy for patients over the age of 50 [35] . The ACG position statement emphasizes that routine use of colon cancer screening tools is recommended for all patients 50 years old, including IBS patients [3] . Mucosal biopsies should be performed in those with persistent and continuous diarrhea to exclude microscopic colitis. (See "Lymphocytic and collagenous colitis (microscopic colitis)").

This limited diagnostic approach rules out organic disease in over 95 percent of patients [36,37] . Stated differently, less than 5 percent of patients with organic disease will be incorrectly diagnosed with IBS using this diagnostic strategy.

Thus, normal diagnostic studies at this point in the evaluation suggest it is reasonable to begin a trial of symptomatic therapy. (See "Treatment of irritable bowel syndrome"). Patients can be reevaluated in three to six weeks to assess the response to treatment. The presence of persistent symptoms does not mean that the diagnosis was incorrect. However, a more extensive evaluation should be considered in patients who have had a change or progression of symptoms.

In addition, because of the positive correlation between abuse and certain gastrointestinal illness patterns, patients with refractory or severe IBS may be gently questioned about physical and sexual abuse once a physician-patient relationship has been established [38] . Consideration should also be given to psychologic factors that may influence the patient to seek medical attention [39,40] . As an example, personal concern about a serious disease precipitated by the recent death of a family member from a gastrointestinal disease may be the primary motivator to seek attention at this particular time.

Other diagnostic studies It may be reasonable to consider additional diagnostic studies in patients who do not respond to general treatment measures. (See "Treatment of irritable bowel syndrome"). The diagnostic evaluation depends upon the predominant symptoms: patients with predominantly constipation should have a work-up similar to other patients with chronic constipation (show algorithm 1) (see "Etiology and evaluation of chronic constipation in adults"); patients with predominantly diarrhea should have a work-up similar to other patients with chronic diarrhea (show algorithm 2A-B). The American Gastroenterological Association (AGA) technical review for the evaluation and management of chronic diarrhea [41] , as well as other AGA guidelines, can be accessed through the AGA web site at http://www.gastro.org/wmspage.cfm?parm1=4453.

INFORMATION FOR PATIENTS Educational materials on this topic are available for patients. (See "Patient information: Irritable bowel syndrome"). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

SUMMARY AND RECOMMENDATIONS Patients with IBS can present with a wide array of symptoms which include both gastrointestinal and extraintestinal complaints. However, the symptom complex of chronic abdominal pain and altered bowel habits remains the nonspecific yet primary characteristic of IBS. Many physicians place great importance on the exclusion of organic causes of symptoms compatible with

IBS. However, to avoid unnecessary and costly testing, the diagnosis of IBS can often be made with confidence in a positive fashion based on a typical presentation rather than by only excluding organic disorders. As discussed above, emphasis should be placed upon identifying a symptom complex compatible with IBS and then using prudent, albeit not exhaustive, diagnostic testing. The Rome and Manning criteria provide guidelines to identify patients with suspected IBS. Multiple diagnostic tests have been recommended for patients with IBS symptoms. However, as noted above, there is limited evidence supporting the routine performance of specific diagnostic testing in patients without alarm features and in those without diarrhea. Nevertheless, some amount of testing is usually obtained. In patients who have symptoms suggestive of IBS based upon the Rome III criteria (show table 3) and no alarm symptoms or signs on the history and physical examination, a limited number of diagnostic studies can rule out organic illness in many patients and a sizeable number require no testing at all. (See "Diagnostic approach" above).

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES Talley, NJ, Zinsmeister, AR, Van Dyke, C, et al. Epidemiology of colonic symptoms and the irritable bowel syndrome. Gastroenterology 1991; 101:927. Drossman, DA, Zhiming, L, Andruzzi, E, et al. US householders survey of functional gastrointestinal disorders: Prevalence, sociodemography, and health impact. Dig Dis Sci 1993; 38:1569. American College of Gastroenterology IBS Task Force. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol 2009; 104:S1. Hahn, BA, Saunders, WB, Maier, WC. Differences between individuals with self-reported irritable bowel syndrome (IBS) and IBS-like symptoms. Dig Dis Sci 1997; 42:2585. Saito, YA, Locke, GR, Talley, NJ, et al. A comparison of the Rome and Manning criteria for case identification in epidemiological investigations of irritable bowel syndrome. Am J Gastroenterol 2000; 95:2816. Thompson, WG, Irvine, EJ, Pare, P, et al. Functional gastrointestinal disorders in Canada: first population-based survey using Rome II criteria with suggestions for improving the questionnaire. Dig Dis Sci 2002; 47:225. Hungin, AP, Whorwell, PJ, Tack, J, Mearin, F. The prevalence, patterns and impact of irritable bowel syndrome: an international survey of 40 000 subjects. Aliment Pharmacol Ther 2003; 17:643. Jones, R, Lydeard, S. Irritable bowel syndrome in the general population. BMJ 1992; 304:87. Heaton, KW, O'Donnell, LJ, Braddon, FEM, et al. Symptoms of irritable bowel syndrome in a British urban community: Consulters and nonconsulters. Gastroenterology 1992; 102:1962. Ford, AC, Forman, D, Bailey, AG, et al. Irritable bowel syndrome: a 10-yr natural history of symptoms and factors that influence consultation behavior. Am J Gastroenterol 2008; 103:1229. Everhart, JE, Renault, PF. Irritable bowel syndrome in office based practice in the United States.

Gastroenterology 1991; 100:998. Schuster, MM. Diagnostic evaluation of the irritable bowel syndrome. Gastroenterol Clin North Am 1991; 20:269. Sandler, RS, Everhart, JE, Donowitz, M, et al. The burden of selected digestive diseases in the United States. Gastroenterology 2002; 122:1500. American Gastroenterological Association medical position statement: irritable bowel syndrome. Gastroenterology 2002; 123:2105. Longstreth, GF, Thompson, WG, Chey, WD, et al. Functional bowel disorders. Gastroenterology 2006; 130:1480. Swarbrick, ET, Bat, L, Hegarty, JE, et al. Site of pain from the irritable bowel. Lancet 1980; 2:443. Connell, AM, Hilton, C, Irvine, G, et al. Variation of bowel habit in two population samples. Br Med J 1965; 5470:1095. Whorwell, PJ, McCallum, M, Creed, FH, Roberts, CT. Non-colonic features of irritable bowel syndrome. Gut 1986; 27:37. White, AM, Stevens, WH, Upton, AR, et al. Airway responsiveness to inhaled methacholine in patients with irritable bowel syndrome. Gastroenterology 1991; 100:68. Hudson, JI, Goldenberg, DL, Pope, HG, et al. Comorbidity of fibromyalgia with medical and psychiatric disorders. Am J Med 1992; 92:363. Manning, AP, Thompson, WG, Heaton, KW, Morris, AF. Towards a positive diagnosis of the irritable bowel. Br Med J 1978; 2:653. Talley, NJ, Phillips, SF, Melton, LJ, et al. Diagnostic value of the Manning criteria in irritable bowel syndrome. Gut 1990; 31:77. Smith, RC, Greenbaum, DS, Vancouver, JB, et al. Gender differences in Manning criteria in the irritable bowel syndrome. Gastroenterology 1991; 100:591. Taub, E, Cuevas, JL, Cook, EW 3rd, et al. Irritable bowel syndrome defined by factor analysis: Gender and race comparisons. Dig Dis Sci 1995; 40:2647. Camilleri, M, Choi, MG. Irritable bowel syndrome. Aliment Pharmacol Ther 1997; 11:3. Kruis, W, Thieme, C, Weinzierl, M, et al. A diagnostic score for the irritable bowel syndrome. Its value in the exclusion of organic disease. Gastroenterology 1984; 87:1. Hammer, J, Talley, NJ. Diagnostic criteria for the irritable bowel syndrome. Am J Med 1999; 107:5S. Frigerio, G, Beretta, A, Orsenigo, G, et al. Irritable bowel syndrome: Still far from a positive diagnosis. Dig Dis Sci 1992; 37:164. Fass, R, Longstreth, GF, Pimentel, M, et al. Evidence- and consensusbased practice guidelines for the diagnosis of irritable bowel syndrome. Arch Intern Med 2001; 161:2081. Vanner, SJ, Depew, WT, Paterson, WG, et al. Predictive value of the Rome criteria for diagnosing the irritable bowel syndrome. Am J Gastroenterol 1999; 94:2912. Suarez, FL, Savaiano, DA, Levitt, MD. A comparison of symptoms after the consumption of milk or lactose-hydrolyzed milk by people with selfreported severe lactose intolerance. N Engl J Med 1995; 333:1. Hyams, JS. Sorbitol intolerance: An unappreciated cause of functional gastrointestinal complaints. Gastroenterology 1983; 84:30. Sanders, DS, Carter, MJ, Hurlstone, DP, et al. Association of adult coeliac disease with irritable bowel syndrome: a case-control study in patients fulfilling ROME II criteria referred to secondary care. Lancet 2001; 358:1504. Cash, BD, Schoenfeld, P, Chey, WD. The utility of diagnostic tests in irritable bowel syndrome patients: a systematic review. Am J Gastroenterol 2002; 97:2812. Drossman, DA, Camilleri, M, Mayer, EA, Whitehead, WE. AGA technical review on irritable bowel syndrome. Gastroenterology 2002; 123:2108. Schmulson, MW, Chang, L. Diagnostic approach to the patient with irritable bowel syndrome. Am J Med 1999; 107:20S. Svendsen, JH, Munck, LK, Andersen, JR. Irritable bowel

syndrome-prognosis and diagnostic safety. A 5-year follow-up study. Scand J Gastroenterol 1985; 20:415. Drossman, DA, Talley, NJ, Leserman, J, et al. Sexual and physical abuse and gastrointestinal illness. Ann Intern Med 1995; 123:782. Katon, WJ, Von Korff, M, Lin, E. Panic disorder: Relationship to high medical utilization. Am J Med 1992; 92:7S. Drossman, DA, Thompson, WG. The irritable bowel syndrome: Review and a graduated multi-component treatment approach. Ann Intern Med 1992; 116:1009. Fine, KD, Schiller, LR. AGA technical review on the evaluation and management of chronic diarrhea. Gastroenterology 1999; 116:1464.

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Treatment of irritable bowel syndrome

Author Arnold Wald, MD Section Editor Nicholas J Talley, MD, PhD Deputy Editor Peter A L Bonis, MD

Last literature review version 17.1: January 2009 | This topic last updated: February 6, 2009 (More)

INTRODUCTION Irritable bowel syndrome (IBS) is a gastrointestinal disorder characterized by chronic abdominal pain and altered bowel habits in the absence of any organic disorder. The approach to therapy of IBS will be reviewed here. The

clinical manifestations and diagnosis of this disorder are discussed separately. (See "Clinical manifestations and diagnosis of irritable bowel syndrome").

GENERAL PRINCIPLES IBS is a chronic condition with no known cure. As a result, the focus of treatment should be on relief of symptoms and in addressing the patient's concerns. An important question to answer is why the patient is seeking help at this time. Recent exacerbating factors (medications, dietary changes), concerns about serious illness, stressors, hidden agenda (disability claims, requests for opiates), or psychiatric comorbidity are critical to establish when developing the optimum therapy [1] .

Therapeutic relationship The most important component of treatment lies in the establishment of a therapeutic physician-patient relationship. The doctor should be non-judgmental, establish realistic expectations with consistent limits, and involve the patient in treatment decisions [1] . Patients with established, positive physician interactions have fewer IBS-related follow-up visits [2] .

The importance of the therapeutic relationship in IBS was emphasized in a study that investigated the components of the placebo effect and patient-provider interaction in 262 patients with IBS [3] . Group 1 was assigned to a waitlist only, whereas Group 2 received sham acupuncture with little interaction with a health care provider (HCP). Group 3 received sham acupuncture but had much more interaction with their HCP. At both three and six weeks, the level of improvement in Group 3 was significantly better than Group 2, which in turn was significantly better than Group 1. The conclusion was that placebo effects are significant in IBS and the patient-health care provider interaction is the key part of that effect.

Patient education Education of the proposed mechanisms of IBS helps to validate the patient's illness experience and sets the basis for therapeutic interventions. (See "Pathophysiology of irritable bowel syndrome"). Patients should be informed of the chronic and benign nature of IBS, that the diagnosis (if well-established) is not likely to be changed, and that he or she should have a normal life span. In a 29-year follow-up study of 112 patients from the Mayo Clinic, for example, only 10 of 112 patients developed an organic gastrointestinal disease; patient survival was similar to expected survival [2] . (See "Patient information: Irritable bowel syndrome").

Dietary modification A careful dietary history may reveal patterns of symptoms related to dairy and gas-producing foods. Given the similarity that may occur in symptoms of IBS and lactose intolerance, an empiric trial of a lactose free diet should be considered in patients suspected of having irritable bowel syndrome [4,5] . Some patients diagnosed with irritable bowel syndrome may have undiagnosed lactose intolerance and can have lasting clinical improvement when placed on a lactose restricted diet [5] . (See "Lactose intolerance"). Similar symptoms may arise from excessive consumption of fructose containing beverages in patients predisposed to fructose intolerance [6] .

Exclusion of foods that increase flatulence (beans, onions, celery, carrots, raisins, bananas, apricots, prunes, brussels sprouts, wheat germ, pretzels, and bagels) should be considered in patients who complain of gas [7] . (See "Intestinal gas and bloating" and see "Patient information: Gas and bloating"). Underlying visceral hyperalgesia in IBS may explain the exaggerated discomfort experienced with consumption of gas-producing foods. (See "Pathophysiology of irritable bowel syndrome").

Whether elimination of other specific foods is beneficial is unclear. While it is possible that food allergy or intolerance may have a role in the development of symptoms, there are no reliable means to identify such individuals. Testing for serum immunoglobulins directed at specific dietary antigens (and elimination of responsible foods) has been proposed but the relationship between results of such testing and improvement of symptoms requires additional study before such an approach can be recommended [8] .

An increase in the intake of fiber is often recommended, either through diet or the use of commercial bulking supplements. However, not all authorities agree; a decrease in fiber intake to 12 g per day (particularly insoluble fiber such as bran) was suggested in a British guideline, because of the potential of fiber to exacerbate symptoms [9] .

The proposed beneficial effects of fiber mechanisms of action include: enhancement of water holding properties of the stool, formation of gels to provide lubrication, bulking of the stool, and binding of agents such as bile [10] . Despite their widespread use, a systematic review that included 13 randomized controlled trials found no convincing evidence that the commonly-used bulking agents were more effective than placebo at relieving global IBS symptoms [11] . Although the efficacy

of fiber supplements has not been proven, some improvement has been demonstrated in patients with IBS whose primary complaints are abdominal pain and constipation [12] .

Synthetic fiber supplements such as polycarbophil and methylcellulose are more soluble than natural fibers (psyllium). However, whether the synthetic supplements cause less bloating or are more effective than natural fiber supplements has not been determined. Some patients may experience increased bloating and gaseousness due to colonic metabolism of non-digestible fiber.

Because of its safety and frequent placebo effect, a trial of fiber is reasonable in all patients with IBS, especially those with constipation-predominant symptoms. Dosages of fiber supplements such as wheat bran or psyllium should be titrated to symptoms. Administration of one-half to one tablespoon once a day is a good starting dose.

Psychosocial therapies Behavioral treatments may be considered for motivated patients who associate symptoms with stressors, although their benefits remain controversial [1,13] . Hypnosis, biofeedback, and psychotherapy help to reduce anxiety levels, encourage health promoting behavior, increase patient responsibility and involvement in the treatment, and improve pain tolerance [14] .

A systematic review that included 25 controlled studies concluded that psychological interventions may be slightly superior to usual care but with marginal clinical significance and unclear durability of benefit [15] . Another review concluded that cognitive behavioral therapy, dynamic psychotherapy and hypnotherapy are more effective than usual care in relieving global symptoms of IBS [11] . One study found that symptom improvement occurred independently of the effects of cognitive behavioral therapy in alleviating comorbid psychological distress [16] .

MEDICATIONS Pharmacologic agents are only an adjunct to treatment in IBS. Furthermore, the drug chosen varies depending on the patient's major symptoms. Thus, diarrhea-predominant IBS is treated differently from constipation-predominant disease.

We suggest that the chronic use of drugs should generally be minimized or avoided because of the lifelong nature of this disorder and the lack of convincing therapeutic benefit. The difficulty in demonstrating efficacy may in part be due to the heterogeneous population diagnosed with IBS, the lack of disease markers, and the high placebo response rates [17] .

Antispasmodic agents Antispasmodic agents are the most frequently used pharmacologic agents in the treatment of IBS. Certain antispasmodics (hyoscine, cimetropium, pinaverium, and peppermint oil) may provide short-term relief but long-term efficacy has not been demonstrated [11] .

The antispasmodic agents include those that directly affect intestinal smooth muscle relaxation (eg, mebeverine and pinaverine), and those that act via their anticholinergic or antimuscarinic properties (eg, dicyclomine and hyoscyamine) [11] . Their selective inhibition of gastrointestinal smooth muscle reduces stimulated colonic motor activity and may be beneficial in patients with postprandial abdominal pain, gas, bloating, and fecal urgency [18] .

A meta-analysis of 23 controlled trials of smooth muscle relaxants found that they were more effective than placebo (risk difference for global improvement of 22 percent, and overall pain improvement of 53 versus 41 percent) [19] . Only weak evidence for a benefit on abdominal pain and global assessment of symptoms was suggested in a second meta-analysis [20] . A systematic review confirmed the support for short-term use of some antispasmodics [11] .

Administration of these medications in the treatment of IBS should be on an as needed basis and/or in anticipation of stressors with known exacerbating effects. Typical doses include dicyclomine (20 mg PO four times daily PRN) and hyoscyamine (0.125 to 0.25 mg PO or sublingual three times daily or four times daily as needed) or sustained release hyoscyamine (0.375 to 0.75 mg PO every 12 hours).

Antidepressants Antidepressants have analgesic properties independent of their mood improving effects and may therefore be beneficial in patients with neuropathic pain [21-24] . The postulated mechanisms of pain modulation with tricyclic antidepressants (TCAs) and possibly serotonin reuptake inhibitors (SSRIs) in IBS is facilitation of endogenous endorphin release, blockade of norepinephrine

reuptake leading to enhancement of descending inhibitory pain pathways, and blockade of the pain neuromodulator, serotonin [24,25] . Tricyclic agents, via their anticholinergic properties, also slow intestinal transit time [24] . They may therefore be beneficial in diarrhea-predominant IBS [26] .

A meta-analysis that included 12 placebo controlled trials of antidepressants in functional gastrointestinal disorders concluded that tricyclic antidepressants were associated with improvement in symptoms [27] . A later systematic review confirmed that TCAs and SSRIs were more effective than placebo at relieving global IBS symptoms, and appeared to reduce abdominal pain [11] . A subsequent, a placebo-controlled trial found amitriptyline to be significantly more effective in adolescents with IBS [28] .

Improvement in neuropathic pain with TCAs occurs at lower doses than required for treatment of depression. As a result, if an antidepressant is chosen for the treatment of IBS, low doses should be administered initially and titrated to pain control or tolerance. Because of the delayed onset of action, three to four weeks of therapy should be attempted before considering treatment insufficient and increasing the dose. Examples of medications used for this purpose include amitriptyline, imipramine, nortriptyline, and desipramine (10 to 25 mg at bedtime). The initial dose should be adjusted based upon tolerance and response. TCAs should be used cautiously in patients with constipation. Paroxetine and fluoxetine (20 mg PO daily), sertraline (100 mg PO daily), or other antidepressant medications can be considered if depression is a cofactor [29] .

There is less published experience with other antidepressants such as SSRIs or serotonin norepinephrine reuptake inhibitors (SNRIs), although they are used clinically. Results of the few published trials (mainly with SSRIs) have been inconsistent [29-33] .

Antidiarrheal agents In diarrhea-prone patients with IBS, the stools characteristically are loose and frequent but of normal total daily volume. A systematic review identified three controlled trials evaluating loperamide in the treatment of IBS [11,34-36] . All were of short duration, enrolled a small number of patients, and did not use standardized criteria for identifying patients. Overall, the trials suggested that loperamide was more effective than placebo for treatment of diarrhea, but not for treatment of global IBS symptoms or abdominal pain. Administration on an as needed basis is preferred to a regular scheduled dosing in

patients with diarrhea. Patients who consistently develop diarrhea after meals may benefit from taking a dose before meals. Loperamide should not be used in patients with constipation and should be used only cautiously in those with symptoms alternating between diarrhea and constipation.

Benzodiazepines Anxiolytic agents are of limited usefulness in IBS because of the risk of drug interactions, habituation, and rebound withdrawal. Furthermore, benzodiazepines may lower pain thresholds by stimulating gamma aminobutyric acid (GABA), thereby decreasing brain serotonin. They may, however, be useful for short-term (less than two weeks') reduction of acute situational anxiety that may be contributing to symptoms [1] .

5-hydroxytryptamine (serotonin) 3 receptor antagonists 5-hydroxytryptamine-3 receptor antagonists (such as alosetron, cilansetron ondansetron and granisetron) modulate visceral afferent activity from the gastrointestinal tract and may improve abdominal pain [37,38] . A meta-analysis that included 14 randomized controlled trials in IBS (involving alosetron or cilansetron) found a benefit in global improvement in IBS and relief of abdominal pain and discomfort [39] .

Alosetron was developed for use in IBS based upon its favorable effects on colonic motility and secretion and afferent neural systems [40] . In clinical trials the drug was most effective in female patients in whom diarrhea was predominant. However, the drug was associated with ischemic colitis and serious complications related to severe constipation, prompting the Food and Drug Administration (FDA) to remove it from the market in the United States. Evaluation of post-marketing data and demand from a subset of patients who had responded to treatment has prompted the FDA to bring the drug back to the market under tight control. (See "Alosetron hydrochloride (Lotronex) for irritable bowel syndrome").

5-hydroxytryptamine (serotonin) 4 receptor agonists Agonists of the 5hydroxytryptamine-4 (5-HT4) receptor stimulate the release of neurotransmitters and increase colonic motility, providing a rationale for their use in constipation predominant IBS [41] . The first of this class of drugs (tegaserod {Zelnorm}, a partial 5-HT4 receptor agonist) was approved for IBS and constipation but removed from the market in March 2007 because of cardiovascular side-effects. It has been subsequently reintroduced under an investigational new drug protocol.

Lubiprostone Lubiprostone is a locally acting chloride channel activator that enhances chloride-rich intestinal fluid secretion. It received initial approval from the United States Food and Drug Administration for treatment of chronic idiopathic constipation but later also received approval for treatment of irritable bowel syndrome with constipation in women 18 years and older.

Approval was based upon two multicenter placebo-controlled trials involving 1154 adults (92 percent women) with irritable bowel syndrome and constipation who were randomly assigned to lubiprostone (8 micrograms twice daily) or placebo for 12 weeks [42] . Patients randomized to lubiprostone were significantly more likely to achieve an overall response (18 versus 10 percent). Serious adverse events were similar to placebo. The most common adverse event was nausea (8 versus 4 percent). A follow-up open-label study involving 522 patients showed that benefits continued or improved at 52 weeks. The approved dose (8 micrograms twice daily) is lower than the approved dose for treatment of chronic idiopathic constipation.

Its role continues to be determined. There have been no comparisons with other options for treatment of IBS with constipation and its long-term safety remains to be established. Furthermore, the placebo response in the studies above was far lower than most studies of IBS and it is not intuitive why a secretory agent would improve symptoms other than constipation in a disorder such as IBS. Until further data are available (and because it is expensive compared with other options), it is best reserved for patients with IBS and severe constipation in whom other approaches have been unsuccessful.

Guanylate cyclase agonists Linaclotide is a guanylate cyclase agonist that stimulates intestinal fluid secretion and transit. A phase IIb study involving 420 patients with IBS-C (reported in preliminary form) found improvement in stool frequency and in global and individual IBS symptoms [11] .

Antibiotics Scattered reports have suggested that some patients with IBS improved with antibiotic treatment [43-46] . Most of the improvement has been with bloating but not for abdominal pain or altered bowel habits. The mechanisms leading to the benefit are unclear but may be due to suppression of gas producing bacteria in the colon. Such studies do not prove the hypothesis that bacterial overgrowth in the small intestine underlies the symptoms of most patients with IBS.

Furthermore, in one report, lactulose breath testing (the method used for suggesting bacterial overgrowth in some of these studies) did not discriminate patients with IBS from healthy controls [47] . Thus, the relationships between bacterial overgrowth, benefits of antibiotics in patients with IBS, and methods to test for bacterial overgrowth in IBS require further study before this approach can be recommended.

Alternative therapies Multiple alternative forms of therapy for IBS have been suggested, such as herbs, probiotics, acupuncture, and enzyme supplementation [48-50] . Their role remains uncertain. (See "Probiotics for gastrointestinal disease" section on irritable bowel syndrome).

MAJOR SOCIETY GUIDELINES Guidelines for the management of IBS have been issued by several organizations including a 2009 guideline from the American College of Gastroenterology (show table 1) [11] .

INFORMATION FOR PATIENTS Educational materials on this topic are available for patients. (See "Patient information: Irritable bowel syndrome"). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

SUMMARY AND RECOMMENDATIONS Treatment of IBS varies with the severity and type (diarrhea versus constipation predominant) of symptoms that are present.

Mild symptoms Patients with mild or infrequent symptoms usually have little or no functional impairment or psychologic disturbance. Thus, we suggest treatment should focus upon the general measures described above (such as establishment of the physician-patient relationship, patient education, reassurance, dietary modification, and, if bloating is not a major factor, fiber supplementation) rather than specific pharmacologic therapy (Grade 2C). (See "General principles" above).

Moderate symptoms Patients with moderate symptoms of IBS experience disruptions of normal daily activities due to exacerbations of symptoms; these patients also may demonstrate psychologic impairment.

We monitor patients' symptoms for several weeks to help identify precipitating factors, such as lactose intolerance, excess caffeine, or specific stressors. Modifications in diet, behavioral changes, and psychotherapy may improve the clinical outcome.

Randomized controlled trials evaluating specific pharmacologic agents have demonstrated their superiority compared with placebo. However, there have been few controlled trials evaluating specific strategies for how these drugs should be used in conjunction with other types of treatment (such as fiber therapy), how long they should be used, or whether they should be given continuously or episodically. We often use pharmacologic intervention to control symptom flares but also use continuous pharmacologic therapy (such as tricyclic antidepressant drugs) for periods of months or years. Our choice of specific therapies is based mainly upon symptoms and response to empiric trials (See "Medications" above).

Intractable symptoms A small subset of patients with IBS present to tertiary care centers with severe, unrelenting symptoms that are often associated with underlying psychiatric impairment and frequent health care utilization. We suggest behavioral modification and the use of psychoactive drugs in such patients (Grade 2C). (See "Medications" above).

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES Drossman, DA, Thompson, WG. The irritable bowel syndrome: Review and a graduated multi-component treatment approach. Ann Intern Med 1992; 116:1009. Owens, DM, Nelson, DK, Talley, NJ. The irritable bowel syndrome: Long-term prognosis and the physician-patient relationship. Ann Intern Med 1995; 122:107. Kaptchuk, TJ, Kelley, JM, Conboy, LA, et al. Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ 2008; 336:999. Vesa, TH, Seppo, LM, Marteau, PR, et al. Role of irritable bowel syndrome in subjective lactose intolerance. Am J Clin Nutr 1998; 67:710. Bohmer, CJ, Tuynman, HA. The effect of a lactose-restricted diet in patients with a positive lactose tolerance test, earlier diagnosed as irritable bowel syndrome: A 5-year follow-up study. Eur J Gastroenterol Hepatol 2001; 13:941. Choi, YK, Johlin, FC Jr, Summers, RW, et al. Fructose intolerance: an under-recognized problem. Am J Gastroenterol 2003; 98:1348. Hasler, WL, Owyang, C. Irritable bowel syndrome. In: Textbook of Gastroenterology, Yamada, T (Ed) 4th edition, JB Lippincott,

Philadelphia 2003. p.1817. Atkinson, W, Sheldon, TA, Shaath, N, Whorwell, PJ. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut 2004; 53:1459. Dalrymple, J, Bullock, I. Diagnosis and management of irritable bowel syndrome in adults in primary care: summary of NICE guidance. BMJ 2008; 336:556. Friedman, G. Diet and the irritable bowel syndrome. Gastroenterol Clin North Am 1991; 20:313. American College of Gastroenterology IBS Task Force. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol 2009; 104:S1. Drossman, DA, Whitehead, WE, Camilleri, M. Irritable bowel syndrome: A technical review for practice guideline development. Gastroenterology 1997; 112:2120. Lackner, JM, Jaccard, J, Krasner, SS, et al. Self-administered cognitive behavior therapy for moderate to severe irritable bowel syndrome: clinical efficacy, tolerability, feasibility. Clin Gastroenterol Hepatol 2008; 6:899. Drossman, DA, Chang, L. Psychosocial factors in the care of patients with gastrointestinal disorders. In: Textbook of Gastroenterology, Yamada, T (Ed) 4th edition, JB Lippincott, Philadelphia 2003. p.636. Zijdenbos, IL, de Wit, NJ, van der Heijden GJ, et al. Psychological treatments for the management of irritable bowel syndrome. Cochrane Database Syst Rev 2009; :CD006442. Lackner, JM, Jaccard, J, Krasner, SS, et al. How does cognitive behavior therapy for irritable bowel syndrome work? A mediational analysis of a randomized clinical trial. Gastroenterology 2007; 133:433. Jailwala, J, Imperiale, TF, Kroenke, K. Pharmacologic treatment of the irritable bowel syndrome: A systematic review of randomized, controlled trials. Ann Intern Med 2000; 133:136. Lynn, RB, Friedman, LS. Irritable bowel syndrome. N Engl J Med 1993; 329:1940. Poynard, T, Regimbeau, C, Benhamou, Y. Meta-analysis of smooth muscle relaxants in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther 2001; 15:355. Quartero, A, Meineche-Schmidt, V, Muris, J, et al. Bulking agents, antispasmodic and antidepressant medication for the treatment of irritable bowel syndrome. Cochrane Database Syst Rev 2005; 18; (2):CD003460. Eisendrath, SJ, Kodama, KT. Fluoxetine management of chronic abdominal pain. Psychosomatics 1992; 33:227. Hameroff, SR, Weiss, JL, Lerman, JC, et al. Doxepin's effects on chronic pain and depression: A controlled study. J Clin Psychiatry 1984; 45:47. Pilowsky, K, Barrow, CG. A controlled study of psychotherapy and amitriptyline used individually and in combination in the treatment of chronic intractable, "psychogenic" pain. Pain 1990; 40:3. Gorard, DA, Libby, GW, Farthing, MJ. Effect of tricyclic antidepressant on small intestinal motility in health and diarrhea predominant irritable bowel syndrome. Dig Dis Sci 1995; 40:86. Bueno, L, Fioramonti, J, Delvaux, M, Frexinos, J. Mediators and pharmacology of visceral hypersensitivity: From basic to clinical investigations. Gastroenterology 1997; 112:1714. Clouse, RE, Lustman, PJ, Geisman, RA, Alpers, DH. Antidepressant therapy in 138 patients with irritable bowel syndrome: A five-year clinical experience. Aliment Pharmacol Ther 1994; 8:409. Jackson, JL, O'Malley, PG, Tomkins, G, et al.Treatment of functional gastrointestinal disorders with antidepressant medications: . A meta-analysis. Am J Med 2000; 108:65. Bahar, RJ, Collins, BS, Steinmetz, B, Ament, ME. Double-blind placebo-controlled trial of

amitriptyline for the treatment of irritable bowel syndrome in adolescents. J Pediatr 2008; 152:685. Tabas, G, Beaves, M, Wang, J, et al. Paroxetine to treat irritable bowel syndrome not responding to high-fiber diet: a double-blind, placebocontrolled trial. Am J Gastroenterol 2004; 99:914. Tack, J, Broekaert, D, Fischler, B, et al. A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome. Gut 2006; 55:1095. Kuiken, SD, Tytgat, GN, Boeckxstaens, GE. The selective serotonin reuptake inhibitor fluoxetine does not change rectal sensitivity and symptoms in patients with irritable bowel syndrome: a double blind, randomized, placebo-controlled study. Clin Gastroenterol Hepatol 2003; 1:219. Vahedi, H, Merat, S, Rashidioon, A, et al. The effect of fluoxetine in patients with pain and constipation-predominant irritable bowel syndrome: a double-blind randomized-controlled study. Aliment Pharmacol Ther 2005; 22:381. Creed, F, Fernandes, L, Guthrie, E, et al. The cost-effectiveness of psychotherapy and paroxetine for severe irritable bowel syndrome. Gastroenterology 2003; 124:303. Cann, PA, Read, NW, Holdsworth, CD, Barends, D. Role of loperamide and placebo in management of irritable bowel syndrome. Dig Dis Sci 1984; 29:239. Hovdenak, N. Loperamide treatment of the irritable bowel syndrome. Scand J Gastroenterol Suppl 1987; 130:81. Efskind, PS, Bernklev, T, Vatn, MH. A doubleblind placebo-controlled trial with loperamide in irritable bowel syndrome. Scand J Gastroenterol 1996; 31:463. Zighelboim, J, Talley, NJ, Phillips, SF, et al. Visceral perception in irritable bowel syndrome: Rectal and gastric responses to distention and serotonin type 3 antagonism. Dig Dis Sci 1995; 40:819. Prior, A, Read, NW. Reduction of rectal sensitivity and post-prandial motility by granisetron, a 5-HT3receptor antagonist, in patients with irritable bowel syndrome. Aliment Pharmacol Ther 1993; 7:175. Andresen, V, Montori, VM, Keller, J, et al. Effects of 5hydroxytryptamine (serotonin) type 3 antagonists on symptom relief and constipation in nonconstipated irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials. Clin Gastroenterol Hepatol 2008; 6:545. Gershon, MD. Serotonin and its implication for the management of irritable bowel syndrome. Rev Gastroenterol Disord 2003; 3 Suppl 2:S25. Scott, LJ, Perry, CM. Tegaserod. Drugs 1999; 58:491. Drossman, DA, Chey, WD, Johanson, JF, et al. Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome--results of two randomized, placebo-controlled studies. Aliment Pharmacol Ther 2009; 29:329. Nayak, AK, Karnad, DR, Abraham, P, Mistry, FP. Metronidazole relieves symptoms in irritable bowel syndrome: the confusion with so-called 'chronic amebiasis'. Indian J Gastroenterol 1997; 16:137. Sharara, AI. Aoun, E, Abdul-Baki, H. et al A randomized double-blind placebo-controled trial of rifaximin in patients with abdominal bloating and flatulence. Am J Gastroenterol 2006; 101:326. Pimentel, M, Chow, EJ, Lin, HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. a double-blind, randomized, placebo-controlled study. Am J Gastroenterol 2003; 98:412. Pimentel, M, Park, S, Mirocha, J, et al. The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med 2006; 145:557. Bratten, JR, Spanier, J, Jones, MP.

Lactulose breath testing does not discriminate patients with irritable bowel syndrome from healthy controls. Am J Gastroenterol 2008; 103:958. Spanier, JA, Howden, CW, Jones, MP. A systematic review of alternative therapies in the irritable bowel syndrome. Arch Intern Med 2003; 163:265. Liu, J, Yang, M, Liu, Y, et al. Herbal medicines for treatment of irritable bowel syndrome. Cochrane Database Syst Rev 2006; :CD004116. Lim, B, Manheimer, E, Lao, L, et al. Acupuncture for treatment of irritable bowel syndrome. Cochrane Database Syst Rev 2006; :CD005111.

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