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Management of the irritable bowel syndrome

  • Michael Camilleri
    Affiliations
    Enteric Neuroscience Program, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, Dr. Camilleri has received research grants and worked as a consultant to several pharmaceutical companies whose medications are discussed in this article
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      Abstract

      Irritable bowel syndrome (IBS) is the most common disorder diagnosed by gastroenterologists and one of the more common ones encountered in general practice. The overall prevalence rate is similar (approximately 10%) in most industrialized countries; the illness has a large economic impact on health care use and indirect costs, chiefly through absenteeism. IBS is a biopsychosocial disorder in which 3 major mechanisms interact: psychosocial factors, altered motility, and/or heightened sensory function of the intestine. Subtle inflammatory changes suggest a role for inflammation, especially after infectious enteritis, but this has not yet resulted in changes in the approach to patient treatment. Treatment of patients is based on positive diagnosis of the symptom complex, limited exclusion of underlying organic disease, and institution of a therapeutic trial. If patient symptoms are intractable, further investigations are needed to exclude specific motility or other disorders. Symptoms fluctuate over time; treatment is often restricted to times when patients experience symptoms. Symptomatic treatment includes supplementing fiber to achieve a total intake of up to 30 g in those with constipation, those taking loperamide or other opioids for diarrhea, and those taking low-dose antidepressants or infrequently using antispasmodics for pain. Older conventional therapies do not address pain in IBS. Behavioral psychotherapy and hypnotherapy are also being evaluated. Novel approaches include alosetron; a 5-HT3 antagonist, tegaserod, a partial 5-HT4 agonist, κ-opioid agonists, and neurokinin antagonists to address the remaining challenging symptoms of pain, constipation, and bloating. Understanding the brain–gut axis is key to the eventual development of effective therapies for IBS.
      GASTROENTROLOGY 2001;120:652-668

      Abbreviations:

      IBS (irritable bowel syndrome), SSRI (selective serotonin reuptake inhibitor)
      In this article on the management of irritable bowel syndrome (IBS), the focus is on (1) the definitions, epidemiology, and pathophysiology as a means of understanding strategies for optimal management; (2) the natural history and “safety” of the disorder that justifies a conservative and reassuring approach to patients; and (3) consideration of older (conventional) and newer treatments of IBS.

      IBS overview: Definitions, epidemiology, pathophysiology

      Irritable bowel syndrome (IBS) is defined as “a functional bowel disorder in which abdominal pain is associated with defecation or a change in bowel habit, with features of disordered defecation and distention.”
      • Drossman DA
      • Corazziari E
      • Talley NJ
      • Thompson WG
      • Whitehead WE
      Rome II: a multinational consensus document on functional gastrointestinal disorders.
      The consensus definition and criteria for IBS have been formalized in the “Rome criteria,” which are based on Manning criteria (Table 1).
      Table 1Criteria for IBS
      Manning criteria
      • Manning AP
      • Thompson WG
      • Heaton KW
      • Morris AF
      Towards a positive diagnosis of the irritable bowel.
       Pain relieved by defecation
       More frequent stools at the onset to pain
       Looser stools at the onset of pain
       Visible abdominal distention
       Passage of mucus
       Sensation of incomplete evacuation
      Rome II criteria
      • Drossman DA
      • Corazziari E
      • Talley NJ
      • Thompson WG
      • Whitehead WE
      Rome II: a multinational consensus document on functional gastrointestinal disorders.
       At least 12 weeks or more, which need not be consecutive, in the previous 12 months of abdominal pain or discomfort that has 2 of 3 features:
        Relief with defecation
        Onset associated with a change in the frequency of stool
        Onset associated with a change in form (appearance) of stool
      Data from Manning et al
      • Manning AP
      • Thompson WG
      • Heaton KW
      • Morris AF
      Towards a positive diagnosis of the irritable bowel.
      . and Drossman et al
      • Drossman DA
      • Corazziari E
      • Talley NJ
      • Thompson WG
      • Whitehead WE
      Rome II: a multinational consensus document on functional gastrointestinal disorders.
      .
      The Rome criteria have come to be accepted as the state-of-the-art criteria for research studies; they have recently been refined and simplified for IBS to focus on the essential elements of abdominal pain and alteration of bowel habits.
      • Drossman DA
      • Corazziari E
      • Talley NJ
      • Thompson WG
      • Whitehead WE
      Rome II: a multinational consensus document on functional gastrointestinal disorders.
      However, validation of these criteria has been hampered by the lack of any biologic marker for IBS. The specificity of the symptoms alone is relatively poor. Specificity is enhanced by the inclusion of limited tests to exclude organic disease.
      • Kruis W
      • Thieme C
      • Weinzierl M
      • Schussler P
      • Holl J
      • Paulus W.
      A diagnostic score for the irritable bowel syndrome. Its value in the exclusion of organic disease.
      • Vanner SJ
      • Depew WT
      • Paterson WG
      • DaCosta LR
      • Groll AG
      • Simon JB
      • Djurfeldt M.
      Predictive value of the Rome criteria for diagnosing the irritable bowel syndrome.
      Thus, IBS is a disorder that can be diagnosed positively on the basis of a series of symptom criteria
      • Manning AP
      • Thompson WG
      • Heaton KW
      • Morris AF
      Towards a positive diagnosis of the irritable bowel.
      • Thompson WG
      • Dotevall G
      • Drossman DA
      • Heaton KW
      • Kruis W.
      Irritable bowel syndrome: guidelines for the diagnosis.
      • Thompson WG
      • Longstreth GF
      • Drossman DA
      • Heaton KW
      • Irvine EJ
      • Muller-Lissner SA
      Functional bowel disorders and functional abdominal pain.
      and limited evaluation to exclude organic disease.
      • Camilleri M
      • Prather CM
      The irritable bowel syndrome: mechanisms and a practical approach to management.
      • Drossman DA
      • Whitehead WE
      • Camilleri M.
      Irritable bowel syndrome: a technical review for practice guideline development.
      • Camilleri M
      • Choi MG
      Review article: irritable bowel syndrome.
      The prevalence data
      • Drossman DA
      • Li Z
      • Andruzzi E
      • Temple RD
      • Talley NJ
      • Thompson WG
      • Whitehead WE
      • Janssens J
      • Funch-Jensen P
      • Corazziari E
      • Richter JE
      • Koch GG
      U.S. householder survey of functional gastrointestinal disorders.
      • Talley NJ
      • Zinsmeister AR
      • Melton LJ
      Irritable bowel syndrome in a community: symptom subgroups, risk factors and health care utilization.
      • Saito YA
      • Locke GR
      • Talley NJ
      • Zinsmeister AR
      • Fett SL
      • Melton LJ
      The effect of new diagnostic criteria for irritable bowel syndrome on community prevalence estimates (abstr).
      from questionnaire studies range from the 2.9% estimate from 6 U.S. surveys of the prevalence of the diagnosis of IBS
      • Sandler RS
      Epidemiology of irritable bowel syndrome in the United States.
      to the prevalence of symptoms in a random sample of the population, which may reach up to 20% depending on the criteria used.
      • Drossman DA
      • Li Z
      • Andruzzi E
      • Temple RD
      • Talley NJ
      • Thompson WG
      • Whitehead WE
      • Janssens J
      • Funch-Jensen P
      • Corazziari E
      • Richter JE
      • Koch GG
      U.S. householder survey of functional gastrointestinal disorders.
      • Talley NJ
      • Zinsmeister AR
      • Melton LJ
      Irritable bowel syndrome in a community: symptom subgroups, risk factors and health care utilization.
      • Saito YA
      • Locke GR
      • Talley NJ
      • Zinsmeister AR
      • Fett SL
      • Melton LJ
      The effect of new diagnostic criteria for irritable bowel syndrome on community prevalence estimates (abstr).
      The precise incidence of IBS is unclear, but it has been estimated at almost 1% per year.
      • Locke GR
      • Yawn BP
      • Wollan PC
      • Lydick E.
      The incidence of clinically diagnosed irritable bowel syndrome in the community (abstr).
      Symptom subgroups based on the predominant bowel habit (i.e., constipation-predominant IBS, diarrhea-predominant IBS, and IBS with alternating bowel movements) have equal prevalence rates (5.2 per 100) in epidemiologic studies in Olmsted County, Minnesota,
      • Talley NJ
      • Zinsmeister AR
      • Melton LJ
      Irritable bowel syndrome in a community: symptom subgroups, risk factors and health care utilization.
      although clinical samples show a different distribution, possibly reflecting regional research expertise or interest. The gender ratio in these subgroups is similar except in constipation-predominant IBS, which is more common in women.
      • Talley NJ
      • Zinsmeister AR
      • Melton LJ
      Irritable bowel syndrome in a community: symptom subgroups, risk factors and health care utilization.
      The female preponderance is more apparent in clinical samples (3–4:1) than in those with symptoms who did not seek medical attention (less than 2:1) and were identified by mailed questionnaires.
      • Locke GR
      • Yawn BP
      • Wollan PC
      • Lydick E.
      The incidence of clinically diagnosed irritable bowel syndrome in the community (abstr).
      In the U.S. householder study, 11.6% had IBS, 3.6% had functional constipation, and 1.8% had functional diarrhea.
      • Drossman DA
      • Li Z
      • Andruzzi E
      • Temple RD
      • Talley NJ
      • Thompson WG
      • Whitehead WE
      • Janssens J
      • Funch-Jensen P
      • Corazziari E
      • Richter JE
      • Koch GG
      U.S. householder survey of functional gastrointestinal disorders.
      The prevalence of IBS is lower in the elderly.
      • Talley NJ
      • O'Keefe EA
      • Zinsmeister AR
      • Melton III, LJ
      Prevalence of gastrointestinal symptoms in the elderly: a population-based study.
      In Olmsted County, Minnesota, the prevalence of IBS among people aged 65–93 years was 10.9%, compared with 17% in those aged 30–64 years.
      • Talley NJ
      • Zinsmeister AR
      • Melton LJ
      Irritable bowel syndrome in a community: symptom subgroups, risk factors and health care utilization.
      Traditionally, IBS is not diagnosed in those patients presenting with the symptom complex for the first time after the age of 60 years.
      • Chaudhary NA
      • Truelove SC
      The irritable colon syndrome. A study of the clinical features, predisposing causes, and prognosis in 130 cases.

       IBS variants unrecognized by the Rome II criteria

      Although the Rome II criteria for IBS are quite robust, they are still not comprehensive and do not encompass some clinical patterns of IBS that are recognized by clinicians and are amenable to newer therapies. First, these criteria exclude subgroups based on predominant bowel dysfunction.
      Second, the criteria do not address the postprandial exacerbation of symptoms. Symptom-based and experimental studies, typically in relatively small samples of patients, suggest that postprandial symptoms and dysfunctions may be important, but this feature has not yet been included in Rome II IBS criteria. Urgency and abdominal pain or diarrhea are frequently encountered in the postprandial period, and a subgroup of patients has a prominent tonic and phasic response to feeding.
      • Choi M-G
      • Camilleri M
      • O'Brien MD
      • Kammer PP
      • Hanson RB
      A pilot study of motility and tone of the left colon in diarrhea due to functional disorders and dysautonomia.
      This can be assessed by specific questions in the clinic and has clear physiologic correlates (increased postprandial propagated contractions in diarrhea-predominant IBS
      • Choi M-G
      • Camilleri M
      • O'Brien MD
      • Kammer PP
      • Hanson RB
      A pilot study of motility and tone of the left colon in diarrhea due to functional disorders and dysautonomia.
      • Bazzocchi G
      • Ellis J
      • Villanueva-Meyer J
      • Reddy SN
      • Mena I
      • Snape Jr, WJ
      Effect of eating on colonic motility and transit in patients with functional diarrhea. Simultaneous scintigraphic and manometric evaluations.
      or reduction of colonic contractions in constipation-predominant IBS
      • Choi M-G
      • Camilleri M
      • O'Brien MD
      • Kammer PP
      • Hanson RB
      A pilot study of motility and tone of the left colon in diarrhea due to functional disorders and dysautonomia.
      ), objectively shown by colonic manometry.
      • Choi M-G
      • Camilleri M
      • O'Brien MD
      • Kammer PP
      • Hanson RB
      A pilot study of motility and tone of the left colon in diarrhea due to functional disorders and dysautonomia.
      • Bazzocchi G
      • Ellis J
      • Villanueva-Meyer J
      • Reddy SN
      • Mena I
      • Snape Jr, WJ
      Effect of eating on colonic motility and transit in patients with functional diarrhea. Simultaneous scintigraphic and manometric evaluations.
      Recent studies confirm the association with food “sensitivity” or “intolerance,” which may merely reflect exacerbation of symptoms by food.
      • Locke III, GR
      • Zinsmeister AR
      • Talley NJ
      • Fett SL
      • Melton LJ
      Risk factors for irritable bowel syndrome: role of analgesics and fool sensitivities.
      • Dainese R
      • Galliani EA
      • De Lazzari F
      • Di Leo V
      • Naccarato R.
      Discrepancies between reported food intolerance and sensitization test findings in irritable bowel syndrome patients.
      In fact, patients with diarrhea-predominant IBS have higher serotonemic responses to a standard meal, suggesting that serotonin might mediate these symptoms.
      • Bearcroft CP
      • Perrett D
      • Farthing MJ
      Postprandial plasma 5-hydroxytryptamine in diarrhoea predominant irritable bowel syndrome: a pilot study.
      Ragnarsson and Bodemar
      • Ragnarsson G
      • Bodemar G.
      Pain is temporally related to eating but not to defecation in the irritable bowel syndrome (IBS). Patients' description of diarrhea, constipation and symptom variation during a prospective 6-week study.
      found that almost 50% of patients with IBS reported worsening of pain postprandially. Other studies with thorough documentation of meal-related symptoms will be needed in the future.
      Third, the Rome II criteria do not encompass patients in whom functional, painless diarrhea may be associated with postprandial urgency, borborygmi, and a sense of incomplete rectal evacuation.
      • Chaudhary NA
      • Truelove SC
      The irritable colon syndrome. A study of the clinical features, predisposing causes, and prognosis in 130 cases.
      Because of the absence of abdominal pain, these patients would not be considered to have IBS on the basis of the Rome II criteria, contrary to the experience and practice of many clinicians, as documented in the literature almost 40 years ago.
      • Chaudhary NA
      • Truelove SC
      The irritable colon syndrome. A study of the clinical features, predisposing causes, and prognosis in 130 cases.

       Impact of IBS

      It is estimated that only 10%–25% of patients with IBS seek medical care; however, the illness has an enormous economic impact. In the United States alone, the economic impact is estimated at $25 billion annually (Table 2) through direct costs of health care use and indirect costs of absenteeism from work.
      • Drossman DA
      • Li Z
      • Andruzzi E
      • Temple RD
      • Talley NJ
      • Thompson WG
      • Whitehead WE
      • Janssens J
      • Funch-Jensen P
      • Corazziari E
      • Richter JE
      • Koch GG
      U.S. householder survey of functional gastrointestinal disorders.
      • Talley NJ
      • Gabriel SE
      • Harmsen WS
      • Zinsmeister AR
      • Evans RW
      Medical costs in community subjects with irritable bowel syndrome.
      • Fullerton S.
      Functional digestive disorders (FDD) in the year 2000–economic impact.
      • Camilleri M
      • Williams DE
      Economic burden of irritable bowel syndrome reappraised with strategies to control expenditures.
      • Stewart WF
      • Liberman JN
      • Sandler RS
      • Woods MS
      • Stemhagen A
      • Chee E
      • Lipton RB
      • Farup CE
      Epidemiology of constipation (EPOC) study in the United States: relation of clinical subtypes to sociodemographic features.
      Table 2Epidemiology and cost statistics of IBS
      Prevalence of IBS varies between 5% and 25%
      Similar prevalence in several countries and ethnic groups (e.g., black, hispanic, and white U.S. population)
      Constipation-predominant IBS is more common in women
      Female predominance (3–4 F:1 M) in those seeking health care; approximately equal M:F ratio among community nonpresenters with IBS symptoms identified by surveys (except constipation IBS, in which F > M)
      10%–25% of IBS patients seek medical care
      IBS accounts for 2.4–3.5 million physician visits and 2.2 million medication prescriptions in the United States annually
      3-Fold absenteeism from work in IBS, roughly equivalent to the common cold
      Annual resource impact of IBS in the United States estimated at $25 billion; two thirds for indirect costs
      Data reviewed by Camilleri and Williams.
      • Camilleri M
      • Williams DE
      Economic burden of irritable bowel syndrome reappraised with strategies to control expenditures.
      In countries with socialized medicine, direct charges are lower,
      • Hahn BA
      • Kirchdoerfer LJ
      • Fullerton S
      • Mayer E.
      Patient-perceived severity of irritable bowel syndrome in relation to symptoms, health resource utilization and quality of life.
      • Hahn BA
      • Yan S
      • Strassels S.
      Impact of irritable bowel syndrome on quality of life and resource use in the United States and United Kingdom.
      • Wells NEJ
      • Hahn BA
      • Whorwell PJ
      Clinical economics review: irritable bowel syndrome.
      • Karampela K
      • Lacey L
      • Hahn B
      • McGuire A.
      Costs associated with healthcare resource use and productivity loss in patients with irritable bowel syndrome (IBS) (abstr).
      but this expenditure may still account for 0.5% of health care budgets.
      • Fullerton S.
      Functional digestive disorders (FDD) in the year 2000–economic impact.
      Patients with IBS undergo more surgical procedures, including hysterectomy, cystoscopy, and appendectomy.
      • Longstreth GF
      Irritable bowel syndrome. Diagnosis in the managed care era.
      • Longstreth GF
      • Preskill DB
      • Youkeles L.
      Irritable bowel syndrome in women having diagnostic laparoscopy or hysterectomy. Relation to gynecologic features and outcome.
      IBS accounts for 2.4–3.5 million physician visits in the United States annually,
      • Everhart JE
      • Renault PF
      Irritable bowel syndrome in office-based practice in the United States.
      making it the most common diagnosis in gastroenterologists' practice (approximately 28% of all patients) and accounting for 12% of primary care visits. Annually, there are 2.2 million medication prescriptions for IBS patients in the United States.
      • Mitchell CM
      • Drossman DA
      Survey of the AGA membership relating to patients with functional gastrointestinal disorders (letter).
      Patients with IBS have 3 times more absenteeism from work and report reduced quality of life.
      • Drossman DA
      • Li Z
      • Andruzzi E
      • Temple RD
      • Talley NJ
      • Thompson WG
      • Whitehead WE
      • Janssens J
      • Funch-Jensen P
      • Corazziari E
      • Richter JE
      • Koch GG
      U.S. householder survey of functional gastrointestinal disorders.

       Overview of mechanisms as a basis for therapy

      Symptoms in IBS have a physiologic basis, but there is no single physiologic mechanism responsible for symptoms of IBS. Table 3 summarizes the pathophysiologic mechanisms that appear to contribute to IBS.
      Table 3Pathophysiology of IBS
      A biopsychosocial disorder
       Altered motility and enhanced visceral perception
       ~50% of IBS patients have psychologic symptoms at the time of presentation
       The role of physical and sexual abuse in the development of IBS is controversial
       Up to one third (range, 7%–31%) of IBS presenters recall an antecedent gastroenteritis
      Proposed mechanisms contributing to IBSa
       Abnormal motility
       Heightened visceral perception: peripheral or central
       Psychologic distress
       Intraluminal factors irritating small bowel or colon
        Lactose, other sugars
        Bile acids, short-chain fatty acids
        Food allergens
       Postinfectious neuroimmune modulation of gut functions
      aInteraction between different mechanisms may occur in individual patients.
      These individual mechanisms are not mutually exclusive. IBS is considered a biopsychosocial disorder resulting from a combination of 3 interacting mechanisms: psychosocial factors, altered motility (Table 4
      • Camilleri M
      • Neri M.
      Motility disorders and stress: significance to the irritable bowel syndrome.
      • Almy TP
      • Tulin M.
      Alterations in man under stress. Experimental production of changes simulating the “irritable colon”.
      • Bazzocchi G
      • Ellis J
      • Villaneuva-Meyer J
      • Jing J
      • Reddy SN
      • Mena I
      • Snape Jr, WJ
      Postprandial colonic transit and motor activity in chronic constipation.
      • Cann PA
      • Read NW
      • Brown C
      • Hobson N
      • Holdsworth CD
      Irritable bowel syndrome: relationship of disorders in the transit of a single solid meal to symptom patterns.
      • Vassallo M
      • Camilleri M
      • Phillips SF
      • Brown ML
      • Chapman NJ
      • Thomforde GM
      Transit through the proximal colon influences stool weight in the irritable bowel syndrome.
      • Stivland T
      • Camilleri M
      • Vassallo M
      • Proano M
      • Rath D
      • Brown M
      • Thomforde G
      • Pemberton J
      • Phillips S
      Scintigraphic measurement of regional gut transit in idiopathic constipation.
      • Hammer J
      • Phillips SF
      • Talley NJ
      • Camilleri M.
      Effect of a 5-HT3 antagonist (ondansetron) on rectal sensitivity and compliance in health and the irritable bowel syndrome.
      • Prior A
      • Maxton DG
      • Whorwell PJ
      Anorectal manometry in irritable bowel syndrome: differences between diarrhoea and constipation predominant subjects.
      • Vassallo MJ
      • Camilleri M
      • Phillips SF
      • Steadman CJ
      • Hanson RB
      • Haddad AC
      Colonic tone and motility in patients with irritable bowel syndrome.
      • Kellow JE
      • Phillips SF
      Altered small bowel motility in irritable bowel syndrome is correlated with symptoms.
      • Gorard DA
      • Libby GW
      • Farthing MJ
      Ambulatory small intestinal motility in diarrhoea predominant irritable bowel syndrome.
      • Schmidt T
      • Hackelsberger N
      • Widmer R
      • Meisel C
      • Pfeiffer A
      • Kaess H.
      Ambulatory 24-hour jejunal motility in diarrhea-predominant irritable bowel syndrome.
      • Evans PR
      • Bennett EJ
      • Bak YT
      • Tennant CC
      • Kellow JE
      Jejunal sensorimotor dysfunction in irritable bowel syndrome: clinical and psychosocial features.
      ) and transit, which may reflect severity of bowel dysfunction,
      • Camilleri M
      • Zinsmeister AR
      Towards a relatively inexpensive, noninvasive, accurate test for colonic motility disorders.
      • Charles F
      • Camilleri M
      • Phillips SF
      • Thomforde GM
      • Forstrom LA
      Scintigraphy of the whole gut: clinical evaluation of transit disorders.
      • Charles F
      • Phillips SF
      • Camilleri M
      • Thomforde GM
      Rapid gastric emptying in patients with functional diarrhea.
      and increased sensitivity (Table 5
      • Ritchie J.
      Pain from distension of the pelvic colon by inflating a balloon in the irritable bowel syndrome.
      • Prior A
      • Maxton DG
      • Whorwell PJ
      Anorectal manometry in irritable bowel syndrome: differences between diarrhoea and constipation predominant subjects.
      • Mertz H
      • Naliboff B
      • Munakata J
      • Niazi N
      • Mayer EA
      Altered rectal perception is a biological marker of patients with irritable bowel syndrome.
      • Lembo T
      • Munakata J
      • Naliboff B
      • Fullerton S
      • Mayer EA
      Sigmoid afferent mechanisms in patients with irritable bowel syndrome.
      • Schmulson M
      • Chang L
      • Naliboff B
      • Lee OY
      • Mayer EA
      Correlation of symptom criteria with perception thresholds during rectosigmoid distension in irritable bowel syndrome patients.
      • Cook IJ
      • van Eeden A
      • Collins SM
      Patients with irritable bowel syndrome have greater pain tolerance than normal subjects.
      ) of the intestine or colon. Preliminary data suggest a genetic contribution to functional bowel disorders
      • Morris-Yates A
      • Talley NJ
      • Boyce PM
      • Nandurkar S
      • Andrews G.
      Evidence of a genetic contribution to functional bowel disorder.
      that requires further validation.
      Table 4Alterations in bowel motility in IBS
      Psychologic
      • Camilleri M
      • Neri M.
      Motility disorders and stress: significance to the irritable bowel syndrome.
      and physical
      • Almy TP
      • Tulin M.
      Alterations in man under stress. Experimental production of changes simulating the “irritable colon”.
      stress increase colonic contractions in experimental studies modeling IBS
      Diarrhea-predominant IBS
       Prominent colonic response to feeding: increased postprandial colonic contractions
      • Bazzocchi G
      • Ellis J
      • Villanueva-Meyer J
      • Reddy SN
      • Mena I
      • Snape Jr, WJ
      Effect of eating on colonic motility and transit in patients with functional diarrhea. Simultaneous scintigraphic and manometric evaluations.
       Fast colonic and propagated contractions increased with diarrhea and decreased in constipation-predominant IBS
      • Bazzocchi G
      • Ellis J
      • Villanueva-Meyer J
      • Reddy SN
      • Mena I
      • Snape Jr, WJ
      Effect of eating on colonic motility and transit in patients with functional diarrhea. Simultaneous scintigraphic and manometric evaluations.
      • Bazzocchi G
      • Ellis J
      • Villaneuva-Meyer J
      • Jing J
      • Reddy SN
      • Mena I
      • Snape Jr, WJ
      Postprandial colonic transit and motor activity in chronic constipation.
       Accelerated whole-gut transit
      • Cann PA
      • Read NW
      • Brown C
      • Hobson N
      • Holdsworth CD
      Irritable bowel syndrome: relationship of disorders in the transit of a single solid meal to symptom patterns.
      ; faster ascending and transverse colon emptying
      • Vassallo M
      • Camilleri M
      • Phillips SF
      • Brown ML
      • Chapman NJ
      • Thomforde GM
      Transit through the proximal colon influences stool weight in the irritable bowel syndrome.
      is positively correlated with stool weight
      Constipation-predominant IBS
       Decreased number of fast colonic and propagated contractions in constipation-predominant IBS
      • Bazzocchi G
      • Ellis J
      • Villanueva-Meyer J
      • Reddy SN
      • Mena I
      • Snape Jr, WJ
      Effect of eating on colonic motility and transit in patients with functional diarrhea. Simultaneous scintigraphic and manometric evaluations.
      • Bazzocchi G
      • Ellis J
      • Villaneuva-Meyer J
      • Jing J
      • Reddy SN
      • Mena I
      • Snape Jr, WJ
      Postprandial colonic transit and motor activity in chronic constipation.
       Idiopathic constipation and normal anorectal and pelvic floor function: delay in whole-gut transit, and rate of ascending and transverse colon emptying
      • Stivland T
      • Camilleri M
      • Vassallo M
      • Proano M
      • Rath D
      • Brown M
      • Thomforde G
      • Pemberton J
      • Phillips S
      Scintigraphic measurement of regional gut transit in idiopathic constipation.
       Rectal and colonic compliance and tone are normal, although few reports suggest minor abnormalities in constipation of unclear clinical significance
      • Hammer J
      • Phillips SF
      • Talley NJ
      • Camilleri M.
      Effect of a 5-HT3 antagonist (ondansetron) on rectal sensitivity and compliance in health and the irritable bowel syndrome.
      • Prior A
      • Maxton DG
      • Whorwell PJ
      Anorectal manometry in irritable bowel syndrome: differences between diarrhoea and constipation predominant subjects.
      • Vassallo MJ
      • Camilleri M
      • Phillips SF
      • Steadman CJ
      • Hanson RB
      • Haddad AC
      Colonic tone and motility in patients with irritable bowel syndrome.
      Pain-predominant IBS
       “Clustered” contractions in the jejunum and ileal propagated giant contractions during episodes of abdominal colic
      • Kellow JE
      • Phillips SF
      Altered small bowel motility in irritable bowel syndrome is correlated with symptoms.
      are not pathognomonic for IBS
      • Gorard DA
      • Libby GW
      • Farthing MJ
      Ambulatory small intestinal motility in diarrhoea predominant irritable bowel syndrome.
      • Schmidt T
      • Hackelsberger N
      • Widmer R
      • Meisel C
      • Pfeiffer A
      • Kaess H.
      Ambulatory 24-hour jejunal motility in diarrhea-predominant irritable bowel syndrome.
       Sensory abnormalities accompany postprandial motor dysfunctions
      • Evans PR
      • Bennett EJ
      • Bak YT
      • Tennant CC
      • Kellow JE
      Jejunal sensorimotor dysfunction in irritable bowel syndrome: clinical and psychosocial features.
      Table 5Enhanced visceral perception in IBS
      Diarrhea-predominant IBS
       Lower thresholds for sensation of gas, stool, discomfort, and urgency by progressive rectal balloon distention, accompanied by excessive reflex contractile activity in the rectum
      • Ritchie J.
      Pain from distension of the pelvic colon by inflating a balloon in the irritable bowel syndrome.
      • Prior A
      • Maxton DG
      • Whorwell PJ
      Anorectal manometry in irritable bowel syndrome: differences between diarrhoea and constipation predominant subjects.
      Constipation-predominant IBS
       Discomfort at greater distention volumes (reduced sensitivity
      • Prior A
      • Maxton DG
      • Whorwell PJ
      Anorectal manometry in irritable bowel syndrome: differences between diarrhoea and constipation predominant subjects.
      ) than in health; others report rectal or sigmoid hypersensitivity
      • Schmulson M
      • Chang L
      • Naliboff B
      • Lee OY
      • Mayer EA
      Correlation of symptom criteria with perception thresholds during rectosigmoid distension in irritable bowel syndrome patients.
       Normal or increased thresholds for somatic pain stimuli
      • Cook IJ
      • van Eeden A
      • Collins SM
      Patients with irritable bowel syndrome have greater pain tolerance than normal subjects.
      Pain-predominant IBS
       Increased visceral perception on rectosigmoid, ileal, and anorectal balloon distention
      • Kellow JE
      • Phillips SF
      Altered small bowel motility in irritable bowel syndrome is correlated with symptoms.
      • Ritchie J.
      Pain from distension of the pelvic colon by inflating a balloon in the irritable bowel syndrome.
      • Prior A
      • Maxton DG
      • Whorwell PJ
      Anorectal manometry in irritable bowel syndrome: differences between diarrhoea and constipation predominant subjects.
      • Mertz H
      • Naliboff B
      • Munakata J
      • Niazi N
      • Mayer EA
      Altered rectal perception is a biological marker of patients with irritable bowel syndrome.
      • Lembo T
      • Munakata J
      • Naliboff B
      • Fullerton S
      • Mayer EA
      Sigmoid afferent mechanisms in patients with irritable bowel syndrome.
      • Schmulson M
      • Chang L
      • Naliboff B
      • Lee OY
      • Mayer EA
      Correlation of symptom criteria with perception thresholds during rectosigmoid distension in irritable bowel syndrome patients.
       Normal bowel compliance
      Gastrointestinal hypersensitivity and anorectal dysfunction have been extensively studied and are so frequently associated with the syndrome
      • Ritchie J.
      Pain from distension of the pelvic colon by inflating a balloon in the irritable bowel syndrome.
      • Prior A
      • Maxton DG
      • Whorwell PJ
      Anorectal manometry in irritable bowel syndrome: differences between diarrhoea and constipation predominant subjects.
      • Mertz H
      • Naliboff B
      • Munakata J
      • Niazi N
      • Mayer EA
      Altered rectal perception is a biological marker of patients with irritable bowel syndrome.
      • Lembo T
      • Munakata J
      • Naliboff B
      • Fullerton S
      • Mayer EA
      Sigmoid afferent mechanisms in patients with irritable bowel syndrome.
      • Schmulson M
      • Chang L
      • Naliboff B
      • Lee OY
      • Mayer EA
      Correlation of symptom criteria with perception thresholds during rectosigmoid distension in irritable bowel syndrome patients.
      that they are reasonable targets for therapy. It has been hypothesized that altered peripheral functioning of visceral afferents (recruitment of silent nociceptors, increased excitability of dorsal horn neurons) and the central processing of afferent information are important in the altered somatovisceral sensation and motor dysfunction in patients with functional bowel disease.
      • Morris-Yates A
      • Talley NJ
      • Boyce PM
      • Nandurkar S
      • Andrews G.
      Evidence of a genetic contribution to functional bowel disorder.
      Vagal nerve dysfunction and abnormal sympathetic adrenergic function have been demonstrated in subgroups of patients with constipation- and diarrhea-predominant IBS, respectively.
      • Aggarwal A
      • Cutts TF
      • Abell TL
      • Cardoso S
      • Familoni B
      • Bremer J
      • Karas J.
      Predominant symptoms in irritable bowel correlate with specific autonomic nervous system abnormalities.
      • Bharucha AE
      • Camilleri M
      • Low PA
      • Zinsmeister AR
      Autonomic dysfunction in gastrointestinal motility disorders.
      Recently, much attention has been focused on possible persisting neuroimmune interactions after infectious gastroenteritis, which might result in continuing sensorimotor dysfunction.
      • Gwee KA
      • Leong YL
      • Graham C
      • McKendrick MW
      • Collins SM
      • Walters SJ
      • Underwood JE
      • Read NW
      The role of psychological and biological factors in postinfective gut dysfunction.
      However, the role of infection in IBS is still controversial. Infectious diarrhea precedes the onset of IBS symptoms in 7%–30% of patients in different series.
      • Chaudhary NA
      • Truelove SC
      The irritable colon syndrome. A study of the clinical features, predisposing causes, and prognosis in 130 cases.
      • Gwee KA
      • Leong YL
      • Graham C
      • McKendrick MW
      • Collins SM
      • Walters SJ
      • Underwood JE
      • Read NW
      The role of psychological and biological factors in postinfective gut dysfunction.
      • Gwee KA
      • Graham JC
      • McKendrick MW
      • Collins SM
      • Marshall JS
      • Walters SJ
      • Read NW
      Psychometric scores and persistence of irritable bowel after infectious diarrhea.
      • 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.
      • Thornley JP
      • Brough J
      • Wright T
      • Neal DR
      • Jenkins D
      • Spiller RC
      Bacterial toxins influence long-term bowel dysfunction following campylobacter enteritis (abstr).
      Certain toxins seem more likely to be associated with long-term symptoms in patients with prior Campylobacter enteritis. It is not clear whether a previous infectious episode could induce a physiologic response, causing persistent symptoms, even in the absence of residual demonstrable inflammation of the gut. Some have hypothesized that microscopic inflammatory changes such as infiltration of the enteric nervous system contribute to the development of IBS. Gwee et al.
      • Gwee KA
      • Leong YL
      • Graham C
      • McKendrick MW
      • Collins SM
      • Walters SJ
      • Underwood JE
      • Read NW
      The role of psychological and biological factors in postinfective gut dysfunction.
      have shown that about a quarter of patients with infectious diarrhea IBS continue to experience symptoms after 3 months. However, these patients were admitted to their local hospital, suggesting they suffered a severe form of diarrhea, raising questions about the generalizability of the observation. In fact, the community diarrhea-based study in Nottingham, England, suggests that fewer than 10% of patients with acute diarrhea went on to develop IBS. From the study of Gwee et al.,
      • Gwee KA
      • Leong YL
      • Graham C
      • McKendrick MW
      • Collins SM
      • Walters SJ
      • Underwood JE
      • Read NW
      The role of psychological and biological factors in postinfective gut dysfunction.
      it appears that the “mind” plays a greater role than “matter” because life event stress and hypochondriasis are predictive factors in the persistence of IBS.
      • Drossman DA
      Mind over matter in the postinfective irritable bowel.
      In contrast, physiologic parameters such as whole-gut transit time and sensory thresholds are not different in patients with and without IBS symptoms 3 months after an episode of “infectious” diarrhea.
      Some patients with IBS also have carbohydrate intolerance, which may contribute to the symptoms of IBS; intolerance of sugars is partly determined by the ethnicity of the patient. Thus, lactose intolerance has a higher prevalence among Hispanic and black patients, whereas fructose and sorbitol intolerance are more prevalent among people of Northern European extraction.
      • Rumessen JJ
      • Gudmand-Hoyer E.
      Malabsorption of fructose-sorbitol mixtures. Interactions causing abdominal distress.
      The clinical effects of lactose intolerance are also dependent on the total carbohydrate load because exposure to the equivalent of an 8-ounce glass of milk per day does not seem to cause symptoms.
      • Suarez FL
      • Savaiano DA
      • Levitt MD
      A comparison of symptoms after the consumption of milk or lactose-hydrolyzed milk by people with self-reported severe lactose intolerance.
      Gas formation as a result of maldigestion in the small intestine and subsequent metabolism in the colon accounts for bloating
      • Haderstorfer B
      • Psycholgin D
      • Whitehead WE
      • Schuster MM
      Intestinal gas production from bacterial fermentation of undigested carbohydrate in irritable bowel syndrome.
      ; formation of osmotically active metabolites leads to diarrhea. Measurements of intestinal gas have not always correlated with symptoms.
      • Chami TN
      • Schuster MM
      • Bohlman ME
      • Pulliam TJ
      • Kamal N
      • Whitehead WE
      A simple radiologic method to estimate the quantity of bowel gas.
      Experimental data suggest that food allergens may also be important in IBS.
      • Jones VA
      • McLaughlan P
      • Shorthouse M
      • Workman E
      • Hunter JO
      Food intolerance: a major factor in the pathogenesis of irritable bowel syndrome.
      One clinical trial showed that symptoms in 40% of patients with IBS persistently improved with dietary exclusions.
      • Nanda R
      • James R
      • Smith H
      • Dudley CRK
      • Jewell DP
      Food intolerance and the irritable bowel syndrome.
      The role of dietary exclusion is still controversial, although there is evidence that the greater rate (although not the quantity) of gas excretion in IBS patients can be reduced by exclusion diets, and this change parallels improvement in symptoms.
      • King TS
      • Elia M
      • Hunter JO
      Abnormal colonic fermentation in irritable bowel syndrome.
      The ileum of patients with IBS is excessively sensitive to the secretory effects of perfused bile acids.
      • Oddsson E
      • Rask-Madsen J
      • Krag E.
      A secretory epithelium of the small intestine with increased sensitivity to bile acids in irritable bowel syndrome associated with diarrhoea.
      Recent studies also emphasize the interaction between gas retention and other cofactors, particularly in patients with constipation-predominant IBS. This led to the experimental use of colonic prokinetics as a means of enhancing gas clearance,
      • Serra J
      • Azpiroz F
      • Malagelada J-R
      Intestinal gas dynamics and tolerance in humans.
      • Serra J
      • Azpiroz F
      • Malagelada J-R
      New insight on functional gut disease: is gas handling the answer? (abstr).
      • Caldarella M-P
      • Serra J
      • Azpiroz F
      • Malagelada J-R
      Stimulation of intestinal gas propulsion is the key to treat gas retention in functional patients (abstr).
      which showed that gas clearance was increased. However, this was associated with exacerbation of abdominal pain, a well-known side effect of the anticholinesterase neostigmine, and other approaches that do not increase pain are needed.
      Stress and emotions affect gastrointestinal function
      • Alvarez WC
      Ways in which emotion can affect the digestive tract. Helps in sizing up the patient.
      and cause symptoms to a greater degree in IBS patients than in healthy controls. Psychologic symptoms that are more common in patients with IBS include somatization, anxiety, hostility, phobia, and paranoia.
      • Lydiard RB
      • Laraia MT
      • Howell EF
      • Ballenger JC
      Can panic disorder present as irritable bowel syndrome?.
      • Whitehead WE
      • Bosmajian L
      • Zonderman AB
      • Costa PT
      • Schuster MM
      Symptoms of psychologic distress associated with irritable bowel syndrome. Comparison of community and medical clinic samples.
      • Whitehead WE
      • Crowell MD
      • Robinson JC
      • Heller BR
      • Schuster MM
      Effects of stressful life events on bowel symptoms: subjects with irritable bowel syndrome compared with subjects without bowel dysfunction.
      Identification of this comorbidity and somatization are key to optimizing patient treatment.
      • Young SJ
      • Alpers DH
      • Norland CC
      • Woodruff Jr, RA
      Psychiatric illness and the irritable bowel syndrome. Practical implications for the primary physician.
      Patients with IBS seen in medical clinics have elevated scales of depression, anxiety, somatization, and neuroticism.
      • Drossman DA
      • McKee DC
      • Sandler RS
      • Mitchell CM
      • Cramer EM
      • Lowman BC
      • Burger AL
      Psychosocial factors in the irritable bowel syndrome: a multivariate study of patients and nonpatients with irritable bowel syndrome.
      • Whitehead WE
      • Bosmajian L
      • Zonderman A
      • Costa PT
      • Schuster MM
      Role of psychologic symptoms in irritable bowel syndrome: comparison of community and clinic samples.
      At the time of presentation, almost half of the IBS patients have one or more of these symptoms. Because psychosocial symptoms modulate experience of somatic symptoms, they contribute to the greater illness behavior, increased physician consultations, and reduced coping capability that are so common among IBS patients. Life event stressors and hypochondriasis are important determinants of patients with postinfectious diarrhea who develop the full picture of IBS at 3 months.
      The role of physical and sexual abuse in the development of the psychosocial factors manifested by patients with functional gastrointestinal disease is controversial.
      • Drossman DA
      • Talley NJ
      • Leserman J
      • Olden KW
      • Barreiro MA
      Sexual and physical abuse and gastrointestinal illness.
      • Talley NJ
      • Fett SL
      • Zinsmeister AR
      • Melton LJ
      Gastrointestinal tract symptoms and self-reported abuse: a population-based study.
      If identified, abuse requires specific and expert care.
      Thus, other therapies focus on the psychotherapeutic angle.
      • Alpers DH
      Why should psychotherapy be a useful approach to management of patients with non-ulcer dyspepsia? (editorial).
      Until relatively recently, attempts to develop effective therapies were hampered by poor trial design.
      • Klein KB
      Controlled treatment trials in the irritable bowel syndrome: a critique.
      The psychopathology or psychologic distress manifested particularly in patients presenting to the clinic
      • Whitehead WE
      • Bosmajian L
      • Zonderman AB
      • Costa PT
      • Schuster MM
      Symptoms of psychologic distress associated with irritable bowel syndrome. Comparison of community and medical clinic samples.
      and in those with a history of abuse
      • Drossman DA
      Diagnosing and treating patients with refractory functional gastrointestinal disorders.
      emphasize the importance of the holistic approach to the patient.

      Natural history of IBS: A “safe diagnosis” and the importance of reassurance

      IBS is a chronic disease whose course is extremely variable in the general population. Although functional gastrointestinal symptoms are common in middle-aged persons, the overall prevalence in a community sample seems relatively stable over 12–20 months. There is a substantial degree of “turnover” because many people's symptoms fluctuate over time, and they therefore move in and out of the IBS cohort.
      • Talley NJ
      • Zinsmeister AR
      • Melton LJ
      Irritable bowel syndrome in a community: symptom subgroups, risk factors and health care utilization.
      • Talley NJ
      • Weaver AL
      • Zinsmeister AR
      • Melton III, LJ
      Onset and disappearance of gastrointestinal symptoms and functional gastrointestinal disorders.
      IBS is a “safe” diagnosis. Patients followed up with such a diagnosis seldom turn out to suffer from serious organic disease, and the time-honored clinical strategy to reassure the patient that the diagnosis is benign without significant risk of missing an organic disease is well justified.
      • Harvey RF
      • Mauad EC
      • Brown AM
      Prognosis in the irritable bowel syndrome: a 5-year prospective study.
      • Owens DM
      • Nelson DK
      • Talley NJ
      The irritable bowel syndrome: long-term prognosis and the physician-patient interaction.
      Fluctuation of symptoms often results in seeking of further health care. Repetitive investigations serve merely to reinforce the illness behavior. On the other hand, it is equally important that physicians not attribute to IBS those symptoms that do not fit the usual syndrome in the individual patient or symptoms that do not conform with the broader characteristics of the symptom complex embodied in the Manning or Rome criteria. The development of rectal bleeding, anemia, and a high erythrocyte sedimentation rate were significant negative predictive factors for IBS in the study of Kruis et al.
      • Kruis W
      • Thieme C
      • Weinzierl M
      • Schussler P
      • Holl J
      • Paulus W.
      A diagnostic score for the irritable bowel syndrome. Its value in the exclusion of organic disease.
      of IBS and constitute alarm features that are easy to elicit in the evaluation of IBS patients presenting with gastrointestinal symptoms. Similarly, in the presence of rectal bleeding (which was not an independent significant predictor in the study of Kruis et al.), further investigation is mandatory.

      Diagnostic strategy in IBS patients

       General principles

      The diagnosis of IBS is based on the identification of symptoms consistent with the syndrome and the exclusion of organic diseases that have similar clinical presentations.
      • Drossman DA
      • Corazziari E
      • Talley NJ
      • Thompson WG
      • Whitehead WE
      Rome II: a multinational consensus document on functional gastrointestinal disorders.
      • Kruis W
      • Thieme C
      • Weinzierl M
      • Schussler P
      • Holl J
      • Paulus W.
      A diagnostic score for the irritable bowel syndrome. Its value in the exclusion of organic disease.
      • Vanner SJ
      • Depew WT
      • Paterson WG
      • DaCosta LR
      • Groll AG
      • Simon JB
      • Djurfeldt M.
      Predictive value of the Rome criteria for diagnosing the irritable bowel syndrome.
      • Manning AP
      • Thompson WG
      • Heaton KW
      • Morris AF
      Towards a positive diagnosis of the irritable bowel.
      • Thompson WG
      • Dotevall G
      • Drossman DA
      • Heaton KW
      • Kruis W.
      Irritable bowel syndrome: guidelines for the diagnosis.
      • Thompson WG
      • Longstreth GF
      • Drossman DA
      • Heaton KW
      • Irvine EJ
      • Muller-Lissner SA
      Functional bowel disorders and functional abdominal pain.
      • Camilleri M
      • Prather CM
      The irritable bowel syndrome: mechanisms and a practical approach to management.
      • Drossman DA
      • Whitehead WE
      • Camilleri M.
      Irritable bowel syndrome: a technical review for practice guideline development.
      A conservative management approach includes identification through symptom-based criteria (e.g., Manning
      • Manning AP
      • Thompson WG
      • Heaton KW
      • Morris AF
      Towards a positive diagnosis of the irritable bowel.
      or Rome II
      • Drossman DA
      • Corazziari E
      • Talley NJ
      • Thompson WG
      • Whitehead WE
      Rome II: a multinational consensus document on functional gastrointestinal disorders.
      criteria) and therapeutic trials. There are now relatively inexpensive diagnostic tests that aid in identification of the underlying mechanism (Figure 1) in patients who do not respond to empiric trials; by definition, tests should follow the empiric trial in this relatively benign syndrome.
      Figure thumbnail gr1
      Fig. 1Algorithm for initial management of patients with IBS according to predominant symptoms. If symptoms fail to respond to initial treatment, further investigations are required. Data from Camilleri et al.
      • Camilleri M
      • Prather CM
      The irritable bowel syndrome: mechanisms and a practical approach to management.
      Recent reviews, endorsed by the Practice Committee of the American Gastroenterological Association,
      • Drossman DA
      • Whitehead WE
      • Camilleri M.
      Irritable bowel syndrome: a technical review for practice guideline development.
      have suggested strategies for diagnosis and management of IBS.
      The first step is a careful assessment of the patient's symptoms. Manning or Rome criteria can be used in a proactive, positive manner to raise the clinical suspicion of IBS. The absence of rectal bleeding is helpful in excluding organic disease. A thorough physical examination and a limited series of initial investigations are needed to exclude organic structural, metabolic, or infectious diseases.
      • Manning AP
      • Thompson WG
      • Heaton KW
      • Morris AF
      Towards a positive diagnosis of the irritable bowel.
      • Thompson WG
      • Dotevall G
      • Drossman DA
      • Heaton KW
      • Kruis W.
      Irritable bowel syndrome: guidelines for the diagnosis.
      • Thompson WG
      • Longstreth GF
      • Drossman DA
      • Heaton KW
      • Irvine EJ
      • Muller-Lissner SA
      Functional bowel disorders and functional abdominal pain.
      • Camilleri M
      • Prather CM
      The irritable bowel syndrome: mechanisms and a practical approach to management.
      These include hematology and chemistry tests; erythrocyte sedimentation rate; stool examination for occult blood, ova, and parasites (in those with diarrhea predominance); flexible sigmoidoscopy; and, in those over 40 years of age or with a family history of colon polyps or cancer, a complete colonic evaluation.
      Formal studies have assessed the role of a more specialized investigation. Ultrasonography or computed tomography of the abdomen and pelvis
      • Longstreth GF
      Irritable bowel syndrome. Diagnosis in the managed care era.
      • Thompson WG
      • Heaton KW
      • Smyth GT
      • Smyth C.
      Irritable bowel syndrome: the view from general practice.
      • Francis CY
      • Duffy JN
      • Whorwell PJ
      • Martin DF
      Does routine abdominal ultrasound enhance diagnostic accuracy in irritable bowel syndrome?.
      and rectal biopsy
      • MacIntosh DG
      • Thompson WG
      • Patel DG
      • Barr R
      • Guindi M.
      Is rectal biopsy necessary in irritable bowel syndrome?.
      provide little incremental value to the simpler work-up proposed for IBS. However, rectal biopsy may be appropriate to exclude lymphocytic/microscopic or collagenous colitis in some patients with painless diarrhea. The controversy of flexible sigmoidoscopy versus colonoscopy as a screening test for organic disease is still unresolved; one approach is to use American Cancer Society or World Health Organization criteria
      • Winawer SJ
      • St. John DJ
      • Bond JH
      • Rozen P
      • Burt RW
      • Waye JD
      • Kronborg O
      • O'Brien MJ
      • Bishop DT
      • Kurtz RC
      Prevention of colorectal cancer: guidelines based on new data. WHO Collaborating Center for the Prevention of Colorectal Cancer.
      • Winawer SJ
      • Fletcher RH
      • Miller L
      • Godlee F
      • Stolar MH
      • Mulrow CD
      • et al.
      Colorectal cancer screening: clinical guidelines and rationale.
      • Bond JH
      Screening guidelines for colorectal cancer.
      to select the endoscopic procedure dictated for screening for colon cancer in patients with suspected IBS.
      A careful search for psychosocial factors, stress, and possibly physical and sexual abuse will identify issues that may require specific attention. Establishing an effective physician–patient relationship and sizing up the patient's agenda are crucial to effective treatment of the patient.
      • Drossman DA
      Diagnosing and treating patients with refractory functional gastrointestinal disorders.
      Figure 1 summarizes the approach to patient care in patients with IBS.
      Pelvic floor dysfunction is a discrete disorder and may present with symptoms consistent with constipation-predominant IBS: constipation, sense of incomplete evacuation, and secondary abdominal pain. These symptoms result from failed coordination of functions that normally result in rectal evacuation. A careful history, physical examination, and simple clinical or radiologic tests can identify these patients, and biofeedback/physical relaxation leads to significant improvement, even cure; no pharmacologic or surgical therapy is useful in this condition. Proper identification and treatment of pelvic floor dysfunction is a key to at least partial relief in patients with coexisting constipation-predominant IBS.
      • Camilleri M
      • Thompson WG
      • Fleshman JW
      • Pemberton JH
      Clinical management of intractable constipation.
      A careful review of the results of the screening tests helps reassure the patient. If any of the test results are abnormal, further specific investigation or treatment may be necessary. When organic structural or biochemical disorders are excluded, it is useful to reassure the patient of the significance of these normal findings.
      A therapeutic trial is part of the diagnostic process (Table 6). Typically, a therapeutic trial should be pursued for at least 4 weeks. There is also evidence that one of the medications in a therapeutic class may be more effective in an individual, and there may be some advantage to sequential trials of different drugs in the same group. This is particularly relevant in trials of antidepressants, as demonstrated by Clouse et al.
      • Clouse RE
      • Lustman PJ
      • Geisman RA
      • Alpers DH
      Antidepressant therapy in 138 patients with irritable bowel syndrome: a five-year clinical experience.
      This clinical observation reflects partly the repetitive response to placebo in IBS. Alternatively, it may reflect the different pharmacologic effects (serotonergic, adrenergic, anticholinergic) of the different antidepressant drugs and the possibility that specific neurochemical modulation may be necessary in different patients. Suggested approaches to the use of therapeutic trials in different patient subgroups are summarized in Table 6.
      Table 6Initial treatment: The therapeutic trial
      Reassurance and an effective doctor–patient relationship
      Diarrhea
       Antidiarrheal agents such as diphenoxylate or loperamide (e.g., 2 mg as needed, up to 4/day)
      Diarrhea and pain
       Alosetron (1 mg 2× daily) approved for women with IBS pain and diarrhea
       Tricyclic antidepressants, such as desipramine, 50 mg 3× daily, or amitriptyline, 10–25 mg 2× daily, significantly relieve diarrhea and associated pain
      Constipation
       Dietary fiber supplementation (20 g/day)
       Osmotic laxatives such as a magnesium salt, lactulose, or polyethylene glycol are usually efficacious
      Pain
       Antispasmodics for pain on an as-needed basis; effectiveness unclear
      Additional diagnostic tests (Figure 1) may be required if the therapeutic trial fails.
      • Drossman DA
      • Whitehead WE
      • Camilleri M.
      Irritable bowel syndrome: a technical review for practice guideline development.
      The most appropriate test will depend on the predominant symptom in the individual patient and the previous therapeutic trials undertaken. In patients with predominant constipation, colonic transit and tests of the stool evacuation process are indicated when a trial of fiber and osmotic laxatives fails. In patients with predominant diarrhea or pain-gas-bloat symptoms, a more detailed dietary history may identify factors that may be aggravating or even causing those symptoms. Among patients with predominant diarrhea, lactose, fructose, or sorbitol intake may induce this symptom. Therefore, a lactose-hydrogen breath test should be performed, or a lactose-exclusion diet should be included in the therapeutic trial. Among patients with predominant pain-gas-bloat, a plain abdominal radiograph during an acute episode of pain provides some reassurance that there is no mechanical obstruction. Thereafter, a therapeutic trial with a smooth muscle relaxant (discussed below) is reasonable. The effectiveness of smooth muscle relaxants in the treatment of IBS is controversial.

      Conventional therapies for IBS

      Effective management requires an effective physician–patient relationship
      • Drossman DA
      Diagnosing and treating patients with refractory functional gastrointestinal disorders.
      and attention to the art of healing in addition to the science of modern medicine. Education of physicians, surgeons, gynecologists, and patients regarding IBS and its management is essential to reduce direct costs; new insights in pathophysiology and mechanisms, novel pharmacotherapy (Table 7), and teaching patient skills to manage the syndrome are likely to reduce indirect or societal costs and may have an impact on intangible costs.
      • Camilleri M
      • Williams DE
      Economic burden of irritable bowel syndrome reappraised with strategies to control expenditures.
      Table 7Novel IBS therapy based on pathophysiology and pharmacodynamics
      Diarrhea
       5-HT3 antagonists (e.g., alosetron): retard small bowel and colonic transit
       Anticholinergics, selective M3 type: antispasmodic with antidiarrheal potential
       CCK antagonist: loxiglumide does not inhibit colonic response to food ingestion in humans
      Constipation
       5-HT4 agonists (e.g., tegaserod and prucalopride): accelerate small bowel and colonic transit
      Pain
       α2-Adrenergic agonist (e.g., clonidine): reduces tone, increases compliance, decreases pain sensation during distention in health
       κ-Opioid agonist (e.g., fedotozine): increases threshold for distention-induced pain in IBS
       5-HT
        5-HT1 agonist: relaxes colonic tone, reduces sensation
        5-HT3 antagonist: reduces colonic tonic response to feeding, colonic compliance, and sensation of volume distentions
        5-HT4 antagonist: ? inhibits colonic sensation in experimental models
       Neurokinin antagonists: reduce visceral sensation; motor actions in colon depend on receptor subtype in experimental models

       Role of fiber in treatment of IBS

      In patients with constipation-predominant IBS, fiber accelerates colonic or oroanal transit
      • Cann PA
      • Read NW
      • Holdsworth CD
      What is the benefit of coarse wheat bran in patients with irritable bowel syndrome?.
      ; this acceleration is associated with increased stool weight and percentage of unformed stools. As a group, patients with constipation-predominant IBS do not consume less dietary fiber than control subjects.
      • Jarrett M
      • Heitkemper MM
      • Bond EF
      • Georges J.
      Comparison of diet composition in women with and without functional bowel disorder.
      It is often postulated that fiber may decrease intracolonic pressure and thereby reduce pain because it is recognized that wall tension is one of the factors that contributes to visceral pain.
      • Distrutti E
      • Azpiroz F
      • Soldevilla A
      • Malagelada J-R
      Gastric wall tension determines perception of gastric distention.
      • Thumshirn M
      • Camilleri M
      • Choi M-G
      • Zinsmeister AR
      Modulation of gastric sensory and motor functions by nitrergic and alpha2-adrenergic agents in humans.
      • Malcolm A
      • Phillips SF
      • Camilleri M
      • Hanson RB
      Pharmacological modulation of rectal tone alters perception of distention in humans.
      Fiber reduces bile salt concentrations in the colon, and it has been speculated that this indirectly reduces colonic contractile activity.
      • Mueller-Lissner SA
      Effect of wheat bran on weight of stool and gastrointestinal transit time: a meta-analysis.
      However, symptom relief was not associated with changes in rectosigmoid motility.
      • Cook IJ
      • Irvine EJ
      • Campbell D
      • Shannon S
      • Reddy SN
      • Collins SM
      Effect of dietary fiber on symptoms and rectosigmoid motility in patients with irritable bowel syndrome.
      Fiber alleviates pain in children with idiopathic chronic abdominal pain.
      • Feldman W
      • McGrath P
      • Hodgson C
      • Ritter H
      • Shipman RT
      The use of dietary fiber in the management of simple, childhood, idiopathic, recurrent abdominal pain: results in a prospective, double-blind, randomized, controlled trial.
      However, the mechanism of this beneficial effect is unclear, and any perceived benefit may be secondary to the relief of constipation. When formally tested, fiber supplementation did not reduce phasic contractile activity in IBS patients,
      • Cook IJ
      • Irvine EJ
      • Campbell D
      • Shannon S
      • Reddy SN
      • Collins SM
      Effect of dietary fiber on symptoms and rectosigmoid motility in patients with irritable bowel syndrome.
      and the effects of fiber supplementation on colonic tone, sensation, and compliance in IBS have not been evaluated adequately. There have been few randomized or mechanistic studies of fiber in patients with IBS. In a crossover comparison of 30 g/day bran or placebo bran in 18 patients, bran increased stool weight and shortened intestinal transit time, but symptoms were not assessed.
      • Arffmann S
      • Andersen JR
      • Hegnhoj J
      • Schaffalitzky de Muckadell OB
      • Mogensen NB
      • Krag E.
      The effect of coarse wheat bran in the irritable bowel syndrome. A double-blind, cross-over study.
      Another crossover study in 14 patients used 15.6 g/day of fiber versus 2.7 g/day (placebo group) and identified significant effects with the first treatment, either bran or placebo,
      • Lucey MR
      • Clark ML
      • Lowndes J
      • Dawson AM
      Is bran efficacious in irritable bowel syndrome? A double-blind, placebo-controlled crossover study.
      a frequent finding in crossover studies of a disorder with high placebo responses. A study from India identified correlations between dose of ispaghula (10–30 g/day) and symptoms and stool weight, but not with whole-gut transit time.
      • Kumar A
      • Kumar N
      • Vij JC
      • Sarin SK
      • Anand BS
      Optimum dosage of ispaghula husk in patients with irritable bowel syndrome: correlation of symptom relief with whole gut transit time and stool weight.
      The authors also reported a significant effect of fiber on symptoms, but there was no placebo arm, and 4 of 14 patients were not included in the final analysis because of drop-out. An 80-patient crossover study of bran versus placebo identified no difference in overall responses and worse “wind-related” symptoms in the bran-treated group.
      • Snook J
      • Shepherd HA
      Bran supplementation in the treatment of irritable bowel syndrome.
      Francis and Whorwell
      • Francis CY
      • Whorwell PJ
      Bran and irritable bowel syndrome: time for reappraisal.
      reported exacerbation of symptoms at the start of treatment that persisted long-term, particularly with citrus fruits.
      In practice, many patients complain of bloating with higher doses of fiber. Bran is reported to be no better than placebo in relief of overall IBS symptoms
      • Snook J
      • Shepherd HA
      Bran supplementation in the treatment of irritable bowel syndrome.
      and may be worse than a normal diet
      • Francis CY
      • Whorwell PJ
      Bran and irritable bowel syndrome: time for reappraisal.
      for some symptoms of IBS caused by intraluminal distention
      • Whitehead WE
      • Holtkotter B
      • Enck P
      • Hoelzl R
      • Holmes KD
      • Anthony J
      • Shabsin HS
      • Schuster MM
      Tolerance for rectosigmoid distention in irritable bowel syndrome.
      by bowel gas produced by bacterial fermentation of fiber.
      • Haderstorfer B
      • Psycholgin D
      • Whitehead WE
      • Schuster MM
      Intestinal gas production from bacterial fermentation of undigested carbohydrate in irritable bowel syndrome.
      • Lasser RB
      • Levitt MD
      The role of intestinal gas in functional abdominal pain.
      Fiber may induce bloating by increasing residue loading and bacterial fermentation without accelerating the onward movement of the increased residue.
      • Hebden JM
      • Blackshaw E
      • Perkins AC
      • D'Amato M
      • Spiller RC
      Impaired ascending colon clearance in response to rapid small bowel transit in bloated irritable bowel syndrome: bran exaggerates the problems (abstr).
      Notwithstanding these limitations, there is a significant improvement in constipation if sufficient quantities of fiber (20–30 g/day) are consumed.
      • Cann PA
      • Read NW
      • Holdsworth CD
      What is the benefit of coarse wheat bran in patients with irritable bowel syndrome?.
      • Voderholzer
      • Schatke W
      • Muhldorfer BE
      • Klauser AG
      • Birkner B
      • Muller-Lissner SA
      Clinical response to dietary fiber treatment of chronic constipation.
      The uncertain benefits of fiber are the basis for the common practice of starting with a low dose, increasing gradually, and abandoning high levels of supplementation (e.g., >30 g/day) if patients experience worsening of symptoms.
      • Francis CY
      • Whorwell PJ
      Bran and irritable bowel syndrome: time for reappraisal.
      Thus, in summary, whereas fiber has a role in treating constipation, its value in the relief of abdominal pain and diarrhea associated with IBS is controversial. The efficacy of fiber in the long term is also questionable because it resulted in equivocal benefit in a group of 14 patients with IBS who were followed up for up to 3 years.
      • Hillman LC
      • Stace NH
      • Pomare EW
      Irritable bowel patients and their long-term response to a high fiber diet.

       Loperamide and antidiarrheal agents in IBS

      Diarrhea-predominant IBS is associated with acceleration of small bowel and proximal colonic transit and responds to opioids.
      • Cann PA
      • Read NW
      • Holdsworth CD
      • Barends D.
      Role of loperamide and placebo in management of irritable bowel syndrome.
      Most prefer to use loperamide over diphenoxylate, which contains atropine and may induce adverse effects that may be worrisome in the elderly, e.g., bladder dysfunction, glaucoma, and tachycardia. Loperamide (2–4 mg, up to 4 times daily), a synthetic opioid, decreases intestinal transit, enhances intestinal water and ion absorption, and increases anal sphincter tone at rest.
      • Cann PA
      • Read NW
      • Holdsworth CD
      • Barends D.
      Role of loperamide and placebo in management of irritable bowel syndrome.
      These physiologic actions seem to explain the improvement in diarrhea, urgency, and fecal soiling observed in patients with IBS.
      • Cann PA
      • Read NW
      • Holdsworth CD
      • Barends D.
      Role of loperamide and placebo in management of irritable bowel syndrome.
      The effect on resting anal tone
      • Read M
      • Read NW
      • Barber DC
      • Duthie HL
      Effects of loperamide on anal sphincter function in patients complaining of chronic diarrhea with fecal incontinence and urgency.
      may help reduce fecal soiling at nighttime, when the internal anal sphincter function is the predominant mechanism of continence at a time when it is enhanced by the voluntary contraction of the external anal sphincter. Because it does not traverse the blood–brain barrier, loperamide is generally preferred to other opiates such as diphenoxylate, codeine, or other narcotics for treating patients with IBS who have predominant diarrhea and/or incontinence. Clinically, loperamide can also be used to reduce postprandial urgency associated with a prominent colonic response to feeding or as a means of improving control at times of anticipated stress or other colonic stimuli (e.g., exercise, social gatherings). One of the drawbacks of opioids is the tendency to induce constipation. As a result, the dose should be titrated for the individual patient, and the use of the liquid formula of loperamide is helpful. A recent study also showed reduced intensity of pain associated with improved stool consistency and reduced frequency of defecation. However, the patients treated with loperamide also experienced increased nightly abdominal pain.
      • Efskind PS
      • Bernklev T
      • Vatn MH
      A double-blind, placebo-controlled trial with loperamide in irritable bowel syndrome.
      Symptoms of patients with constipation-predominant IBS given loperamide are not improved.
      • Hovdenak N.
      Loperamide treatment of the irritable bowel syndrome.
      Cholestyramine is considered a third-line treatment in IBS with predominant diarrhea because of poor palatability and low patient compliance. The rationale for its use is based on the documentation of bile acid malabsorption in some patients with functional, typically painless diarrhea
      • Thaysen EH
      • Pedersen L.
      Idiopathic bile salt catharsis.
      • Luman W
      • Williams AJ
      • Merrick MV
      • Eastwood MA
      Idiopathic bile acid malabsorption: long-term outcome.
      that mimics IBS with diarrhea. Cholerrheic diarrhea is most typically confirmed by a therapeutic trial, although it can be diagnosed with 75SeHCAT retention test or measurement in serum of 7α-hydroxycholesten-3-one
      • Brydon WG
      • Nyhlin H
      • Eastwood MA
      • Merrick MV
      Serum 7 alpha-hydroxy-4-cholesten-3-one and selenohomocholyltaurine (SeHCAT) whole body retention in the assessment of bile acid induced diarrhoea.
      in a few centers. Bile acid sequestration may relieve the cholerrheic effect of bile acids in patients who have idiopathic bile acid malabsorption.
      • Sciarretta G
      • Fagioli G
      • Fumo A
      • Vicini G
      • Cecchetti L
      • Grigolo B
      • Verri A
      • Malaguti P.
      75Se HCAT test in the detection of bile acid malabsorption in functional diarrhoea and its correlation with small bowel transit.
      However, it is conceivable that a component of bile acid malabsorption may result from rapid ileal transit. The simpler, often more acceptable approach for patients who find cholestyramine distasteful would be to use loperamide as a first measure for bile acid malabsorption.

       Use of smooth muscle relaxants in IBS?

      As noted previously by Klein,
      • Klein KB
      Controlled treatment trials in the irritable bowel syndrome: a critique.
      the field of antispasmodic and anticholinergic therapy in IBS is bedeviled with methodologic problems. In many trials, significant numbers of patients drop out during follow-up (up to 60 %), and high placebo response rates (as high as 69%) are noted. Nevertheless, full randomized, double-blind, placebo-controlled studies
      • Camilleri M
      • Choi MG
      Review article: irritable bowel syndrome.
      of at least 2 weeks' duration show that abdominal pain was relieved in 68% (mean range, 23%–87%) for active medication and 31% (mean range, 22%–66%) for placebo. Similarly, for global assessment, mean responses to drug and placebo were 73% (range, 39%–89%) and 41% (range, 13%–69%), respectively. Meta-analysis of available studies suggests that some of these agents, such as mebeverine, octylonium, and cimetropium,
      • Camilleri M
      • Choi MG
      Review article: irritable bowel syndrome.
      • Poynard T
      • Naveau S
      • Mory B
      • Chaput JC
      Meta-analysis of smooth muscle relaxants in the treatment of irritable bowel syndrome.
      may be effective although the trial methodology was inadequate by modern standards.
      • Klein KB
      Controlled treatment trials in the irritable bowel syndrome: a critique.
      In the meta-analysis by Poynard et al.
      • Poynard T
      • Naveau S
      • Mory B
      • Chaput JC
      Meta-analysis of smooth muscle relaxants in the treatment of irritable bowel syndrome.
      of smooth muscle relaxants in IBS, 5 drugs showed efficacy over placebo: cimetropium bromide (an antimuscarinic compound); pinaverium bromide and octylonium or otilinium bromide (quaternary ammonium derivatives with calcium-antagonist properties); trimebutine (a peripheral opiate antagonist); and mebeverine (a derivative of β-phenyl-ethylamine that has antimuscarinic cholinergic activity). None of these drugs underwent extensive trials in North America or received approval from the Food and Drug Administration. The commonly prescribed dicyclomine and hyoscine were not effective in the meta-analysis. Eight trials of peppermint oil for IBS, including a meta-analysis of 5 placebo-controlled, double-blind trials, have not established a role for this treatment in IBS.
      • Poynard T
      • Naveau S
      • Mory B
      • Chaput JC
      Meta-analysis of smooth muscle relaxants in the treatment of irritable bowel syndrome.
      In clinical practice, antispasmodics and anticholinergic agents are best used on an as-needed basis up to 2 times per day for acute attacks of pain, distention, or bloating. Agents such as dicyclomine or mebeverine seem to retain efficacy when used on an as-needed basis but become less effective with long-term use. Clidinium is no longer available as a separate drug and is combined with a benzodiazepine, chlorodiazepoxide. Although these drugs have generally fallen out of favor, it remains to be conclusively demonstrated that the newer medications (discussed below) are actually superior for pain in IBS in head-to-head comparisons. This has been demonstrated in a phase III trial of alosetron versus mebeverine (discussed below). The development of more gastrointestinal-specific agents with antispasmodic or anticholinergic activity and fewer adverse effects (e.g., salivation, bladder, cardiac dysfunction) may lead to more effective use of this class of agents.

       Psychotrophic agents

      To date, psychotrophic agents have probably been best reserved for those patients with diarrhea and pain-predominant IBS.
      • Drossman DA
      • Whitehead WE
      • Camilleri M.
      Irritable bowel syndrome: a technical review for practice guideline development.
      However, there is increasing interest in the potential application of selective serotonin reuptake inhibitors (SSRIs), which tend not to cause constipation and may even induce diarrhea in some patients. One uncontrolled study
      • Clouse RE
      Antidepressants for functional gastrointestinal syndromes.
      supports the efficacy of SSRIs in treating patients with IBS.
      Tricyclic agents (e.g., amitriptyline, imipramine, doxepin) are now frequently used to treat patients with IBS, particularly those with more severe or refractory symptoms, impaired daily function, and associated depression or panic attacks. Initially they were used because a high proportion of patients with IBS reported significant depression.
      • Heefner JD
      • Wilder RM
      • Wilson JD
      Irritable colon and depression.
      • Hislop IG
      Psychological significance of the irritable colon syndrome.
      • Lancaster-Smith MJ
      • Prout BJ
      • Pinto T
      • Anderson JA
      • Schiff AA
      Influence of drug treatment on the irritable bowel syndrome and its interaction with psychoneurotic morbidity.
      Antidepressants have neuromodulatory and analgesic properties, which may benefit patients independently of the psychotrophic effects of the drugs.
      • Hislop IG
      Psychological significance of the irritable colon syndrome.
      It seems that the clinical effects of agents such as amitriptyline result from their central actions. Thus, amitriptyline had no significant effects on esophageal and rectal sensory thresholds and compliance in healthy subjects,
      • Gorelick AB
      • Koshy SS
      • Hooper FG
      • Bennett TC
      • Chey WD
      • Hasler WL
      Differential effects of amitriptyline on perception of somatic and visceral stimulation in healthy humans.
      and clinical benefit in the functional upper gastrointestinal disorder nonulcer dyspepsia seemed to be associated with better sleep rather changes in gastric sensitivity.
      Neuromodulatory effects may occur sooner and with lower doses in IBS patients than the doses used in the treatment of depression (e.g., 10–25 mg amitriptyline or 50 mg desipramine). Because antidepressants must be used on a continual rather than an as-needed basis, they are generally reserved for patients with frequently recurrent or continual symptoms. A 2–3-month trial is usually needed before a therapeutic benefit can be excluded.
      The placebo-controlled trials of antidepressants in IBS have been summarized elsewhere.
      • Drossman DA
      • Whitehead WE
      • Camilleri M.
      Irritable bowel syndrome: a technical review for practice guideline development.
      In 2 large studies,
      • Myren J
      • Groth H
      • Larssen SE
      • Larsen S.
      The effect of trimipramine in patients with the irritable bowel syndrome.
      • Myren J
      • Lovland B
      • Larssen S-E
      • Larsen S.
      A double-blind study of the effect of trimipramine in patients with the irritable bowel syndrome.
      trimipramine decreased abdominal pain, nausea, and depression but did not alter stool frequency. The beneficial effect seems to be greater in those with abdominal pain and diarrhea. For example, desipramine improved abdominal pain and diarrhea,
      • Greenbaum DS
      • Mayle JE
      • Vanegeren LE
      • Jerome JA
      • Mayor JW
      • Greenbaum RB
      • Matson RW
      • Stein GE
      • Dean HA
      • Halvorsen NA
      • Rosen LW
      The effects of desipramine on IBS compared with atropine and placebo.
      whereas in an earlier study
      • Heefner JD
      • Wilder RM
      • Wilson JD
      Irritable colon and depression.
      that combined patients with diarrhea and those with constipation, there was no significant benefit for desipramine over placebo. Nortriptyline, in combination with fluphenazine, reduced abdominal pain and diarrhea in 2 studies.
      • Lancaster-Smith MJ
      • Prout BJ
      • Pinto T
      • Anderson JA
      • Schiff AA
      Influence of drug treatment on the irritable bowel syndrome and its interaction with psychoneurotic morbidity.
      • Ritchie JA
      • Truelove SC
      Comparison of various treatments for irritable bowel syndrome.
      Antidepressants do not result in improvement in constipation-predominant IBS. However, this may reflect aggravation of constipation by the confounding anticholinergic effects. The role of serotonin-reuptake inhibitors, which may cause diarrhea,
      • Gram LF
      Fluoxetine.
      is currently the focus of prospective studies.

       Hypnotherapy and other psychologic treatments

      An alternative therapeutic strategy for patients with significant pain is to use hypnotherapy or psychotherapy, but these approaches are generally less readily available to the practicing physician.
      • Whorwell PJ
      • Prior A
      • Faragher EB
      Hypnotherapy in irritable bowel syndrome.
      • Svedlund J.
      Psychotherapy in irritable bowel syndrome: a con-trolled outcome study.
      • Guthrie E
      • Creed F
      • Dawson D
      • Tomerson B.
      A controlled trial of psychological treatment for the irritable bowel syndrome.
      Factors indicating a favorable response to psychotherapy include predominance of diarrhea and pain, association of IBS with overt psychiatric symptoms, and intermittent pain exacerbated by stress.
      • Guthrie E
      • Creed F
      • Dawson D
      • Tomerson B.
      A controlled trial of psychological treatment for the irritable bowel syndrome.
      In contrast, patients with constant abdominal pain do poorly with psychotherapy
      • Guthrie E
      • Creed F
      • Dawson D
      • Tomerson B.
      A controlled trial of psychological treatment for the irritable bowel syndrome.
      or hypnotherapy.
      • Whorwell PJ
      Hypnotherapy in the irritable bowel syndrome.
      The role of psychologic treatments is discussed in detail in a recent review.
      • Drossman DA
      • Whitehead WE
      • Camilleri M.
      Irritable bowel syndrome: a technical review for practice guideline development.
      In a systematic review of the literature, Talley et al.
      • Talley NJ
      • Owen BK
      • Boyce P
      • Paterson K.
      Psychological treatments for irritable bowel syndrome: a critique of controlled treatment trials.
      concluded that the efficacy of psychologic treatment for IBS has not been established because of methodologic inadequacy. Although 8 studies reported psychologic treatments superior to control therapy, 5 failed to detect a significant effect.

       Alternative therapies in IBS

      Several reports have documented the greater use of alternative medicine consultations and therapies in IBS than in “organic” diseases such as Crohn's disease, ulcerative colitis, and organic upper gut disorders; these include reports from the United Kingdom, Denmark, and Canada.
      • Smart HL
      • Mayberry JF
      • Atkinson M.
      Alternative medicine consultations and remedies in patients with irritable bowel syndrome.
      • Mortensen NH
      • Bisgard C.
      Irritable colon and ulcerative colitis. Alternative treatment is used frequently.
      • Verhoef MJ
      • Sutherland LR
      • Brkich L.
      Use of alternative medicine by patients attending a gastroenterology clinic.
      Use of alternative medical care was positively correlated with scepticism toward conventional medicine and negatively related to perceived health status and satisfaction with a university clinic's physicians.
      • Sutherland LR
      • Verhoef MJ
      Why do patients seek a second opinion of alternative medicine?.
      Efficacy of alternative therapies has been difficult to ascertain in view of the lack of controlled trials
      • Bittinger M
      • Barnert J
      • Wienbeck M.
      Alternative therapy methods in functional disorders of the gastrointestinal system.
      ; however, a first parallel-group, placebo-controlled 16-week trial of alternative medicine has recently been reported. In this study, individualized or conventional Chinese herbal medicines significantly improved bowel symptom scores and global symptoms and reduced IBS-related interference with life relative to placebo, which was administered in a capsule and was designed to taste, smell, and look similar to a Chinese herb formula.
      • Bensoussan A
      • Talley NJ
      • Hing M
      • Menzies R
      • Guo A
      • Ngu M.
      Treatment of the irritable bowel syndrome with Chinese herbal medicine: a randomised controlled trial.
      Patients receiving individualized Chinese herbal medicine continued to report benefits beyond the actual treatment period.
      • Bensoussan A
      • Talley NJ
      • Hing M
      • Menzies R
      • Guo A
      • Ngu M.
      Treatment of the irritable bowel syndrome with Chinese herbal medicine: a randomised controlled trial.

      5-HT3 antagonism in IBS

      In the past several years, there have been significant improvements in the design of therapeutic trials. These improvements include better characterization of patient subgroups, exclusion of physiologic disturbances that overlap with or complicate IBS (such as pelvic floor dyssynergia), and use of appropriately powered studies with patient-derived, definable, clinically relevant global endpoints.
      Serotonin type 3 and 4 receptors are involved in sensory (Figure 2) and motor (Figure 3) functions of the gut, and are targets for pharmacotherapy in IBS (Table 7).
      Figure thumbnail gr2
      Fig. 2Location of 5-HT3 and 5-HT4 receptors on sensory apparatus related to the gastrointestinal tract. 5-HT3 receptors are located on vagal afferents and in dorsal root ganglion (DRG) nerve cell bodies, as well as in the vomiting center. 5-HT4 agonists have been shown to reduce visceral afferent firing during nociceptive stimulation. Reprinted with permission from the American College of Gastroenterology, 2000, Vol 95, pp 2698–2709.
      • Kim D-Y
      • Camilleri M.
      Serotonin: a mediator of brain-gut connection.
      Figure thumbnail gr3
      Fig. 3Location of serotonin type 3 (5-HT3) and 4 (5-HT4) receptors on intrinsic neurons in the myenteric plexus. A 5-HT4 agonist induces muscle contraction by stimulation of excitatory cholinergic neurons; such an agonist also has potential to stimulate inhibitory nitrergic neurons, causing viscus relaxation. The latter has been demonstrated in human stomach. Reprinted with permission from the American Journal of Gastroenterology, 2000, Vol 95, pp 2698–2709.
      • Kim D-Y
      • Camilleri M.
      Serotonin: a mediator of brain-gut connection.
      Alosetron hydrochloride, a selective 5-HT3 antagonist, is effective in relieving pain (Figure 4), normalizing bowel frequency, and reducing urgency in female patients with diarrhea-predominant IBS.
      • Camilleri M
      • Mayer EA
      • Drossman DA
      • Heath A
      • Dukes GE
      • McSorley D
      • Kong S
      • Mangel AW
      • Northcutt AR
      Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5HT3-receptor antagonist.
      Figure thumbnail gr4
      Fig. 4Effect of alosetron and placebo on adequate relief of pain and stool consistency seen in female patients with diarrhea-predominant IBS. Note the rapid onset of symptom relief and persistence of effect until cessation of medication (vertical line at 12 weeks). Reprinted with permission.
      • Camilleri M
      • Northcutt AR
      • Kong S
      • Dukes GE
      • McSorley D
      • Mangel AW
      Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial.
      Alosetron was recently approved for the treatment of women with IBS whose predominant bowel symptom is diarrhea. 5-HT3 receptors are extensively distributed on enteric motor neurons and in peripheral afferents and central locations such as the vomiting center. Antagonism of these receptors reduces visceral pain, colonic transit, and small intestinal secretion. Clinical pharmacology studies of alosetron suggest that it dose-dependently reduces the arterial depressor response to noxious rectal distention in rats
      • Kozlowski CM
      • Green A
      • Grundy D
      • Boissonade FM
      • Bountra C.
      The 5-HT3 receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetised rat.
      ; relaxes the colon, increasing thresholds for volume-associated distentions in IBS patients
      • Delvaux M
      • Louvel D
      • Mamet JP
      • Campos-Oriola R
      • Frexinos J.
      Effect of alosetron on responses to colonic distension in patients with irritable bowel syndrome.
      ; and retards small bowel and colonic transit in IBS patients, with significantly greater effects in female than in male patients.
      • Viramontes B
      • McKinzie S
      • Pardi DS
      • Burton D
      • Thomforde G
      • Camilleri M.
      Alosetron retards small bowel and overall colonic transit in diarrhea-predominant irritable bowel syndrome (D-IBS) (abstr).
      Alosetron is rapidly absorbed after oral administration, with peak plasma concentrations after 1 hour. The drug can be taken with or without food.
      In large placebo-controlled trials, alosetron was more effective than placebo in inducing adequate relief of pain and discomfort and improvement in bowel frequency, consistency, and urgency
      • Bardhan KD
      • Bodemar G
      • Geldof H
      • Schutz E
      • Heath A
      • Mills JG
      • Jacques LA
      A double-blind, randomized, placebo-controlled dose-ranging study to evaluate the efficacy of alosetron in the treatment of irritable bowel syndrome.
      • Mangel AW
      • Camilleri M
      • Chey WY
      • Hamm LR
      • Harding JP
      • Lawler C
      • Dukes GT
      • McSorley D
      • Koug S
      • Heath AT
      • Northcult AR
      Treatment of female IBS patients with alosetron, a potent and selective 5HT3-receptor antagonist (abstr).
      • Camilleri M
      • Northcutt AR
      • Kong S
      • Dukes GE
      • McSorley D
      • Mangel AW
      Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial.
      in women with diarrhea-predominant IBS. Another study compared alosetron (1 mg twice daily) with mebeverine, an antispasmodic approved in Europe for treatment of IBS, and showed similar results over the active comparator.
      • Jones RH
      • Holtmann G
      • Rodrigo L
      • et al.
      Alosetron relieves pain and improves bowel function compared with mebeverine in female nonconstipated irritable bowel syndrome patients.
      The beneficial response for pain and bowel dysfunction was observed within 1–4 weeks of the start of therapy and was sustained throughout the duration of the trial. Within 1 week after discontinuation of the drug, symptoms were comparable to those in women receiving placebo. Benefit was observed only in female patients with diarrhea-predominant IBS symptoms, and further studies in male patients are awaited.
      The most common adverse event with alosetron treatment is constipation, which in one trial was significantly more common among women receiving alosetron than among those receiving placebo (28% vs. 5%). The majority of patients reporting constipation had mild to moderate symptoms; only 10% of those patients withdrew from the study because of constipation. A significant adverse event with an unclear relationship to alosetron is acute ischemic colitis, estimated to occur in 0.1%–1% of patients. The reported cases resolved after several days to weeks without sequelae. Risk factors were not identified. The manufacturer initially recommended that the drug should be discontinued in patients who experience rectal bleeding or a sudden worsening of pain. This medication was withdrawn from the market in November 2000. Other drugs in this class (e.g., cilantetron) are being studied.

      Experimental medications for IBS

      The availability of agents with visceral analgesic and sensorimotor-modulatory properties have stimulated much interest in the field of IBS therapy (Table 7). These include the κ-opioid agonist fedotozine,
      • Dapoigny M
      • Abitbol JL
      • Fraitag B.
      Efficacy of peripheral kappa agonist, fedotozine, vs. placebo in treatment of irritable bowel syndrome. A multicenter dose-response study.
      other 5-HT3 and 5-HT4 antagonists, other serotonergic agents, and NK antagonists, some of which are now becoming available for routine clinical usage.
      New partial or full 5-HT4 agonists appear promising in the treatment of constipation or constipation-predominant IBS and are in phase III trials. The partial agonist tegaserod was recently shown to enhance peristalsis in an in vitro model and to do so at least in part by stimulating the intrinsic primary afferent neuron, activating excitatory and inhibitory intrinsic neurons that result in ascending contraction and descending relaxation, respectively (Figure 5
      • Grider JR
      • Foxx-Orenstein AE
      • Jin JG
      5-Hydroxytryptamine4 receptor agonists initiate the peristaltic reflex in human, rat, and guinea pig intestine.
      ).
      Figure thumbnail gr5
      Fig. 5Model of the effect of serotonin on activation of intrinsic primary afferent neurons in the lamina propria after being released from enterochromaffin cells. Similarly, this figure depicts the effect of absorbed tegaserod, a partial 5-HT4 agonist, on activation of intrinsic primary afferent neurons (e.g., releasing calcitonin gene-related peptide, CGRP), which in turn stimulate myenteric neurons to activate the “peristaltic reflex.” This involves an orad contraction, mediated through excitatory transmitters such as acetylcholine (ACh) or substance P (SP), and a caudad relaxation, mediated through inhibitory neurotransmitters such as vasoactive intestinal peptide (VIP), pituitary adenylate cyclase–associated peptide (PACAP), or nitric oxide synthase (NOS). Adapted and reprinted with permission.
      • Grider JR
      • Foxx-Orenstein AE
      • Jin JG
      5-Hydroxytryptamine4 receptor agonists initiate the peristaltic reflex in human, rat, and guinea pig intestine.
      Tegaserod may also stimulate motility via a systemic action because it increases small bowel and colonic contractions after intravenous administration in the dog.
      • Nguyen A
      • Camilleri M
      • Kost LJ
      • Metzger A
      • Sarr MG
      • Hanson RB
      • Fett SL
      • Zinsmeister AR
      SDZ HTF 919 stimulates colonic motility and transit in vivo.
      It reduces visceral afferent firing during rectal distention and reduces abdominal contractions in response to noxious rectal distention, a pseudoaffective model of visceral pain.
      • Coelho A-M
      • Rovira P
      • Fioramonti J
      • Bueno L.
      Antinociceptive properties of HTF 919 (tegaserod), a 5-HT4 receptor partial agonist, on colorectal distension in rats (abstr).
      Tegaserod reduces visceral afferents firing during noxious rectal distention.
      • Schikowski A
      • Mathis C
      • Thewissen M
      • Ross H-G
      • Pak MA
      • Enck P.
      Dose-dependent modulation of rectal afferent sensitivity by a 5-HT4 receptor agonist (abstr).
      Tegaserod results in global relief of IBS symptoms in female patients with constipation-predominant IBS.
      • Mueller-Lissner S
      • Fumagalli I
      • Bardhan KD
      • Pace F
      • Nault B
      • Pecher EC
      • et al.
      Tegaserod, a 5-HT4 receptor partial agonist, relieves key symptoms of irritable bowel syndrome (abstr).
      The effective doses of tegaserod are 4–12 mg/day in 2 divided doses (2 mg or 6 mg twice daily). Tegaserod resulted in significant relief of the subjects' global assessment of relief at the study endpoint, which was preset at the last 4 weeks of a 12-week trial. Global relief was measured as at least “somewhat relieved” for all 4 weeks or “complete/considerable relief” of IBS symptoms. It had been demonstrated that “somewhat” relief was associated with significant improvement of a number of secondary endpoints such as pain-free days, frequency of bowel movements, and stool consistency (Figure 6).
      Figure thumbnail gr6
      Fig. 6Effect of tegaserod on weekly assessment of mean pain score and number of bowel movements in patients with constipation-predominant IBS. Data on file at Novartis Pharmaceuticals; presented at the Advisory Committee Meeting of the Food and Drug Administration, June 2000.
      To date, the tegaserod drug development program consisted of 3 phase III trials; one of the trails involved a titration step. Efficacy observed in the 3 trials was not uniform. However, pooled analysis shows significant benefit of tegaserod over placebo, and this was especially evident when subgroups were analyzed. Specifically, the drug is significantly effective with an approximately 15% advantage over placebo in female patients and in those with documented constipation during the baseline run-in period. Tegaserod's greater efficacy over placebo was also more pronounced if patients who used laxatives more than 5 times during the 12-week study or took any laxative during the last 4 weeks of the study were included.
      Tegaserod also appeared to provide benefit on several secondary endpoints assessed by daily diary responses, e.g., daily pain score, bloating score, and frequency and consistency of bowel movements. The effect on bloating, in particular, deserves further study, because this would be the first demonstration that any medication has a significant impact on this enigmatic symptom. The efficacy of tegaserod on bloating would be consistent with the hypothesis that gas transit is abnormal and a potential target for pharmacotherapy.
      • Serra J
      • Azpiroz F
      • Malagelada J-R
      Intestinal gas dynamics and tolerance in humans.
      • Serra J
      • Azpiroz F
      • Malagelada J-R
      New insight on functional gut disease: is gas handling the answer? (abstr).
      • Caldarella M-P
      • Serra J
      • Azpiroz F
      • Malagelada J-R
      Stimulation of intestinal gas propulsion is the key to treat gas retention in functional patients (abstr).
      Tegaserod appears quite safe. No serious adverse events have been reported in the clinical trials program and in the cohort treated in open evaluation for more than 6 months. It is anticipated that the medication will be approved for prescription in 2001.
      The full 5-HT4 agonist prucalopride induces strong contractions in the proximal colon in vivo in dogs
      • Briejer MR
      • Ghoos E
      • Eelen J
      • Schuurkes JAJ
      Serotonin 5-HT4 receptors mediate the R093877-induced changes in contractile patterns in the canine colon (abstr).
      and accelerates colonic transit in healthy participants (Figure 7)
      • Emmanuel AV
      • Kamm MA
      • Roy AJ
      • Antonelli K.
      Effect of a novel prokinetic drug, R093877, on gastrointestinal transit in healthy volunteers.
      • Bouras EP
      • Camilleri M
      • Burton DD
      • McKinzie S.
      Selective stimulation of colonic transit by the benzofuran 5-HT4 agonist, prucalopride, in healthy humans.
      and, most importantly, in patients with functional constipation.

      Bouras EP, Camilleri M, Burton DD, Thomforde G, McKinzie S, Zinsmeister AR. Prucalopride accelerates gastrointestinal and colonic transit in patients with constipation without a rectal evacuation disorder. Gastroenterology (in press).

      Figure thumbnail gr7
      Fig. 7Effect of prucalopride on rate of emptying of the ascending and transverse colon in healthy participants. Note the overall acceleration of transit on prucalopride compared with placebo and the lack of a significant dose-related effect. Reprinted with permission.
      • Bouras EP
      • Camilleri M
      • Burton DD
      • McKinzie S.
      Selective stimulation of colonic transit by the benzofuran 5-HT4 agonist, prucalopride, in healthy humans.
      Prucalopride induced a significant increase in the number of spontaneous and complete bowel movements in phase II trials of patients with functional constipation.
      • Johanson JF
      • Miner PB
      • Parkman HP
      • Wojcik MA
      • Lambert R
      • Karcher K
      • Woods M.
      Prucalopride improves bowel movement frequency and symptoms in patients with chronic constipation: results of two double-blind, placebo-controlled trials (abstr).
      • Miner PB
      • Nichols Jr, T
      • Silvers DR
      • Joslyn A
      • Woods M.
      The efficacy and safety of prucalopride in patients with chronic constipation (abstr).
      Although this group is theoretically distinct from those with constipation-predominant IBS, the differences in these 2 subgroups of patients are probably small, and in clinical practice, patients often receive both diagnoses at different times. The effects of prucalopride on abdominal pain have not been thoroughly assessed, and further studies are needed. However, phase III clinical trials are currently on hold while a more thorough evaluation of potential intestinal carcinogenicity in animal species is evaluated.
      Other investigational agents and new approaches (Table 7) that are currently being explored in phase II studies include newer type 3 antimuscarinic agents, cholecystokinin antagonisits, the α2-adrenergic agonists, clonidine,
      • Bharucha AE
      • Camilleri M
      • Zinsmeister AR
      • Hanson RB
      Adrenergic modulation of human colonic motor and sensory function.
      a 5-HT1 agonist, buspirone,
      • Tack J
      • Piessevaux H
      • Coulie B
      • Fischler B
      • De Gucht V
      • Janssens J.
      A placebo-controlled trial of buspirone, a fundus-relaxing drug, in functional dyspepsia: effect on symptoms and gastric sensory and motor function (abstr).
      and an SSRI, citalopram.
      • Tack JF
      • Vos R
      • Broekaert D
      • Fischler B
      • Janssens J.
      Influence of citalopram, a selective serotonin reuptake inhibitor, on colonic tone and sensitivity in man (abstr).
      At doses of up to 0.3 mg, clonidine has been shown to reduce sensation of gastric and colonic distentions in health without significantly altering gastrointestinal or colonic transit. Clonidine also enhances rectal compliance in health and in IBS.
      • Malcolm A
      • Camilleri M
      • Kost L
      • Burton DD
      • Fett SL
      • Zinsmeister AR
      Towards identifying optimal doses for alpha-2 adrenergic modulation of colonic and rectal motor and sensory function.
      • Malcolm A
      • Camilleri M
      • Kellow JE
      Clonidine alters rectal motor and sensory function in irritable bowel syndrome (abstr).
      Formal trials of its clinical efficacy are awaited.
      Buspirone reduces gastric and colonic responses to volume distentions
      • Tack J
      • Piessevaux H
      • Coulie B
      • Fischler B
      • De Gucht V
      • Janssens J.
      A placebo-controlled trial of buspirone, a fundus-relaxing drug, in functional dyspepsia: effect on symptoms and gastric sensory and motor function (abstr).
      and may similarly have potential in functional disorders. Citalopram reduces colonic sensation to volume distention.
      • Tack JF
      • Vos R
      • Broekaert D
      • Fischler B
      • Janssens J.
      Influence of citalopram, a selective serotonin reuptake inhibitor, on colonic tone and sensitivity in man (abstr).
      Buspirone's anxiolytic activity may have an impact on the symptomatic benefits demonstrated in a small clinical trial.
      • Tack J
      • Piessevaux H
      • Coulie B
      • Fischler B
      • De Gucht V
      • Janssens J.
      A placebo-controlled trial of buspirone, a fundus-relaxing drug, in functional dyspepsia: effect on symptoms and gastric sensory and motor function (abstr).
      Similarly, the sensory and motor effects of citalopram must be evaluated in IBS patients.
      Neurokinin antagonists also have therapeutic potential in IBS. Three types of receptor antagonists have been developed and confer benefit through their effects on smooth muscle, intrinsic excitatory neurons, and visceral afferents. Pharmacodynamic studies need to be performed to clarify the subgroups of IBS patients most likely to respond to these agents.
      Bloating remains a significant symptom, for which no there is no evidence-based effective therapy. As noted above, tegaserod, a colonic prokinetic, has shown some efficacy on bloating in the phase III program. The parenterally administered anticholinesterase neostigmine reduces experimentally induced intestinal gas, with reduced abdominal girth. However, it also results in a significant increase in abdominal cramping.
      • Caldarella M-P
      • Serra J
      • Azpiroz F
      • Malagelada J-R
      Stimulation of intestinal gas propulsion is the key to treat gas retention in functional patients (abstr).
      The prokinetic approach is promising as a means to reduce abdominal bloating, but proper studies in IBS patients with predominant bloating are needed.

      Summary and conclusion

      Management of IBS involves positive diagnosis, limited exclusion of organic disease, and reassurance. With insights into enteric neuroscience and a greater understanding of the brain–gut axis, novel therapies are being developed that make a more comprehensive approach possible. Much has been learned about this condition and the ways to study the pathophysiology and develop clinical trials in IBS. The role of infectious agents and neuroimmune interactions and the neurotransmitters involved in pain mediation will be clarified in the next decade and will enhance the management of IBS. However, development of optimal therapies will require collaboration between gastroenterologists, basic neuroscientists, pain pharmacologists, applied physiologists, and clinical trialists.

      Acknowledgements

      The author thanks Cindy Stanislav for excellent secretarial assistance.

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