Therapeutic Approach to the Patient with IrritableBowel Syndrome

Michael Camilleri, MD

This article reviews briefly the evidence to supportcurrent therapies in irritable bowel syndrome (IBS)and the novel therapeutic approaches on the thresh-old of clinical application. Fiber is indicated at a doseof at least 12 grams per day in patients with consti-pation-predominant IBS. Loperamide (and probablyother opioid agonists) are of proven benefit in diar-rhea-predominant IBS; loperamide may also aid con-tinence by enhancing resting anal tone, but there isno evidence that it results in pain relief. In general,smooth muscle relaxants are best used sparingly, onan as-needed basis, because their overall efficacy isunclear. The 5-HT3 antagonist, alosetron, results inadequate relief of pain and improvements in bowelfunction in female nonconstipated patients with IBS.Psychotropic agents are important in relieving de-pression and are of proven benefit for pain and diar-rhea in patients with depression associated with IBS.Further trials with selective serotonin reuptake inhib-itors are awaited. Psychological treatments includ-ing hypnotherapy are less widely available but mayplay an important role in the relief of pain. In sum-mary, current therapies targeted on the predominantsymptoms in IBS are moderately successful. As thebowel sensorimotor and limbic system disturbancesof IBS are more clearly understood, we should antic-ipate other pharmacologic approaches in the nearfuture, including a-adrenergic agonists and 5-HT4

agonists. New therapies directed at treatment of thesyndrome, rather than relief of symptoms, areneeded. Am J Med. 1999;107(5A):27S–32S. © 1999 byExcerpta Medica, Inc.

Several authoritative reviews have evaluated the re-sults of single trials and meta-analyses of pharma-cotherapies for irritable bowel syndrome (IBS).1–3

This brief article focuses on a more clinical and practicalappraisal of effectiveness and presents a somewhat em-pirical therapeutic approach to the patient with IBS,based on targeting therapy to the predominant symptom.

There follows a brief review of the clinical evidence tosupport current medical and psychological treatments inIBS (Figure 1): fiber for constipation; loperamide for di-arrhea; smooth muscle relaxants for pain; psychotropicagents and their role in treating depression, diarrhea, andpain; and psychological treatments.4

Finally, our focus will turn to the future application ofnewer therapies (e.g., 5-HT3 antagonists, fedotozine, oc-treotide; and 5-HT4 agonists and antagonists), which areaimed at correcting the underlying mechanisms that re-sult in this biopsychosocial disorder.

The classic paper of Klein1 appropriately questionedthe role of anticholinergic and antispasmodic agents inIBS, chiefly because of poor trial design and statisticalanalyses. However, there has been a great deal of im-provement in the design of more recent trials, includingthe improved characterization of patient subgroups, ex-clusion of physiologic disturbances that overlap with orcomplicate IBS (such as pelvic floor dyssynergia) andmodify response to treatment, and better trial design ofappropriately powered studies with definable, clinicallyrelevant endpoints. Recent reviews, endorsed by the Prac-tice Committee of the American Gastroenterological As-sociation,2 have suggested strategies for diagnosis andmanagement of IBS. A greater understanding of sensori-motor pathophysiology, the brain– gut axis, and novelpharmacologic agents are reviewed elsewhere5 and in an-other section of this supplement6 and should lead to im-proved future management of IBS.

ROLE OF FIBER IN TREATMENT OF IBS

In patients with constipation-predominant IBS, fiber ac-celerates colonic or oro-anal transit.7 Increased dietaryfiber or psyllium products are frequently recommendedfor patients with constipation-predominant IBS, eventhough, as a group, these patients do not consume lessdietary fiber than control subjects.8 There is evidence thatfiber decreases whole gut transit time, which may allevi-ate constipation; fiber also may decrease intracolonicpressures, which could reduce pain, because it is recog-

From the Departments of Medicine and Physiology, Mayo Clinic andMayo Foundation, Rochester, Minnesota.

Requests for reprints should be addressed to Michael Camilleri, MD,Mayo Clinic, GI Unit, Alfred 2-435, 200 First Street SW, Rochester,Minnesota 55905.

© 1999 by Excerpta Medica, Inc. 0002-9343/99/$20.00 27SAll rights reserved. PII S0002-9343(99)00279-x

nized that wall tension is one of the factors that contrib-utes to visceral pain.9 –11 Fiber also serves to reduce bilesalt concentrations in the colon, and it has been specu-lated that this indirectly reduces colonic contractile activ-ity.12 However, one must recognize that, when formallytested, fiber supplementation did not reduce phasic con-tractile activity in patients with IBS13; the effects of fibersupplementation on colonic tone, sensation, and compli-ance in IBS have not been evaluated.

At the clinical level, bran is reported to be no betterthan placebo in relief of overall IBS symptoms14 and maypossibly be worse than a normal diet15 for some of thesymptoms of IBS. The reason for this aggravation of IBSsymptoms with fiber is unclear. Patients with IBS have alower threshold to report pain from intraluminal disten-tion16 and, as a result, they may be more sensitive thanother patients to bowel gas produced by bacterial fermen-tation of fiber.17,18 Whereas fiber accelerates small boweltransit in health, it has no effect on small bowel and prox-imal colonic emptying. The authors postulated that fiberinduced bloating because it increased loading of residueand bacterial fermentation in the colon without acceler-ating the onward movement of the increased residue.19

In practice, many patients complain of bloating withhigher doses of fiber. However, there is a significant im-provement in constipation if sufficient quantities of fiber(20 to 30 g/day) are consumed.7,20 The uncertain benefitsreported in several other clinical studies have led to a needto reappraise formally the ubiquitous recommendationto increase intake of fiber in IBS.14

Thus, whereas fiber has a role in treating constipation,its value for IBS or, specifically, in the relief of abdominalpain and diarrhea associated with IBS is controversial. Intwo randomized crossover studies of patients withIBS13,21 receiving increased fiber (15 g of bran or 20 g ofcorn fiber), the control groups had similar degrees ofsymptomatic improvement. Moreover, symptom relief

was not associated with changes in rectosigmoid motili-ty13 or stool weight,21 suggesting that improvement wasunrelated to the expected actions of fiber. Fiber alleviatespain in children with idiopathic chronic abdominalpain.22 The efficacy of fiber in the long term is also ques-tionable, because it resulted in equivocal benefit in agroup of 14 patients with IBS followed for up to 3 years.23

LOPERAMIDE AND ANTIDIARRHEALAGENTS IN IBSDiarrhea-predominant IBS is associated with accelera-tion of small bowel and proximal colonic transit.7,24 Lop-eramide (2 to 4 mg, up to four times daily), a syntheticopioid, decreases intestinal transit, enhances intestinalwater and ion absorption, and increases anal sphinctertone at rest. These physiologic actions seem to explain theimprovement in diarrhea, urgency, and fecal soiling ob-served in patients with IBS.25 The effect on resting analtone26 –30 may help reduce fecal soiling at nighttime whenthe internal anal sphincter function is the predominantmechanism of continence at a time when it is not en-hanced by the voluntary contraction of the external analsphincter. Because it does not traverse the blood– brainbarrier, loperamide is generally preferred to other opi-ates, such as diphenoxylate, codeine, or other narcotics,for treating patients with IBS who have predominant di-arrhea and/or incontinence. Clinically, loperamide canalso be used to reduce postprandial urgency associatedwith a prominent colonic response to feeding or as ameans of improving control at times of anticipated stressor other colonic stimuli (e.g., exercise, social gatherings,etc.).

Cholestyramine is considered as a second-line treat-ment in diarrhea-predominant IBS. The rationale isbased on the documentation of bile acid malabsorptionin patients with functional diarrhea31,32 that mimics IBSwith diarrhea and can be diagnosed with selenohomo-

Figure 1. Current approach to managing patients with IBS, based on predominant symptom. (Adapted and reproduced withpermission from Ann Intern Med.4)

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cholyltaurine (75SeHCAT) retention test or measure-ment in serum of 7a-hydroxycholesten-3-one.33 Bileacid sequestration may relieve the cholerrheic effect ofbile acids in patients who have idiopathic bile acid mal-absorption.34 However, it is conceivable that a compo-nent of bile acid malabsorption may result from rapidileal transport, offering further support for the use of lop-eramide as a first-line measure in the treatment of thisdisorder.

WHEN SHOULD SMOOTH MUSCLERELAXANTS BE USED IN IBS?

As indicated previously by Klein,1 the field of antispas-modic and anticholinergic therapy in IBS is bedeviledwith methodologic problems. Because several reviewshave already assessed these trials,1–3,5 this will not be dis-cussed further except to reiterate that these trials are char-acterized by significant numbers of patients dropping outduring follow-up, short duration, and very high or vari-able placebo response rates. Whereas the meta-analysisby Poynard et al3 concluded that, as a therapeutic class,smooth muscle relaxants or antispasmodics were signifi-cantly better than placebo for global assessment (62% vs35% placebo improvement) and abdominal pain (64% vs45% placebo improvement, both P ,0.01), there are onlya few studies that individually show significant benefit.

In Poynard’s meta-analysis, five drugs showed efficacyover placebo in IBS: cimetropium bromide, an antimus-carinic compound; primaverium bromide and octylo-nium or otilinium bromide, quaternary ammonium de-rivatives with calcium-antagonist properties; trimebu-tine, a peripheral opiate antagonist; and mebeverine, aderivative of beta-phenylethylamine that has anticholin-ergic activity. Interestingly, none of these drugs under-went extensive trials in North America, and none have yetbeen approved by the Food and Drug Administration.Eight trials with peppermint oil for IBS, including a meta-analysis of five placebo-controlled, double-blind trials,have not established a role for this treatment in IBS.35

Further well-designed studies and pharmacologic ap-proaches are needed. Antispasmodics and anticholin-ergic agents are best used on an as-needed basis up to twotimes per day for acute attacks of pain, distention, orbloating. Such agents as dicyclomine or mebeverine seemto retain efficacy when used on a prn basis but becomeless effective with chronic use. Clidinium is no longeravailable as a separate drug and is combined with thebenzodiazepine, chlorodiazepoxide.

PSYCHOTROPIC AGENTS

To date, psychotropic agents have typically been reservedfor those patients with diarrhea and pain-predominantIBS.2,5 However, there is increasing interest in the poten-tial application of selective serotonin reuptake inhibitors

(SSRIs), which tend not to cause constipation and mayeven induce diarrhea in some patients. One uncontrolledstudy36 supports the efficacy of SSRIs as well as tricyclicantidepressants in treating patients with IBS.

Tricyclic agents (e.g., amitriptyline, imipramine, dox-epin) are now frequently used to treat patients with IBS,particularly those with more severe or refractory symp-toms, impaired daily function, and associated depressionor panic attacks. Initially their use was based on the factthat a high proportion of patients with IBS reported sig-nificant depression.37–39 Antidepressants have neuro-modulatory and analgesic properties, which may benefitpatients independently of the psychotropic effects of thedrugs,36,40 although the effects of amitriptyline on esoph-ageal and rectal sensory thresholds and compliance arenot significant,41 suggesting that central effects predom-inate. Neuromodulatory effects may occur sooner andwith lower dosages than those used in the treatment ofdepression (e.g., 10 to 25 mg amitriptyline or 50 mg des-ipramine). Because antidepressants must be used on acontinual rather than an as-needed basis, they are gener-ally reserved for patients having frequently recurrent orcontinual symptoms. A 2- to 3-month trial is usuallyneeded before abandoning this therapeutic approach.

Table 1 summarizes placebo-controlled trials of anti-depressants in IBS. In two large studies,43,44 trimipraminedecreased abdominal pain, nausea, and depression butdid not alter stool frequency. The beneficial effect seemsto be greater in those with abdominal pain and diarrhea.For example, desipramine improved abdominal pain anddiarrhea,45 but in an earlier study37 that combined pa-tients with either diarrhea or constipation, there was nosignificant benefit for desipramine over placebo. In twostudies,39,46 nortriptyline in combination with fluphena-zine reduced abdominal pain and diarrhea. Antidepres-sants do not result in improvement in constipation-pre-dominant IBS, although this may reflect the anticholin-ergic effects that aggravate constipation; the role of SSRIs,which may cause diarrhea,47 is currently the focus of pro-spective studies.

HYPNOTHERAPY AND OTHERPSYCHOLOGICAL TREATMENTSAn alternative therapeutic strategy for patients with sig-nificant pain is to use hypnotherapy or psychotherapy,but these approaches are generally less readily available tothe practicing physician.48 –50 Factors indicating a favor-able response to psychotherapy include predominant di-arrhea and pain, association of IBS with overt psychiatricsymptoms, and intermittent pain exacerbated by stress.50

In contrast, patients with constant abdominal pain dopoorly with psychotherapy50 or hypnotherapy.51 The roleof psychological treatments is discussed in detail in a re-cent review.2 In a systematic review of the literature, Tal-ley et al52 concluded that the efficacy of psychological

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treatment for IBS has not been established because ofmethodological inadequacies. Whereas eight studies re-ported psychological treatments superior to control ther-apy, five failed to detect a significant effect.

NEWER THERAPIES

Pharmaceutical industries have identified agents with vis-ceral analgesic properties, and this has stimulated much

interest in the field of IBS therapy (Figure 2). Severalnovel approaches are in the process of thorough evalua-tion in phase II or phase III trials, such as the kappa opi-oid agonist, fedotozine,53 and 5-HT3 and 5-HT4 antago-nists. Alosetron, a 5-HT3 antagonist, is effective in reliev-ing pain (Figure 3), normalizing bowel frequency, andreducing urgency in nonconstipated IBS female pa-tients.54 In recent years, well-structured and designed

Figure 2. Potential new pharmacologic therapies in the treatment of irritable bowel syndrome, based on experimental studiesperformed in healthy subjects or patients with the syndrome. SSRI 5 selective serotonin reuptake inhibitors. (Reproduced withpermission from Aliment Pharmacol Ther.5)

Figure 3. Effect of alosetron (1, 2, 4, and 8 mg bid) on adequate relief of pain in nonconstipated patients with IBS. Note thebeneficial effect in women (*p , 0.05 vs. placebo) but not in men. (Reproduced with permission from Aliment Pharmacol Ther.53)

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studies with adequate power and meaningful endpointshave been conducted, and our hope is that these studieswith novel agents will have an impact on clinical practicein the future. Meanwhile, the practicing physician mustexclude organic disease safely and cost effectively, andprovide comforting, compassionate care to these patientswhile attempting symptomatic relief with fiber, opioids,and antispasmodics. When indicated, low doses of anti-depressants may also relieve symptoms, probablythrough their central rather than peripheral41 effects.

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syndrome. Gastroenterology. 1988;95:232–241.2. Drossman DA, Whitehead WE, Camilleri M. Irritable bowel

syndrome: a technical review for practice guideline devel-opment. Gastroenterology. 1997;112:2120–2137.

3. Poynard T, Naveau S, Mory B, Chaput JC. Meta-analysis ofsmooth muscle relaxants in the treatment of irritable bowelsyndrome. Aliment Pharmacol Ther. 1994;8:499–510.

4. Camilleri M, Prather CM. The irritable bowel syndrome:mechanisms and a practical approach to management.Ann Intern Med. 1992;116:1001–1008.

5. Camilleri M, Choi MG. Irritable bowel syndrome. AlimentPharmacol Ther. 1997;11:3–15.

6. Mayer EA. Emerging disease model for functional gastro-intestinal disorders. Am J Med. 1999;107(4A):5S–11S.

7. Cann PA, Read NW, Holdsworth CD. What is the benefit ofcoarse wheat bran in patients with irritable bowel syn-drome? Gut. 1984;25:168–173.

8. Jarrett M, Heitkemper MM, Bond EF, Georges J. Compar-ison of diet composition in women with and without func-tional bowel disorder. Gastroenterol Nursing. 1994;6:253.

9. Distrutti E, Azpiroz F, Soldevilla A, Malagelada J-R. Gastricwall tension determines perception of gastric distention.Gastroenterology. 1999;116:1035–1042.

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11. Malcolm A, Phillips SF, Camilleri M, Hanson RB. Pharma-cological modulation of rectal tone alters perception ofdistention in humans. Am J Gastroenterol. 1997;92:2073–2079.

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13. Cook IJ, Irvine EJ, Campbell D, Shannon S, Reddy SN,Collins SM. Effect of dietary fiber on symptoms andrectosigmoid motility in patients with irritable bowel syn-drome. Gastroenterology. 1990;98:66–72.

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Table 1. Placebo-Controlled Psychotropic Drug Trials in Patients with IBS

Drug(s) Comments Ref. No.

Desipramine 150 mg No effect on abdominal pain or stoolfrequency. Constipation-predominantand diarrhea-predominant patients werecombined.

35

Desipramine 150 mg Diarrhea-predominant were separated fromconstipation-predominant patients andcontrolled for anticholinergic activity.Diarrhea, abdominal pain, anddepression, but not constipation,improved more on drug than on atropineor placebo.

42

Trimipramine 50 mg HS Significant decreases in vomiting,sleeplessness, depression, and mucuscontent of stools.

40

Trimipramine 50 mg HS 110 mg, 3 times daily

Abdominal pain, nausea, sleeplessness, anddepression decreased more on drug thanon placebo.

41

Nortriptyline 30 mg 1fluphenazine 1.5 mg

Reductions in abdominal pain and diarrhea,but not constipation or bloating.

43

Nortriptyline 30 mg 1fluphenazine 1.5 mg

Combination antidepressant/anxiolytic-reduced diarrhea and pain.

37

Adapted with permission from Gastroenterology.42

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syndrome: bran exaggerates the problems. Gastroenterol-ogy. 1999;116:A1004. Abstract.

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33. Brydon WG, Nyhlin H, Eastwood MA, Merrick MV. Serum7alpha-hydroxy-4-cholesten-3-one and selenohomocholyl-taurine (SeHCAT) whole body retention in the assessmentof bile acid induced diarrhoea. Eur J Gastroenterol Hepatol.1996;8:117–123.

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53. Dapoigny M, Abitbol JL, Fraitag B. Efficacy of peripheralkappa agonist, fedotozine, vs. placebo in treatment of irri-table bowel syndrome. A multicenter dose-response study.Dig Dis Sci. 1995;40:2244–2249.

54. Camilleri M, Mayer EA, Drossman DA, et al. Improvement inpain and bowel function in female irritable bowel patientswith alosetron, a 5HT3-receptor antagonist. Aliment Phar-macol Ther. 1999;13:610–620.

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