Systematic Review on the Management of IrritableBowel Syndrome in North AmericaLawrence J. Brandt, M.D., Chairman,1 David Bjorkman, M.D.,2 M. Brian Fennerty, M.D.,3G. Richard Locke, M.D.,4 Kevin Olden, M.D.,5 Walter Peterson, M.D.,6 Eamonn Quigley, M.D.,7Philip Schoenfeld, M.D., M.S.Ed., M.Sc. (Epi),8 Marvin Schuster, M.D.,9 and Nicholas Talley, M.D., Ph.D.101Albert Einstein College of Medicine, Bronx, NY; 2University of Utah School of Medicine, Salt Lake City,UT; 3Oregon Health Sciences University, Portland, OR; 4Mayo Clinic, Rochester, MN; 5Mayo Clinic,Scottsdale, AZ; 6University of Texas Southwestern Medical School, Dallas, TX; 7National University ofIreland, Cork, Ireland; 8University of Michigan School of Medicine, Ann Arbor, MI; 9Johns Hopkins BayviewMedical Center, Baltimore, MD; and 10Nepean Hospital, Penrith, New South Wales, Australia 2.1 METHODS
ments have been described, and IBS experts on the TaskForce contributed their advice about the effect of individual patient preferences on these recommendations.
a. a transparent link between the evidence and the recom- Literature Search
In order to identify relevant IBS therapy trials for inclusion b. explicit criteria for inclusion of studies to serve as the in this guideline, the following literature search techniques were employed. Separate PUBMED, MEDLINE, and EM- c. comprehensive searching of the literature for relevant BASE searches of English language articles from 1980 to 2001 were performed with different combinations of the d. a standardized and explicit system for grading the meth- following search terms: "antispasmodics," "antimusca- rinics," "dicyclomine," "hyoscyamine," "constipation," "fi- e. a standardized and explicit system for grading recom- ber," "polycarbophil," "bulking agents," "laxatives," "anti- f. recommendations should acknowledge the magnitude of "alosetron," "antidiarrheal agents," "loperamide," "behav- treatment benefit, the adverse events associated with the ioral therapy," "irritable bowel syndrome," "clinical trial," treatment, and individual patient preferences that may and "randomized (pt)." The bibliographies of IBS therapy guide the application of guideline recommendations (1-3).
trials, selected review articles, and selected meta-analyseswere manually searched. Multiple pharmaceutical compa-nies, including AstraZeneca, Pfizer, Salix, Novartis, Solvay, In order to fulfill these requirements, Task Force members Merck, and GlaxoSmithKline, were contacted to identify used several techniques. Each section of the systematic relevant unpublished trials of IBS therapies and to obtain review has been numbered to provide a link between the additional data from published trials of IBS therapies.
evidence and the recommendations. Standard techniques for In order to identify relevant trials about the epidemiology literature searching and study selection were used for each of IBS and the diagnostic approach to patients with IBS section of this document (4, 5). Data on study methodology symptoms, the following literature search techniques were and study results were extracted onto standard forms and employed. Separate MEDLINE and EMBASE searches of summaries of data are presented in tables and graphs, en- English language articles were performed with different suring that the methodologic rigor of individual studies is combinations of the following search terms. For epidemi- defined and that the magnitude of treatment benefit is quan- ology of IBS, "colonic diseases, functional" was exploded tified. A commonly used system for grading recommenda- with key words "incidence," "prevalence," "prognosis," and tions in evidence-based guidelines (6) was adapted for this "natural history." Similar combinations were exploded us- document (see Section 2.2), ensuring that an explicit and ing "irritable colon." For diagnostic approach to the patient transparent process was used to make recommendations with IBS symptoms, search terms were "colonic diseases, based on the strength of the evidence. Adverse events and functional (diagnosis)" or "irritable, functional, or spastic individual patient preferences may affect the application of colon." These terms were then exploded with the descriptive guideline recommendations. Therefore, adverse events have key words "blood," "parasite," "stool analysis," "radiogra- been assessed, relative contraindications to specific treat- phy," "hydrogen breath testing," "endoscopy," "barium en- ACG Functional GI Disorders Task Force
ema," "colonoscopy or flexible sigmoidoscopy." Bibliogra- Table 2.1.1. Quantitative Assessment of Study Methodology
phies from all potentially relevant articles were manually 1. ROME criteria to identify patients with IBS.
A medical education and research company (EBMed, 2. Randomization.
3. Parallel study design (i.e., no crossover studies).
LLC, Anaheim Hills, CA) assisted the Task Force with literature searches, application of study selection criteria, data extraction and analysis, and assessment of method- ologic quality of individual trials.
7. Baseline observation of patients to assess symptoms.
8. Treatment duration of 8-12 weeks or longer.
9. Follow-up after treatment to assess symptoms.
Study Selection Criteria
10. Compliance with the treatment is measured.
The titles and abstracts of all citations identified by the 11. Sample size calculation is provided and adequate sample literature searches were reviewed. Potentially relevant stud- ies were retrieved, and the selection criteria were applied.
12. Primary outcome of the trial is improvement in global IBS Since a North American perspective was used, only treat- 13. Primary outcome is based on patient assessment.
ments available in the United States were examined and 14. Validated scale used to measure improvement in IBS only epidemiologic studies from North American popula- tions were reviewed. For IBS therapy trials, the selection Data from Veldhuyzen van Zanten SJO, Talley NJ, Bytzer P, et al. Design of treatment criteria were 1) randomized controlled trial (RCT); 2) pop- trials for functional gastrointestinal disorders. Gut 1999;45(suppl II):II69 -77.
* The members of the Committee on Design of Treatment Trials for Functional ulation of adult patients with IBS; 3) comparison of IBS Gastrointestinal Disorders of the Rome II committee also noted additional recom- therapy vs placebo or control therapy; 4) evaluation of relief mendations for the design of clinical trials, including a priori defined study endpointand definition of patient setting (primary care vs tertiary care). However, published of IBS symptoms; 5) results published in English in full reports rarely provided adequate information to assess the use of these additional manuscript form (or adequate data available after written techniques in the conduct of treatment trials. Therefore, these additional techniqueswere not included in the scale. communication with investigators); and 6) therapy availablein the United States. For epidemiology of IBS studies, theselection criteria were 1) studies of population-based sam- study endpoints, and dosages of study medication, no at- ples of IBS patients in North America; 2) use of Manning, tempt was made to combine results into meta-analyses.
ROME I, or ROME II criteria to identify IBS patients; 3) In this data analysis, improvement in global IBS symp- population of adult patients; 4) results reported on preva- toms was considered the primary outcome of interest. The lence, incidence, or natural history of IBS; and 5) results Task Force agrees with the recommendations of the ROME published in English and in full manuscript form. For trials Committee (7): "The primary outcome measure should about the diagnostic approach to the patient with IBS symp- .integrate the key symptoms of [IBS].allowing the pa- toms, the selection criteria were 1) use of a cohort of IBS tient to integrate the contribution of a disparate group of patients explicitly diagnosed via symptom-based criteria symptoms (abdominal pain, bloating, and altered bowel (e.g., Manning or ROME criteria); 2) performance of a function) into a single global clinical rating." This assess- commonly applied diagnostic test with a blinded compari- ment should be done by the patient, as it is doubtful that a son to an appropriate gold standard diagnostic test for or- physician's assessment of a patient's improvement in global ganic GI disease; and 3) quantification of the results as IBS symptoms would be more accurate or more reliable than either normal or abnormal, in which case an additional or alternative diagnosis of organic disease was made based on For epidemiology of IBS studies, data on study method- ology and study results were also abstracted onto standardforms. Data were abstracted about 1) symptom-based defi- Data Extraction and Analysis
nition of IBS (e.g., Manning Criteria or ROME Criteria); 2) For IBS therapy trials, data on study methodology and study sample size and case ascertainment technique to identify results were abstracted onto standard forms for the perfor- IBS patients; 3) prevalence, incidence, prevalence of IBS mance of systematic reviews. Data were extracted about 1) subgroups, gender distribution, and mean age of onset of study population, including proportion of female patients; 2) symptoms; and 4) disease activity (e.g., prevalence of IBS intervention: dosage and schedule of administration of treat- over time and frequency of IBS flares within a specified ment vs placebo or control therapy; 3) study duration; and 4) period of time). For trials about the diagnostic approach to proportion of patients achieving improvement in global IBS the patient with IBS symptoms, data were abstracted about symptoms, abdominal pain, bloating, changes in bowel hab- 1) symptom-based criteria used to identify IBS patients; 2) its, and adverse events. The ROME committee recom- diagnostic evaluation performed and gold standard compar- mended study design techniques to minimize bias in trials of ison; 3) prevalence of confirmed organic GI disease, result- functional GI disorders (7) (Table 2.1.1). Data on the use of ing in an alternative diagnosis to explain IBS symptoms; and these techniques were extracted and summarized in tabular 4) the accuracy of diagnostic tests in a population of IBS form; however, because of wide variation in study design, Management of IBS
produce a Type I error. Intermediate-quality RCTs may also RECOMMENDATIONS
be susceptible to Type II errors due to inadequate samplesize. Level III-V evidence comes from nonrandomized tri- Quantitative Assessment of Study Methodology
als or case studies. These are observational studies and are Previous reviews and epidemiologic studies (8 -10) have prone to multiple biases that produce Type I errors. For this established methodologic criteria that minimize bias and review, Level III-V evidence was not used to make recom- enhance validity of trials about therapy, including the use of mendations about IBS therapies. Level III-V evidence was randomization, concealed allocation, double blinding, and only used to make recommendations about the diagnostic complete patient follow-up. Additionally, the ROME com- approach to the patient with IBS symptoms or about epide- mittees described the preferred design of treatment trials for miology of IBS because data on these topics may only be functional gastrointestinal disorders (7) (Table 2.1.1). In available from observational studies.
order to assess the methodologic strength of individualstudies about IBS therapies, a quantitative scale of study Grading of Recommendations
quality was developed. This scale uses the ROME commit- Recommendations are listed as Grade A, Grade B, or Grade tee recommendations for design of treatment trials for func- C (see Table 1.0.2 in Evidence-Based Position Statement on tional gastrointestinal disorders (Table 2.1.1). Each meth- Management of IBS). Grade A recommendations are sup- odologic criterion on the scale was assigned one point.
ported by the strongest (Level I) evidence. Task Force Therefore, a study could receive a maximum score of 14 members strongly believe that these recommendations are points for quality of study methodology. This scale esti- accurate, based on the evidence. Grade B recommendations mates the methodologic rigor of an individual trial: a trial are supported by intermediate-quality (Level II) evidence.
with a low quality score may be more likely to produce Task Force members believe that Grade B recommendations inaccurate or biased results and a trial with a high quality may have important limitations due to the intermediate score may be more likely to produce accurate and unbiased quality of the evidence. These recommendations may change in the future if high-quality (Level I) evidence be- No standard criteria are available to rate the methodologic comes available. Grade C recommendations are supported strength of epidemiologic studies in a systematic review.
by Level III-V evidence. Because these recommendations Population-based studies may be preferable to studies of are based largely on observational studies, the strength of referral populations as referral populations may provide evidence behind these recommendations is limited. Grade C inflated estimates of the prevalence and incidence of a recommendations are only provided because they represent disorder. Therefore, epidemiologic studies in this review are the best evidence about the epidemiology of IBS and the limited to population-based studies. In order to assess the diagnostic approach to patients with IBS symptoms.
methodologic strength of studies about the diagnostic tests,a standard scale was used to evaluate the methodologicquality of studies (11). The quality of each diagnostic test REFERENCES: SECTION 2.1 AND 2.2
study was determined by assessing the methodology for 1) 1. Hayward R, Wilson M, Tunis S, et al. User's guides to the study population; 2) verification bias; 3) blinded interpreta- medical literature. VIII. How to use clinical practice guideline tion of test results; 4) biased patient selection; 5) data recommendations. A. Are the recommendations valid? JAMA collection; 6) details of diagnostic tests; 7) details of refer- 2. Wilson M, Hayward R, Tunis S, et al. User's guide to the ence tests; and 8) details of the study population. The total medical literature. VIII. How to use clinical practice guide- lines. B. What are the recommendations and will they help youin caring for your patients? JAMA 1995:274;1630 -2.
Levels of Evidence
3. Guyatt G, Sackett D, Sinclair J, et al. User's guide to the Levels of evidence have been previously defined (see Table medical literature. IX. A method for grading health care rec-ommendations. JAMA 1995;274:1800 - 4.
1.0.2 in Evidence-Based Position Statement on Manage- 4. Egger M, Smith GD. Principles of and procedures for system- ment of IBS). Level I evidence represents high-quality atic reviews. In: Egger M, Smith GD, Attman DG, eds. Sys- RCTs. These RCTs have few limitations in their study tematic reviews in health care, 2nd ed. London: BMJ, 2001: design, which should minimize Type I errors. Thus, if the trial does show a significant difference between treatment 5. Oxman A, Guyatt G, Cook D, et al. Summarizing the evi- dence. In: Guyatt G, Rennie D, eds. User's guide to the and placebo, then it will be unlikely that this finding is due medical literature: A manual for evidence-based clinical prac- to biased study design. High-quality RCTs also have ade- tice. Chicago: AMA Press, 2001:155-75.
quate power to minimize Type II errors. Thus, if the trial 6. Cook D, Guyatt G, Laupacis A, et al. Rules of evidence and does not show a significant difference between treatment clinical recommendations on the use of anti-thrombotic and placebo, then it will be unlikely that this finding is due agents. Chest 1992;102(suppl 4):3055-115.
7. Veldhuyzen van Zanten SJO, Talley NJ, Bytzer P, et al.
to an inadequate sample size of patients. Level II evidence Design of treatment trials for functional gastrointestinal dis- represents intermediate-quality RCTs. These RCTs have orders. Gut 1999;45(suppl II):II69 -77.
important limitations in their study design, which could 8. Schoenfeld P, Cook D, Hamilton F, et al. An evidence-based ACG Functional GI Disorders Task Force
Table 2.3.1. Symptom-Based Criteria for the Diagnosis of IBS
At least 12 weeks of continuous or recurrent At least 12 weeks, which need not be consecutive, in the preceding 12 months of abdominal discomfortor pain that has two of the following threefeatures: Onset associated with a change in frequency of stool (2) associated with a change in frequency Onset associated with a change in form (appearance) Two or more of the following, at least on (4) Passage of mucus, or(5) Bloating or feeling of abdominal 1. Manning AP, Thompson WG, Heaton KW, et al. Towards a positive diagnosis of the irritable bowel syndrome. BMJ 1978;2:653- 4.
2. Thompson WG, Dotewall G, Drossman DA, et al. Irritable bowel syndrome: Guidelines for the diagnosis. Gastroenterol Int 1989;2:92-5.
3. Thompson WG, Longstreth GF, Drossman DA, et al. Functional bowel disorders and functional abdominal pain. Gut 1999;45(suppl II):II43-7.
approach to gastroenterology therapy. Gastroenterology 1998; diagnosis of IBS in research studies (4 - 8). These criteria, which include the Manning criteria and ROME I and ROME 9. Schulz KF, Chalmers I, Hayes RJ, et al. Empirical evidence of II Committee criteria (Table 2.3.1), are widely used to bias: Dimensions of methodological quality associated withestimates of treatment effects in controlled trials. JAMA 1995; identify IBS patients for epidemiologic studies and to ensure that appropriate IBS patients are enrolled in trials of IBS 10. Chalmers TC, Celano P, Sacks HS, et al. Bias in treatment therapies; however, the usefulness of these detailed criteria assignment in controlled clinical trials. N Engl J Med 1983; in the clinical setting is uncertain. Few primary care physi- cians use these criteria in practice or even know that these 11. Lijmer JG, Mol BW, Heisterkamp S, et al. Empirical evidence of design-related bias in studies of diagnostic tests. JAMA criteria exist (9). Overall, these criteria emphasize that IBS is characterized by abdominal discomfort associated withaltered bowel habits. Given the varied symptoms of IBS andthe uncertain clinical utility of Manning and ROME criteria, 2.3 SYMPTOM-BASED CRITERIA FOR IRRITABLE BOWEL
Task Force members suggest that physicians should use a SYNDROME AND THRESHOLD TO TREAT IRRITABLE
broad definition of IBS: "abdominal discomfort associated BOWEL SYNDROME
The ROME I committee of IBS experts has characterized IBS is defined as abdominal discomfort associated with subgroups of functional gastrointestinal disorders, including altered bowel habits (Grade C recommendation). IBS sig- diarrhea-predominant IBS and constipation-predominant nificantly diminishes the quality of life among most IBSpatients who actively seek medical care (Grade C recom- IBS (10). These subgroup classifications have been used to mendation). Treatment of IBS patients is indicated when the enroll patients in trials of IBS therapies; however, the patient and physician believe that the IBS symptoms dimin- ROME II committee of IBS experts noted that subgroup ish the quality of life of the patient (Grade C recommenda- classifications are unstable over time (11). IBS with consti- tion). IBS therapies should improve global IBS symptoms, pation may change to constipation alone or IBS alternating including abdominal discomfort, bloating, and altered between constipation and diarrhea. Given this symptom bowel habits (Grade C recommendation). instability, the ROME II committee discouraged the use of IBS lacks a biological marker. No structural, biochemical, IBS subtypes to categorize patients, and the Task Force or physiological abnormalities are consistently demon- members agree and endorse this recommendation. Task strated in IBS patients. Thus, the definition of IBS is symp- Force members recommend that IBS patients should be tom-based and obtaining an accurate history of the patient's identified using symptom-based criteria: IBS alternating be- symptoms is crucial. Symptoms of IBS may include, but are tween diarrhea and constipation; IBS associated with ab- not limited to, abdominal discomfort/pain, bloating, diar- dominal discomfort, bloating, and constipation; or IBS as- rhea, fecal urgency, and constipation (1-3).
sociated with abdominal discomfort, fecal urgency, and Multiple symptom scores and symptom-based criteria for IBS have been developed by IBS experts to facilitate the IBS symptoms significantly diminish the quality of life of Management of IBS
IBS patients who actively seek medical care for their symp- 7. Thompson WG, Longstreth FG, Drossman DA, et al. Func- toms (12-16). Trials using validated scales of quality of life tional bowel disorders and functional abdominal pain. Gut1999;45(suppl II):II43-7.
demonstrate that IBS patients have worse quality of life than 8. Kruis W, Thieme CH, Weinzierl M, et al. A diagnostic score healthy controls and patients with gastroesophageal reflux for the irritable bowel syndrome: Its value in the exclusion of disease (GERD). Their quality of life was similar to patients organic disease. Gastroenterology 1984;87:1-7.
with diabetes mellitus but better than patients with end-stage 9. Thompson WG, Heaton KW, Smyth GT, et al. Irritable bowel renal disease (12, 16). The ability to generalize the findings syndrome: The view from general practice. Eur J Gastroen-terol Hepatol 1997;9:689 -92.
of these studies to all patients with IBS is limited because 10. Drossman DA, Thompson WG, Talley NJ, et al. Identification many of these studies evaluated patients with moderate- of subgroups of functional gastrointestinal disorders. Gastro- severe IBS being seen in subspecialty clinics. Observational studies of IBS patients also indicate that IBS symptoms lead 11. Veldhuyzen van Zanten SJO, Talley NJ, Bytzer P, et al.
to increased absenteeism and lost productivity at work (17, Design of treatment trials for functional gastrointestinal dis-orders. Gut 1999;45(suppl II):II69 -77.
12. El-Serag HB, Olden K, Bjorkman D. Health-related quality of Although IBS diminishes quality of life, no data are life among persons with irritable bowel syndrome: A system- available to guide recommendations about the threshold to atic review. Aliment Pharmacol Ther 2002;16:1171- 85.
treat IBS. Therefore, Task Force members developed an 13. Whitehead WE, Burnett CK, Cook EW, et al. Impact of expert-based recommendation about this topic. Some IBS irritable bowel syndrome on quality of life. Dig Dis Sci 1996;41:2248 -53.
patients may seek medical care simply for reassurance.
14. O'Keefe EA, Talley NJ, Zinsmeister AR, et al. Bowel disor- When such patients are reassured that their symptoms do not ders impair functional status and quality of life in the elderly: represent cancer or another life-threatening disorder, no A population-based study. J Gerontol A Biol Sci Med 1995; further treatment may be needed; however, treatment should be offered if the patient and physician believe that the IBS 15. McGee HM, O'Boyle CA, Hickey A, et al. Assessing the quality of life of the individual: The SEIQoL with a healthy symptoms diminish the quality of life of the patient.
and a gastroenterology unit population. Psychol Med 1991; The ROME committee of IBS experts opined that im- provement in global IBS symptom improvement should be 16. Gralnek I, Hays RD, Kilbourne A, et al. The impact of irritable the primary outcome in trials of IBS therapies (11): "The bowel syndrome on health-related quality of life. Gastroenter- symptoms that result in a diagnosis [of IBS] are varied and 17. Hahn BA, Yan S, Strassels S. Impact of irritable bowel syn- interact in complex ways. Thus, there is a strong argument drome on quality of life and resource use in the United States for a primary outcome measure that allows the patient to and United Kingdom. Digestion 1999;60:77- 81.
integrate the contribution of a disparate group of symptoms 18. Drossman DA, Li Z, Andruzzi E, et al. US Householder into a single global rating." The Task Force members agree survey of functional gastrointestinal disorders: Prevalence, sociodemography, and health impact. Dig Dis Sci 1993;38:1569 - 80.
In clinical practice, IBS may be defined as abdominal discomfort associated with altered bowel habits. IBS signif-icantly diminishes the quality of life among most IBS pa- 2.4 EPIDEMIOLOGY OF IRRITABLE BOWEL SYNDROME
tients seeking medical care, and treatment should be offered IN NORTH AMERICA
to these patients. IBS therapies should improve global IBSsymptoms, including abdominal discomfort, bloating, and The prevalence of IBS in North America is approximately 10 -15%, equally divided among IBS with constipation, IBSwith diarrhea, and IBS alternating between diarrhea andconstipation. There is a 2:1 female predominance of IBS in REFERENCES: SECTION 2.3
North America in population-based studies (Grade C rec-ommendation). 1. Maxton DG, Whorwell PJ. Abdominal distention in the irri- Knowledge about the epidemiology of IBS serves several table bowel syndrome: The patient's perspective. Eur J Gas-troenterol Hepatol 1992;101:927-34.
purposes. Understanding the natural history of IBS facili- 2. Maxton DG, Morris JA, Whorwell PJ. Ranking of symptoms tates patient education. Data on the use of diagnostic tests, in the irritable bowel syndrome. BMJ 1989;299:1138.
surgeries, and medications in IBS patients may educate 3. Lembo T, Naliboff B, Munakata J, et al. Symptoms and physicians about the management of IBS. Finally, simply visceral perception in patients with pain-predominant IBS.
confirming that IBS is very common may justify renewed Am J Gastreonterol 1999;94:1320 - 6.
4. Manning AP, Thompson WG, Heaton KW, et al. Towards research about this disorder. In this portion of the mono- positive diagnosis of the irritable bowel. BMJ 1978;2:653- 4.
graph, the objectives were to systematically review the IBS 5. Kruis W, Thieme CH, Weinzierl M, et al. A diagnostic score epidemiology literature about 1) the prevalence of IBS and for the irritable bowel syndrome: Its value in the exclusion of the prevalence of IBS subtypes in North America; 2) the age organic disease. Gastroenterology 1984;87:1-7.
of onset and gender distribution of IBS in North America; 6. Thompson WG, Creed FH, Drossman DA, et al. Functional bowel disorders and functional abdominal pain. Gastroenterol and 3) the natural history of IBS in North America.
Nine population-based North American studies (1-9) ACG Functional GI Disorders Task Force
Table 2.4.1. Population-Based IBS Prevalence Studies in North America
* Manning 2 reflects that patient only needed to meet two Manning criteria to be diagnosed with IBS.
Data from Saito YA, Schoenfeld P, Locke GR. The epidemiology of irritable bowel syndrome in North America: A systematic review. Am J Gastroenterol 2002;97:1910 -5.
quantified the prevalence of IBS, the gender distribution of IBS at the beginning of the study did not meet diagnostic IBS, and prevalence of IBS subtypes. Literature search criteria for IBS after 1 year. Data from referral populations techniques, study selection criteria, and data analysis are suggest that other causes of IBS symptoms are rarely iden- outlined in Section 2.1. In these studies, the diagnosis of IBS tified during long-term follow-up (11, 12) and that patients was made using symptom-based criteria (either Manning with active IBS symptoms experience frequent flares, char- criteria, ROME criteria, or a modification of ROME crite- acterized by several days with more severe symptoms fol- ria). The literature search did not reveal any North American lowed by several days with minimal symptoms (12, 13).
population-based studies about the natural history of IBS.
Data from Europe (12, 14 -16) demonstrate that IBS patients Also, no studies specified the age of onset of IBS symptoms.
are two times more likely to undergo abdominal surgery The prevalence of IBS varied between 3% and 20% than healthy controls. Future studies should report on the across different studies (1- 4, 9), although most estimates disease activity (e.g., frequency, duration, and intensity of were concentrated between 10% and 15% (Table 2.4.1). The symptoms) of IBS and current management of IBS, includ- differences in the reported prevalence of IBS probably re- ing use of diagnostic tests, surgery, and medication. As flect different definitions of IBS (e.g., Manning criteria vs noted in previous systematic reviews (12), ideal natural ROME criteria) and differences in study design rather than history studies would 1) use a population-based sample of true differences in the prevalence of IBS. Three studies (1, IBS patients followed from the time of diagnosis; 2) use an 2, 9) estimated a 2:1 female predominance of IBS, and two appropriate and objective standard for the diagnosis of IBS population-based studies limited to Olmsted County, MN (e.g., ROME II criteria); 3) use repeated surveys of the (3, 4) estimated a 1:1 distribution. These results are in cohort over time; and, 4) provide sufficiently long and contrast to studies of referral populations, which have usu- complete follow-up of the cohort of IBS patients.
ally demonstrated a 3:1 or 4:1 female predominance of IBS Overall, the quality and quantity of studies about IBS (10). Patients younger than 45 years of age were more likely epidemiology are limited. IBS is a common disorder in to be diagnosed with IBS than were those older than 45 North America, and equivalent numbers of IBS patients years (13.5% vs 9.4%) (2), although one study from Olm- suffer from constipation, diarrhea, and alternating between sted County found that the prevalence of IBS rose from 8% constipation and diarrhea. It is prevalent in young and in the 65-74-year-old age group to 12% in the group older elderly patients and in men and women, although younger than 85 years (5). Two population-based studies (6, 9) patients and women are more likely to be diagnosed with assessed the prevalence of IBS subgroups: constipation- IBS in North America. Data from population-based studies predominant IBS ϭ 5.2-5.4%; diarrhea-predominant IBS ϭ about the natural history of IBS in North America is non- 5.0 -5.5%; IBS alternating between diarrhea and constipa- existent. Limited data from Europe confirm that IBS patients tion ϭ 5.2%. A study about constipation, the Epidemiology are unlikely to be diagnosed with other significant medical of Constipation study (EPOC) (7), estimated the prevalence disorders over long-term follow-up. of constipation-predominant IBS at 2.1% and the prevalenceof IBS with rectal outlet symptoms at 3.5%.
No population-based study in North America has esti- REFERENCES: SECTION 2.4
mated the incidence of IBS or described the natural historyof IBS. One study of Olmsted County, MN residents (8) 1. Hahn BA, Saunders WB, Maier WC. Differences between found that 38% of patients who met Manning criteria for individuals with self-reported irritable bowel syndrome Management of IBS
(IBS) and IBS-like symptoms. Dig Dis Sci 1997;42:2585- with alarm symptoms or signs. Alarm symptoms or signs may include, but are not limited to, hematochezia, weight 2. Drossman DA, Zhiming L, Andruzzi E, et al. US householder loss greater than 10 pounds, family history of colon cancer, survey of functional gastrointestinal disorders. Dig Dis Sci1993;38:1569 - 80.
recurring fever, anemia, and chronic severe diarrhea 3. Talley NJ, Zinsmeister AR, Van Dyke C, et al. Epidemiology (Grade C recommendation). Routine use of colon cancer of colonic symptoms and the irritable bowel syndrome. Gas- screening tools is recommended for all patients Ն50 years 4. Saito YA, Locke GR, Talley NJ, et al. A comparison of the Rome and Manning criteria for case identification in epidemi- Multiple diagnostic tests have been recommended as ological investigations of irritable bowel syndrome. Am J screening tests for patients with IBS symptoms (1-5). These diagnostic tests, which include complete blood cell count 5. Talley NJ, O'Keefe EA, Zinsmeister AR. Prevalence of gas- (CBC), erythrocyte sedimentation rate (ESR), serum chem- trointestinal symptoms in the elderly: A population-based istries, thyroid function tests, stool culture and examination study. Gastroenterology 1992;102:895-901.
6. Talley NJ, Zinsmeister AR, Melton LJ. Irritable bowel syn- for ova and parasites (stool O & P), fecal occult blood test drome in a community: Symptom subgroups, risk factors, and (FOBT), colonic visualization with flexible sigmoidoscopy healthcare utilization. Am J Epidemiol 1995;142:76 - 83.
(FS), barium enema (BE), or colonoscopy, and hydrogen 7. Stewart WF, Liberman JN, Sandler RS, et al. Epidemiology of breath tests (1-5), are intended to rule out organic diseases, constipation (EPOC) study in the United States: Relation of including hyper/hypothyroidism, inflammatory bowel dis- clinical subtypes to sociodemographic features. Am J Gastro-enterol 1999;94:3530 - 40.
ease, colorectal cancer, infectious diarrhea, and lactose mal- 8. Talley NJ, Weaver AL, Zinmeister AR, et al. Onset and absorption. When deciding if a diagnostic test is needed to disappearance of gastrointestinal symptoms and functional rule out an organic disease, clinicians should consider the gastrointestinal disorders. Am J Epidemiol 1992;136:165- pretest probability or prevalence of the organic disease in 9. Thompson WG, Irvine EJ, Pare P, et al. Functional gastroin- patients with specific symptoms (6). If the pretest probabil- testinal disorders in Canada: First population based survey ity or prevalence is sufficiently high to justify performance using ROME II criteria with suggestions for improving the of a diagnostic test, then the clinician should also consider questionnaire. Dig Dis Sci 2002;47:225-35.
the accuracy (e.g., sensitivity, specificity) of the diagnostic 10. Owens DM, Nelson DK, Talley NJ. The irritable bowel test before ordering it. (Note: the following analysis does syndrome: Long-term prognosis and the patient-physician in-teraction. Ann Intern Med 1995;122:107-12.
not apply to IBS patients with alarm symptoms or signs. The 11. Harvey RF, Mavad EC, Brown AM. Prognosis in the irritable presence of alarm symptoms or signs suggests a higher bowel syndrome: A 5-year prospective study. Lancet 1987;I: pretest probability or prevalence of organic disease and may justify the performance of diagnostic tests. Alarm symptoms 12. Saito YA, Schoenfeld P, Locke GR. The epidemiology of irritable bowel syndrome in North America: A systematic or signs include, but are not limited to, hematochezia, ane- review. Am J Gastroenterol 2002;97:1910 -5.
mia, persistent fevers, weight loss Ͼ10 pounds, chronic 13. Hahn B, Watson M, Yan S, et al. Irritable bowel syndrome severe diarrhea, and family history of colon cancer.) symptom patterns: Frequency, duration, and severity. Dig Dis Six studies (7-12) addressed the pretest probability or prevalence of organic disease in patients with IBS symp- 14. Kennedy TM, James RH. Epidemiology of cholecystectomy and irritable bowel syndrome in a UK population. Br J Surg toms (Table 2.5.1). Literature search techniques, study se- lection criteria, and data analysis are outlined in Section 2.1.
15. Harvey RF, Mavad EC, Brown AM. Prognosis in the irritable In these six studies (7-12), the diagnosis of IBS was made bowel syndrome: A 5-year prospective study. Lancet 1987;1: using symptom-based criteria (either Manning criteria, 16. Kay L, Jorgensen T, Jensen KH. The epidemiology of irritable ROME criteria, or a modification of ROME criteria). Qual- bowel syndrome in a random population: Prevalence, inci- ity scores for these studies ranged from 5 to 6 on a 0 - 8 point dence, and natural history and risk factors. J Intern Med scale, suggesting intermediate-high quality design of a di- agnostic test study. The symptom-based diagnosis of IBSwas made prior to the performance of diagnostic tests in allstudies. Several caveats about these studies should be con- 2.5 DIAGNOSTIC APPROACH TO THE PATIENT WITH IBS
sidered. First, most studies (8 -10, 12) examined relatively SYMPTOMS
small populations (100 -200) of IBS patients. Therefore, the Among IBS patients without alarm symptoms, the routine ability to generalize these results is limited. Second, several use of flexible sigmoidoscopy, barium enema, colonoscopy, studies (7-9) examined referral populations of IBS patients fecal occult blood tests, stool for ova and parasites, stool for who had already undergone colonoscopy. It is possible that culture, or thyroid function tests cannot be recommended patients with organic diseases were diagnosed at the primary (Grade C recommendation). Among IBS patients with diar- care level and that patients seen in referral settings do not rhea, testing for celiac sprue may be considered (Grade C provide an accurate estimate of the prevalence of organic recommendation). Endoscopic studies, stool studies, and diseases among patients with IBS symptoms. Finally, no other radiologic tests may be indicated among IBS patients studies properly used a gold standard test to estimate the ACG Functional GI Disorders Task Force
2.5.1. Trial
Table 2.5.2. Prevalence of Organic Disease in Patients Meeting
Data from Cash BD, Schoenfeld P, Chey WD. The utility of diagnostic tests in IBS patients: A systematic review. Am J Gastroenterol (in press).
growth syndrome) and did not use an appropriate control group to determine if antibiotics effectively decreased the Despite the absence of data to recommend diagnostic testing in IBS patients, the value of diagnostic testing ispartly derived from the reassurance value of normal diag- accuracy of diagnostic tests for organic GI diseases among nostic tests. In other words, both physicians and patients may be reassured after a negative evaluation for organic FS, colonoscopy, and BE identified an organic GI disease disease. The value of this "reassurance" is unclear and responsible for symptoms in 0 -1.3% of patients with IBS symptoms (7-10). Neither abdominal ultrasound (10) nor Overall, available data do not support the performance of rectal biopsy (9) identified organic disease that was respon- diagnostic tests among patients with IBS. IBS patients do sible for symptoms. The use of CBC, serum chemistries, and not appear to have an increased likelihood of most organic FOBT identified an organic disease responsible for symp- diseases compared with control populations without IBS toms in 0 -1.3% of patients (8, 11). Positive tests for stool O symptoms. Patients with alarm symptoms (e.g., hematoche- & P were found in 0 -1.6% of patients with IBS symptoms, zia, weight loss, etc.) may have a higher prevalence of although it is unclear if treatment for these infections re- organic disease and routine diagnostic testing in these pa- solved the symptoms of IBS (7, 8). Abnormal TSH was tients may be appropriate. Also, celiac sprue may be more identified in 0.6 - 6% of patients with IBS symptoms, and prevalent among patients with IBS symptoms, and routine abnormal breath tests for lactose intolerance were found in evaluation of celiac sprue may be considered. The quality 22-26% of patients with IBS symptoms (7, 8). It is unclear, and quantity of studies about the diagnostic approach to however, if these disorders accounted for IBS symptoms, patients with IBS symptoms is limited, and definitive rec- and the prevalence of abnormal TSH and abnormal breath ommendations await further research. tests in IBS patients is similar to the prevalence of theseabnormalities in control populations (13, 14). Further re-view (Table 2.5.2) indicates that the pretest probability or REFERENCES: SECTION 2.5
prevalence of inflammatory bowel disease and colorectal 1. Drossman DA. An integrated approach to the irritable bowel cancer is not elevated among patients with IBS symptoms syndrome. Aliment Pharmacol Ther 1999;13(suppl 2):3-14.
compared with that of control populations (15).
2. Camilleri M, Prather CM. The irritable bowel syndrome: A single study (11) found that approximately 5% of Mechanisms and practical approach to management. Ann In-tern Med 1992;116:1001- 8.
patients with IBS symptoms had celiac sprue, while the 3. American Gastroenterological Association Medical Position prevalence of celiac sprue in a control population was less Statement: Irritable bowel syndrome. Gastroenterology 1997; than 1%. The prevalence of celiac sprue varies based on heritage and across geographic region. Therefore, wide- 4. Schmulson MW, Chang L. Diagnostic approach to the patient spread screening for celiac sprue with endomysial antibod- with irritable bowel syndrome. Am J Med 1999;107:20S- 6S.
5. Camilleri M. Management of the irritable bowel syndrome.
ies is not routinely recommended for screening of patients Gastroenterology 2001;120:652- 68.
with IBS symptoms until additional data are available to 6. Schoenfeld P, Guyatt G, Hamilton F, et al. An evidence-based support this recommendation. A single study (12) of patients approach to gastroenterology diagnosis. Gastroenterology with IBS symptoms referred for breath tests to rule out bacterial overgrowth syndrome found that 78% of these 7. Hamm LR, Sorrells SC, Harding JP, et al. Additional inves- tigations fail to alter the diagnosis of irritable bowel syndrome patients had bacterial overgrowth. Although these data are in subjects fulfilling the ROME criteria. Am J Gastroenterol provocative, this study examined a select population (i.e., patients referred for breath tests to rule out bacterial over- 8. Tolliver BA, Herrera JL, DiPalma JA. Evaluation of patients Management of IBS
Table 2.6.1. Trial Characteristics: Antispasmodic Agents
who meet clinical criteria for irritable bowel syndrome. Am J or sublingual q.i.d. The systematic review was limited to antispasmodic agents available in the United States.
9. MacIntosh DG, Thompson WG, Patel DG, et al. Is rectal Eighteen RCTs evaluated the effectiveness of antispas- biopsy necessary in irritable bowel syndrome? Am J Gastro-enterol 1992;87:1407-9.
modic agents available for the treatment of IBS (1-18), but 10. Francis CY, Duffy JN, Whorwell PJ, et al. Does routine only three RCTs (1, 4, 12) evaluated the effectiveness of ultrasound enhance diagnostic accuracy in irritable bowel syn- dicyclomine and hyoscyamine (Table 2.6.1). Trials of dicy- drome? Am J Gastroenterol 1996;91:1348 -50.
clomine and hyoscyamine were low-intermediate quality 11. Sanders DS, Carter MJ, Hurlstone DP, et al. Association of (quality scores of 5-7 of possible 14) based on ROME adult coeliac disease with irritable bowel syndrome: A case-control study in patients fulfilling the ROME II criteria re- committee criteria for the design of treatment trials for ferred to secondary care. Lancet 2001;358:1504 - 8.
functional GI disorders. None of these trials used ROME 12. Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal committee criteria (or Manning criteria) to identify IBS bacterial overgrowth reduces symptoms of irritable bowel patients, and none of the trials followed patients after dis- syndrome. Am J Gastroenterol 2000;95:3503- 6.
continuation of therapy. Only one trial (12) was of at least 13. Helfand M, Redfern CC. Screening for thyroid disease: An update. Ann Intern Med 1998;129:144 -158.
8 weeks duration. Sample sizes were not calculated a priori 14. Scrimshaw NS, Murray EB. The acceptability of milk and in any of these trials, and all of these trials enrolled fewer milk products in populations with a high prevalence of lactose intolerance. Am J Clin Nutr 1988;48(4 suppl):1079 -159.
Only one (4) of the three studies (1, 4, 12) demonstrated 15. Cash BD, Schoenfeld P, Chey WD. The utility of diagnostic tests in IBS patients: A systematic review. Am J Gastroenterol a statistically significant improvement in global IBS symp- toms with antispasmodic agents compared with placebo.
This trial had poor study design (quality score of 5) and usedthe maximum dose of dicyclomine (40 mg q.i.d.), which 2.6 EFFECTIVENESS OF ANTISPASMODIC AGENTS IN
may have led to significantly more adverse events among THE MANAGEMENT OF IRRITABLE BOWEL SYNDROME
dicyclomine-treated patients (69% vs 16% of placebo- There are insufficient data to make a recommendation about treated patients). Also, 15% of dicyclomine-treated patients the effectiveness of the antispasmodic agents available in withdrew from the study, while no placebo-treated patients the United States (Grade B recommendation). withdrew. In the other two studies (1, 12), no significant While the exact pathophysiology of IBS remains un- difference in outcomes was noted between patients treated known, investigators have postulated that disturbances in with antispasmodic agents and placebo.
intestinal motility result in symptoms of abdominal pain, At higher doses, antispasmodic agents may exhibit atro- bloating, and disturbed defecation. Antispasmodic agents pine-like side effects related to their antimuscarinic proper- include those that directly affect intestinal smooth muscle ties. This atropine-like effect can lead to intolerance of the relaxation (e.g., mebeverine, pinaverine) and those that act agent because of visual disturbances, urinary retention, con- in similar fashion via anticholinergic or antimuscarinic stipation, and dry mouth. Data on adverse events demon- properties (e.g., dicyclomine, hyoscyamine) (1-18). The strate that increasing doses of anticholinergic compounds mechanism of action of antispasmodics is likely through a appear to produce more frequent adverse events (4, 20).
decrease in spontaneous activity of intestinal smooth mus- Specific data on the effect of antispasmodic agents on the cle. Outside the United States, several antispasmodic agents frequency of bowel movements in constipated patients are that directly affect intestinal smooth muscle relaxation (e.g., lacking. RCTs (20, 21) suggest that constipation is a poten- mebeverine, pinaverine) are available (19). Currently, the tial complication of antispasmodic agents, which is most only antispasmodics available in the United States are di- likely due to their muscle relaxant properties. Therefore, cyclomine and hyoscyamine. The recommended dose for Task Force members felt that antispasmodics should be used dicyclomine is 20 - 40 mg by mouth q.i.d. (20), although with caution among patients with constipation.
dicyclomine is commonly used at lower doses. The recom- This review was limited to studies published in the En- mended dose for hyoscyamine is 0.125- 0.25 mg by mouth glish language. A previous meta-analysis (19) noted that one ACG Functional GI Disorders Task Force
large trial of hyoscyamine had been published in German blocker: A randomized double-blind placebo-controlled trial.
(22). Although this large (n ϭ 360), non-English language Acta Gastroent Latinoamer 1995;25:137- 44.
15. Moshal MG, Herron M. A clinical trial of trimebutine (Me- trial did not meet criteria for inclusion in this review, this butin) in spastic colon. J Int Med Res 1979;7:231- 4.
trial found no difference between hyoscyamine and placebo 16. Battaglia G, Morselli-Labate AM, Camarri E, et al. Otilonium for relief of abdominal pain or distention and no significant bromide in irritable bowel syndrome: A double blind, placebo- difference for global IBS symptom improvement. Previous controlled, 1-week study. Aliment Pharmacol Ther 1998;12: meta-analyses (19, 23) have produced conflicting recom- 17. CentonzeV, Imbimbo BP, Campanozzi F, et al. Oral ci- mendations about the effectiveness of direct smooth muscle metropium bromide, a new antimuscarinic drug, for long-term relaxants available outside the United States. A complete treatment of irritable bowel syndrome. Am J Gastroenterol discussion of these agents (mebeverine, pinaverine, ci- metropium, and otilonium) is beyond the scope of this 18. Ghidini O, Saponati G, Intrieri L. Single drug treatment for monograph, but it should be noted that most RCTs of these irritable colon: Rociverine versus trimebutine maleate. CurrTher Res 1986;39:541- 8.
agents demonstrate poor methodologic quality, limiting the 19. Poynard T, Regimbeau, Benhamou Y. Meta-analysis of strength of recommendations based on these data.
smooth muscle relaxants in the treatment of irritable bowel Overall, trials of therapy with antispasmodic agents were syndrome. Aliment Pharmacol Ther 2001;15:355- 61.
generally of short duration, studied small numbers of pa- 20. Package Insert. Dicyclomine.
21. Poynard T, Naveau S, Mory B, et al. Meta-analysis of smooth tients, were of suboptimal quality, and demonstrated incon- muscle relaxants in the treatment of IBS. Aliment Pharmacol sistent effectiveness. Adverse events with these compounds limit their dose range. Antispasmodics should be used with 22. Schafer VE, Ewe K. Behandlung des colon irritabile. Fortschr caution in patients with constipation. 23. Jailwala J, Imperiale T, Kroenke K. Pharmacologic manage- ment of IBS: A systematic review of randomized controlledtrials. Ann Intern Med 2000;133:136 - 47.
1. Wheatley D. Irritable colon syndrome treated with an anti- spasmodic drug. The Practitioner 1976;217:276 - 80.
2. Greenbaum DS, Ferguson RK, Kater LA, et al. A controlled MANAGEMENT OF IRRITABLE BOWEL SYNDROME
therapeutic study of the irritable bowel syndrome. N EnglJ Med 1973;288:13- 6.
Bulking agents commonly available in the United States are 3. Tasman-Jones C. Mebeverine in patients with the irritable not more effective than placebo at relieving global IBS colon syndrome: Double blind study. N Z Med J 1973;77: symptoms (Grade B recommendation). Randomized con- trolled trials about treatment of IBS with laxatives have not 4. Page J, Dirnberger GM. Treatment of the irritable bowel syndrome with bentyl (dicyclomine hydrochloride). J ClinGastroenterol 1981;3:153-56.
IBS patients with constipation exhibit delayed intestinal 5. Fielding JF. Double blind trial of trimebutine in the irritable transit. Therefore, bulking agents that accelerate intestinal bowel syndrome. Irish Med J 1980;73:377-9.
transit may be beneficial for these patients. Types of bulking 6. Luttecke K. A trial of trimebutine in spastic colon. J Int Med agents studied include wheat bran, corn fiber, calcium poly- carbophil, ispaghula husk, and psyllium. Psyllium husk is 7. Piai G, Mazzacca G. Pirifinium bromide in the treatment of the irritable colon syndrome. Gastroenterology 1979;77:500 -2.
the outer coat of the psyllium seed (known in India as 8. Dobrilla G, Imbimbo BP, Piazzi L, et al. Longterm treatment ispaghula seed) from the plant Plantago ovata.
of irritable bowel syndrome with cimetropium bromide: A Thirteen RCTs evaluated the effectiveness of bulking double blind placebo controlled trial. Gut 1990;31:355- 8.
agents in the treatment of IBS (1-13) (Table 2.7.1). These 9. Kruis W, Weinzierl M, Schussler P, et al. Comparison of the trials were low-intermediate quality (quality scores 5-9 of therapeutic effect of wheat bran, mebeverine and placebo in possible 14) based on ROME committee criteria for the patients with the irritable bowel syndrome. Digestion 1986;34:196 -201.
design of treatment trials for functional GI disorders. None 10. Piai G, Visconti M, Imbimbo BP, et al. Long-term treatment of the trials used ROME committee criteria to identify IBS of irritable bowel syndrome with cimetropium bromide, a new patients as all of these trials were conducted before the first antimuscarinic compound. Curr Ther Res 1987;41:967-77.
ROME committee conference was held. None of the trials 11. Luttecke K. A three-part controlled trial of trimebutine in the followed patients after the cessation of study drug. Few treatment of irritable colon syndrome. Curr Med Res Opin1980;6:437- 43.
trials were of at least 8 weeks in duration, used a parallel 12. Ritchie JA, Truelove SC. Treatment of irritable bowel syn- study design, or reported the patient's assessment of global drome with lorazepam, hyoscine butylbromide, and ispaghula IBS symptom improvement (Table 2.7.1). None pre- sented sample size calculations, and most trials had small 13. Baldi, Longanesi A, Blasi A, et al. Clinical and functional sample sizes (Ͻ30 patients), which could have led to evaluation of the efficacy of otilonium bromide: A multicenterstudy in Italy. Ital J Gastroenterol 1991;23(suppl 1):60 -3.
14. Awad D, Dibildox M, Ortiz F. Irritable bowel syndrome The single study of corn fiber (quality score ϭ 8) found treatment using pinaverium bromide as a calcium channel that pain severity, stool frequency, or stool consistency Management of IBS
Table 2.7.1. Trial Characteristics: Bulking Agents
improved with both corn fiber and placebo, but there was no lism of fiber by intestinal bacteria (14, 15), and IBS significant difference between the two. Pain frequency and experts note that increases in fiber intake may increase duration were not significantly improved with either agent bloating and abdominal discomfort in IBS patients (16, (1). The single study of calcium polycarbophil (quality score ϭ 7) found no significant difference in overall Overall, none of the trials of bulking agents demonstrated preference but did report preference of calcium polycar- high-quality methodology. Sample sizes in most of these bophil in IBS patients with constipation or alternating trials were particularly small, which could have produced constipation and diarrhea. There was no significant dif- Type II errors. Available evidence clearly indicates that ference in abdominal pain between active agent and pla- corn and wheat fiber are ineffective for global IBS symptom cebo (7). Of the five trials (2- 6) of wheat bran (quality improvement. Neither calcium polycarbophil nor psyllium scores 5- 6), only one study (3) without a placebo control was shown to be more effective than placebo for global IBS found improvement in pain frequency, severity, and stool symptom improvement. Although the majority of ispaghula frequency with wheat bran. The other four were striking husk studies demonstrated global improvement, this may for the similarity in effectiveness for wheat bran and have resulted from increasing frequency of bowel move- placebo. The single study of psyllium (quality score ϭ 9) ments in IBS patients with constipation. Although adverse found that IBS symptoms were not improved with psyl- event data from RCTs of fiber products are unavailable, lium compared to placebo (8). Global IBS symptoms were anecdotal experience and laboratory data suggest that fiber improved in patients taking ispaghula husk in 4 of 5 studies products increase intestinal gas, bloating, and abdominal (9 -13) (quality scores 6 -9). In these studies, subgroup discomfort in IBS patients. Therefore, fiber is appropriate analysis of specific symptoms noted that abdominal pain for treatment of constipation but may not be recommended was not improved with ispaghula husk, but ease of bowel movements was improved. The definition of global IBSsymptom improvement was poorly defined in many of thesestudies, making it difficult to determine if global IBS symp- REFERENCES: SECTION 2.7
tom improvement simply reflected treatment of constipa- 1. Cook IJ, Irvine EJ, Campbell D, et al. Effect of dietary fiber on tion. Patients in the negative study were all taking 30 g/day symptoms and rectosigmoid motility in patients with irritable of bran in addition to ispaghula husk or placebo.
bowel syndrome. Gastroenterology 1990;98:66 -72.
Data on adverse events associated with bulking agents 2. Soltoft J, Gudmand-Hoyer E, Krag B, et al. A double-blind trial of the effect of wheat bran on symptoms of irritable were not reported in these trials, precluding evidence- bowel syndrome. Lancet 1976;1:270 -2.
based comments on possible adverse events associated 3. Manning AP, Heaton KW, Harvey RF, et al. Wheat fibre and with bulking agents. Bowel gas is produced by metabo- irritable bowel syndrome. Lancet 1977;2:417- 8.
ACG Functional GI Disorders Task Force
Table 2.8.1. Trial Characteristics: Antidiarrheal Agents
4. Arffmann S, Andersen JR, Hegnhoj J, et. al. The effect of eramide is the only antidiarrheal agent appropriately eval- coarse wheat bran in the irritable bowel syndrome. Scand J uated for treatment of IBS, precluding evidence-based com- ments about the effectiveness of other antidiarrheal agents.
5. Lucey MR, Clark ML, Lowndes JO, et al. Is bran efficacious in irritable bowel syndrome? A double-blind, placebo con- In these trials, loperamide has been used in dosages of 2-12 trolled crossover study. Gut 1987;28:221-5.
6. Snook J, Shepherd HA. Bran supplementation in the treatment Three RCTs evaluated the effectiveness of loperamide in of irritable bowel syndrome. Aliment Pharmacol Ther 1994; the treatment of IBS (3-5) (Table 2.8.1). These trials were low-intermediate quality (quality scores ranging from 5 to 7 7. Toskes PP, Connery KL, Ritchey TW. Calcium polycarbophil compared with placebo in irritable bowel syndrome. Aliment of possible 14). None of the trials used ROME committee criteria to identify IBS patients as all of these trials were 8. Longstreth GF, Fox DD, Youkeles L, et al. Psyllium therapy conducted before the first ROME committee conferences for irritable bowel syndrome. Ann Intern Med 1981;95:53- 6.
were held. None of the trials was longer than 5 weeks in 9. Ritchie JA, Truelove SC. Treatment of irritable bowel syn- drome with lorazepam, hyoscine butylbromide, and ispaghula duration, and none presented sample size calculations. All trials had relatively small sample sizes (30 -90 patients), 10. Golechha AC, Chadda VS, Chadda S, et al. Role of ispaghula which could have led to Type II errors.
husk in the management of irritable bowel syndrome (a ran- In the first study (3), loperamide decreased stool fre- domized double-blind crossover study). J Assoc Physicians quency from 1.9/day to 1.3/day, decreased the percentage 11. Arthurs Y, Fielding JF. Double blind trial of ispaghula/polax- of unformed stools from 60% to 31%, and decreased the amer in the irritable bowel syndrome. Irish Med J 1983;76: incidence of urgency from 2.4 days/wk to 1.1 days/wk (all p Ͻ 0.05). Placebo produced no significant decrease 12. Prior A, Whorwell PJ. Double blind study of ispaghula in in these outcomes. There was no significant difference in irritable bowel syndrome. Gut 1987;28:1510 -3.
abdominal distension or abdominal pain with either lop- 13. Jalihal A, Kurian G. Ispaghula therapy in irritable bowel syndrome: improvement in overall well-being is related to eramide or placebo. There was no significant difference reduction in bowel dissatisfaction. J Gastroenterol Hepatol in global IBS symptom improvement between loperam- ide-using patients and placebo-using patients. In the sec- 14. Haderstorfer B, Psycholgin D, Whitehead WE, et al. Intestinal ond study (4), results were only reported for patient gas production from bacterial fermentation of undigested car-bohydrate in IBS. Am J Gastroenterol 1989;84:375- 8.
subgroups defined by the investigators: patients with 15. Lasser RB, Levitt MD. The role of intestinal gas in functional painless diarrhea, patients with painless constipation, pa- abdominal pain. N Engl J Med 1975;293:524 - 6.
tients with pain and alternating diarrhea and constipation, 16. Francis CY, Whorwell PJ. Bran and IBS: Time for reappraisal.
and patients without pain but with alternating diarrhea and constipation. Among patients with painless diarrhea, 17. Camilleri M. Review article: Clinical evidence to support current therapies of IBS. Aliment Pharmacol Ther 1999; loperamide-using patients were more likely than placebo- using patients to note improvement in stool frequency(100% vs 40%), stool consistency (100% vs 50%), and 2.8 EFFECTIVENESS OF THE ANTIDIARRHEAL AGENT
overall symptoms (100% vs 25%) (p Ͻ 0.01 for alloutcomes). Among patients without pain who alternated LOPERAMIDE IN THE MANAGEMENT OF IRRITABLE
between constipation and diarrhea, there was no signifi- BOWEL SYNDROME
cant difference between loperamide and placebo. Among The antidiarrheal agent loperamide is not more effective patients with painless constipation, loperamide-using pa- than placebo at relieving global IBS symptoms (Grade B tients had "worse" symptoms, but such worsening was recommendation). Randomized controlled trials about not significantly different from placebo-using patients.
treatment of IBS with other antidiarrheal agents have not Among patients with pain who alternated between con- stipation and diarrhea, loperamide-using patients im- IBS patients with diarrhea demonstrate accelerated intes- proved significantly more than placebo-using patients tinal transit (1, 2). Therefore, antidiarrheal agents that delay with regard to stool frequency (95% vs 25%) and stool intestinal transit may be beneficial for these patients. Lop- consistency (95% vs 45%) (p Ͻ 0.02 for both). In the Management of IBS
Table 2.9.1. Trial Characteristics: Antidepressant Agents
third study (5), loperamide-using patients improved sig- 2.9 EFFECTIVENESS OF ANTIDEPRESSANTS IN THE
nificantly more than placebo-using patients with regard to MANAGEMENT OF IRRITABLE BOWEL SYNDROME
stool frequency (35% vs 10%) and stool consistency(50% vs 20%) during weeks one to five (p Ͻ 0.05). There Tricyclic antidepressants (TCAs) are not more effective than was no significant difference in abdominal pain. Improve- placebo at relieving global IBS symptoms. TCAs improve ment in global IBS symptoms was not reported.
abdominal pain in IBS patients (Grade B recommendation). Only one study (1) reported data on adverse events. In Randomized controlled trials about the effectiveness of se- this trial, 29% of loperamide-treated patients reported ad- lective serotonin re-uptake inhibitors (SSRIs) in the treat- verse events vs 36% of placebo-treated patients (p Ͼ 0.05).
ment of IBS have not been published in manuscript form. No other details were provided. Because of the relative lack IBS patients exhibit visceral hypersensitivity. In other of adverse event data, no evidence-based comments about words, IBS patients sense pain or discomfort with less possible adverse events associated with loperamide can be distention of the colon than do control patients. TCAs,including doxepin, desipramine, amitriptyline, and trimipra- mine, ameliorate enhanced nociception and may treat the Overall, none of the trials of antidiarrheal agents (e.g., chronic pain of IBS patients. By decreasing the experience loperamide) demonstrated high-quality methodology. of abdominal pain, TCAs enhance the patient's sense of Trial results indicate that loperamide is an effective well-being and decrease their distress from their IBS symp- treatment for diarrhea, but loperamide is not more effec- toms. For the management of chronic pain, TCAs were tive than placebo for treatment of global IBS symptoms or prescribed in doses that were subtherapeutic for the treat- abdominal pain. Adverse event data are sparse. Given the ment of depression but were appropriate for the manage- mechanisms of action of loperamide, it should not be used in IBS patients with constipation, and it should be used Seven RCTs evaluated the effectiveness of TCAs in the with caution in IBS patients alternating between diarrhea treatment of IBS (1-7). One RCT was eliminated from analysis because the dropout rate was 45% (7). Of the sixremaining trials (Table 2.9.1), all were of low quality (qual-ity scores of 5- 6 of possible 14) based on ROME committee REFERENCES: SECTION 2.8
criteria for the design of treatment trials of functional GIdisorders. None of the studies used ROME committee cri- 1. Vassallo MJ, Camilleri M, Phillips SF, et al. Colonic tone and teria to identify IBS patients, measured compliance, or pre- motility in patients with IBS. Mayo Clin Proc 1992;67:725-31.
sented sample size calculations. Most trials had small sam- 2. Camilleri M. Review article: Clinical evidence to support cur- rent therapies of IBS. Aliment Pharmacol Ther 1999;13(suppl ple sizes (Յ31 patients) in each arm, and no trial was more than 8 weeks in duration. In addition to these limitations in 3. Cann PA, Read NW, Holdsworth CD, et al. Role of loperamide study design, primary and secondary study endpoints were and placebo in management of irritable bowel syndrome (IBS).
poorly defined. Frequently, results were not presented in a straightforward fashion. These additional flaws made inter- 4. Hovdenak N. Loperamide treatment of the irritable bowel syn- pretation of study results difficult. This is not surprising, as drome. Scand J Gastroenterol Suppl 1987;130:81- 4.
5. Efskind PS, Bernklev T, Vatn MH. A double-blind placebo- almost all of these studies were performed prior to the controlled trial with loperamide in irritable bowel syndrome.
publication of standards for the design of treatment trials for Scand J Gastroenterol 1996;31:463- 8.
ACG Functional GI Disorders Task Force
Two studies examined the effectiveness of desipramine methods and results. The second meta-analysis indicated (1, 5). In the first study (1), global improvement of IBS that TCAs improve the symptoms of functional GI disor- symptoms was not measured, although 92% (12/13) of ders, although it may not have adequately accounted for the desipramine-using patients noted improvement in interfer- limitations in design of these studies and the flaws in re- ence of IBS symptoms with daily life compared with 60% (9/15) of placebo-using patients (p Ͼ 0.05). In the second In these trials, TCAs were not used in therapeutic doses trial (5), a p value was not reported for analysis of global for treatment of depression but were used at lower doses for improvement in IBS symptoms, although 54% (15/28) of the management of chronic pain. Overall, trials of therapy desipramine-using patients had global improvement com- with TCAs were of short duration and examined small pared with 18% (5/28) of placebo-using patients and 21% numbers of patients and study designs were suboptimal. (6/28) of atropine-using patients. Abdominal pain was im- Evidence is inadequate to support the effectiveness of TCAs proved with desipramine in both studies, achieving statisti- for improvement of global IBS symptoms. There is, however, cal significance in one (5) among patients with IBS with limited evidence that TCAs may decrease abdominal pain. diarrhea only. In the single study of amitriptyline (2), "im- Adverse event data with TCAs indicate that these agents provement" in symptoms was noted more often with drug may cause constipation and should be used with caution in than placebo, but the p value was 0.08 and the supporting tables were not interpretable. There were no significantdifferences in improvement of individual symptoms be- REFERENCES: SECTION 2.9
tween amitriptyline and placebo. Two studies from one 1. Heefner JD, Wilder RM, Wilson ID. Irritable colon and de- group of investigators assessed trimipramine (3, 4). In the pression. Psychosomatics 1978;19:540 -7.
first, patients taking trimipramine had significantly greater 2. Steinhart MJ, Wong PY, Zarr ML. Therapeutic usefulness of improvement in scores for vomiting, sleeplessness, depres- amitriptyline in spastic colon syndrome. Int J Psychiatry Med sion, and mucus in stools. There was no significant differ- ence in scores for pain, belching, headache, and tiredness.
3. Myren J, Groth H, Larssen S-E, et al. The effect of trimipra- mine in patients with irritable bowel syndrome. Scand J Gas- Overall symptom improvement occurred in 25/30 (83%) patients taking drug compared with 21/31 (68%) taking 4. Myren J, Lovland B, Larssen S-E, et al. A double-blind study placebo, but no p value was reported. In the follow-up study, of the effect of trimipramine in patients with irritable bowel trimipramine was given in three different doses. Scores for syndrome. Scand J Gastroenterol 1984;19:835- 43.
abdominal pain were significantly better than placebo only 5. Greenbaum DS, Mayle JE, Vanegeren LE, et al. Effects of desipramine on irritable bowel syndrome compared with at- for the 50-mg dose. The single study of doxepin reported ropine and placebo. Dig Dis Sci 1987;32:257- 66.
significant overall clinical improvement for drug compared 6. Vij JG, Jiloha RG, Kumar N, et al. Effect of antidepressant to placebo (11/21 [55%] vs 5/23 [21%]). Abdominal pain drug (doxepin) on irritable bowel syndrome patients. Indian improved in 56% of patients taking doxepin compared with 7. Rajagopalan M, Kurian G, John J. Symptom relief with ami- triptyline in the irritable bowel syndrome. J Gastroenterol Adverse events were sporadically reported in these trials.
Constipation was significantly worse for desipramine-using 8. Creed FH, Fernandes L, Guthrie E, et al. The cost-effective- patients than for atropine-using patients in one trial (5).
ness of psychotherapy and SSRI antidepressants for severe "Tiredness" was significantly worse in trimipramine-using irritable bowel syndrome. Gastroenterology 2001;120:A115.
patients compared with control patients during the first two 9. Tanum L, Malt UF. A new pharmacologic treatment of func- tional GI disorders: A double-blind placebo-controlled study with mianserin. Scand J Gastroenterol 1996;31:318 -25.
This review was limited to trials published in full manu- 10. Clouse RE, Prakash C, Anderson RJ, et al. Antidepressants for script form and to medications available in the United functional gastrointestinal symptoms and syndromes: A meta- States. One abstract (8) evaluated the effectiveness of par- analysis. Gastroenterology 2001;120:A642.
oxetine, an SSRI, for the treatment of IBS and reportedly 11. Jackson JL, O'Malley PG, Tomkins G, et al. Treatment of functional gastrointestinal disorders with antidepressant demonstrated improvement in symptoms; however, the medications: A meta-analysis. Am J Med 2000;108:65-72.
methodology and full results of this trial are not available,precluding evidence-based recommendations about the ef- 2.10 EFFECTIVENESS OF THE 5HT (SEROTONIN)
fectiveness of SSRIs. Mianserin, which blocks noradrena- RECEPTOR AGONIST TEGASEROD IN THE MANAGEMENT
line re-uptake, is another antidepressant that has been eval- OF IRRITABLE BOWEL SYNDROME
uated for treatment of functional GI disorders (9), but it isnot available in the United States. Meta-analyses did not The 5HT receptor agonist tegaserod is more effective than serve as the basis for evidence-based recommendations, placebo at relieving global IBS symptom in female IBS although two meta-analyses (10, 11) have evaluated the patients with constipation (Grade A recommendation). effectiveness of TCAs to improve symptoms in functional Currently, the only available 5HT (serotonin) receptor GI disorders. One meta-analysis (10) has only been pub- agonist is tegaserod. This agent stimulates the peristaltic lished in abstract form, precluding a full evaluation of its reflex, increases intestinal and colonic transit, reduces the Management of IBS
Table 2.10.1. Trial Characteristics: 5-HT Receptor Agonist Tegaserod
Muller-Lissner Tegaserod vs placebo 6 mg b.i.d. Parallel Tegaserod vs placebo 6 mg b.i.d. Parallel Tegaserod vs placebo 6 mg b.i.d. Parallel Tegaserod vs placebo 6 mg b.i.d. Parallel * Study 307 (9) did not treat patients with the approved dosage (6 mg b.i.d.) throughout the trial. Therefore, it is not included in this analysis.
firing rate of rectal afferent nerves, and reduces visceral All four trials of tegaserod 6 mg b.i.d. (1, 4 - 8) demon- sensitivity (1-3). Tegaserod is the only FDA-approved strated statistically significant improvement in global IBS agent for the treatment of IBS patients with constipation.
symptoms for tegaserod-using patients compared with pla- The recommended dosage is 6 mg b.i.d., and the following cebo-using patients. Based on the prescribed endpoint, ap- analysis will be limited to results achieved with this dose.
proximately 5-19% more tegaserod-using patients had sig- Four RCTs have evaluated the effectiveness of tegaserod nificant improvement in global IBS symptoms compared 6 mg b.i.d. in the management of IBS (1, 4 - 8) (Table with placebo-using patients (Figure 2.10.1). In subgroup 2.10.1). All of these trials were high-quality trials (quality analysis, tegaserod-using patients experienced less bloating, scores of 12-13 of possible 14) based on ROME committee less abdominal discomfort, and improved satisfaction with criteria for the design of treatment trials for functional their bowel habits compared with placebo-using patients (1, gastrointestinal disorders. Trial duration was 12 weeks in all 4, 6). The magnitude of these improvements varied across trials. The patient population in these trials was Ͼ80% trials as a result of the use of different scales to measure women and Ͼ80% Caucasian and had a mean age of ap- individual symptoms in different trials.
proximately 45 years and mean duration of IBS symptoms Diarrhea is the most common adverse event associated of more than 10 years (6). Patients met ROME I criteria for with tegaserod use and was reported as an adverse event in the diagnosis of IBS. Most patients met criteria for IBS with 9 -10% of tegaserod-using patients vs 4 -5% of placebo- constipation, although a minority of patients had IBS with using patients (1, 4 -7, 9). Approximately 1-2% of tegas- bowel habits alternating between constipation and diarrhea.
erod-using patients discontinued medication because of this A comprehensive evaluation of the tegaserod data reveals adverse event. Among tegaserod-using IBS patients and some variability in study methodology. The definition of placebo-using IBS patients, the rates of abdominal surgery global IBS symptom improvement was changed after data and ovarian cyst formation were similar.
analysis of the first clinical trial (5) because this definition When prescribing tegaserod, physicians should remem- was not sensitive enough to detect changes in global IBS ber that the FDA-approved indication for tegaserod is symptoms (1). Therefore, the first clinical trial (5) used a "for the short-term treatment of women with IBS whose retrospectively defined study endpoint. Global IBS symp- primary bowel symptom is constipation." Secondary tom improvement was determined based on IBS symptoms analysis demonstrated significant increase in frequency of during the last 4 weeks of 12-week trials, although numer-ically larger differences between tegaserod and placebowere seen with 12-week longitudinal analyses or analyses ofIBS symptoms during the first 4 weeks. In the most recentstudy (8), improvement in global IBS symptoms was mea-sured during the first 4 weeks of the trial with a binaryendpoint (i.e., IBS symptoms improved vs IBS symptomsnot improved). This trial produced the largest numericalbenefit observed with tegaserod. Thus, the definition ofglobal IBS symptom improvement appears to influence themagnitude of benefit observed with tegaserod. Finally, oneRCT (9) is not presented in this analysis as this was adose-ranging trial and no patients took the approved dosage Figure 2.10.1. Percentage of patients with improvement in global
of tegaserod (6 mg b.i.d.) throughout the trial.
ACG Functional GI Disorders Task Force
bowel movements for tegaserod-using male patients com- 2.11. EFFECTIVENESS OF THE 5HT (SEROTONIN)
pared with placebo-using male patients and a nonstatis- RECEPTOR ANTAGONIST ALOSETRON IN THE
tically significant trend for improvement in global IBS MANAGEMENT OF IRRITABLE BOWEL SYNDROME
symptoms. Because of the relatively small sample of menin these trials, this finding could represent a Type II error.
The 5HT receptor antagonist alosetron is more effective Randomized controlled trial data demonstrate effective- than placebo at relieving global IBS symptoms in female IBSpatients with diarrhea (Grade A recommendation). ness of tegaserod up to 12 weeks. Given the episodic and Currently, the only available 5HT (serotonin) receptor fluctuating course of IBS, intermittent therapy appears antagonist is alosetron. This agent slows colonic transit and appropriate. The effectiveness of long-term maintenance decreases discomfort during distension of the colon (1, 2).
therapy requires further study. Finally, some patients Alosetron is the only FDA-approved agent for the treatment with IBS alternating between diarrhea and constipation of IBS patients with diarrhea. In November 2000, distribu- were included in these trials, but the effectiveness of tion of alosetron was halted because of concerns about tegaserod in this subgroup of IBS patients has not been ischemic colitis and serious complications of constipation.
In June 2002, the FDA approved restricted marketing of Overall, the trials of tegaserod consistently demonstrate alosetron for "the treatment of women with severe, diarrhea- high-quality study methodology and effectiveness for the predominant IBS who have failed to respond to conven- treatment of IBS with constipation. The ability to generalize tional IBS therapy." The recommended dosage is 1 mg trial results to male IBS patients and IBS "alternators" is b.i.d., and the following analysis will be limited to results not adequately defined. As diarrhea is the most common adverse event associated with tegaserod use, it may be Four RCTs have evaluated the effectiveness of alosetron prudent to advise patients to temporarily discontinue tega- 1 mg b.i.d. in the management of IBS (3- 6) (Table 2.11.1).
serod if significant diarrhea occurs. All of these trials were high-quality trials (quality scores of12 of possible 14) based on ROME committee criteria forthe design of treatment trials for functional GI disorders.
Patients met ROME I or ROME II criteria for the diagnosisof IBS. Most patients had IBS with diarrhea, and a minority REFERENCES: SECTION 2.10
had IBS with bowel habits alternating between diarrhea andconstipation. The patient population in these trials was 1. Camilleri M. Review article: Tegaserod. Aliment Pharmacol Ͼ90% women and Ͼ90% Caucasian and had a mean age of 2. Prather CM, Camilleri M, Zinsmeister AR, et al. Tegaserod A comprehensive evaluation of the alosetron data reveals accelerates oro-cecal transit in patients with constipation-pre-dominant irritable bowel syndrome. Gastroenterology 2000; several methodologic issues. First, three of these trials (3-5) were conducted before publication of ROME committee 3. Degen L, Matzinger D, Merz M, et al. Tegaserod, a 5-HT recommendations about the design of treatment trials for receptor partial agonist, accelerates gastric emptying and gas- functional GI disorders. Thus, only one trial (6) used global trointestinal transit in healthy male subjects. Aliment Pharma- IBS symptom improvement as a secondary endpoint. Im- provement in abdominal pain or improvement in fecal ur- 4. Muller-Lissner S, Fumagalli I, Bardhan KD, et al. Tegaserod, a gency was the primary endpoint in these trials, although 5-HT4 receptor partial agonist, relieves symptoms in irritablebowel syndrome patients with abdominal pain, bloating, and individual IBS symptoms of stool consistency, stool fre- constipation. Aliment Pharmacol Ther 2001;15:1655- 66.
quency, and satisfaction with bowel habits were examined 5. Whorwell PJ, Krumholz S, Muller-Lissner S, et al. Tegaserod in all trials. The definition of a "responder" for symptom has a favorable safety and tolerability profile in patients with improvement was not consistent across trials, limiting com- constipation-predominant and alternating forms of irritable parisons between trials. One RCT (4) compared alosetron bowel syndrome. Gastroenterology 2000;118:A1204.
with an active control, mebeverine. One additional RCT (7) 6. Schoenfeld P, Chey W, Drossman D, et al. Effectiveness and is not presented in this analysis as this was a dose-ranging safety of tegaserod in the treatment of irritable bowel syndrome:a meta-analysis of randomized controlled trials. Gastroenterol- trial and no patients took the approved dose of alosetron (1 7. Novick J, Miner P, Krause R, et al. A randomized, double- All four trials (3- 6) demonstrated statistically significant blind, placebo-controlled trial of tegaserod in female patients improvement in the primary study endpoint (i.e., improve- suffering from irritable bowel syndrome with constipation. Al- ment in abdominal pain or improvement in fecal urgency) iment Pharmacol Ther 2002;16:1877- 88.
for alosetron-using patients vs control patients. Based on the 8. Kellow J, Lee O, Chang F, et al. Tegaserod is an effective prescribed definition for improvement in abdominal pain, therapy for non-diarrheal IBS in an Asian-Pacific population.
Gut (in press) (Abstract).
approximately 10 -27% more alosetron-using patients had 9. Study #307. Data on file. Novartis Pharmaceuticals Corpora- significant improvement in abdominal pain compared with control patients (Figure 2.11.1). In the single study measur- Management of IBS
Table 2.11.1. Trial Characteristics: 5-HT Receptor Antagonist Alosetron
Camilleri (3) Alosetron vs placebo 1, 2, 4 or 8 mg b.i.d. Parallel Camilleri (5) Alosetron vs placebo 1 mg b.i.d.
symptoms, global IBSsymptom improvement,adverse events * Primary outcome measure was relief of abdominal pain in three trials (3-5) and was relief of fecal urgency in one trial (6).
ing global IBS symptom improvement (6), approximately pected ischemic colitis and 113 cases of suspected serious 32% more alosetron-using patients noted significant im- constipation complications associated with alosetron use.
provement in global IBS symptoms compared with control Based on available data, the proportion of IBS patients with patients (76% vs 44%, respectively; p Ͻ 0.01). In analysis diarrhea who develop ischemic colitis or serious constipa- of individual IBS symptoms, alosetron-using patients con- sistently demonstrated significant improvement in stool fre- When prescribing alosetron, physicians should consider quency, stool consistency, and fecal urgency compared with the following issues. Since three of the four RCTs examined control patients. The magnitude of these improvements var- only women, the effectiveness of this agent in men is un- ied across trials owing to the use of different scales to clear. RCT data on the effectiveness of alosetron are only measure individual symptoms in different trials.
available from 12-week trials. The appropriate duration of Constipation is the most common adverse event associ- treatment with alosetron is uncertain. Although global IBS ated with use of alosetron. In these trials (3- 6), constipation symptom improvement was not the primary study endpoint was reported as an adverse event in 22-39% of alosetron- in these trials, all of these trials assessed improvement in using patients vs 3-14% of control patients, and approxi- multiple IBS symptoms, and alosetron was consistently mately 10% of alosetron-using patients discontinued medi- better than control agents for improvement in all of these cation because of this adverse event. Two cases of ischemic symptoms. As constipation is the most common adverse colitis were reported in these trials, although pathologic event associated with alosetron use, it may be prudent to examination of the surgical specimen in one case revealed advise patients to temporarily discontinue alosetron if sig- that the cause of colitis was Escherichia coli O157:H7.
nificant constipation occurs. Physicians should follow FDA Another trial (4) reported a case of "colitis/sigmoiditis," but guidelines for use of alosetron: 1) alosetron is prescribed for it was unclear if this case was consistent with ischemic "women with severe, diarrhea-predominant IBS who have colitis. In March 2002, the FDA reported 84 cases of sus- failed conventional IBS therapy"; 2) physicians must edu-cate patients about the potential risks of alosetron use; and,3) patients should assess the risk-benefit ratio before decid-ing to use alosetron.
Overall, the trials of alosetron consistently demonstrate high-quality study methodology and effectiveness for thetreatment of IBS with diarrhea in women. Physicians shouldfollow the FDA-approved indication for alosetron: "womenwith severe, diarrhea-predominant IBS who have failed torespond to conventional IBS therapy." Therefore, given therisk of serious adverse events with alosetron, physician andpatient judgment will guide selection of patients who areappropriate candidates for alosetron. Physicians shouldeducate patients about the potential risks of alosetron andinstruct patients to discontinue alosetron if constipation Figure 2.11.1. Percentage of patients with improvement in abdom-
inal pain.
ACG Functional GI Disorders Task Force
Table 2.12.1. Behavioral Therapies for Treatment of IBS
1. Relaxation therapy: Based on the hypothesis that stress 1. Forster JM, Houghton LA, Whorwell PJ. Alosetron slows co- stimulates the autonomic nervous system and exacerbates IBS lonic transit in patients with irritable bowel syndrome. Gastro- symptoms. Patients learn techniques to release tension and relax.
enterology 1996;110:A630 1996;110:A630 (abstract).
2. Biofeedback: Patients learn to sense changes in rectal 2. Delvaux M, Louvel D, Mamet JP, et al. Effect of alosetron on distention and to regulate bowel habits using biofeedback responses to colonic distension in patients with irritable bowel syndrome. Aliment Pharmacol Ther 1998;12:849 -55.
3. Hypnotherapy: Based on the hypothesis that hypnotherapy 3. Camilleri M, Mayer E, Drossman D, et al. Improvement in pain may induce a lasting state of relaxation and may positively and bowel function in female irritable bowel syndrome patients affect gut motility and intestinal smooth muscle contraction.
with alosetron, a 5HT3 receptor antagonist. Aliment Pharmacol 4. Cognitive therapy: Based on the hypothesis that patient's learned resposne to stressful events exacerbates IBS 4. Jones R, Holmann G, Rodrigo L, et al. Alosetron relieves pain symptoms. In cognitive therapy, patients accept responsibility and improves bowel function compared with mebeverine in for their IBS symptoms, learn to identify stressful events and female non-constipated irritable bowel syndrome patients. Al- actively seek solutions to these events.
iment Pharmacol Ther 1999;13:1419 -27.
5. Psychotherapy: Based on the hypothesis that IBS symptoms 5. Camilleri M, Northcutt AR, Kong S, et al. The efficacy and may be a manifestation of traumatic life events.
safety of alosetron in female patients with irritable bowel Psychotherapy provides insight about these life events and syndrome: A randomized, placebo controlled study. Lancet the association between these events and IBS symptoms.
Through this insight, patients may experience long-term 6. Lembo T, Wright RA, Bagby B, et al. Alosetron controls bowel urgency and provides global symptom improvement in womenwith diarrhea-predominant irritable bowel syndrome. Am JGastroenterol 2001;96:2662-70.
7. Bardhan K, Bodemar G, Geldor H, et al. A double-blind pla- of these studies enrolled an inadequate sample of patients.
cebo-controlled study to evaluate the efficacy of alosetron in the Generally, sample sizes were small with almost all studies treatment of irritable bowel syndrome. Aliment Pharmacol Ther Previous reviews have noted multiple biases unique to 2.12 EFFECTIVENESS OF BEHAVIORAL THERAPY IN THE
behavioral therapy studies (3). Attention from health careproviders may produce therapeutic benefits (3). These ben- MANAGEMENT OF IRRITABLE BOWEL SYNDROME
efits may derive from: 1) the empathic attitude of the pro- Behavioral therapy is more effective than placebo at reliev- vider toward patient's symptoms and life stresses; 2) the ing individual IBS symptoms (Grade B recommendation). enthusiasm of the provider about the effectiveness of the Psychological disorders, especially depression and anxi- therapy; and, 3) the quality and quantity of contact time with ety disorders, are comorbid conditions in most IBS patients the provider; however, only two studies (12, 15) attempted who actively seek subspecialist medical care. Of IBS pa- to control for differences in attention from health care pro- tients who actively sought subspecialist medical care, 54 - viders. Expectancy of improvement with behavioral therapy 94% met DSM-III-R criteria for a primary (Axis I) psycho- may also influence results and should be measured pre- and logical disorder (1), but only 18% of IBS patients in a post-therapy (3) (i.e., if a patient expects that behavioral population-based study met DSM-III criteria for a primary therapy will improve IBS symptoms, then this expectation psychiatric disorder (2). Comorbid psychological disorders will bias the patient's assessment of IBS symptom improve- may influence health-care seeking behaviors of IBS patients, ments). Controlling for patient expectations is particularly but these psychological disorders are not the cause of IBS important in unblinded trials, but only two trials (12, 13) symptoms. Given the overlap between psychological disor- assessed patients' expectations of improvement with behav- ders and IBS, behavioral therapies (Table 2.12.1) have been ioral therapy. Future behavioral therapy studies of IBS pa- tients should adhere to published recommendations for the Sixteen RCTs have evaluated the effectiveness of behavioral therapies in the management of IBS (4 -19) (Table 2.12.2).
Eleven studies reported that behavioral therapy improved Multiple studies combined different types of behavioral ther- individual IBS symptoms (5-11, 16 -19), and five studies (4, apy (e.g., relaxation therapy plus biofeedback) into a multi- 12-15) did not demonstrate a statistically significant im- component behavioral therapy (Table 2.12.2). Behavioral ther- provement in IBS symptoms between treatment and control apy trials were of intermediate quality (quality scores 7-10 of groups (Table 2.12.2). Results provided some support of possible 14) based on ROME committee criteria for the design effectiveness with all types of behavioral therapy, including of treatment trials for functional GI disorders. In most trials, relaxation therapy, biofeedback, hypnotherapy, cognitive more than 80% of patients had a concurrent psychological therapy, psychotherapy, and different combinations of these disorder with IBS. None of these trials used adequate blinding, behavioral therapies (Table 2.12.2). Improvement in indi- although complete blinding in behavioral therapy studies is vidual IBS symptoms correlated with improvement in psy- difficult. None of the trials evaluated improvement in global chological symptoms in most trials. As noted above, atten- IBS symptoms, and all trials evaluated individual IBS symp- tion from health care providers may positively affect toms. Only two studies (12, 13) reported sample sizes, and one patient's symptoms, but only two trials (12, 15) adequately Management of IBS
Table 2.12.2. Trial Characteristics: Behavioral Therapy
ACG Functional GI Disorders Task Force
Table 2.12.2. Trial Characteristics: Behavioral Therapy (continued)
* Study outcome: (ϩ) indicates that treatment patients demonstrated significantly more improvements in IBS symptoms compared with controls; (Ϫ) indicates that treatmentpatients did not demonstrate significantly more improvement in IBS symptoms compared with controls.
controlled for this variable. Neither of these trials showed a 6. Greene B, Blanchard EB. Cognitive therapy for irritable bowel significant difference in IBS symptom improvement be- syndrome. J Consult Clin Psychol 1994;62:576 - 82.
tween treatment patients and control patients, although IBS 7. Guthrie E, Creed F, Dawson D, et al. A randomized controlled trial of psychotherapy in patients with refractory irritable symptoms improved from baseline in both groups. This bowel syndrome. Br J Psychiatry 1993;163:315-321.
finding suggests that IBS symptom improvement may result 8. Lynch PM, Zamble EA. Controlled behavioural treatment study from attention given by health care providers and may not of irritable bowel syndrome. Behav Ther 1989;20:509 -23.
result from specific behavioral therapy (20).
9. Shaw G, Srivistava ED, Sadlier M, et al. Stress management No adverse events were reported with hynotherapy, psy- for irritable bowel syndrome: A controlled trial. Digestion1991;50:36 - 42.
chotherapy, cognitive therapy, or biofeedback using a bal- 10. Svedlund J, Sjodin I, Ottoson JO, et al. Controlled study of psychotherapy in irritable syndrome. Lancet 1983;2:589 -92.
Psychological disorders and IBS are frequently comorbid 11. Whorwell PJ, Prior A, Farragher EB. Controlled trial of hyp- conditions among patients who actively seek subspecialist notherapy in the treatment of severe refractory irritable bowel medical care for IBS. None of the trials of behavioral therapies demonstrated high-quality methodology. These 12. Blanchard EB, Schwarz SP, Suls JM, et al. Two controlled evaluations of multicomponent psychological treatment of ir- trials lacked adequate blinding and rarely corrected for ritable bowel syndrome (study 1). Behav Res Ther 1992;30:175- differences in attention from health care providers. Trial results suggest that relaxation therapy, hypnotherapy, 13. Blanchard EB, Schwarz SP, Suls JM, et al. Two controlled biofeedback, cognitive therapy, and psychotherapy may im- evaluations of multicomponent psychological treatment of irrita- prove individual IBS symptoms. Behavioral therapy im- ble bowel syndrome (study 2). Behav Res Ther 1992; 30:175- 89.
14. Corney RH, Stanton R, Newell R, et al. Behavioural psycho- proved both IBS symptoms and psychological symptoms therapy in the treatment of irritable bowel syndrome. J Psy- among patients with comorbid psychological disorders; however, given the limitations of trial design, "no trial has 15. Harvey RF, Hinton RA, Gunary RM, et al. Individual and provided unequivocal evidence that psychological treatment group hypnotherapy in treatment of refractory irritable bowel is efficacious in irritable bowel syndrome" (3). syndrome. Lancet 1989;1(8635):424 -5.
16. Rumsey N. Group stress management programmes vs phar- REFERENCES: SECTION 2.12
macological treatment in the treatment of irritable bowel syn-drome. In: Heaton KW, Creed F, Goeting NLM, eds. Towards 1. Whitehead W, Palsson O, Jones KR. Systematic review of the confident management of irritable bowel syndrome: Current comorbidity of irritable bowel syndrome with other disorders: approaches. London: Duphar Medical Relations, 1991:33-5.
What are the causes and implications? Gastroenterology 2002; 17. Galovski T, Blanchard E. The treatment of irritable bowel syndrome with hypnotherapy. Appl Psychopathophysiol 2. Walker EA, Katon WJ, Jemelka R, et al. Comorbidity of gastrointestinal complaints, depression and anxiety in the Ep- 18. Heymann-Monnikes I, Arnold R, Florin I, et al. The combi- idemiologic Catchment Area (ECA) Study. Am J Med 1992; nation of medical treatment plus multicomponent behavioral therapy is superior to medical treatment alone in the therapy of 3. Talley N, Owen B, Boyce P, et al. Psychological treatments irritable bowel syndrome. Am J Gastroenterol 2000;95:981- for irritable bowel syndrome: A critique of controlled treat- ment trials. Am J Gastroenerol 1996;91:277- 86.
19. Payne A, Blanchard E. A controlled comparison of cognitive 4. Bennett P, Wilkinson SA. Comparison of psychological and therapy and self-help support groups in the treatment of irri- medical treatment of the irritable bowel syndrome. Br J Clin table bowel syndrome. J Consult Clinical Psychology 1995; 5. Blanchard EB, Greene B, Scharff L, et al. Relaxation training 20. Blanchard E, Schwarz SP, Neff D. Two-year follow-up of as a treatment for irritable bowel syndrome. Biofeedback Self behavioral treatment of irritable bowel syndrome. Behav Ther


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