Current Concepts and Management of Irritable Bowel Syndrome Christopher D. Lind, M.D. Associate Professor of Medicine

Irritable Bowel Syndrome Chronic or recurrent  Lower abdominal pain  Disturbed defecation  Bloating Not explained by structural or known biochemical abnormalities IBS - Definition Definition of IBS - Rome I

Definition “A variable combination of chronic or recurrent gastrointestinal symptoms (attributed to the pharynx, esophagus, stomach, biliary tree, small or large intestine, or anorectum) not explained by structural or biochemical abnormalities.” “A variable combination of chronic or recurrent gastrointestinal symptoms (attributed to the pharynx, esophagus, stomach, biliary tree, small or large intestine, or anorectum) not explained by structural or biochemical abnormalities.” Rome criteria, 1990 Functional GI Drossman DA, et al., Degnon and Associates, 1994 Drossman DA, et al., Gastroenterology International 1990; 3:159 Drossman DA, et al., Degnon and Associates, 1994 Drossman DA, et al., Gastroenterology International 1990; 3:159 Functional GI Disorders

Functional GI Disorders -(Rome II) Esophageal Biliary Gastroduodenal Bowel Anorectal / pelvic floor Esophageal Biliary Gastroduodenal Bowel Anorectal / pelvic floor Drossman DA, et al., Gut 1999; 45:II1 Rome II Functional GI Disorders

IBS - Epidemiology 15% 9% 23% 16% 14% 19% Drossman DA, et al., Gastroenterology 1997; 112:2137 World Prevalences

Gender Differences in IBS: Epidemiology

USA AFRICA INDIA Doctor Visits by Gender IBS - Epidemiology Drossman DA, et al., Gastroenterology 1997; 112:2137 Doctor Visits by Gender

U.S. Prevalence >45 Age in Years % % Female Male IBS - Epidemiology Drossman DA, et al., Dig Dis Sci 1993; 38:1569 U.S. Prevalence

Other 88% Other 88% IBS 12% Other GI 15% Other GI 15% IBS Other Functional 13% IBD 14% IBD 14% Peptic 20% Peptic 20% Liver 10% Liver 10% 28% Primary Care Practice Primary Care Practice Gastroenterology Practice Gastroenterology Practice Prevalence of Diagnosis IBS - Epidemiology Mitchell CM,et al., Gastroenterology 1987; 92:1282 Prevalence of Diagnosis in Clinical Practice

Annual Economic Burden of IBS in the United States Versus Other Chronic Conditions

IBS - Epidemiology Sandler RS, et al.,. Gastroenterology 1984; 87:314 Health Care Seeking

Work or School Absences IBS Normal Days per Year Days per Year IBS - Epidemiology Drossman DA, et al., Dig Dis Sci 1993; 38:1569 Work and School Absences - U.S. Data

IBS - Epidemiology MD Visits Per Year MD Visits Per Year IBS Normal Complaints 6 6 Non-GI GI Drossman DA, et al., Dig Dis Sci 1993; 38:1569 Physician Visits per Year

IBS - Epidemiology Up to 15% of population Females > males Younger > older 2/3 do not seek health care Sociocultural factors affect M.D. visits 12% primary care practice, 28% GI practice >3x work loss, M.D. visits Drossman DA, et al., Gastroenterology 1997; 112:2137 Epidemiology Summary

Patients with IBS vs People with IBS 50% of IBS patients have psychiatric symptoms 20% of patients with organic disorders, 15% of healthy controls have psychiatric symptoms 15% of people with IBS have psychiatric symptoms IBS patients exhibit learned illness behaviors

Rome Criteria for IBS (1) Abdominal pain relieved with defecation and/or Abdominal pain associated with change in frequency of stool and/or Abdominal pain associated with change in consistency of stool Symptoms present for at least 3 mos

Rome Criteria for IBS (2) Altered stool frequency Altered stool form (lumps/hard or loose/watery) Passage of mucus Bloating or feeling of abdominal distension Two or more of these symptoms on at least a quarter of occasions or days

IBS - Rome Criteria Validation 63% Sensitivity 100% Specificity % PPV 63% Sensitivity 100% Specificity % PPV Rome I Absence of red flags  Weight loss  Nocturnal symptoms  Blood in stools  Recent antibiotics  + FH colon cancer  Abnormal PE Absence of red flags  Weight loss  Nocturnal symptoms  Blood in stools  Recent antibiotics  + FH colon cancer  Abnormal PE + + = = Rome Criteria Validation (Summary slide) Vanner et. al., Am J. Gastro 1999; 94:2912

Pathophysiology of IBS Abnormal intestinal motility Enhanced visceral sensitivity Psychosocial factors Additional factors in some patients: luminal irritants, post-infectious

IBS - Physiologic Research Stress affects GI function Motility Meals Pain / motility Myoelectrical Marker Brain-Gut Interactions Visceral Hypersensitivity Mechanisms Pain sensitivity 3 cpm motility Clustered contractions CNS / ENS Autonomic reactivity Visceral hypersensitivity Post-infectious IBS Inflammation Time Line of Physiologic Research in IBS

Effects of Stress Abdominal pain Bowel dysfunction % People Reporting GI Symptoms % People Reporting GI Symptoms IBS Normal IBS - Physiology Drossman DA, et al., Gastroenterology 1982; 83:529 Effects of Stress on GI Symptoms

Normal Colonic Response to Stress Contractile State Contractile State Minutes “Discovery” of Cancer “Discovery” of Cancer Hoax Explained Hoax Explained IBS - Physiology Almy TP, AM J Med. 1951; 10:60 Normal Colonic Response to Stress - Almy, 1951

Sigmoid Motility Index Minutes IBS Normal Meal IBS - Physiology Rogers J, et al., Gut 1989; 30:634 Increased Meal-Stimulated Sigmoid Motility in IBS - Rogers, 1989

IBS - Physiology Motility Index Minutes Meal IBS - Placebo IBS - Anticholinergic Sullivan MA, et al., New Engl J Med. 1978; 298:878 Effect of Anticholinergic on Meal-Simulated Sigmoid Motility - Sullivan, 1978

Effect of Stress on Jejunal Motor Activity IBSUCNormal (N=22)(N=5)(N=10) Abolition of MMC700 Irregular motor1801 activity Pain associated with motor801 activity IBSUCNormal (N=22)(N=5)(N=10) Abolition of MMC700 Irregular motor1801 activity Pain associated with motor801 activity IBS - Physiology Kumar DL, Wingate DL, Lancet. 1985; 2:973-7 Stress-induced Effects on Jejunal Activity - Kumar, 1985

IBS - Physiology 60 % Reporting Pain % Reporting Pain Rectosigmoid balloon volume (ml) IBS Normal Whitehead WE, et al., Dig Dis Sci 1980; 25:6:404 Pain Produced from Rectosigmoid Distension - Whitehead, 1980

Pain Tolerance IBS - Physiology Colonic Distension IBS Normal Ice Water Immersion Cook IJ, et al., Gastroenterology 1987; 93:727 Lower Pain Tolerance in IBS Occurs Primarily in the Bowel - Whitehead, 1990

CNS Modulation IBS - Pathophysiology Asleep Stressed Awake MMC’s per 8 hr. MMC’s per 8 hr. IBS Normal Kellow JE, et al., Gastroenterology 1990; 98:1208 Effect of CNS on ENS Activity

Health Status Severe life events Psychologic traits Psychologic state Maladaptive coping Sex / physical abuse IBS - Predictive Psychosocial Factors Drossman et, al., Gastroenterlogy, 2002; 123:2108 Psychosocial Factors Affecting Health Status

SOM SEN DEP OBS ANX HOS PHO PAR PSY IBS Non-patients IBS Patients Normals SCL-90 average raw score SCL-90 average raw score Whitehead et. al., Gastroenterology 1988; 95:709 IBS – Psychosocial Psychological Distress (SCL-90): IBS Patients, IBS Non-Patients and Normals

IBS – Psychosocial & Quality of Life Wells et. al., Aliment Pharmacol Ther 1997; 11: Physical functioning Physical functioning Physical role Body pain General health Vitality Social functioning Social functioning Emotional role Emotional role Mental health MeanSF-36scoreMeanSF-36score National norm Diabetes type II IBSIBS Clinical depression Quality of Life (SF-36) of IBS and Other Medical Disorders

IBS and Abuse Drossman DA, et al. Gastroenterology International. 1995; 8:47 IBS and Abuse - Abuse Reporting Based on IBS Severity and Treatment Site

Post-infectious IBS

IBS - Post Infectious Neal R, BMJ, 1997; 314:779 Gwee et al, Gut 1999; 44:400 Neal R, BMJ, 1997; 314:779 Gwee et al, Gut 1999; 44:400 Duration of abdominal pain Duration of diarrhea Females Factors Predicting GI Symptoms Factors Predicting GI Symptoms Younger age Psychologic distress Factors Predicting GI Symptoms in Post-infectious IBS

Gwee et. al., Gut 1999; 44: Acute Gastroenteritis 94 Acute Gastroenteritis 72 No GI symptoms 22 IBS + Rome I 18 Controls Psych - Psych + Abnormal physiology Rectal inflammation Abnormal physiology Rectal inflammation Psych testing Rectal biopsy + Psych testing Rectal biopsy + 3 months IBS - Post-infection Gut Dysfunction Post-infection Gut Dysfunction – Study Summary

IBD/IBS - Variable Responses to Infection Controlled inflammation Acute inflammation Post inflammatory Sensitization Infection Immune dysregulation Recovery Marked inflammation Controlled inflammation IBD IBS Normal ENS / CNS Variable Responses to Infection

IBS - CNS Response to Somatic Pain during Hypnosis Rainville Science 1997; 277:968 Somatosensory cortex Anterior cingulate cortex High Low Unpleasantness t-value High Low CNS Response to Somatic Pain during Hypnosis

IBS - fMRI During Rectal Distention Mertz et. al., Gastroenterology 2000; 118:842 Active pixels (# per ROI) Active pixels (# per ROI) InsulaInsulaThalamusThalamus ACCACC * PrefrontalPrefrontal Controls IBS ControlControl ACCACC PFCPFC ICIC ThalamusThalamus IBSIBS CNS Activation (fMRI) of Normals and IBS Subjects to Rectal Distension

IBS Physiology Serotonin (5-HT) in the Human Gut 5-HT 1 5-HT 3 5-HT 4 Gastric accommodation Transit Colonic tone Sensation Secretion 5-HT 1 5-HT 3 5-HT 4 Gastric accommodation Transit Colonic tone Sensation Secretion ? ? Serotonin (5-HT) Receptor Subtyped and Their Effects

IBS Physiology Serotonin (5-HT) in the Gut  95% GI tract (EC cells, mast cells); 5% CNS  Mediates GI function in ENS / CNS  Motility  Sensation / perception  Secretion  Mechanical / chemical stimuli 5-HT  Plasma 5-HT increased after a meal (IBS > controls)  95% GI tract (EC cells, mast cells); 5% CNS  Mediates GI function in ENS / CNS  Motility  Sensation / perception  Secretion  Mechanical / chemical stimuli 5-HT  Plasma 5-HT increased after a meal (IBS > controls) EC cells Mast cells EC cells Mast cells Serotonin (5-HT) in the Gut

IBS - Early Life Influences Levy RL, Am J Gastro 2000; 95: OPD Health Care Costs Health Care Visits Diarrhea Abdominal Pain Abdominal Pain Any GI visits Any GI visits % % $ $ Children of IBS parents Children of non-IBS parents Children of IBS parents Children of non-IBS parents Influence of IBS in Family on Children

REM Sleep NormalsIBS REM 36% 64% REM 18% REM 18% 82% IBS - Pathophysiology Kumar D, et al., Gastroenterology 1992; 103:12 Increased REM Sleep in IBS

Diagnostic Strategies Rule out organic disease Build trust and reassure patient that other diseases are ruled out

IBS - Diagnosis Drossman DA, et al., Gastroenterology 1997; 112:2137 Initial Evaluation

IBS - Diagnosis Rome II Criteria Pain relieved with defecation At least 12 weeks in preceding 12 months of abdominal discomfort or pain and 2 of following: At least 12 weeks in preceding 12 months of abdominal discomfort or pain and 2 of following: Onset associated with change in frequency of stool Onset associated with change in frequency of stool Onset associated with change in form (appearance) of stool Onset associated with change in form (appearance) of stool and / or Thompson, Gut 1999; 45:II-43 Rome II Criteria for IBS

Identify Red Flags

IBS: Prevalence by Subgroups

Diagnostic Strategies – Subgroup Analysis Constipation predominant: colonic transit study, anorectal manometry, defecography Diarrhea predominant: stool studies, jejunal aspirate, serology for Celiac dz, SB or colonic transit studies Pain/gas/bloating: abdominal films, gastric emptying studies or manometry, SBFT

IBS - Diagnosis Owens DM, et al., Ann Intern Med. 1995; 122:107 Change in Diagnosis After Initial Evaluation

IBS - Diagnosis Sensitivity and Specificity for Rectal Distension in IBS % patients Thresholds (mm Hg) * * * = Sensitivity 96%; Specificity 72%, PPV 85%, NPV 90% SensitivitySpecificity Sensitivity and Specificity of Barostat at Different Levels of Distension Bouin, M, et. al., Gastroenterlogy 2002;122:1771

Therapeutic Strategies Patient education Dietary factors Stress management/Psychotherapy Pharmacological therapy

IBS - Clinical Spectrum Drossman DA, et al., Gastroenterology 1997; 112:2137 Spectrum of Severity in IBS

IBS - Physician Patient Relationship Drossman DA, Thompson WG Ann Intern Med. 1992; 116:1009 Physician-Patient Relationship

IBS - Treatment Potential Targets CNS Altered motility / secretion Alteredsensation  Opioid agonist 5-HT agents  2 Adrenergic agents  2 Adrenergic agents SSRIs / SNRIs Tricyclics NK receptor antagonists NK receptor antagonists Probiotics Probiotics Anti-spasmodics Anti-spasmodics CCK antagonists Potential Targets for Treatment of IBS

Rationale for Antidepressants  Treatment of psychiatric co-morbidity  Peripheral effects  Motility / secretion  Afferent  Central pain modulatory effects  Treatment of psychiatric co-morbidity  Peripheral effects  Motility / secretion  Afferent  Central pain modulatory effects IBS - Treatment Rationale for Antidepressants

IBS - Tricyclic Antidepressants Improvement in GI Symptoms Heefner (1978) Myren (1982) Tripathi (1983) Vij (1991) Tanum (1996) Rajagopalan (1998) Mertz (1998) Overall (95% CI) Heefner (1978) Myren (1982) Tripathi (1983) Vij (1991) Tanum (1996) Rajagopalan (1998) Mertz (1998) Overall (95% CI) ( ) 25 O. R. Jackson JL et. al., Amer J Med 2000; 108:65 Meta-analysis of Tricyclic Antidepressants in IBS: GI symptoms

Improvement in Mean Abdominal Pain Scores IBS - Tricyclic Antidepressants Mertz NUD (1998) Heefner (1978) Tanum (1996) Rajagopalan (1998) Steinhart (1982) Loldrup NUD(1989) Greenbaum (1987) Loldrup NUD (1989) Myren (1984) Overall (95% CI) Mertz NUD (1998) Heefner (1978) Tanum (1996) Rajagopalan (1998) Steinhart (1982) Loldrup NUD(1989) Greenbaum (1987) Loldrup NUD (1989) Myren (1984) Overall (95% CI) ( ) Standardized mean difference Meta-analysis of Tricyclic Antidepressants in IBS: Abdominal Pain Jackson JL et. al., Amer J Med 2000; 108:65

Zelnorm® (tegaserod maleate)

Zelnorm Has a Molecular Structure Designed to Mimic Serotonin (5-HT)

Zelnorm Clinical Trials

Zelnorm Efficacy Assessment

Zelnorm Monthly Results

Pharmacologic Therapy – IBS Diarrhea predominant IBS: loperamide, diphenoxylate, cholestyramine, Ca channel blockers, alosetron (Lotronex) Constipation predominant IBS: fiber supplements, osmotic laxatives (Miralax), tegaserod (Zelnorm) Post prandial symptoms: anticholinergics Low dose tricyclics: useful for diarrhea predominant IBS or alternating BM with pain