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

2. 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

3. 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

4. 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

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

6. Gender Differences in IBS: Epidemiology

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

8. U.S. Prevalence 15 - 34 35 - 44 >45 Age in Years 0 0 2 2 4 4 6 6 8 8 10 12 14 % % Female Male IBS - Epidemiology Drossman DA, et al., Dig Dis Sci 1993; 38:1569 U.S. Prevalence

9. 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

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

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

12. Work or School Absences IBS Normal 0 0 2 2 4 4 6 6 8 8 10 12 14 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

13. IBS - Epidemiology MD Visits Per Year MD Visits Per Year IBS Normal 0 0 1 1 2 2 3 3 4 4 5 5 Complaints 6 6 Non-GI GI Drossman DA, et al., Dig Dis Sci 1993; 38:1569 Physician Visits per Year

14. 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

15. 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

16. 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

17. 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

18. IBS - Rome Criteria Validation 63% Sensitivity 100% Specificity 98-100% PPV 63% Sensitivity 100% Specificity 98-100% 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

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

20. 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 197019501960198019902000 Post-infectious IBS Inflammation Time Line of Physiologic Research in IBS

21. Effects of Stress Abdominal pain Bowel dysfunction 0 20 40 60 80 100 % 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

22. Normal Colonic Response to Stress Contractile State Contractile State 3+ 2+ 1+ 0 0 0 0 10 20 30 40 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

23. 100 2000 1500 1000 2000 1500 1000 0 0 0 0 50 500 500 130 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

24. IBS - Physiology Motility Index Minutes 1600 800 800 0 0 0 0 - 20 20 40 60 80 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

25. 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

26. IBS - Physiology 60 % Reporting Pain % Reporting Pain Rectosigmoid balloon volume (ml) 0 0 20 40 20 60 100 140 180 IBS Normal Whitehead WE, et al., Dig Dis Sci 1980; 25:6:404 Pain Produced from Rectosigmoid Distension - Whitehead, 1980

27. 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

28. CNS Modulation IBS - Pathophysiology Asleep Stressed Awake 0 0 2 2 4 4 6 6 8 8 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

29. 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

30. SOM SEN DEP OBS ANX HOS PHO PAR PSY 0 0.5 1 1 1.5 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

31. IBS – Psychosocial & Quality of Life Wells et. al., Aliment Pharmacol Ther 1997; 11:1019 30 40 50 60 70 80 90 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

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

33. Post-infectious IBS

34. 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

35. Gwee et. al., Gut 1999; 44:400 94 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

36. 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

37. IBS - CNS Response to Somatic Pain during Hypnosis Rainville Science 1997; 277:968 Somatosensory cortex Anterior cingulate cortex High Low Unpleasantness t-value - 6.00 - 3.00 - 5.00 - 4.00 High Low CNS Response to Somatic Pain during Hypnosis

38. IBS - fMRI During Rectal Distention Mertz et. al., Gastroenterology 2000; 118:842 Active pixels (# per ROI) Active pixels (# per ROI) InsulaInsulaThalamusThalamus 0 20 40 60 80 ACCACC * PrefrontalPrefrontal Controls IBS ControlControl ACCACC PFCPFC ICIC ThalamusThalamus IBSIBS CNS Activation (fMRI) of Normals and IBS Subjects to Rectal Distension

39. 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

40. 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

41. IBS - Early Life Influences Levy RL, Am J Gastro 2000; 95:451 0 0 500 1000 1500 2000 OPD Health Care Costs Health Care Visits 0 0 5 5 10 15 20 25 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

42. 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

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

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

45. 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

46. Identify Red Flags

47. IBS: Prevalence by Subgroups

48. 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

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

50. IBS - Diagnosis Sensitivity and Specificity for Rectal Distension in IBS 12182024283236404448 60 80 100 0 20 40 % 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

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

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

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

54. 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

55. 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

56. 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).01 1 1 100 10 5 5 2 2 4.2 (2.3-7.9) 25 O. R. Jackson JL et. al., Amer J Med 2000; 108:65 Meta-analysis of Tricyclic Antidepressants in IBS: GI symptoms

57. Improvement in Mean Abdominal Pain Scores IBS - Tricyclic Antidepressants 0 0 4 4 - 4 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) 1 1 2 2 3 3 0.9 (0.6-1.2) Standardized mean difference Meta-analysis of Tricyclic Antidepressants in IBS: Abdominal Pain Jackson JL et. al., Amer J Med 2000; 108:65

58. Zelnorm® (tegaserod maleate)

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

60. Zelnorm Clinical Trials

61. Zelnorm Efficacy Assessment

62. Zelnorm Monthly Results

63. 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