1. IRRITABLE BOWEL SYNDROME Kimberly M. Persley, MD

2. Earliest descriptions of symptoms defining IBS 1849 – W Cumming 1 1849 – W Cumming 1 “ The bowels are at one time constipated, at another lax, in the same person. How the disease has two such different symptoms I do not profess to explain....” IBS – History Other historical terms Other historical terms – mucous colitis – colonic spasm – neurogenic mucous colitis – irritable colon – unstable colon – nervous colon – spastic colon – nervous colitis – spastic colitis 1962 – Chaudhary & Truelove 2 1962 – Chaudhary & Truelove 2 Irritable colon syndrome 1966 – CJ DeLor 3 1966 – CJ DeLor 3 Irritable bowel syndrome References: 1. Cumming. Lond Med Gazette. 1849;NS9;969-973. 2. Chaudhary and Truelove. Q J Med. July 1962;31:307-322. 3. DeLor. Am J Gastroenterol. May 1967;47:427-434.

3. Historical perspective Long dismissed as a psychosomatic condition 1 Long dismissed as a psychosomatic condition 1 – no clear etiology – affects predominantly women (~70% of sufferers are women) 2 – condition not fatal Attitudes now changing Attitudes now changing Incidence and prevalence not extensively monitored in past Incidence and prevalence not extensively monitored in past IBS – History References: 1. Maxwell et al. Lancet. December 1997;350:1691-1695. 2. Sandler. Gastroenterology. August 1990;99:409-415.

4. Hallmark symptoms of IBS Chronic or recurrent GI symptoms Chronic or recurrent GI symptoms – lower abdominal pain/discomfort – altered bowel function (urgency, altered stool consistency, altered stool frequency, incomplete evacuation) – bloating Not explained by identifiable structural or biochemical abnormalities Not explained by identifiable structural or biochemical abnormalities IBS – Signs and symptoms Reference: Thompson et al. Gut. 1999;45(suppl 2):1143-1147.

5. Key facts about IBS Up to 20% of the US population report symptoms consistent with IBS 1 Up to 20% of the US population report symptoms consistent with IBS 1 The most common GI diagnosis among gastroenterology practices in the US 2 The most common GI diagnosis among gastroenterology practices in the US 2 One of the top 10 reasons for PCP visits 3 One of the top 10 reasons for PCP visits 3 Affects predominantly females (~70% of sufferers) 4 Affects predominantly females (~70% of sufferers) 4 The most common functional bowel disorder 5 The most common functional bowel disorder 5 IBS – Overview References: 1. Camilleri and Choi. Aliment Pharmacol Ther. 1997;11:13-15. 2. Everhart and Renault. Gastroenterology. April 1991;100:998-1005. 3. Physician Drug & Diagnosis Audit (PDDA), April 1999, Scott-Levin. 4. Sandler. Gastroenterology. August 1990;99:409-415. 5. Thompson et al. Gastroenterol Int. 1992;5:75-91.

6. Key facts about IBS (cont.) Can cause great discomfort, sometimes intermittent or continuous, for many decades in a patient’s life 1 Can cause great discomfort, sometimes intermittent or continuous, for many decades in a patient’s life 1 Can significantly disrupt daily life 2 Can significantly disrupt daily life 2 Can have negative impact on quality of life 2 Can have negative impact on quality of life 2 Current treatment options 3 Current treatment options 3 – dietary modification – fiber supplements – pharmacologic agents – psychotherapy Success of current treatment options in addressing multiple symptoms of IBS has been limited 4 Success of current treatment options in addressing multiple symptoms of IBS has been limited 4 IBS – Overview References: 1. Hahn et al. Dig Dis Sci. December 1998;43:2715-2718. 2. Hahn et al. Digestion. 1999;60:77-81. 3. Drossman. Aliment Pharmacol Ther. 1999;13(suppl 2):3-14. 4. Klein. Aliment Pharmacol Ther. 1999;13(suppl 2):15-30.

7. IBS consultation pattern Specialists 1 Primary care 1 ~25% Consulters 1 ~75% Nonconsulters 1 ~70% Female 2 ~30% Male 2 IBS – Epidemiology References: 1. Drossman and Thompson. Ann Intern Med. June 1992;116(pt 1):1009-1016. 2. Sandler. Gastroenterology. August 1990;99:409-415.

8. IBS vs other important disease states US prevalence up to 20% 1 US prevalence up to 20% 1 US prevalence rates for other common diseases 2 : US prevalence rates for other common diseases 2 : – diabetes 3% – asthma4% – heart disease 8% – hypertension11% IBS – Epidemiology References: 1. Camilleri and Choi. Aliment Pharmacol Ther. 1997;11:3-15. 2. Adams and Benson. Vital Health Stat 10. December 1991:83. DHHS publication no (PHS)92-1509.

9. Direct medical costs associated with IBS IBS results in an estimated $8 billion in direct medical costs annually 1 IBS results in an estimated $8 billion in direct medical costs annually 1 IBS sufferers incur 74% more direct healthcare costs than non-IBS sufferers 1 IBS sufferers incur 74% more direct healthcare costs than non-IBS sufferers 1 IBS patients have more physician visits for both GI and non-GI complaints 2 IBS patients have more physician visits for both GI and non-GI complaints 2 IBS – Burden of disease References: 1. Talley et al. Gastroenterology. December 1995;109:1736-1741. 2. Drossman et al. Dig Dis Sci. September 1993;38:1569-1580.

10. Productivity burden IBS – Burden of disease 0 2 4 6 8 10 12 14 IBSNon-IBS Days per year P=0.0001 Absenteeism from work or school during the last 12 months Reference: Drossman et al. Dig Dis Sci. September 1993;38:1569-1580.

11. Impact on work due to IBS Patients with some missed workdays30% Average number missed workdays*1.7 Patients who cut back some days46% Average number days cut back* 3 *Over the previous 4 weeks. IBS – Burden of disease Adapted from Hahn et al. Digestion. 1999;60:77-81.

12. Evolution of mechanistic hypotheses in IBS IBS – Physiology Abnormal motility 1 Visceral hypersensitivity 1 Brain-gut interaction 1 5-HT mediated visceral sensitivity and gut motility 2 19502000 References: 1. Drossman. Aliment Pharmacol Ther. 1999;13(suppl 2):3-14. 2. Prior and Read. Aliment Pharmacol Ther. 1993;7:175-180.

13. Irritable Bowel Syndrome Biopsychosocial Disorder Biopsychosocial Disorder – Psychosocial – Motility – Sensory – ? Infectious Prevalence 10%, Incidence 1-2% per Year Prevalence 10%, Incidence 1-2% per Year Disturbs QOL, Social Function, Healthcare Utilization Disturbs QOL, Social Function, Healthcare Utilization Psychosocial Factors Altered Motility S2,3,4 Vagal nuclei Sympathetic Altered Sensation

14. Enteric nervous system Controls motility and secretory functions of the intestine Controls motility and secretory functions of the intestine Semiautonomous Semiautonomous –actions modified by parasympathetic and sympathetic nervous systems –may function independently Contains many neurotransmitters, including 5-HT, substance P, VIP (vasoactive intestinal peptide), and CGRP (calcitonin gene-related peptide) Contains many neurotransmitters, including 5-HT, substance P, VIP (vasoactive intestinal peptide), and CGRP (calcitonin gene-related peptide) IBS – Pathophysiology

15. IBS: Current thinking on pathophysiology Visceral hypersensitivity 1 Visceral hypersensitivity 1 – Increased visceral afferent response to normal as well as noxious stimuli – Mediators include 5-HT, bradykinin, tachykinins, CGRP, and neurotropins Primary motility disorder of GI tract 2 Primary motility disorder of GI tract 2 – Mediated by 5-HT, acetylcholine, ATP, motilin, nitric oxide, somatostatin, substance P, and VIP IBS – Pathophysiology References: 1. Bueno et al. Gastroenterology. May 1997;112:1714-1743. 2. Goyal and Hirano. N Engl J Med. April 1996;334:1106-1115. Defects in the enteric nervous system may lead to the hallmark symptoms of IBS.

16. Physiological distribution of 5-HT CNS – 5% enterochromaffin cells –enterochromaffin cells neuronal –neuronal IBS – Pathophysiology GI tract – 95% Reference: Gershon. Aliment Pharmacol Ther. 1999;13(suppl 2):15-30.

17. IBS – Pathophysiology 5-HT initiates peristaltic reflex mediated by the ENS Intraluminal Pressure Mucosa Mucosal Enterochromaffin Cell 5-HT 5-HT Receptor [Enteric Nervous System]

18. 5-HT receptor effects Mediate reflexes controlling gastrointestinal motility and secretion Mediate reflexes controlling gastrointestinal motility and secretion Mediate perception of visceral pain Mediate perception of visceral pain IBS – Pathophysiology Reference: Gershon. Aliment Pharmacol Ther. 1999;13(suppl 2):15-30.

19. 2060100140180 Comparison of pain thresholds of IBS patients and controls IBS – Physiology % Reporting Pain Rectosigmoid balloon volume (mL) Reference: From Whitehead et al. Dig Dis Sci. June 1980;25:404-413. With permission. 0 20 40 60 IBS Normal Pain produced by rectosigmoid balloon distension

20. Comparison of pain thresholds IBS – Physiology Colonic Distension Ice Water Immersion IBS Normal Reference: Whitehead et al. Gastroenterology. May 1990;98:1187-1192.

21. Make a positive diagnosis 1,2 IBS – Diagnosis Identify abdominal pain as dominant symptom with altered bowel function Perform diagnostic tests/physical exam to rule out organic disease Initiate treatment program as part of diagnostic approach Follow up in 3 to 6 weeks Look for “red flags” References: 1. Paterson et al. Can Med Assoc J. July 1999;161:154-160. 2. American Gastroenterological Association. Gastroenterology. June 1997;112:2120-2137. Make/confirm diagnosis

22. History of diagnostic approaches 1950s – Increased gut motility 1 1950s – Increased gut motility 1 1970s – Specific motility markers 1 1970s – Specific motility markers 1 1980 to 1999 – Symptom-based criteria 1 1980 to 1999 – Symptom-based criteria 1 – Manning criteria – Rome criteria 1999 – Rome II criteria 2 1999 – Rome II criteria 2 IBS – Diagnosis References: 1. Drossman. Aliment Pharmacol Ther. 1999;13(suppl 2):3-14. 2. Thompson et al. Gut. 1999;45(suppl 2):1143-1147.

23. IBS ROME II CRITERIA At Least 12 Weeks, Which Need Not Be Consecutive, in the Preceding 12 Months, of Abdominal Discomfort or Pain That Has Two of Three Features: At Least 12 Weeks, Which Need Not Be Consecutive, in the Preceding 12 Months, of Abdominal Discomfort or Pain That Has Two of Three Features: 1. Relieved with Defecation; and/or 2. Onset Associated with a Change in Frequency of Stool; and/or 3. Onset Associated with a Change in Form (Appearance) of Stool ConstipationDiarrhea

24. “Red flags” may suggest an alternative or coexisting diagnosis Anemia Anemia Fever Fever Persistent diarrhea Persistent diarrhea Rectal bleeding Rectal bleeding Severe constipation Severe constipation Weight loss Weight loss IBS – Diagnosis Reference: Paterson et al. Can Med Assoc J. July 1999;161:154-160. Additional diagnostic screening needed for atypical presentations such as Nocturnal symptoms of pain and abnormal bowel function Nocturnal symptoms of pain and abnormal bowel function Family history of GI cancer, inflammatory bowel disease, or celiac disease Family history of GI cancer, inflammatory bowel disease, or celiac disease New onset of symptoms in patients 50+ years of age New onset of symptoms in patients 50+ years of age

25. Diagnostic tests—What? When? Who? If patient has typical features of IBS: If  50 years of age, order CBC, electrolytes, LFTs, screen stool for occult blood, and consider sigmoidoscopy. 1 If  50 years of age, order CBC, electrolytes, LFTs, screen stool for occult blood, and consider sigmoidoscopy. 1 If  50 years of age, order CBC, electrolytes, LFTs, and perform a colonoscopy or air-contrast barium enema with sigmoidoscopy. 1,2 If  50 years of age, order CBC, electrolytes, LFTs, and perform a colonoscopy or air-contrast barium enema with sigmoidoscopy. 1,2 IBS – Diagnosis References: 1. American Gastroenterological Association. Gastroenterology. June 1997;112:2120-2137. 2. Paterson et al. Can Med Assoc J. July 1999;161:154-160.

26. Differential diagnosis Malabsorption 1 Malabsorption 1 Dietary factors 1 Dietary factors 1 Infection 1 Infection 1 Inflammatory bowel disease 1 Inflammatory bowel disease 1 Psychological disorders 1 Psychological disorders 1 Gynecological disorders 2 Gynecological disorders 2 Miscellaneous 1 Miscellaneous 1 IBS – Diagnosis References: 1. Drossman. Aliment Pharmacol Ther. 1999;13(suppl 2):3-14. 2. Moore et al. Br J Obstet Gynaecol. December 1998;105:1322-1325.

27. Current management of IBS Establish a positive diagnosis 1 Establish a positive diagnosis 1 Reassure patient that there is no serious organic disease or alarming symptoms 1 Reassure patient that there is no serious organic disease or alarming symptoms 1 Success of current treatment options in addressing multiple symptoms of IBS has been limited 2 Success of current treatment options in addressing multiple symptoms of IBS has been limited 2 IBS – Diagnosis References: 1. Drossman. Aliment Pharmacol Ther. 1999;13(suppl 2):3-14. 2. Klein. Gastroenterology. July 1988;95:232-241.

28. Current management components of IBS Education Education Reassurance Reassurance Dietary modification Dietary modification Fiber Fiber Symptomatic treatment Symptomatic treatment Psychological/behavioral options Psychological/behavioral options Realistic goals Realistic goals IBS – Management Reference: Drossman. Aliment Pharmacol Ther. 1999;13(suppl 2):3-14.

29. Currently available Rx treatments for IBS Dicyclomine HCl 1 Dicyclomine HCl 1 Hyoscyamine sulfate (± other anticholinergics/sedatives) 2 Hyoscyamine sulfate (± other anticholinergics/sedatives) 2 Belladonna and phenobarbital 1 Belladonna and phenobarbital 1 Clidinium bromide with chlordiazepoxide 1 Clidinium bromide with chlordiazepoxide 1 Tegaserod Tegaserod Alosetron Alosetron IBS – Management References: 1. PDR ® Generics ™. 1998:314, 559-561, 873-875. 2. Physicians’ Desk Reference ®. 1999:2910-2911.

30. Antispasmodics/anticholinergics Symptomatic treatment—pain 1 Smooth muscle relaxants via anticholinergic effects and/or direct action on smooth muscle 2 Smooth muscle relaxants via anticholinergic effects and/or direct action on smooth muscle 2 IBS – Management References: 1. Drossman. Aliment Pharmacol Ther. 1999;13(suppl 2):3-14. 2. Drug Facts and Comparisons ®. 1999:298-298c.

31. Antidiarrheals Symptomatic treatment—d iarrhea Increase stool firmness Increase stool firmness Decrease stool frequency Decrease stool frequency – Examples: loperamide, diphenxylate-atropine IBS – Management Reference: Drug Facts and Comparisons ®. 1999:324b.

32. Laxatives and bulking agents Symptomatic treatment—constipation IBS – Management References: 1. American Gastroenterological Association. Gastroenterology. June 1997;112:2120-2132. 2. Camilleri and Choi. Aliment Pharmacol Ther. 1997;11:3-15. 3. Drug Facts and Comparisons ®. 1999:316-317a. Increased dietary fiber or psyllium 1 Increased dietary fiber or psyllium 1 Osmotic laxatives (MgSO 4, lactulose) 2 Osmotic laxatives (MgSO 4, lactulose) 2 Stimulant laxatives 3 Stimulant laxatives 3 Some laxatives and bulking agents can exacerbate abdominal pain and bloating 3 Some laxatives and bulking agents can exacerbate abdominal pain and bloating 3

33. Tricyclic antidepressants and SSRIs Symptomatic treatment—pain Reserved for patients with severe or refractory pain Reserved for patients with severe or refractory pain IBS – Management Reference: Drossman and Thompson. Ann Intern Med. 1992;116(pt 1):1009-1016.

34. Multiple medications needed to treat multiple symptoms IBS – Management Anticholinergics 1 XX Tricyclic antidepressantsX and SSRIs 2 Antidiarrheals 1 XXX Bulking agents 1 X XX Laxatives 3 XX Lower abdominal pain Bloating Altered stool form Altered stool passage Urgency References: 1. American Gastroenterological Association. Gastroenterology. June 1997;112:2120-2137. 2. Drossman and Thompson. Ann Intern Med. 1992;116(pt 1):1009-1016. 3. Drug Facts and Comparisons ®. 1999:316.

35. A comprehensive multicomponent approach Treatment program is based on dominant symptoms and their severity and on psychosocial factors Medical management Medical management Diet Diet Psychological or behavioral options Psychological or behavioral options – psychotherapy – stress management IBS – Management Reference: Drossman. Aliment Pharmacol Ther. 1999;13(suppl 2):3-14.

36. INITIAL MANAGEMENT OF IBS Review Diet History Re: Fiber Intake Yes Increase Fiber (20g), Osmotic Laxative Yes H2 Breath Test Celiac panel Antidiarrheal Yes Abdominal X-ray (KUB During Pain) Antispasmodic + Antidepressant No Camilleri & Prather. 1992 Additional Tests Therapeutic Trial Constipation DiarrheaPain/Gas/Bloat Symptom Features

37. Tegaserod (Zelnorm) (serotinin 4 receptor agonist) Approved for constipation predominant IBS Approved for constipation predominant IBS 1 pill given twice daily 1 pill given twice daily Improvement of symptoms in women but not men Improvement of symptoms in women but not men Use up to 12 weeks Use up to 12 weeks Mild side effects: diarrhea the most prominent side effect Mild side effects: diarrhea the most prominent side effect

38. Non-Traditional Remedies Chinese Herbal Medicine Chinese Herbal Medicine – 116 pts randomized to CHM did better than pts receiving placebo Peppermint Oil Peppermint Oil – Relaxation of GI smooth muscle – Meta-analysis showed significant improvement of IBS symptoms Acupunture Acupunture Probiotics Probiotics Antibiotics Antibiotics Benoussan A. JAMA 1998 Pittler M. AJG 1998

39. Surgical Therapy for IBS IBS symptoms may be attributed to: IBS symptoms may be attributed to: – Non-functioning gallbladder disease, chronic appendicitis, uterine fibroids, tortuous colon IBS symptoms rarely improve after surgery IBS symptoms rarely improve after surgery IBS patients 2 to 3 times more likely to undergo unnecessary surgery IBS patients 2 to 3 times more likely to undergo unnecessary surgery

40. Take Home Points IBS is a chronic medical condition characterized by abdominal pain, diarrhea or constipation, bloating, passage of mucus and feelings of incomplete evacuation IBS is a chronic medical condition characterized by abdominal pain, diarrhea or constipation, bloating, passage of mucus and feelings of incomplete evacuation Precise etiology of IBS is unknown and therefore treatment is focused on relieving symptoms rather that “curing disease” Precise etiology of IBS is unknown and therefore treatment is focused on relieving symptoms rather that “curing disease”

41. Take Home Points Although many IBS patients complain of symptoms after eating, true food allergies are uncommon Although many IBS patients complain of symptoms after eating, true food allergies are uncommon Specific therapies are determined by individual patient symptoms Specific therapies are determined by individual patient symptoms Life-style modifications and possible alternative therapies may relieve symptoms Life-style modifications and possible alternative therapies may relieve symptoms Surgery has NO Role in treatment of IBS Surgery has NO Role in treatment of IBS