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IBS: Evidence-Based Update on Diagnosis and Treatment

IBS: Evidence-Based Update on Diagnosis and Treatment. William D. Chey, MD, FACG Associate Professor University of Michigan. “A good set of bowels is worth more to a man than any quantity of brains”. Josh Billings (Henry Wheeler Shaw) 1818-1885.

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IBS: Evidence-Based Update on Diagnosis and Treatment

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  1. IBS: Evidence-Based Update on Diagnosis and Treatment William D. Chey, MD, FACG Associate Professor University of Michigan

  2. “A good set of bowels is worth more to a man than any quantity of brains” Josh Billings (Henry Wheeler Shaw) 1818-1885

  3. “There is nothing in life as underrated as a good bowel movement” William D. Chey, MD 1960-?

  4. Arriving at a confident diagnosis of IBS

  5. Rome II Criteria for IBS • Abdominal pain or discomfort for at least 12 weeks (which need not be consecutive) in the preceding 12 months • Abdominal pain or discomfort has 2 of 3 features: • Relieved with defecation • Onset associated with a change in stool frequency • Onset associated with a change in stool form • 97% of patients with IBS have no changes in diagnosis over 5 years Thompson WG, et al. Gut. 1999;45(suppl II):II43-II47

  6. The Confident Diagnosis of IBS:A Symptom-based Approach Use symptom-based diagnostic criteria for IBS Exclude Alarm Symptoms (weight loss, fever, bleeding, family history of cancer/IBD) Perform physical exam and selected diagnostic tests to rule out organic disease Make a confident diagnosis of IBS Initiate a treatment plan based on symptoms Follow up in 3 to 6 weeks Modified from Paterson WE, et al. Can Med Assoc J. 1999;161:154; American Gastroenterological Association. Gastroenterology. 1997;112:2120; Camilleri M, Choi MG. Aliment Pharmacol Ther. 1997;11:3.

  7. Confident diagnosis of IBS: Validity of a symptom-based approach • A 2-year retrospective study confirmed the validityof an approach combining the Rome I criteria and absence of Red Flags. Results showed: • At 2-years follow-up, no patients required revisionof diagnosis 100% 100% 65% Sensitivity Specificity Positive predictive value Vanner et al, Am J Gastroenterol 1999; 94: 2912

  8. Limitations of the Rome II criteria in clinical practice Gold standard = Dx of IBS by MD Chey. Am J Gastroenterol 2002;97:2803

  9. Practical Definition of IBS • Rome criteria were developed for clinical research and are currently being revised • Practical definition for clinical practice: • IBS is a chronic medical condition characterized by abdominal painor discomfort in association with alterations in bowel function • pain relieved with defecation • alteration in stool frequency • alteration in stool form

  10. IBD ulcerative colitis Crohn’s disease microscopic colitis Malabsorption celiac sprue post-surgical pancreatic Psychologic anxiety/panic depression somatization Miscellaneous endometriosis endocrine tumors Differential Diagnosis of IBS Infection Giardia, Ameba bacterial overgrowth Dietary factors lactose, sorbitol fructose caffeine, alcohol fatgas-producing foods Differentialdiagnosis

  11. Organic GI Disease IBS Patients (Pretest Probability %) General Population(Prevalence %) Colitis / IBD 0.51-0.98 0.3-1.2 Colorectal cancer 0-0.51 4-6 Celiac disease 4.67 0.25-0.5 Gastrointestinal infection 0-1.7 N/A Thyroid dysfunction 6 5-9 Lactose malabsorption 22-26 25 Which tests are necessary in suspected IBS?Pretest Probability of Organic Disease Cash, et al. Am J Gastroenterol 2002;97:2812

  12. Celiac Disease and IBS • US prevalence of celiac disease1 • Overall 1:133, First degree relative 1:22, Symptomatic pts 1:56 • UK study: 14/300 (5%) IBS pts had biopsy proven celiac sprue2 • Irish study: 30/150 (20%) sprue pts met Rome criteria vs 8/162 (5%) controls3 • German study: of 102 IBS-D pts, 0% had serum Ab but 30% had Ab in duodenal aspirate4 1Fasano. Arch Int Med 2003;163:286. 2Sanders. Lancet 2001;358:1504. 3O'Leary. Am J Gastroenterol 2002;97:1463. 4Wahnschaffe. Gastroenterol 2001;121:1329.

  13. Is it cost-effecitve to test for Celiac Disease in IBS? • Decision analytic model assessed the cost-effectiveness of celiac testing vs. empiric IBS therapy in pts with suspected IBS • Testing cost an incremental $11K for one additional symptomatic improvement • ICER >%50K when prevalence of CS<1% • Testing dominant when prevalence of CS>8% • Factors affecting the decision to test: • Prevalence of CS, test accuracy, cost of IBS therapy, likelihood that symptoms improve on a gluen-free diet Speigel, et al. Gastroenterol 2004;126:1721

  14. Bacterial Overgrowth and IBS * * * *P<0.05 Pimental. Am J Gastroenterol 2003;98:412

  15. Post-infectious IBS • Incidence of IBS after acute bacterial gastroenteritis ranges from 7% to 32%1-3 • ~60% remain symptomatic over 6 years of follow-up • Usually diarrhea predominant • Psychological distress and severity/duration are predictive • Campylobacter/Shigella > Salmonella • Results from immune system activation • Altered gut transit4 • Increased rectal sensitivity2 • Increased intestinal permeability4 • Increased 5-HT–containing enterochromaffin cells in the colon4 1Neal KR, et al. BMJ. 1997;314:779-782 3Gwee KA, et al. Lancet. 1996;347:150-153. 2McKendrick MW, et al. J Infect. 1994;29:1-3.4Spiller RC, et al. Gut. 2000;47:804-811.

  16. Mucosal and Enteric Inflammation Celiac Sprue Inflammation Stress Post-infectious Small Bowel Bacterial Overgrowth Inflammation and IBS

  17. Increased frequency of IBS and dyspepsiain adults with an affected first-degree relative Mayo Clinic study, Olmstead County, MN1 Monozygotic twins more likely to be concordant for IBS than dizygotic twins. US twin study2 >50% of liability to functional bowel disorders might be subjectto genetic control3 Australian twin study3 Evidence of heredity in IBS 1Locke et al, Mayo Clin Proc 2000; 75: 907 2Levy et al, Gastroenterology 2001; 121 : 799 3Morris-Yates et al, Am J Gastroenterology 1998; 93: 1311

  18. Treatment of IBS:Where are we now?

  19. Symptom-based medical treatment of IBS • Abdominal pain / discomfort • Antispasmodics • Antidepressants • TCAs / SSRIs • Alosetron • Tegaserod • Diarrhea • Loperamide • Other opioids • Alosetron Abdominal pain /discomfort Bloating /distention Altered bowel function • Constipation • Fiber • MOM/PEG solution • Tegaserod Brandt, AJG 2002;97:S7 Drossman, Gastroenterology 2002;123;2108

  20. Fiber/Bulking Agents for IBS • 14 RCTs published in English • All have significant methodological flaws • Psyllium/Ispaghula husk (20-30 grm/day) improves constipation • Bran does not appear to be effective • Data does not support the use of fiber for abdominal pain or diarrhea • No RCTs have evaluated other laxatives for IBS Brandt, AJG 2002;97:S7

  21. Anti-spasmodics for IBS • Anti-cholintergics, anti-muscarinics, Ca-channel blockers • 18 RCTs published in English • Substantial methodological flaws • Several agents found to improve global symptoms or pain • None available in the US • No convincing evidence that dicyclomine or hyoscyamine are effective Brandt, AJG 2002;97:S7 Jailwala, Annals Int Med 2000;133:136 Poynard, APT 2001;15:355

  22. Loperamide for IBS • Loperamide favored over other opiates • does not cross the blood-brain barrier • effects on anal sphincter pressure? • Dose: 2-4 mg up to QID • 3 RCTs published in English • Trials small (28-69) and of short duration (3-5wk) • Improvements in diarrhea but not global symptoms or pain Brandt, AJG 2002;97:S7

  23. Anti-depressants for IBS • Reserve for moderate to severe symptoms • Tricyclic antidepressants • 7 RCTs for Tricyclics published in English • Studies of low quality1 • TCAs appear to be effective at low doses • Recent meta-analysis found improvement in global symptoms (OR=4.2) and pain2 • NNT = 3.2 • Constipation, sedation, weight gain common • Selective serotonin reuptake inhibitors3 • Conflicting results • Venlafaxin but not fluoxetine may decrease colonic sensation • Likely more effective with co-morbid anxiety or depression 1Brandt, AJG 2002;97:S7 4Chial, Clin Gastroenterol Hepatol 2003;1:211 2Jackson, Am J Med 2000;108:65 5Kuiken Clin Gastroenterol Hepatol 2003;1:211 3Clouse, Gut 2003;52:598

  24. (12 wks) P=0.006 NNT=4 P=0.13 Better response in pts with moderate symptoms and IBS-D TCA vs. Placebo for Moderate to Severe FGIDs % Responders Drossman, Gastro 2003;125:19

  25. TCA's for FGID's: Moderate / Severe Side Effects % Reporting AE • 8 fold increase in study drop outs with TCA • Multiple side effects common (mean = 3.5) Drossman, Gastro 2003;125:19

  26. Paroxetine vs. Placebo for IBS unresponsive to fiber (12 wks) P=0.001 P=0.01 No improvements in abdominal pain, bloating, social fxning % Responders Tabas, Am J Gastro 2004;99:914

  27. Treatment of IBS:Where are we headed?

  28. Evolving model of IBS Brain-Gut Interactions Psycho-social Factors ANS AlteredMotility/Secretion VisceralHypersensitivity Inflammation Adapted from Coulie. Clin Perspect Gastroenterol. 1999;2:329-338.

  29. Emerging Therapies for IBS • Pain modulation • Serotonin modulators • Benzodiazepine derivatives • R-tofisopam • Neurokinin antagonists • NK 1, 2, 3 receptor antagonists in development • CRF antagonists • Opioid receptor modulators • Asimadoline, fedotozine • M3 antagonists • Zamifenacin • Octreotide

  30. Relevance of Serotoninto IBS • Modulates gastrointestinal motility and secretion • Important to visceral perception • Involved in CNS function

  31. 5-HT3 Antagonists for IBS • Visceral afferent effects • ENS effects • delays colonic transit • decreases colonic tone • inhibits CI- secretion • Blunts the gastro-colonic response • Central Effects • anti-emetic properties • benefits in anxious or neurotic? Kim, Am J Gastro 2000;95:2698

  32. Clinical trials of Alosetron vs. placebo for D-IBS D-IBS=IBS with diarrhea Primary outcome = abdominal pain* or urgency**

  33. Long-term efficacy of Alosetron in women with IBS-D 48 wks P = 0.001 NNT = 8 P = 0.01 NNT=12 % Responders Chey, Am J Gastroenterol. 2004;99:2195.

  34. Alosetron: A long strange trip… • Alosetron • approved 2/00: improved abdominal pain and bowel-related symptoms in diarrhea-predominant females with IBS1 • side effects: constipation, ischemic colitis, death • voluntarily withdrawn (11/00) • re-approved July 2002 • for females with severe diarrhea-predominant IBS who have failed to respond to conventional therapies • 12 month safety and efficacy trials completed2,3 1Camilleri, APT 1999;13:1149 2Wolfe, AJG 2001;96:803 3Chey, AJG 2004;99:2195

  35. Cilansetron for IBS-D: Phase III Study Results P=<0.073 P=<0.006 P=<0.001 % Responders US Study1 N = 205 Multinational Study2 N = 358 1Miner Am J Gastroenterol 2004;99:S277 2Bradette Gastroenterol 2004;126:A42

  36. Phase III Clinical trials with Cilansetron: Safety data 1Miner Am J Gastroenterol 2004;99:S277 2Bradette Gastroenterol 2004;126:A42

  37. 5-HT4 Agonists for IBS • Tegaserod is a specific 5-HT4 agonist • ENS effects • Augments the peristatic reflex1 • Accelerates orocecal transit and cecal emptying2 • Stimulation of CI-/H20 secretion3 • Possible visceral afferent effects4 1Grider, Gastro 1998;115:370 2Prather, Gastro 2000;118:463 3Stoner, Gastro 2000;116:A648 4Coffin, Gastro 2002;124:A407

  38. Clinical trials of Tegaserod vs. placebo for C-IBS Müller-Lissner. Aliment Pharmacol Ther 2001;15:1655–66 Krumholz. Gut 1999;45(Suppl.V):A260 Novick. Aliment Pharmacol Ther 2002;16:1877–88 Kellow. Gut 2003;52:671 Global endpoint Kellow – non-D IBS

  39. Secondary efficacy variables:Effect of tegaserod • Tegaserod produced a statistically significant reduction in abdominal discomfort / pain • Patients on tegaserod experienced a significant increase in the number of bowel movements • Tegaserod significantly improved stool consistency vs placebo • Tegaserod produced a significantly greater reduction in bloating score vs placebo Müller-Lissner et al, Aliment Pharmacol Ther 2001; 15: 1655 Novick et al, Aliment Pharmacol Ther 2002; 16: 1877 Kellow et al, Gut 2003; 52: 671

  40. Tegaserod: Safety Summary • Safety similar to placebo except for diarrhea and headache • Diarrhea • tegaserod 8.8% vs. placebo 3.8% • occurred early and was typically transient • more common in alternating constipation/diarrhea • Headache • tegaserod 15% vs. placebo 12% • does not cross the blood-brain barrier • No significant increase in abdominal or pelvic surgery in patients treated with tegaserod • Safety data available for up to 12 months Tougas, APT 2002;16:1701

  41. IBS and Ischemic Colitis • Little data on the background prevalence of IC in general population or pts with suspected IBS • Systematic review1 reported a rate of IC in the general population of 4.5 to 44 cases/100,000 person years • United Healthcare data base: prevalence of IC in IBS = 43:100K person years vs. 7.2:100K in controls (RR-3.4)2 • Medi-Cal data base: prevalence of IC in IBS = 179:100K person years vs. 47:100K in controls (RR-3.15)3 1Higgins APT 2004;19:729 2Cole Am J Gastro 2004;99:486 3Singh Gastroenterol 2004:126:A41

  42. IBS and Ischemic Colitis:Why the Association? • Misdiagnosis? • Case Finding? • Common link in pathogenesis of IBS and ischemic colitis? • Molecular changes in serotonin signaling identified in IBS and UC1 1Coates Gastroenerol 2004;126:1657

  43. Serotonin Modulators and Ischemic Colitis Cases per 100K Person-years *All cases of IC in post-marketing **After adjudication Higgins APT 2004;19:729 Cole AJG 2004;99;486 Singh DDW 04 Chey DDW 05 Novartis data on file

  44. Emerging Therapies for IBS • Candidates for IBS-C • 5-HT4 agonists • Chloride channel activators • SPI-0211 • Opioid antagonists • Naloxone, methylnaltrexone, LY 246736 • 5-HT3 agonists? • MKC-733

  45. Emerging Therapies for IBS • Candidates for IBS-D • 5-HT3 antagonists • α-receptor agonists • Clonidine • 5-HT4 antagonists? • Piboserod, sulamserod

  46. Emerging Therapies for IBS Brain-Gut Interactions R-tofisopam Psycho-social Factors • Serotonergic agents • CRF antagonists • NK antagonists • α-receptor agonists AlteredMotility/Secretion VisceralHypersensitivity Opioid agonists Inflammation Opioid antagonists Cl-CA

  47. It’s not just yellow snow you shouldn’t eat!

  48. Treatment of IBS:Psychological Therapies

  49. Psychological Therapies for IBS • Cognitive-behavioral therapy • Hypnotherapy • Relaxation/Stress management • Interpersonal therapy Drossman, Gastroenterology 2002;123;2108

  50. P<0.001 NNT=3 P<0.001 NNT=3 12 wks CBT vs. Education for Moderate to Severe FGID's % Responders Drossman, Gastro 2003;125:19

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