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Outline Definition Epidemiology Impact and burden of disease Pathophysiology Treatment: What is the evidence? Novel therapies Concluding Remarks Definition.

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Presentation on theme: "Outline Definition Epidemiology Impact and burden of disease Pathophysiology Treatment: What is the evidence? Novel therapies Concluding Remarks Definition."— Presentation transcript:

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2 Outline Definition Epidemiology Impact and burden of disease Pathophysiology Treatment: What is the evidence? Novel therapies Concluding Remarks Definition Epidemiology Impact and burden of disease Pathophysiology Treatment: What is the evidence? Novel therapies Concluding Remarks

3 What is IBS? A common functional GI disorder manifested by a group of symptoms –Abdominal pain/discomfort –Bloating/distention –Constipation and/or diarrhea No known structural or biochemical abnormalities Symptoms may be exacerbated by eating, stress and some pharmacologic agents Significantly affects quality of life A common functional GI disorder manifested by a group of symptoms –Abdominal pain/discomfort –Bloating/distention –Constipation and/or diarrhea No known structural or biochemical abnormalities Symptoms may be exacerbated by eating, stress and some pharmacologic agents Significantly affects quality of life

4  12 weeks in the last 12 months of abdominal discomfort or pain that has 2 out of 3 features –Relieved with defecation –Onset associated with a  in frequency of stool –Onset associated with a  in consistency of stool The following symptoms are not essential, but the more of them that are present, the more confident is the diagnosis –Abnormal stool frequency (>3/day or <3/week) –Abnormal stool form or abnormal stool passage –Passage of mucus –Bloating or feeling of abdominal distention  12 weeks in the last 12 months of abdominal discomfort or pain that has 2 out of 3 features –Relieved with defecation –Onset associated with a  in frequency of stool –Onset associated with a  in consistency of stool The following symptoms are not essential, but the more of them that are present, the more confident is the diagnosis –Abnormal stool frequency (>3/day or <3/week) –Abnormal stool form or abnormal stool passage –Passage of mucus –Bloating or feeling of abdominal distention THE ROME CRITERIA

5 Anemia Fever Persistent diarrhea Rectal bleeding Severe constipation Weight loss Anemia Fever Persistent diarrhea Rectal bleeding Severe constipation Weight loss Nocturnal symptoms of pain and abnormal bowel function Family history of GI cancer, inflammatory bowel disease, or celiac disease New onset of symptoms in patients 50+ years of age Nocturnal symptoms of pain and abnormal bowel function Family history of GI cancer, inflammatory bowel disease, or celiac disease New onset of symptoms in patients 50+ years of age RED FLAGS!

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7 WORLDWIDE PREVALENCE OF IBS 1 Heaton K et al. 1992; 2 Longstreth G, Wolde-Tsadnik P 1993; 3 Welch G, Pomare W 1990; 4 Bommalaer G et al. 1986 5 Bi-zhen W, Qi-Ying P 1988; 6 Olubuyide O et al. 1995; 7 Kay L et al. 1994 UK 1 USA 2 NewFrance 4 China 5 Nigeria 6 Denmark 7 Zealand 3 UK 1 USA 2 NewFrance 4 China 5 Nigeria 6 Denmark 7 Zealand 3 Rome II = 5%

8 IBS versus Other Important Disease States US prevalence of IBS/functional bloating up to 20% 1 US prevalence rates for other common diseases 2 –Diabetes 3% –Asthma 4% –Heart disease 8% –Hypertension 11% US prevalence of IBS/functional bloating up to 20% 1 US prevalence rates for other common diseases 2 –Diabetes 3% –Asthma 4% –Heart disease 8% –Hypertension 11% 1 Camilleri M et al. Aliment Pharmacol Ther 1997;11:3–15 2 Adams P, et al. Vital Health Stat 10 1991;181:1–212

9 Drossman DA et al. Dig Dis Sci 1993; AGA Teaching Unit in IBS, 1997 PHYSICIANS VISITS PER YEAR

10 The Burden of Gastrointestinal Diseases. AGA 2001 COST OF IBS (in millions)

11 30 40 50 60 70 80 90 Role- Physical Bodily Pain Vitality Social Functioning Role- Emotional Mental Health Mean SF-36 score US Norm IBS Adapted from Wells et al. Aliment Pharmacol Ther. 1997;11:1019-1030. Impact of IBS on Quality of Life Compared with US Norms General Health Physical Functioning 100

12 30 40 50 60 70 80 90 Mean SF-36 score US Norm Diabetes type II IBS Clinical depression Adapted from Wells et al. Aliment Pharmacol Ther. 1997;11:1019-1030. Impact of IBS on Quality of Life Compared with Other Medical Conditions Role- Physical Bodily Pain Vitality Social Functioning Role- Emotional Mental Health General Health Physical Functioning 100

13 Abnormal motility 2 Visceral hypersensitivity 2 Brain-gut interaction 2 5-HT mediated visceral sensitivity and gut motility 1 5-HT mediated visceral sensitivity and gut motility 1 1950 2000 1 Prior A, Read N. Aliment Pharmacol Ther 1993 2 Drossman D. Aliment Pharmacol Ther 1999 EVOLUTION OF MECHANISTIC HYPOTHESES IN IBS Small bowel bacterial overgrowth

14 % REPORTING PAIN IBS PATIENT

15 H. Mertz, 2000. ABERRANT ACTIVATION OF CNS PAIN CENTERS IN IBS ABERRANT ACTIVATION OF CNS PAIN CENTERS IN IBS

16 Unpleasentness at 45 mm Hg (cm) Unpleasentness at 45 mm Hg (cm) Dickhaus et al. Am J Gastroenterol 2003;98:135-43 Anger rating * * *p<0.05 * * AUDITORY STRESS ALTERS PERCEPTUAL AND EMOTIONAL RATINGS OF VISCERAL STIMULI Controls IBS

17 CNS – 5% –Enterochromaffin cells –Neuronal –Enterochromaffin cells –Neuronal GI tract – 95% Gershon MD. Aliment Pharmacol Ther 1999;13(Suppl. 2):15–30 PHYSIOLOGIC DISTRIBUTION OF 5-HT

18 5-HT Excitatory motor neuron (contraction) Excitatory motor neuron (contraction) 5-HT receptors Inhibitory motor neuron (relaxation) Inhibitory motor neuron (relaxation) Enterochromaffin cells Interneurons Sensory neuron Sensory neuron MOTOR ACTIVITY IN IBS 5-HT 4 5-HT 3

19 IBSIBS Gas retention Genetic polymorphism: SERT/Cytokines Inflammation Social stress ?Food hypersensitivity Altered ANS Sleep dysfunction Colonic flora ?Small bowel bacterial overgrowth Heightened visceral nociception Gut-Brain Axis dysfunction Post-Infectious IBS Altered serotonergic function

20 Education/reassurance Dietary modification Focus on health Set realistic goals Pharmacotherapy of GI symptoms Monitoring and modification Psychological treatments Referral to pain management Education/reassurance Dietary modification Focus on health Set realistic goals Pharmacotherapy of GI symptoms Monitoring and modification Psychological treatments Referral to pain management KEYS TO TREATMENT OF IBS

21 27 studies: Median placebo response 47% (range 5 – 84%) REASONS: –On-going attention and care –Expectation of “treatment” response –Placebo response may represent, in part, natural fluctuations in symptoms –Chance 27 studies: Median placebo response 47% (range 5 – 84%) REASONS: –On-going attention and care –Expectation of “treatment” response –Placebo response may represent, in part, natural fluctuations in symptoms –Chance HIGH PLACEBO RESPONSE RATES IN IBS

22 Anticholinergics SM relaxants mebeverine cimetropium pinaverium otilonium trimebutine zamifenacin darifenacin Anticholinergics SM relaxants mebeverine cimetropium pinaverium otilonium trimebutine zamifenacin darifenacin inhibiting gut spasms inhibiting gut spasms modulating visceral pain pathway & anti-nociceptive effect modulating visceral pain pathway & anti-nociceptive effect 5-HT 3 -antagonists Alosetron, cilansetron 5-HT 4 -agonist tegaserod Antidepressants Tricyclics, SSRI NK2-receptor antagonist nepadutant kappa-opioid agonist fedotozine 5-HT 3 -antagonists Alosetron, cilansetron 5-HT 4 -agonist tegaserod Antidepressants Tricyclics, SSRI NK2-receptor antagonist nepadutant kappa-opioid agonist fedotozine TREATMENT OF IBS  Pain & bloating bloating

23 Meta-analysis of 23 RCTs with comparable outcomes (1888 pts) 5 superior to placebo: mebeverine, pinaverium, otilium, trimebutine, cimetropium Meta-analysis of 23 RCTs with comparable outcomes (1888 pts) 5 superior to placebo: mebeverine, pinaverium, otilium, trimebutine, cimetropium Poynard et al. Aliment Pharmacol Ther 2001;15:355-61. EFFICACY OF ANTISPASMODIC AGENTS *** ** *** p<0.001 ** p=0.008

24 Anticholinergics SM relaxants mebeverine cimetropium pinaverium otilonium trimebutine zamifenacin darifenacin Anticholinergics SM relaxants mebeverine cimetropium pinaverium otilonium trimebutine zamifenacin darifenacin inhibiting gut spasms inhibiting gut spasms modulating visceral pain pathway & anti-nociceptive effect modulating visceral pain pathway & anti-nociceptive effect 5-HT 3 -antagonists Alosetron, cilansetron 5-HT 4 -agonist tegaserod Antidepressants Tricyclics, SSRI NK2-receptor antagonist nepadutant kappa-opioid agonist fedotozine 5-HT 3 -antagonists Alosetron, cilansetron 5-HT 4 -agonist tegaserod Antidepressants Tricyclics, SSRI NK2-receptor antagonist nepadutant kappa-opioid agonist fedotozine TREATMENT OF IBS  Pain & bloating bloating

25 7 trials: Only 1 met high quality criteria 1 4 reported significant improvement in: –Abdominal pain –diarrhea 1 7 trials: Only 1 met high quality criteria 1 4 reported significant improvement in: –Abdominal pain –diarrhea 1 LOW-DOSE TRICYCLIC ANTIDEPRESSANTS 1 Jailwala et al. Ann Intern Med 2000; 2 Jackson et al. Am J Med 2000

26 A Randomized Double-Blind Placebo-Controlled Trial of Imipramine in IBS Sharara A et al. Oral presentation at the Annual Scientific Meeting of the American College of Gastroenterology 2006 and Winner of ACG/Novartis Research Award Sharara A et al. Oral presentation at the Annual Scientific Meeting of the American College of Gastroenterology 2006 and Winner of ACG/Novartis Research Award

27 NS15 (31.3%)14 (23.7%)Mixed (alternating) NS7 (14.6%)11 (18.6%)Diarrhea (D) NS100% Prior medical Rx NS15 (31.3%)17 (28.8%)Constipation (C) NS40 (83.3%)45 (76.3%)Flatulence NS47 (97.9%)58 (98.3%)Pain NS46 (95.8%)57 (96.6%)Bloating/Distention NS29 (60.4%) referrals38 (64.4%) referralsType of recruitment NS29 (60.4%)33 (55.9%)Sex (% Male) NS45.3±13.842.6±12.4Mean Age p-value Placebo (n=48) Imipramine (n=59) Patient Characteristics

28 Drop-outs Imipramine*Placebo Premature withdrawal614 Lost to follow-up33 Protocol violation51 Side-effects145

29 Patient Global Relief (Per Protocol) p<0.05 Sharara A et al. Oral presentation ACG 2006. Winner of ACG/Novartis Research Award

30 Patient Global Relief (intent-to-treat) p=0.053 Sharara A et al. Oral presentation ACG 2006. Winner of ACG/Novartis Research Award

31 Imipramine-Associated Side Effects

32 Mean % Change in SF36 Scores p<0.01

33 Anticholinergics SM relaxants mebeverine cimetropium pinaverium otilonium trimebutine zamifenacin darifenacin Anticholinergics SM relaxants mebeverine cimetropium pinaverium otilonium trimebutine zamifenacin darifenacin inhibiting gut spasms inhibiting gut spasms modulating visceral pain pathway & anti-nociceptive effect modulating visceral pain pathway & anti-nociceptive effect 5-HT 3 -antagonists Alosetron, cilansetron 5-HT 4 -agonist tegaserod Antidepressants Tricyclics, SSRI NK2-receptor antagonist nepadutant kappa-opioid agonist fedotozine 5-HT 3 -antagonists Alosetron, cilansetron 5-HT 4 -agonist tegaserod Antidepressants Tricyclics, SSRI NK2-receptor antagonist nepadutant kappa-opioid agonist fedotozine TREATMENT OF IBS  Pain & bloating bloating

34 Effect of Alosetron on Relief of Abdominal Pain and Discomfort and Stool Consistency (D-IBS) Camilleri M et al. Lancet 2000;355:1035–40 With relief (%) 123456789101112+1+2+3+4 LOCF Placebo b.i.d. Alosetron 1mg b.i.d. *p<0.05 70 60 50 40 30 20 10 0 70 60 50 40 30 20 10 0 12 weeks treatment 4 weeks follow-up * * * * * * * * * * * * * * * * * * * * * * * * Stool consistency score Alosetron 1mg b.i.d. Placebo LOCF **p<0.001 Hard Very hard Formed 0123456789101112+1+2+3+4 12 weeks treatment 4 weeks follow-up 43214321 43214321 Loose **

35 Tegaserod Aminoguanidine indole derivative of serotonin Specific 5-HT 4 partial agonist Actions: –Stimulates small and large intestinal motility –Accelerates whole oro-cecal transit time –Stimulated peristalsis and gastric emptying –Stimulates intestinal chloride secretion –Inhibits visceral hypersensitivity Aminoguanidine indole derivative of serotonin Specific 5-HT 4 partial agonist Actions: –Stimulates small and large intestinal motility –Accelerates whole oro-cecal transit time –Stimulated peristalsis and gastric emptying –Stimulates intestinal chloride secretion –Inhibits visceral hypersensitivity

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37 TEGASEROD in C-IBS Satisfactory relief by week (ITT) *p<0.05; **p<0.01 vs placebo ** * * –124681012WD2WD4 placebo tegaserod

38 Melatonin and the Gut Barajas-Lopez C et al 1996; Storr M et al 2000; Roberts-Thomson IC 1988; Lu WZ et al 2005 Barajas-Lopez C et al 1996; Storr M et al 2000; Roberts-Thomson IC 1988; Lu WZ et al 2005 Melatonin exerts both excitatory & inhibitory effects on the gut but mechanism unclear ? blockade of nicotinic channels and/or interaction with Ca 2+ -activated K + channels ?mediating gut visceral sensation Melatonin exerts both excitatory & inhibitory effects on the gut but mechanism unclear ? blockade of nicotinic channels and/or interaction with Ca 2+ -activated K + channels ?mediating gut visceral sensation

39 RCT of Melatonin in IBS Song, G H et al. Gut 2005;54:1402-1407

40 Melatonin in IBS Melatonin did not change rectal pressures during squeezing, pushing, or resting states indicating that melatonin did not influence gut motility 3 mg melatonin at bedtime for two weeks did not improve subjective or objective sleep parameters Melatonin did not change rectal pressures during squeezing, pushing, or resting states indicating that melatonin did not influence gut motility 3 mg melatonin at bedtime for two weeks did not improve subjective or objective sleep parameters Song, G H et al. Gut 2005;54:1402-1407

41 Probiotics in IBS 77 patients with IBS randomized to Lactobacillus salivarius or Bifidobacterium infantis (1 x 10 10 live bacterial cells) for 8 weeks Symptoms, QoL, stool microbiologic studies, and PBMC release of IL-10 and IL-12 done at beginning and end of study 77 patients with IBS randomized to Lactobacillus salivarius or Bifidobacterium infantis (1 x 10 10 live bacterial cells) for 8 weeks Symptoms, QoL, stool microbiologic studies, and PBMC release of IL-10 and IL-12 done at beginning and end of study O’Mahoney L et al. Gastroenterology 2005;128:541-551

42 Probiotics in IBS O’Mahoney L et al. Gastroenterology 2005;128:541-551

43 1 Balsari A et al. Microbiology 1982;5:185-94 2 King TS et al. Lancet 1998;352:1187-9 1 Balsari A et al. Microbiology 1982;5:185-94 2 King TS et al. Lancet 1998;352:1187-9 Probiotics in IBS

44 Which of the following do you find as the most disturbing-and difficult to treat- symptom in IBS? Which of the following do you find as the most disturbing-and difficult to treat- symptom in IBS? 1. Abdominal pain 2. Constipation 3. Diarrhea 4. Bloating 5. Feeling of incomplete evacuation 6. Alternating diarrhea & constipation 1. Abdominal pain 2. Constipation 3. Diarrhea 4. Bloating 5. Feeling of incomplete evacuation 6. Alternating diarrhea & constipation

45 The colon is the major site of intestinal H 2 formation (>99% in fasting state and after lactose) H 2 production depends upon delivery of non- absorbable CHO to colon bacteria (10 14 bacteria) Large quantities can be liberated with relatively small amounts of CHO (85 mL over 90-min period 1 ) Symptoms of gaseous distention after certain foods are temporally related to breath H 2 concentration 2 The colon is the major site of intestinal H 2 formation (>99% in fasting state and after lactose) H 2 production depends upon delivery of non- absorbable CHO to colon bacteria (10 14 bacteria) Large quantities can be liberated with relatively small amounts of CHO (85 mL over 90-min period 1 ) Symptoms of gaseous distention after certain foods are temporally related to breath H 2 concentration 2 Hydrogen Gas in Man 1 Levitt MD. N Engl J Med 1969;281:122-7 2 Calloway D. Gastroenterology 1966;51:383-9 1 Levitt MD. N Engl J Med 1969;281:122-7 2 Calloway D. Gastroenterology 1966;51:383-9

46 Rifaximin Rifamycin derivative: inhibits bacterial RNA synthesis Non-absorbable & free of side-effects Good activity against aerobic & anaerobic bacteria 1 Low level of resistance strains with chronic use 2, 3 Causes significant  in H 2 production in GI tract 4 Shown in open-label studies to reduce symptoms of flatulence and bloating 4, 5 Rifamycin derivative: inhibits bacterial RNA synthesis Non-absorbable & free of side-effects Good activity against aerobic & anaerobic bacteria 1 Low level of resistance strains with chronic use 2, 3 Causes significant  in H 2 production in GI tract 4 Shown in open-label studies to reduce symptoms of flatulence and bloating 4, 5 1 Drugs 1995;49:467-84; 2 Drugs Exp Clin Res 1986;12:979-81; 3 Chemotherapy2000;46:253-66; 4 Aliment Pharmacol Ther 2000;14:551-6; 5 Int J Colorectal Dis 2003;18:55-62 1 Drugs 1995;49:467-84; 2 Drugs Exp Clin Res 1986;12:979-81; 3 Chemotherapy2000;46:253-66; 4 Aliment Pharmacol Ther 2000;14:551-6; 5 Int J Colorectal Dis 2003;18:55-62

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49 Global Assessment of Relief * * Sharara AI et al. Am J Gastroenterol 2006 * p < 0.05

50 * * IBS patients Sharara AI et al. Am J Gastroenterol 2006 * p < 0.05 Global Assessment of Relief

51 Symptom score vs. LHBT RifaximinPlacebo

52 Bloating score vs. LHBT RifaximinPlacebo

53 Constipation With IBS Constipation With IBS Diarrhea pred. IBS Diarrhea pred. IBS Pain pred. IBS Pain pred. IBS Fiber, exercise Fluid intake Osm. Laxative Antispasmodic agents Serotonin-4 agonist ? Low-dose TCA Trial diet excluding lactose/caffeine Loperamide, Antispasmodic agent Serotonin-3 antagonist Serotonin-3 antagonist if diarrhea occurs Consider psychotherapy, careful reevaluation mild Antispasmodic agent moderate severe Modified from Mertz HR. N Engl J Med 2003;349;2136-46. Low-dose TCA Education, reassurance, stress management Low-dose TCA Proposed Algorithm

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