Slide #43. Disclosure of Financial Relationships. IBS: Is it in Your Head or Gut? Anthony Lembo, M.D. Associate Professor of Medicine

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1 Disclosure of Financial Relationships : Is it in Your Head or Gut? Anthony Lembo, M.D. Associate Professor of Medicine Beth Israel Deaconess Medical Center Harvard Medical School Boston, MA Anthony Lembo, MD Has disclosed relationships with any entity producing, marketing, reselling, or distributing health care goods or services consumed by, or used on, patients. Consultantship Ironwood/Forest, Astra-Zeneca, Furiex, Salix, Prometheus, Astellas, GSK Honoraria Ironwood/Forest, Astra-Zeneca, Furiex, Salix, Prometheus, GSK Research Grants/Contracts Prometheus, Furiex Rome III Criteria* Recurrent abdominal pain or discomfort at least 3 days/month associated with two or more of the following: Improvement with defecation Onset associated with a change in the frequency of stool Onset associated with a change in the form of stool *Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis % with Rome II is More Common in Women OR =.55 (.5-.61) Andrews 25 OR =.52 ( ) Thompson 22 OR=.67 ( ) Sperber 25 OR =.81 OR =.62 (.6-1.9) ( ) Gwee 24 Men Women Talley 21 Longstreth GF, et al. Gastro 26;13:148 D3 E4

Prevalence According to Age is Associated with other Conditions 3 % Rome II 2 1 USA W. Europe Japan China 1 2 3 4 5 6 7 8 Age (years) Hungin APS et al.

Dig Dis Sci 22; 47:621 E5 Ladabaum et al, Gastroenterology 27; 132: W1172 Whitehead et al, Am J Gastroenterol 27; 12: 2767 76 Vandvik et al, Aliment Pharmacol Ther

2 Prevalence According to Age is Associated with other Conditions 3 % Rome II 2 1 USA W. Europe Japan China Age (years) Hungin APS et al. APT 25; 21:136 Kumano H et al. AJG 24; 99:37 Lau EMC et al. Dig Dis Sci 22; 47:621 E5 Ladabaum et al, Gastroenterology 27; 132: W1172 Whitehead et al, Am J Gastroenterol 27; 12: Vandvik et al, Aliment Pharmacol Ther 24; 2: Head or Gut? Pathophysiology of Evolution of Pathophysiologic Hypotheses in Biochemical Receptors Brain-Gut Interaction Visceral Hypersensitivity Abnormal Motility adapted from Camilleri et al, Aliment Pharmacol Ther 1997;11(1):3-7 Adapted from AGA Teaching Series

Pathophysiology of Dysmotilityof the Small Intestine Reported in Irritable Bowel Syndrome

psychological stress Gastrointestinal infection Alterations in gut microbiota Changes in

Physiological disturbance symptoms Abnormal propagation pattern of duodenal contractions

especially postprandially, CCK Subtle alterations in jejunal MMC: Phase 3 periodicity and

transit B1 B16 Dysmotilityof the Colon Reported in Irritable Bowel Syndrome Altered numbers

transit: accelerated in -D, delayed in -C Attenuated rectal tone increases in response to

3 Pathophysiology of Dysmotilityof the Small Intestine Reported in Irritable Bowel Syndrome Genes Early learning Family influences External stressor Adverse life events Chronic psychological stress Gastrointestinal infection Alterations in gut microbiota Changes in diet Susceptible individual Courtesy of Robin Spiller Psychological disturbance Physiological disturbance symptoms Abnormal propagation pattern of duodenal contractions Impaired segmental gas handling Increase in highamplitude propagated contractions in ileum especially postprandially, CCK Subtle alterations in jejunal MMC: Phase 3 periodicity and amplitude Phase 2 duration and pattern Postprandial duration and pattern Alterations in transit B1 B16 Dysmotilityof the Colon Reported in Irritable Bowel Syndrome Altered numbers of highamplitude propagated contractions (HAPCs): increased in -D, decreased in -C Altered transit: accelerated in -D, delayed in -C Attenuated rectal tone increases in response to colonic distension Reduced rectal compliance Altered colonic motor response to feeding: exaggerated +/or delayed B12 B114

Am J Gastroenterol 21; 96:1499 Health B13 B117 Whitehead et al, Gastroenterology, 199; 98:1187-1192.

4 Dysmotility is Common in Evidence for Visceral but not Somatic Hypersensitivity Ouch! Highamplitude propagated contractions (no./hour) Health Amplitude of contraction (mmhg) Colonic Distension Ice Water Immersion Normal Fasting Meal Cholecystokinin Chey WY et al. Am J Gastroenterol 21; 96:1499 Health B13 B117 Whitehead et al, Gastroenterology, 199; 98: % 5 patients with moderate 4 symptom 3 severity 2 Hypersensitivity is Associated with Greater Symptom Severity 1 ** Pain *** ** Bloating Constipation Diarrhea Posserud I et al. Gastroenterology 27; 133:1113 Pain and bloating independently associated with rectal hypersensitivity (r 2 =.22) Rectal hypersensitivity (n=67) ** Satiety Normal sensitivity (n=42) *** Total GI symptoms Anxiety B15 * * P<.5 ** P<.1 *** P<.1 Depression Distension pressure (mmhg) Stress is Associated with Visceral Hypersensitivity 2 1 Defecatory urge in response to rectal distension P<.1 Before stress Posserud I et al. Gut 24; 53:112 During stress P<.1 Distension sequence P<.5 After stress : *Rectal hypersensitivity after stress (Stroop test, mental arithmetic) *Also enhanced CRF and ACTH responses during stress in Health B16

Patients Show Greater Activation in dacc, INS, and Dorsal Brain Stem, Including Locus Coeruleus, To Distension Evidence of Increased Immunoreactivity -C Red = activation Green = activation Control

5 Patients Show Greater Activation in dacc, INS, and Dorsal Brain Stem, Including Locus Coeruleus, To Distension Evidence of Increased Immunoreactivity -C Red = activation Green = activation Control Increased histamine release from colonic biopsies Increased rat mesenteric afferent discharge from (but not healthy) colonic biopsies supernatant MCC ACCsg ACCig DBS Histamine release 3 (ng/ml/mg) 2 P<.1 * afferent discharge (imp/s) P<.5 vs health Health Saline ains pins AMYG 1 Health mmhg Time (sec) Berman SM et al. J Neurosci. 28; 28:349 BI-17 Barbara G et al. Gastroenterology 27; 132:26 B18 Role of the Microbiota in EVIDENCE OF ALTERED INTESTINAL PERMEABILITY Paracellular Permeability in Colonic Biopsies 16 * Permeability to FITCsulfonic acid (ng/ml) Healthy subjects (n=5) (n=12) -C (n=3) -D (n=4) -A (n=5) B19 *P<.5 vs healthy subjects -A= with alternating symptoms; -C=constipation-predominant ; -D=diarrhea-predominant. Piche T, et al. Gut. 29;58:

motility / Gut immune Visceral Peripherally acting Diets secretion interactions hypersensitivity Fiber Antibiotics Probiotics/Prebiotics GC-C Agonist 5-HT3

28;17:117 T143 T21 Adequate Relief -QOL Antidepressants in Low-dose Amitriptyline for -D Most studies are of low quality 1 TCAs appear to be more effective

6 : Is it in Your Head or Gut? Psychosocial factors Agents acting in CNS (+ peripheral) Placebo Antidepressants Serotonin modulators 5-HT3 Antagonist Brain Gut Interactions Altered motility / Gut immune Visceral Peripherally acting Diets secretion interactions hypersensitivity Fiber Antibiotics Probiotics/Prebiotics GC-C Agonist 5-HT3 Antagonist Saad R, Chey WD. Expert Opin Invest Drugs. 28;17:117 T143 T21 Adequate Relief -QOL Antidepressants in Low-dose Amitriptyline for -D Most studies are of low quality 1 TCAs appear to be more effective in D-, especially at higher doses (e.g., >5 mg/d) OR = 4.1 for TCAs in FBD 2 % Complete Responders Amitriptyline Placebo P=.1 P= ITT n=54 PP n=5 (8 weeks) 1 mg HS No significant difference in AEs between groups 1. Lesbros-Pankoflickova Et al. APT, 2: Jackson JL, Et al. American Journal of Medicine (18), 2. Vahedi H et al. Aliment Pharmacol Ther. 28;27:

Psychological Therapy for : Meta-analysis Dietary Management of 2 studies (various psychological therapies), 1278 patients Improvement: Psychological therapy (%) Improvement: Usual management or

7 Psychological Therapy for : Meta-analysis Dietary Management of 2 studies (various psychological therapies), 1278 patients Improvement: Psychological therapy (%) Improvement: Usual management or control therapy (%) RR symptoms remain (95% CI) ( ) Significant heterogeneity and funnel plot asymmetry ACG Task Force Recommendation: Psychological therapies, including cognitive therapy, dynamic psychotherapy, and hypnotherapy, but not relaxation therapy, are more effective than usual care in relieving global symptoms of (Grade 1B) Ford AC et al. BMJ. 28;337:a FODMAPs Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols. Impact of FODMAP Diet on Breath Hydrogen Production and Symptoms Excess Fructose Fructans Sorbitol Raffinose Honey, apples, pears, peaches, mangos, fruit juice, dried fruit Wheat (large amounts), rye (large amounts), onions, leeks, zucchini Lentils, cabbage, brussels sprouts, asparagus, green beans, legumes 2-day consumption of high- FODMAP diet (5 g/d) or low-fodmap diet (9 g/d) Gastrointestinal symptoms and lethargy induced by high FODMAP diet in but not control patients Breath hydrogen (ppm) Breath hydrogen production 4 N= Hours Health-HFD -HFD Healthy-LFD -LFD 1. Shepherd SJ, et al. Clin Gastroenterol Hepatol. 28;6: Shepherd SJ, Gibson PR. J Am Diet Assoc. 26;16: HFD=high-FODMAP diet; LFD=low-FODMAP diet Ong DK et al. J Gastroenteorl Hepatol. 21;25:

8 Low FODMAP Diet Reduces Symptoms A randomized, controlled, single-blind, cross-over trial Halmos, et al. Gastroenterology, 214,146,1, Similar & significant differences for: Abdominal pain, bloating, tiredness & satisfaction with stool consistency A Controlled Trial of Gluten-Free Diet in -D Psyllium vs Bran vs Placebo Proportion of Patients With Adequate Relief of Symptoms Each Week 5 * *P<.5. Responders, % 4 * Psyllium, 1 g/day (n=85) Bran, 1 g/day (n=97) Placebo (rice flour), 1 g/day (n=93) Study Duration (weeks) * * Bijkerk CJ, et al. BMJ. 29:339:b3154-B316. Vazquez-Roque, Camilleri, et al. Gastroenterology 213 Volume 144, Issue 5 32

Antispasmodics in : Limited Evidence Polyethylene glycol (PEG) Bowel Function But Not Pain in -C Most are anticholinergics --- reduce bowel contractions Low quality studies Only

Pain Responder FDA Responder CSBM +1 Responder % FDA Responders 13.9% 33.

9 Antispasmodics in : Limited Evidence Polyethylene glycol (PEG) Bowel Function But Not Pain in -C Most are anticholinergics --- reduce bowel contractions Low quality studies Only peppermint oil was more effective than placebo in based on meta-analysis Examples include: Dicyclomine (e.g., Bentyl ) Hyoscyamine alone (e.g., Hyo-Max ) Peppermint oil (e.g., Elanco ) Hyoscyamine, atropine, scopolamine, phenobarbital (e.g., Donnatal ) ) Chapman et al. Am J Gastroenterol 213; 18: Lubiprostone, a Selective Chloride Channel Activator for -C Pooled data from 2 Phase III studies Linaclotide, a GC-C agonist, for -C Abdominal Pain Responder FDA Responder CSBM +1 Responder % FDA Responders 13.9% 33.7%**** Overall responder = monthly responder for 2 of 3 months Monthly responder = at least moderate relief 4 out of 4 weeks or significant relief 2 out of 4 weeks Drossman et al, Alimentary Pharmacology and Therapeutics; 29 3% abdominal pain reduction + increase 1 CSBM from baseline; in the same week for 5% of weeks (i.e, 6 out of 12 weeks) Placebo N=43 Chey WD et al. AJG 213. Lin 29 µg N=41

Rifaximin for with Diarrhea ReTreatment with Rifaximin in -D -related Abdominal Pain and Stool Consistency (Worst Case Analysis) First and Second Repeat Treatment Phases Rifaximin Placebo = 7.6 = 8.

211;364:22-32. Percentage of Responders = 9.

10 Rifaximin for with Diarrhea ReTreatment with Rifaximin in -D -related Abdominal Pain and Stool Consistency (Worst Case Analysis) First and Second Repeat Treatment Phases Rifaximin Placebo = 7.6 = identical phase 3, double-blind, placebo-controlled trials (Target 1 and 2) Randomized to rifaximin 55 mg or placebo, TID x 2 weeks 1. Pimintel M, Lembo A et al; TARGET Study Group. N Engl J Med. 211;364: Percentage of Responders = 9. Responder: Patient responding to -related Abdominal Pain (>3% improvement) nd Stool consistency (>5% decrease in # BMs with type 6 or 7) from Consistency for 2 of the 4 weeks Bifidobacterium infantis for Alosetron, a 5-HT3 Antagonist 1 8 P<.2 N=9 6 Treatment Follow-up SGA: % responders at 4 weeks Whorwell PJ et al. J Gastroenterol 26; 11:1581 BI BI 1x1 8 BI 1x1 6 Placebo 1x1 1 n=9 n=9 n=92 Improvements in abdominal pain, bloating, bowel dysfunction were seen T39 % With Adequate Relief Alosetron (n=279) Placebo (n=29) ? Months Chey WD et al. Am J Gastroenterol. 24; 99:

Responders (%) Eluxadoline, a mu opioid agonist and delta opioid antagonist for -D 35 3 25 2 15 1 5 9.5* 1.

11 Responders (%) Eluxadoline, a mu opioid agonist and delta opioid antagonist for -D * 1.3* Responder: Patient responding to Abdominal Pain (>3% improvement) and Stool consistency (BSS score <5or in absence of BM, if accompanied by 3% improvement in WAP compared to average baseline pain) for 5% of the weeks *p<.1 7.2* 11.5* N=88 N=86 N=89 N=88 N=86 N=89 Weeks 1 12 Weeks 1 26 ACG Task Force Recommendations for -D Recommendation Quality Comments Diets Weak Very low Likely to relate to only some pts Prebiotics Insufficient Evidence Probiotics Weak Very low Likely only some pts will respond Rifaximin Weak Moderate Cost Antispasmodics Weak Low Likely to be effective only short-term Loperamide Strong Very low Improves bowel function with limited effects on pain Antidepressants Weak High Associate with AE with a NNH of 9 Alosetron Weak Moderate Ischemic colitis, restricted to women Ford et al., AJG, 214 ACG Task Force Recommendations for -C Recommendation Quality Comments Diets Weak Very low Likely to relate to only some pts Fiber Weak Moderate Psyllium may be more effective than insoluble fiber Probiotics Weak Very low Likely only some pts will respond Polyethylene glycol Weak Very Low No evidence that PEG improves overall symptoms and pain in Lubiprostone Strong Moderate Cost Linaclotide Strong High Cost Summary is a hetergenous disorder with both peripheral and central mechanisms Both peripheral and centeral acting agents have been shown to be effective Ford et al., AJG, 214

12 Thank You

Slide #43. Functional Disorders - An Update 11/8/ MA ACP Annual Scientific Meeting. Functional Disorders: An Update

Slide #43. Functional Disorders - An Update 11/8/ MA ACP Annual Scientific Meeting. Functional Disorders: An Update Functional Disorders: An Update Anthony Lembo, M.D. Associate Professor of Medicine Beth Israel Deaconess Medical Center Harvard Medical School Boston, MA Disclosure of Financial Relationships Anthony