Prevalence of IBS : Diagnosis Past, Present, and Future IBS 12% IBS

G. Nicholas Verne, M.D. Other GI 28% 15% IBD Professor and Division Director 14% Division of Gastroenterology, Hepatology, Nutrition All Other PC Peptic Other 20% Functional Diagnoses 13% Department of Internal Medicine 88% 10% Ohio State University Columbus, OH Primary Care Gastroenterology Practice Practice

Mitchell & Drossman, Gastroenterology, 1987

Prevalence of IBS in Quality-of-life impact of the US IBS vs other conditions Subscale score (100=good; 0=bad) 14 100 12 Male 90

10 Female 80 70 8

% 60

6 50 40 IBS 4 US General Population 30 Migraine 2 20 Asthma female (15-34) 10 GERD 0 0 15-34 35-44 >45 Physical Role Bodily General Vitality Social Role Mental Functioning Physical Functioning Health Ages in Years Pain Health Emotional Drossman et al., Dig Dis Sci, 1993 Frank et al, Clin Ther 2002

1 Medical Costs Stool Character- Associated With IBS Description

• IBS results in an estimated $8 billion in direct medical costs annually

• IBS sufferers incur 74% more direct healthcare costs than non-IBS sufferers

• IBS patients have more physician visits for both GI and non-GI complaints

Talley et al., Gastroenterology, 1995

IBS: Symptoms Prevalence by IBS subgroups Chronically recurring symptoms Survey respondents (%) 9 Abdominal pain 8 Overall 6.7 Females 9 Altered bowel function 5.6 5.6 Males 5.2 5.5 5.3 5.2 Alternator 4.7 3022 residents 3.5 Diarrhea surveyed in predominant predominant Minnesota 536 respondents 9 Incomplete evacuation 0 9 Urgency IBS- IBS- IBS- 9 Bloating constipation diarrhea alternating Talley et al, 1995

2 Rome I-II Criteria Rome III Criteria Visceral 1. At least 3 months of continuous 1. At least 12 weeks, which need or recurrent symptoms of not be consecutive, in the Hypersensitivity in IBS abdominal pain or discomfort that past 12 months of abdominal is: discomfort or pain that has 2 9 Relieved by and/or of 3 features: Pain 9 Associated with a change in 9 Relieved by defecation; frequency of stool; and/or and/or Brain stem Ascending pain pathway 9 Associated with a change in Dorsal root ganglion consistency of stool 9 Onset associated with a change in frequency of 2. 2 or more of the following at least stool; and/or 25% of the time: Spinal 9 Onset associated with a 9 Altered stool frequency cord change in form 9 Altered stool form (appearance) of stool Viscera 9 Altered stool passage (straining, urgency, feeling of incomplete evacuation) 9 Passage of mucous; and/or 9 Bloating or feeling of abdominal distension Longstreth, Gastroenterology, 2006 Verne & Price, 2002

IBS-Pathophysiology CNS / ENS Visceral Pain Thresholds Stress affects Pain Clustered Autonomic GI function sensitivity contractions reactivity Pain produced by rectosigmoid balloon distension 60 Meals 3 cpm Visceral Post-infectious IBS Pain / motility motility hypersensitivity IBS

1950 19601970 1980 1990 2000 40

Mechanisms Brain-Gut 20 Interactions Normal Motility Pain Reporting % Myoelectrical Marker

Inflammation 0 20 60 100 140 180 Visceral/Somatic Rectosigmoid balloon volume (mL) Hypersensitivity

Whitehead et al., Dig Dis Sci, 1980

3 Distender Series ®/Barostat Visceral Stimulation Protocol

Barostat Catheter/Balloon Somatic Hypersensitivity in IBS Patients • IBS patients also exhibit a number of extra- intestinal symptoms such as migraine headaches, back and muscle pain • Consistent with central hyperalgesic mechanism(s) • Recent studies have suggested that somatic hyperalgesia may also occur in IBS patients

Verne & Price, 2002

4 Thermal Hyperalgesia Hot Water Immersion in IBS

*P<0.001

*

*

Verne et al., Pain 2001.

Mechanical Visual Viscerosomatic Analogue Scale Convergence

Foot

Anterolateral Colon Tract axon

Price et al., Pain, 1994 Verne et al., Gut, 2006

5 Visceral Some Possible Mediators of Hypersensitivity:Pathophysiology Motility and Visceral Sensitivity • Triggers: chemical, environmental, physical, stress, inflammatory • Motility: • Visceral sensitivity: • Postulated mechanisms: - serotonin - serotonin 9hyperexcitability/activation of neurotransmitters - acetylcholine - tachykinins (sub P, CGRP) - nitric oxide - calcitonin gene-related 9modulation of nociceptive transmission (NMDA) - substance P peptide 9recruitment of silent nociceptors - vasoactive intestinal - neurokinin A 9loss of inhibitory modulation to dorsal horn peptide - enkephalins neurons - cholecystokinin 9neuroplasticity leading to chronic visceral hypersensitivity

Mayer & Raybould, Gastroenterology, 1990; Kim and Camilleri, Am J Gastroenterol 2000 Mayer & Gebhart, Gastroenterology, 1994 Grider et al., Gastroenterology 1998

Sensitization Following Plasma 5-HT levels Peripheral Injury in IBS Mechanosensitive afferent 5-HT (nmol/l) 5-HT (nmol/l) Sensitized Controls (n=6) IBS patients (n=5) 1 1400 Meal 1400 Meal spinal 2 10 7 circuits 1200 3 1200 8 4 9 1000 5 1000 10 800 6 800 11 Dorsal root 9 ganglion 600 600

400 400 7 8 200 200 11 0 0 0 1.0 2.0 3.0 4.0 0 1.0 2.0 3.0 4.0 Peripheral Time (h after meal) Time (h after meal) Injury

Bearcroft et al., Gut, 1998

6 Serotonin and EC cells Diagnostic Tests for IBS in Altered GI Motility If patient has typical features of IBS:

Increased circulating 5-HT Diarrhea • Labs: 9CBC, electrolytes, LFTs, TSH • Stool studies: Increased number of EC cells Constipation in post-infectious IBS 9Occult blood, leukocytes, O & P, Giardia lamblia antigen • : Decreased number of EC cells in constipation 9Sigmoidoscopy ± air-contrast barium enema or if ≥ 50 yrs Bearcroft et al., Gut 1998 Spiller et al, Gut 2000

IBS - Pathophysiology “Red Flags” Input Integration Effect Additional diagnostic screening needed for Cognition atypical presentations such as: Affect • Anemia • Nocturnal symptoms of Sight Sound pain and abnormal bowel Smell • Fever function Somatosensory • Persistent diarrhea • Family history of GI cancer, • Rectal bleeding inflammatory bowel Motility disease, Viscerosensory Secretion Blood Flow • Severe constipation or celiac disease • Weight loss • New onset of symptoms in patients 50+ years of age

7 Case Presentation • 19 yo wf with hx “refractory IBS” • 12 year hx constipation, abdominal pain, and marked abdominal distension • Previous workup including endoscopy: negative • 3 weeks noted between spontaneous bowel movements • On exam, marked distension of abdomen is noted with decreased bowel sounds • KUB obtained:

8 Current Management of IBS Available Treatments • Establish a positive diagnosis for IBS

• Reassure patient that there is no Antispasmodics Anticholinergic/ serious organic disease or alarming Pain Bloating Antiflatulents symptoms Antispasmodics TCAs/SSRIs • No “gold standard” treatment Altered • Existing therapies: Bowel Motility 9marginal efficacy Loperamide Calcium polycarbophil 9side effects Lactulose Cholestyramine 70% sorbitol Psyllium PEG solution 9target only 1 symptom Methylcellulose

Psychological Therapy of Functional Gut Treatments for IBS Pain: A Unique Problem

• Some patients with IBS may also benefit from: • Current treatment modalities are based on 9 Referral to a psychologist or psychiatrist unproven pathophysiological concepts 9 Hypnotherapy • Placebo response rates vary from 20-88 % 9 Biofeedback • Few therapies have ever been 9 Psychodynamic therapy conclusively been shown to be superior to 9 Stress management/relaxation placebo in well designed studies 9 Cognitive behavioral programs

Drossman DA et al. The Functional GI Disorders, 2000.

9 Placebo Response Low Dose TCAs: Possible Rate in IBS Mechanisms of Analgesic Action 31 controlled treatment trials 1966-98, n= 2469 • Reuptake inhibition of NE and 5HT • Receptor antagonism of H1, 5HT-2, D2, • Overall range 17-84% muscarinic sites • Median 52 % • Mean 55.6 % • NMDA receptor antagonist • Range 17-40 % : 10 studies, n = 472 • Induction of glucocorticoid receptor • Range 41-60 %: 8 studies, n = 557 expression • Range 61-84 %: 13 studies, n = 1440 • Direct effect on peripheral afferent nerves

Tricyclic Antidepressants Physiological and SSRIs Distribution of 5-HT

• Used for pain CNS – 5% • Reserved for patients with severe or refractory symptoms 9Are effective for neuropathic pain GI tract – 95% • enterochromaffin cells 9Have central analgesic/anticholinergic effects • neuronal

Drossman & Thompson, Ann Intern Med., 1992 Gershon, Aliment Pharmacol Ther.,1999

10 Serotonin (5-HT) Serotonin (5-HT) Receptors in the Gut Receptors in the Gut 5-HT3 5-HT4 • Currently 14 5-HT receptor or recognition Pharmacologic Action Antagonists Agonists sites identified: Accelerates UGI Transit + + • 5-HT , 5-HT , 5-HT , 5-HT2, 5-HT3, 5- Increased colonic motor - + 1A 1P 1C activity HT4 found in gut Slows colonic transit + -

• 5-HT1: Inhibition of neurotransmitter Anti-emetic properties + ? release and increased smooth muscle contraction Analgesic + ? • 5-HT2: Contraction of gut smooth muscle Anxiolytic + ?

Nodose Ganglion to Brain Serotonin Agents 5-HT 3 5-HT Aδ 5-HT4 3 5-HT3 Receptor Antagonists CGR Alosetron (Lotronex®) P Odansetron (Zofran®) 5-HT Distention Cilansetron Stimulation

5-HT4 Receptor Agonists EC Cells Cisapride (Propulsid®) ® Mast Cells Prucalopride (Resolor ) Tegaserod (Zelnorm®)

5-HT from EC cells activates 5-HT3 & 5-HT4 receptors on extrinsic afferents

11 ® Alosetron (Lotronex®)in IBS Alosetron (Lotronex ): Contraindications

9 Selective 5-HT3 receptor antagonist • Chronic or severe constipation 9 Enhances jejunal water/salt absorption • History of intestinal obstruction, adhesions, perforation, or toxic megacolon 9 Increases colonic compliance 9 Slows colonic transit • Diverticulitis 9 FDA approved for women with diarrhea- • History of Crohn’s disease or ulcerative colitis predominant IBS • Ischemic colitis

Alosetron (Lotronex®) Serotonin (5-HT) and Pain Relief in IBS Motor Activity Proximal Distal

↑ Treatment ↑ Follow-up

70 Interneurons Movement of ** **** **** ** ** in the gut content 60 ** myenteric plexus 50 **p<0.001 *p<0.05 40 Orad Caudad motor neurons CGRP Sensory Motor neurons 30 (contraction) neuron (relaxation) Ach / SP VIP / NO 20 placebo 5-HT 10 alosetron 4

% WithRelief% Receptors 0 5-HT 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Week Enterochromaffin cells release 5-HT

Camilleri et al., Lancet, 2000 Adopted from Grider et al, Gastroenterology 1998; 115: 370

12 Tegaserod (Zelnorm®) • Selective 5HT receptor agonist 4 Motility Disorders • Increases release of CGRP and Sub P • Accelerates colonic transit Carlo Di Lorenzo, MD • Inhibition of afferent nerve activity Professor of Clinical Pediatrics • Previously approved for women with Nationwide Children’s Hospital constipation-predominant IBS • Previously approved for men and women with chronic constipation

New Directions in IBS Treatment Objectives

• 5-HT3 receptor antagonists • To describe normal and abnormal upper and lower GI tract motility • 5-HT4 receptor agonists • Opioid-like agents (Mu, kappa receptor) • To discuss methodology to study gastrointestinal motility • Enkephalin/endorphin analogs • To discuss treatment for motility • NMDA receptor antagonists disorders • Substance P (NK-1) and CGRP antagonists • Amitiza: Secretion at Chloride channel

13 Pathophysiology of FGID Manometry studies tell us: • If we are dealing with a motility problem (vs emotional, sensory, parental hypervigilance, etc) • What works and what does not • Why it does not work (?) • How to make it work better Achalasia (directs rx) Hirschsprung’s • Whether it will it ever work (prognosis) • What organs to transplant

Enteric Nervous System (ENS) Comprises the Myenteric and Submucosal Plexus

Interganglionic Myenteric ganglion She has received: fiber tract

• Esophageal manometry Myenteric plexus • Antroduodenal manometry Submucosal • Colonic manometry Longitudinal muscle plexus Circular muscle •

Submucosal Mucosa ganglion

14 Enteric Nervous System: ENS Contains a Limited Library of Programs for The “Brain-In-The-Gut” Concept Specific Patterns of Intestinal Motor Behavior

Postprandial Interdigestiv Brain-like program eprogram functions of ENS (Mixing pattern) (MMC pattern) Small intestine ENS •Program library Emetic •Feedback Aboral power Programmed Propulsion program control Defense (Oral power program propulsion) •Reflexes Small and Small intestine “Brain-in-the Gut” •Information processing Physiologic Haustral ileus program (Contraction (Segmental Small and absent) Large intestine contractions) large intestine

Sensory, Motor, and Interneurons Bidirectional Communication Between are Synaptically Interconnected to the ENS and the CNS

Form the Microcircuits of the ENS Sensory Central neurons nervous system Enteric nervous system Enteric nervous Interneurons Motor system neurons • Reflexes Interneurons • Muscle • Program • Reflexes • Muscle • Motility patterns library • Secretory Sensory • Information epithelium • Program • Secretory • Secretory neurons processing • Blood library epithelium patterns vessels Motor • Information neurons • Blood • Circulatory • Motility patterns processing vessels patterns • Secretory patterns Gut Behavior • Feedback • Circulatory control patterns Gut Behavior

15 “The problem is in Bodily changes during your head” experimental “headache” 120 Pulse 80 z Powerful influence of emotions and CNS 3 on gut mucosal and motor function Contractile state 2 of the bowel Examples: finals, big game, getting married, 1 z Efficacy of reassurance, behavioral 3 Engorgement of 2 modifications and relaxation techniques the bowel 1

0 Tightening the 30 Time ”head device”

Colonic changes accompanying baseless fear in a healthy subject

3 Contractile state of the bowel 2 1 Time

3

Engorgement of 2 the bowel 1

Discovery of Hoax explained “carcinoma of ”

Almy TP et al. Gastroenterology. 1950;15:95-103

16 Emerging Parameters & Techniques • Wall motion: Motility: • Ultrasonography, SPECT, MRI • Organ volumes, contractile activity, gastric accommodation Methods & Manometry:

Measurements • The “SmartPill”

• Other biomechanical properties: • High frequency intraluminal ultrasound, impedance planimetry • Wall tension, wall stress, wall strain

Established Parameters & Motor Patterns in the Gut Fasting Fed

Techniques Fundic relaxation Periodic motor activity Vagovagal reflex with 3 sequential phases • Intraluminal pressure: (MMC) Sustained but irregular and non- • Manometry (stationary, ambulatory) no motor activity periodic activity until all nutrient has left the ¾Phasic contractions : rhythmic phasic, HAPC, sporadic activity propulsive / nonpropulsive regular activity ENS modulated by vagal receptors • Barostat (single, dual) ENS modulated by CNS ¾ Tonic contractions Increase in high ¾ Tonic reflexes amplitude propagated contractions, phasic contractions & tone •Myoelectric activity: Sporadic, mixing • Electromyography activity; absent in sleep ENS modulated by CNS ¾ Slow wave, spike bursts Defecation ENS + Defecation ENS + CNS CNS

17 The Stomach is Divided into Three Anatomic and Two Functional Motor Regions Barostat = Constant Pressure

Anatomic regions Functional motor contraction regions Pressure relaxation mmHg

Gastric Fundus reservoir Pylorus Tonic Lower contractions esophageal sphincter non-compliant balloon Body (corpus) Antrum

Antral pump Volume Phasic contractions ml Functional motor and anatomic regions do not correspond

Onset and Rate of Gastric Emptying Swallowing Evokes Reflex Gastric Varies with the Composition of the Meal Relaxation and Increased Volume Emptying Lag phase phase 100

Solid meal Brain 75 Enteric Medulla nervous system 50 Interneuronal % Meal Semi-solid remaining in circuits Vagal Vagal stomach meal ellerents allerents 25 Inhibitory Liquid meal motor neurons Gastric stretch 0 Muscle receptors 06020 4080 100 relaxation Time after meal (min) 19

18 Adaptive Relaxation in the Dyspepsia Gastric Reservoir is Pathophysiologic defect Lost After determines the symptom 25 Mechanism Symptom 20 Impaired Early satiety and weight 15 Post vagotomy loss Intragastric Normal accommodation pressure (cm H O) 10 Discomfort 2 Nausea, vomiting, and Delayed gastric Fullness postprandial fullness 5 emptying

0 Pain, belching, weight 0100 200 300 400 500 600 700 Hyperalgesia loss Barostat volume (ml)

19

Functional Dyspepsia Impaired proximal stomach Gastric accommodation dysrhythymias Delayed gastric Antral dilatation emptying Motility: Abnormal intragastric Altered distribution and antroduodenal reflexes Small Intestine contractions

19 The Migrating Motor Complex (MMC) is the Small Intestinal Motility Pattern of the Interdigestive State CNS Modulation

Normal 8 IBS

6

MMC’s per 4 8 hr.

MMC activity 2 front

Time (min) 0 0 5 10 15 20 25 Pressure recording AsleepAwake Stressed ports on catheter

Feeding Shifts Neural Programming from the Interdigestive Motility Pattern (MMC) to the Digestive Pattern (Segmentation)

Interdigestive Meal Digestive

Segmenting motility Why is Motility Segmenting motility Phase III Abnormal? Segmenting motility Phase II Phase I Ileum Segmenting motility

Segmenting motility 1 2 3 4 Time (hours)

20 Acquired Intestinal Aganglionosis and Circulating Autoantibodies withour Activated mast cells in IBS Neoplasia or Other Neural Involvement Close proximity (<5 µm) between mast cells and nerves correlates with abdominal pain in IBS

Control

N IBS

IBS Degranulating

Barbara et al. Gastroenterology 2004;126:693-702

Eosinophilic Ganglionitis Constipation ? Delayed gastric emptying

Altered small bowel motility

Delayed colonic Reduced/absent HAPCs; transit: Absence of normal segmental, predefecatory generalized propagating sequences

Attenuated colonic response to meals and waking Impaired low amplitude contractile activity dyssynergia Schappi MG, et al. Gut 2003; 52: 752-5

21 Anorectal Manometry Biofeedback Training Defecation Disorders Abnormal

• Assesses the internal and external anal sphincters, rectal Rectal pressure sensations and expulsion patterns Increase • A pressure-sensitive catheter is pressure inserted into the anorectum to measure resting and squeeze pressures of the anal canal

Balloon Distension in the Rectum Evokes Relaxation of the Internal Anal Sphincter and Contraction of the Biofeedback Training Defecation Disorders External Anal Sphincter Normal

Distend Rectal pressure rectum Decrease

Internal anal sphincter Anal canal pressure

External anal sphincter

Pressure recording

22 Components of the Continence Apparatus Defecography

• Detects structural abnormalities of the Symphysis rectum pubis

• Thickened barium is instilled into the rectum Puborectalis Internal Superficial anal external anal • Radiographic films are sphincter sphincter (EAS) taken during defecation

The Ano-Rectal Angle is Determined by the Contractile State of the Puborectalis Muscle Colonic Transit Study

• Measures rate at which fecal residue moves through colon • The patient swallows a capsule filled with radiopaque markers • Serial abdominal radiographs are taken 120 hours later • Hinton technique

23 Colonic Transit Study FDA-Approved Treatment (Metcalf Technique) Options for Constipation Osmotic agents Lactulose Indicated for the treatment • Ingest 24 radiopaque R L markers on 3 successive of constipation days Polyethylene Indicated for the short-term glycol (PEG) treatment of occasional • No laxatives, enemas, or constipation medicines that affect 5-HT4- Tegaserod* Indicated for: bowel function Receptor Men and women < 65 years old Agonist with chronic idiopathic • Days 4&7: abdominal plain constipation Women with irritable bowel film syndrome with constipation *(Suspended 3/30/07, IND 21/07/07) • Colonic transit = markers Chloride Lubiprostone Indicated for: (on day 4 and 7), normal <70 Channel Chronic idiopathic constipation activator in adults markers 101 Physicians’ Desk Reference 2005. Montvale, NJ. Thomson PDR; 2005

Types of Prokinetics Pathophysiology of

Dopamine-2 5-HT4 5-HT3 Motilin Cholinesterase QT antagonist agonist antagonist Receptor Inhibitor prolon- FGID agonist gation

Metoclopramide ++

Domperidone + +

Cisapride + + + + +

Erythromycin, + + + + ABT-229

Itopride + + + +

Tegaserod ++

24