1

Irritable Bowel Syndrome:Past, Present, and Future

G. Nicholas Verne, M.D.Professor and Division Director

Division of Gastroenterology, Hepatology, NutritionDepartment of Internal Medicine

Ohio State University Columbus, OH

Drossman et al., Dig Dis Sci, 1993

Prevalence of IBS in the US

Ages in Years

0

2

4

6

8

10

12

14

15-34 35-44 >45

%

Male

Female

IBS

Primary CarePractice

GastroenterologyPractice

All Other PC Diagnoses

88%

12%

IBS

28%Other GI15%

IBD14%

Peptic20%

Liver10%

Other Functional

13%

Mitchell & Drossman, Gastroenterology, 1987

Prevalence of IBS Diagnosis

Quality-of-life impact of IBS vs other conditions

Subscale score (100=good; 0=bad)

PhysicalFunctioning

Role Physical

BodilyPain

Role Emotional

Mental Health

Social Functioning

General Health

Vitality0

102030405060708090

100

IBSUS General Population

MigraineAsthma female (15-34)

GERD

Frank et al, Clin Ther 2002

2

Medical Costs Associated With IBS

• 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: SymptomsChronically recurring symptoms

Abdominal painAltered bowel function

Incomplete evacuationUrgencyBloating

Diarrheapredominant

Constipationpredominant

Alternator

Stool Character-Description

Prevalence by IBS subgroups

Talley et al, 1995

Survey respondents (%)

IBS-constipation

5.2

6.7

3.5

IBS-diarrhea

5.5 5.3 5.6

0

8 OverallFemalesMales

3022 residents surveyed in Minnesota

536 respondents

IBS-alternating

5.2 5.64.7

3

Longstreth, Gastroenterology, 2006

Rome I-II Criteria Rome III Criteria1. At least 3 months of continuous

or recurrent symptoms of abdominal pain or discomfort that is:

Relieved by defecation and/orAssociated with a change in frequency of stool; and/orAssociated with a change in consistency of stool

2. 2 or more of the following at least 25% of the time:

Altered stool frequencyAltered stool formAltered stool passage (straining, urgency, feeling of incomplete evacuation)Passage of mucous; and/orBloating or feeling of abdominal distension

1. At least 12 weeks, which need not be consecutive, in the past 12 months of abdominal discomfort or pain that has 2 of 3 features:

Relieved by defecation; and/orOnset associated with a change in frequency of stool; and/orOnset associated with a change in form (appearance) of stool

IBS-PathophysiologyStress affects

GI function

Motility

MealsPain / motility

Myoelectrical Marker

Brain-Gut Interactions

Visceral/SomaticHypersensitivity

Mechanisms

Pain sensitivity

3 cpmmotility

Clusteredcontractions

CNS / ENSAutonomic reactivity

Visceralhypersensitivity

19701950 1960 1980 1990 2000

Post-infectiousIBS

Inflammation

Viscera

Visceral Hypersensitivity in IBS

Ascending pain pathwayBrain stem

Spinal cord

Dorsal root ganglion

Pain

Verne & Price, 2002

Visceral Pain Thresholds

Whitehead et al., Dig Dis Sci, 1980

20 60 100 140 180

% R

epor

ting

Pain

Rectosigmoid balloon volume (mL)

0

20

40

60

IBS

Normal

Pain produced by rectosigmoid balloon distension

4

Distender Series ®/Barostat

Barostat Catheter/Balloon

Visceral Stimulation Protocol

Verne & Price, 2002

Somatic Hypersensitivityin 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

5

Hot Water Immersion

Mechanical Visual Analogue Scale

Price et al., Pain, 1994

Thermal Hyperalgesiain IBS

*

*

*P<0.001

Verne et al., Pain 2001.

ViscerosomaticConvergence

Colon AnterolateralTract axon

Foot

Verne et al., Gut, 2006

6

Visceral Hypersensitivity:Pathophysiology• Triggers: chemical, environmental, physical,

stress, inflammatory• Postulated mechanisms:

hyperexcitability/activation of neurotransmitters (sub P, CGRP)modulation of nociceptive transmission (NMDA)recruitment of silent nociceptorsloss of inhibitory modulation to dorsal horn neuronsneuroplasticity leading to chronic visceral hypersensitivity

Mayer & Raybould, Gastroenterology, 1990;Mayer & Gebhart, Gastroenterology, 1994

Sensitization Following Peripheral Injury

Dorsal root ganglion

Mechanosensitiveafferent

Sensitized spinal circuits

Peripheral Injury

Some Possible Mediators of Motility and Visceral Sensitivity

• Visceral sensitivity:- serotonin- tachykinins- calcitonin gene-related

peptide - neurokinin A- enkephalins

Kim and Camilleri, Am J Gastroenterol 2000Grider et al., Gastroenterology 1998

• Motility:- serotonin- acetylcholine- nitric oxide- substance P- vasoactive intestinal

peptide - cholecystokinin

Plasma 5-HT levelsin IBS

123456

Controls (n=6)

Meal

0 1.0 2.0 3.0 4.00

200

400

600

800

1000

1200

1400

Time (h after meal)

7891011

IBS patients (n=5)

0 1.0 2.0 3.0 4.00

200

400

600

800

1000

1200

1400

Time (h after meal)

Meal

9

8

10

11

7

5-HT (nmol/l) 5-HT (nmol/l)

Bearcroft et al., Gut, 1998

7

Serotonin and EC cells in Altered GI Motility

Decreased number of EC cellsin constipation

Increased number of EC cellsin post-infectious IBS

Increased circulating 5-HT Diarrhea

Constipation

Bearcroft et al., Gut 1998 Spiller et al, Gut 2000

Integration EffectInput

SightSoundSmell

Somatosensory

ViscerosensoryMotility

SecretionBlood Flow

CognitionAffect

IBS - Pathophysiology

Diagnostic Tests for IBSIf patient has typical features of IBS:• Labs:

CBC, electrolytes, LFTs, TSH• Stool studies:

Occult blood, leukocytes, O & P, Giardialamblia antigen

• Endoscopy:Sigmoidoscopy ± air-contrast barium enema or colonoscopy if ≥ 50 yrs

“Red Flags”

• Anemia

• Fever

• Persistent diarrhea

• Rectal bleeding

• Severe constipation

• Weight loss

Additional diagnostic screening needed for atypical presentations such as:

• 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

8

• 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:

Case Presentation

9

Current Management of IBS• Establish a positive diagnosis• Reassure patient that there is no

serious organic disease or alarming symptoms

• No “gold standard” treatment• Existing therapies:

marginal efficacyside effectstarget only 1 symptom

Psychological Treatments for IBS

• Some patients with IBS may also benefit from:Referral to a psychologist or psychiatristHypnotherapyBiofeedbackPsychodynamic therapyStress management/relaxationCognitive behavioral programs

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

Available Treatments for IBS

AntispasmodicsAntiflatulentsAnticholinergic/

AntispasmodicsTCAs/SSRIs

LoperamideCholestyraminePsylliumMethylcellulose

Calcium polycarbophilLactulose70% sorbitolPEG solution

Pain Bloating

AlteredBowel

Motility

Therapy of Functional Gut Pain: A Unique Problem

• Current treatment modalities are based on unproven pathophysiological concepts

• Placebo response rates vary from 20-88 %

• Few therapies have ever been conclusively been shown to be superior to placebo in well designed studies

10

Placebo Response Rate in IBS

31 controlled treatment trials 1966-98, n= 2469

• Overall range 17-84%• Median 52 %• Mean 55.6 %• Range 17-40 % : 10 studies, n = 472• Range 41-60 %: 8 studies, n = 557• Range 61-84 %: 13 studies, n = 1440

Tricyclic Antidepressants and SSRIs

• Used for pain

• Reserved for patients with severe or refractory symptoms

Are effective for neuropathic pain

Have central analgesic/anticholinergic effects

Drossman & Thompson, Ann Intern Med., 1992

Low Dose TCAs: Possible Mechanisms of Analgesic Action• Reuptake inhibition of NE and 5HT

• Receptor antagonism of H1, 5HT-2, D2, muscarinic sites

• NMDA receptor antagonist

• Induction of glucocorticoid receptor expression

• Direct effect on peripheral afferent nerves

Physiological Distribution of 5-HT

CNS – 5%

• enterochromaffin cells• neuronal

GI tract – 95%

Gershon, Aliment Pharmacol Ther.,1999

11

Serotonin (5-HT) Receptors in the Gut• Currently 14 5-HT receptor or recognition

sites identified: • 5-HT1A, 5-HT1P, 5-HT1C, 5-HT2, 5-HT3, 5-

HT4 found in gut• 5-HT1: Inhibition of neurotransmitter

release and increased smooth muscle contraction

• 5-HT2: Contraction of gut smooth muscle

EC Cells

5-HT3

Nodose Ganglionto Brain

5-HT from EC cells activates 5-HT3 & 5-HT4receptors on extrinsic afferents

DistentionStimulation

5-HT

5-HT4CGR

P

5-HT3Aδ

Mast Cells

Pharmacologic Action

5-HT3 Antagonists

5-HT4 Agonists

Accelerates UGI Transit + +

Increased colonic motor activity

- +

Slows colonic transit + -

Anti-emetic properties + ?

Analgesic + ?

Anxiolytic + ?

Serotonin (5-HT) Receptors in the Gut

Serotonin Agents5-HT3 Receptor Antagonists

Alosetron (Lotronex®)Odansetron (Zofran®)Cilansetron

5-HT4 Receptor AgonistsCisapride (Propulsid®)Prucalopride (Resolor®)Tegaserod (Zelnorm®)

12

Alosetron (Lotronex®) in IBS

Selective 5-HT3 receptor antagonist

Enhances jejunal water/salt absorption

Increases colonic compliance

Slows colonic transit

FDA approved for women with diarrhea-predominant IBS

Alosetron (Lotronex®) Pain Relief in IBS

**p<0.001 *p<0.05

0102030

40506070

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

placebo alosetron %

With

Rel

ief

Week

*** * ** ** ** ** **

↑

↑

Treatment Follow-up

**

Camilleri et al., Lancet, 2000

Alosetron (Lotronex®): Contraindications

• Chronic or severe constipation

• History of intestinal obstruction, adhesions, perforation, or toxic megacolon

• Diverticulitis

• History of Crohn’s disease or ulcerative colitis

• Ischemic colitis

Serotonin (5-HT) andMotor Activity

Adopted from Grider et al, Gastroenterology 1998; 115: 370

Enterochromaffin cells release 5-HT

5-HT

Oradmotor neurons(contraction)Ach / SP

5-HT4Receptors

CaudadMotor neurons(relaxation)VIP / NO

Interneuronsin the

myentericplexus

SensoryneuronCGRP

Proximal Distal

Movement of gut content

13

Tegaserod (Zelnorm®)• Selective 5HT4 receptor agonist• Increases release of CGRP and Sub P• Accelerates colonic transit• Inhibition of afferent nerve activity • Previously approved for women with

constipation-predominant IBS• Previously approved for men and women

with chronic constipation

New Directions in IBS Treatment

• 5-HT3 receptor antagonists• 5-HT4 receptor agonists• Opioid-like agents (Mu, kappa receptor)• Enkephalin/endorphin analogs• NMDA receptor antagonists• Substance P (NK-1) and CGRP antagonists• Amitiza: Secretion at Chloride channel

Motility DisordersCarlo Di Lorenzo, MD

Professor of Clinical PediatricsNationwide Children’s Hospital

Objectives• To describe normal and abnormal

upper and lower GI tract motility• To discuss methodology to study

gastrointestinal motility• To discuss treatment for motility

disorders

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Pathophysiology of FGID

AchalasiaHirschsprung’s

She has received:• Esophageal manometry• Antroduodenal

manometry• Colonic manometry • Anorectal manometry

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

(directs rx)• Whether it will it ever work

(prognosis)• What organs to transplant

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

Longitudinal muscleCircular muscle

Mucosa

Myenteric plexus

Submucosal plexus

Myenteric ganglion

Submucosal ganglion

Interganglionic fiber tract

15

Enteric Nervous System:The “Brain-In-The-Gut” Concept

Brain-like functions of ENS•Program library•Feedbackcontrol•Reflexes•Informationprocessing

“Brain-in-the Gut”

ENS

Interneurons•Reflexes•Program

library• Information

processingSensory neurons

Motor neurons

•Muscle•Secretory

epithelium•Blood

vessels•Motility patterns•Secretory patterns•Circulatory

patterns

Gut Behavior

Enteric nervous system

Sensory, Motor, and Interneuronsare Synaptically Interconnected to Form the Microcircuits of the ENS

ENS Contains a Limited Library of Programs for Specific Patterns of Intestinal Motor Behavior

Postprandial program

(Mixing pattern)

Aboral powerPropulsion

program

Physiologicileus

(Contraction absent)

Small and large intestine

Small and large intestine

Small intestine

Small intestine

Large intestine

Small intestine

Haustralprogram(Segmental

contractions)

Interdigestive program

(MMC pattern)

Emetic program

(Oral power propulsion)

ProgrammedDefense

Central nervous system

Interneurons•Reflexes

•Program library

• Information processing

•Feedback control

Sensory neurons

•Muscle

•Secretory epithelium

•Blood vessels

•Motility patterns

•Secretory patterns

•Circulatory patterns

Gut Behavior

Bidirectional Communication Betweenthe ENS and the CNS

Motor neurons

Enteric nervous system

16

Powerful influence of emotions and CNS on gut mucosal and motor functionExamples: finals, big game, getting married,

Efficacy of reassurance, behavioral modifications and relaxation techniques

“The problem is in your head”

Bodily changes during experimental “headache”

Tightening the ”head device”

Engorgement ofthe bowel

Contractile state of the bowel

Time

1

32

123

Pulse80

120

0 30

Colonic changes accompanying baseless fear in a healthy subject

Discovery of “carcinoma of rectum”

Hoax explained

Engorgement ofthe bowel

Contractile state of the bowel

Time

1

3

2

1

2

3

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

17

Motility:Methods &

Measurements

Established Parameters & Techniques

• Intraluminal pressure:• Manometry (stationary, ambulatory)

Phasic contractions : rhythmic phasic, HAPC, propulsive / nonpropulsive

• Barostat (single, dual)Tonic contractionsTonic reflexes

•Myoelectric activity:• Electromyography

Slow wave, spike bursts

• Wall motion:

• Ultrasonography, SPECT, MRI

• Organ volumes, contractile activity, gastric accommodationManometry:

• The “SmartPill”

• Other biomechanical properties:

• High frequency intraluminal ultrasound, impedance planimetry

• Wall tension, wall stress, wall strain

Emerging Parameters & Techniques

Motor Patterns in the GutFasting Fed

Defecation ENS + CNS

Periodic motor activity with 3 sequential phases

(MMC)

no motor activity

sporadic activity

regular activity

ENS modulated by CNS

Fundic relaxationVagovagal reflex

Sustained but irregular and non-periodic activity until all nutrient has left the stomach

ENS modulated by vagal receptors

Sporadic, mixing activity; absent in sleepENS modulated by CNS

Defecation ENS + CNS

Increase in high amplitude propagated contractions, phasic contractions & tone

18

The Stomach is Divided into Three Anatomic and Two Functional Motor Regions

Anatomic regions

Body(corpus)

Functional motor regions

Fundus

Antrum

PylorusLower

esophageal sphincter

Gastric reservoir

Tonic contractions

Antral pumpPhasic contractions

Functional motor and anatomic regions do not correspond

Onset and Rate of Gastric Emptying Varies with the Composition of the Meal

% Meal remaining in

stomach

Lag phase Emptying phase

19Time after meal (min)

Solid meal

Liquid meal

100

75

50

25

0

200 6040 10080

Semi-solid meal

Barostat = Constant Pressure

PressuremmHg

Volumeml

non-compliant balloon

contraction relaxation

Swallowing Evokes Reflex Gastric Relaxation and Increased Volume

Gastric stretch receptors

Vagal allerents

BrainMedulla

Vagal ellerents

Enteric nervous system

Interneuronalcircuits

Inhibitory motor neurons

Muscle relaxation

19

Adaptive Relaxation in the Gastric Reservoir isLost After Vagotomy

Barostat volume (ml)

Post vagotomyIntragastric

pressure(cm H2O)

Normal

DiscomfortFullness

25

20

15

10

5

01000 300200 500400 700600

19

Functional DyspepsiaGastric

dysrhythymias

Impaired proximal stomach accommodation

Delayed gastric emptying

Altered antroduodenal

contractions

Antral dilatation

Abnormal intragastric distribution and reflexes

Dyspepsia Pathophysiologic defect determines the symptom

SymptomImpaired accommodation

Delayed gastric emptying

Hyperalgesia

Mechanism Early satiety and weightloss

Nausea, vomiting, and postprandial fullness

Pain, belching, weight loss

Motility:Small Intestine

20

25

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

Pressure recording ports on catheter

MMC activity

front

20151050Time (min)

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

Pattern (Segmentation)

Interdigestive

4321 Time (hours)

Meal Digestive

Ileum

Segmenting motility

Segmenting motility

Segmenting motility

Segmenting motility

Segmenting motility

Phase I

Phase III

Phase II

CNS Modulation

Asleep StressedAwake0

2

4

6

8

MMC’sper

8 hr.

IBS

Normal

Why is Motility Abnormal?

21

Acquired Intestinal Aganglionosis and Circulating Autoantibodies withour

Neoplasia or Other Neural Involvement

Eosinophilic Ganglionitis

Schappi MG, et al. Gut 2003; 52: 752-5

Control

IBS

IBS

Activated mast cells in IBS

N

Degranulating

Close proximity (<5 µm) between mast cells and nerves correlates with abdominal pain in IBS

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

Constipation

Delayed colonic transit:segmental, generalized

Reduced/absent HAPCs;Absence of normal predefecatorypropagating sequences

Altered small bowel motility

? Delayed gastric emptying

Attenuated colonic response to meals and waking

Pelvic floor dyssynergia

Impaired low amplitudecontractile activity

22

Anorectal Manometry

•Assesses the internal and external anal sphincters, rectal sensations and expulsion patterns

•A pressure-sensitive catheter is 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

External Anal Sphincter

Internal anal sphincter

External anal sphincter

Pressure recording

Distend rectum

Rectal pressure

Anal canal pressure

Abnormal

Increase

Biofeedback Training Defecation Disorders

Biofeedback Training Defecation Disorders

Rectal pressure

Anal canal pressure

Normal

Decrease

23

Components of the Continence Apparatus

Puborectalis

Symphysispubis

Superficial external anal sphincter (EAS)

Internal anal sphincter

Coccyx

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

Defecography•Detects structural

abnormalities of the rectum

• Thickened barium is instilled into the rectum

•Radiographic films are taken during defecation

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

24

R L

Colonic Transit Study (Metcalf Technique)

• Ingest 24 radiopaque markers on 3 successive days

• No laxatives, enemas, or medicines that affect bowel function

• Days 4&7: abdominal plain film

• Colonic transit = markers (on day 4 and 7), normal <70 markers 101

Types of ProkineticsDopamine-2 5-HT4 5-HT3 Motilin Cholinesterase QTantagonist agonist antagonist Receptor Inhibitor prolon-

agonist gation

Metoclopramide + +

Domperidone + +

Cisapride + + + + +

Erythromycin, + + + +ABT-229

Itopride + + + +

Tegaserod + +

FDA-Approved Treatment Options for Constipation

Physicians’ Desk Reference 2005. Montvale, NJ. Thomson PDR; 2005

Osmotic agents Lactulose Indicated for the treatmentof constipation

Polyethylene Indicated for the short-termglycol (PEG) treatment of occasional

constipation

5-HT4- Tegaserod* Indicated for:Receptor Men and women < 65 years oldAgonist with chronic idiopathic

constipationWomen with irritable bowelsyndrome with constipation*(Suspended 3/30/07, IND 21/07/07)

Chloride Lubiprostone Indicated for:Channel Chronic idiopathic constipationactivator in adults

Pathophysiology of FGID