F. Shammas / 04

IBS – Epidemiology, Pathogenesis

Presentation and Diagnosis

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Worldwide Prevalence of IBS

Denmark 7%Denmark 7%

New Zealand 17%New Zealand 17%

UK 22%UK 22%

Nigeria 30%Nigeria 30%

Japan 25%Japan 25%

Australia 12%Australia 12%

China 23%China 23%Germany 12%Germany 12%Netherlands 9%Netherlands 9%

France 20%

Spain 13%US

10–20%

Sweden 13%Sweden 13%Belgium 8%Belgium 8%

IBS data not includedIBS data not included

Canada12%

F. Shammas / 04

Worldwide Prevalence of IBS

0

10

20

30

40

50

60

Pre

vale

nce

(%

)

UK France New US China Nigeria DenmarkZealand

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Prevalence of IBS Diagnosis in Primary Care and Gastroenterology Practices

Primary CarePractice

GastroenterologyPractice

All Other PC Diagnoses

88%

12%IBS

IBS

28%Other GI15%

IBD14%

Peptic20%

Liver10%

Other Functional

13%

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Rates of self-reported IBSin the US by sex and age

Drossman D et al, Dig Dis Sci 1993;38:1569

Age (years)Age (years)

13.513.0

9.4

Female

Male

14

0

Pre

vale

nce

(%

)

15–34 35–44 >45

F. Shammas / 04

IBS Physician Visits

Physician Visits Per YearPhysician Visits Per YearV

isit

s P

er

Ye

ar

Vis

its

Pe

r Y

ea

r

• Patients with IBS tend to require medical attention more than other persons

• IBS accounts for an estimated 12% of primary care visits annually

F. Shammas / 04

US Householder Survey

4.9

13.4

0 5 10 15

Non-IBSPatients

IBS Patients

Days Missed From Work or School in Past Year

Illness-related Absenteeism in IBS vs. Non-IBS Patients

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IBS prevalence versus other important disease states

1Camilleri M, Choi M. Aliment Pharmacol Ther 1997;11:3–152Adams P, Benson V. Vital Health Stat 1991;181:1–212

US prevalence of IBS is 10–15%1

US prevalence rates for other common diseases2

– diabetes 3%

– asthma 4%

– heart disease 8%

– hypertension 11%

F. Shammas / 04

Irritable Bowel Syndrome (IBS) Epidemiology

● Affects approximately 15-20% of the population

worldwide

● 3 times more common in females than males

● Appears in early adolescence or early adulthood. Less

common in children

● Onset declines with advancing age

● Source of suffering, embarrassment, social disability,

and increased healthcare costs

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Other Important Facts About the Epidemiology of IBS

Only 33–50% of people with IBS seek medical attention

GI disorders of function comprise

– 50% of gastroenterology referrals in the UK

– 41% of gastroenterology visits in the US

IBS is estimated to cost the US healthcare system $8 billion per year

IBS is the second most common cause of sick leave after the common cold

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Irritable bowel syndrome

impairs the Quality of Life

(QoL) of patients

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Measuring Quality Of Life (SF-36)

Used extensively in clinical trials Has a well-established validity and reliability Measures 8 dimensions of health:

• physical functioning

• social functioning

• physical role

• emotional role

• mental health

• vitality (degree of energy or fatigue)

• bodily pain

• general health

F. Shammas / 04

Decreased QOL in All 8 SF-36 Domains23 (N=1000)

Domain IBS Non-IBS

Physical Functioning 84.78 93.10

Social Functioning 73.66 88.32Physical Role 71.28 87.24Emotional Role 78.01 91.37Mental Health 72.46 81.18Vitality 52.82 66.31Bodily Pain 60.54 77.42General Health 55.72 75.20

F. Shammas / 04

Comparative QoL in IBS Patients and Healthy Controls

100

80

60

40

20

0

Mea

n s

core

Physic

al

funct

ionin

g

Role p

hysic

al

Bodily p

ain

Gener

al h

ealth

Vitalit

y

Social

funct

ionin

g

Role e

motio

nal

Men

tal h

ealth

SF-36 scale

US norms

UK norms

US study sample

UK study sample

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Measured Decrease in Patient QOL

SF-36 Results by Survey Group

30

40

50

60

70

80

90

PhysicalFunctioning

SocialFunctioning

PhysicalRole

EmotionalRole

MentalHealth

Vitality Bodily Pain GeneralHealth

IBS US General Population Migraine Asthma Female (15-34) GERD

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Impaired QoL in IBS

100

80

60

40

20

0

Asymptomatic controlsIBSChronic heart failure

Sco

re

Physic

al

funct

ionin

g

Role p

hysic

al

Bodily p

ain

Gener

al h

ealth

Vitalit

y

Social

funct

ionin

g

Role e

motio

nal

Men

tal h

ealth

SF-36 scale

F. Shammas / 04

IBS Impact on Quality of Life (QOL)

Decrease patient QOL

Interfere with daily activities, work, and leisure time

Impact sleep, diet, ability to travel, and sexual functioning

Affect ability to function in family- and work-related roles

Contribute to lost productivity and work absenteeism

F. Shammas / 04

Irritable Bowel Syndrome (IBS)Pathogenesis

• Altered intestinal motility

• Abnormal visceral perception/sensitivity

The cause of IBS is poorly understood. However,

improvements in assessment of gut functioning, have

improved the understanding of the syndrome, which is

now considered to be through:

F. Shammas / 04

PathogenesisAltered Motility

Hypomotility

Bowel movements

Hypermotility

C-IBS D-IBS

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PathogenesisAbnormal Visceral Perception/Sensitivity

Physiologicstimuli

Noxiousstimuli

IBS

Physiologicstimuli

Filteringmechanism

Noxiousstimuli

Normal

GI tractGI tract

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Possible Mechanisms of Visceral Hypersensitivity

Altered sensation

AbnormalCNS motor

control

Abnormal GIsmooth muscle

activity

AbnormalCNS sensoryprocessing

Abnormal GImechanoreceptor

sensitivity

F. Shammas / 04

• Food and dietary substances• Chocolate, Dairy products, Fatty meals, Gas-producing food (beans)

• Drugs and medications• Laxatives

• Narcotics

• Calcium Channel Blockers

• Stress• Anxiety, depression, alcohol abuse, and eating disorders

• Hormones• Alteration of sex hormones (menstrual cycle)

• Inflammation and Infection

Irritable Bowel Syndrome (IBS) Trigger Factors

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Psychologic Factors that AffectGI Function

Anxiety, panic, depression

Somatoform disorders (unexplained bodily symptoms)

Physical, sexual or emotional abuse

Alcohol or substance abuse

Eating disorders

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Psychiatric Illness in Patients with IBS / Functional Bowel Disorders and Organic GI Diseases

100

80

60

40

20

0 McDonald Colgan Craig Ford Blanchardand Bouchier, et al., and Brown, et al., et al.,

1980 1998 1984 1987 1990

IBS/functional bowel disorder

Organic GI disease

Pat

ien

ts (

%)

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Classification of IBS According to Predominant Symptom

Other factors to consider include duration and severity of symptoms, disease course, patient demography, referral status and psychosocial features

C-IBS D-IBSA-IBS

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Irritable Bowel Syndrome (IBS)Diagnosis

IBS is a condition that can be diagnosed

positively on the basis of an established

series of criteria, together with limited

exclusion of organic, metabolic or

infectious diseases

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IBS Diagnostic Criteria

• The Manning Criteria

• Rome I Criteria

• Rome II Criteria

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The Manning Criteria (1978)

Four symptoms significantly more common in IBS than in organic disease:

– pain relieved by defecation

– more frequent stools at the onset of pain

– looser stools at the onset of pain

– visible abdominal distention

A strong trend for the following:

– passage of mucus

– sensation of incomplete bowel emptying

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1. At least 3 months of continuous or recurrent symptoms of abdominal pain or discomfort that is

– relieved by defecation and/or– associated with a change in

frequency of stool; and/or– associated with a change in

consistency of stool

2. Two or more of the following at least25% of the time– altered stool frequency

– altered stool form– altered stool passage (straining,

urgency, feeling of incomplete evacuation)

– passage of mucus; and/or– bloating or feeling of abdominal

distention

Rome I Criteria1 Rome II Criteria2

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

– relieved by defecation; and/or– onset associated with a change in

frequency of stool; and/or

– onset associated with a change in form (appearance) of stool

2. The following symptoms are not essential but the more of them that are present, the more confident is the diagnosis: – abnormal stool frequency – abnormal stool form – abnormal stool passage

– passage of mucus – bloating or feeling of abdominal

distention

F. Shammas / 04

Rome II Criteria for Diagnosis of IBS

Abdominal pain or discomfort for at least 12 weeks (not necessarily consecutive) in the preceding 12 months, that has at least two of the following features

– Relieved by defecation

– A change in stool frequency

– A change in stool form or appearance

F. Shammas / 04

Rome II Criteria for Diagnosis of IBS

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 (lumpy/hard or loose/watery stool)–Abnormal stool passage (straining, urgency or feeling

of incomplete evacuation)–Passage of mucus–Bloating or feeling of abdominal distention

F. Shammas / 04

Irritable Bowel Syndrome (IBS)Recognizing IBS

Careful interpretation of the

pain and stool characteristics

is the most important step in

recognizing IBS

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Irritable Bowel Syndrome (IBS)Bristol Stool Form Scale

Separate hard lumps, like nuts (hard to pass). Results from slow transit

Sausage-shaped but lumpy

Like a sausage but with cracks on its surface

Like a sausage or snake – smooth and soft

Soft lumps with clear cut edges (easy to pass)

Fluffy pieces with ragged edges

Watery, no solid pieces. Results from very fast transit

Stool Form Appearance Type

1

2

3

4

5

6

7

Tru

e c

on

stip

atio

nT

rue

dia

rrhe

aId

ea

l n

orm

al

F. Shammas / 04

The positive diagnosis of IBS:a symptom-based approach

Identify current primary symptoms

Initiate a treatment plan based on symptoms

Look for ‘Red Flags’ based on:● history● physical examination● laboratory tests

Follow up in 3–6 weeks

Perform selected diagnostic tests to rule out organic disease

Make a positive diagnosis

IBS with constipation● abdominal pain/discomfort● bloating● constipation

IBS with diarrhea● abdominal pain/discomfort● bloating● diarrhea

F. Shammas / 04

Identify ‘Red Flags’

History

Unintentional weight loss

Onset in older patient (>50 years)

Family history of cancer or IBD

Initial labs

↓ HGB

↑ WBC

↑ ESR

Abnormal chemistry

↑ TSH

Physical

Abnormal exams

Rectal bleeding/obstruction

Positive Flexible sigmoidoscopy or colonoscopy (>50 years)

Red Flags

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Irritable Bowel Syndrome (IBS)Investigations

• Endoscopy (sigmoidoscopy)

• Stool analysis

• Occult blood

• Parasites

• Leukocytes

• Excessive fat

• Radiography

• Hematology

• RBC and WBC counts

• ESR

• C-reactive protein

• Thyroid function tests

F. Shammas / 04

Further Evaluation Based on Symptom Subtype

Constipation Diarrhea Pain/gas/bloating

No Lactose-H2 breath testAdditional tests:

Plain abdominal X-ray

If intractable, consider:

Small bowel X-ray Trial of amitriptyline

Other carbohydrate-H2

breath test GI manometry

? Balloon distention test

Colonic transit testAnal manometry +balloon expulsion

Measure rectoanal angleRectal sensation and emptying

Defecating protography

Stool OSM, ELEC, LaxativesJejunal aspirate for O and PTransit test: SB and colon

Rectal sensation75SeHCAT test/cholestyramine

Predominant symptoms

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Differential diagnosis of IBS

Hyper/hypothyroidism

Inflammatory bowel disease (IBD)

Colorectal cancer

Infectious diarrhea

Lactose malabsorption

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IBS is a stable diagnosis

No change in IBS diagnosis: 97%

Evidence suggests that clinicians can be confident once an IBS diagnosis is made

After an initial diagnosis of IBS, there was no change over time in the diagnosis of 97% of patients (median follow up: 29 years) from Olmsted County, Minnesota

F. Shammas / 04

Irritable Bowel Syndrome (IBS)Principals of Management

• General principles

• Lifestyle modification (dietary changes)

• Psychotherapy/hypnotherapy

• Drug therapy

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Irritable Bowel Syndrome (IBS)Management – General Principles

• Establishing confidence

• Educating the patient about IBS

• Patient reassurance that IBS could be treated

• Dispelling the patient’s fears and misconceptions

• Individualizing a treatment plan based on the patient’s need

• Scheduling appointments for return visits

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Patient Education in IBS

Education and reassurance are essential elements of clinical management

Patients need information about the nature of their condition, such as its high prevalence, the causes, triggers, symptoms, and disease course

Patients should be made aware of the available treatment options e.g. pharmacologic and non-pharmacologic therapies

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Dietary and Lifestyle Modification in IBS

Stress management/reduction techniques have been shown to improve patient well being

Diet diaries may be used to identify dietary factors that tend to trigger IBS symptoms. Elimination or reduction in intake of these foods may reduce the frequency and severity of symptoms

F. Shammas / 04

• Dietary measures

• avoid foodstuff that may cause symptoms as legumes, caffeine, artificial

sweeteners, dairy products, chocolate, fat-rich diets

• encourage high-fiber diets

• prescribe wheat bran

• Avoid drugs that disturb bowel function

Dietary and Lifestyle Modification in IBS

– Drugs causing constipation

• Opiates, Anticholinergics• Tricyclic anti-depressants

• 5-HT3 antagonists• Calcium channel blockers

– Drugs causing diarrhea• Misoprostol• Cisapride

• Antacids containing MgOH• Herbal teas containing senna• Alcohol, caffeine

F. Shammas / 04

Psychotherapy/Hypnotherapy in IBS

Stress management

Interpersonal psychotherapy

Cognitive behavioral therapy

Relaxation techniques to reduce anxiety

Hypnotherapy may also be useful for treating both psychologic and physical symptoms

F. Shammas / 04

Other Complementary Therapies

Herbal medicine (ex: peppermint, ginger, etc…)

Traditional Chinese medicine (herbs, acupuncture)

Traditional Japanese medicine (Kampo)

Traditional Indian medicine (ayurveda)

‘Probiotics’

F. Shammas / 04

Drug Therapy in IBS - Highlights

• There is currently no cure for IBS

• Current treatments for IBS are mainly

symptomatic (end-organ treatments)

• There is a profound placebo response to any

IBS treatment

• Most treated patients end up receiving a

combination of different drugs

F. Shammas / 04

The IBS Prescription Market

Antidiarrheals 5%

Anticholinergics/Antimuscarinics/Antispasmodics

51%

Other (eg, sucralfate) 4%

Cisapride 3%

PPIs8%

H2RAs19%

Antiemetics (including metoclopramide) 3%

Carhartics and Laxatives 7%

F. Shammas / 04

Multiple Prescription Therapies Used

One-year Data for Continuously Enrolled Patients Who Used GI Drugs

Switch22%

Augment42%

Single18%

Continuous7%

Intermittent11%

64%

• 64% of IBS patients switched or augmented their initial prescriptions

F. Shammas / 04

Irritable Bowel Syndrome (IBS)End-Organ Drug Therapy

Predominantsymptom

Treatment Increase fiberOsmotic laxative

Bulk laxative

Antidiarrheal Antispasmodic agentsAntidepressants

DiarrheaConstipation

Abdominal pain/distension

(post-prandial/chronic)

Altered bowel function

F. Shammas / 04

Drug Therapy

LaxativesAnti-Diarrheal AgentsAntispasmodicsAntidepressantsAnxiolyticsOther Medications

F. Shammas / 04

Irritable Bowel Syndrome (IBS)Drug Therapy - Laxatives

LaxativeLaxative MembersMembers Mode of ActionMode of Action

Stimulants Phenolpthalein, bisacodyl,

senna, castor oil

Increase intestinal motility (peristalsis)

Decrease absorption of water and electrolytes

Saline/osmotic Magnesium salts, sodium

phosphate, lactulose,

sorbitol

Retain water in intestinal lumen (osmosis)

Increase intestinal motility (peristalsis)

Bulk-forming Bran, psyllium,

methylcellulose

Cause intestinal distension induce peristalsis

Fecal softeners Docusate, mineral oil,

glycerin

Lower surface tension intestinal fluids penetrate

fecal mass soft, easily passed stools

F. Shammas / 04

Irritable Bowel Syndrome (IBS)Anti-Diarrheal Agents

• Loperamide (Imodium)

- Acts on the circular and longitudinal muscles of the gut- Decrease GI motility and reduce mucosal secretion.- can have a constipating effect and can lead to dependence

• Diphenoxylate (Lomotil)

F. Shammas / 04

Irritable Bowel Syndrome (IBS)Antispasmodics

• Anticholinergics

• Buscopan (hyoscine), Fybogel (mebeverine), dicyclomine

• Probanthine (propanthalene)

• Smooth Muscle Relaxants

• Duspatalin (mebeverine)

• Spasmo-canulase

• Spasmonal (alverine)

• Dicetel, Eldicet (pinaverium bromide)

F. Shammas / 04

Irritable Bowel Syndrome (IBS)Drug Therapy – Centrally-Acting Agents

• Antidepressants

• TCA: Tofranil (imipramine), Desipramine

• Elavil (amitriptyline)

• SSRI: Prozac (fluoxetine)

• Anxiolytics

• Librax (benzodiazepine)

F. Shammas / 04

Irritable Bowel Syndrome (IBS)Drug Therapy – Other Medications

• Opioid Agonists (Fedotozine)

• Somatostatin (Sandostatin-octreotide)

• Cholecystokinin (CCK) antagonists (Loxiglumide)

• Selective Muscarinic M3 Antagonists

(zamifenacin and darifenacin - Pfizer)

F. Shammas / 04

Treatment of C-IBS

Currently there is no approved drug treatment on the market that has consistently proved to be more effective than placebo in the management of ALL symptoms of C-IBS

There is a need for new effective treatments that are well tolerated and target each individual symptom of C-IBS

F. Shammas / 04

Irritable Bowel Syndrome New Therapeutic Approaches

The 5-HydroxyTryptamine (5-HT) Modulators

F. Shammas / 04

New Therapeutic Approaches in IBS

Psychosocialfactors

Alteredsensation

Alteredmotility

Sympathetic

S2, 3, 4

Vagal nuclei

F. Shammas / 04

Alteration of 5-HT (serotonin)

function has been implicated in

the pathogenesis of IBS,

namely in the altered motility

and visceral hypersensitivity…

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Serotonin (5-hydroxytryptamine)

• Serotonin is an important neurotransmitter in both the CNS

and ENS. It is found in 3 main areas in the body; intestinal

wall, blood vessels and CNS

• Approximately 90% of the body’s 5-HT is found in the GIT

• The remainder acts as a neurotransmitter in the myenteric

plexus

• Serotonin has various effects on the intestine, including:

• Inhibition of gastric acid secretion

• Stimulation of synthesis and release of gastric and colonic mucus

• Contraction or relaxation of the GI smooth muscles

F. Shammas / 04

CGRP5-HT4

receptor

Enterochromaffin cells5-HT

Grider JR et al. Gastroenterology 1998;115:370–80

Release ofCGRP, VIP, SP

ACh/SPMotorneurons

VIP/PACAP/NOSMotor neurons

5-HT triggers the peristaltic reflex in Humans

F. Shammas / 04

GI Serotonin (5-HT)Actions

Food reaches the gut

Intestinal distension

stimulates peristalsis

Release of 5-HT from the intestinal mucosa

modulates visceral sensitivity

Stimulates ions and water secretion in the lumen of small intestine & colon

F. Shammas / 04

The GI Serotonin Receptors

• Receptors for serotonin are located on the

afferent neurons and interneurons in the

ENS

• They are involved in the perception of

abdominal pain and GI motility

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The Serotonin Receptors Subtypes

• Approximately 15 subtypes of 5-HT receptors have

been identified in the body

• Only 2 receptors are involved in GI motility and

abdominal pain

• Subtype 3 (5-HT3)

• Subtype 4 (5-HT4)

F. Shammas / 04

The Serotonin Receptors Subtypes

• Subtype 3 (5-HT3)

• Mediate visceral pain

• Reduces colonic transit (induces peristalsis)

• Increases intestinal secretions

• Subtype 4 (5-HT4)

• Stimulates peristalsis

• Involved in modulation of intestinal absorption/secretions

that influences stool consistency and visceral sensitivity

F. Shammas / 04

Role of 5-HT in the GI Tract

5-HT has multiple roles in GI physiology with its effects being due to different mechanisms and different receptor subtypes

5-HT3 receptor activation increases intestinal secretion, motility and colonic tonus

5-HT4 receptor activation leads to peristalsis and increased water/chloride secretion. It can also result in inhibition of intestinal tone and enhanced visceral sensitivity

95% of body’s serotonin in GIT

• 90% in EC cells• 10% in enteric neurons

F. Shammas / 04

The 5-HydroxyTryptamine (5-HT)

Receptors

Agonists & Antagonists

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5-HT4

receptor

Partial agonist

Full agonist

antagonist

The 5-HydroxyTryptamine (5-HT) Receptors

Agonists, Partial Agonists & Antagonists

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5-HT3 Antagonists

5-HT3 antagonists cause constipation and increase colonic transit time.

5-HT3 antagonists have potential use in nausea and vomiting as well as in D- IBS

Ondansetron (Zofran) and Granisetron (Kytril) are currently used to treat chemotherapy-induced nausea and vomiting

Alosetron (Lotronex) and Cilansetron (Calmactin) are being developed for use in D-IBS patients

F. Shammas / 04

5-HT3 Antagonists in D- IBS

Alosetron (Lotronex) approved for treatment of D-IBS in female patients (not effective in men)

– Relieves abdominal pain / discomfort within 1-4 weeks– Decreases fluid secretion in small intestine– Relieves stool frequency and bowel urgency within 1

week– Principal side effect: constipation in 20–30% of patients

Cilansetron (Calmactin) decreased colonic contractile responses to distention

F. Shammas / 04

5-HT4 Receptor Effects

Enhances esophageal clearance and gastric emptying, and hastens intestinal and colonic transit

Mediate reflexes controlling GI motility and secretion

Mediate perception of visceral pain

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5-HT4 Receptor Agents

5-HT4 partialagonists

Zelmac®

• A selective 5-HT4 receptorpartial agonist

• Normalizes bowel function and rapidly relieves abdominal pain/discomfort, and bloatingin IBS patients

5-HT4

antagonists

Prucalopride

Enterokinetic activity

• Being evaluated inpatients with chronicconstipation (phase III trials)

Piboserod

• Alleviates symptoms of D-IBS

• In phase II trials

5-HT4

agonists

F. Shammas / 04

Combined 5-HT3 antagonists/5-HT4 agonists

Cisapride (Prepulsid® - Janssen)

– Gastroprokinetic agent

– Approved for use in GERD

– Off-label use in IBS

– Withdrawn from US market in July 2000 due to cardiac safety concerns (80 fatalities)

F. Shammas / 04

The 5-HydroxyTryptamine (5-HT) Receptors

Agonists, Partial Agonists & Antagonists

Product Mode of Action Indication Principal Claims

Alosteron (Lotronex)

GSK

Selective 5-HT3 antagonist

Women with D-IBS ♦ Relieves abdominal pain / discomfort within 1-4 weeks

♦ Decreases fluid secretion in small intestine

♦ Relieves stool frequency within 1 week

♦ Relieves bowel urgency within 1 week

Prucalopride

Phase III - Janssen

Selective 5-HT4 full agonist

♦ Chronic constipation ♦ IBS (pipeline)

♦ Enhances intestinal motility ♦ Normalization of stool frequency,

consistency and completeness of evacuation

Cisapride

Prepulsid - Janssen

5-HT3 antagonist / 5-HT4 agonist

♦ GERD

♦ IBS (off-label)

♦ Promotes gastric motility

♦ Reduces heartburn due to GERD

Tegaserod

Zelmac - Novartis

5-HT4 partial agonist

♦ C-IBS ♦ A new GI sensorimotor modulator

♦ Normalizes altered motility in IBS ♦ Rapid relief of abdominal pain,

bloating and constipation ♦ Excellent cardiac safety profile

F. Shammas / 04

Targeting the 5-HT4 Receptor

Should Benefits

the

Constipation- Predominant

IBS Patients