Understanding Irritable Bowel Syndrome (IBS)

IBS Background

Functional Gastrointestinal (GI) Disorders

Lower GI tract Upper GI tract
Dysphagia Noncardiac chest pain Heartburn Gastroesophageal reflux disease (GERD) Functional abdominal pain/bloating Irritable bowel syndrome (IBS) Functional constipation/diarrhea Functional dyspepsia (FD)

Functional biliary disorders

Overlap in the Symptomatology of Functional GI Disorders

Functional abdominal pain Functional abdominal bloating

Functional diarrhea IBS

Functional constipation

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
Thompson WG et al. Gut 1999;45(Suppl. 2):437

IBS History
. . . occasional pain in the intestines and derangement of their powers of digestion, with flatulence . . .
Powell, 1818

. . . spasmodic stricture of the colon an occasional cause for confinement of the bowels . . .
Howship, 1830

. . . the bowels are at one time constipated, at another time lax, in the same person . . . how the disease has two such different symptoms I do not profess to explain . . .
Cumming, 1849

Historical Perspective
Long dismissed as a psychosomatic condition
No clear etiology Predominantly affects women 2 (~70% of sufferers are women) Condition not fatal
1

Attitudes now changing

Incidence and prevalence not extensively monitored in past

2

Maxwell R et al. Lancet 1997;350:16915 Sandler S. Gastroenterology 1990;99:40915

Epidemiology and Impact of IBS

Worldwide Prevalence of IBS

70 60

Prevalence (%)

50 40 30 20 10 0

UK1

USA2

New Zealand3
1

France4

China5

Nigeria6

Denmark7

Heaton K et al. 1992; 2Longstreth G, Wolde-Tsadnik P 1993 3 Welch G, Pomare W 1990; 4Bommalaer G et al. 1986 5 Bi-zhen W, Qi-Ying P 1988; 6Olubuyide O et al. 1995; 7Kay L et al. 1994

Rates of Self-reported IBS in the USA by Sex and Age

Average rate per 1,000 subjects 20

Male
15 Female

10

<45

4565 Age (years)

>65

Sandler RS. Gastroenterology 1990;99:40915

IBS versus Other Important Disease States

US prevalence of IBS up to 20%1
US prevalence rates for other common diseases2
Diabetes Asthma Heart disease Hypertension 3% 4% 8% 11%

Camilleri M, Choi M. Aliment Pharmacol Ther 1997;11:315 2 Adams P, Benson V. Vital Health Stat 10 1991;181:1212

IBS in General Practice

Approached (3,157) Screened (3,111) Gut problem (300) Reclassified, refused, died (21) Interviewed (279) Screen Patient interview Doctor interview Moved, died (2) 6-month follow-up Other functional (36) IBS (76) Organic (100) Unknown (43)

Not GI (22)

Gut problem (255)

Thompson WG et al. Gut 2000;46:7882

IBS Consultation Pattern

Specialists1 ~25% Consulters1 Primary care
1

~75% Nonconsulters1

~70% Female2
1

~30% Male2

Drossman D, Thompson WG. Ann Intern Med 1992;116(Pt 1):100916 2 Sandler S. Gastroenterology 1990;99:40915

Key Facts About IBS

Up to 20% of the US population report symptoms consistent with IBS1 The most common GI diagnosis among gastroenterology practices in the US2 One of the top 10 reasons for PCP visits3 Predominantly affects females (~70% of sufferers)4 The most common functional bowel disorder5
Camilleri M, Choi M. Aliment Pharmacol Ther 1997;11:135 Everhart J, Renault P. Gastroenterology 1991;100:9981005 3 Physician Drug and Diagnosis Audit (PDDA), April 1999, ScottLevin 4 Sandler S. Gastroenterology 1990;99:40915 5 Thompson W et al. Gastroenterol Int 1992;5:7591
2 1

Productivity Burden
14 12

Absenteeism from work or school during the last 12 months

Days per year

10 8

6
4 2

p=0.0001

IBS

Non-IBS
Drossman D et al. Dig Dis Sci 1993;38:156980

Impact on Work Due to IBS

Patients with some missed workdays Average number missed workdays* Patients who cut back some days Average number days cut back*
*Over the previous 4 weeks

30% 1.7 46% 3

Adapted from Hahn B et al. Digestion 1999;60:7781

Physician Visits Per Year

Number of visits per year
6 5 4 3 2 1 0 IBS Non-IBS
GI Non-GI

Drossman DA et al. Dig Dis Sci 1993;38:156980 AGA Teaching Unit in IBS, 1997

Direct 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

IBS Symptoms Reduce Quality of Life

Sense of bowel urgency1,2 Lower abdominal pain/discomfort1 Diarrhea1,2 Constipation1,2 Alternating diarrhea and constipation1,2

Abdominal pain

Altered bowel habits

Psychologic factors

Reduced sense of well-being1

All can contribute to a significant negative quality-of-life impact3

1

Drossman D. Aliment Pharmacol Ther 1999;13(Suppl. 2):314 2 Thompson WG et al. Gut 1999;45(Suppl. 2):9437 3 Hahn B et al. Digestion 1999;60:7781

Impact of IBS on Quality of Life Compared with Other Medical Conditions

90 Mean SF-36 score 80 70 60 50 40
Clinical depression Diabetes type II National norm

IBS

30

Adapted from Wells N et al. Aliment Pharmacol Ther 1997;11:101930

IBS in American Women

The 1999 IBS in American women survey, conducted by a national public opinion research organization, is the largest, most comprehensive national survey ever conducted on IBS More than 1,000 women with IBS, >1,000 women in the general public, >700 healthcare providers were surveyed in July and August 1999

Of >1,000 women diagnosed with IBS

Nearly 40% experience abdominal pain and discomfort, which they describe as intolerable without relief Regardless of severity of abdominal pain, women with IBS reported their symptoms forced them to miss days from work, limit travel, or avoid social outings

Of women in the general public

8% reported having a diagnosis of IBS 12% reported experiencing repeated pain or discomfort in the lower abdomen that is characteristic of IBS
The Landmark Survey

IBS in American Women (Contd)

Women with active IBS, compared with women in the general public, reported
Taking three times as many sick days Being twice as likely to limit the kind or amount of work they can do

Nearly one in 20 reported being hospitalized in the previous year 25% reported being hospitalized for IBS in the past

71% reported more abdominal or intestinal surgeries than women without IBS (58% versus 34%)
Rates of reported gallbladder operations, hysterectomies and appendectomies were higher

The Landmark Survey

IBS in American Women (Contd)

Women with IBS reported seeing an average of three physicians over a 3-year period before they were given a definitive diagnosis of IBS

Most women reported seeing physicians as a primary source of health information

Almost all doctors (87%) admitted that physicians need better education about IBS

The Landmark Survey

Epidemiology of IBS: Summary

Affects up to 20% of the population More common in women Prevalence decreases with age Most with IBS do not seek a physicians help IBS accounts for a large percentage of primary care and gastroenterologists practices Can be a considerable health burden
Drossman DA et al. Gastroenterology 1997;112:212037

Pathophysiology of IBS

Pathophysiology Findings: Motility in IBS

Over 50 years ago
Stress found to affect colonic function in normal subjects1

Beginning in the 1950s

Motor reactivity of the sigmoid colon shown to be much greater in IBS patients than in control subjects2

1970s
An anticholinergic drug shown to reduce mealstimulated sigmoid motility in IBS patients3
1

Almy TP 1951; 2Rogers J et al. 1989; 3Sullivan MA et al. 1978

Pathophysiology Findings: Motility in IBS

Findings in the 1980s
IBS involves the small as well as the large intestine, and dysmotility does not always cause symptoms1 The migrating motor complex (MMC), the 3-phase cycle that sweeps intestinal contents from duodenum to colon, may be disrupted in IBS2 Discrete clustered contractions (DCCs) and prolonged propagated contractions (PPCs), are more common and more often cause pain in IBS patients than controls3,4

Kumar D, Wingate DL 1985; 2Camilleri M, Phillips SF 1989; 3 Kellow JE, Phillips SF 1987; 4Quigley EM et al. 1984

Evolution of Mechanistic Hypotheses in IBS

5-HT mediated visceral sensitivity and gut motility1

Brain-gut interaction2

Visceral hypersensitivity2

Abnormal motility2

1950

2000

Prior A, Read N. Aliment Pharmacol Ther 1993;7:17580 Drossman D. Aliment Pharmacol Ther 1999;13(Suppl. 2):314

Altered Intestinal Motility in IBS

Hypomotility
Bowel movements

Hypermotility

Constipation

Diarrhea

IBS with symptoms of constipation

IBS with symptoms of diarrhea

Pathogenesis of IBS: Visceral Hypersensitivity

Altered sensation

Abnormal CNS motor control

Abnormal CNS sensory processing

Abnormal GI smooth muscle activity

Abnormal GI mechanoreceptor sensitivity

Visceral Sensitivity
Visceral hypersensitivity
Can be induced in normal subjects Is more prevalent in IBS patients1,2

Ness TJ et al. Pain 1990;43:37786 Munakata J et al. Gastroenterology 1997;122:5563

Comparison of Pain Thresholds in IBS Patients and Controls

60 Reporting pain (%) IBS 40

20 Normal 0 20 60 100 140 180 Rectosigmoid balloon volume (mL)

Whitehead WE et al. Dig Dis Sci 1980;25:40413.

Comparison of Pain Thresholds

IBS Normal

Colonic distention

Ice water immersion

Whitehead W et al. Gastroenterology 1990;98:118792

Pathogenesis of IBS: The Brain-gut Axis

Central nervous system (CNS)

Autonomic nervous system (ANS) (brain-gut axis)

Enteric nervous system (ENS)

Phillips S, Wingate DL. Churchill Livingstone, 1998

Enteric Nervous System

Controls motility and secretory functions of the intestine Semiautonomous
Actions modified by parasympathetic and sympathetic nervous systems May function independently

Contains many neurotransmitters, including 5-HT, substance P, VIP (vasoactive intestinal peptide), and CGRP (calcitonin gene-related peptide)

IBS: Current Thinking on Pathophysiology

Defects in the ENS may lead to the hallmark symptoms of
IBS Visceral hypersensitivity1
Increased visceral afferent response to normal as well as noxious stimuli Mediators include 5-HT, bradykinin, tachykinins, CGRP and neurotropins

Primary motility disorder of GI tract2

Mediated by 5-HT, acetylcholine, ATP, motilin, nitric oxide, somatostatin, substance P and VIP
1

Bueno L et al. Gastroenterology 1997;112:171443 Goyal R, Hirano I. N Engl J Med 1996;334:110615

Physiologic Distribution of 5-HT

CNS 5%

GI tract 95%
Enterochromaffin cells Neuronal

Gershon MD. Aliment Pharmacol Ther 1999;13(Suppl. 2):1530

Motor Activity in IBS

Interneurons

Excitatory motor neuron (concentration)

5-HT receptors 5-HT

Sensory neuron

Inhibitory motor neuron (relaxation)

Enterochromaffin cells

Grider JR et al. Gastroenterology 1998;115:37080

5-HT Receptor Effects

Mediate reflexes controlling GI motility and secretion Mediate perception of visceral pain

Gershon M. Aliment Pharmacol Ther 1999;13(Suppl. 2):1530

Pathogenesis of IBS: Intestinal Inflammation

IBS-type symptoms reported in one-third of patients after salmonella gastroenteritis Inflammation may lead to persistent dysfunction of GI motility via changes in enteric nerve and muscle function Possible mechanisms
Changes in smooth muscle contraction Changes in muscle growth Changes in neurotransmitter release

Psychologic Factors in IBS

Motility

Sensitivity

Psychology
Life stress Psychologic state Coping Social support

Psychologic Factors that Affect GI Function

Anxiety, panic, depression Somatoform disorders (unexplained bodily symptoms)

Physical, sexual or emotional abuse

Alcohol or substance abuse

Eating disorders

IBS or Functional GI Disorder (FGID) and Organic GI Disease Patients with Psychiatric Illnesses
100 80 Patients (%) 60 40 IBS/FGID Organic GI

20
0 McDonald and Bouchier 1980 Colgan et al. 1998 Craig and Brown 1984 Ford et al. 1987 Blanchard et al. 1990

Camilleri M, Choi C. Aliment Pharmacol Ther 1997;11:315

Conceptual Model of IBS

Psychosocial factors
Life stress Psychologic state Coping Social support

Early life
Genetics Environment

IBS CNS ENS

Symptom experience Behavior

Outcome
Medications MD visits Daily function Quality of life

Physiology
Motility Sensation

Pathogenesis of IBS: Contributory Factors/Triggers

Food and other dietary substances Drugs and medications Psychologic problems/stress Hormones (menstrual cycle) Seasonal changes

Diagnosis of IBS

History of Diagnostic Approaches

1950s Increased gut motility1
1970s Specific motility markers1

1980 to 1999 Symptom-based criteria1

Manning criteria Rome criteria

1999 Rome II criteria2

Drossman D. Aliment Pharmacol Ther 1999;13(Suppl. 2):314 2 Thompson WG et al. Gut 1999;45(Suppl. 2):437

Altered Bowel Function in IBS

Altered bowel function

Change in frequency of bowel movement

Urgency

Change in stool consistency

Straining

Bloating (fullness/swelling)

Feeling of incomplete bowel movement

Passage of mucus

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
Manning AP et al. Br Med J 1978;2:6534

The Rome Criteria (1992)

3 months continuous/recurrent symptoms of the following Abdominal pain or discomfort that is
Relieved with defecation Associated with a change in frequency of stool and/or Associated with a change in consistency of stool; and

Two or more of the following at least on one quarter of the time

Altered stool frequency (>3/day or <3/week) Altered stool form (lumpy/hard or loose/watery stool) Altered stool passage (straining, urgency) Passage of mucus

Bloating or feeling of abdominal distention

Thompson WG et al. Gastroenterol Int 1992;5:7591

Rome I Criteria

Rome II Criteria

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

At least 12 weeks, which need not be consecutive, in the last 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

Two or more of the following at least 25% 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

Thompson WG et al. Gastroenterol Int 1992;5:7591 2 Thompson WG et al. Gut 1999;45(Suppl. 2):437

The Rome II Criteria

12 weeks or more in the last 12 months of abdominal discomfort or pain that has two out of three features Relieved with defecation; and/or Onset associated with a change in frequency of stool; and/or Onset associated with a change 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 Abnormal stool passage Passage of mucus Bloating or feeling of abdominal distention
Thompson WG et al. Gut 1999;45(Suppl. 2):437

Differential Diagnosis of IBS

Malabsorption Dietary factors Infection Inflammatory bowel disease Psychologic disorders Gynecologic disorders Miscellaneous
1 1 1 1 2 1
1

Drossman D. Aliment Pharmacol Ther 1999;13(Suppl. 2):314 2 Moore J et al. Br J Obstet Gynaecol 1998;105:13225

Red Flags May Suggest an Alternative or Coexisting Diagnosis

Additional diagnostic screening needed for atypical presentations such as
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

Paterson WG et al. CMAJ 1999;161:15460

Basic Diagnosis of IBS

Symptom assessment1
Abdominal pain/discomfort and disturbed defecation Change in stool frequency or consistency Bloating and visible distention

Check for red flags Limited screen for organic disease2

Blood work Thyroid function tests Stools (e.g. occult blood) Fiberoptic sigmoidoscopy
1 2

Hammer J, Talley NJ. Am J Med 1999;107(5A):5S11S Schmulson MW, Chang L. Am J Med 1999;107(5A):20S6S

Make a Positive Diagnosis

Identify abdominal pain as dominant symptom with altered bowel function Look for red flags

1,2

Perform diagnostic tests/physical exam to rule out organic disease

Make/confirm diagnosis Initiate treatment program as part of diagnostic approach Follow up in 3 to 6 weeks
Paterson WG et al. CMAJ 1999;161:15460 American Gastroenterological Association. Gastroenterology 1997;112:212037
1

Persistence of Diagnosis and Symptoms of IBS

No change in diagnosis, 97%

Symptoms retained at 5 years, 75%

Most have no change in diagnosis after adequate initial evaluation

Majority retain symptoms at 5 years after initial diagnosis

AGA Teaching Unit on IBS, 1997

Management of IBS

Keys to Treatment of IBS

Education/reassurance Dietary modification Focus on health

Pharmacotherapy of GI symptoms
Set realistic goals Monitoring and modification

Psychologic treatments
Antidepressants Referral to pain management
AGA Teaching Unit on IBS, 1997

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

Dietary and Lifestyle Modification

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

Drugs for Dominant Symptoms in IBS

Anticholinergic/ Antispasmodics TCAs SSRIs
Abdominal pain

Bloating

Antispasmodics Antiflatulents

Altered bowel motility Loperamide Cholestyramine Psyllium Methylcellulose Tegaserod Calcium polycarbophil Lactulose 70% sorbitol PEG solution

New Therapeutic Approaches to the Treatment of IBS

Psychosocial factors

Vagal nuclei 5-HT Sympathetic S2, 3, 4

Altered motility

Altered sensation
Camilleri M, Choi M-G. Aliment Pharmacol Ther 1997;11:315

Psychologic Treatments for IBS

Some patients with IBS may also benefit from
Referral to a psychologist or psychiatrist Hypnotherapy Biofeedback Psychodynamic therapy Stress management/relaxation Cognitive behavioral programs

Drossman DA et al. The Functional GI Disorders, 2000

A Comprehensive Multicomponent Approach

Treatment program is based on dominant symptoms and their severity, and on psychosocial factors

Medical management
Diet Psychologic or behavioral options
Psychotherapy Stress management
Drossman D. Aliment Pharmacol Ther 1999;13(Suppl. 2):314

Conclusion
Current treatment of symptoms of IBS often requires use of more than one medication to control the multiple symptoms

Current medical therapies for symptoms of IBS have been insufficiently effective and there is a need for novel approaches to treatment

Camilleri M. Aliment Pharmacol Ther 2001;15(3):27790