IBS – current status

Peter Laszlo Lakatos

Semmelweis University

1st Department of Medicine

Functional gastrointestinal disorders

• Chronic or fluctuating functional gastrointestinal

symptoms that can not be explained by structural

and/or laboratory changes

Camilleri M. Gastroenterology 2001;120:652-668

IBS

•A real and chronic gastrointestinal (GI) disorder of

function manifested by a group of symptoms

– abdominal pain/discomfort

– bloating/distension

– constipation and/or diarrhea

•No known structural or biochemical abnormalities

•Significantly affects quality of life

•Need to treat the multiple symptoms of IBS

Camilleri M. Gastroenterology 2001;120:652.

Thompson et al. Gut 1999;45:43–7

Functional gastrointestinal disorders

Rome II (1998)

Functional oesophageal disorders

Functional gastroduodenal disorders

Functional bowel disorders

– Irritable bowel syndrome (IBS)

– Functional abdominal bloating

– Functional constipation

– Functional diarrhoea

– Unspecified functional bowel disorders

Functional biliary disorders

Functional anorectal disorders functional pediatric gastrointestinal disorders

Drossmann DA Gut 1999;45(SuppIII):II1

IBS and RomeThe definition matters

IBS and bacteriaThe bacteria hypothesis

Lin HC Jama 2004

IBS and bacteria - clinical relevance

Pimentel Expert Opin. Investig. Drugs 2009

Comparison of rates of positive breath

testing in IBS

The Epidemiology of

Irritable Bowel Syndrome

(IBS)

Worldwide prevalence of IBS

Camilleri et al. Aliment Pharmacol Ther 1997;11:3–15Drossman. Dig Dis Sci 1993;38:1569–80Talley et al. Gastroenterology 1991;101:927–34

Müller-Lissner et al. Digestion 2001;64:200–4Talley. Balliêre’s Clin Gastroenterol 1999;13:371–84Thompson et al. Dig Dis Sci 2002;47:225–35

Denmark 7%

New Zealand 17%

UK 22%

Nigeria 30%

Japan 25%

Australia 12%

China 23%Germany 12%

Netherlands 9%France 20%

Spain 13%

US

10–20%

Sweden 13%

Belgium 8%

IBS data not included

Canada

12%

Differences between age-groups

Age at onset is predominantly at young adulthood

In the adolescence:

8-15%

In the elderly:

in the US in 65-90 year-olds: 11%

in the 30-64 year-olds: 17%

Talley NJ. Gastroenterology 1992;102:895

IBS: Diversity in estimates

of prevalence

Confounding factor Example

Varying definition Presence of one or more

symptoms

Diagnosis Manning criteria

Rome I or Rome II criteria

diagnostic practice

Population Consulters, non-consulters,

racial groups, institutional

groups, general population

Kang YJ Aliment Pharmacol Ther 2005;21:663-676

Gender/Ethnical differences

Female predominance (2-4:1)

Background:

Sex hormones, different brain serotonin synthesis

Stress and psychological abnormalities

Real prevalence is almost the same between man and

women, „consulter behavior” is more common in

females

Cultural differences: e.g. in India IBS is more

prevalent in men

De Giorgio R et al. Aliment Pharmacol Ther 2004;20: 10.

Talley NJ Ball Clin Gastroenterol 1999;13:371

Kang YJ Aliment Pharmacol Ther 2005;21:663-676

Health care utilization and QoL

in IBS

IBS: Consultation pattern

Specialists

Primary care

~75%

non-consulters

~70%

female

~30%

male

~25%

consulters

IBS consulters

family doctor: 20-25%,

specialist: 3-5%

IBS: Consultation patterns

in the US

Mild Severe

IBS IBS

Physician visits * 5.6 9.0

In-patient stays * 0.1 0.2

Emergency room visits * 0 0.4

* over previous 12 months

Hahn et al, 1997

Health care utilization in IBS

Direct costs healthcare consultations

1.5-3.5 Mio visit/year in the US diagnostic tests medications

1.8-2.2 prescriptions/visit in the US preventative measures

Absenteeism from work:

IBS: 3x as many days from work

Cash BD et al. Aliment Pharmacol Ther 2004;19:1235.

Koloski NA. Am J Gastroenterol 2001;96:1440

Drossmann DA. Dig Dis Sci 1993;38:1596

Talley NJ. Gastroenterology 1995;109:1736

• cholecystectomy 3x

• appendectomy and hysterectomy 2x

• back surgery 1.5x

IBS was an independent risk factor

Longstreth GF et al. Gastroenterology 2004;126:1665.

High surgical rates in IBS

Health care utilization in IBS

• COSTS of IBS:

– ~$1.7–10 billion in annual direct medical costs in the US

– ~ $ 41 billion in the 8 most industrialized countries

– additional ~$10–20 billion in indirect costs, largely

resulting from work absenteeism and decreased

productivity in the US

Cash BD et al. Aliment Pharmacol Ther 2004;19:1235.

Koloski NA. Am J Gastroenterol 2001;96:1440

Drossmann DA. Dig Dis Sci 1993;38:1596

Talley NJ. Gastroenterology 1995;109:1736

Annual economic burden of IBS in the

US versus other chronic conditions

1National Asthma Education and Prevention Program. Asthma statistics, 1999

2Hu et al. Arch Intern Med 1999;159:813–18

3American Gastroenterological Association. The Burden of Gastrointestinal Diseases, 2001

4Martin et al. Am J Manag Care 2001:7(8 Suppl.):S268–S275

5American Heart Association. 2002 Heart and Stroke Statistical Update, 2002

6Praemer et al. Musculoskeletal Conditions in the United States (2nd ed), 1999

7American Diabetes Association. Diabetes Care 1998;21:296–309

Annual costs (billions of US dollars)

Productivity costs

0 20 40 60 80 100

Asthma1

Migraine2

IBS3,4

Hypertensive disease5

Stroke5

Arthritis6

Diabetes7

Quality of life (HRQOL)

HRQOL is lower in patients

with gastrointestinal diseases

compared to other chronic

conditions (e.g. depression,

diabetes mellitus or heart failure)

It is even lower in functional gastrointestinal

diseases (compared to non-functional)

Lower in consulters vs non-consulters

Oberndorff-Klein Woolthuis et al. Scand J Gastroenterol 2004;39:17

Stewart S. JAMA 1989;262:907

O'Sullivan M. Gastroenterology 1997;112:A801

Relative QoL in IBS (SF-36)Comparison with other diseases

0

10

20

30

40

50

60

70

80

90

Mea

n s

cale

sco

re

US female norms (n=1,412)

IBS (n=1,302)

IBD (n=546)

Congestive heart failure (n=216)

Eisen G, 2000; Mayer EM et al, 1999: Ware J, 1993

Symptoms of multiple functional disorders may be present

Patients with IBS often complain to have

symptoms of:

Other gastrointestinal (pl. dyspepsia) and/or

Non-gastrointestinal (pl. fibromyalgia, non-

cardiac chest pain, pelvic pain, urogenital

problems (dysuria, dysmenorrhea), migraine-

like headache, etc.) functional syndromes

Pathogenesis of IBS

Motility disorder, motor function (1950s)

Visceral hypersensitivity (1970s)

Brain-gut interaction (1980s)

More recent mechanisms:

Altered CNS perception of visceral events

Psychosocial factors

5-HT (mediated visceral hypersensitivity and gut motility)

Genetical, host factors (SERT, IL-10, TGF-b)

Others (acute infection/low-grade inflammation, diet, change in the gut-microflora)

Barbara G et al. Aliment Pharmacol Ther 2004;20:1-9.

The Diagnosis of

Irritable Bowel Syndrome

(IBS)

Diagnostic approach

Positive

Identify symptom pattern

(psychosocial background)

Negative

Rule out

• Four symptoms significantly more common among patients

with IBS:

• looser stools at onset of pain

• more frequent bowel movements at onset of pain

• pain eased after bowel movement

• visible [abdominal] distension

• Two further symptoms were more common among patients

with IBS:

• passage of mucus

• feeling of incomplete evacuation

• Sensitivity: 55-60%, specificity 75-80%

IBS: Manning criteria

Manning et al, Br Med J 1978;2:653-4

IBS: Rome II criteria (2000)

At least 12 weeks or more, which need not be

consecutive, in the preceding 12 months of abdominal

discomfort or pain that has two out of three features:

(1) Relieved with defecation; and/or

(2) Onset associated with a change in frequency of

stool; and/or

(3) Onset associated with a change in form

(appearance) of stool.

Thompson WG Gut 1999;45(SuppIII):II43

IBS: Rome II criteria (2000)

Symptoms that cumulatively support the

diagnosis of IBS:

1. Fewer than three bowel movements a week

2. More than three bowel movements a day

3. Hard or lumpy stools

4. Loose or watery stools

5. Straining during a bowel movement

6. Urgency

7. Feeling of incomplete emptying

8. Passing mucus during a bowel movement

9. Abdominal fullness, bloating or swelling

Thompson WG Gut 1999;45(SuppIII):II43

Symptoms in IBS

Major gastrointestinal symptoms (Rome-Manning criteria)

Additional gastrointestinal symptoms

Diverse symptoms of upper GI functional diseases and other GI signs (e.g. disturbing sound of bowel movement, anorectal discomfort)

Extraintestinal functional symptoms

Psychological alterations

Interpretation of the symptoms is TYPICAL

– detailed; „insufferable, intolerable”

IBS: Alarm symptoms (‘Red flags’)

• Rectal bleeding

• Weight loss

• Persistent diarrhea, steathorrea

• Constant and recent abdominal distension

• Anaemia, abnormal ESR

• Fever

• Thyroid dysfunction

• New onset in patients >50 years

• Family history of bowel cancer, IBD

• Nocturnal symptoms

• Rapid progression of symptoms/ change of the „usual” symptom pattern

Heaton & Thompson, 1999; Paterson et al, 1999, Cash et al. 2005

IBS: Further evaluation

• Sigmoidoscopy-

colonoscopy

• Examination of stool

• Blood studies

• Imaging studies

Drossman et al, 1997; Drossman, 1999

IBS: Differential diagnosis

• Malabsorption

• Dietary factors

• Infection

• Inflammatory bowel disease

• Psychological disorders

• Miscellaneous, GI tumors

Drossman, 1999

IBS is a stable diagnosis

After 6-30 years of

follow-up

organic GI

disease developed

in 2-5% of IBS

patients

after negative

baseline

investigationEl-Serag et al. Aliment Pharmacol Ther 2004;19:861.

Owens et al. Ann Intern Med. 1995;122:107–22

No change in

IBS diagnosis: 95-98%

IBS: sub-classification

• IBS is sub-classified into three types based

on the primary bowel symptom

– constipation: IBS-C

– diarrhea: IBS-D

– alternation between constipation

and diarrhea: IBS-A

• Patients may present with one or more

mild-severe primary symptoms

Sub-classification of IBS:

can vary with time

• 156 IBS patients from a population survey

Time

0 months

(%)

6 months

(%)

12 months

(%)

IBS-C 12 10 7

IBS-D 34 32 34

IBS-A 54 58 59

BUT: 36% at 6 months and 37% at 12 months had changed sub-group

Koloski et al. Gastroenterology 2002;122(Suppl. 1):A507

Characteristics of IBS patients

several medical reports

more operations in the medical history

know exactly how the medical system is working:

„utilization of health care resources”

„doctor shopping”

refuse „functional diagnosis” => „organic” alterations

frustration for both parties, (patient and doctor)

establishment of a strong patient-physician relationship is key

use of alternative medicine

Treatment / patient management

Treatment of IBS

„not a single study offers convincing

evidence that any therapy is effective

in treating the IBS symptom complex”

Klein KB. Gastroenterology 1988;95:232-241

Spiller RC. Am J Med 1999;107: 91S–97S.

Placebo effect in IBS

Management of IBS

Detailed patient history, physical examination => presumptive diagnosis

Limited examinations

Laboratory examinations

Abdominal UH

Fecal blood testing, microbiology

Sigmoidoscopy (>50 years colonoscopy?)

Symptom directed treatment

Patient education

Diet, life style

Medication (symptomatic treatment)

Special examinations in intractable cases

IBS: Management philosophy

• Identify concerns of the patient

• Explain the nature of the condition

• Reassure: IBS is a recognised clinical entity

• Involve patient: symptoms can fluctuate;

diet or stress may precipitate symptoms

• Provide continuity: ongoing review may be

important to the patient

• Set realistic expectations

Drossman et al, 1997

Treatment paradigm in IBSFrom symptoms to hypothesis

Pimentel Curr Treat Options in GE 2007

Medical therapy of IBS

Anti-spasmodic, smooth muscle relaxants:

mebeverine, pinaverium bromide, cimetropium, trimebutine

Constipation:

Fibre, osmotic laxatives (magnesium salt, lactulose)

Anti-diarrheal agents:

loperamide, diphenoxylate

Antidepressants

tricyclic antidepressants (desipramine, amitriptyline) and SSRI’s (e.g. paroxetine)

Camilleri M. Gastroenterology 2001;120:652-68.

Jackson JL. Am J Med 2000;108:65-72.

Johanson JF Neurogastroenterol Motil 2004;16:701-16.

Efficacy of conventional drug therapies in IBS

Mertz HR NEJM 2003

Psychoterapy

Psychological therapy

cognitive behavior, relaxation, psychotherapy, hypnotherapy, (50% reduction of symptoms): OR= 12, NNT 2!!

For patients with severe IBS, both psychotherapy and

paroxetine improve health-related quality of life at

no additional cost

psychotherapy, $976 [SD, $984], paroxetine, $1252

[SD, $1616]; and treatment as usual, $1663 [SD, $3177]

Lackner JM J Consult Clin Psychol. 2004;72:1100-13.

CreedF Gastroenterology 2003;124:303-17.

Novel therapeutic possibilities

Diarrhea

• 5-HT3 antagonists (e.g., alosetron, cilansetron):

– retard small bowel and colonic transit

– alosetron, number needed to treat (NNT) of 7

– Constipation (1/4), ischaemic colitis (2/1000/3 months, 3/1000/6months)

• Anticholinergics, selective M3 type:

– antispasmodic with antidiarrheal potential

• CCK antagonist: dexloxiglumide

– IBS-C: Phase III trials were negative

Constipation

• 5-HT4 partial agonists (e.g., tegaserod and prucalopride):

– accelerate small bowel and colonic transit,

– tegaserod 12 mg (RR 1.19), tegaserod 4 mg (RR 1.15), NNT of 14 and 20

Patel S Expert Opin Pharmacother. 2004;5:2369-79.

Evans BW Cochrane Database Syst Rev. 2004;(1):CD003960.

Pain•a2-adrenergic agonist (e.g., clonidine)

•reduces tone, increases compliance, decreases pain

sensation during distention in health

•k-Opioid agonist (e.g., fedotozine, asimadoline)

•increases threshold for distention-induced pain in IBS

(partly through blockade of sodium channels)

•5-HT

•5-HT1A agonist? (buspirone): relaxes colonic tone,

reduces sensation

•5-HT3 antagonist: reduces colonic tonic response to

feeding, colonic compliance, and sensation of volume

distentions

•5-HT4 antagonist: inhibits colonic sensation in

experimental models

•5HT4 agonist/5HT3 antagonist (renzapride): favorable

in IBS-C

•Neurokinin antagonists (NK1-2-3):

•reduce visceral sensation; motor actions in colon

depend on receptor subtype in experimental model

Rifaximin and SIBO: Percentage of Patients with Adequate Relief of Global IBS Symptoms in the TARGET 1 and TARGET 2 Studies

Combined

Pimentel M et al. N Engl J Med 2011;364:22-32

Treatment possibilities in IBS

Mertz HR NEJM 2003;349:2136-46.

Summary

Symptoms usually develop in early adulthood

Duration is long (decades)

Diagnosis is stable

Impairs QoL

High health care costs

Prognosis

Quo ad vitam good, quo ad sanationem bad

Functional disease does not protect against organic diseases (alarm symptoms)

Camilleri M, Lancet 2000;355:1035–1040.

Alosteron

Chang L. Am J Gastroenterol 2005;100:115-123.

•Equally effective in IBS-D in male patients

•53% vs placebo 40%

•Phase II trial

Alosteron-Male patients

Chang WD. Am J Gastroenterol 2004;99:2195-2203.

•Long term efficacy (48week):

•Pain, discomfort: 52.1% vs. 43.9%, NNT: 12

•Urgency control: 63.8% vs 52%, NNT 8

Alosteron-Long term use

Chang WD. Am J Gastroenterol 2004;99:2195-2203.

Alosteron-Long term use

Long term safety

Constipation: 23% vs 5%,

NNH 7 (first month)

NNH 35 (subsequent months)

Cremonini F Neurogastroenterol Motil 2003;15:79-86.

Tegaserod: pivotal clinical

studies

Placebo

Tegaserod 2 mg b.i.d.

Tegaserod 6 mg b.i.d.

4 weeks

Baseline

12 weeks

Daily/weeklyDaily

Diary (paper or IVRS)

B3011, B3512, B3583

B3011, B3512

B3011, B3512, B3583

Inclusion: IBS-C, female

Efficacy variables: Subject’s Global Assessment (SGA) of relief of IBS symptoms

SGA of relief of abdominal pain/discomfort

Secondary: Bowel movements, stool consistency, severity of bloating

1Müller-Lissner et al. Aliment Pharmacol Ther 2001;15:1655–66

2Schmitt et al. Gut 1999;45(Suppl.V):A260

3Novick et al. Aliment Pharmacol Ther 2002;16:1877–88

Müller-Lissner. Aliment Pharmacol Ther 2001;15:1655-66.

Camilleri M. Gastroenterology 2001;120:652-68.

Tegaserod

Tegaserod: relapse/retreatment

84% relapse / 8 weeks

Müller-Lissner. Aliment Pharmacol Ther 2005;21:11-20

Hippocrates (465–370 BC)

“Practice two things in your dealings with disease: either help or do not harm the patient.”