Outline Definition Epidemiology Impact and burden of disease Pathophysiology Treatment: What is the evidence? Novel therapies Concluding Remarks Definition.

OutlineOutline

• Definition• Epidemiology• Impact and burden of disease• Pathophysiology• Treatment: What is the evidence?• Novel therapies• Concluding Remarks

What is IBS?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

• 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

12 weeks in the last 12 months of abdominal discomfort or pain that has 2 out of 3 features

– Relieved with defecation– Onset associated with a in frequency of stool– Onset associated with a 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 or abnormal stool passage – Passage of mucus – Bloating or feeling of abdominal distention

12 weeks in the last 12 months of abdominal discomfort or pain that has 2 out of 3 features

– Relieved with defecation– Onset associated with a in frequency of stool– Onset associated with a 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 or abnormal stool passage – Passage of mucus – Bloating or feeling of abdominal distention

THE ROME CRITERIATHE ROME CRITERIA

• Anemia

• Fever

• Persistent diarrhea

• Rectal bleeding

• Severe constipation

• Weight loss

• Anemia

• Fever

• Persistent diarrhea

• Rectal bleeding

• Severe constipation

• Weight loss

• Nocturnal symptoms ofpain 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

• Nocturnal symptoms ofpain 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

RED FLAGS!RED FLAGS!

WORLDWIDE PREVALENCE OF IBSWORLDWIDE PREVALENCE OF IBS

1Heaton K et al. 1992; 2Longstreth G, Wolde-Tsadnik P 1993; 3Welch G, Pomare W 1990; 4Bommalaer G et al. 19865Bi-zhen W, Qi-Ying P 1988; 6Olubuyide O et al. 1995; 7Kay L et al. 1994

UK1 USA2 New France4 China5 Nigeria6 Denmark7

Zealand3

UK1 USA2 New France4 China5 Nigeria6 Denmark7

Zealand3

Rome II = 5%Rome II = 5%

IBS versus Other Important Disease States

• US prevalence of IBS/functional bloating up to 20%1

• US prevalence rates for other common diseases2

– Diabetes 3%– Asthma 4%

– Heart disease 8%– Hypertension 11%

• US prevalence of IBS/functional bloating up to 20%1

• US prevalence rates for other common diseases2

– Diabetes 3%– Asthma 4%

– Heart disease 8%– Hypertension 11%

1Camilleri M et al. Aliment Pharmacol Ther 1997;11:3–152Adams P, et al. Vital Health Stat 10 1991;181:1–212

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

IBS Non-IBS

Non-GI

IBS Non-IBS

Non-GI

PHYSICIANS VISITS PER YEARPHYSICIANS VISITS PER YEAR

Direct Indirect

The Burden of Gastrointestinal Diseases. AGA 2001The Burden of Gastrointestinal Diseases. AGA 2001

COST OF IBS (in millions)COST OF IBS (in millions)

Role-Physical

Bodily Pain

VitalityVitality Social Functioning

Social Functioning

Role-Emotional

Mental HealthMental Health

US NormUS Norm

IBSIBS

Adapted from Wells et al. Aliment Pharmacol Ther. 1997;11:1019-1030. Adapted from Wells et al. Aliment Pharmacol Ther. 1997;11:1019-1030.

Impact of IBS on Quality of Life Compared with US Norms

General Health

PhysicalFunctioning

100100

US NormUS Norm

Diabetes type IIDiabetes type II

IBSIBS

Clinical depressionClinical depression

Adapted from Wells et al. Aliment Pharmacol Ther. 1997;11:1019-1030. Adapted from Wells et al. Aliment Pharmacol Ther. 1997;11:1019-1030.

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

Role-Physical

Bodily Pain

VitalityVitality Social Functioning

Social Functioning

Role-Emotional

Mental HealthMental Health

General Health

PhysicalFunctioning

100100

Abnormal motility2Abnormal motility2

Visceral hypersensitivity2Visceral hypersensitivity2

Brain-gut interaction2Brain-gut interaction2

5-HT mediated visceralsensitivity and gut motility1

19501950 20002000

1Prior A, Read N. Aliment Pharmacol Ther 19932Drossman D. Aliment Pharmacol Ther 1999

EVOLUTION OF MECHANISTIC HYPOTHESES IN IBS

Small bowel bacterial overgrowthSmall bowel bacterial overgrowth

% REPORTING PAIN

IBS PATIENT

H. Mertz, 2000.H. Mertz, 2000.

ABERRANT ACTIVATION OF CNS PAIN CENTERS IN IBS

2.83.4

8.48.6

10.29.4

Relaxing sounds Conflicting sounds Relaxing sounds Conflicting sounds

2.83.4

8.48.6

10.29.4

Relaxing sounds Conflicting sounds Relaxing sounds Conflicting sounds

Unpleasentness at 45 mm Hg (cm)Unpleasentness

at 45 mm Hg (cm)

Dickhaus et al. Am J Gastroenterol 2003;98:135-43Dickhaus et al. Am J Gastroenterol 2003;98:135-43

Anger ratingAnger rating

***p<0.05*p<0.05

AUDITORY STRESS ALTERS PERCEPTUAL AND EMOTIONAL RATINGS OF VISCERAL STIMULI

ControlsControls

IBSIBS

CNS – 5%CNS – 5%

– Enterochromaffin cells– Neuronal– Enterochromaffin cells– Neuronal

GI tract – 95% GI tract – 95%

Gershon MD. Aliment Pharmacol Ther 1999;13(Suppl. 2):15–30Gershon MD. Aliment Pharmacol Ther 1999;13(Suppl. 2):15–30

PHYSIOLOGIC DISTRIBUTION OF 5-HTPHYSIOLOGIC DISTRIBUTION OF 5-HT

5-HT5-HT

Excitatorymotor neuron(contraction)

5-HTreceptors5-HTreceptors

Inhibitorymotor neuron (relaxation)Inhibitorymotor neuron (relaxation)

Enterochromaffin cellsEnterochromaffin cells

InterneuronsInterneurons

SensoryneuronSensoryneuron

MOTOR ACTIVITY IN IBSMOTOR ACTIVITY IN IBS

5-HT45-HT4 5-HT35-HT3

IBSIBSIBSIBS

Gas retention

Genetic polymorphism: SERT/Cytokines

Inflammation

Social stress

?Foodhypersensitivity

Altered ANS

Sleep dysfunction

Colonic flora

?Small bowel bacterial

overgrowth

Heightened visceral

nociception

Gut-Brain Axis dysfunction

Post-Infectious IBS

Altered serotonergic

function

• Education/reassurance

• Dietary modification

• Focus on health

• Set realistic goals

• Pharmacotherapy of GI symptoms

• Monitoring and modification

• Psychological treatments

• Referral to pain management

• Education/reassurance

• Dietary modification

• Focus on health

• Set realistic goals

• Pharmacotherapy of GI symptoms

• Monitoring and modification

• Psychological treatments

• Referral to pain management

KEYS TO TREATMENT OF IBSKEYS TO TREATMENT OF IBS

• 27 studies: Median placebo response 47% (range 5 – 84%)

• REASONS:

– On-going attention and care

– Expectation of “treatment” response

– Placebo response may represent, in part, natural fluctuations in symptoms

– Chance

• 27 studies: Median placebo response 47% (range 5 – 84%)

• REASONS:

– On-going attention and care

– Expectation of “treatment” response

– Placebo response may represent, in part, natural fluctuations in symptoms

– Chance

HIGH PLACEBO RESPONSE RATES IN IBS

Anticholinergics

SM relaxants

• mebeverine

• cimetropium

• pinaverium

• otilonium

• trimebutine

• zamifenacin

• darifenacin

Anticholinergics

SM relaxants

• mebeverine

• cimetropium

• pinaverium

• otilonium

• trimebutine

• zamifenacin

• darifenacin

inhibiting

spasms

inhibiting

spasms

modulating

visceral pain

pathway &

anti-nociceptive

effect

modulating

visceral pain

pathway &

anti-nociceptive

effect

5-HT3-antagonists

• Alosetron , cilansetron

5-HT4-agonist

• tegaserod

Antidepressants• Tricyclics, SSRI

NK2-receptor antagonist

• nepadutant

kappa-opioid agonist

• fedotozine

5-HT3-antagonists

5-HT4-agonist

• tegaserod

• nepadutant

• fedotozine

TREATMENT OF IBSTREATMENT OF IBS

Pain &Pain &bloatingbloating Pain &Pain &bloatingbloating

• Meta-analysis of 23 RCTs with comparable outcomes (1888 pts)

• 5 superior to placebo: mebeverine , pinaverium, otilium, trimebutine, cimetropium

• Meta-analysis of 23 RCTs with comparable outcomes (1888 pts)

• 5 superior to placebo: mebeverine , pinaverium, otilium, trimebutine, cimetropium

Poynard et al. Aliment Pharmacol Ther 2001;15:355-61.Poynard et al. Aliment Pharmacol Ther 2001;15:355-61.

EFFICACY OF ANTISPASMODIC AGENTSEFFICACY OF ANTISPASMODIC AGENTS

Global Improvement Pain Improvement Abdominal DistentionImprovement

Active

Placebo56

Global Improvement Pain Improvement Abdominal DistentionImprovement

Active

Placebo

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

*** p<0.001 ** p=0.008 *** p<0.001 ** p=0.008

Anticholinergics

SM relaxants

• mebeverine

• cimetropium

• pinaverium

• otilonium

• trimebutine

• zamifenacin

• darifenacin

Anticholinergics

SM relaxants

• mebeverine

• cimetropium

• pinaverium

• otilonium

• trimebutine

• zamifenacin

• darifenacin

inhibiting

spasms

inhibiting

spasms

modulating

visceral pain

pathway &

anti-nociceptive

effect

modulating

visceral pain

pathway &

anti-nociceptive

effect

5-HT3-antagonists

5-HT4-agonist

• tegaserod

• nepadutant

• fedotozine

5-HT3-antagonists

5-HT4-agonist

• tegaserod

• nepadutant

• fedotozine

• 7 trials: Only 1 met high quality criteria1

• 4 reported significant improvement in:

– Abdominal pain

– diarrhea1

• 7 trials: Only 1 met high quality criteria1

• 4 reported significant improvement in:

– Abdominal pain

– diarrhea1

LOW-DOSE TRICYCLIC ANTIDEPRESSANTS

1Jailwala et al. Ann Intern Med 2000; 2 Jackson et al. Am J Med 20001Jailwala et al. Ann Intern Med 2000; 2 Jackson et al. Am J Med 2000

A Randomized Double-Blind Placebo-Controlled Trial of

Imipramine in IBS

A Randomized Double-Blind Placebo-Controlled Trial of

Imipramine in IBSSharara A et al.

Oral presentation at the Annual Scientific Meeting of the American College of Gastroenterology 2006

and Winner of ACG/Novartis Research Award

Sharara A et al. Oral presentation at the Annual Scientific Meeting of the American College of Gastroenterology 2006

and Winner of ACG/Novartis Research Award

NS15 (31.3%)14 (23.7%)Mixed (alternating)

NS7 (14.6%)11 (18.6%)Diarrhea (D)

NS100%100%Prior medical Rx

NS15 (31.3%)17 (28.8%)Constipation (C)

NS40 (83.3%)45 (76.3%)Flatulence

NS47 (97.9%)58 (98.3%)Pain

NS46 (95.8%)57 (96.6%)Bloating/Distention

NS29 (60.4%) referrals 38 (64.4%) referralsType of recruitment

NS29 (60.4%)33 (55.9%)Sex (% Male)

NS45.3±13.8 42.6±12.4Mean Age

p-valuePlacebo(n=48)

Imipramine(n=59)

Patient Characteristics

Drop-outs

Imipramine* Placebo

Premature withdrawal 6 14

Lost to follow-up 3 3

Protocol violation 5 1

Side-effects 14 5

80.6%83.3%85.4%

48.0%51.4%52.5%

0 4 8 12 16

Imipramine Placebo

Patient Global Relief (Per Protocol)

p<0.05

Sharara A et al. Oral presentation ACG 2006. Winner of ACG/Novartis Research AwardSharara A et al. Oral presentation ACG 2006. Winner of ACG/Novartis Research Award

0 4 8 12 16

Imipramine Placebo

Patient Global Relief (intent-to-treat)

p=0.053

Sharara A et al. Oral presentation ACG 2006. Winner of ACG/Novartis Research AwardSharara A et al. Oral presentation ACG 2006. Winner of ACG/Novartis Research Award

Sweating1

Genitourinary symptoms

Dizziness3

Dry mouth1

Disturbed sleep

Palpitations 2

GI disturbance

3 Anxiety1

Imipramine-Associated Side Effects

Placebo Imipramine

Mean % Change in SF36 Scores

p<0.01

Anticholinergics

SM relaxants

• mebeverine

• cimetropium

• pinaverium

• otilonium

• trimebutine

• zamifenacin

• darifenacin

Anticholinergics

SM relaxants

• mebeverine

• cimetropium

• pinaverium

• otilonium

• trimebutine

• zamifenacin

• darifenacin

inhibiting

spasms

inhibiting

spasms

modulating

visceral pain

pathway &

anti-nociceptive

effect

modulating

visceral pain

pathway &

anti-nociceptive

effect

5-HT3-antagonists

5-HT4-agonist

• tegaserod

• nepadutant

• fedotozine

5-HT3-antagonists

5-HT4-agonist

• tegaserod

• nepadutant

• fedotozine

Effect of Alosetron on Relief of Abdominal Pain and Discomfort and Stool Consistency (D-IBS)Effect of Alosetron on Relief of Abdominal Pain and Discomfort and Stool Consistency (D-IBS)

Camilleri M et al. Lancet 2000;355:1035–40Camilleri M et al. Lancet 2000;355:1035–40

1 2 3 4 5 6 7 8 9 10 11 12 +1 +2 +3 +41 2 3 4 5 6 7 8 9 10 11 12 +1 +2 +3 +4

LOCFLOCF

Placebo b.i.d.Placebo b.i.d.

Alosetron 1mg b.i.d.Alosetron 1mg b.i.d.

*p<0.05*p<0.05

12 weeks treatment12 weeks treatment 4 weeks follow-up4 weeks follow-up

** **** ** **

**** ** ****

Alosetron 1mg b.i.d.Alosetron 1mg b.i.d.

PlaceboPlacebo

LOCFLOCF

**p<0.001**p<0.001

0 1 2 3 4 5 6 7 8 9 10 11 12 +1 +2 +3 +40 1 2 3 4 5 6 7 8 9 10 11 12 +1 +2 +3 +4

12 weeks treatment12 weeks treatment 4 weeks follow-up4 weeks follow-up

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

TegaserodTegaserod

• Aminoguanidine indole derivative of serotonin• Specific 5-HT4 partial agonist• Actions:

– Stimulates small and large intestinal motility– Accelerates whole oro-cecal transit time– Stimulated peristalsis and gastric emptying– Stimulates intestinal chloride secretion– Inhibits visceral hypersensitivity

• Aminoguanidine indole derivative of serotonin• Specific 5-HT4 partial agonist• Actions:

– Stimulates small and large intestinal motility– Accelerates whole oro-cecal transit time– Stimulated peristalsis and gastric emptying– Stimulates intestinal chloride secretion– Inhibits visceral hypersensitivity

TEGASEROD in C-IBSSatisfactory relief by week (ITT)

*p<0.05; **p<0.01 vs placebo*p<0.05; **p<0.01 vs placebo

%) **** ****

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

–1 2 4 6 8 10 12 WD2 WD4–1 2 4 6 8 10 12 WD2 WD4

placeboplacebo tegaserodtegaserod

Melatonin and the GutMelatonin and the Gut

Barajas-Lopez C et al 1996; Storr M et al 2000; Roberts-Thomson IC 1988; Lu WZ et al 2005Barajas-Lopez C et al 1996; Storr M et al 2000; Roberts-Thomson IC 1988; Lu WZ et al 2005

• Melatonin exerts both excitatory & inhibitory effects on the gut but mechanism unclear

• ? blockade of nicotinic channels and/or interaction with Ca2+-activated K+ channels

• ?mediating gut visceral sensation

• Melatonin exerts both excitatory & inhibitory effects on the gut but mechanism unclear

• ? blockade of nicotinic channels and/or interaction with Ca2+-activated K+ channels

• ?mediating gut visceral sensation

RCT of Melatonin in IBSRCT of Melatonin in IBS

Song, G H et al. Gut 2005;54:1402-1407Song, G H et al. Gut 2005;54:1402-1407

Melatonin in IBSMelatonin in IBS

• Melatonin did not change rectal pressures during squeezing, pushing, or resting states indicating that melatonin did not influence gut motility

• 3 mg melatonin at bedtime for two weeks did not improve subjective or objective sleep parameters

• Melatonin did not change rectal pressures during squeezing, pushing, or resting states indicating that melatonin did not influence gut motility

• 3 mg melatonin at bedtime for two weeks did not improve subjective or objective sleep parameters

Song, G H et al. Gut 2005;54:1402-1407Song, G H et al. Gut 2005;54:1402-1407

Probiotics in IBSProbiotics in IBS

• 77 patients with IBS randomized to Lactobacillus salivarius or Bifidobacterium infantis (1 x 1010 live bacterial cells) for 8 weeks

• Symptoms, QoL, stool microbiologic studies, and PBMC release of IL-10 and IL-12 done at beginning and end of study

• 77 patients with IBS randomized to Lactobacillus salivarius or Bifidobacterium infantis (1 x 1010 live bacterial cells) for 8 weeks

• Symptoms, QoL, stool microbiologic studies, and PBMC release of IL-10 and IL-12 done at beginning and end of study

O’Mahoney L et al. Gastroenterology 2005;128:541-551O’Mahoney L et al. Gastroenterology 2005;128:541-551

1Balsari A et al. Microbiology 1982;5:185-94 2King TS et al. Lancet 1998;352:1187-9

Which of the following do you find as the most disturbing-and difficult to treat-

symptom in IBS?

Which of the following do you find as the most disturbing-and difficult to treat-

symptom in IBS?

1. Abdominal pain2. Constipation3. Diarrhea4. Bloating5. Feeling of incomplete evacuation6. Alternating diarrhea & constipation

• The colon is the major site of intestinal H2 formation (>99% in fasting state and after lactose)

• H2 production depends upon delivery of non-absorbable CHO to colon bacteria (1014 bacteria)

• Large quantities can be liberated with relatively small amounts of CHO (85 mL over 90-min period1)

• Symptoms of gaseous distention after certain foods are temporally related to breath H2 concentration2

• The colon is the major site of intestinal H2 formation (>99% in fasting state and after lactose)

• H2 production depends upon delivery of non-absorbable CHO to colon bacteria (1014 bacteria)

• Large quantities can be liberated with relatively small amounts of CHO (85 mL over 90-min period1)

• Symptoms of gaseous distention after certain foods are temporally related to breath H2 concentration2

Hydrogen Gas in ManHydrogen Gas in Man

1Levitt MD. N Engl J Med 1969;281:122-7 2Calloway D. Gastroenterology 1966;51:383-9

RifaximinRifaximin• Rifamycin derivative: inhibits bacterial RNA

synthesis

• Non-absorbable & free of side-effects

• Good activity against aerobic & anaerobic bacteria1

• Low level of resistance strains with chronic use2, 3

• Causes significant in H2 production in GI tract4

• Shown in open-label studies to reduce symptoms of flatulence and bloating4, 5

• Rifamycin derivative: inhibits bacterial RNA synthesis

• Non-absorbable & free of side-effects

• Good activity against aerobic & anaerobic bacteria1

• Low level of resistance strains with chronic use2, 3

• Causes significant in H2 production in GI tract4

• Shown in open-label studies to reduce symptoms of flatulence and bloating4, 5

1Drugs 1995;49:467-84; 2Drugs Exp Clin Res 1986;12:979-81;3Chemotherapy2000;46:253-66;4Aliment Pharmacol Ther 2000;14:551-6; 5Int J Colorectal Dis 2003;18:55-62

Global Assessment of ReliefGlobal Assessment of Relief

Sharara AI et al. Am J Gastroenterol 2006Sharara AI et al. Am J Gastroenterol 2006

* p < 0.05

IBS patients

Sharara AI et al. Am J Gastroenterol 2006Sharara AI et al. Am J Gastroenterol 2006

* p < 0.05

Global Assessment of ReliefGlobal Assessment of Relief

Symptom score vs. LHBTSymptom score vs. LHBT

Rifaximin Placebo

Bloating score vs. LHBTBloating score vs. LHBT

Rifaximin Placebo

Constipation With IBS

Diarrhea pred.IBS

Pain pred.IBS

Fiber, exercise

Fluid intake

Osm. LaxativeAntispasmodic

agents

Serotonin-4 agonist

? Low-doseTCA

Trial diet excluding

lactose/caffeine

Loperamide, Antispasmodic

Serotonin-3 antagonist

Serotonin-3 antagonist if

diarrhea occurs

mildmild

Antispasmodic agent

moderatemoderate severesevere

Modified from Mertz HR. N Engl J Med 2003;349;2136-46.

Low-dose TCA

Proposed AlgorithmProposed Algorithm

Outline Definition Epidemiology Impact and burden of disease Pathophysiology Treatment: What is the evidence? Novel therapies Concluding Remarks Definition.

aliment pharmacol ther

millionsimpact of ibs

cost of ibs

quality of life

inflammatory bowel disease

adams p

heart disease

welch g

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