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(1)

Irritable Bowel Syndrome

and

Chronic Constipation

Irritable Bowel Syndrome

and

Chronic Constipation

Title slide - part 1

Susan Lucak, M.D.

Columbia University Medical Center

Susan Lucak, M.D.

Columbia University Medical Center

What is IBS?

• a chronic, intermittent gastrointestinal condition

• a functional bowel disorder without evidence of

structural or biochemical abnormalities

• characterized by abdominal pain or discomfort

associated with altered bowel function:

– diarrhea: >3BMs/day, loose stools, urgency

– constipation:<3BMs/wk, hard/lumpy stools,

straining

– bloating or feeling of distension

– sense of incomplete evacuation

– passage of mucus

Drossman et al, Gastroenterology 1997; 112: 2120

(2)

U.S. Prevalence

U.S. Prevalence

15 - 34

15 - 34

35 - 44

35 - 44

>45

>45

Age in Years

Age in Years

0

0

2

2

4

4

6

6

8

8

10

10

12

12

14

14

%

%

Female Female Male Male

IBS - Epidemiology

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

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

U.S. Prevalence

IBS - Physiologic Research

Stress affects

GI function

Motility

Motility

Meals

Pain / motility

Myoelectrical Marker

Myoelectrical Marker

Brain-Gut

Interactions

Brain-Gut

Interactions

Visceral Hypersensitivity

Visceral Hypersensitivity

Mechanisms

Mechanisms

Pain

sensitivit

y

3 cpm

motility

Clustered

contractions

CNS / ENS

Autonomic

reactivity

Visceral

hypersensitivity

1970

1950

1960

1980

1990

2000

Post-infectious

IBS

Inflammation

Inflammation

(3)

Brain-gut connection in IBS

Brain-gut connection in IBS

Adapted from Camilleri and Choi, Aliment Pharmacol Ther 1997; 11: 3 Hunt and Tougas, Best Prac and Research Clin Gastroenterol 2002; 16: 869

Adapted from Camilleri and Choi, Aliment Pharmacol Ther 1997; 11: 3 Hunt and Tougas, Best Prac and Research Clin Gastroenterol 2002; 16: 869

IBS

-Pathophysiology

Enteric Nervous System Anatomy

Muscularis

mucosa

Muscularis

mucosa

Submucosa

Submucosa

Circular

muscle layer

Circular

muscle layer

Longitudinal

muscle layer

Longitudinal

muscle layer

Epithelium

Epithelium

Mucosal plexus

Mucosal plexus

Myenteric plexus

Myenteric plexus

Meissner’s

Auerbach’s

Goyal RK, Hirano I, New Engl J Med. 1996; 334:1106

Goyal RK, Hirano I, New Engl J Med. 1996; 334:1106

(4)

Physiologic distribution of serotonin

(5-HT)

After Wood JD, Gastroenterol Endosc News 2000; (Suppl): S1

After Wood JD, Gastroenterol Endosc News 2000; (Suppl): S1

Some possible mediators of

motility and visceral sensitivity

Motility:

„

Serotonin

„

Acetylcholine

„

Nitric oxide

„

Substance P

„

Vasoactive intestinal

peptide

„

Cholecystokinin

Motility:

„

Serotonin

„

Acetylcholine

„

Nitric oxide

„

Substance P

„

Vasoactive intestinal

peptide

„

Cholecystokinin

Kim et al, Am J Gastroenterol 2000; 95: 2698 Grider et al, Gastroenterology 1998; 115: 370

Kim et al, Am J Gastroenterol 2000; 95: 2698 Grider et al, Gastroenterology 1998; 115: 370

Visceral sensitivity:

„

Serotonin

„

Tachykinins

„

Calcitonin

gene-related peptide

„

Neurokinin A

„

Enkephalins

Visceral sensitivity:

„

Serotonin

„

Tachykinins

„

Calcitonin

gene-related peptide

„

Neurokinin A

„

Enkephalins

(5)

Serotonin (5-HT) and motor

activity

Adapted from Grider et al, Gastroenterology 1998; 115: 370 Gershon, Rev Gastroenterol Dis 2003; 3: S25

Adapted from Grider et al, Gastroenterology 1998; 115: 370 Gershon, Rev Gastroenterol Dis 2003; 3: S25

(6)

IBS - Serotonin Receptors on Sensory Afferents

IBS - Serotonin Receptors on Sensory Afferents

Mechanical

noxious

stimulation

Mechanical

noxious

stimulation

5-HT3 5-HT3

Serotonin

(5-HT)

Serotonin

(5-HT)

5-HT

3

receptor on vagal

or spinal afferent

5-HT

3

receptor on vagal

or spinal afferent

Mucosal enterochromaffi n cell Mucosal enterochromaffi n cell

Vagal /

spinal

afferent

Vagal /

spinal

afferent

Nodose /

Dorsal root

ganglion

Nodose /

Dorsal root

ganglion

Dorsal

vagal

complex

Dorsal

vagal

complex

ENS

ENS

Serotonin Receptors on Sensory Afferents
(7)

B. Vogt, et. al., Human Nervous System, 2003

B. Vogt, et. al., Human Nervous System, 2003

IBS - Cingulate Cortex - Functional Associations

Vogt, J Comp Neurology 1995; 359:490

Vogt, J Comp Neurology 1995; 359:490

Affective

Affective

Motivational

/somatic

Motivational

/somatic

Visuospatial

Visuospatial

Unpleasantness / fear

Unpleasantness / fear

Autonomic

Autonomic

Memory

Memory

Infragenual

Infragenual

Anterior

Anterior

Perigenu

al ACC

Perigenu

al ACC

Midcingulate

Midcingulate

Posterio

r

Posterio

r

Retrosplenial

Retrosplenial

24b

'

24b

'

24a

'

24a

'

32

'

32

'

24c

'

24c

'

24c

24c

'

'

Anterior

Midcingulate

Cortex

Anterior

Midcingulate

Cortex

Anterior Cingulate Cortex Typography

Descending Visceral Pain Pathway

Descending Visceral Pain Pathway

AC

C

AC

C

Colon

Colon

Noradrenergic

Noradrenergic

Thalamus Thalamus PAG PAG Locus coeruleus Locus coeruleus Caudal raphe nucleus Caudal raphe nucleus

Opioidergic

Opioidergic

Rostral ventral medulla Rostral ventral medulla Amygdala Amygdala

Serotonergi

c

Serotonergi

c

(8)

Drossman DA, Ann Intern Med. 1995; 123:688

Drossman DA, Ann Intern Med. 1995; 123:688

Brain - Gut Inhibitory Pain Pathway (“Gate” Control)

Treatment of IBS

Abdominal pain /

discomfort

• Antispasmodics

• Antidepressants

– TCAs / SSRIs

• Alosetron

• Tegaserod

Abdominal

Abdominal

pain /

pain /

discomfort

discomfort

Bloating /

Bloating /

distention

distention

Altered bowel

Altered bowel

function

function

Brandt, Am J Gastroenterol 2002; 97: S7 Drossman, Gastroenterology 2002; 123; 2108

Constipation

• Fiber

• MOM/PEG solution

• Tegaserod

Diarrhea

• Loperamide

• Other opioids

• Alosetron

Bloating

 Tegaserod  Dietary changes  ? Probiotics  ? Antibiotics
(9)

Alosetron

C

N

OUT

IN

OUT

IN

Na

+

, Ca

++

K

+

5-HT

5-HT

Alosetron (Lotronex)

2000

5-HT

3

Antagonist: Mechanisms of Action

(10)

IBS - Serotonin Receptors on Sensory Afferents

IBS - Serotonin Receptors on Sensory Afferents

Mechanical

noxious

stimulation

Mechanical

noxious

stimulation

5-HT3 5-HT3

Serotonin

(5-HT)

Serotonin

(5-HT)

5-HT

3

receptor on vagal

or spinal afferent

5-HT

3

receptor on vagal

or spinal afferent

Mucosal enterochromaffi n cell Mucosal enterochromaffi n cell

Vagal /

spinal

afferent

Vagal /

spinal

afferent

Nodose /

Dorsal root

ganglion

Nodose /

Dorsal root

ganglion

Dorsal

vagal

complex

Dorsal

vagal

complex

ENS

ENS

Serotonin Receptors on Sensory Afferents

Mechanisms of Action of

5-HT 3 receptor antagonists

• Delay small bowel and colonic transit

1,2

- treat diarrhea

• Increase colonic compliance

1

- improve fecal urgency

• Inhibit chloride secretion

1

- make stools more formed

• Blunt the gastrocolonic response

1

- improve urgency

• Affect visceral afferent

1

-

diminish abdominal pain

1. Kim D-Y, Camilleri M. Am J Gastroenterol.2000;95:2698–2709. 2. Viramontes BE et al. Am J Gastroenterol.2001;96:2671–2676.

(11)

Tegaserod (Zelnorm)

2002

Tegaserod (Zelnorm)

2002

Tegaserod is a 5-HT

4

receptor agonist

new class of compound: aminoguanidine indoles

Structure similar to serotonin

Camilleri, Aliment Pharmacol Ther 2001; 15: 277 Camilleri, Aliment Pharmacol Ther 2001; 15: 277

Serotonin (5-HT)

NH OH NH2

Tegaserod

O N NH NH NH NH

Tegaserod is a 5-HT

4

agonist

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

Gershon, Rev Gastroenterol Dis 2003; 3: S25

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

Gershon, Rev Gastroenterol Dis 2003; 3: S25

(12)

IBS Treatment

Prather et. al., Gastroenterology 2000;

Prather et. al., Gastroenterology 2000;

118:463

118:463

Effect of 5HT

4

Agonist on Colonic

Transit

Effect of 5HT

Effect of 5HT

4

4

Agonist on Colonic

Agonist on Colonic

Transit

Transit

24 hr

24 hr

48 hr

48 hr

Pre

Pre

-

-treatment

treatment

Post

Post

-

-Tegaserod

Tegaserod

6 hr

6 hr

C

C

-

-

IBS

IBS

Effect of Tegaserod on Colonic Transit

Effect of tegaserod on additional

dysmotility symptoms of IBS-C

1

Effect of tegaserod on additional

dysmotility symptoms of IBS-C

1

Relieved bloating

Relieved bloating

Reduced abdominal pain / discomfort

Reduced abdominal pain / discomfort

Reduced straining

Reduced straining

Increased number of BMs/wk

Increased number of BMs/wk

Improved stool consistency

Improved stool consistency

 In a double-blind RCT (tegaserod n=1645; placebo n=405): IBS-C QoL was significantly better in patients treated with tegaserod, p=0.005 vs placebo2

 Efficacy beyond 12 weeks has not been studied

 Response rates vs placebo were greater at month 1 than at month 3

1Kellow et al, Gut 2003; 52: 671 2Patrick et al, Gastroenterol 2005; 128: A287

(13)

Serotonin Transporter

(SERT)

• Single protein

• Mediates reuptake of 5-HT from the

synaptic cleft

• SERT in the

gut

is similar to SERT in the

brain

of the same species

• neurons (ENS) and crypt epithelial cells

synthesize SERT proteins

• Function of the SERT: to control the

concentration + actions of 5-HT in the gut

and limit desensitization of 5-HT receptors

Chen J-X, Pan H, Rothman TP, et al. Am J Physiol 1998; 275:G433-8 Wade PR, Chen J, Jaffe B et al. J Nuerosci 1996; 16:2352-64
(14)

SRI

N RI

?

M1 ?

(S)SRI

Escitalopram (Lexapro) 10-20 mg

Citalopram (Celexa) 20-60 mg Paroxetine (Paxil) 20-80 mg

Sertraline (Zoloft) 50-250 mg

Fluoxetine (Prozac) 20-80 mg

Fluvoxamine (Luvox) 100-300 m

Therapeutic effects of fluoxetine in IBS-C

patients: A randomized-controlled study

Therapeutic effects of fluoxetine in IBS-C

patients: A randomized-controlled study

„ At week 4, all symptoms evaluated (bloating, discomfort, stool consistency, change in bowel habit <3 bowel movements / week) less frequent in the fluoxetine patients vs placebo (p<0.05)

„ Mean number symptoms per patient decreased from 4.6–0.7 in fluoxetine patients vs 4.5–2.9 in control patients (p<0.001)

„ Low dose fluoxetine effective in IBS-C patients, but there is need for further studies

(15)

Efficacy of rifaximin for chronic

bloating and flatulence in IBS patients

Efficacy of rifaximin for chronic

bloating and flatulence in IBS patients

Rifaximin 400 mg bd (n=37)

Placebo (n=33)

NB 38% IBS-C

 Antibiotic

 Modest effect in short term management of gas-related abdominal symptoms

 Study limitations: short duration of treatment and follow-up, small sample size

Sharara et al, Am J Gastroenterol 2006; 101: 326

*p<0.05 vs placebo

CHRONIC

CONSTIPATION

(16)

Overlap in IBS-C and

chronic constipation (CC)

Overlap in IBS-C and

chronic constipation (CC)

 

Two or more of the following:

z<3 BMs per week

z>25% of BMs:

fhard or lumpy stool

fstraining fincomplete evacuation fsensation of anorectal obstruction / blockage fmanual maneuvers to facilitate

At least 12 weeks, which need not be consecutive, in the preceding 12 months:

IBS-C

CC

Thompson et al, Gut 1999; 45: II43 BM = bowel movement

 Abdominal pain / discomfort associated with two or more of the following:

z<3 BMs per week zhard or lumpy stools zrelieved with BM

 May also be associated with:

zbloating, feeling of abdominal distension, passage of mucus, straining

zincomplete evacuation zmay alternate with diarrhea

(17)
(18)
(19)

Pathophysiologic-based treatment

approach for chronic constipation

Slow transit / functional constipation

IBS-C / Constipation

and overlap syndromes Dyssynergia

PEG compounds Tegaserod Lubiprostone Tegaserod Biofeedback therapy 0% 20% 40% 60% 80%

Biofeedback Therapy for

Dyssynergic Constipation

(Randomized Controlled Trial )

Biofeedback Sham Standard n=21 n=21 n=23 Baseline End Active *P = 0.0018 vs. baseline †P = 0.048 vs. standard

*

7 6 5 4 3 2 Mean CSBMs p er w eek + S.E.M . 1

Rao SSC, et al. Gastroenterology. 2005;128:S1851.

100% % o f pa tien ts w ith d y ss y n erg ia af ter trea tme n t *P = 0.0001 vs. sham, standard, and baseline

*

Biofeedback Sham Standard n=21 n=21 n=23

(20)

2.9

2.7

<2

**

4.5

*

4.2

2

0 5

Baseline

Week 1

Week 2

PEG-3350

Placebo

Efficacy of PEG-3350 in constipation

• Osmotic action targets only the stool, not the colon • Slows gastric emptying in healthy subjects

• Side effects: Diarrhea, nausea, abdominal bloating, cramps, and flatulence • Indicated for occasional use and should be used for 2 weeks or less

*p<0.01 **p<0.001

DiPalma et al, Am J Gastroenterol 2000; 95: 446 Physician’s Desk Reference 2005; 1025 Coremans et al, Dig Liver Dis 2005; 37: 97

n=151 (87% F)

(21)

Johanson et al, Am J Gastroenterol 2005; 100: S324 Johanson et al, Am J Gastroenterol 2005; 100: S328 Chronic constipation = <3 SBM per week. Minimum of 6-month history

SBM = Any BM that did not occur within 24 hours of rescue laxative use

Placebo (n=118)

Lubiprostone 24 ug bid (n=119)

SBM 24 hours post-first dose (%)

***p<0.00011

„Phase III, double-blind, placebo-controlled trial of lubiprostone vs placebo 28 days

Lubiprostone in the treatment

of chronic idiopathic constipation

0 31.4 61.3 80 ***

Comparison of lubiprostone

and tegaserod in CC

Tegaserod 62% Diarrhea (7%) Headache (15%)** Abdominal pain (5%) Nausea (5%) Diarrhea (13%) Headache (13.2%) Abdominal pain (6.7%) Nausea (31.1%) Adverse Events in CC*

Stimulates the peristaltic reflex Stimulates intestinal secretion Inhibits visceral sensitivity Increases intestinal fluid secretion

Mechanism of action Lubiprostone 61.3% Patients experiencing SBM in first 24 hours3,4†

Twice daily orally before meals Twice daily orally with food

Administration

CC in male and female patients <65 years, IBS-C in female patients

CC in male and female patients Indications

5-HT4agonist Chloride channel activator

Description

Tegaserod

2

Lubiprostone

1

†Different endpoints make the trials difficult to compare

*AE rates for tegaserod in IBS-C are not listed here **Rate reported in IBS-C, only aggravated

headache listed for CC (1%)

1Lubiprostone PI 2Tegaserod PI 3Johanson, Am J Gastroenterol 2005; 100: S324 4Kamm, Am J Gastroenterol 2005; 100: 362

(22)

FDA-approved prescription

medications for constipation

Chronic

All constipation

Occasional

Laxatives

Laxatives

y yPEGPEG y ylactuloselactulose

Tegaserod

Tegaserod

Lubiprostone

Lubiprostone

Chronic idiopathic constipation IBS with constipation

Duration

Tegaserod

Tegaserod

THE END

References

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