Transcript Slide 1

Outline
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Definition
Epidemiology
Impact and burden of disease
Pathophysiology
Treatment: What is the evidence?
Novel therapies
Concluding Remarks
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
THE ROME CRITERIA
 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
RED FLAGS!
• 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
WORLDWIDE PREVALENCE OF IBS
70
Prevalence (%)
60
50
Rome II = 5%
40
30
20
10
0
UK1
1
USA2
New
Zealand3
France4
China5
Nigeria6
Denmark7
Heaton K et al. 1992; 2Longstreth G, Wolde-Tsadnik P 1993; 3Welch 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
IBS versus Other
Important Disease States
• US prevalence of IBS/functional bloating
up to 20%1
• US prevalence rates for other common
diseases2
– Diabetes
– Asthma
– Heart disease
– Hypertension
1
2
3%
4%
8%
11%
Camilleri M et al. Aliment Pharmacol Ther 1997;11:3–15
Adams P, et al. Vital Health Stat 10 1991;181:1–212
PHYSICIANS VISITS PER YEAR
Number of visits per year
6
5
GI
Non-GI
4
3
2
1
0
IBS
Drossman DA et al. Dig Dis Sci 1993; AGA Teaching Unit in IBS, 1997
Non-IBS
COST OF IBS (in millions)
25000
20000
15000
10000
5000
0
Direct
The Burden of Gastrointestinal Diseases. AGA 2001
Indirect
Impact of IBS on Quality of Life
Compared with US Norms
Mean SF-36 score
100
90
80
US Norm
70
60
IBS
50
40
30
Physical RoleFunctioning Physical
Bodily
Pain
General
Health
Vitality
Social
Role- Mental
Functioning Emotional Health
Adapted from Wells et al. Aliment Pharmacol Ther. 1997;11:1019-1030.
Impact of IBS on Quality of Life
Compared with Other Medical Conditions
100
Mean SF-36 score
90
Diabetes type II
80
US Norm
70
60
IBS
50
Clinical
depression
40
30
Physical RoleFunctioning Physical
Bodily
Pain
General
Health
Vitality
Social
Role- Mental
Functioning Emotional Health
Adapted from Wells et al. Aliment Pharmacol Ther. 1997;11:1019-1030.
EVOLUTION OF MECHANISTIC
HYPOTHESES IN IBS
5-HT mediated visceral
sensitivity and gut motility1
Small bowel bacterial
overgrowth
Brain-gut interaction2
Visceral hypersensitivity2
Abnormal motility2
1950
1
Prior A, Read N. Aliment Pharmacol Ther 1993
Drossman D. Aliment Pharmacol Ther 1999
2
2000
% REPORTING
PAIN
IBS PATIENT
ABERRANT ACTIVATION OF CNS
PAIN CENTERS IN IBS
H. Mertz, 2000.
AUDITORY STRESS ALTERS PERCEPTUAL AND
EMOTIONAL RATINGS OF VISCERAL STIMULI
Unpleasentness
at 45 mm Hg (cm)
12
*
10
9.4
8.6
Controls
IBS
10.2
*p<0.05
8.4
8
Anger rating
6
*
4.6
*p<0.05
4
2.8
3
3.4
2
0
Relaxing sounds
Conflicting sounds
Dickhaus et al. Am J Gastroenterol 2003;98:135-43
Relaxing sounds
Conflicting sounds
PHYSIOLOGIC DISTRIBUTION OF 5-HT
CNS – 5%
GI tract – 95%
– Enterochromaffin cells
– Neuronal
Gershon MD. Aliment Pharmacol Ther 1999;13(Suppl. 2):15–30
MOTOR ACTIVITY IN IBS
Interneurons
Excitatory
motor neuron
(contraction)
5-HT4
Sensory
neuron
5-HT
receptors
5-HT
Inhibitory
motor neuron (relaxation)
5-HT3
Enterochromaffin cells
Altered
serotonergic
function
Altered ANS
Gas retention
?Food
hypersensitivity
Colonic flora
Social stress
IBS
?Small bowel
bacterial
overgrowth
Gut-Brain Axis
dysfunction
Heightened
visceral
nociception
Genetic
polymorphism:
SERT/Cytokines
Post-Infectious
IBS
Sleep
dysfunction
Inflammation
KEYS TO TREATMENT OF IBS
• Education/reassurance
• Dietary modification
• Focus on health
• Set realistic goals
• Pharmacotherapy of GI symptoms
• Monitoring and modification
• Psychological treatments
• Referral to pain management
HIGH PLACEBO RESPONSE RATES IN
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
TREATMENT OF IBS
5-HT3-antagonists
• Alosetron , cilansetron
Anticholinergics
5-HT4-agonist
SM relaxants
• mebeverine
• cimetropium
• pinaverium
• otilonium
• trimebutine
• zamifenacin
modulating
inhibiting
gut
spasms
visceral pain
 Pain &
pathway &
bloating
anti-nociceptive
effect
• tegaserod
Antidepressants
• Tricyclics, SSRI
NK2-receptor
antagonist
• nepadutant
• darifenacin
kappa-opioid agonist
• fedotozine
EFFICACY OF ANTISPASMODIC AGENTS
• Meta-analysis of 23 RCTs with comparable outcomes
(1888 pts)
• 5 superior to placebo: mebeverine , pinaverium, otilium,
trimebutine, cimetropium
80
60
***
***
56
53
**
40
38
41
Active
Placebo
44
35
*** p<0.001
** p=0.008
20
0
Global Improvement
Pain Improvement
Poynard et al. Aliment Pharmacol Ther 2001;15:355-61.
Abdominal Distention
Improvement
TREATMENT OF IBS
5-HT3-antagonists
• Alosetron , cilansetron
Anticholinergics
5-HT4-agonist
SM relaxants
• mebeverine
• cimetropium
• pinaverium
• otilonium
• trimebutine
• zamifenacin
modulating
inhibiting
gut
spasms
visceral pain
 Pain &
pathway &
bloating
anti-nociceptive
effect
• tegaserod
Antidepressants
• Tricyclics, SSRI
NK2-receptor
antagonist
• nepadutant
• darifenacin
kappa-opioid agonist
• fedotozine
LOW-DOSE TRICYCLIC
ANTIDEPRESSANTS
• 7 trials: Only 1 met high quality criteria1
• 4 reported significant improvement in:
– Abdominal pain
– diarrhea1
1Jailwala
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
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
Patient Characteristics
Imipramine
Placebo
(n=59)
(n=48)
Mean Age
42.6±12.4
45.3±13.8
NS
Sex (% Male)
33 (55.9%)
29 (60.4%)
NS
Type of recruitment
38 (64.4%) referrals
29 (60.4%) referrals
NS
Bloating/Distention
57 (96.6%)
46 (95.8%)
NS
Pain
58 (98.3%)
47 (97.9%)
NS
Flatulence
45 (76.3%)
40 (83.3%)
NS
Constipation (C)
17 (28.8%)
15 (31.3%)
NS
Diarrhea (D)
11 (18.6%)
7 (14.6%)
NS
Mixed (alternating)
14 (23.7%)
15 (31.3%)
NS
100%
100%
NS
Prior medical Rx
p-value
Drop-outs
Imipramine*
Placebo
Premature withdrawal
6
14
Lost to follow-up
3
3
Protocol violation
5
1
Side-effects
14
5
Patient Global Relief (Per Protocol)
85.4%
90%
83.3%
p<0.05
80.6%
80%
70%
60%
52.5%
51.4%
50%
58.1%
48.0%
40%
30%
28.0%
20%
10%
Imipramine
0%
Placebo
0%
0
4
8
12
16
Weeks
Sharara A et al. Oral presentation ACG 2006. Winner of ACG/Novartis Research Award
Patient Global Relief (intent-to-treat)
70%
59.3%
60%
50.8%
50%
43.8%
p=0.053
42.4%
37.5%
40%
30.5%
30%
25.0%
20%
14.6%
10%
Imipramine
0%
Placebo
0%
0
4
8
12
16
Weeks
Sharara A et al. Oral presentation ACG 2006. Winner of ACG/Novartis Research Award
Imipramine-Associated
Side Effects
GI
disturbance
3
Anxiety
1
Sweating
1
Palpitations
2
Genitourinary
symptoms
2
Disturbed
sleep
1
Dry mouth
1
Dizziness
3
Mean % Change in SF36 Scores
p<0.01
15.0%
12.1%
10.0%
5.0%
3.0%
0.0%
Placebo
Imipramine
TREATMENT OF IBS
5-HT3-antagonists
• Alosetron , cilansetron
Anticholinergics
5-HT4-agonist
SM relaxants
• mebeverine
• cimetropium
• pinaverium
• otilonium
• trimebutine
• zamifenacin
modulating
inhibiting
gut
spasms
visceral pain
 Pain &
pathway &
bloating
anti-nociceptive
effect
• tegaserod
Antidepressants
• Tricyclics, SSRI
NK2-receptor
antagonist
• nepadutant
• darifenacin
kappa-opioid agonist
• fedotozine
Loose
Effect of Alosetron on Relief of Abdominal Pain
and Discomfort and Stool Consistency (D-IBS)
70 Alosetron 1mg b.i.d.
*
40
Placebo b.i.d.
30
20
10
*p<0.05
LOCF
0
Formed
Placebo
* * *
3
**
Hard
*
** **
** ** ** ** ** **
** ** **
Alosetron 1mg b.i.d.
2
**p<0.001
Very hard
50
*
* * * * * *
Stool consistency score
With relief (%)
60
4
LOCF
1
1 2 3
4 5 6 7
8 9 10 11 12 +1 +2 +3 +4
12 weeks treatment
4 weeks follow-up
0 1 2 3 4 5 6 7 8 9 10 11 12 +1 +2 +3 +4
12 weeks treatment
Camilleri M et al. Lancet 2000;355:1035–40
4 weeks follow-up
Tegaserod
• 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-IBS
Satisfactory relief by week (ITT)
placebo
tegaserod
80
Patients (%)
70
60
**
50
** **
** ** ** **
**
** ** ** **
*
40
30
20
10
0
–1
*p<0.05; **p<0.01 vs placebo
2
4
6
8
Week
10
12
WD2 WD4
Melatonin and the Gut
• 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
Barajas-Lopez C et al 1996; Storr M et al 2000;
Roberts-Thomson IC 1988; Lu WZ et al 2005
RCT of Melatonin in IBS
Song, G H et al. Gut 2005;54:1402-1407
Melatonin 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
Song, G H et al. Gut 2005;54:1402-1407
Probiotics 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
O’Mahoney L et al. Gastroenterology 2005;128:541-551
Probiotics in IBS
O’Mahoney L et al. Gastroenterology 2005;128:541-551
Probiotics in IBS
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 treatsymptom in IBS?
1. Abdominal pain
2. Constipation
3. Diarrhea
4. Bloating
5. Feeling of incomplete evacuation
6. Alternating diarrhea & constipation
Hydrogen Gas in Man
• The colon is the major site of intestinal H2 formation
(>99% in fasting state and after lactose)
• H2 production depends upon delivery of nonabsorbable 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
1Levitt
MD. N Engl J Med 1969;281:122-7
2Calloway D. Gastroenterology 1966;51:383-9
Rifaximin
• 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
4,
5
of flatulence and bloating
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 Relief
* p < 0.05
*
*
Sharara AI et al. Am J Gastroenterol 2006
Global Assessment of Relief
IBS patients
* p < 0.05
*
*
Sharara AI et al. Am J Gastroenterol 2006
Symptom score vs. LHBT
Rifaximin
Placebo
Bloating score vs. LHBT
Rifaximin
Placebo
Diarrhea pred.
IBS
Pain pred.
IBS
mild
Fiber,
exercise
Fluid intake
Osm. Laxative
Antispasmodic
agents
Serotonin-4
agonist
Trial diet
excluding
lactose/caffeine
Loperamide,
Antispasmodic
agent
Low-dose
TCA
Antispasmodic
agent
moderate
Low-dose
TCA
Consider psychotherapy, careful reevaluation
Constipation
With IBS
Education, reassurance, stress management
Proposed Algorithm
? Low-dose
TCA
Serotonin-3
antagonist
Serotonin-3
antagonist if
diarrhea occurs
severe
Modified from Mertz HR. N Engl J Med 2003;349;2136-46.