1. No category

11/2/2011
A Practical Approach to
Diagnosis and Management
of Irritable Bowel Syndrome
(IBS)
Recognizing IBS
Brooks D. Cash, MD
1
11/2/2011
IBS Patient Case
• 28 year-old female with 3-year history
of abdominal pain and bloating
associated with intermittent diarrhea
• Symptoms impact daily activities
• Frequently bothered by sensations
of urgency
• Needs to be close to a restroom at
work
• Reluctant to go out to movies and
restaurants with friends
• Tried multiple dietary manipulations
and OTC drugs without success
3
WHAT IS IBS?
IBS is a functional bowel disorder in which
abdominal pain or discomfort is associated with
defecation or a change in bowel habit, and with
features of disordered defecation
Longstreth GF, et al. Gastroenterology. 2006;130:1480-1491.
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11/2/2011
IBS IS A HIGHLY PREVALENT CONDITION
Prevalence
5%-10% in North America1
Resource Utilization
• IBS accounted for 3 million ambulatory care visits in 20042
• IBS care consumes >$20 billion in direct and indirect costs3
• IBS accounts for 14 hours of lost productivity per 40-hour
work week1
1. ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.
2. National Institutes of Health. The burden of digestive diseases in the United States. NIH Publication 09-6443; January 2010.
3. American Gastroenterological Association. The burden of gastrointestinal diseases. 2001:1-89.
5
IBS PROFOUNDLY AFFECTS QOL
Average QOL Scores
in IBS Patients
IBS Severity*
Food Avoidance 32.0
Severe
20.3%
Emotional Distress 45.6
Mild
31.4%
Interferes With Activities 48.8
Social Reaction 53.4
Health Worry 53.7
Body Image 56.8
Moderate
48.3%
Sexual 60.2
Relationship 62.9
Average Score 51.1
Worst
Possible
IBS-QOL Score
Best
*QOL=quality of life.
*Severity levels determined by FBDSI, with mild severity <36, moderate=36-109, and severe ≥110.
QOL determined by the IBS-QOL.
(n=1966 patients with physician-diagnosed IBS participating in an Internet survey)
FBDSI=Functional Bowel Disorder Severity Index; IBS-QOL=Irritable bowel syndrome quality of life.
IFFGD. IBS patients: their illness experience and unmet needs. www.aboutibs.org/pdfs/IBSpatients.pdf. Accessed March 29, 2010.
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11/2/2011
IBS AND COMORBIDITIES
• Increased prevalence of psychiatric disorders in patients
with IBS compared with controls1,2
• Major depression
• Anxiety
• Somatoform disorders
• Nongastrointestinal, nonpsychiatric disorders commonly
associated with IBS include1
•
•
•
•
•
Fibromyalgia
Temporomandibular joint disorder
Chronic fatigue syndrome
Chronic pelvic pain
Painful bladder syndrome/interstitial cystitis
1. Whitehead WE, et al. Gastroenterology. 2002;122:1140-1156.
2. Levy RL, et al. Gastroenterology. 2006;130:1447-1458.
7
IBS AND SYMPTOM OVERLAP
CC
Dyspepsia
IBS
IBS
GERD
CC=chronic constipation; GERD=gastroesophageal reflux disease; IBS=irritable bowel syndrome.
Used with permission from Christine Frissora, MD.
Frissora CL, Koch, KL. Curr Gastroenterol Rep. 2005;7:264-271.
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11/2/2011
Understanding IBS
EVOLVING PATHOPHYSIOLOGY OF IBS
Genetics
Microbial-mucosal
Neuroimmune
Brain-gut interaction
Visceral hyperalgesia
Abnormal motor function
Purely psychological disorder
1950
1960
1970
1980
1990
2000
2011
10
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11/2/2011
PATHOPHYSIOLOGY OF IBS
Acute
Gastroenteritis
• Enteric Neuropathy
• Gastrointestinal (GI)
Motor Disturbances
Food
• Visceral
Genetic
Factors
Hypersensitivity
Symptoms
• Abnormal Central
Environment
Abuse
History
Other
Precipitating
Factors
Processing of
Sensations
• Psychological
Stress
Disturbances
Consultation
Used with permission.
Adapted from Rome Foundation Functional GI Disorders Specialty Modules.
11
VISCERAL HYPERSENSITIVITY AND IBS:
THE BRAIN-GUT CONNECTION
Visceral Analgesia
Changes in Motility
Smooth Muscle
Relaxation
Used with permission.
Adapted from Rome Foundation Functional GI Disorders Specialty Modules.
12
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11/2/2011
GUT FLORA AND IBS:
AN EMERGING CONNECTION
• Postinfectious IBS (PI-IBS)
• Acute onset of new IBS symptoms
(ie, in an individual who has not
previously met the Rome criteria for
IBS) following an acute illness
characterized by ≥2 of the following:
fever, vomiting, diarrhea, positive
bacterial stool culture1
• Altered gut flora
Used with permission.
1. Spiller R, Garsed K. Gastroenterology. 2009;136:1979-1988.
2. Posserud I, et al. Gut. 2007;56:802-808.
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13
RISK OF POST-INFECTIOUS IBS INCREASES 7-FOLD
AFTER INFECTIOUS GASTROENTERITIS*
Protective Effect
Increased Risk
Study (year/bacteria)
OR (95% Cl)
Ji (2005/Shigella)
2.8 (1.0-7.5)
Mearin (2005/Salmonella)
8.7 (3.3-22.6)
Wang (2004/Unspecified)
10.7 (2.5-45.6)
Okhuysen (2004/Unspecified)
10.1 (0.6-181.4)
Cumberland (2003/Unspecified)
6.6 (2.0-22.3)
llnyckyj (2003/Unspecified)
2.7 (0.2-30.2)
Parry (2003/Bacterial NOS)
9.9 (3.2-30.0)
Rodriguez (1999/Bacterial NOS)
11.3 (6.3-20.1)
Pooled estimate
7.3 (4.8-11.1)
0.1
0.5
1
10
50
9.8% IBS
in cases
vs
1.2% IBS
in controls
OR
OR=odds ratio.
*Systematic review of 8 studies involving 588,061 subjects; follow-up ranged from 3 to 12 months.
Halvorsen HA, et al. Am J Gastroenterol. 2006;101:1894-1899.
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11/2/2011
NORMAL INTESTINAL MICROFLORA AND pH
Duodenum
101–103
cfu/mL
pH ~6.4
Stomach
101–103
cfu/mL
Colon
1011–1012
cfu/mL
Proximal
pH~6.2
Distal pH~7.3
Most Common Bacteria
Anaerobic Genera
Aerobic Genera
Bifidobacterium
Escherichia
Clostridium
Enterococcus
Jejunum/Ileum Bacteroides
104–107 cfu/mL
Eubacterium
Ileal pH~7.6
Streptococcus
Klebsiella
cfu=colony forming units.
1. O’Hara AM, Shanahan F. EMBO Rep. 2006;7:688-693.
2. Kloetzer L, et al. Gastroenterol. 2007;132 (suppl 2):A461.
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IBS PATIENTS HAVE INCREASED COUNTS OF
SMALL-BOWEL BACTERIA
Subjects, %
Controls (n=26)
IBS Patients (n=162)
P=.002
43%
P<.02
24%
12%
P=NS
4%
4%
4%
>10,000 cfu/mL,
Any Bacteria
>5,000 cfu/mL,
Any Bacteria
≥105 cfu/mL,
Colonic Bacteria
NS=not significant.
Posserud I, et al. Gut. 2007;56:802-808.
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11/2/2011
EVOLVING EVIDENCE OF
IMMUNE REACTIVITY IN IBS
Increased inflammatory cells found in
rectal biopsies of patients with PI-IBS1
Mast cells are increased and closer to
nerve fibers in colonic mucosa in IBS2
Mast-cell mediators excite visceral
sensory neurons in IBS2
Cytokine studies in IBS patients
demonstrate mixed results3-6
1. Spiller RC, et al. Gut. 2000;47:804-811.
2. Barbara G, et al. Gastroenterology. 2007;132:26-37.
3. Dinan TG, et al. Gastroenterology. 2006;130:304-311.
4. Liebregts T, et al. Gastroenterology. 2007;132:913-920.
5. Macsharry J, et al. Scand J Gastroenterol. 2008;43:1467-1476.
6. Chang L, et al. Neurogastroenterol Motil. 2009;21:149-159.
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IBS PATHOPHYSIOLOGY: SUMMARY
•
IBS symptoms have traditionally been linked to
disturbed GI motility, visceral hypersensitivity, and
psychological distress
•
Growing evidence suggests that alterations in
intestinal and colonic microflora play a role in IBS
•
•
•
Infectious gastroenteritis significantly increases the risk of
developing IBS
Quantitative changes in gut flora have been noted in IBS
patients
The role of cytokine activity and inflammation are
emerging areas of research in IBS
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Diagnosing IBS
ROME III DIAGNOSTIC CRITERIA FOR IBS
•
Recurrent abdominal pain or discomfort for ≥3 days
per month in the last 3 months, associated with ≥2
of the following:
•
•
•
•
Improvement with defecation
Onset associated with a change in stool frequency
Onset associated with a change in stool form
(appearance)
Diagnostic criteria fulfilled for the last 3 months with
symptom onset ≥6 months prior to diagnosis
Longstreth GF, et al. Gastroenterology. 2006;130:1480-1491.
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11/2/2011
IBS SUBTYPES BASED ON STOOL FORM
Bristol Stool Form Scale1,2
Type 1
Separate
hard lumps,
like nuts
(hard to
pass)
Type 2
Sausageshaped
but lumpy
IBS-C
Hard/lumpy stools ≥25%
Loose/watery stools <25%
Type 3
Like a
sausage
but with
cracks on
its surface
Type 4
Like a
sausage
or snake,
smooth
and soft
Type 5
Soft blobs
with
clear-cut
edges
(passed
easily)
IBS-M
Hard/lumpy stools ≥25%
Loose/watery stools ≥25%
Type 6
Fluffy pieces
with ragged
edges, a
mushy stool
Type 7
Watery,
no solid
pieces,
entirely
liquid
IBS-D
Hard/lumpy stools <25%
Loose/watery stools ≥25%
IBS-C=constipation-predominant IBS; IBS-D=diarrhea-predominant IBS; IBS-M=mixed IBS.
1. O’Donnell LJD et al. BMJ. 1990;300:439-440.
2. Longstreth GF, et al. Gastroenterology. 2006;130:1480-1491.
3. Adapted from Lewis SJ, Heaton KW. Scan J Gastroenerol. 1997;32:920-924.
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DIAGNOSTIC INVESTIGATION RECOMMENDED
IN PATIENTS WITH ALARM FEATURES
• Onset of symptoms after age 50
• GI bleeding or iron-deficiency anemia
• Nocturnal diarrhea
• Weight loss
• Family history of organic GI
disease (colorectal cancer, IBD,
celiac disease)
IBD=inflammatory bowel disease.
ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.
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11/2/2011
INVESTIGATION IN PATIENTS WITHOUT
ALARM FEATURES: SYSTEMATIC REVIEW
Prevalence of Organic Diseases in Patients
Meeting Symptom-based Criteria for IBS1,2
IBS
Patients, %
General
Population, %
0.51-0.98
0.3-1.2
Colorectal cancer
0-0.51
0-6
(varies with age)
Thyroid dysfunction
4.2
5-9
Event
Colitis/IBD
GI infection
0-1.5
NA
Celiac disease
3.6
0.7
Lactose intolerance
38
26
The value
of alarm
symptoms is
their negative
predictive
value.
1. Cash BD, et al. Am J Gastroenterol. 2002;97:2812-2819.
2. ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.
23
ROUTINE DIAGNOSTIC TESTING IS NOT RECOMMENDED
IN PATIENTS WITHOUT ALARM FEATURES
•
CBC/serum chemistries
•
Thyroid function studies
•
Stool for ova and parasites
•
Abdominal imaging
•
Colonoscopy (in patients <50 years of age)
CBC=complete blood count.
ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.
24
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11/2/2011
BREATH TESTING IN IBS: META-ANALYSIS OF
AGE- AND SEX-MATCHED CASE CONTROL
Author
Type of
Breath Test
Grover
sucrose
2.29 (0.89, 5.87)
Lupascu
glucose
10.89 (3.52, 33.71)
Pimentel
lactulose
20.67 (5.29, 80.69)
Parodi
glucose
4.30 (1.24, 14.98)
Scarpellini
lactulose
24.27 (7.35, 80.15)
Collin
lactulose
18.04 (6.55, 49.71)
OR (95% CI)
9.64 (4.26, 21.82)
Overall (I-squared=67.9%, P=0.008)
NOTE: Weights are from random effects analysis
.1
.2
.5
1
2
5
10 20
Used with permission.
Shah ED, et al. Dig Dis Sci. 2010;9:2441-2449.
25
SUMMARY OF DIAGNOSIS OF IBS
•
Patients with typical symptoms and no red flags
can be confidently diagnosed with IBS
•
•
•
IBS-D and IBS-M
– Consider celiac disease, microscopic colitis, SIBO
IBS-C
– Low yield for specific testing for organic disease
Patients with red flags (eg, anemia, weight loss,
family history of organic disease) or symptom
onset after 50 years of age should be referred for a
more detailed evaluation
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11/2/2011
Managing IBS
Philip Schoenfeld, MD
PATIENT PERCEPTIONS OF IBS
Common
Misconceptions
Common
Knowledge
• IBS is a combination of
abdominal pain and
constipation and/or
diarrhea, and/or
bloating
• IBS triggers include
stress at work,
relationships, and
combinations of other
factors
• IBS can develop into:
•
•
•
•
Colitis
A problem requiring
surgery
Malnutrition
Cancer
Most Desired
Information
• What foods to avoid?
• What causes IBS?
• Coping strategies to
reduce symptoms
• IBS will worsen with
age
Data from national sample of IBS patients (N=1242) who responded to the IBS-Patient Education
Questionnaire via mail and online.
Halpert A, et al. Am J Gastroenterol. 2007;102:1972-1982.
Halpert A, et al. Am J Gastroenterol. 2007;102:1972-1982.
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11/2/2011
MEDICATION USAGE IN IBS PATIENTS
Current Medication Usage
Antibiotics 1.0
IBS-targeted drugs* 1.8
Anti-constipation drugs 4.6
Anxiolytics 12.5
Narcotic analgesics 18.1
Antispasmodics 18.5
Antidiarrheals 23.6
Acid reducers 27.7
Antidepressants 30.8
Non-narcotic analgesic 31.3
Complementary therapies 36.9
Patients, %
*Alosetron and tegaserod.
Data from an Internet survey of 1966 respondents diagnosed with IBS.
1. IFFGD. IBS patients: their illness experience and unmet needs. www.aboutibs.org/pdfs/IBSpatients.pdf.
2. Drossman D, et al. J Clin Gastroenterol. 2009;43:541-550.
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DIETARY CONSIDERATIONS IN IBS
Lactose
intolerance1
FODMAPs2,3
Excess Honey, apples, pears,
Fructose peaches, mangos,
fruit juice, dried fruit
Wheat (large
Food
intolerances1
Fructans amounts), rye (large
amounts), onions,
leeks, zucchini
Sorbitol
Soluble fiber
intake1
Apricots, peaches,
artificial sweeteners,
artificially sweetened
gums
Lentils, cabbage,
Raffinose brussels sprouts,
asparagus, green
beans, legumes
FODMAPs=Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols.
1. Somers SC, Lembo A. Gastroenterol Clin North Am. 2003;32:507-529.
2. Shepherd SJ, et al. Clin Gastroenterol Hepatol. 2008;6:765-771.
3. Shepherd SJ, Gibson PR. J Am Diet Assoc. 2006;106:1631-1639.
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11/2/2011
PHYSICAL ACTIVITY CAN IMPROVE
GI SYMPTOMS IN IBS
Start
12 Weeks
IBS Severity Score
500
P=.001
400
300
200
100
0
Control Group
(n=38)
Physical Activity Group
(n=37)
Used with permission.
Johannesson E, et al. Am J Gastroenterol. 2011. [Epub ahead of print.]
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PHARMACOLOGIC THERAPY IS DIRECTED
TOWARD THE DOMINANT SYMPTOMS
Diarrhea
Constipation
Abdominal pain/
discomfort
Bloating
Loperamide*
Diphenoxylate*
Alosetron
Antibiotics*
Fiber*
Osmotic and stimulant
laxatives*
Lubiprostone
Antibiotics
Antispasmodics
Antidepressants*
Alosetron
Lubiprostone
Antibiotics*
Probiotics*
Lubiprostone
*Not FDA approved for IBS.
1. Camilleri M. Gastroenterology. 2001;120:652-668.
2. Drossman DA, et al. Gastroenterology. 2002;123:2108-2131.
3. ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.
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11/2/2011
EVIDENCE-BASED SUMMARY OF
MEDICAL THERAPIES FOR IBS-D SYMPTOMS
Improvements in Symptoms
Global
Symptoms
Pain
Bloating
Alosetron
+
+
+
Antibiotics
(rifaximin)
+
Antidepressants
+
+
Antispasmodics
±
+
Probiotics
(Bifidobacteria/
some combos)
+
Stool
Stool
Frequency Consistency
+
2A/1B
+
1B
1B
+
Loperamide
Grade*
+
2C
2C
2C
Note: Antidepressants and antibiotics are not FDA approved for IBS.
*Recommendations—based on the balance of benefits, risks, burdens, and sometimes cost: Grade 1=strong, Grade 2=weak.
Assessment of quality of evidence—according to the quality of study design, consistency of results among studies, directness
and applicability of study endpoints: Grade A=high, Grade B=moderate, Grade C=low.
Adapted from ACG Task force on IBS. Am J Gastroenterol. 2009;104 (suppl 1):S1-S35.
33
ANTIDIARRHEALS FOR IBS-D
•
Loperamide is the only antidiarrheal evaluated in randomized
controlled trials (2 studies, N=42)1
•
Loperamide is effective for treatment of diarrhea, reducing
stool frequency and improving stool consistency1
•
No impact shown on bloating, abdominal discomfort, or
global IBS symptoms1
•
Low doses (eg, 2 mg QD or BID) may be effective2
•
Adverse effects may include dizziness, constipation,
abdominal pain, distension, fatigue, dry mouth3
1. ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.
2. Mayer EA. N Engl J Med. 2008;358:1692-1699.
3. Loperamide and loperamide-simethicone product monograph. McNeil Consumer Healthcare. Fort Washington, PA.
34
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11/2/2011
ALOSETRON USE IN IBS
•
Alosetron is a 5-HT3 receptor antagonist that has been shown to
relieve global IBS symptoms, abdominal pain, urgency, and
diarrhea-related complaints in patients with IBS-D1
•
Indicated for use in female patients with chronic, severe IBS-D who
have not responded adequately to conventional therapy2
•
Alosetron use limited by risk of rare but serious adverse effects
•
•
•
0.95 cases of ischemic colitis per 1000 patient-years3
0.36 cases of serious complications of constipation per 1000 patient-years3
Use regulated by prescribing program designed by FDA
1. ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.
2. Physicians’ Desk Reference. 64th ed. Montvale, NJ: Thompson Reuters; 2010.
3. Chang L, et al. Am J Gastroenterol. 2010;105:866-875.
35
CLINICAL RESPONSE TO ANTIBIOTICS IN
PATIENTS WITH IBS
N*
Clinical
Response
(Placebo), %
Neomycin1
1 g, 10 d
1 g, 10 d (subset of IBS-C)
55
19
43
37
<.05†
<.001†
Chlortetracycline1
1 g, 7 d
11
27
NS
10
30
63
43
14
624
70
60
41 (23)
36 (21)
64
41 (32)
<.01§
<.001¶
.03†
.02†
—
<.001
Antibiotic
(Daily Dose, Duration)
Same study
Rifaximin1,2
1200 mg, 7 d
1200 mg, 7 d
800 mg, 10 d
1200 mg, 10 d
800-1200 mg, 10 d (IBS-C)
1650 mg, 14 d (non IBS-C)2
P-value
Measure of Clinical Response
50% improvement in composite score‡
Global improvement of IBS symptoms
Normalized breath test results
Normalized breath test results
Normalized breath test results
Improvement in IBS symptoms
Global improvement in IBS symptoms
Improvement in bloating and constipation
Adequate relief of global IBS symptoms
Note: Neomycin, chlortetracycline, and rifaximin are not FDA approved for IBS.
*Number of patients treated with antibiotics; †vs placebo; ‡Based on symptoms of abdominal pain,
diarrhea, and constipation; § vs chlortetracyline 1 g/day x 7 days; ¶vs rifaximin 600 mg/day x 7 days.
Used with permission.
1. Adapted from Frissora CL, Cash BD. Aliment Pharmacol Ther. 2007;25:1271-1281.
2. Pimentel M, et al. N Engl J Med. 2011;364:22-32.
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EFFICACY OF RIFAXIMIN IN IMPROVING GLOBAL
IBS SYMPTOMS AND IBS-RELATED BLOATING
IBS-Related Bloating
During First 4 Weeks
P=.01
TARGET 1
P=.03
P<.001
TARGET 2
Combined
Analysis
Patients With Adequate Relief
of IBS-Related Bloating, %
Patients With Adequate Relief
of Global IBS Symptoms, %
Global IBS Symptoms
During First 4 Weeks
P=.005
TARGET 1
Rifaximin 550 mg TID
P<.001
TARGET 2
Combined
Analysis
Placebo
Pimentel M, et al. N Engl J Med. 2011;364:22-32.
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EFFICACY OF ANTIBIOTIC RETREATMENT
Efficacy of Antibiotic Retreatment in IBS
(n=24)
Efficacy, %
100%
25%
Rifaximin
(n=16)
Neomycin
25%
25%
Amoxicillin/ Doxycycline
Clavulanate
(n=8)
Yang
J, et vs
al.rifaximin.
Dig Dis Sci. 2008;53:169-174.
*P<.0001
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ANTIBIOTICS IN IBS: CLINICAL CONSIDERATIONS
• Rifaximin most extensively studied
antibiotic for IBS
• High concentration to GI tract (<0.4%
systemic absorption)1
• In vitro activity against Gram-positive and
Gram-negative aerobic and anaerobic
bacteria1
• Most likely beneficial in IBS-D patients with
bloating as predominant symptom2
• Most common side effects include flatulence,
headache, abdominal pain1
• No RCTs for systemically absorbed antibiotics
Note: Rifaximin is not FDA approved for IBS.
1. Rifaximin [package insert]. Morrisville, NC: Salix Pharmaceuticals, Inc.; March 2010.
2. ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.
39
ANTISPASMODICS FOR IBS
22 RCTs compared 12 different
antispasmodics with placebo
(n=1778)
Most data available for
otilonium, trimebutine,
cimetropium,
hyoscine,
and
pinaverium
Symptoms persisted in 39% of patients
treated with antispasmodics
vs 56% of placebo-treated patients
(relative risk 0.68; 95% CI=0.57-0.81)5
• Significant
heterogeneity
among studies
• Most agents are not
available in US
• Appear most useful
for abdominal pain
Ford AC, et al. BMJ. 2008;337:a2313.
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11/2/2011
UNDERSTANDING PROBIOTICS
Common Probiotics3-5
• Probiotics
•
•
•
Live, viable microorganisms that, when
administered in adequate amounts, confer a
health benefit on the host1
May be found in foods, supplements, or drugs2
Available as single-organism or combination
products2
Bifidobacterium
B infantis 35624
B animalis DN-173010
Lactobacillus
L salivarius UCC4331
L reuteri
L casei
L plantarum 299v
L rhamnosus GG
• Prebiotics
•
•
•
1.
2.
3.
Usually carbohydrates2
Found in food1,2
Promote the growth or activity of a limited
number of bacterial species for the benefit of
host health2
Saccharomyces
boulardii
E coli Nissle 1917
Food and Agriculture Organization of the United Nations and World Health Organization. 2001. Accessed at:
http://www.who.int/foodsafety/publications/fs_management/en/probiotics.pdf.
Douglas LC, Sanders ME. J Am Diet Assoc. 2008;108:510-521. 4. Quigley EMM, Flourie B. Neurogastroenterol Motil. 2007;19:166-172..
Brenner DM, et al. Am J Gastroenterol. 2009;104:1033-1049.
5. Shanahan F. Am J Physiol Gastrointest Liver Physiol. 2005;288:417-421.
41
POTENTIAL MECHANISMS OF PROBIOTICS
Maintain barrier function
Colonization resistance
Competitive exclusion
P
slp
Reduce
mocromolecular
permeability and
bacterial translocation
Maintain tight junctions
(ZO-1, claudin1)
PB
G
Metabolic effects
Innate/Adaptive Immunomodulation
Modulation of signal transduction
NF-κB
IFNγ
Enhance microbial flora
Probiotics
• Bacteriocins
• Decrease pH
• Quorum sensing
MAPK
IgA, IgG, IgM
Increase mucin
production
Enhance
cytokines
(IL-10, TGFβ)
PC
TC
DC
Used with permission.
Sherman PM, et al. Nutr Clin Pract. 2009;24:10-14.
42
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11/2/2011
EFFICACY OF B INFANTIS IN IMPROVING
ABDOMINAL PAIN/DISCOMFORT IN IBS
Abdominal Pain/Discomfort
8
Likert Scale* Mean
Symptom Score
6
10
P=.056
P=.023
P=.027
*Likert scale=0 (none) to 5 (severe); treatment was stopped at 4 weeks.
Whorwell PJ, et al. Am J Gastroenterol. 2006;101:1581-1590.
43
B INFANTIS IMPROVES IBS SYMPTOMS BUT
INSUFFICIENT EVIDENCE FOR OTHER PROBIOTICS
4648 probiotics in IBS
citations retrieved
21 probiotic
studies assessed
RCTs
16 RCTs
included
• Adults with IBS defined by
Manning or Rome II criteria
• Single or combination
probiotic vs placebo
• Improvement in IBS
symptoms and/or decrease
in frequency of AEs reported
B infantis 35624 demonstrated
efficacy in 2 appropriately
designed RCTs
No other probiotic showed
significant improvement in IBS
symptoms in appropriately
designed RCTs
RCTs=randomized controlled trials.
Brenner DM, et al. Am J Gastroenterol. 2009;104:1033-1049.
44
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11/2/2011
PROBIOTICS FOR IBS:
CLINICAL CONSIDERATIONS
• Not all probiotics are created equal1-3
• Health benefits are strain-specific and
dose-specific
• Clinical support to substantiate claims must
be for each probiotic strain
• Some products do not meet label claim for
content or quality
• All probiotics in US are foods or dietary
supplements2,3
•
•
No products in US currently regulated as
drugs
Claims regarding disease benefits not
allowed on product label
1. Food and Agriculture Organization of the United Nations and World Health Organization. 2002.
http://www.who.int/foodsafety/fs_management/en/probiotic_guidelines.pdf.
2. Douglas LC, Sanders ME. J Am Diet Assoc. 2008;108:510-521.
3. Sanders ME. Funct Food Rev. 2009;1:3-12.
45
EVIDENCE-BASED SUMMARY OF MEDICAL
THERAPIES FOR IBS-C SYMPTOMS
Improvements in Symptoms
Global
Symptoms
Pain
Lubiprostone
+
+
Antidepressants
+
+
Tegaserod†
+

Bloating
Grade*
Stool
Stool
Frequency Consistency
+
1B
1B
+
+
+
2A
Fiber (psyllium)
+
+
2C
Laxatives (PEG)
+
2C
Note: Antidepressants, psyllium, and laxatives are not FDA approved for IBS.
*Recommendations—based on the balance of benefits, risks, burdens, and sometimes cost: Grade 1=strong, Grade 2=weak.
Assessment of quality of evidence—according to the quality of study design, consistency of results among studies, directness
and applicability of study endpoints: Grade A=high, Grade B=moderate, Grade C=low.
†Available only under Emergency IND program; PEG=polyethylene glycol.
Adapted from ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.
46
23
11/2/2011
PSYLLIUM BENEFICIAL FOR IBS SYMPTOMS
Proportion of Patients With Adequate Relief
of Symptoms Each Week
Responders, %
50
*
*
40 *
30
*
20
Psyllium, 10 g (n=85)
Bran, 10 g (n=97)
Placebo (rice flour), 10 g (n=93)
10
0
1
2
3
4
5
6
7
8
9
10
11
12
Study Duration (weeks)
*P<.05.
Used with permission.
Bijkerk CJ, et al. BMJ. 2009:339:B3154-B3160.
47
POLYETHYLENE GLYCOL (PEG) FOR IBS-C
• Laxatives have not
been studied in RCTs
in IBS1
P<.05
Mean
• PEG improved
frequency of bowel
movements but not
pain in adolescents
with IBS-C (n=27)2
Effect of PEG in IBS-C
(n=27)2
Frequency of Bowel
Movements/Week
Pretreatment
Pain Level
Post-treatment
RCTs=randomized controlled trials.
1. ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.
2. Khoshoo V, et al. Aliment Pharmacol Ther. 2006;23:191-196.
48
24
11/2/2011
EFFICACY OF THE SELECTIVE CLC-2 CHLORIDE
CHANNEL ACTIVATOR LUBIPROSTONE FOR IBS-C
Overall Responders*
17.9%
7.8% Difference
P=.001
10.1%
n=769
n=385
Placebo
Lubiprostone
8 µg BID
Combined analysis in Rome II IBS-C patients using intent-to-treat,
last-observation-carried-forward analysis
*Data combined from 2 studies; monthly responder for at least 2 of the 3 months during treatment.
Drossman DA, et al. Aliment Pharmacol Ther. 2009;29:329-341.
49
LUBIPROSTONE IN IBS-C:
CLINICAL CONSIDERATIONS
• Approved at dosage of 8 μg BID for IBS-C in women
•
Contraindicated in mechanical GI obstruction
•
Negative pregnancy test and contraception
recommended in women of childbearing age
• Take with food and water to minimize nausea
Lubiprostone
8 µg BID
(N=1011)
%
Placebo
(N=435)
%
Nausea
8
4
Diarrhea
7
4
Abdominal pain
5
5
Abdominal
distension
3
2
Effect
Lubiprostone [package insert]. Bethesda, MD: Sucampo Pharmaceuticals, Inc. 2008.
50
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ANTIDEPRESSANT ACTION IN IBS
Antidepressant Action
Visceral Analgesia
Changes in Motility
Smooth Muscle
Relaxation
Adapted from Rome Foundation Functional GI Disorders Specialty Modules.
51
51
EFFICACY OF TCAS IN RELIEVING
GLOBAL IBS SYMPTOMS*
Treatmen
t n/N
Control
n/N
10/22
12/22
Myren (1982, trimipramine 50 qd)
5/30
10/31
Nigam (1984, amitriptyline 12.5 qd)
14/21
21/21
Boerner (1988, doxepin 50 qd)
16/42
19/41
Study (Year, Drug, Dose)
Heefner (1978, desipramine 150 qd)
Bergmann (1991, trimipramine 50 qd)
5/19
14/16
Vij (1991, doxepin 75 qd)
14/25
20/25
Drossman (2003, desipramine 50-150 qd)
60/115
36/57
Talley (2008, imipramine 50 qd)
0/18
5/16
Vahedi (2008, amitriptyline 10 qd)
8/27
16/27
319
256
Subtotal (95% CI)
RR (Random) 95% CI
RR=0.68
(95% CI=0.56-0.83)
0.1
0.2
0.5
1
Favors Treatment
2
5
10
Favors Control
Note: TCAs are not FDA approved for IBS.
TCA=Tricyclic antidepressant.
*Significant heterogeneity among studies may limit conclusions. Study duration ranged from 4 weeks to 3 months.
Ford AC, et al. Gut. 2009;58:367-378.
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EFFICACY OF SSRIS IN RELIEVING
GLOBAL IBS SYMPTOMS*
Treatment
n/N
Control
n/N
Kuiken (2003, fluoxetine 20 qd)
9/19
12/21
Tabas (2004, paroxetine 10-40 qd)
25/44
36/46
Vahedi (2005, fluoxetine 20 qd)
6/22
19/22
Tack (2006, citalopram 20-40 qd)
5/11
11/12
Talley (2008, citalopram 40 qd)
5/17
5/16
113
117
Study (Year, Drug, Dose)
Subtotal (95% CI)
RR (Random) 95% CI
RR=0.62
(95% CI=0.45-0.87)
0.1
0.2
0.5
1
Favors Treatment
2
5
10
Favors Control
Note: SSRIs are not FDA-approved for IBS.
*Significant heterogeneity among studies may limit conclusions. Study duration ranged from 6 weeks to 12 weeks.
Ford AC, et al. Gut. 2009;58:367-378.
53
INVESTIGATION OF RECURRENT ABDOMINAL
PAIN/DISCOMFORT WITH DISORDERED BOWEL HABIT
Patient with recurrent
abdominal
pain/discomfort
associated
with disordered
bowel habit
Medical and
psychosocial history,
physical examination
Alarm
features?
no
Consider
limited
screening
tests
any
abnormality
identified?
yes
Refer to
GI
yes
no
IBS
Evaluation of stool consistency
(using Bristol Stool Form Scale)
IBS-D
IBS-M
Diet
Loperamide
Antibiotics
Antidepressants
Adequate
response?
no
IBS-C
Diet
Psyllium
PEG
Lubiprostone
Antidepressants
yes
Continue and follow up
as needed
Spiller RC, Thompson WG. Am J Gastroenterol. 2010;105:775-785.
54
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WHO SHOULD BE REFERRED?
• Patients with unclear diagnosis and/or
alarm features
• Patients failing conventional therapies
•
Candidates for alosetron treatment
– Women with severe IBS-D, defined as:
- Frequent and severe abdominal
pain/discomfort
- Frequent bowel urgency or fecal incontinence
- Disability or restriction of daily activities due
to IBS
Alosetron [package insert]. San Diego, CA: Prometheus Laboratories; 2008.
55
MANAGEMENT OF IBS: SUMMARY
•
Current pharmacologic therapies are largely directed at the
predominant symptoms
•
Evidence-based treatments include
•
•
•
IBS-D: alosetron*, TCAs, nonabsorbable antibiotics
IBS-C: lubiprostone, SSRIs
Nonabsorbable antibiotics may be effective for global
improvement of IBS symptoms
•
May be particularly helpful for bloating and gas-related
symptoms and pain
•
Many probiotics have been studied in IBS, but efficacy to
date has been demonstrated only with B infantis
•
Centrally directed therapies for IBS may reduce global
symptoms and improve well-being in selected patients
Note: Nonabsorbable antibiotics, TCAs, and SSRIs are not FDA approved for IBS.
*Restricted use through the alosetron prescribing program. Available only under an Emergency IND program.
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28