IBS: Evidence-Based Update on Diagnosis and Treatment

William D. Chey, MD, FACG

Associate Professor

University of Michigan

“A good set of bowels is worth more to a man than any

quantity of brains”

Josh Billings (Henry Wheeler Shaw) 1818-1885

“There is nothing in life as underrated as a good bowel

movement”

William D. Chey, MD

1960-?

Arriving at a confident diagnosis of IBS

Rome II Criteria for IBS

Thompson WG, et al. Gut. 1999;45(suppl II):II43-II47Thompson WG, et al. Gut. 1999;45(suppl II):II43-II47

• Abdominal pain or discomfort for at least 12 weeks (which need not be consecutive) in the preceding 12 months

• Abdominal pain or discomfort has 2 of 3 features:

—Relieved with defecation

—Onset associated with a change in stool frequency

—Onset associated with a change in stool form

• 97% of patients with IBS have no changes in diagnosis over 5 years

The Confident Diagnosis of IBS:A Symptom-based Approach

Modified from Paterson WE, et al. Can Med Assoc J. 1999;161:154; American Gastroenterological Association. Gastroenterology. 1997;112:2120; Camilleri M, Choi MG. Aliment Pharmacol Ther. 1997;11:3.

Use symptom-based diagnostic criteria for IBSUse symptom-based diagnostic criteria for IBS

Exclude Alarm SymptomsExclude Alarm Symptoms(weight loss, fever, bleeding, family history of cancer/IBD)(weight loss, fever, bleeding, family history of cancer/IBD)

Perform physical exam and selected diagnostic tests Perform physical exam and selected diagnostic tests to rule out organic diseaseto rule out organic disease

Make a confident diagnosis of IBSMake a confident diagnosis of IBS

Initiate a treatment plan based on symptomsInitiate a treatment plan based on symptoms

Follow up in 3 to 6 weeksFollow up in 3 to 6 weeks

Confident diagnosis of IBS: Validity of a symptom-based approach

• A 2-year retrospective study confirmed the validityof an approach combining the Rome I criteria and absence of Red Flags. Results showed:

• At 2-years follow-up, no patients required revisionof diagnosis

Vanner et al, Am J Gastroenterol 1999; 94: 2912

Sensitivity Specificity Positive predictive value

65%

100% 100%

Limitations of the Rome II criteria in clinical practice

83

47

85

49

82

47

0

20

40

60

80

100

Rome I Rome II

Difference in sensitivity largely due to pain requirement of Rome II

Sen

siti

vity Total n=1014

GI n=313

Non-GI n=701

Chey. Am J Gastroenterol 2002;97:2803

Gold standard =Dx of IBS by MD

Practical Definition of IBS

• Rome criteria were developed for clinical research and are currently being revised

• Practical definition for clinical practice:

• IBS is a chronic medical condition characterized by abdominal pain or discomfort in association with alterations in bowel function

• pain relieved with defecation• alteration in stool frequency • alteration in stool form

Differential Diagnosis of IBS

Differentialdiagnosis

Differentialdiagnosis

Dietary factorslactose, sorbitol

fructosecaffeine, alcohol

fatgas-producing foods

Dietary factorslactose, sorbitol

fructosecaffeine, alcohol

fatgas-producing foods

IBDulcerative colitisCrohn’s disease

microscopic colitis

IBDulcerative colitisCrohn’s disease

microscopic colitis

Malabsorptionceliac spruepost-surgicalpancreatic

Malabsorptionceliac spruepost-surgicalpancreatic

Miscellaneousendometriosis

endocrine tumors

Miscellaneousendometriosis

endocrine tumors

Psychologicanxiety/panic

depressionsomatization

Psychologicanxiety/panic

depressionsomatization

InfectionGiardia,Ameba

bacterial overgrowth

InfectionGiardia,Ameba

bacterial overgrowth

Which tests are necessary in suspected IBS?

Pretest Probability of Organic Disease

2522-26Lactose malabsorption

5-96Thyroid dysfunction

N/A0-1.7Gastrointestinal infection

0.25-0.54.67Celiac disease

4-60-0.51Colorectal cancer

0.3-1.20.51-0.98Colitis / IBD

General Population (Prevalence %)

IBS Patients (Pretest Probability %)

Organic GI Disease

Cash, et al. Am J Gastroenterol 2002;97:2812

Celiac Disease and IBS• US prevalence of celiac disease1

– Overall 1:133, First degree relative 1:22, Symptomatic pts 1:56

• UK study: 14/300 (5%) IBS pts had biopsy proven celiac sprue2

• Irish study: 30/150 (20%) sprue pts met Rome criteria vs 8/162 (5%) controls3

• German study: of 102 IBS-D pts, 0% had serum Ab but 30% had Ab in duodenal aspirate4

1Fasano. Arch Int Med 2003;163:286. 2Sanders. Lancet 2001;358:1504.3O'Leary. Am J Gastroenterol 2002;97:1463. 4Wahnschaffe. Gastroenterol 2001;121:1329.

Is it cost-effecitve to test for Celiac Disease in IBS?

• Decision analytic model assessed the cost-effectiveness of celiac testing vs. empiric IBS therapy in pts with suspected IBS

• Testing cost an incremental $11K for one additional symptomatic improvement– ICER >%50K when prevalence of CS<1%– Testing dominant when prevalence of CS>8%

• Factors affecting the decision to test:– Prevalence of CS, test accuracy, cost of IBS therapy,

likelihood that symptoms improve on a gluen-free diet

Speigel, et al. Gastroenterol 2004;126:1721

Bacterial Overgrowth and IBS

11

35

15

40

2

20

0

10

20

30

40

50

Placebo n=56 Neomycin n=55

%

ITT decrease CompositeScore

Normal symptoms

Normal LBT

*

*

*

Pimental. Am J Gastroenterol 2003;98:412

*P<0.05

Post-infectious IBS• Incidence of IBS after acute bacterial gastroenteritis ranges

from 7% to 32%1-3

– ~60% remain symptomatic over 6 years of follow-up

– Usually diarrhea predominant

• Psychological distress and severity/duration are predictive

– Campylobacter/Shigella > Salmonella

• Results from immune system activation

– Altered gut transit4

– Increased rectal sensitivity2

– Increased intestinal permeability4

– Increased 5-HT–containing enterochromaffin cells in the colon4

1Neal KR, et al. BMJ. 1997;314:779-782 3Gwee KA, et al. Lancet. 1996;347:150-153.

2McKendrick MW, et al. J Infect. 1994;29:1-3. 4Spiller RC, et al. Gut. 2000;47:804-811.

1Neal KR, et al. BMJ. 1997;314:779-782 3Gwee KA, et al. Lancet. 1996;347:150-153.

2McKendrick MW, et al. J Infect. 1994;29:1-3. 4Spiller RC, et al. Gut. 2000;47:804-811.

Inflammation and IBS

InflammationInflammation

Celiac SprueCeliac Sprue Mucosal and Enteric Inflammation

Mucosal and Enteric Inflammation

Post-infectious

Post-infectious

Small Bowel

BacterialOvergrowth

Small Bowel

BacterialOvergrowth

StressStress

Evidence of heredity in IBS

• Increased frequency of IBS and dyspepsiain adults with an affected first-degree relative

Mayo Clinic study, Olmstead County, MN1

• Monozygotic twins more likely to be concordant for IBS than dizygotic twins. US twin study2

• >50% of liability to functional bowel disorders might be subject to genetic control3

Australian twin study3

1Locke et al, Mayo Clin Proc 2000; 75: 907

2Levy et al, Gastroenterology 2001; 121 : 7993Morris-Yates et al, Am J Gastroenterology 1998; 93: 1311

Treatment of IBS:Where are we now?

Symptom-based medical treatment of IBS

Diarrhea Loperamide Other opioids Alosetron

Abdominal pain / discomfort Antispasmodics Antidepressants

• TCAs / SSRIs• Alosetron• Tegaserod

Constipation Fiber MOM/PEG solution Tegaserod

AbdominalAbdominalpain /pain /

discomfortdiscomfort

AbdominalAbdominalpain /pain /

discomfortdiscomfort

Bloating /Bloating /distentiondistentionBloating /Bloating /distentiondistention

Altered bowelAltered bowelfunctionfunction

Altered bowelAltered bowelfunctionfunction

Brandt, AJG 2002;97:S7Drossman, Gastroenterology 2002;123;2108

Fiber/Bulking Agents for IBS

• 14 RCTs published in English• All have significant methodological flaws• Psyllium/Ispaghula husk (20-30 grm/day)

improves constipation– Bran does not appear to be effective

• Data does not support the use of fiber for abdominal pain or diarrhea

• No RCTs have evaluated other laxatives for IBS

Brandt, AJG 2002;97:S7

Anti-spasmodics for IBS• Anti-cholintergics, anti-muscarinics, Ca-channel

blockers• 18 RCTs published in English• Substantial methodological flaws• Several agents found to improve global symptoms or

pain – None available in the US

• No convincing evidence that dicyclomine or hyoscyamine are effective

Brandt, AJG 2002;97:S7Jailwala, Annals Int Med 2000;133:136Poynard, APT 2001;15:355

Loperamide for IBS

• Loperamide favored over other opiates– does not cross the blood-brain barrier– effects on anal sphincter pressure?

• Dose: 2-4 mg up to QID

• 3 RCTs published in English– Trials small (28-69) and of short duration (3-5wk)

• Improvements in diarrhea but not global symptoms or pain

Brandt, AJG 2002;97:S7

Anti-depressants for IBS• Reserve for moderate to severe symptoms• Tricyclic antidepressants

– 7 RCTs for Tricyclics published in English• Studies of low quality1

– TCAs appear to be effective at low doses – Recent meta-analysis found improvement in global symptoms (OR=4.2) and pain2

• NNT = 3.2– Constipation, sedation, weight gain common

• Selective serotonin reuptake inhibitors3

– Conflicting results• Venlafaxin but not fluoxetine may decrease colonic sensation

– Likely more effective with co-morbid anxiety or depression

1Brandt, AJG 2002;97:S7 4Chial, Clin Gastroenterol Hepatol 2003;1:2112Jackson, Am J Med 2000;108:65 5Kuiken Clin Gastroenterol Hepatol 2003;1:2113Clouse, Gut 2003;52:598

TCA vs. Placebo for Moderate to Severe FGIDs

Drossman, Gastro 2003;125:19

60

73

47 49

0

20

40

60

80

100

ITT n=201 PP n=153

Desipramine Placebo

P=0.13

P=0.006NNT=4

Better responsein pts with moderatesymptoms and IBS-D

(12 wks)

% R

esp

on

der

s

TCA's for FGID's: Moderate / Severe Side Effects

26

20

1613

1113

8

2

0

10

20

30

40

Dry Mouth Sleep Constipation Flush

Desipramine (n=135) Placebo (n=55)

Drossman, Gastro 2003;125:19

•8 fold increase in study drop outs with TCA•Multiple side effects common (mean = 3.5)

% R

epo

rtin

g A

E

Paroxetine vs. Placebo for IBS unresponsive to fiber

Tabas, Am J Gastro 2004;99:914

63

84

26

37

0

20

40

60

80

100

Overall WB Wished to continue

Paroxetine n=38 Placebo n=43

P=0.01

P=0.001

No improvements in abdominal pain, bloating, social fxning

(12 wks)

% R

esp

on

der

s

Treatment of IBS:Where are we headed?

Adapted from Coulie. Adapted from Coulie. Clin Perspect GastroenterolClin Perspect Gastroenterol. 1999;2:329-338. . 1999;2:329-338.

Brain-Gut Brain-Gut InteractionsInteractions

ANSANS

Evolving model of IBS

AlteredAlteredMotility/SecretionMotility/Secretion

VisceralVisceralHypersensitivityHypersensitivity

InflammationInflammation

Psycho-socialPsycho-socialFactorsFactors

Emerging Therapies for IBS

• Pain modulation– Serotonin modulators– Benzodiazepine derivatives

• R-tofisopam– Neurokinin antagonists

• NK 1, 2, 3 receptor antagonists in development – CRF antagonists– Opioid receptor modulators

• Asimadoline, fedotozine– M3 antagonists

• Zamifenacin– Octreotide

Relevance of Serotoninto IBS

• Modulates gastrointestinal motility and secretion

• Important to visceral perception

• Involved in CNS function

5-HT3 Antagonists for IBS

• Visceral afferent effects

• ENS effects– delays colonic transit– decreases colonic tone– inhibits CI- secretion

• Blunts the gastro-colonic response

• Central Effects– anti-emetic properties– benefits in anxious or neurotic?

Kim, Am J Gastro 2000;95:2698

Clinical trials of Alosetron vs. placebo for D-IBS

% Responders for Primary Outcome

Reference Pts%

Female Alosetron PlaceboTherapeutic

gain

Camilleri* 370 53 60% 33% 27%

Camilleri* 647 100 41% 29% 12%

Camilleri* 626 100 43% 26% 17%

Lembo** 801 100 73% 57% 16%

D-IBS=IBS with diarrhea Primary outcome = abdominal pain* or urgency**

Long-term efficacy of Alosetron in women with IBS-D

Chey, Am J Gastroenterol. 2004;99:2195.

52

64

4452

0

20

40

60

80

100

Abd pain Urgency

Alosetron, n=279 Placebo, n=290

P = 0.01NNT=12

P = 0.001NNT = 8

48 wks

% R

espo

nder

s

Alosetron: A long strange trip…• Alosetron

– approved 2/00: improved abdominal pain and bowel-related symptoms in diarrhea-predominant females with IBS1

– side effects: constipation, ischemic colitis, death– voluntarily withdrawn (11/00)– re-approved July 2002

• for females with severe diarrhea-predominant IBS who have failed to respond to conventional therapies

• 12 month safety and efficacy trials completed2,3

1Camilleri, APT 1999;13:11492Wolfe, AJG 2001;96:8033Chey, AJG 2004;99:2195

41

5255

18

37

45

0

10

20

30

40

50

60

70

3 months 3 months 6 months

Cilansetron (males)

Placebo (males)

% R

espo

nder

s

US Study1

N = 205Multinational Study2

N = 358

P=<0.001

P=<0.006P=<0.073

Cilansetron for IBS-D: Phase III Study Results

1Miner Am J Gastroenterol 2004;99:S2772Bradette Gastroenterol 2004;126:A42

Adverse event (% C vs P)

Study [ref] Constipation Headache Abdominal Pain Ischemic colitis

US [1] 19 vs 4 6 vs 3 6 vs 1 0.29 vs 0

Multinational [2]

12 vs 3 10 vs 10 5 vs 4 0.76 vs 0

C: Cilansetron; n: number of subjects; NR: not reported; P: Placebo

Phase III Clinical trials with Cilansetron: Safety data

1Miner Am J Gastroenterol 2004;99:S2772Bradette Gastroenterol 2004;126:A42

5-HT4 Agonists for IBS

• Tegaserod is a specific 5-HT4 agonist

• ENS effects– Augments the peristatic reflex1

– Accelerates orocecal transit and cecal emptying2

– Stimulation of CI-/H20 secretion3

• Possible visceral afferent effects4

1Grider, Gastro 1998;115:3702Prather, Gastro 2000;118:4633Stoner, Gastro 2000;116:A6484Coffin, Gastro 2002;124:A407

Clinical trials of Tegaserod vs. placebo for C-IBS

% Responders for Primary Outcome

Reference

Pts

% Female

Tegaserod

Placebo

Therapeutic Gain

Muller 881 83 38%% 30 8%

Krumholz 799 87 46% 33% 13%

Novicki 1519 100 44% 39% 5%

Kellow 520 88 47% 28% 19%

Global endpoint

Kellow – non-D IBS

Müller-Lissner. Aliment Pharmacol Ther 2001;15:1655–66Krumholz. Gut 1999;45(Suppl.V):A260Novick. Aliment Pharmacol Ther 2002;16:1877–88Kellow. Gut 2003;52:671

Secondary efficacy variables:Effect of tegaserod

• Tegaserod produced a statistically significant reduction in abdominal discomfort / pain

• Patients on tegaserod experienced a significant increase in the number of bowel movements

• Tegaserod significantly improved stool consistency vs placebo

• Tegaserod produced a significantly greater reduction in bloating score vs placebo

Müller-Lissner et al, Aliment Pharmacol Ther 2001; 15: 1655Novick et al, Aliment Pharmacol Ther 2002; 16: 1877

Kellow et al, Gut 2003; 52: 671

Müller-Lissner et al, Aliment Pharmacol Ther 2001; 15: 1655Novick et al, Aliment Pharmacol Ther 2002; 16: 1877

Kellow et al, Gut 2003; 52: 671

Tegaserod: Safety Summary• Safety similar to placebo except for diarrhea and headache

• Diarrhea– tegaserod 8.8% vs. placebo 3.8%

– occurred early and was typically transient

– more common in alternating constipation/diarrhea

• Headache– tegaserod 15% vs. placebo 12%

– does not cross the blood-brain barrier

• No significant increase in abdominal or pelvic surgery in patients treated with tegaserod

• Safety data available for up to 12 months

Tougas, APT 2002;16:1701

IBS and Ischemic Colitis• Little data on the background prevalence of

IC in general population or pts with suspected IBS– Systematic review1 reported a rate of IC in the

general population of 4.5 to 44 cases/100,000 person years

– United Healthcare data base: prevalence of IC in IBS = 43:100K person years vs. 7.2:100K in controls (RR-3.4)2

– Medi-Cal data base: prevalence of IC in IBS = 179:100K person years vs. 47:100K in controls (RR-3.15)3

1Higgins APT 2004;19:729 2Cole Am J Gastro 2004;99:4863Singh Gastroenterol 2004:126:A41

IBS and Ischemic Colitis:Why the Association?

• Misdiagnosis?

• Case Finding?

• Common link in pathogenesis of IBS and ischemic colitis?

– Molecular changes in serotonin signaling identified in IBS and UC1

1Coates Gastroenerol 2004;126:1657

Serotonin Modulators and Ischemic Colitis

Higgins APT 2004;19:729Cole AJG 2004;99;486Singh DDW 04Chey DDW 05Novartis data on file

Gen Pop IBS Alosetron Tegaserod

4.5-47 43-179

190*

110** 7Cases per 100KPerson-years

*All cases of IC in post-marketing**After adjudication

Emerging Therapies for IBS

• Candidates for IBS-C–5-HT4 agonists–Chloride channel activators

• SPI-0211

–Opioid antagonists• Naloxone, methylnaltrexone, LY 246736

–5-HT3 agonists?• MKC-733

Emerging Therapies for IBS

• Candidates for IBS-D–5-HT3 antagonists–α-receptor agonists

• Clonidine

–5-HT4 antagonists?• Piboserod, sulamserod

Brain-Gut Brain-Gut InteractionsInteractions

Emerging Therapies for IBS

AlteredAlteredMotility/SecretionMotility/Secretion

VisceralVisceralHypersensitivityHypersensitivity

InflammationInflammation

Psycho-socialPsycho-socialFactorsFactors

Serotonergic agentsSerotonergic agentsCRF antagonistsCRF antagonistsNK antagonistsNK antagonists

αα-receptor agonists-receptor agonists

Opioid antagonistsOpioid antagonistsClCl--CACA

Opioid agonistsOpioid agonists

R-tofisopamR-tofisopam

It’s not just yellow snow you shouldn’t eat!

Treatment of IBS:Psychological Therapies

Psychological Therapies for IBS

• Cognitive-behavioral therapy

• Hypnotherapy

• Relaxation/Stress management

• Interpersonal therapy

Drossman, Gastroenterology 2002;123;2108

CBT vs. Education for Moderate to Severe FGID's

70 73

3741

0

20

40

60

80

100

ITT n=201 PP n=168

CBT

Education

P<0.001NNT=3

P<0.001NNT=3

12 wks

Drossman, Gastro 2003;125:19

% R

esp

on

der

s

Awarenessof stress

Non-constantpain

Shortsymptomduration

Predominantpain or diarrhea

Anxiety/depressionPredictors of good

response

Predictors of Response to Psychotherapy

Drossman, Gastroenterology 2002;123;2108

Treatment of IBS:Alternative therapies?

Use of Alternative Medicine in the US

• Use of Alternative Medicine increased from 34% in 1990 to 42% in 1997

• Relaxation techniques (16%), herbal remedies (12%), massage (11%) most common

• Most commonly for chronic conditions– Back pain, anxiety, depression, headache– IBS most common amongst GI problems2

– >20% of IBS/FD pts use alternative medicine3

• $21.2 billion in 1997– $12.2 billion out of pocket

Eisenberg, JAMA 1998; 280:15692Smart, Gut 1986;27:8263Koloski, APT 2003;17:841

Chinese Herbal Medicine for IBS

0

40

80

120

160

200

BSS

Plac. n=35

Standard n=43

Individualized n=38

End of therapy 14 wk FU

Bensoussan, JAMA 1998; 280:1585

IBS=Rome I

5 caps TID x 16 wks

* p < 0.05

* * *

Acupuncture for IBS

4.1

3.6

4.13.7

0

1

2

3

4

5

Ge

ne

ral

we

ll-b

ein

g (

VA

S)

Visit 1 Visit 2

No change in pain or stool characteristics

Acupuncture

Placebo

11 wk crossover trial n = 25 (PP analysis)

Acupuncture at LI-4

*p=0.05*p=0.15

Fireman, Digestion 2001;64:100

Probiotics for IBS• Probiotic bacteria may have anti-

inflammatory effects on the GI mucosa

• 2 four wk studies found that L plantarum was better than placebo for IBS– abd pain1,2, flatulence2

• VSL #3 improved bloating but not global symptoms, pain, urgency or transit in IBS with diarrhea3

1Niedzielin Eur J Gastro Hepatol 2001;13:11432Nobaek Am J Gastroenterol 2000;95:12313Kim APT 2003;17:895

Treatment of IBS: Summary• Much of the traditional treatment of IBS is

based on faith rather than evidence• Evidence suggests that newer therapies

including alosetron and tegaserod are beneficial– Other classes of drugs are in development

• Psychological therapies may be effective• Alternative therapies appear promising but

require further study