Management of Functional Bowel DisordersAmy Foxx-Orenstein, DO, FACG, FACPProfessor of MedicineMayo Clinic

Tucson Osteopathic Medical FoundationMay 1, 2016

Objectives• Review epidemiology and pathophysiology of

IBS

• Explore workup and importance of lean diagnostic evaluation

• Learn newer treatments and management strategies

What is a Functional Disorder?• Identified only by symptoms

• Absence of a structural or biochemical disorder

• Symptoms are attributable to the upper (egfunctional dyspepsia) or lower abdomen

• Research supports multiple etiologies

What are the functional disorders?

• Irritable Bowel Syndrome • Functional constipation• Functional diarrhea• Functional dyspepsia• Functional heartburn• Functional bloating• Functional biliary pain• Chronic functional abdominal pain

What are the functional bowel disorders?• Irritable Bowel Syndrome• Functional constipation• Functional diarrhea• Functional dyspepsia• Functional heartburn• Functional bloating• Functional biliary pain• Chronic functional abdominal pain

IBSDefined as

• Lower abdominal pain or discomfort that is associated with a change in bowel habit and features of disordered defecation, with two of three of the following symptoms:

• Symptoms improve with defecation• Onset associated with a change in stool

frequency• Onset is associated with change in stool

form

Longstreth GF et al. Gastroenterology. 2006;130:1480-1491.

IBS epidemiology• Most common functional bowel disorder

• Affects up to 25% adults and adolescents

• 3:1 female predominance

• Symptoms• Significantly impair quality of life• Frequent overlap with other functional disorders• Result in high health care costs• Anxiety and depression have been linked to

functional abdominal pain

Longstreth GF et al. Gastroenterology 2006;130:1480.

Walter SA et al. Neurogastroenterol Motil 2013;25:741.

IBS is classified into subtypes based on stool form

Longstreth GF et al. Gastroenterology 2006;130:1480.

Hard or lumpy stools (%)

IBS-C IBS-M

IBS-U IBS-D

100

75

50

25

0

25 50 75 100

Loose or watery stools (%)

IBS-M: Hard and loose stools

IBS-U: Unsubtyped IBS

Bristol Stool Form Scale

Separate hard lumps

Sausage-like but lumpy

Sausage-like but with cracks in the surface

Smooth and soft

Soft blobs with clear-cut edges

Fluffy pieces with ragged edges, a mushy stool

Watery, no solid pieces

Type 1

Type 2

Type 3

Type 4

Type 5

Type 6

Type 7

ACG task force recommendations for thediagnosis of IBS in patients without alarm symptoms

Diagnostic Test Recommendation

CBC Not recommended

Chemistries Not recommended

Thyroid function studies Not recommended

Stool for ova and parasites Not recommended

Abdominal imaging Not recommended

Serologic screening for celiac sprue

Pursue in patients with IBS-D or IBS-M

Lactose breath testing Consider if symptoms persist after dietary modification

Breath testing for SIBO Insufficient data to recommend

Colonoscopy Perform in patients with alarm features and in those aged >50

Brandt LJ et al. Am J Gastroenterol 2009;104 Suppl 1:S1.ACG: American College of Gastroenterology

Colonoscopy and/or Abdominal Imaging is Not Recommended in IBS without Alarm Features Because

LesionsIBS

Patients(n=466) N (%)

Controls(n=451) N (%)

P value

Adenomas 36 (7.7) 118 (26.1)

• Onset of symptoms after age 50

• GI bleeding or iron-deficiency anemia

• Nocturnal diarrhea

• Unintended weight loss

• Family history of organic GI disease (colorectal cancer, IBD, celiac disease)

Alarm Features

IBS Pathophysiology: An Interaction Between Biological and Psychosocial Factors

Physiologic features

• Altered motility

• Visceral hyperalgesia

• Disturbance of brain gut interaction

• Abnormal central processing

• Autonomic and hormonal events

• Genetic/Environmental factors

• Post-infectious events

Psychosocial features

• Sleep disturbance

• Dysfunctional coping

• Generalized anxiety disorder

• Mood disorder

• Post traumatic stress disorder

• Panic disorder

• Psychiatric disorders

• History of childhood abuse is common

Rome Foundation Functional GI Specialty Modules

Abdominal Pain is Associated with Anxiety and Depression Scores in the General Adult Population without Organic GI Disease

• N=272

• Colonoscopy, lab, GI questionnaire x 1 week, Rome II criteria met, anxiety and depression q’nairres

• 12% fulfilled Rome II criteria for IBS

• Anxiety and Depression scores higher in subjects who reported abdominal pain vs those who did not (p< 0.0005 and p< 0.0005)

• QOL scores were lower in patients with abdominal pain

Walter SA et al. Neurogastroenterol Motil 2013;5:741.

Evaluation Algorithm

yes

yes

no

no

investigations as indicated:

eg, colonoscopy, blood & stool tests,duodenal biopsy

Patient with recurrent abdominal

pain/discomfort associated with disordered bowel habit

celiac disease, giardiasis, inflammatory bowel disease,

microscopic colitis,small intestinal bacterial overgrowth,

colorectal neoplasia

medical and psychosocial history, physical examination

evaluation of stool

consistency(using

Bristol Stool Form Scale)

IBS-C

IBS-M

IBS-D

IBSyes

noalarm

features?

anyabnormalityidentified?

anyabnormalityidentified?

consider limited

screening tests

Diagnosis and Pathophysiology Summary • Make a positive diagnosis

• Limit the diagnostic workup in patients without alarm symptoms

• Physiological and Psychological factors contribute to pathophysiology

• Abdominal pain correlates with psychological scores

Treatment• Management will depend on

• A confident diagnosis• Explanation why symptoms occur• Suggestions for coping with symptoms

• Education about healthy lifestyle behaviors, reassurance that symptoms are due to a non-life threatening illness, establishing a therapeutic relationship, lifestyle modification, and counseling impact change.

Koloski NA et al. Gut 2012;61:1284.Longstreth GF et al. Gastroenterology 2006;130:1480.

Diets and IBS

• Patients often indicate a link between diet and IBS symptoms

• Food elimination diets may be effective in some patients

• Lactose free• Gluten free• Fructose free• Low-FODMAP

Austin GL et al. Clin Gastroenterol Hepatol 2009;7:706.Ong DK et al. J Gastroenterol Hepatol. 2010;25:1366.

FODMAP

Lentils, cabbage, brussel sprouts, asparagus, green beans, legumes

Sorbitol

Raffinose

Honey, apples, pears, peaches, mangos, fruit juice, dried fruit

Apricots, peaches, artificial sweeteners, artificially sweetened gums

Wheat (large amounts), rye (large amounts), onions, leeks, zucchini

Excess Fructose

Fructans

Fermentable oligo-, di-, monosaccharides and polyols

Fructose and Fructans as Dietary Triggers for IBS Symptoms

25 IBS patients with fructose malabsorption who improved with a FODMAP diet

90

80

70

60

50

40

30

20

10

0Glucose Fructose Fructans F&F

Not

con

trol

led

(%)

P≤.002 vsglucose *

* *

Shepherd SJ et al. Clin Gastroenterol Hepatol. 2008;6:765

Psychological Therapy is Effective in Many Patients With IBS

• 20 studies (various psychological therapies), 1278 patients

Improvement: Psychological therapy

(%)

Improvement: “Usual management” or

control therapy (%)RR symptoms remain

(95% CI)

49.1 27.5 0.67(0.57-0.79)

Ford AC et al. BMJ. 2008;337:a2313.Walter SA et al. Neurogastroenterol Motil 2013;25:741.Halland M, Talley NJ. Nat Rev Gastroenterol Hepatol 2013;10:13.

Psychological factors may alter symptom perception.Patients reaction to a symptom may be more important than the symptom itself.Most patients respond to psychological support, strong physician-patient

relationship, and multicomponent treatments

Exercise Has a Positive Impact on IBS Symptoms

• Subjects (N=75) randomized to physical activity* or to maintain their lifestyle

• Physical activity improved IBS symptom scores (P=.003)

• Patients in the control group had significantly higher IBS symptom scores than patients in physical activity group

Johannesson E et al. Am J Gastroenterol. 2011;106:915-922.

500

400

300

200

100

0

IBS

Seve

rity

Scor

eControl group Physical activity group

P = 0.001

Start 12 Weeks

*Intervention: 20-60 minutes moderate to vigorous exercise 3-5 times weekly

More studies needed. Further work on mechanisms and ideal ‘dose’

Truth about Dyssynergy, Biofeedback and IBS-C• N=50 patients with dyssynergic defecation

• 29/50 met Rome II IBS-C criteria

• Both groups had similar response to biofeedback (16 0f 29 vs 14 of 21, p>0.05)

• IBS symptoms disappeared in 12/29 patients who had IBS symptoms before treatment

• Disappearance of IBS symptoms was observed more frequently in those who responded to biofeedback than to those who did not (p

Non-Pharmacologic Treatment Summary:• Confident diagnosis

• Nurturing physician/patient relationship

• Teach coping strategies

• Lifestyle changes play an important role in treatment

Pharmacologic Management of IBS

Altered bowel function

Abdominal pain and

discomfort

Bloatingand

distension

Drugs targeting pain & hypersensitivity

• Probiotics

• SSRI

• TCA

• Peripheral opioid antagonists

• Antispasmodics

•SSRI

•TCA

•Gabapentin

IBS-D

• Adsorbents

• Rifaximin

• Bile-acid modulators

• 5HT3 antagonists

IBS-C

• Fiber

• PEG

• Cl channel activator

• Osmotic laxatives

• Guanylate cyclase C

• 5HT4 agonists

Proportion of Patients With Adequate Relief of Symptoms Each Week

*P

Polyethylene Glycol (PEG) for IBS-C

•Laxatives have not been studied in RCTs in IBS

•PEG improved frequency of bowel movements but not pain in adolescents with IBS-C (n=27)

Pre-treatment Post-treatment

Frequency of Bowel Movements/Week

Mea

n

Pain Level

P

Efficacy of the Selective Cl Channel Activator Lubiprostone in IBS-C

Drossman DA, et al. Aliment Pharmacol Ther. 2009;29:329.

10.1% P=.0017.8% Difference

Lubiprostone8 µg BID

Placebo

n=769 n=385

17.9%O

vera

ll Re

spon

ders

*, %

Combined analysis in Rome II IBS-C patients using intent-to-treat, last observation carried forward analysis

Chart1

Rifaximin

Placebo

Rifaximin (n=63)

17.9

10.1

Sheet1

Rifaximin (n=63)Column2

Rifaximin17.9

Placebo10.1

To resize chart data range, drag lower right corner of range.

The Guanylate Cyclase C Agonist, Linaclotide in IBS-C

Study weekEnd of

treatment

Mea

n ch

ange

Mean change in CSBM rate

Study weekEnd of

treatment

Mea

n ch

ange

Mean change in abdominal pain

Johnston JM, et al. Gastroenterology. 2010;139:1877.

Chart1

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Placebo

75 mcg

150 mcg

300 mcg

600 mcg

0.83

2.73

2.64

3.09

2.7

1

2.75

2.11

2.93

2.76

0.9

2.9

1.96

3.43

2.96

1.42

3.06

1.93

4

2.65

1.31

2.5

2.24

3.81

2.64

1.25

2.98

1.84

3.94

2.98

1.37

3.29

2.1

3.92

2.8

1.16

3.04

2.24

4.1

3.04

1.67

3.23

2.2

3.7

2.75

1.39

3.63

2.53

4

2.78

1.48

3.53

2.39

4

2.96

1.36

3.33

2.42

4.44

3.02

1.28

1.57

1.17

1.39

0.88

0.9

1.37

0.77

1.08

0.65

Sheet1

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Placebo0.8310.91.421.311.251.371.161.671.391.481.361.280.9

75 mcg2.732.752.93.062.52.983.293.043.233.633.533.331.571.37

150 mcg2.642.111.961.932.241.842.12.242.22.532.392.421.170.77

300 mcg3.092.933.4343.813.943.924.13.7444.441.391.08

600 mcg2.72.762.962.652.642.982.83.042.752.782.963.020.880.65

Chart1

11111

22222

33333

44444

55555

66666

77777

88888

99999

1010101010

1111111111

1212121212

1313131313

1414141414

Placebo

75 mcg

150 mcg

300 mcg

600 mcg

-0.393

-0.611

-0.624

-0.624

-0.654

-0.41

-0.628

-0.739

-0.75

-0.739

-0.53

-0.812

-0.778

-0.85

-0.803

-0.457

-0.782

-0.761

-0.906

-0.923

-0.415

-0.714

-0.782

-0.919

-0.966

-0.556

-0.833

-0.8

-1.021

-1.085

-0.624

-0.919

-0.855

-1.004

-1.145

-0.543

-0.897

-0.795

-1

-1.162

-0.679

-0.893

-0.885

-1.047

-1.175

-0.714

-0.957

-0.893

-1.103

-1.132

-0.697

-0.885

-0.9

-1.047

-1.128

-0.607

-0.927

-0.795

-1.068

-1.128

-0.607

-0.739

-0.756

-0.722

-0.9

-0.581

-0.615

-0.611

-0.585

-0.611

Sheet1

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Placebo-0.393-0.41-0.53-0.457-0.415-0.556-0.624-0.543-0.679-0.714-0.697-0.607-0.607-0.581

75 mcg-0.611-0.628-0.812-0.782-0.714-0.833-0.919-0.897-0.893-0.957-0.885-0.927-0.739-0.615

150 mcg-0.624-0.739-0.778-0.761-0.782-0.8-0.855-0.795-0.885-0.893-0.9-0.795-0.756-0.611

300 mcg-0.624-0.75-0.85-0.906-0.919-1.021-1.004-1-1.047-1.103-1.047-1.068-0.722-0.585

600 mcg-0.654-0.739-0.803-0.923-0.966-1.085-1.145-1.162-1.175-1.132-1.128-1.128-0.9-0.611

Study (Year, Drug, Dose)Treatment

n/NControl

n/N RR (Random) 95% CIHeefner (1978, desipramine 150 qd) 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

Bergmann (1991, trimipramine 50 qd) 5/19 14/16

Vij (1991, doxepin 75 qd) 14/25 20/25Drossman (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

Subtotal (95% CI) 319 256

RR=0.68(95% CI=0.56-0.83)

0.2 0.5 1 2 5

Favors Treatment Favors Control0.1 10

Efficacy of TCAs in Relieving IBS Symptoms

TCA=tricyclic antidepressant

Ford AC et al. Gut 2009;58:367.

Efficacy of SSRI’s in Relieving Symptoms of IBS

Ford A et al. Gut 2009;58:367-378

Study (Year, Drug, Dose)Treatment

n/NControl

n/N RR (Random) 95% CIKuiken (2003, fluoxetine 20 qd) 9/19 12/21Tabas (2004, paroxetine 10-40 qd) 25/44 36/46Vahedi (2005, fluoxetine 20 qd) 6/22 19/22Tack (2006, citalopram 20-40 qd) 5/11 11/12Talley (2008, citalopram 40 qd) 5/17 5/16

Subtotal (95% CI) 113 117

RR=0.62(95% CI=0.45-0.87)

Evidence-based summary of Medical Treatments for IBS-D Symptoms

Improvements in Symptoms

Grade*Global Symptoms Pain Bloating

Stool Frequency

Stool Consistency

Alosetron + + + + 2A/1BAntibiotics (rifaximin) + + 1B

Antidepressants + + 1B

Loperamide + + 2C

Antispasmodics ± + 2CProbiotics (Bifidobacteria/some combos)

+ 2C

ACG Task Forces on IBS. Am J Gastroenterol 2009;104:S1.

Antidiarrheals for IBS

• Loperamide is effective for treatment of diarrhea, reducing stool frequency and improving consistency

• No impact on bloating, abdominal discomfort, or global IBS symptoms

• Low doses (2 mg QD or BID) can be effective

• No other antidiarrheal has been studied in clinical trials

Mayer EA. NEJM 2008;358:1692.

Antispasmodics for IBS

22 RCTs compared 12 different antispasmodics with placebo

(n=1778)

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)

Most data available for otilonium, trimebutine,

cimetropium, hyoscine,

and pinaverium

•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

Ford AC, et al. Am J Gastroenterol. 2009;104:1831.

Study (Year)Treatmen

t n/NControl

n/NRR (Random)

95% CIRR (Random)

95% CICamilleri (1999) 179/290 54/80 0.91 [0.77, 1.09]Bardhan (2000) 166/345 57/117 0.99 [0.80, 1.23]Camilleri (2000) 191/324 229/323 0.83 [0.74, 0.93]Camilleri (2001) 182/309 235/317 0.79 [0.71, 0.89]Lembo (2001) 144/532 156/269 0.47 [0.39, 0.55]Chey (2004) 167/351 197/363 0.88 [0.76, 1.01]Chang (2005) 268/534 77/128 0.83 [0.71, 0.98]Krause (2007) 279/529 122/176 0.76 [0.67, 0.86]

Subtotal (95% CI) 3,214 1,773 0.79 [0.69, 0.90]

Global IBS Symptoms or Abdominal Pain Unimproved or Persistent After Therapy

RR=0.79 (95% CI=0.69-0.90)

0.20.1Favors Treatment

0.5 1 2 5Favors Control

10

Efficacy of Alosetron in IBS

35

Rifaximin for IBS symptoms and IBS-related bloating

Pimental M et al. NEJM 2011;364:22.

Rifaximin 550 mg TID Placebo

Target 1

Patie

nts

With

Ade

quat

e Re

lief

of G

loba

l IBS

Sym

ptom

s, %

Global IBS Symptoms During First 4 Weeks

IBS-Related Bloating During First 4 Weeks

Target 2 Combined analysis

P=.01 P=.03 P

Probiotics for IBS

Brenner DM et al. Am J Gastroenterol 2009;104:1033.

RCTs

• 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

4648 probiotics in IBS citations retrieved

21 probiotic studies assessed

included16 RCTs

B infantis 35624 demonstrated efficacy in 2 appropriately designed RCTs

No other probiotic showed significant improvement in IBS symptoms in appropriately designed RCTs

Management Algorithm

Constipation

PsylliumPEG

Lubiprostone Linaclotide

Absorbents Loperamide

AlosetronRifaximin

PainDiarrhea (exclude FI) Gas/Bloating

Coping skills AntispasmodicsAntidepressants

AlosetronLubiprostone

Rifaximin Gabapentin

Hypnotherapy CBT

Psychotherapy

RifaximinProbiotics

Lubiprostone

IBS

Lifestyle Modifications: Diet, Coping Skills, Counseling, Exercise, Biofeedback, Better Understanding Less Medication

Summary Management Strategies for IBS

IBS-D•Loperamide

• Alosetron

• Probiotics

• FODMAP

• Rifaximin

Centrally acting therapies• SSRI

• TCA

• SNRI

• Gabapentin?

IBS-C• Fiber

• Cl - Ch activators

• 5-HT4 agonists

• Guanylate cyclase C agonist

• Osmotic laxatives?

Brandt LJ . AJG. 2009;104 Suppl 1:S1-35; Brandt LJ et al. AJG. 2002;97:S7-26; Drossman DA Gastroenterology. 2002;123:2108-2131.

? Fecal microbiota transplant

Biofeedback

Diet

Exercise

Physician-patient relationship

Hypnotherapy

CBT & mindfulness

Psychotherapy

Psychiatry

Thank You!

�Management of Functional Bowel DisordersObjectivesWhat is a Functional Disorder?What are the functional disorders?What are the functional bowel disorders?IBSIBS epidemiologyIBS is classified into subtypes based on stool formSlide Number 9ACG task force recommendations for the�diagnosis of IBS in patients without alarm symptomsColonoscopy and/or Abdominal �Imaging is Not Recommended in IBS �without Alarm Features BecauseSlide Number 12IBS Pathophysiology: An Interaction Between Biological and Psychosocial FactorsAbdominal Pain is Associated with Anxiety and Depression Scores in the General Adult Population without Organic GI DiseaseEvaluation AlgorithmDiagnosis and Pathophysiology Summary TreatmentDiets and IBSFODMAPFructose and Fructans as Dietary Triggers for IBS SymptomsPsychological Therapy is Effective in Many Patients With IBSExercise Has a Positive Impact on IBS SymptomsTruth about Dyssynergy, Biofeedback and IBS-CNon-Pharmacologic Treatment Summary:Pharmacologic Management of IBSSlide Number 26Polyethylene Glycol (PEG) for IBS-CEfficacy of the Selective Cl Channel Activator Lubiprostone in IBS-CThe Guanylate Cyclase C Agonist, Linaclotide in IBS-CSlide Number 30Efficacy of SSRI’s in Relieving Symptoms of IBSEvidence-based summary of Medical Treatments for IBS-D SymptomsAntidiarrheals for IBSAntispasmodics for IBSEfficacy of Alosetron in IBSRifaximin for IBS symptoms and IBS-related bloatingProbiotics for IBSManagement Algorithm Summary Management Strategies for IBS Thank You!