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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
11111
22222
33333
44444
55555
66666
77777
88888
99999
1010101010
1111111111
1212121212
1313131313
1414141414
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
1234567891011121314
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
1234567891011121314
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!