Getting Back on Track: Improving IBS Assessment and Management in Primary Care

Getting Back on Track:
Improving IBS Assessment and
Management in Primary Care
April 11, 2012
Anaheim, California
Educational Partner:
CME Incite, LLC
Session 4: Getting Back on Track:
Improving IBS Assessment and Management in Primary Care
Learning Objectives
1.
2.
3.
4.
Recognize the symptoms and accurately diagnose patients who have IBS.
Implement strategies to overcome barriers in diagnosing and treating patients with IBS.
Compare the safety and efficacy of currently available treatments when selecting therapy for patients with IBS.
Explain novel agents in development for the treatment of IBS and their potential implications for practice.
Faculty
Lawrence R. Schiller, MD
Program Director
Gastroenterology Fellowship
Baylor University Medical Center
Dallas, Texas
Dr Lawrence Schiller was born in Philadelphia and attended Pennsylvania State University and Jefferson Medical College of Philadelphia.
He completed his internal medicine training at Temple University Hospital, also in Philadelphia, and then served in the US Army Medical
Corps for two years. Dr Schiller moved to Dallas in 1978 for gastroenterology training at the University of Texas (UT) Southwestern
Medical Center, where he remained on the faculty at the medical school; he was also an attending physician at the Dallas VA Hospital for
five years. In 1985, Dr Schiller moved to Baylor University Medical Center to continue research with Dr John Fordtran, and has been there
ever since, most recently serving as program director for the Gastroenterology Fellowship.
Dr Schiller has been involved in patient care as a founding partner of Digestive Health Associates of Texas, one of the largest singlespecialty gastroenterology practices in America, and has continued with research and education activities at Baylor and UT Southwestern.
He is currently attending physician and chairman of the Institutional Review Board for Human Subject Protection at Baylor as well as
clinical professor of internal medicine at UT Southwestern, where he has won two fellow teaching awards.
Dr Schiller has been elected to fellowships in the American College of Physicians and the American College of Gastroenterology (ACG)
and has served as ACG governor of the North Texas region. Dr Schiller is currently ACG president-elect. He also has served as president
of the Texas Society for Gastroenterology and Endoscopy. Dr Schiller has published more than 80 papers and 45 book chapters dealing
with gastric physiology, intestinal transport, diarrheal diseases, and motility disorders.
Lucinda A. Harris, MD
Associate Professor of Medicine
Mayo School of Medicine
Consultant, Division of Gastroenterology and Hepatology
Department of Medicine
Mayo Clinic Scottsdale
Scottsdale, Arizona
Dr Lucinda Harris is currently an associate professor of medicine at the Mayo School of Medicine and a consultant in the division of
gastroenterology and hepatology at the Mayo Clinic Scottsdale in Arizona. She is a graduate of the University of Connecticut Medical
School. She completed her internal medicine residency at the New York Presbyterian Hospital of Columbia University and a fellowship in
gastroenterology and hepatology at the New York Hospital/Weill Medical College of Cornell University.
At the Mayo Clinic, Dr Harris is co-director of the Motility Group, where she has led a patient support group for irritable bowel syndrome
(IBS). She is a fellow of the American College of Gastroenterology as well as the American College of Internal Medicine. She is also a
member of the International Foundation for Functional Gastrointestinal Disorders, the American Neurogastroenterology and Motility
Society, and the American Medical Women’s Association. Her special clinical and research interests lie in IBS, chronic constipation, pelvic
floor disorders, and celiac disease. Dr Harris has also written and lectured extensively on these topics, and looks forward to hearing your
questions.
Faculty Financial Disclosure Statements
The presenting faculty report the following:
Dr Schiller has no financial relationships to disclose.
Dr Harris serves as an advisor to Ironwood Pharmaceuticals, Inc.; Procter & Gamble; Prometheus, Inc.; Salix Pharmaceuticals, Inc.;
and Takeda Pharmaceuticals North America, Inc.
Session 4
Education Partner Financial Disclosure Statement
The content collaborators at CME Incite, LLC, report the following:
Rose O’Connor, PhD, has no financial relationships to disclose.
Acronym List
Acronym
IBS-C
IBS-D
IBS-M
IBS-U
SERT
SSRI
TCA
FODMAP
PCP
Definition
Irritable bowel syndrome constipation
Irritable bowel syndrome diarrhea
Irritable bowel syndrome mixed
Irritable bowel syndrome unsubtyped
Serotonin transporter
selective serotonin reuptake
inhibitor
Tricyclic antidepressant
Fructose, Oligosaccharides,
Disaccharides,
Monosaccharides and Polyols
Primary care physician
Acronym
GI
CBC
CMP
TSH
Stool O&P
HRQOL
GERD
ESRD
HLA
B. infantis
PEG
CBT
Definition
Gastrointestinal
Complete blood count
Basic metabolic panel
Thyroid stimulating
hormone
Stool ova and parasites test
Health related quality of
life
Gastroesphageal reflux
disease
End stage renal disease
Human leukocyte antigen
Bifidobacter Infantis 35624
Polyethylene glycol
Cognitive Behavioral
Therapy
Suggested Reading List
Biesiekierski JR, Newnham ED, Irving PM, et al. Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind
randomized placebo-controlled trial. Am J Gastroenterol. 2011;106(3):518-514.
Brandt LJ, Chey WD, Foxx-Orenstein AE, et al; American College of Gastroenterology Task Force on Irritable Bowel Syndrome. An
evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.
Cash BD, Chang E, Talley NJ, Wald A.. Fresh perspectives in chronic constipation and other functional bowel disorders. Rev Gastroenterol
Disord. 2007;7(3):116-133.
Ford AC, Talley NJ. IBS in 2010: advances in pathophysiology, diagnosis and treatment. Nat Rev Gastroenterol Hepatol 2011;8(2):76-78.
Halpert A, Dalton CB, Palsson O, et al. What patients know about irritable bowel syndrome (IBS) and what they would like to know.
National Survey on Patient Educational Needs in IBS and development and validation of the Patient Educational Needs Questionnaire
(PEQ). Am J Gastroenterol. 2007;102(9):1972-1982.
Hasler WL. Traditional thoughts on the pathophysiology of irritable bowel syndrome. Gastroenterol Clin North Am. 2011;40(1):21-43.
Johannesson E, Simrén M, Strid H, Bajor A, Sadik R. Physical activity improves symptoms in irritable bowel syndrome: a randomized
controlled trial. Am J Gastroenterol 2011;106(5):915-922.
Johnston JM, Kurtz CB, Macdougall JE, et al. Linaclotide improves abdominal pain and bowel habits in a phase IIb study of patients with
irritable bowel syndrome with constipation. Gastroenterology. 2010;139(6):1877-1886.
Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology.
2006;130(5):1480-1491.
Pimentel M, Lembo A, Chey WD, et al; TARGET Study Group. Rifaximin therapy for patients with irritable bowel syndrome without
constipation. N Engl J Med. 2011;364:22-32.
Session 4
Lawrence R. Schiller, MD, FACG
Anaheim, California
April 11, 2012
Digestive Health Associates of Texas
Baylor University Medical Center
Dallas, Texas
Disclosures
Learning Objectives
y None
y Recognize the symptoms and accurately diagnose
patients who have IBS
y Implement strategies to overcome barriers in
diagnosing and treating patients with IBS
y Compare the safety and efficacy of currently
available treatments when selecting therapy for
patients with IBS
y Explain novel agents in development for the
treatment of IBS and their potential implications for
practice
Drug List
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
A3309
Alosetron
Alvimopan
Amitriptyline
Asimadoline
Cholestyramine
Citalopram
Desvenlafaxine
Desipramine
Dextofisopam
Doxepin
Duloxetine
Escitalopram
Fluoxetine
Imipramine
Linaclotide
Loperamide
Lubiprostone
Methylnaltrexone
Mosapride
Neurotrophin-3
Nortriptyline
Paroxetine
Prucalopride
Psyllium
Rifaximin
Sertraline
Venlafaxine
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
Pretest Question 1
No trade name
Lotronex
Entereg
Elavil, Tryptizol, Laroxyl, etc
No trade name
Questran
Celexa
Pristiq
Norpramin, Pertofane
No trade name
Adapin, Silenor, Sinequan, etc
Cymbalta
Lexapro
Prozac, Sarafem, Fontex, etc
Antideprin, Deprimin, Deprinol, etc
No trade name
Imodium, Diar-Aid, Diamode, etc
Amitiza
Relistor
Gasmotin
Ampipenin
Aventyl, Pamelor
Paxil, Aropax, Seroxat, Pexeva, etc
Resolor
Fiberall, Benefiber, Metamucil, etc
Xifaxan
Zoloft
Effexor
?
A 43-year-old patient presents with IBS symptoms
for >3 months prior to initial visit without the
presence of alarm features. What should be your
next course of action?
1. Watch and wait for emergence of alarm features
2. Perform routine lab tests (CBC, CMP, TSH, stool O+P,
3.
4.
5.
6.
1
abdominal imaging)
Refer for colonoscopy
Begin treatment for IBS immediately
None of the above
Unsure
Pretest Question 2
?
Pretest Question 3
Based on clinical efficacy demonstrated in randomized,
controlled clinical trials, which of the following
nonpharmaceutical therapies would you implement in your
patients with IBS to yield optimal outcomes?
1.
2.
3.
4.
5.
6.
?
Which of the following practice changes is most likely
to provide the most effective strategy for treating your
patients with suspected IBS?
1.
Probiotics
Probiotics and acupuncture
Herbal remedies
Psychological therapy and acupuncture
Probiotics and psychological therapy
Unsure
2.
3.
4.
5.
6.
Obtaining results from several diagnostic tests before diagnosing IBS
Directly asking your patients about stress levels and possible correlation
to exacerbation of symptoms
Opening a dialogue with patients during which you can discuss
complaints, talk about reducing stress, and educate them about IBS
Highlighting the need for prompt treatment of IBS, as it relates to
decreased quality of life and increased healthcare costs
Encouraging patients to reduce stress levels to control IBS symptoms
before trying other pharmacologic or nonpharmacologic therapies
Unsure
Case History
Case History
y Mary S., a 40-year-old woman with a 6-year history
y Married, 3 children, teacher, occ. ethanol, no
of abdominal pain, bloating, and constipation
y Pain relieved by defecation
y Occasional episodes of diarrhea, sometimes
associated with high intake of fruit
y Misses time from work due to symptoms
tobacco use
y Father died 1 year ago of colon cancer Æ
depression; currently on SSRI
y She has increased fiber intake, but this led to more
bloating
y Laxatives relieve constipation, but no effect on
abdominal pain
Case History
Diagnostic Paradigm for IBS
y Physical examination is normal
y IBS is a syndrome, a collection of symptoms
y Basic laboratory tests are normal
y Therefore, diagnosis should be possible by
taking a good history of symptoms
y Complete blood count
y Comprehensive metabolic profile
y Since symptoms may be due to some other
y Thyroid stimulating hormone
disorders, the physician must consider
alternative organic diagnoses
y Serious organic illnesses typically produce alarm
symptoms
WHAT IS YOUR DIAGNOSIS?
2
IBS: Prevalence and Patterns
Rome III Criteria for IBS
y Worldwide prevalence: 7% to 10%
Recurrent abdominal pain or discomfort
at least 3 days/month in the last 3 months
associated with 2 or more of the following:
y 1.5 times more prevalent in women
y More commonly diagnosed in patients younger than
50 years of age
y More common in lower socioeconomic groups
Improvement with
defecation
Onset associated with
a change in frequency
of stool
y Patients with IBS have more doctor visits, more
Onset associated
with a change in
form of stool
hospitalizations, more missed workdays, more
prescriptions, more diagnostic tests
Criteria fulfilled for the last 3 months with symptom onset
at least 6 months prior to diagnosis
Longstreth GF, et al. Gastroenterology. 2006;130:1480-1491; erratum: Gastroenterology. 2006;131:688.
Brandt LJ, et al. ACG IBS Task Force. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.
IBS Subtypes
IBS: A Durable Diagnosis
Hard or Lumpy Stools (%)
IBS-C: Constipation predominant IBS
100
92% of patients had
unresolved IBS symptoms
10-13 years after initial IBS
diagnosis
IBS-D: Diarrhea predominant IBS
75
IBS-M: Hard and loose stools over
periods of weeks and months
50
IBS-C
N = 75
IBS-M
IBS-U: Unsubtyped IBS
25
IBS-U
0
0
IBS-D
25
50
75
100
Loose or Watery Stools (%)
Longstreth GF, et al. Gastroenterology. 2006;130:1480-1491; erratum: Gastroenterology. 2006;131:688.
Adeniji OA, et al. Am J Gastroenterol. 2002;97(9 suppl):S273.
Proposed Pathophysiology: 2011
y Dysmotility
y Hypersensitivity
y Disordered brain
processing
y Enteric nervous system
dysfunction
y SERT activity
y Postinfectious IBS
y Small intestinal bacterial
overgrowth
y Mast cell dysfunction
y Dysbiosis
y Food intolerances
Criteria-Based Diagnosis
Differential Diagnosis
y Food allergy
y Genetics
y Somatization syndrome
Hasler WL. Gastroenterol Clin North Am. 2011;40:21-43. Ford AC, et al. Nat Rev Gastroenterol Hepatol. 2011;8:76-78.
3
?
ARS Question 1
Rome III Criteria for IBS
How often do you abide by the strict Rome III
criteria in diagnosing IBS?
Recurrent abdominal pain or discomfort
at least 3 days/month in the last 3 months
associated with 2 or more of the following:
1. 0% to 25% of the time
2. 26% to 50% of the time
Improvement with
defecation
Onset associated with
a change in frequency
of stool
3. 51% to 75% of the time
Onset associated
with a change in
form of stool
4. 76% to 100% of the time
5. Always
Criteria fulfilled for the last 3 months with symptom onset
at least 6 months prior to diagnosis
Longstreth GF, et al. Gastroenterology. 2006;130:1480-1491; erratum: Gastroenterology. 2006;131:688.
Differential Diagnosis of IBS
With Constipation
Differential Diagnosis of IBS
y Other functional gastrointestinal disorders
y Gastrointestinal
y Functional constipation, functional diarrhea
y Pain less prominent than bowel disturbance
y Colorectal cancer
y Diverticular disease
y Functional abdominal pain
y Bowel disturbance less prominent
y Gynecological
y Metabolic/endocrine
y Hypothyroidism
y Diabetes
y Neurological
y Ovarian cancer
y Parkinson’s disease
y Endometriosis
y Multiple sclerosis
y Drugs
y Opiates
y Autonomic neuropathy
y Other
y Anticholinergics
y Amyloidosis
y Antidepressants
y Scleroderma
Candelli M, et al. Hepatogastroenterology. 2001;48:1050-1070. Locke GR, et al. Gastroenterology. 2000;119:1766-1778.
Differential Diagnosis of IBS
With Diarrhea
y Dietary factors
y Lactose
y Inflammatory bowel
disease
y Gluten
y Crohn’s disease
y Other FODMAPs*
y Ulcerative colitis
y Infection
y Giardiasis
y Amebiasis
y Malabsorption
y Celiac disease
y Microscopic colitis
y Psychological
y Panic disorder
y Somatization
y Depression
*FODMAPs, fructose, oligosaccharides, disaccharides, monosaccharides, and polyols.
Candelli M, et al. Hepatogastroenterology. 2001;48:1050-1070. Locke GR, et al. Gastroenterology. 2000;119:1766-1778.
4
IBS Experts Use Fewer Tests
Than Nonexperts
Utility of Tests in Diagnosing IBS
Organic Disease
Colitis/IBD
IBS Patients, %
Control/Population,*%
1.1
0.7
Colorectal cancer
0.4
4-6
Celiac disease
0.41
0.44
Thyroid dysfunction
5.5
6.0
Lactose malabsorption
22.3
26.6/25.0
PCPs, Nurse
Practitioners, and
Gastroenterologists
(n=281)
IBS
Experts
(n=45)
IBS is diagnosis of exclusion?
(% yes)
*Prevalence in the US population.
P Value
72
8
IBS-C
Diagnostic tests, n
Cost of testing, $
<0.0001
2.2
550
1.4
288
0.06
0.03
IBS-D
Diagnostic tests, n
Cost of testing, $
4.1
658
2
297
<0.01
<0.01
Organic disease is no more likely in IBS patients than in controls
Cash BD, et al. Gastroenterology. 2007;132(suppl 2):W1182 & 986. Cash BD, et al. Gastroenterology. 2006;130(4 suppl
2):A111. Bratten JR, et al. Am J Gastroenterol. 2008;103:958-963. Cash BD, et al. Gastroenterology. 2011;141:1187-1193.
Spiegel BM, et al. Gastroenterology. 2006;130(suppl 2):S1134.
Alarm Features in IBS
Limitations of Alarm Features
y Rectal bleeding, nocturnal pain
y Refractory or worsening abdominal
y
y
y
y
y
y
symptoms
Older patient (50 years of age or older;
45 years of age or older if black)
Blood in stools
Anemia
Weight loss (unintentional)
Anorexia
Family history of organic GI disease
y Little discriminative value: IBS vs organic disease
y Anemia, weight loss
y Poor sensitivity for organic disease
If present, investigate
and treat appropriately;
colonoscopy may be
indicated
y Very good specificity for organic disease
y Therefore, in presence of specific criteria for IBS,
absence of alarm symptoms supports a diagnosis of IBS
Brandt LJ, et al. ACG IBS Task Force. Am J Gastroenterol. 2009;104(suppl 1):S1-S35. Furman DL, et al. Gastroenterol Clin
North Am. 2011;40:105-119.
Lembo A, et al. N Engl J Med. 2003;349:1360-1368. Brandt LJ, et al. Am J Gastroenterol. 2005;100(suppl 1):S5-S21.
Cash BD, et al. Rev Gastroenterol Disord. 2007;7:116-133.
Initial Management of IBS:
A Symptom-Based Approach
ACG Recommendations:
Evaluation of IBS With No Alarm
Features
Identify IBS symptoms, presence of alarm features
Meets criteria, no
alarm features Æ make
dx of IBS
y Routine lab tests (CBC, CMP) and TSH, stool O+P,
abdominal imaging Æ not recommended
y Serologic testing for celiac disease (IBS-D/M) Æ
recommended
y Lactose breath testing Æ selected cases
y Colonoscopy Æ recommended if older than 50 years
of age, with biopsies in refractory IBS-D (to exclude
microscopic colitis)
Doesn’t meet criteria,
has alarm features:
look for alternative dx
Symptomatic treatment for predominant symptoms
Assess response to treatment
Good response Æ continue Rx
ACG-American College of Gastroenterology
Poor response Æ reassess
Longstreth GF, et al. Gastroenterology. 2006;130:1480-1491; erratum: Gastroenterology. 2006;131:688. Brandt LJ, et al. ACG IBS
Task Force. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.
Brandt LJ, et al. ACG IBS Task Force. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.
5
Presence of Nongastrointestinal
Symptoms and Other Comorbidities
Why Do Patients Come
for Care?
y Abdominal pain1
y Depression
y Fear of cancer2
y Migraine
y Fear of inflammatory bowel disease3
y Anxiety
More severe IBS dx
y Concern about malnutrition4
y Neuralgia
y Concern about shortening life3
y Chronic fatigue
More anxiety and
depression
y Chronic pain
y Fibromyalgia
Lower quality of life
More absences from
work
Chang L. Aliment Pharmacol Ther. 2004;20(suppl 7):31-39. Frissora CL, et al. Curr Gastroenterol Rep. 2005;7:264-271.
Hershfield NB. Can J Gastroenterol. 2005;19:231-234. Whitehead WE, et al. Am J Gastroenterol. 2007;102:2767-2776.
1. Lembo T, et al. Am J Gastroenterol. 1999;94:1320-1326. 2. Lacy B, et al. Am J Gastroenterol. 2005;100:S324.
3. Noddin L, et al. Am J Gastroenterol. 2005;100:S323. 4. Lee DH, et al. Am J Gastroenterol. 2005;100:S336.
Barriers to Effective Management
y Recognizing IBS in patients with many other
symptoms
y Sorting out why the patient is there Æ what
his/her expectations are
y Dealing with those expectations
y Diagnostic tests
Lucinda Harris, MD
y Goals of therapy
Associate Professor of Medicine
Mayo School of Medicine
Consultant, Division of Gastroenterology and Hepatology
Department of Medicine
Mayo Clinic Scottsdale
Scottsdale, Arizona
y Sufficient time for education, questions
Disclosures
Impact of IBS
y Economic
y Advisory Board: Forest Laboratories; Ironwood
y Healthcare costs1,2
y Direct cost ($348-$8750 per patient/year) vs indirect cost
($355-$3344 per patient/year)—2002 data
Pharmaceuticals, Inc.; Proctor & Gamble;
Prometheus, Inc.; Salix Pharmaceuticals, Inc.;
Takeda Pharmaceuticals North America, Inc.
y Decreased work productivity2,3
y Average work days missed 8.5-21.6 days/year
y 20% more work impairment
y Utilization of healthcare services4-6
y IBS patients use more healthcare services for GI and non-GI
reasons
y More surgical procedures including cholecystectomy,
appendectomy, hysterectomy, etc
1. Sandler RS, et al. Gastroenterology. 2002;122:1500-1511. 2. Maxion-Bergemann S, et al. Pharmacoeconomics. 2006;24:2137. 3. Dean BB, et al. Am J Manag Care. 2005;11(1 suppl):S17-S26. 4. Longstreth GF, et al. Am J Gastroenterol. 2003;98:600607. 5. Spiegel BM, et al. Am J Gastroenterol. 2005;100:2262-2273. 6. Longstreth G F, et al. Gastroenterology. 2004;126:16651673.
6
Biopsychosocial Model
IBS Burden of Illness
Early Life
Genetics
Environment
y Health-related quality of life (HRQOL)
y Decreased HRQOL compared with healthy controls
and patients with GERD, diabetes, and ESRD1,2
y HRQOL of IBS patients related to abdominal pain,
symptom flares, extraintestinal symptoms, and
disease-related concerns1,3
y Patient-assessed disease severity in IBS predicted by
Psychosocial
Factors
Life stress
Psychologic state
Coping
Social Support
CNS
abdominal pain, bloating, straining, urgency, myalgias
and disease-related concerns4
ENS
Physiology
Motility
Secretion
1. El-Serag HB, et al. Aliment Pharmacol Ther. 2002;16:1171-1185. 2. Gralnek IM, et al. Gastroenterology. 2003;119:654-660.
3. Spiegel BM, et al. Arch Intern Med. 2004;164:1773-1780. 4. Naliboff BD, et al. Eur J Surg Suppl. 1998:57-59.
IBS
Symptoms
Behavior
Outcomes
Medications
MD visits
Daily function
QoL
Halpert A, et al. Biopsychosocial Issues in IBS. J Clin Gastroenterol. 2005;39:665-669.
Treatment Depends on
Severity of IBS
•
•
•
•
•
•
•
•
•
Psychological treatments
Goal: improved function
Continuing care
+
Follow-up visit
Manage stress
Drug therapy
+
Diet, lifestyle advice
Positive diagnosis
Severe
(25%)
Moderate
(35%)
Mild
(40%)
Explain, reassure
Drossman DA , et al. Am J Gastroenterol. 2011;106:1749-1759.
Diet and IBS
Sleep and IBS Symptoms
y Lifestyle1
y IBS patients report more difficulties with sleep
impairment
y Survey of 1242 patients, following improved symptoms
y More time to fall asleep
y Small meals (69%), avoiding fat (64%), increasing fiber
y Waking up from sleep
(58%), avoiding milk products (54%), etc
y Excessive sleepiness on the following day
y Poor sleep associated with exacerbation of
y Food allergy2—limited evidence
y Lactose3—higher % of lactose maldigestion
symptoms the following day
y Gluten4,5—studies indicate possible link
y Better sleep habits may result in some improvement
y Fructose intolerance6—studies indicate possible
in IBS symptoms
link
1. Halpert A, et al. Am J Gastroenterol. 2007;102:1972-1982. 2. Locke GR 3rd, et al. Am J Gastroenterol. 2000;95:157-165.
3. Brandt LJ. et al. Am J Gastroenterol. 2009;104(suppl 1):S1-S35. 4. Wahnschaffe U, et al. Clin Gastroenterol Hepatol. 2007;5:
844-850. 5. Biesiekierski JR, et al. Am J Gastroenterol. 2011;106:508-514. 6. Shepherd SJ, et al. J Am Diet Assoc.
2006;106:1631-1639.
1. Rotem AY, et al. Sleep. 2003;26:747-752. 2. Jarrett M, et al. Dig Dis Sci. 2000;45:952-959.
7
Can Exercise Reduce IBS
Symptoms?
y 12-week randomized trial of 20-60 min of aerobic activity
3-5 times/week vs usual activity (N=75)
Results
y IBS Symptom Severity Scoring System (IBS-SSS) before
study began and at 12 weeks
y A significant difference in improvement in IBS-SSS score
between physical activity group and control group: -51
(-130 and 49) vs -5 (-101 and 118) (P=0.003)
Johannesson E, et al. Am J Gastroenterol. 2011;106:915-922.
What Is a Probiotic?
How Does It Work?
Nonpharmacologic
Treatments
y Probiotics (in US, food or dietary supplement)
y Complementary therapies
y Exogenous live bacteria, primarily lactobacillus and bifidobacteria,
y Probiotics*
introduced into the gut to exert a healthful benefit
y Acupuncture—inconclusive results
y Multifactorial mechanism
y Herbals*—systematic review, some therapies
y
y Generally regarded as “safe”
To assess benefit, more studies need
y History of safe use in food prior to 1958 or
y Psychological and behavioral therapy
y Identified as safe by expert judgment under conditions of intended
y Cognitive behavioral therapy
use
y Hypnotherapy
y Not all created equal; labeling, benefits dose/strain
y Psychotherapy
specific
y Stress management
y Rare fungemia/bacteremia in immunocompromised
patients
*These agents are not currently FDA approved for IBS.
Answering “Yes” at
Week 4 (%)
Global Assessment Symptom Relief:
Bifidobacteria Infantis 35624 for IBS
80
70
Psychological Treatments Show
Greater Efficacy Than Usual Care
Treatment
Modality
P=0.0118
60
50
40
30
20
B Infantis
1 x 1010
B Infantis
1 x 108
B Infantis
1 x 106
PLA
Studies,
N
Pts
C
Cognitive behavioral
therapy (CBT)
7
279
212
0.60 (0.42-0.87)
Hypnotherapy
2
20
20
0.48 (0.26-0.87)
4
106
105
0.69 (0.56-0.86)
Stress management
1
18
17
0.34 (0.16-0.73)
2
138
135
0.60 (0.39-0.93)
Dynamic psychotherapy
Please consider how you felt in the past week regarding your IBS, in particular your general
well-being, and symptoms of abdominal discomfort or pain, bloating or distension, and
altered bowel habit. Compared with the way you felt before beginning the medication, have
you had adequate relief of your IBS symptoms?
Ford AC, et al. Gut. 2009;58:367-378.
8
RR
(95% CI)
Multicomponent
psychological therapy
SGA: (Subjects’ Global Assessment) a Y/N response to the following question:
Whorwell PJ, et al. Am J Gastroenterol. 2006;101:1581-1590.
N
Cognitive Behavioral
Therapy and IBS
y Randomized, controlled-trials demonstrated improvement
in GI symptoms, psychological distress, and QoL1-3
y After 12 weeks, percentage of patients who reported adequate
relief of IBS symptoms was greater in those who underwent either
therapist or self-administered CBT compared with wait-list
patients (P<0.0001)1
y After 4-10 weekly sessions of CBT, 30% of patients were rapid
responders, with 90% to 95% of those patients maintaining
improvements in symptoms at immediate and 3-month follow-up
exams*2
y CBT had greater improvements on IBS symptoms compared with
education alone in patients with functional bowel disorders, after
12 weeks (P=0.0001)3
*Statistical significance not reported.
1. Lackner JM, et al. Clin Gastroenterol Hepatol. 2008;6:899-906. 2. Lackner JM, et al. Clin Gastroenterol Hepatol. 2010;8:426-432.
3. Drossman DA, et al. Gastroenterology. 2003;125:19-31.
IBS-C Evidence-Based
Summary of Medical Therapies1
IBS Pharmacologic
Therapies by Symptom
Abdominal pain/discomfort
y Antispasmodics*
y Antidepressants*
y TCAs/SSRIs
y Alosetron
(5HT-3
antagonist)
Abdominal
pain/
discomfort
Constipation
y Fiber*
y MOM/PEG solution*
y Lubiprostone
(Chloride channel activator)
Level of
Evidence2
Bulking
2C
Laxatives
Osmotic/
stimulant
2C
Lubiprostone3
Chloride
Channel
activator
1B
Fiber
Bloating/
distension
Altered bowel
function
Mechanism
Therapy
Bloating
y Rifaximin*
y ? Probiotics
Diarrhea
y Loperamide*
y Cholestyramine*
y Alosetron
y Rifaximin*
*These agents are not currently FDA approved for IBS.
Global
Symptom
Relief
FDA
Indication
+
IBS-C in
women only
1. Brandt LJ, et al. Am J Gastroenterol. 2002;97:S7-S26. 2. Graham L. Am Fam Physician. 2009;79:1108-1117.
3. Drossman DA, et al. Gastroenterology. 2008;132:2586-2587.
Brandt LJ, et al. Am J Gastroenterol. 2002;97(11 suppl):S7-26. Drossman DA, et al. Gastroenterology. 2002;123:2108-2131.
Psyllium Can Improve
IBS Symptoms
Polyethylene Glycol (PEG)
for IBS-C
y Randomized, PLA-controlled trial (N=275 pts with IBS)
y No adult studies of
y 12 weeks of treatment
laxatives in IBS-C1
y 10 g psyllium (n=85)
y 27 adolescents: PEG
y 10 g bran (n=97)
improved number of
bowel movements
(P<0.05) but not pain
in IBS-C patients2
y 10 g placebo (rice flour) (n=93)
y Primary endpoint: adequate symptom relief ≥2 weeks in
previous month, analyzed after 1, 2, and 3 months
RESULTS
y Higher % responders in psyllium vs placebo group during
1st month (57% vs 35%; RR: 1.60; 95% CI: 1.13-2.26)
y Higher % responders through 2 months of treatment
(59% vs 41%; RR: 1.44; 95% CI: 1.02-2.06)
1. Brandt L, et al. Am J Gastroenterol. 2009;104(suppl):S1-S35. 2. Khoshoo V, et al. Aliment Pharmacol Ther. 2006;23:191-196.
Bijkerk CJ, et al. BMJ. 2009;339:3154-3160.
9
Lubiprostone: Therapeutic
Considerations
Lubiprostone: Overall
Responder Rate in IBS-C Trials
y Dosage for IBS-C in women only: 8 µg BID
y Most common adverse effects
y 2 Phase 3, randomized,
y Nausea (8%)
double-blind, PLA-controlled
12-week trials
y Results: patients receiving
lubiprostone (8 μg BID)
twice as likely to achieve
overall response
y 7.8% difference (P=0.001)
vs placebo
y Diarrhea (7%)
y Abdominal pain (5%)
y Abdominal distention (3%)
y Administer with food to minimize incidence of nausea
n=388
y Pregnancy class C; no studies in pregnant women
y Contraception recommended in women of childbearing age
y Check pregnancy test prior to dispensing in women of
childbearing age
n=783
y Ensure absence of mechanical obstruction before
beginning therapy
Drossman DA, et al. Aliment Pharmacol Ther. 2009;29:329-341.
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed July 22, 2011.
IBS-D Evidence-Based Summary
of Medical Therapies
Therapy
Mechanism
y Low doses, 2 mg QD to BID, may be effective to
Level of
Evidence
Global
Symptom
Relief
FDA Indication
Mu-opioid
antagonist
2C
No
Diarrhea
Alosetron2
5HT-3
receptor
antagonist
2A/1B
+
IBS-D
(women)
+
Traveler’s diarrhea,
hepatic
encephalopathy
Antibiotic
decrease stool frequency, improve stool consistency
y No impact on symptoms of abdominal discomfort,
Loperamide1
Rifaximin3
Loperamide for IBS-D
bloating, or global IBS
y 2 randomized controlled trials in IBS (N=42) show
efficacy for diarrhea
1B
y Adverse effects: dizziness, abdominal pain/bloat,
constipation, dry mouth, fatigue
1. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed July 22, 2011.
2. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed July 22, 2011.
3. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=XIFAXAN&CFID
=59783989&CFTOKEN=e3ee8c9cd8da47cd-5283D39A-E9F2-6CB3-CF7C067AE8023F58. Accessed July 22, 2011.
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed July 22, 2011.
Alosetron for IBS-D
Antibiotics and IBS
y Female patients with chronic, severe IBS-D who failed
y Direct evidence suggests that patients with postinfectious
other treatments
IBS experience low-grade persistent inflammation and
immune activation in small and large intestines
y Indirect evidence: correction of abnormal breath tests in
IBS patients suggestive of small intestinal bacterial
overgrowth/bacterial fermentation
y Rifaximin, most extensively studied antibiotic for IBS
y Dose: 0.5-1.0 mg QD to BID
y Patient education regarding possible serious adverse
effects of severe constipation or ischemic colitis
y 0.95 cases of ischemic colitis/1000 patient-years
y 0.36 cases of severe constipation/1000 patient-years
y Ischemic colitis usually occurs within the first month of
y Not systemically absorbed
therapy if it occurs
y Prescribing program mandated by FDA
y Doses studied for IBS: 400 mg BID to 550 mg TID
y Primary adverse effects include flatulence, abdominal pain,
headache
y Requires patient to sign attestation form
Collins SM, et al. Dig Liver Dis. 2009;41:850-853. Pimentel M, et al. Am J Gastroenterol. 2003;98:412-419. Ford AC, et al.
Clin Gastroenterol Hepatol. 2009;7:1279-1286.
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed July 22, 2011.
10
Evidenced-Based Summary of
Medical Therapies for IBS-Pain
Rifaximin* Trials: Global Relief
of IBS Symptoms
y 2 Phase 3 double-blind,
y
y
y
y
PLA-controlled,
randomized trials
N=1260 patients
Rifaximin 550 mg TID x
2 weeks
Patients followed an
additional 10 wks
40.7% vs 31.7% with
adequate relief of global
symptoms (P<0.001)
550 mg TID vs placebo
Global
Level of
Symptom
Evidence
Relief
FDA
Indication
for IBS1-3
Therapy
Mechanism
Antispasmodics
Anticholinergic
effect slows
motility
1B
+
Yes
Antidepressants
Visceral
analgesia,
change in
motility,
smooth muscle
relaxation
2C
+/-
No
T-I , TARGET 1 trial; T-II, TARGET 2 trial; Comb, combination of both trials.
*Rifaximin is not currently FDA approved for IBS.
Pimentel M, et al. N Engl J Med. 2011;364:22-32.
1. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/007409s041lbl.pdf. 2. Ford AC, et al. BMJ. 2008;337:a2313.
3. Ford AC, et al Gut. 2009;58:367-378.
Antidepressants*: Available Agents
and Typical Doses in IBS Treatment
Antispasmodics for IBS
y 22 RCTs compared 12 different antispasmodics vs
placebo (N=1778 patients)
y Significant heterogeneity among studies
y Many agents not available in US
y Appear most useful for abdominal pain
y In meta-analysis, symptoms persist in 39% of
patients receiving antispasmodics vs 56% of
placebo-treated patients (RR: 0.68; 95% CI:
0.57-0.81)
Agents
Dose range
Time to action
TCAs
SSRIs
SNRIs
Amitriptyline
Nortriptyline
Imipramine
Doxepin
Desipramine
Fluoxetine
Paroxetine
Sertraline
Citalopram
Escitalopram
Duloxetine
Venlafaxine
Desvenlafaxine
10-200 mg
10-100 mg
30-90 mg (duloxetine)
75-225 mg (venlafaxine)
Few days to
2 weeks (low doses)
2-6 weeks (high
doses)
3-6 weeks
3-6 weeks
TCAs, tricyclic antidepressants; NSRI, norepinephrine-serotonin reuptake inhibitors;
SSRIs, selective substance reuptake inhibitors.
*These agents are not currently FDA approved for IBS.
Ford AC, et al. BMJ. 2008;337:a2313.
Grover M, et al. Gastrointestinal Endoscopy Clin N Am. 2009:19:151-170.
Clinical Considerations for
Using Antidepressants in IBS
Novel Agents*
IBS-C
y Linaclotide (guanylate cyclase-C agonist)
y Target specific symptoms, eg, tricyclics for IBS-D,
y Increases chloride and bicarbonate secretion into intestinal lumen
SSRIs, for IBS-C*
y Consider adverse effect profile
y Start with low dose (TCA) and titrate up every 1-2
weeks assessing response, adverse effects, and
efficacy
y If good response, continue effective dose 6-12
months
y If poor response, switch or combine agents,
psychiatry consultation
y Currently under review by the FDA
y Prucalopride (5HT-4 agonist)
y Increases intestinal motility
y Currently approved in Canada/Europe for chronic constipation
y A3309 (bile acid transport inhibitor)
y Stimulates colonic motility and secretion
y Completed Phase 2 studies in chronic constipation
IBS-D
y Asimadoline
y Activates opioid receptors; may reduce visceral perception
*Investigational drugs; not currently FDA approved for IBS.
Khan S, et al. Nat Rev Gastroenterol Hepatol. 2010;7:565-581. Chey WD, et al. Am J Gastroenterol. 2011;106:1803-1812.
*These agents are not currently FDA approved for IBS.
11
Linaclotide* (Guanylate
Cyclase-C Agonist) for IBS-C
CSBM and Abdominal Pain During and
After 12 Weeks of Linaclotide* Treatment
CSBM Rates Decline and Abdominal Pain Scores Rose
Within 2 Weeks of Stopping Linaclotide Treatment
y Phase 2b, placebo-controlled, randomized, dose-ranging
study (N=420) given 75, 150, 300, or 600 μg daily for 12
weeks
y Endpoints: change from baseline in daily bowel habits, daily
abdominal symptoms, and weekly global assessments
Results
y Significant improvement in bowel habits, including complete
spontaneous bowel movements
y Abdominal pain significantly reduced from baseline (-0.71,
-0.71, -0.90, and -0.86 for linaclotide doses of 75, 150, 300,
and 600 μg, respectively, compared with -0.49 for placebo)
y Primary adverse effect was diarrhea, mild to moderate
CSBM, complete spontaneous bowel movement.
*Investigational drug - not currently FDA approved for IBS
Johnston JM, et al. Gastroenterology. 2010;139:1877-1886.
*Investigational drug - not currently FDA approved for IBS
Johnston JM, et al. Gastroenterology. 2010;139:1877-1886.
Prucalopride* for Chronic
Constipation
Linaclotide* for Chronic Constipation
y 2 placebo-controlled, randomized, 12-week Phase 3 studies
(N=1272) with doses of 145 μg or 290 μg linaclotide daily
y 3 placebo-controlled, randomized, 12-week Phase 3 studies
(N=1974) with doses of 2 mg or 4 mg prucalopride daily1-3
y Primary endpoint: 3 or more CSBMs per week and an increase of
1 or more CSBM per week (from baseline) during at least 9 of the
12 weeks
Results (patients with ≥3 CSBMs/week)
y 24% of patients taking 2 mg or 4 mg compared with 12% of
patients receiving placebo (n=641)1
y 30.9% of patients receiving 2 mg and 28.4% of patients
receiving 4 mg vs 12.0% with placebo (P<0.001 for both
comparisons vs placebo; n=620)2
y 19.5% of patients receiving 2 mg (P<0.01) and 23.6% taking
4 mg (P<0.001) vs 9.6% with placebo (n=713)3
y Adverse events included headache and diarrhea, but no
increase in cardiovascular events were reported1-3
Results
Significant improvement
in bowel habits, including
rate of complete
spontaneous bowel
movements
N=1272
*P≤0.001; **P≤0.01 vs placebo.
*Investigational drug; not currently FDA approved for IBS.
*Investigational drug - not currently FDA approved for IBS
Lembo AJ, et al. N Engl J Med. 2011;365:527-536.
1. Quigley EM, et al. Aliment Pharmacol Ther. 2009;29:315-328. 2. Camilleri M, et al. N Engl J Med. 2008;358:2344-2354.
3. Tack J, et al. Gut. 2009;58:357-365.
Summary of IBS Therapy
Posttest Question 1
y Begin treatment immediately for patients who present with IBS
?
A 43-year-old patient presents with IBS symptoms for >3
months prior to initial visit without the presence of alarm
features. What should be your next course of action?
symptoms for >3 months, without presence of alarm features
y Open patient-provider discussions key to successful outcomes
y Address patient complaints
y Talk about reducing stress
y Educate patients about IBS as a disease
y Diet, exercise, and sleep build foundation for therapy success
1.
2.
y Nonpharmaceutical therapies (ie, psychological therapy and
3.
probiotics) demonstrated efficacy in clinical trials
y Evidence-based pharmacologic therapies include
4.
5.
y IBS-C: lubiprostone, SSRIs
6.
y IBS-D: alosetron, TCAs, nonabsorbable antibiotics
y Novel agents in development may provide additional treatment
options
y Linaclotide, prucalopride, rifaximin, and others
12
Watch and wait for emergence of alarm features
Perform routine lab tests (CBC, CMP, TSH, stool O+P, abdominal
imaging)
Refer for colonoscopy
Begin treatment for IBS immediately
None of the above
Unsure
Posttest Question 2
?
Posttest Question 3
?
Which of the following practice changes is most likely to provide the
most effective strategy for treating your patients with suspected IBS?
Based on clinical efficacy demonstrated in randomized,
controlled clinical trials, which of the following
nonpharmaceutical therapies would you implement in
your patients with IBS to yield optimal outcomes?
1.
2.
1. Probiotics
3.
2. Probiotics and acupuncture
3. Herbal remedies
4. Psychological therapy and acupuncture
4.
5. Probiotics and psychological therapy
5.
6. Unsure
6.
Obtaining results from several diagnostic tests before diagnosing
IBS
Directly asking your patients about stress levels and possible
correlation to exacerbation of symptoms
Opening a dialogue with patients during which you can discuss
complaints, talk about reducing stress, and educate them about
IBS
Highlighting the need for prompt treatment of IBS, as it relates to
decreased quality of life and increased healthcare costs
Encouraging patients to reduce stress levels to control IBS
symptoms before trying other pharmacologic or nonpharmacologic
therapies
Unsure
Case History
y AC, a 45-year-old woman, presents with a 6-year
history of abdominal pain and variable bowel habits
y Crampy pain is located in left lower quadrant
y Pain peaks just before bowel movement
y Pain is relieved by defecation
y Bowel movements vary in consistency: loose to hard
y Frequency of bowel movements varies from once
weekly to 4 times per day
ARS Question: What additional
history would you obtain?
Case History (cont’d)
y Other symptoms include indigestion, early satiety,
bloating, excess flatus, and belching
1. Past surgical history
y She has had no weight loss or rectal bleeding
2. History of migraine headaches
y Previous evaluation included colonoscopy with
3. Discussion of life stresses and relation to
biopsies (negative), endoscopy with biopsies
(negative), abdominal sonogram (negative)
y She had tried lactose-free diet, increased dietary
fiber, dicyclomine, and hyoscyamine without benefit
y Physical examination is unremarkable
symptoms
4. Discussion of physical and sexual abuse
5. Family history of digestive symptoms
13
?
ARS Question: What would you
do next?
?
1. Lab tests: complete blood count, comprehensive
metabolic profile, TSH
2. Pelvic examination
3. Diet and symptom diary for 2 weeks
4. CT scan of abdomen/pelvis
5. Repeat colonoscopy and endoscopy
Case History
Case History (cont’d)
y K, referred by GI colleague, 62-year-old female
y PMH notable for
y Hyperlipidemia
y GERD
y Depression
y Hyperplastic colon polys on colonoscopy 3 years ago
y Past surgical history
y Vaginal hysterectomy
y Appendectomy
y Medications: daily multivitamins, frequent loperamide
health educator
y Experienced daily diarrhea (3-5 times/day) for more
than 20 years with urgency/rare incontinence
y Leads a busy, active lifestyle
y Frequently under high stress from work and personal
life
y Sleep schedule is not consistent, usually getting only
4-5 hours per night
y Does not exercise regularly
ARS Question: What would
you do next?
and bismuth subsalicylate
?
Questions & Answers
Knowing she has had a trial of tricyclic antidepressants
without success, what would be your next step?
?
1. Lab tests: complete blood count, comprehensive
metabolic profile, TSH
2. Pelvic examination
3. Trial of FODMAP diet
4. Prescribe alosetron
5. Repeat colonoscopy with biopsy
6. Psychiatry consultation to treat anxiety
14