optimizing the diagnosis, treatment, and management … files/spring 2015 syllabus... · optimizing...

February 5, 2015

9:15 AM – 10:30 AM

Fort Lauderdale, FL

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Sponsored by pmiCME

Optimizing the Diagnosis, Treatment, and Management ofIrritable Bowel Syndrome

Session 2

Session 2: Optimizing the Diagnosis, Treatment, and Management of Irritable Bowel Syndrome Learning Objectives

1. Diagnose IBS and differentiate from other bowel disorders using established clinical guidelines. 2. Summarize the efficacy and safety of pharmacologic and nonpharmacologic treatment options for IBS. 3. Implement patient-specific methods for managing IBS symptoms and improving function and quality of life.

Faculty

Brooks D. Cash, MD Professor of Medicine University of South Alabama Mobile, Alabama

Brooks D. Cash, MD, is a professor of medicine at the University of South Alabama (USA) in Mobile, Alabama, where he has held a faculty position since 2013. He previously was a professor of medicine at the Uniformed Services University of the Health Sciences in Bethesda, Maryland. He currently serves as the director of the Motility and Physiology Service at the USA Digestive Health Center. Prior to his relocation to USA, Dr Cash served in the United States Navy for 24 years, retiring in 2013 at the rank of Captain as the Deputy Commander for Medicine at Walter Reed National Military Medical Center, Bethesda, Maryland. Dr Cash received his undergraduate degree in business administration (finance) with honors from The University of Texas at Austin. He earned his medical degree from the Uniformed Services University of Health Sciences and completed his internship, residency, and gastroenterology fellowship at the National Naval Medical Center, also in Bethesda. Dr Cash is a diplomate of the American Board of Gastroenterology. He is a fellow of the American College of Physicians, American College of Gastroenterology (ACG), American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy. Dr Cash serves on the Rome Foundation Committee for Functional Gastrointestinal Disorders and has authored multiple articles and book chapters on a variety of gastrointestinal topics, including irritable bowel syndrome and chronic constipation, colorectal cancer screening, CT colonography, acid peptic disorders, Barrett esophagus, and evidence-based medicine. He serves as an associate editor for The American Journal of Gastroenterology and is an editorial board member and reviewer for numerous internal medicine and gastroenterology medical journals. Dr Cash most recently served as the Governor of ACG’s Military Region.

Session 2

Brian Lacy, PhD, MD Professor of Medicine Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire

Brian E. Lacy, PhD, MD, is professor of medicine at the Geisel School of Medicine at Dartmouth, section chief of the Division of Gastroenterology and Hepatology, and director of the GI Motility Laboratory at the Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire. He received his doctorate in cell biology from Georgetown University in Washington, DC, and his medical degree from the University of Maryland in Baltimore, Maryland. Dr Lacy was a resident in internal medicine at the Dartmouth-Hitchcock Medical Center, where he continued his training as chief resident and then as a fellow in Gastroenterology. He is board certified in Gastroenterology. Dr Lacy's clinical and basic science research interests focus on disorders of gastrointestinal motility, with an emphasis on irritable bowel syndrome, dyspepsia, gastroparesis, acid reflux disease, constipation, intestinal pseudo-obstruction, achalasia, and visceral pain. He is the author or co-author of more than 85 peer-reviewed articles and the author or co-author of numerous textbook chapters on gastrointestinal motility disorders and functional bowel disorders. Dr Lacy is a reviewer for a number of scientific journals, and is a member of the American College of Gastroenterology, the American Gastroenterological Association, the American Neurogastroenterology and Motility Society, and the Rome Committee. Dr Lacy co-authored Healing Heartburn and is the author of Making Sense of IBS: A Physician Answers Your Questions about Irritable Bowel Syndrome, both books for the general public, the first regarding acid reflux disease and the second discussing irritable bowel syndrome. He is the editor and author of 2 books for health care providers titled Curbside Consultation in IBS: 49 Clinical Questions and Functional and Motility Disorders of the Gastrointestinal Tract: A Case Study Approach. Dr Lacy serves as editor-in-chief of the journal Clinical and Translational Gastroenterology. Faculty Financial Disclosure Statements The presenting faculty reports the following: Dr Cash receives Consulting fees from Zx Pharma; Medical Advisory Board fees from Forest, Ironwood, Paion, Salix, and Takeda; Speakers Bureau honorarium from Forest, Ironwood, Salix, and Takeda.

Dr Lacy receives Medical Advisory Board fees from Forest, Furiex, Ironwood, and Salix

Education Partner Financial Disclosure Statement The content collaborators at Miller Medical Communications, LLC, report the following: Lyerka D. Miller, PhD, has no financial relationships to disclose.

Session 2

Suggested Reading List American College of Gastroenterology Task Force on Irritable Bowel Syndrome, Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol. 2009;104 suppl 1:S1-S35. Canavan C, West J, Card T. The epidemiology of irritable bowel syndrome. Clin Epidemiol. 2014;6:71-80. Chey WD, Maneerattaporn M, Saad R. Pharmacologic and complementary and alternative medicine therapies for irritable bowel syndrome. Gut Liver. 2011;5(3):253-266. Drossman DA, Morris CB, Schneck S, et al. International survey of patients with IBS: symptom features and their severity, health status, treatments, and risk taking to achieve clinical benefit. J Clin Gastroenterol. 2009;43(6):541-550. Engsbro AL, Begtrup LM, Kjeldsen J, et al. Patients suspected of irritable bowel syndrome—cross-sectional study exploring the sensitivity of Rome III criteria in primary care. Am J Gastroenterol. 2013;108(6):972-980. Harkness EF, Harrington V, Hinder S, et al. GP perspectives of irritable bowel syndrome—an accepted illness, but management deviates from guidelines: a qualitative study. BMC Fam Pract. 2013;14:92. Jarrett ME, Cain KC, Burr RL, Hertig VL, Rosen SN, Heitkemper MM. Comprehensive self-management for irritable bowel syndrome: randomized trial of in-person vs. combined in-person and telephone sessions. Am J Gastroenterol. 2009;104(12):3004-3014. Jellema P, van der Windt DA, Schellevis FG, van der Horst HE. Systemic review: accuracy of symptom-based criteria for diagnosis of irritable bowel syndrome in primary care. Aliment Pharmacol Ther. 2009;30(7):695-706. Ladabaum U, Boyd E, Zhao WK, et al. Diagnosis, cormorbidities, and management of irritable bowel syndrome in patients in a large health maintenance organization. Clin Gastroenterol Hepatol. 2012;10(1):37-45. Lee V, Guthrie E, Robinson A, et al. Functional bowel disorders in primary care: factors associated with health-related quality of life and doctor consultation. J Psychosom Res. 2008;64(2):129-138. Lembo AJ, Conboy L, Kelley JM, et al. A treatment trial of acupuncture in IBS patients. Am J Gastroenterol. 2009;104(6):1489-1497. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology. 2006;130(5):1480-1491. MacPherson H, Tilbrook H, Bland JM, et al. Acupuncture for irritable bowel syndrome: primary care based pragmatic randomised controlled trial. BMC Gastroenterol. 2012;12:150. McKenzie YA, Alder A, Anderson W, et al. British Dietetic Association evidence-based guidelines for the dietary management of irritable bowel syndrome in adults. J Hum Nutr Diet. 2012;25(3):260-274. National Institute for Health and Care Excellence (NICE). Irritable bowel syndrome in adults: diagnosis and management of irritable bowel syndrome in primary care. February 2008;CG61. Rao S, Lembo AJ, Shiff SJ, et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 2012;107(11):1714-1724. Spiegel BMR, Farid M, Esrailian E, Talley J, Chang L. Is irritable bowel syndrome a diagnosis of exclusion? A survey of primary care providers, gastroenterologists, and IBS experts. Am J Gastroenterol. 2010;105(4):848-858. Wilkins T, Pepitone C, Alex B, Schade RR. Diagnosis and management of IBS in adults. Am Fam Physician. 2012;86(5):419-426. Yoon SL, Grundmann O, Koepp L, Farrell L. Management of irritable bowel syndrome (IBS) in adults: conventional and complementary/alternative approaches. Altern Med Rev. 2011;16(2):134-151.

9:15 – 10:30am

Optimizing the Diagnosis, Treatment, and Management of Irritable Bowel Syndrome

SPEAKERSBrooks D. Cash, MD

Brian E. Lacy, PhD, MD

Presenter Disclosure Information

Off-Label/Investigational Discussion

► In accordance with pmiCME policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.

The following relationships exist related to this presentation:

►Dr. Cash receives Consulting fees from Zx Pharma; Medical Advisory Board fees from Forest, Ironwood, Paion, Salix, and Takeda; Speakers Bureau honorarium from Forest, Ironwood, Salix, and Takeda.

►Dr. Lacy receives Medical Advisory Board fees from Forest, Furiex, Ironwood, and Salix

Learning Objectives

After participating in this educational activity the participant should be able to:

• Diagnose IBS and differentiate from other bowel disorders using established clinical guidelines

• Summarize the efficacy and safety of pharmacologic and nonpharmacologic treatment options for IBS

• Implement patient-specific methods for managing IBS symptoms and improving function and quality of life

Generic Name Trade Name

Alosetron Lotronex

Amitriptyline Elavil, Endep, Vanatrip

Cholestyramine Cholestyramine Light, Prevalite, Questran, Questran Light

Citalopram CeleXA

Desipramine Norpramin

Dicyclomine Bentyl

Diphenoxylate‐atropine Lomotil

Doxepin Adapin, Silenor, Sinequan

Elobixibat Elobixibat

Eluxadoline Eluxadoline

Fluoxetine Prozac, Sarafem

Hyoscyamine Anaspaz, Cystospaz, Donnamar, Levsin

Imipramine Tofranil, Tofranil‐PM

Generic Name Trade Name

Ispaghula Fybogel, Ispagel

Linaclotide Linzess

Loperamide Imodium, Imodium A‐D, Kaopectate II, Maalox Anti‐Diarrheal Caplets, Pepto Diarrhea Control

Lubiprostone Amitiza

Mesalamine/Mesalazine Apriso, Asacol, Lialda, Pentasa

PEG 3350+E Colyte, GaviLyte‐C, GolytelyGlycoLax,MiraLax

Paroxetine Paxil, Paxil CR, Pexeva

Plecanatide Plecanatide

Prucalopride Resolor

Psyllium Konsyl, Metamucil, Reguloid

Rifaximin Xifaxan

Brooks D. Cash, MDProfessor of MedicineUniversity of South AlabamaMobile, Alabama

Worldwide prevalence: 7% to 10%

1.5 times more prevalent in women

More commonly diagnosed in patients <50 years of age

More common in lower socioeconomic groups

Patients with IBS have more physician visits, hospitalizations, missed workdays, prescriptions, and diagnostic tests than those without

IBS=irritable bowel syndrome.

American College of Gastroenterology Task Force on Irritable Bowel Syndrome; Brandt LJ et al. Am J Gastroenterol. 2009;104 suppl 1:S1‐S35.

Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis

Onset associated with a change in frequency of

stool

Onset associated with a change in form of stool

Recurrent abdominal pain or discomfortat least 3 days/month in the last 3 months

associated with ≥2 of the following:

Improvement with defecation

Additional IBS “testing,” including routine laboratory tests and colonoscopy, unnecessary unless alarm features present

American College of Gastroenterology Task Force on Irritable Bowel Syndrome; Brandt LJ et al. Am J Gastroenterol.2009;104 suppl 1:S1‐S35.

IBS-C IBS-M

IBS-U IBS-D

100

75

50

25

0

0 25 50 75 100

Loose or watery stools (%)

Hard or Lumpy Sto

ols (%)

IBS‐C: Constipation‐predominant IBS

IBS‐D: Diarrhea‐predominant IBS

IBS‐M: Mixed IBS (hard and loose stools over periods of weeks and months)

IBS‐U: Unsubtyped IBS

LongstrethGF et al. Gastroenterology. 2006;130(5):1480‐1491; Erratum in: Gastroenterology. 2006;131(2):688.

Abdominal pain – 29% state this is the predominant symptom

Misinformation 15% believe IBS will turn into cancer 30% believe IBS increases risk for IBD 17% believe IBS will lead to malnutrition

Lack of information Prevalent physician belief IBS due to anxiety (80.5%) or

depression (63.2%) Only 2/3 of patients recognize that IBS does not shorten

life expectancy

LemboT et al. Am J Gastroenterol. 1999;94(5):1320–1326. ; Lacy et al. Am J Gastroenterol. 2005;100(s9):S324; Noddin et al. Am J Gastroenterol. 2005;100(s9):S323; Lee et al. Am J Gastroenterol. 2005;100(s9):S336.

IBD=inflammatory bowel disease.

35‐year‐old woman presents with a 2‐year history of constipation alternating with diarrhea

She reports generalized abdominal pain on days with diarrhea pain is relieved with bowel movements

Denies rectal bleeding, nocturnal symptoms, weight loss, family history of organic gastrointestinal diseases

She also suffers from migraine headaches

Employed as an elementary school teacher Her GI symptoms have caused her to call in sick 3 times over the past 6 months

She has tried over‐the‐counter laxatives, antidiarrheal agents, and probiotics without success

Her physical examination is unremarkable

GI=gastrointestinal.

Enteric nervous system dysfunction Gastrointestinal

dysmotility Visceral hypersensitivity

Disordered CNS pain processing

Post‐infectious

Small intestinal bacterial overgrowth Dysbiosis

Food intolerance

Genetics

Mast cell dysfunction

Somatization

CNS=central nervous system.

HaslerWL. Gastroenterol Clin North Am. 2011;40(1):21‐43; Ford AC, Talley NJ. Nat Rev Gastroenterol Hepatol. 2011;8(2):76‐ 78.

Gastrointestinal

Colorectal cancer

Diverticular disease

Gynecologic

Ovarian cancer Endometriosis

Drugs

Opiates

Anticholinergics

Antidepressants

Metabolic/Endocrine

Hypothyroidism

Diabetes

Neurologic

Parkinson disease

Multiple sclerosis

Autonomic neuropathy

Other

Amyloidosis

Scleroderma

Candelli M et al. Hepatogastroenterology. 2001;48(40):1050‐1057; Locke GR 3rd et al. Gastroenterology. 2000;119(6):1766‐1778.

Dietary factors

Lactose Gluten Other FODMAPs

Drugs

Infection

Giardiasis Amebiasis C difficile

Malabsorption

Celiac disease

Inflammatory bowel disease

Crohn’s disease Ulcerative colitis Microscopic colitis

Psychological

Panic disorder Somatization Depression

FODMAPs=fermentable oligosaccharides, disaccharides, monosaccharides, and polyols.

Candelli M et al. Hepatogastroenterology. 2001;48(40):1050‐1057; Locke GR 3rd et al. Gastroenterology. 2000;119(6):1766‐1778.

IBS is a syndrome—a collection of symptoms

Diagnosis possible via a thorough history of symptoms and physical examination

Because symptoms are non‐specific, must consider alternative organic diagnoses

Serious organic illnesses typically produce alarm symptoms (eg, bleeding, weight loss, etc)

302 Danish patients aged 18‐50 years referred from primary care. No alarm features. Randomized to:

▪ Exclusionary strategy: Blood work, stool samples, lower endoscopy with biopsy

▪ Positive strategy: CBC and CRP only

Followed for 1 year

No difference in any outcome measure (symptoms, HRQL, use of health care resources, etc)

No cases of IBD, CRC, or celiac disease identified

Exclusionary strategy more expensive▪ Direct costs: $863 greater▪ Mean total costs: $1915 greater

Begtrup LM et al. ClinGastroenterol Hepatol. 2013;11(8):956‐962.

CBC=complete blood count; CRC=colorectal cancer; CRP=C‐reactive protein; HRQL=health‐related quality of life.

8

72

Co

nsi

der

IB

S a

Dia

gn

osi

s o

f E

xclu

sio

n,

%

IBS Experts(n=27)

Community Clinicians(n=281)

Clinicians who believed IBS was a diagnosis of exclusion ordered 1.6 times more tests and spent $364more on diagnostic tests per patient (P<.0001)

Spiegel BM et al. Am J Gastroenterol. 2010;105(4):848‐858.

Histologic Findings in IBS Patients and Controls;Populations Not Matched for Age or Sex

LesionIBS Patients

n=466 (%)

Controlsn=451 (%)

P Value

Adenomas 36 (7.7) 118 (26.1) <.0001

Hyperplastic polyps 39 (8.4) 52 (11.5) NS

Cloorectal adenocarcinoma 0 (0.0) 1 (0.2) NS

IBD 2 (0.4) 0 (0.0) NS

Microscopic colitis 7 (1.5) N/A N/A

Microscopic colitis was more common in a subset of patients with IBS‐D who were ≥45 years (2.3%).

N/A, not applicable; NS=not significant.

CheyWD et al. Am J Gastroenterol. 2010;105(4):859‐865.

There is a paucity of evidence guiding radiologic imaging in IBS

Imaging study should be influenced by predominant symptoms

Data suggest very low yield of CT and U/S

Definitive recommendations must await further research

O’Connor OJ et al. Radiology. 2012;262(2):485‐494.

U/S=ultrasonography.

Up to 10% of chronic idiopathic abdominal pain Entrapment of anterior cutaneous branch of thoracic intercostal nerve

Sharply localized pain and superficial tenderness + Carnett sign: accentuated localized tenderness with abdominal wall tensing

Reassurance and avoidance of precipitating causes often sufficient

Anesthetic/corticosteroid injection effective in ≈ 75%▪ Also serves as diagnostic confirmation

Srinivassan R, et al. Am J Gastroenterol. 2002;3(4):824‐30.

1% of the adult population; 25% of those diagnosed with IBS‐D

Tests that directly assess bile acid malabsorption (SeHCAT, 14C‐glycocholate breath tests, serum C4, fecal bile acids) either not available in United States or not validated

Therapeutic trial only option Bile acid sequestrants

Vijayvargiya P et al. ClinGastroenterol Hepatol. 2013;11(10):1232‐1239.

SeHCAT= 75selenium homotaurocholic acid test.

Crohn’s disease, ulcerative colitis, undifferentiated IBD

IBS symptoms ARE common in IBD patients in “remission”

35% overall; higher in Crohn’s disease

Opinion divided as to what they mean

Unrecognized [latent] IBD

Real or coincident IBS; linked to psychosocial issues

Halpin SJ, et al. Am J Gastroenterol. 2012;107(10):1474‐1482.Keohane J et al. Am J Gastroenterol. 2010;105(8):1789‐1794. Quigley EM, et al. Am J Gastroenterol. 2012;107(10):1483‐1485. Vivinus‐NébotM et al. Gut. 2014;63(5):744‐752.Jonefjäll B et al. Neurogastroenterol Motil. 2013;25(9):756‐e578 Berrill JW et al. Aliment PharmacolTher. 2013;38(1):44‐51.

“Post‐diverticulitis IBS” 2204 subjects at Los Angeles Veterans Administration medical center

who had an episode of diverticulitis and followed for 6.3 years▪ Almost 5 times more likely to be diagnosed with IBS later

Symptomatic uncomplicated diverticular disease (SUDD) 229 treated with mesalazine ± L casei vs L casei alone vs placebo for 10

days per month for 12 months▪ Higher remission rates in treatment groups▪ Symptomatic diverticulitis in 6 on placebo and 1 in probiotic group

345 patients with uncomplicated diverticulitis

Mesalamine 3 g daily vs placebo for 48 weeks % recurrence‐free at 48 weeks: 68% mesalamine, 74% placebo

Cohen E et al. ClinGastroenterol Hepatol. 2013;11(12):1614‐1619.TursiA. et al. DDW 2013. KruisW. et al. DDW 2013

General Practice Research Database in the United Kingdom Celiac patients were 3 times more likely to have a prior

diagnosis of IBS, even for 10 years previously

38% of celiac disease patients have IBS symptoms; especially if non‐adherent with gluten free diet

Should you screen for celiac disease? YES

Mohseninejad L et al. Eur J Health Econ. 2013;14(6):947‐957.

NOCash BD et al. Gastroenterology. 2011;141(4):1187‐1193.

Card TR et al. Scand J Gastroenterol. 2013;48(7):801‐807. Sainsbury A et al. ClinGastroenterol Hepatol. 2013;11(4):359‐365.

IBS patients (physician diagnosis)Positive for both tTGA and EMACeliac disease not biopsy‐proven

Non‐constipated IBS patients (Rome II)Biopsy‐proven celiac disease

Case‐Control Study Prospective Study

0.5

1

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Patients w

ith celiac

disease (%)

0.4 0.4

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Patients w

ith celiac

disease (%)

N=566N=555

Controls IBS Patients

Saito‐Loftus Y, et al. Am J Gastroenterol. 2008;103(suppl 1):S472. Abstract 1208; Cash BD et al. Gastroenterology. 2011;141(4):1187‐1193.

N=492N=458

Controls IBS Patients

P=NS P=NS

Prospective study: 7.3% IBS and 4.8% controls had at least 1 abnormal gluten‐directed serology (most often IgG AGA)

Adapted from Verdu EF et al. Am J Gastroenterol. 2009;104(6):):1587‐1594.

CD=celiac disease.

IBS symptoms Spectrum of CD

Is it IBS, Celiac Disease or Something in Between?

Motility / visceral sensationBrain – gut interactionsImmune activationAltered gut microbiome

Potential / asymptomatic CD

Symptomatic CD

Non‐celiac glutenor

wheat sensitivity

Routine laboratory tests: CBC, CMP, TSH, stool O&P, abdominal imaging not recommended

Serologic testing for celiac disease (IBS‐D/M)

strongly consider

Lactose breath testing selected cases

Colonoscopy recommended if ≥50 years of age, with biopsies in refractory IBS‐D (to exclude microscopic colitis)

ACG=American College of Gastroenterology; CMP=Comprehensive Metabolic Panel; TSH=thyroid‐stimulating hormone.

American College of Gastroenterology Task Force on Irritable Bowel Syndrome; Brandt LJ et al. Am J Gastroenterol. 2009;104 suppl 1:S1‐S35.

Refractory or worsening abdominalsymptoms

Older patient (≥50 years of age;≥45 years of age if black) at onset

Blood in stools (hematochezia)

Anemia

Weight loss (unintentional)

Anorexia

Family history of organic GI disease

Further investigation warranted

Lembo A, Camilleri M. N Engl J Med. 2003;349(14):1360‐1368; Brandt LJ et al. Am J Gastroenterol. 2005;100 suppl 1:S5‐S21; Cash BD et al. Rev Gastroenterol Disord. 2007;7(3):116‐133.

Only 1% to 9% with IBS diagnosed with an alternative organic GI disorder after 30 years of follow‐up

Long‐term follow‐up: 2% to 18% worse, 30% to 50% of patients unchanged

Prior surgery (1 study), higher somatic scores (1 study), higher baseline anxiety (2 studies), depression (1 study) predicted worse symptoms during long‐term follow‐up

Short duration and constipation: better outcome

El‐Serag HB et al. Aliment PharmacolTher. 2004;19(8):861‐870.

Identify IBS symptoms, presence of alarm features

Meets criteria, no alarm features make diagnosis of IBS

Does not meet criteria, has alarm features look for alternative diagnosis

Symptomatic treatment for predominant symptoms

Assess response to treatment

Good response continue Rx Poor response reassess

LongstrethGF et al. Gastroenterology. 2006;130(5):1480‐1491; Erratum in: Gastroenterology. 2006;131(2):688; American College of Gastroenterology Task Force on Irritable Bowel Syndrome; Brandt LJ et al. Am J Gastroenterol. 2009;104 suppl 1:S1‐S35.

Poor response reassess

Brian E. Lacy, PhD, MDProfessor of MedicineGeisel School of Medicine at DartmouthChief, Section of Gastroenterology & HepatologyDartmouth‐Hitchcock Medical CenterLebanon, New Hampshire

EM, a 33‐year‐old woman, presents with an 8‐year history of abdominal pain and altered bowel habits Crampy left lower quadrant pain

Pain peaks just before bowel movement

Pain is relieved by defecation

Bowel movements are frequently urgent and vary in consistency from loose to semi‐formed

Frequency of bowel movements varies from once daily to 4 times per day

Other symptoms: occasional episodes of reflux and bloating

Weight has remained stable; no history of anemia or rectal bleeding

Previous evaluation included colonoscopy with biopsies (negative), endoscopy with biopsies (negative), and abdominal sonogram (negative)

Patient has tried lactose‐free diet, increased dietary fiber, dicyclomine, and hyoscyamine, all without benefit

Physical examination is unremarkable

They want you to listen

Understand their history (symptoms, work, home)

Education about their condition

Address questions or concerns Address uncertainty of IBS

Reassurance

A positive diagnosis

Review results with patients

Symptom improvement

Diet, lifestyle advice

Positive diagnosis

Explain, reassure

Follow-up visit

Manage stress

Drug therapy

+

Psychological treatments

Goal: improved function

Continuing care +

Mild

(40%)

Moderate

(35%)

Severe

(25%)

Abdominal pain/Discomfort Antispasmodics* Antidepressants*

TCAs/SSRIs Alosetron

(5HT‐3 antagonist)

Abdominalpain/

Discomfort

Bloating/Distension

Altered bowelfunction

Constipation Fiber* MOM/PEG solution* Lubiprostone (chloride

channel activator) Linaclotide (guanylate

cyclase‐C agonist)

Diarrhea Loperamide* Diphenoxylate‐

atropine* Cholestyramine* Alosetron Rifaximin*

Bloating

Rifaximin* Probiotics

*These agents are not currently FDA approved for IBS.

Ford AC et al; Task Force on the Management of Functional Bowel Disorders. Am J Gastroenterol. 2014;109 suppl 1:S2‐S26.

Diet

Antidiarrheal agents

Probiotics

Antibiotics

Smooth muscle antispasmodics

5‐HT3 antagonists

Antidepressants (TCAs and SSRIs)

Low carbohydrate

Low fructose/fructan

Low gluten

Low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyol)

R, DB, PC, rechallenge study

34 IBS patients (Rome III); celiac excluded

Prior improvement in Sx on gluten‐free diet

16 g of nonfermentable gluten/d vs 16 g of gluten

Primary end point: adequate symptom relief

Gluten‐group had less improvement in Sx than those on gluten‐free (68% vs 40%; P=.001)

Biesiekierski JR et al. Am J Gastroenterol. 2011;106(3):508‐514.

Fermentable Oligo‐, Di‐, Monosaccharides And Polyols

Shepherd SJ, Gibson PR. J Am Diet Assoc. 2006;106(10):1631‐1639; Shepherd SJ et al. Clin Gastroenterol Hepatol. 2008;6(7):765‐771;Gibson PR, Shepherd SJ. J Gastroenterol Hepatol. 2010;25(2):252‐258.

Excess Fructose

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

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

SorbitolApricots, peaches, artificial sweeteners, artificially sweetened gums

RaffinoseLentils, cabbage, Brussels sprouts, asparagus, green beans, legumes

Lean proteins

Gluten‐free breads, rolls, pasta

Rice, corn, oat products

Quinoa

Safe fruits and vegetables: Snow peas, bok choy, mandarin oranges

82 consecutive IBS patients (NICE criteria)

Detailed symptom and dietary evaluation

9‐month evaluation – performed in United Kingdom

Individual symptoms and global IBS symptoms measured

39 in the standard diet group

42 in the low‐FODMAP diet group

Staudacher HM et al. J Hum Nutr Diet. 2011;24(5):487‐495.

NICE=National Institute for Health and Care Excellence.

0

10

20

30

40

50

60

70

80

90

100

Patients W

ith Improve

d

Sympto

m Resp

onse

, %

Standard Diet

Low FODMAP Diet** † †

††

*P≤.001† P<.05

Staudacher HM et al. J Hum Nutr Diet. 2011;24(5):487‐495.

What is the cut‐off for FODMAP content?

Resources differ on low‐FODMAP diets

Total meal FODMAPs should be counted, \not individual FODMAP

Low doses 2 mg once or twice daily may be effective to decrease stool frequency, improve stool consistency

2 randomized controlled trials in IBS (N=42) show efficacy for diarrhea

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

Adverse Effects: dizziness, abdominal pain/bloat, constipation, dry mouth, fatigue


Lactobacilli – anaerobic, gram (+) rods casei plantarum acidophilus reuteri

Bifidobacteria – anaerobic, gram (+) rods

VSL #3 (8 separate organisms: 3 bifidobacteria, 1 Streptococcus, 4 lactobacilli)

Enterococcus

Streptococcus salivarius

Saccharomyces

Moayyedi P et al. Gut. 2010:59(3):325‐332.

Competitive inhibition

Barrier protection

Immune effects

Anti‐inflammatory effects

Production of various substances (enzymes, SCFA, bactericidal agents)

Ability to alter local pH and physiology

Provides nutrition to colonocytes

SCFA=short‐chain fatty acid.

Camilleri M. J Clin Gastroenterol. 2006;40(3):264‐269.

SGA: (Subjective Global Assessment) a Yes/No response to the following question:

“Please consider how you felt in the past week in regard to 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?”

80

70

60

50

40

30

PlaceboB infantis1 x 106

B infantis1 x 108

B infantis1 x 1010

Answ

ering “Yes” at Week

4 (%)

P=.0118

20

Whorwell PJ et al. Am J Gastroenterol. 2006;101(7):1581‐1590.

Gut‐directed antibiotic

Not systemically absorbed

Doses studied for IBS: 400 mg bid to 550 mg tid

Generally well tolerated

Adverse effects include headache, abdominal pain, and upper respiratory tract infection

*Rifaximin is not currently FDA approved for IBS.

Ford AC,et al. Clin Gastroenterol Hepatol. 2009;7(12):1279‐1286; Pimentel M et al; TARGET Study Group. N Engl J Med.2011;364(1):22‐32.

Two phase 3 randomized controlled trials; N=1260 patients

Rifaximin 550 mg tidx 2 weeks; patients followed additional 10 weeks

40.7% vs 31.7% with adequate relief of global symptoms (P<.001) 0

5

10

15

20

25

30

35

40

45

T‐I T‐II Comb

Rifaximin

Placebo

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; TARGET Study Group. N Engl J Med.2011;364(1):22‐32.

23 randomized controlled trials comparing 12 different antispasmodics vs placebo (N=2154 patients)

Significant heterogeneity among studies

Only 2 agents available in United States Hyoscyamine and dicyclomine

Appear most useful for abdominal pain

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)

NNT=5CI=confidence interval; NNT=number needed to treat; RR=relative risk.


Study NFemale,

%Response:

Alosetron, %Response: Placebo, %

Therapeutic Gain, %

Camilleri1 370 53 60 33 27

Camilleri2 647 100 41 29 12

Camilleri3 626 100 43 26 17

Lembo4 801 100 73 57 16

Jones5* 623 100 58 48 10

*Comparison mebeverine† instead of placebo.

†Mebeverine not available in the United States.

1. Camilleri M et al. Aliment Pharmacol Ther. 1999;13(9):1149‐1159. 2. Camilleri M et al. Lancet. 2000;355(9209): 1035‐1040. 3. Camilleri M et al. Arch Intern Med. 2001;161(14):1733‐1740. 4. LemboT et al; Lotronex Investigator Team. Am J Gastroenterol. 2001;96(9):2662‐2670. 5. Jones RH et al. Aliment Pharmacol Ther. 1999;13(11):1419‐1427.

Female patients with chronic, severe IBS‐D who failed other treatments Dose: 0.5‐1.0 mg qd to bid

Patient education regarding possible serious adverse effects of severe constipation or ischemic colitis 0.95 cases of ischemic colitis/1000 patient‐years 0.36 cases of severe constipation/1000 patient‐years

If ischemic colitis occurs, it is usually within the first month of therapy

Prescribing program mandated by FDA Requires patient to sign attestation form

BID, twice a day; QD, once a day.

TCAs: 11 studies (N=416 drug vs 328 placebo) Imipramine, desipramine, amitriptyline, doxepin*; doses

10‐150 mg Meta‐analysis favors treatment: NNT=4

SSRIs: 7 studies (N=176 drug vs 180 control) Fluoxetine, paroxetine, citalopram*; dose 10‐40 mg Meta‐analysis favors treatment: NNT=4 Meta‐analysis favors treatment

*These agents are not currently FDA approved for IBS.

TCAs have more analgesic properties and SSRI efficacy is most likely in patients with significant anxiety/depression.


MH is a 40‐year‐old woman with a 6‐year history of constipation symptoms sent for a second opinion

She describes hard stool with straining and feelings of incomplete evacuation

She has lower abdominal pain, which transiently improves after having a bowel movement

Symptoms are present more days than not

She frequently feels bloated and describes herself as looking “5 months pregnant”

She is not anemic; her weight has been stable

All: none

Medications: OC

PMH: migraine HA; interstitial cystitis

PSH: appendectomy as a child

PE: BMI = 26; mild tenderness in left lower quadrant; otherwise normal

Question: What’s the diagnosis and what treatment options are available?

BMI=body mass index; HA=headache; OTC=over‐the‐counter; PE=physical examination; PMH=past medical history; PSH=past surgical history.

Diet

Bulking agents

Probiotics

Osmotic agents

Secretagogues Chloride channel activators (lubiprostone) Guanylate cyclase activators (linaclotide)

CAM

CAM=complementary and alternative medicines.

Randomized, placebo‐controlled trial (N=275 patients with IBS; 53%‐58% were IBS‐C)

Psyllium (10 gm) vs bran (10 gm) vs placebo

Primary End Point: adequate symptom relief ≥2 weeks in previous month, analyzed after 1, 2, and 3 months

RESULTS

Higher % responders in psyllium vs placebo group during first month (57% vs 35%)

Higher % responders through 2 months of treatment (59% vs 41%), but no difference at 3 months

High dropout rate in the bran group because of worsening of IBS

No significant improvement was noted in measurement of abdominal pain relief

BijkerkCJ et al. BMJ. 2009;339:3154‐3160.

RCTs NResponse*

Fiber Placebo

RR of Unimproved Symptoms(95% CI)

NNT(95%CI)

Overall 14 906 48% 43% 0.87 (0.76‐1.0) 11 (5‐100)

Ispaghula 6 321 48% 36% 0.78 (0.63‐0.96) 6 (3‐50)

Bran 5 221 46% 46% 1.02 (0.82‐1.27)

*Improved or resolved symptoms.

Insoluble fiber was not more effective and sometimes worsened symptoms

Soluble fiber improved global symptoms

4 out of 5 bran studies of poor qualityRCTs=randomized controlled trials.


Resp

onders

Abdominal Disco

mfort

(FDDQL), %

65 63

48*

57

0

10

20

30

40

50

60

70

80

90

100

Week 3 Week 6

Probiotic (n=135)

Placebo (n=132)

*P=.003

Stool frequency increased in patients with <3 bowel movements/week

Probiotic: fermented milk product (Activia®) containing B animalis 1.25 x 1010 CFU per serving, Streptococcus thermophilus, and Lactobacillus bulgaricus

CFU=colony forming unit; FDDQL=Functional Digestive Disorders Quality of Life questionnaire..Guyonnet D et al. Aliment Pharmacol Ther. 2007;26(3):475‐486.

Prospective, multi‐center, R, DB, PC

Rome III criteria

139 patients (mean age=41 years; 83% women)

28=day study; 13.8 gm/sachet

1‐3 sachets/d vs placebo

Primary End Point: mean # of SBM/d

Results: at week 4, 4.4 SBM/wk vs 3.1 SBM/wk (PEG vs placebo; P<.0001)

SBM=spontaneous bowel movement.

Chapman RW et al. Am J Gastroenterol. 2013;108(9):1508‐1515.

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

# SBMs Pain Level

Mean at Week 4

Placebo (n=71)

PEG 3350+E(n=68)

PEG 3350+E is not approved for use in the United States.

Chapman RW et al. Am J Gastroenterol. 2013;108(9):1508‐1515.

*

*P<.0001

0%

2%

4%

6%

8%

10%

12%

14%

16%

Trial 1 Trial 2

Placebo

Lubiprostone

*

**

**P=.023*P=.029†Therapeutic gain = treatment response rate minus placebo response rate.

Trial 1=6.0%; Trial 2=6.4%.Lubiprostone is approved to treat IBS‐C in women.

Overall responders defined as subjects who were monthly responders for 2 out of any 3 months

Drossman DA et al. Aliment PharmacolTher. 2009 Feb1,29(3):329‐41

Mean SBM Frequency per Month

8

7

6

5

4

3

2

1

01 2 3 4 5 6 7 8 9 10 11 12 13

Baseline

Phase 3Studies

RandomizedWithdrawal/Extension Studies

Month of Treatment

Abdominal Pain/Discomfort

‐0.25

Month of Treatment

‐0.50

‐0.75

‐1.00

‐1.25

‐1.50

Change From Base

line

P/L Group(n=179)

L/P/L Group(n=80)

L/L Group(n=261)

N=520 IBS‐C patients who completed 12 or 16 weeks of a placebo‐controlled phase 3 trial;patients enrolled in the extension study all received lubiprostone 8 µg bid.CheyWD et al. Aliment Pharmacol Ther. 2012;35(5):587‐599.

1 2 3 4 5 6 7 8 9 10 11 12 13

Summary of SBM Frequency

CSBM M

ean Change

From

Base

line +/‐SEM

3

2

1

0

Weeks

BL 1 2 3 4 5 6 7 8 9 10 11 12

Treatment Period*

Treatment PeriodPlaceboLinaclotide 290 µg

13 14 15 16

RW Period†

RW Treatment SequencePlacebo/Linaclotide 290 µgLinaclotide 290 µg/Linaclotide 290 µgLinaclotide 290 µg/Placebo

z

Weeks

N=800

*P<.0001 for linaclotide patients vs placebo patients (ANCOVA).†P<.001 for linaclotide/linaclotide patients vs linaclotide/placebo patients (ANCOVA).

ANCOVA=analysis of covariance; RW=randomized withdrawal.

Rao S et al. Am J Gastroenterol. 2012;107(11):1714‐1724.

ITT population, observed cases, LS‐mean presented: P‐values based on ANCOVA at each week. Bars represent 95% CI.

P=.0007 for week 1P<.0001 for weeks 2-26

Change in W

orst

Abdominal Pain, %

‐60

‐50

‐40

‐30

‐20

‐10

0

Trial Week

BL 2 4 6 8 10 12 14 16 18 20 22 24 26

Linaclotide 290 µg Placebo

N=804

ITT=intention to treat; LS=least squares.

CheyWD et al. Aliment Pharmacol Ther. 2012;35(5):587‐599.

RR NNTTrials N 95% CI 95% CI

Cognitive behavior 9 610 0.60 3therapy 0.44‐0.83 2‐6

Relaxation 6 255 0.77

training 0.57‐1.04

Dynamic 2 273 0.60 3.5psychotherapy 0.39‐00.93 2‐25

Hypnotherapy 5 278 0.74 40.63‐0.87 3‐8

Ford AC et al. Am J Gastroenterol. 2014;109(9):1350‐1365.

Eluxadoline (for IBS‐D)

Elobixibat (for IBS‐C)

Plecanatide (for IBS‐C)

Prucalopride (for IBS‐C)

FMT – fecal microbiota transplant

Every patient is different

Identify the predominant symptom

“Curing” is not possible – set expectations

Fiber is not a magical cure for all IBS patients

Dietary interventions may help – but use an evidence‐based approach

Consider medications that improve global symptoms – this may reduce polypharmacy

optimizing the diagnosis, treatment, and management … files/spring 2015 syllabus... · optimizing...

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