Session 3: The Fast Track: Improving the Management of Chronic Constipation and IBS-C in the Primary Care Setting

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2 Session 3: The Fast Track: Improving the Management of Chronic Constipation and IBS-C in the Primary Care Setting Learning Objectives List the criteria for the diagnosis of chronic constipation and irritable bowel syndrome-constipation (IBS-C) to recognize symptom differences in their presentation to make an improved and accurate diagnosis of patients who suffer from these conditions. Describe evidence-based management strategies for individuals, including special populations (women, elderly) with chronic constipation and IBS-C to resolve gastrointestinal symptoms and improve patient outcomes. Faculty Brian E. Lacy, PhD, MD Associate Professor of Medicine Dartmouth Medical School Director, GI, Motility Laboratory Dartmouth Hitchcock Medical Center Lebanon, New Hampshire Dr Lacy is currently an associate professor of medicine at Dartmouth Medical School and director of the GI Motility Laboratory at the Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire. Dr Lacy s clinical and basic science research interests focus on disorders of gastrointestinal motility, with an emphasis on irritable bowel syndrome, achalasia, dyspepsia, gastroparesis, acid reflux disease, constipation, intestinal pseudoobstruction, and visceral pain. He is the author of numerous articles and 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 a number of different scientific organizations, including the American College of Gastroenterology, the American Gastroenterology Association, the American Motility Society, and the Functional Brain-Gut Research Group. Dr Lacy is the coauthor of a book for the general public on acid reflux disease, Healing Heartburn, and is also the author of Making Sense of IBS, a book for the general public on irritable bowel syndrome. Dr Lacy received his doctorate in cell biology from Georgetown University in Washington, DC, and his medical degree from the University of Maryland in Baltimore. Dr Lacy was a resident in internal medicine at the Dartmouth-Hitchcock Medical Center, where he continued his training as chief resident and as a fellow in gastroenterology. He is board certified in both internal medicine and gastroenterology. Susan Lucak, MD Assistant Professor of Clinical Medicine Digestive and Liver Disease Columbia University Medical Center New York, New York Dr Lucak is an assistant professor of clinical medicine in the Division of Digestive and Liver Disease at Columbia University Medical Center, New York, New York. Her clinical interest is in functional bowel disorders, particularly irritable bowel syndrome (IBS). Her research efforts have focused on evaluating the clinical safety and efficacy of treatments for patients with IBS. Dr Lucak is a member of several professional organizations including the American Gastroenterological Association, the American College of Gastroenterology, the American Society for Gastrointestinal Endoscopy, the American College of Physicians, the Functional Brain Gut Research Group, and the International Foundation for Functional Gastrointestinal Disorders. Dr Lucak received her bachelor s degree in biology from Barnard College and her medical degree from the Albert Einstein College of Medicine, both in New York. Dr Lucak then went on to complete her clinical fellowship in gastroenterology at the Montefiore Medical Center in New York and her research fellowship under Dr Michael Field at Columbia-Presbyterian Medical Center. Session 3

3 Faculty Financial Disclosure Statement(s) The presenting faculty reported the following: Dr Lacy has a grant for research from Takeda Pharmaceuticals North America, Inc. Dr Lucak receives honoraria from Forest Laboratories, Inc.; Ironwood Pharmaceuticals; Novartis Pharmaceuticals Corporation; Prometheus Laboratories; Salix Pharmaceuticals, Inc.; Sucampo Pharmaceuticals, Inc.; and Takeda Pharmaceuticals North America, Inc.; and is a medical expert for Novartis Pharmaceuticals Corporation. Dr Lucak is also a speaker for Prometheus Laboratories; Sucampo Pharmaceuticals, Inc.; and Takeda Pharmaceuticals North America, Inc.; and receives consulting fees from Forest Laboratories, Inc.; Ironwood Pharmaceuticals; Prometheus Laboratories; Salix Pharmaceuticals, Inc.; Sucampo Pharmaceuticals, Inc.; and Takeda Pharmaceuticals North America, Inc. Education Partner Financial Disclosure Statement(s) The content collaborators at The Foundation for Better Health Care have reported the following: Annika Dronge, MD, has nothing to disclose. Judy Seraphine, executive vice president, has nothing to disclose. Sejal Patel, account manager, has nothing to disclose. Susan Duff, managing editor, has nothing to disclose. Drug List Generic lubiprostone psyllium methylcellulose polycarbophil docusate sodium senna/bisocodyl polyethylene glycol lactulose citalopram desipramine Trade Amitiza various Citrucel various various various various various Celexa Norpramin Generic magnesium hydroxide loperamide cholestyramine tegaserod dicyclomine alosetron rifaximin Trade Milk of Magnesia, Phillips Milk of Magnesia Anti-Diarrheal Formula, Imodium Prevalite, Questran, Cholybar, Locholest Zelnorm Bentyl Lotronex Xifaxan Acronym List EP BM CC IBS-C ACG education partner bowel movement chronic constipation irritable bowel syndromeconstipation American College of Gastroenterology GERD IBD PLA TCA SNRI ARM PEG gastroesophageal reflux disease inflammatory bowel disease placebo tricyclic antidepressant selective norepinephrine reuptake inhibitor anorectal manometry polyethylene glycol Suggested Reading List Pare P, Ferrazzi S, Thompson WG, et al. An epidemiological survey of constipation in Canada: definitions, rates, demographics, and predictors of healthcare seeking. Am J Gastroenterol. 2001;96: Brandt LJ, Prather CM, Quigley EM, et al. Systematic review on the management of chronic constipation in North America. Am J Gastroenterol. 2005;100(suppl 1):S5-S21. Lembo A, Camilleri M. Chronic constipation. N Engl J Med. 2003;349(14): Locke GR III, Pemberton JH, Phillips SF. AGA technical review on constipation. AGA. Gastroenterology. 2000;119: Quah HM, et al. Constipation and retention in coloproctology. Tech Coloprotol. 2006;10:111. Session 3

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5 The Fast Track: Improving the Management of Chronic Constipation (CC) and Irritable Bowel Syndrome With Constipation (IBS-C) in the Primary Care Setting Susan Lucak, MD Assistant Professor of Clinical Medicine Digestive and Liver Disease Columbia University Medical Center New York, NY Brian E. Lacy, PhD, MD Associate Professor of Medicine Dartmouth Medical School Director, GI, Motility Laboratory Dartmouth Hitchcock Medical Center Lebanon, NH Case Scenario 1 50-year-old woman presents with longstanding history of constipation Prolonged straining with bowel movements (BMs) Sense of incomplete evacuation after BMs Hard and lumpy stools Occasional need for manual maneuvers to disimpact stool Her stool caliber has not changed. She has no vomiting, weight loss, or rectal bleeding She does not have abdominal pain or discomfort She was prescribed a fiber supplement by her primary physician, but complained that it caused bloating and did not improve her symptoms She is not taking any other medications Participant Question? Discussion Questions Based on the history provided, what is your leading diagnosis for her bowel symptoms? 1. Pelvic dyssynergia 2. IBS-C 3. Diverticular disease 4. Slow-transit constipation 5. Hypothyroidism Should this patient undergo colonoscopy? Is it appropriate to check a TSH? Is anorectal manometry (ARM) warranted at this point? Would a Sitz-mark study be helpful? TSH = thyroid-stimulating hormone. Epidemiology of Constipation in the US Prevalence: Men = 12% Women = 16% 40 to 45 Million adult Americans Increased prevalence in the elderly approaching 40% 2.5 Million physician visits (1998) Constipation: Rome III Criteria CC must include 2 of the following: Straining Lumpy or hard stools Sensation of incomplete evacuation Sensation of anorectal obstruction/blockage Manual maneuvers <3 BMs/wk >25% of Defecations for 3 Mo Loose stools are rarely present without the use of laxatives There are insufficient criteria for IBS Drossman DA, et al. Gastroenterol Clin Biol. 1990;14:37C 41C; Pare P, et al. Am Gastroenterol. 2001;96: ; Stewart WF, et al. Am J Gastroenterol. 1999;94: ; Shiotani A, et al. J Gastroenterol. 2006;41:562. Longstreth GF, et al. Gastroenterology. 2006;130:

6 Bristol Stool Scale Physical Examination CC Perianal excoriation Skin tags/hemorrhoids Anocutaneous reflex Anal fissure Prolapse during straining Rectal examination Mass/tenderness/occult blood Squeeze Bearing down Heaton KW, O'Donnell LJ. J Clin Gastroenterol. 1994;19: Schmulson MW, et al. Am J Med. 1999;107:20S 26S; Drossman DA, et al. Gastroenterology. 2002;123: ; ACG Functional GI Disorders task force. Am J Gast. 2002;97:S1 S5; Rao SS. Gastroenterol Clin North Am. 2003;32: ; Lembo A, et al. N Engl J Med. 2003;349: Distinguishing IBS-C vs CC Subtypes of IBS and CC Symptom-based criteria for CC and IBS may overlap Abdominal bloating or discomfort creates a spectrum between CC and IBS - ABDOMINAL DISCOMFORT + IBS Functional Causes of CC CC IBS-C IBS-D IBS-M IBS-C Normal-transit constipation Slow-transit constipation Defecatory disorders Brandt LJ, et al. Am J Gastroenterol. 2005;100(suppl 1):S5. Constipation: Primary Causes Dyssynergic defecation Inability to coordinate abdominal, rectoanal, and pelvic floor muscles to facilitate defecation Slow-transit constipation Absent or decreased number of pacemaker cells (interstitial cells of Cajal) and enteric neurons Decreased colonic motility and frequency of mass movements CC Subtypes Symptoms suggestive of slow-transit Lack of urge Decreased stool frequency Symptoms suggestive of disordered defecation Hard stools Impaction Need for digital maneuvers Feelings of anal blockage Severe straining Rao SS. Gastroenterol Clin N Am. 2003;32: Mertz H, et al. Am J Gastroenterol. 1999;94: ; Lembo A, et al. N Engl J Med. 2003;349: ; Talley NJ. Rev Gastroenterol Disord. 2004;4:S3-S10. 2

7 Primary Constipation Syndromes Causes of Secondary Constipation Slow- transit Dietary / lifestyle Endocrine and metabolic Low residue diet Diabetes / thyroid / hypercalcemia Outlet obstruction (dyssynergic) IBS-C Neurologic Spinal cord / MS / Parkinson s / CVA / Hirschsprung s disease Anorectal Anal fissures and strictures / IBD Normal transit Psychogenic Depression / eating disorders latrogenic Drugs / surgery Schiller LR. Aliment Pharmacol Ther. 2001;15(6): ]; Mertz H, et al. Am J Gastroenterol. 1999;94(3): Schiller LR. Aliment Pharmacol Ther. 2001;15(6): Clinical Alarm Features Constipation: History Refractory or worsening symptoms Blood in stools Iron deficiency anemia Unintentional weight loss or anorexia Family history of organic GI disease New-onset constipation in an elderly patient; older patient ( 50 y) Red flag Primary and secondary symptoms Establish timeline Presence of warning signs/alarm signals Family history: Functional disorders, IBD, colorectal cancer Diet (fiber and fluid intake), daily routines, exercise Review medication use (antibiotics, iron supplements, etc) Prior tests Review prior medication trials If alarm features are present, investigate, and treat appropriately Lembo A, et al. N Engl J Med. 2003;349(14): Constipation: Physical Exam What to look for in the exam Signs of systemic and local diseases that might cause constipation Relevant abnormalities (ie, abdominal mass, prior surgery, etc) Assess the structure and function of the anorectum and pelvic floor muscles Tegaserod for Emergency Use Only As of April 2008, may be requested through the FDA for emergency situations, defined as one that is life threatening or serious enough to qualify for hospitalization. Conditions that are cause for denial of request: History of MI or stroke Smoking Unstable angina Obesity Hypertension Depression Hyperlipidemia Anxiety Diabetes Suicidal ideation Age >55 yrs 3

8 Secondary Causes of Constipation FDA-Approved Treatment Options for Constipation GI Colorectal neoplasm Ischemia Volvulus Megacolon Diverticular disease Anorectal: Prolapse, rectocele, stenosis, megarectum Metabolic/Endocrine Hypercalcemia Hyperparathyroidism Diabetes mellitus Hypothyroidism Diverticular disease Anorectal: Prolapse, rectocele, stenosis, megarectum Surgical Abdominal/pelvic surgery Colonic/anorectal surgery Lifestyle Inadequate fiber/fluid Inactivity CONSTIPATION Psychologic Depression Eating disorders Systemic Amyloidosis Scleroderma Polymyositis Pregnancy Drugs Opiates Antidepressants Anticholinergics Antipsychotics Antacids (AI, Ca) Calcium channel blockers Iron supplements Neurologic Parkinson s disease Multiple sclerosis (MS) Autonomic neuropathy Aganglionosis (Hirschsprung s, Chagas s) Spinal lesions Cerebrovascular disease Osmotic agents 5-HT 4 - receptor agonist Chloride channel activator Lactulose Polyethylene glycol (PEG) Tegaserod Lubiprostone Indicated for the treatment of constipation Indicated for the short-term treatment of occasional constipation Indicated for Adults <65 y with chronic idiopathic constipation Women with IBS-C *Sales suspended 4/07; restricted to emergency use only 4/08 Indicated for chronic idiopathic constipation + IBS-C in adults Candelli M, et al. Hepatogastroenterology. 2001;48: ; Locke GR III, et al. Gastroenterology. 2000;119: Physicians Desk Reference. Montvale, NJ: Thomson PDR; Efficacy of Stimulant Laxatives 4 Randomized comparative trials None placebo-controlled Low-quality study design No difference between stimulant and control laxatives in stool frequency or consistency In 1 study Lactulose was superior to the irritant laxative : 58% vs 42% were passing normal stool by day 7 Insufficient evidence to make a recommendation regarding efficacy No. of BMS/Wk Efficacy of PEG 3350 for CC PEG P < Baseline 1 2 Time (wk) Placebo P <.001 FDA-approved for occasional use ( 2 wk) Adverse effects (AEs) include diarrhea, nausea, abdominal bloating, cramps, and flatulence Brandt LJ, et al. Am J Gastroenterol. 2005;100:S5. N = 151 (87% female). DiPalma JA, et al. Am J Gastroenterol. 2000;95: ; Brandt LJ, et al. Am J Gastroenterol. 2005;100:S5 S21. Tegaserod Suspended from the US market March 30, 2007 Increased incidence of cardiac events and CVAs between those randomized to tegaserod vs placebo in clinical trials No. of Events Patients (N) Incidence (%) Tegaserod 13 11, * Placebo The Role of Chloride Channels in CC and IBS Ion Transport Chloride channels located on the apical surface of epithelial cells are driving force for intestinal fluid secretion Restricted use program July 2007 For women <55 y with chronic idiopathic constipation or IBS-C CVAs = cerebrovascular accidents. *P =.02; 3 myocardial infarcts, 1 sudden cardiac death, 6 unstable angina, 3 CVAs (blinded, adjudicated data) Tegaserod patients who developed events had history of cardiac disease or risk factors. FDA Website. Accessed January 11, Image courtesy of Ryuji Ueno MD, PhD. 4

9 Lubiprostone for CC Effects of Lubiprostone on Number of Spontaneous BM Lubiprostone 24 mcg bid Locally activates intestinal chloride channels-2 increases intestinal fluid secretion without altering Na+ and K+ in the serum Increased intestinal fluid secretion increases intestine motility and passage of stool May restore mucosal barrier function Softens stool and promotes spontaneous BMs Reduces abdominal discomfort, pain, and bloating Most common AEs-nausea, diarrhea, abdominal pain, HA BM/Wk Lubiprostone (24 µg bid) Placebo P =.0001 P =.0017 P =.0002 P =.0002 Intent-to-Treat (ITT) Population N = 242 Baseline Time (wk) Lubiprostone Prescribing Information Accessed January 11, 2008; Johanson J, et al. Am J Gastroenterol. 2005;100:S329. Abstract 899; Johanson J, et al. Am J Gastroenterol. 2005;100:S331. Abstract 903. Johanson JF. Gastroenterology. 2003;124:A48. Safety of CC Therapies on Pregnancy Biofeedback vs PEG-3350 for Treatment of Dyssynergic Constipation Treatment Lactulose PEG 3350 Lubiprostone Pregnancy Category Category B Category C Category C Patient Response at 6 Mo (%) PEG g/d (n = 55) Biofeedback (n = 54) * Major Symptom Improvement *P <.001; P <.01; all comparisons vs PEG Beneficial effect of biofeedback was sustained at 12 and 24 mo Biofeedback also produced greater reductions in Straining Sensations of incomplete evacuation and anorectal blockage Use of enemas and suppositories Abdominal pain Mosby s Drug Consult Website. Accessed April 29, Chiarioni G, et al. Gastroenterology. 2006;130: Case Scenario 1 (cont) Colonoscopy done 6 mo ago was unremarkable She responded poorly to fiber supplements, bisacodyl, and lactulose Balloon expulsion test is normal ARM has not been performed Participant Question What treatment would you select next? 1. PEG 2. Biofeedback therapy for pelvic training 3. Lubiprostone 4. Sorbitol 5. Milk of magnesia 6. Mineral oil? 5

10 Bloating Probiotics Antibiotics Pharmacologic Treatments Bloating/ distension Diarrhea Loperamide Diphenoxylate Alosetron Altered bowel function Abdominal pain/ discomfort TCAs = tricyclic antidepressants; SSRIs = selective serotonin reuptake inhibitors. Brandt LJ, et al. Am J Gastroenterol. 2002;97:S7; Drossman DA, et al. Gastroenterology. 2002;123: Abdominal Pain/ Discomfort Antispasmodics Antidepressants TCAs/SSRIs Alosetron Constipation Fiber Osmotic laxatives Lubiprostone Take-Away Messages CC is a common problem and may be difficult to distinguish from IBS-C Diagnosis is based on Rome III criteria, alarm features, targeted work-up Primary CC: slow-transit constipation, pelvic floor dysfunction Secondary CC: Important to rule out Treatment for pelvic floor dysfunction: biofeedback Drugs proven efficacious in randomized placebo-controlled trials include: PEG solutions, lactulose Lubiprostone Case Scenario 2 IBS-C in the Primary Care Setting Brian E. Lacy, PhD, MD Associate Professor of Medicine Dartmouth Medical School Director, GI, Motility Laboratory Dartmouth Hitchcock Medical Center Lebanon, NH 32-year-old female editorial assistant comes for initial consultation CC: bloating, abdominal pain since teen years Worse with menstrual cycle; predominantly constipated passing small pebble-like stools (Type 1) with rare episodes of loose stools Past medical history Fibromyalgia Migraine headaches GERD Case Scenario 2 (cont) Family history: Mother had similar symptoms. No history of IBD or colon cancer. Past treatments: Did not tolerate fiber supplements. Has tried alternative therapies without relief. Now uses intermittent stimulant laxatives and occasional loperamide. What Is our Patient s Most Likely Diagnosis? 1. IBS 2. IBD 3. CC 4. Acute constipation (AC) 5. Celiac disease (CD)? IBD = inflammatory bowel disease. 6

11 Epidemiology & Impact of IBS Pelvic floor and anorectal functions: Continence Affects 10-15% of the population 1 Women are more likely to be diagnosed than men - 2:1 ratio 2 IBS patients are 3 times more likely to miss days at work Direct/indirect costs in US estimated at $30 billion/year Continence requires: Contraction of puborectalis Maintenance of anorectal angle Normal rectal sensation Contraction of sphincters At rest Pubis Puborectalis Coccyx External anal Anorectal angle sphincter Internal anal sphincter 1. Locke GR III, et al. Gastroenterology. 2000;119(6): ;[Evidence Level B] 2. Brandt LJ, et al. Am J Gastroenterol. 2002;97(Suppl):S7.[Evidence Level A] Lembo A & Camilleri M. N Engl J Med. 2003;349(14): IBS: Challenging the Patient-Physician Partnership Patient misconceptions about IBS Sense of frustration Sense of isolation 15% KNOW that IBS will turn into cancer 22% KNOW that IBS increases the risk of developing cancer of the colon or rectum 30% KNOW that IBS will turn into Crohn s disease Existing comorbidities Lacy et al Aliment Pharmacol Ther 2007 Videlock EJ, et al. Gastroenterol Clin North Am. 2007;36 (3): ; Bertram S, Kurland M, et al. J Fam Pract. 2001;50(6): The Physician-Patient Relationship Establish a mutual and cooperative relationship Listen to patients Understand their needs Identify with their condition Give them explanations and information Reassure their concerns Advise them on what should be done Make sure they understand what they ve been told Ask them if they want to be involved in decision-making and treatment choices Improvement with defecation Rome III Criteria for IBS At least 3 d/mo in the last 3 mo with onset at least 6 mo previously of recurrent abdominal pain or discomfort associated with 2 of the following: and/or Onset associated with a change in frequency of stool and/or Onset associated with a change in form (appearance) of stool Manzoni GC. Neurol Sci. 2007;28 (suppl 2):S130-S133. Longstreth GF, et al. Gastroenterology. 2006;130:

12 Diagnostic testing as indicated Investigate further Symptom-Based Approach to Diagnosis Evaluate predominant symptoms Evaluate for presence of red flags (history, physical examination, laboratory tests) Red flag(s) No response Van Zanten SV. Rev Gastroenterol Disord. 2003;3(suppl 2):S12. No red flags Make a positive diagnosis and treat according to primary bowel symptom Assess response in 4 6 wk Response Continue therapy Identify Red Flags History Physical examination Unintended weight loss Relevant abnormalities Anorexia (eg, abdominal mass, arthritis) Nocturnal symptoms Laboratory results Rectal bleeding Anemia Patient >50 y Leukocytosis Family history High ESR GI cancer Abnormal blood chemistries IBD Abnormal thyroid studies CD ESR = erythrocyte sedimentation rate. Lembo A, et al. N Engl J Med. 2003;349: Overlap of GI motility and sensory disorders Regurgitation Heartburn Discomfort GERD IBS Dyspepsia Chronic Constipation (CC) Belching Bloating Diagnostic Work-up? Appropriate diagnostic testing in this patient would include which of the following? 1. Check thyroid function 2. Check celiac sprue panel 3. Perform colonoscopy 4. Obtain stool for giardia antigen Abdominal pain Diagnosis can shift from one disorder to another over time Constipation Locke 3rd, et al. Neurogastroenterol Motil. 2005;17(1):29 34 Corazziari. Best Pract Res Clin Gastroenterol. 2004;18(4): Talley et al. Am J Gastroenterol. 2003;98(11): Commonly Used Tests in the Evaluation of Constipation Text Colonoscopy/Sigmoidoscopy Barium enema Abdominal and pelvic CT scan Defecography Colonic transit studies ARM Balloon expulsion test Electromyography Diagnostic information * FI = fecal incontinence; IAS = internal anal sphincter; EAS = external anal sphincter. R/o structural lesion, eg, mass, diverticulosis, stricture, bleeding source R/o structural lesion R/o structural lesion Analysis of pelvic floor function descent of pelvic muscles, rectocele, cystocele R/o colonic inertia, Hirschsprung s disease Assess IAS and EAS function in CC and Fl, r/o Hirschsprung s diease Assess for pelvic dyssynergia Assess pudendal nerve function in EAS Organic Disease Colitis/IBD Colorectal cancer Celiac disease GI infection Thyroid dysfunction Lactose malabsorption Pretest Probability of Organic Disease IBS Patients (pretest probability, %) General Population (prevalence, %) * N/A Adapted from Candelli M, et al. Hepatogastroenterology. 2001;48(40): ; Lembo A, et al. N Engl J Med. 2003;349(14): ; Rao SS. Gastroenterol Clin North Am. 2003;32(2): ; Jacobs TQ, et al. J Natl Med Assoc. 2001;93(1): *Lifetime prevalence of colorectal cancer. Cash B, et al. Am J Gastroenterol. 2002;97:

13 Goals of IBS Pharmacotherapy Global relief of symptoms Including impact on patient overall wellbeing Target most dominant symptom Abdominal pain/discomfort Bloating Altered bowel habits (constipation, diarrhea) Brandt LJ, et al. Am J Gastroenterol. 2002;97(suppl):S7; ACG Functional GI Disorders task force. Am J Gastroenterol. 2002;97(suppl):S1. ACG Recommendations for the Treatment of IBS: Traditional Approaches Antispasmodics Insufficient data Loperamide Not more effective than placebo Not FDA approved for IBS Bulking Agents Not more effective than PLA All grade B recommendations: Intermediate-quality RCTs ± statistical significance Behavioral Therapy May be more effective than placebo TCAs Not more effective than placebo May improve abdominal pain ACG Functional GI Disorders task force. Am J Gastroenterol. 2002;97(suppl):S1; Brandt LJ, et al. Am J Gastroenterol. 2002;97(suppl):S7. IBS & Diet Consider FODMAPs (Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols) Closely linked - all highly fermentable Lactose & Fructose Fructans = fructo-oligosaccharides (onions) Galacto-oligosaccharides (raffinose) Polyols = sorbitol Probiotics & IBS Non-pathogenic live microbial food supplements Organisms that, when administered in adequate amounts, exert a positive influence on the health of the host animal Live organisms that benefit the host animal by improving intestinal microbial balance Usually administered in yogurt or capsules Global 80 Assessment of Symptom Relief % Answering yes at week p = P = What about small intestinal bacterial overgrowth (SIBO) and the role of antibiotics in the treatment of IBS? 30 B infantis B infantis B infantis Placebo Whorwell PJ, et al. Am J Gastroenterol. 2006;101:

14 Patients (%) Prevalence of Small Intestinal Bacterial Overgrowth in IBS * 5 x cfu / ml cfu / ml Jejunal culture Control IBS GHBT LHBT double peak LHBT 90 min LHBT 180 min Yield of lactulose breath tests is similar in healthy controls and a IBS patients There is no established relationship between IBS and SIBO Improvement, % Rifaximin Placebo Rifaximin N = 162; *P* <0.01 vs. controls. GHBT, glucose hydrogen breath test; LHBT, lactulose hydrogen breath test. Posserud I, et al. Gut ; 56: Time beyond treatment, wk Not FDA approved for IBS Pimentel M, et al. Ann Intern Med. 2006;145: Rifaximin for the treatment of IBS IBS-C & Lubiprostone A more recent study presented at DDW 2008: IBS-D, men and women DB, R, PC; 12 week trial 550 mg b.i.d. x 14 days N = 388; mean age = 45 Bloating (p =.04) and global IBS Sx (p =.03) improved Effects lasted until the end of 12 week trial Not FDA approved for IBS Lembo et al, Gastroenterology 2008; 134: abstract A type-2-chloride channel activator Approved by the FDA for the treatment of CC in both men and women in January 2006 A multicenter, double-blind, placebo-controlled dose ranging study in 195 IBS-C patients found that 8 ug b.i.d. was efficacious and had fewer side effects than higher doses Johanson et al, APT, 2008; 27: Lubiprostone: Mechanism of Action Lubiprostone: Overall Responder Rate in IBS-C Trials Cash & Lacy 2006, Gastroenterol & Hepatol Two 12-wk, Phase III, Multicenter, Double-Blind, Randomized, Placebo-Controlled Studies Lubiprostone is indicated for the Treatment of Women with IBS-C at 8 µg BID Patients (N = 1154) receiving lubiprostone were nearly twice as likely to achieve overall response compared to placebo Primary efficacy assessment* How would you rate your relief of IBS symptoms over the past week compared to how you felt before you entered the study? Secondary endpoints significantly improved by lubiprostone vs placebo Abdominal discomfort/pain, stool consistency, straining, constipation severity, and quality of life US Food and Drug Administration Website. Available at: Accessed May 22, Patients (%) Placebo Lubiprostone (8 µg BID) Study 1 Study 2 Patients Achieving Overall Response * Question on 7-point Likert scale; Statistically significant. 10

15 Case Scenario 2 (cont) Case Scenario 2 (cont)? Further discussion with the patient revealed no history of sexual or child abuse, but significant job stresses and marital issues Abdominal and rectal exam were normal No further diagnostic evaluation was felt necessary Treatment options for this patient might include all the following except 1.PEG daily 2.Citalopram 3.Probiotic 4.Cognitive behavioral therapy 5.Alosetron Summary: IBS Pharmacotherapy Options Antibiotics, probiotics, SSRIs, possibly NSRIs show promise Traditional agents (bulking agents, antispasmodics, TCAs, loperamide, behavioral therapy) May benefit patients with 1 predominant symptom Do not provide global relief of IBS symptoms Can be tried in a subset of patients Lubiprostone has good quality studies and has been FDA approved for (IBS-C) in women 18 years of age as of April 2008 Tegaserod provides global relief of the multiple symptoms of IBS-C Emergency use only Alosetron provides global relief of the multiple symptoms but is limited to women with severe IBS-D Clinical Pearls IBS can pose a challenge to both patients and physicians It s important to make an accurate diagnosis Involve patients in decisions regarding treatment Set expectations for treatment SSRIs = selective serotonin reuptake inhibitors. 11