Irritable Bowel Syndrome

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1 68 TH ANNUAL MCGILL REFRESHER COURSE FOR FAMILY PHYSICIANS 2017 Irritable Bowel Syndrome Gad Friedman, MDCM, FRCPC Jewish General Hospital

2 DISCLOSURES I have no disclosures

3 LEARNING OBJECTIVES 1. Review the epidemiology and pathophysiology of IBS 2. Discuss how to arrive at the diagnosis of IBS in terms of history and investigation. 3. Learn how to manage and treat IBS

EPIDEMIOLOGY OF COMMON GI DISORDERS 14.0% Prevalence 12.0% 11.2% 1 12.0% 2 10.0% 8.0% 6.0% 4.0% 2.0% 0.0% Irritable Bowel Syndrome (IBS) Chronic Idiopathic Constipation 0.1% 3 0.57% 4 0.

4 EPIDEMIOLOGY OF COMMON GI DISORDERS 14.0% Prevalence 12.0% 11.2% % % 8.0% 6.0% 4.0% 2.0% 0.0% Irritable Bowel Syndrome (IBS) Chronic Idiopathic Constipation 0.1% % 4 0.4% 5 Microscopic Colitis Inflammatory Bowel Disease (IBD) Celiac Disease 1. Lovell RM, Ford AC. Clin Gastroenterol Hepatol. 2012;10(7): Suares NC, Ford AC. Am J Gastroenterology. 2011;106(9): Tysk C, et al. Ann Gastroenterol. 2011;24(4): Ye Y, et al. Int J Clin Exp Med. 2015;8(12): Cash BD, et al. Gastroenterology. 2011;141(4):

IBS AND QUALITY OF LIFE Mean SF-36 score 90 80 70 60 50 National norm

physical Body pain General health Vitality Social functioning Role

5 IBS AND QUALITY OF LIFE Mean SF-36 score National norm Type 2 diabetes IBS 40 Clinical depression 30 Physical functioning Role physical Body pain General health Vitality Social functioning Role emotional Mental health Wells, et al: Aliment Pharmacol Ther. 1997;11:

6 IBS IS A CONSTELLATION OF SYMPTOMS When asked about a list of symptoms, a majority of IBS-C patients report experiencing all within the last year, with constipation and abdominal discomfort being the most common. Among IBS-D patients, a majority report experience with all (except loss of bowel control), with abdominal pain and loose watery stools most common. DIAGNOSED IBS-C DIAGNOSED IBS-D Constipation 96 Abdominal pain 94 Abdominal discomfort Abdominal pain Loose watery stools 90 Bloating 79 Cramping 86 Straining Infrequent stools Hard lumpy stools Nausea Other Frequency Frequency of bowel of bowel movements movements Urgency Bloating Loss of Loss bowel of bowel control/fecal incontinence fecal incontinence Q1: Which of the following symptoms have you experienced during the past 12 months? Base: total respondents, Diagnosed IBS C (N=1000), Diagnosed IBS D (N=1001) IBS IN AMERICA SUMMARY FINDINGS CONDUCTED BY AGA; Data Extracted from Full Raw Data Set; December 2015.

PAIN AND BLOATING ARE KEY CONTRIBUTORS TO IBS

1% 45.9% 45.7% 26.6% 20% 10% 0% Paré P et al.

7 PAIN AND BLOATING ARE KEY CONTRIBUTORS TO IBS SEVERITY 70% Symptoms Associated with the Worst Distress as Reported by Patients with IBS N=1501 Percentage of patients (%) 60% 50% 40% 30% 57.6% 55.1% 45.9% 45.7% 26.6% 20% 10% 0% Paré P et al. Clin Ther, 2006 Abdominal pain/ discomfort Bloating Gas Constipation Diarrhea

8 PATHOPHYSIOLOGY OF IBS

9 PATHOPHYSIOLOGY OF IBS

10 IBS-C PATHOPHYSIOLOGY Potential contributing factors: CNS Brain-Gut Dysfunction Visceral Hypersensitivity ENS Altered Motility Feldman, et al. Sleisenger and Fordtran s Gastrointestinal and Liver Disease, 9th ed Altered Fluid Homeostasis

11 VISCERAL HYPERSENSITIVITY Hypersensitivity may present as Hyperalgesia -an increase in pain intensity for a given painful stimulus compared with a control population Allodynia - pain from a stimulus not considered painful by healthy individuals Hypervigilance - increased attention to noxious stimulation Exaggerated pain referral patterns -perception of pain outside the normal anatomic sites mal partout

12 IRRITABLE BODY Genitourinary Pelvic pain, dysuria Musculoskeletal Low back pain, fibromyalgia Constitutional Headaches, chronic fatigue Psychiatric Depression, anxiety, somatization

13 DIAGNOSIS

14 ROME CRITERIA

15 DIAGNOSTIC APPROACH TO IBS & CIC ASSESS FOR ALARM FEATURES History Age 50 Red flags Family history of a GI diseases Severe constipation/ obstruction Medications Examination Relevant findings (arthritis, skin abnormalities, lymphadenopathy, abdominal mass) Digital rectal examination Min Labs: TSH, Hgb and calcium, CRP, fecal calprotectin, celiac serology Modified from: Chey WD J Fam Practice. 2009; 58(5):S8-S12

16 FECAL CALPROTECTIN Calprotectin is a major protein found in inflammatory cells that can be measured in a fecal sample Levels over 250 ug/g stool is suggestive of IBD while a level below 50 ug/g stool is normal

17 SOCIAL HISTORY Smoking Alcohol Recreational drugs Lifestyle changes (stressors) History of abuse Recent travel

18 FOOD TRIGGERS Caffeine Alcohol Spicy, fatty foods Tomato sauces Junk food Wheat products Dairy products Raw fruits, vegetables Eating too fast Eating too much Eating at irregular times Eating under stress

19 Stool Cultures Small Bowel Bacterial Overgrowth The ACG IBS Task Force does not recommend the routine use of stool studies to evaluate for infectious causes of IBS symptoms in the absence of a relevant travel history or specific alarm features (severe uncontrollable diarrhea, hematochezia, weight loss). The ACG Task Force echoed this conclusion when they indicated that there was insufficient evidence to support the routine use of breath tests for SIBO in the evaluation of patients with suspected IBS. Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evidence-based systematic review on the management of irritable bowel syndrome. Am J Gastroenterol 2009;104(Suppl 1):S1 35.

20 A POSITIVE DIAGNOSTIC STRATEGY IS NON-INFERIOR TO A STRATEGY OF EXCLUSION FOR PATIENTS WITH IRRITABLE BOWEL SYNDROME [CLIN GASTRO HEP 2013;11:956] Danish study of 302 patients ages referred by GPs who fulfilled the Rome 3 criteria followed for 1 year Exclusion Strategy : full blood work including CRP and celiac, stool for O&P, sigmoidoscopy with biopsies Positive strategy: CBC, CRP Results: no difference in QOL or patient satisfaction, no cases of IBD, celiac disease or colon cancer Greater cost in the exclusion strategy

21 TREATMENT

22 IBS PATIENTS ARE FRUSTRATED, SELF CONSCIOUS AND EMBARRASSED DIAGNOSED IBS-D Frustrated Self-conscious Embarrassed Fed up Depressed Accepting Angry Lacking answers Fine, it is no big deal Other None of the above Q9. When YOUR GI symptoms are bothering you how does that make you feel? Base: total respondents, Diagnosed IBS D (N=1001) IBS IN AMERICA SUMMARY FINDINGS CONDUCTED BY AGA; Data Extracted from Full Raw Data Set; December 2015.

23 PATIENT EDUCATION Patients should be informed of the chronic and benign nature of IBS, Informed that the diagnosis (if well-established) is not likely to be changed He or she will have a normal life span. Establish realistic expectations with consistent limits

24 PHYSICIAN PATIENT RELATIONSHIP Establish of a good therapeutic physician-patient relationship is paramount Patients with established, positive physician interactions have fewer IBS-related follow-up visits

25 Am Fam Phys. 86(5)419

26 QUALITY OF LIFE Mild Intermittent symptoms Worse after meals, stress, menses Maintains normal daily activities Moderate Intermittent Related to diet, travel, distressing experiences Occasional disruption in activities Severe Constant and often refractory Significantly impairs daily function 1. American Gastroenterological Association Patient Care Committee: Gastroenterology 1997:112; Drossman DA: Aliment Pharmacol Ther 1999:13(suppl 2);3-14.

28 THERAPEUTIC OPTIONS FOR PATIENTS WITH IBS Antispasmodics Bulking agents Antidiarrheal Antidepressants Prucalopride Eluxadoline Linaclotide Psychotherapy Alternative treatments Brandt et al. Am J Gastroenterol. 2002;97(suppl 11):S7.

29 FODMAP DIET F - fermentable O - oligosaccharides D - disaccharides M monosaccharides A and P polyols

30 FODMAP Subjects with IBS had lower overall gastrointestinal symptom scores (22.8 vs. 44.9) and the subjects' habitual diet. Bloating, pain, and passage of wind also were reduced while IBS patients were on the low-fodmap diet. 1 Most patients (72.1%) were satisfied with their symptoms Gastro 2013 Sep 25. pii: S (13) Int J Clin Pract Sep;67(9):

31 BULKING AGENTS 14 trials assessed bulking agents wheat bran, corn fiber, calcium polycarbophil, psyllium, ispaghula husk may be effective for constipation Bulking agents are not more effective than placebo at relieving global IBS symptoms Psyllium is best

32 LOPERAMIDE Only antidiarrheal agent studied in RCTs Loperamide successfully decreased stool frequency and improved consistency is effective for diarrhea but not for other symptoms

33 CHOLESTYRAMINE is a bile acid sequestrant which binds bile in the gastrointestinal tract to prevent its reabsorption. It is used to prevent bile acid malabsorption leading to bile acid diarrhea. Studies show that many patients with IBS-D have bile acid malabsorption and will respond to cholestyramine. Aliment Pharmacol Ther Oct;30(7):707-17

34 ANTISPASMODIC AGENTS Dicyclomine (Bentylol) 10 mg QID more effective than placebo Global improvement reported with hyoscyamine (Levsin) Pinaverium Bromide (Dicetel ) shows Improvement in quality of life Trimebutine Maleate (Modulon ) shows improvement in abdominal pain at eight weeks, but not at four weeks compared to placebo Brandt et al. Am J Gastroenterol. 2002;97(suppl 11):S7; Jailwala et al. Ann Intern Med. 2000;133:136; Page and Dirnberger. J Clin Gastroenterol. 1981;3:153; Ritchie and Truelove. Br Med J. 1979;1:376, Poynard T, et al: Aliment Pharmacol Ther 1994; 8(5): , Moshal MG, Herron M. J Int Med Res 1979; 7(3):231-4

35 PSYCHOTROPIC MEDICATIONS

36 ANTIDEPRESSANTS TCA are often most effective at low doses of mg qhs 2 nd generation TCA (Nortryptilline or Desipramine) have less side effects Active anxiety/depression will need SSRI treatment

37 5-HT4 AGONISTS There were 2 previous 5-HT4 agonists on the market, Cisapride(Prepulsid ) and Tegaserod(Zelnorm ). Both were removed due to cardiac side effects

38 PRUCALOPRIDE (RESOTRAN ) The most common adverse events were headaches, abdominal pain, and diarrhea, with most occurring within the first 24 hours of treatment. Therap Adv Gastroenterol January; 5(1):

39 PROBIOTICS

40 PROBIOTICS 2 positive studies in IBS Reduction in pain, bloating, gas passage over placebo over a 4 week trial Bifidobacterium infantis Am J Gastroenterol 2006;101: Gastro 2005;128:541

41 RIFAXIMIN Non-absorbable antibiotic available in US Pimental et al [N Engl J Med 2011; 364:22-32] 1260 patients who had IBS without constipation Rifaximin 550 mg tid vs. placebo More patients on Rifaximin had adequate relief of global IBS symptoms during the first 4 weeks after treatment (40.7% vs. 31.7%, P<0.001) and adequate relief of bloating (40.2% vs. 30.3%, P<0.001).

42 TREATMENT OF IBS: BEHAVIORAL THERAPIES Relaxation therapy Biofeedback Hypnotherapy Cognitive therapy Dynamic psychotherapy Brandt et al. Am J Gastroenterol. 2002;97(suppl 11):S7.

43 NEWER DRUGS Linaclotide (Constella) Eluxadoline (Viberzi)

Forest Laboratories Canada Inc. May 12, 2014.

44 LINACLOTIDE IS THOUGHT TO WORK IN TWO WAYS, BASED ON NON-CLINICAL STUDIES Constella (linaclotide) Product Monograph. Forest Laboratories Canada Inc. May 12, *Clinical relevance of the effect on pain fibers in nonclinical studies has not been established.

45 Weekly results for abdominal pain and CSBMs % Change Abdominal Pain % Change Ab. Pain Weekly CSBMs Weekly CSBMs Treatment Period RW Period p<0.001 for all 12 weeks in the Treatment Period BL Trial Week p< for all 12 weeks in the Treatment Period BL Trial Week Treatment Groups 290 µg linaclotide Placebo Rao S et al. Am J Gastroenterol, 2012

DOSING AND ADMINISTRATION RECOMMENDED DOSAGE & DOSAGE ADJUSTMENT IBS-C CIC 290 μg 145 μg Linaclotide is recommended to be taken orally once daily on an empty stomach, at least 30 minutes prior to the

46 DOSING AND ADMINISTRATION RECOMMENDED DOSAGE & DOSAGE ADJUSTMENT IBS-C CIC 290 μg 145 μg Linaclotide is recommended to be taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day Exceeding the daily dose of 145 μg for the treatment of CIC is not expected to increase efficacy No dose adjustment required for patients with hepatic or renal impairment Constella (linaclotide) Product Monograph. Forest Laboratories Canada Inc. May 12, 2014.

47 Diarrhea was the most common adverse event in linaclotide clinical trials Majority of diarrhea was mild to moderate in severity First reported within first 2 weeks of treatment Represents an extension of linaclotide s mode of action Discontinuation due to diarrhea was 5.3% in IBS-C trials and 4.2% in CIC trials (vs. <1% placebo) Constella (linaclotide) Product Monograph. Forest Laboratories Canada Inc. May 12, 2014.

ELUXADOLINE: MECHANISM OF ACTION VIBERZI

VIBERZI (eluxadoline) is the first and only

48 ELUXADOLINE: MECHANISM OF ACTION VIBERZI (eluxadoline) Targets Receptors in the GI Tract VIBERZI (eluxadoline) is the first and only mixed-opioid receptor modulator for IBS-D = Eluxadoline E E E 1. VIBERZI Product Monograph January 26, Dove LS, Lembo A, Randall CW, et al. Gastroenterology. 2013;145: e1. 3. Wade PR, Palmer JM, McKenney S, et al. Br J Pharmacol. 2012;167(5):

Dove LS, Lembo A, Randall CW, et al. Gastroenterology. 2013;145:329 338.e1.

49 VIBERZI MECHANISM OF ACTION VIBERZI is Thought to Treat IBS-D in 2 Ways, Though the Exact Mechanism of Action is Unknown Based on nonclinical data 1. Dove LS, Lembo A, Randall CW, et al. Gastroenterology. 2013;145: e1. 2. Wade PR, Palmer JM, McKenney S, et al. Br J Pharmacol. 2012;167(5):

Pain Compared to Placebo In addition, the proportion of patients who were responders to the 75 mg dose was numerically

50 SIGNIFICANT RELIEF OF IBS-D DIARRHEA AND ABDOMINAL PAIN Eluxadoline 100 mg (n=382) Placebo (n=382) A Significantly Greater Percentage of Patients Receiving VIBERZI 100 mg Had Simultaneous Improvement in Both Diarrhea and Abdominal Pain Compared to Placebo In addition, the proportion of patients who were responders to the 75 mg dose was numerically greater than placebo at 3 and 6 months. 1. VIBERZI Product Monograph January 26, Data on file. Forest Laboratories, LLC.

51 SAFETY PROFILE Most Common Adverse Events in Phase 3 Trials (>4% in either treatment arm and > placebo) 1 Adverse Events Placebo (n=808) Eluxadoline 75 mg (n=859) n (%) Eluxadoline 100 mg (n=807) Constipation* 20 (2.5) 60 (7.4) 74 (8.6) Nausea 41 (5.1) 65 (8.1) 64 (7.5) Abdominal pain 33 (4.0) 47 (5.9) 62 (7.2) Vomiting 11 (1.4) 32 (4.0) 36 (4.2) Gastroenteritis 27 (3.4) 36 (4.4) 19 (2.2) Sphincter of Oddi spasm events 0.6% (10/1666) patients receiving eluxadoline 2/10 with 75 mg All cases without gallbladder Pancreatitis 5 additional cases with eluxadoline (3 associated with excessive alcohol use and 1 with biliary sludge) URI 32 (4.0) 27 (3.3) 47 (5.5) Nasopharyngitis 27 (3.3) 33 (4.1) 23 (2.7) URI = upper respiratory infection. *All constipation events were non-serious 1.4% of patients receiving eluxadoline and 0.2% receiving placebo discontinued due to non-serious constipation; Abdominal pain = abdominal pain upper, abdominal pain lower; Gastroenteritis = gastroenteritis and viral gastroenteritis. 1. Lembo AJ et al. N Engl J Med. 2016;374:

52 DOSAGE AND ADMINISTRATION 100 mg Twice daily with food Recommended dose 75 mg Twice daily with food Starting dose for patients who are 65 years If well tolerated but not efficacious, dose could be increased to 100 mg For patients who cannot tolerate 100-mg dose Periodically assess the need for continued treatment with Viberzi. Discontinue in patients who develop severe constipation for more than 4 days. VIBERZI Product Monograph January 26, 2017.

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54 TAKE HOME MESSAGE Make a Positive Diagnosis Inspire patient confidence Explain the pathophysiology so patient can appreciate that IBS is a real disease Extensive testing is not required Tailor treatment to predominant symptoms

Irritable Bowel Syndrome Now. George M. Logan, MD Friday, May 5, :35 4:05 PM

Irritable Bowel Syndrome Now. George M. Logan, MD Friday, May 5, :35 4:05 PM Irritable Bowel Syndrome Now George M. Logan, MD Friday, May 5, 2017 3:35 4:05 PM Dr. Logan indicated no potential conflict of interest to this presentation. He does not intend to discuss any unapproved/investigative