Calming the Colon: A Review of Irritable Bowel Syndrome

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1 Objectives for Pharmacists Calming the Colon: A Review of Irritable Bowel Syndrome Tyler Sandahl, Pharm.D. PGY 1 Pharmacy Resident Iowa City Veterans Affairs Healthcare System At the end of this presentation PHARMACISTS should be able to: Differentiate between constipation predominant (IBS C) and diarrhea predominant (IBS D) irritable bowel syndrome Recall two red flag symptoms requiring referral to a specialist Explain three dietary modifications patients with IBS should consider to reduce symptoms Identify factors that limit use of alosetron (Lotronex ) Using evidence based medicine, develop a treatment plan for a patient with IBS C Objectives for Technicians At the end of this presentation PHARMACY TECHNICIANS should be able to: Recall three medications used to treat IBS D symptoms Compare IBS C and IBS D based on stool frequency and appearance Given a patient case, create a lifestyle modification plan to improve IBS symptoms Describe the financial impact of IBS on patients and the healthcare system Epidemiology Most commonly diagnosed GI condition Prevalence in North America approximately 12% Symptoms 1.5 2x more prevalent in females in US and Canada Incidence similar in children, adolescents and adults Prevalence decreases with age 2% disappearance rate Enck et al. Nature Reviews, 2016 IBS Subtypes Diarrhea predominant (IBS D) Constipation predominant (IBS C) Mixed subtype (IBS M) Undetermined subtype (IBS U) Pooled IBS Prevalence By Country Enck et al. Nature Reviews,

2 Costs of IBS Burden Etiology 3.1 million ambulatory care visits 5.9 million prescriptions 2 nd most common reason for work absences Total direct and indirect expenditures exceed $20 billion annually Host Factors Altered pain perception Altered brain gut interaction Dysbiosis Increased intestinal permeability Increased gut mucosa immune activation Visceral hypersensitivity Environmental Factors Early life stressors Food intolerances Antibiotics Enteric infection Biopsychosocial Model Presentation Typical Features Loose/frequent stools Constipation Bloating Abdominal cramping Brought on by food Dynamic over time Concerning Features Onset after 50 yrs Severe or progressively worsening Unexplained weight loss Nocturnal diarrhea Family history of organic GI diseases Rectal bleeding or melena Unexplained iron deficiency anemia Johns Hopkins Gastroenterology & Hepatology, 2016 Patient Case Case Continued MJ is a 32 y/o Caucasian female presents with abdominal discomfort, bloating, and more frequent diarrhea. Noticed change in bowel habits 6 8 months ago No specific origin of pain Worsened by fast food and microwave dinners PMH includes: PTSD Depressive disorder (in remission) Obesity (BMI= 32.3 kg/m 2 ) Family History: Father: PUD, Hypothyroidism s/p thyroid ablation Mother: HLP, MDD, DMII What factors support IBS in the differential diagnosis? 2

3 IBS Guidelines American College of Gastroenterology (ACG) Monograph on The Management of Irritable Bowel Syndrome and Chronic Idiopathic Constipation published in 2014 Meta analysis with recommendations for IBS management American Gastroenterological Association (AGA) IBS pharmacologic management guideline published in 2014 Recommendations based on systematic review of existing literature NICE Guidelines National Institute for Health and Care Excellence UK guidelines on diagnosis, management, referral and follow up last updated in 2015 Rome Criteria Consensus panel for diagnosis and classification of functional GI disorders Last update released May 2016 (Rome IV) Initial Assessment Presence of following for at least 6 months Abdominal pain or discomfort Bloating Change in bowel habits Pain or discomfort relieved by defecation or associated with altered bowel frequency/form accompanied by at least 2 of the following Altered stool passage (straining, urgency, incomplete evacuation) Abdominal bloating, distention, tension, or hardness Symptoms made worse by eating Passage of mucus Diagnostic Tests Full blood count ESR or plasma viscosity CRP Antibody testing for celiac disease Endomysial antibodies Tissue transglutaminase Not recommended Ultrasound Sigmoidoscopy Colonoscopy or barium enema Thyroid function tests Fecal ova and parasite test Fecal occult blood Hydrogen breath test Rome IV Criteria Recurrent abdominal pain or discomfort, on average, at least 1 day/week in last 3 months Associated with 2 or more of the following Related to defecation Associated with change in stool frequency Associated with change in form (appearance) of stool Lacy et al. Gastroenterol, 2016 Bristol Stool Form Scale (BSFS) Lacy et al. Gastroenterol, 2015 IBS Subtypes According to the Bristol Stool Form Scale Lacy et al. Gastroenterol,

4 Red Flag Symptoms Unintentional or unexplained weight loss Rectal bleeding Family history of bowel or ovarian cancer Change in bowel habit to looser and/or more frequent stools for >6 weeks in patients >60 years Anemia Abdominal masses Rectal masses Inflammatory markers Case Continued MJ reports loose watery stools 3 4 days each week No problems with constipation noted Celiac ( ) C. diff. ( ) No inflammatory markers present How would you classify MJ s IBS? a) IBS C b) IBS M c) IBS D d) IBS U Lifestyle Modification LIFESTYLE MODIFICATIONS Increase activity level Exercise found to improve overall symptoms 20 minute walk each day (roughly 1 mile) Increase distance and pace as tolerated Identify and make the most of leisure time Create relaxation time Attention to impaired sleep Identification and avoidance of triggers Cognitive behavioral therapy if indicated Lacy et al. Gastroenterol, 2016 Enck et al. Nature Reviews, 2016 Dietary Modification Regular meals Avoid missing meals or long gaps 8 oz fluid daily (noncaffeinated) Restrict tea and coffee to 3 cups daily Reduce alcohol and carbonated beverage intake Limit high fiber foods Avoid processed and recooked foods Limit fresh fruit to 3 portions/day IBS D: avoid sorbitol ACG: weak recommendation; very low quality evidence for dietary modification FODMAP Diet Low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols FODMAPs increase small intestinal and colonic water secretion and fermentation Ford et al., Am J Gastroenterol, 2014 Enck et al. Nature Reviews, and alow fodmap diet/ 4

5 Medical Management IBS C Laxative agents Fiber supplements Prosecretory agents IBS D Antidiarrheals Mixed opioid agonist/antagonist 5 HT 3 receptor antagonists Antispasmodics Adjunct Therapies Probiotics Antibiotics Antidepressants FDA Consensus Guideline Goal: standardize outcome measures in clinical trials Provides responder definitions for functional GI disorders Introduced May 2012 Applies to studies in IBS C and IBS D IBS C Treatment Options IBS C Treatment Strategies Laxative Agents Polyethylene glycol: osmotic laxative Stimulant laxatives Fiber Supplements Bulk forming laxatives improve stool consistency and frequency Prosecretory Agents Linaclotide (Linzess ): guanylate cyclase agonist Lubiprostone (Amitiza ): chloride channel activator Laxative Agents Polyethylene Glycol (Miralax ) Osmotic laxative 17 gm in 8 oz liquid once daily (titrate to effect) ACG: weak recommendation based on low quality evidence AGA: suggest PEG laxatives over no other drug treatment Conditional recommendation; low quality evidence Prospective, multi center, randomized, double blind, placebocontrolled, parallel group study compared PEG 3350+E to placebo Variable Between Group Difference at Week 4 Spontaneous BMs 1.56 ( ) P< Severity of discomfort/pain 0.04 ( ) P>0.05 Spontaneous complete BMs 0.77 ( ) P< Severity of Straining 0.69 ( ) P< Severity of Bloating 0.15 ( ) P=0.06 Feeling of incomplete evacuation 0.57 ( ) P<0.05 Chapman et al. Am J Gastroenterol, 2013 Ford et al. Am J Gastroenterol, 2014 Weinberg et al. Gastroenterol, 2014 Laxative Agents Cont. NICE Guidelines recommend laxative agents first line Discourage use of lactulose Stimulant laxatives Commonly used Efficacy demonstrated in chronic constipation, but no controlled trials in IBS C patients Common adverse effects: abdominal pain and cramping 5

6 Fiber Supplements Cornerstone of IBS management Modest benefit with fiber for global symptoms (RR 0.86; 95% CI ) Subgroup analysis found soluble fibers, not insoluble fiber (bran) associated with improvement in IBS symptoms Wheat bran contains fructans which can exacerbate symptoms Gradually titrate dose to grams of psyllium daily Ensure adequate water intake ACG guidelines provide a weak recommendation due to low quality of evidence IBS C Responder Definition Abdominal Pain Intensity: weekly average of worst daily abdominal pain (WAP) score of 3 on a 0 10 point scale Responder: decrease of at least 30% compared to weekly average Stool Frequency: fewer than 3 complete spontaneous bowel movements (CSBMs) per week Responder: increase in at least one CSBM/week from baseline Ford et al. Am J Gastroenterol, 2014 Linaclotide (Linzess ) Guanylate cyclase agonist that stimulates intestinal fluid secretion and transit Strong recommendation; high quality evidence ACG AGA NICE: recommend in patients without improvement on max tolerated laxative dose Dose: 290 mcg daily Linaclotide for IBS C Phase 3, double blind, parallel group, randomized placebocontrolled trial 290 mcg linaclotide daily vs. placebo Patients 18 yrs who met Rome II criteria for IBS C 21 day initial screening period Patients discontinued any anti cholinergics, NSAIDs, narcotics, and other laxatives day baseline period where symptoms were reported 26 week treatment period Layer et al. Aliment Pharmacol Ther, 2014 Chey et al. Am J Gastroenterol, 2012 End Points Primary End Points: FDA Consensus Guideline Outcomes 9/12 weeks: 30% improvement from baseline in average daily WAP 3 CSBMs and increase of 1 from baseline Combined endpoint defined patient as a responder Secondary End Points: 12 week and 26 week change from baseline in WAP, discomfort, bloating, stool frequency, stool consistency, severity of straining Safety End Points: All patient reported adverse events Physical exams, ECG, vitals, clinical lab testing Results FDA End Point 30% decrease abdominal pain 3 CSBMs & increase of 1 Combined responder Placebo (N=403)% Weeks 1 12 Weeks 1 26 Linaclotide (N=401)% NNT (95% CI) ( ) ( ) ( ) ( ) *P value <0.001 for all analyses Placebo (N=403)% Linaclotide (N 401)% NNT (95% CI) ( ) ( ) ( ) ( ) Chey et al. Am J Gastroenterol, 2012 Chey et al. Am J Gastroenterol,

7 Adverse Events Adverse Event Placebo (N=403) Linaclotide (N=402) At least 1 TEAE* (P<0.05) 228 (56.6) 263 (65.4) Diarrhea (P<0.001) 10 (2.5) 79 (19.7) URIs 22 (5.5) 22 (5.5) Abdominal Pain 16 (4.0) 18 (4.5) Flatulence 9 (2.2) 15 (3.7) Viral Gastroenteritis 9 (2.2) 15 (3.7) Headache 11 (2.7) 13 (3.2) Abdominal Distention 6 (1.5) 9 (2.2) GERD 6 (1.5) 9 (2.2) *TEAE= Treatment emergent adverse effects Lubiprostone (Amitiza ) Locally acting chloride channel activator enhances chloride rich intestinal fluid secretion ACG: strong recommendation based on moderate quality evidence AGA: Conditional recommendation; moderate quality evidence NICE: no recommendation Dose: 8 mcg twice daily Chey et al. Am J Gastroenterol, 2012 Davis et al. Curr Oncol Rep Lubiprostone for IBS C End Points Post hoc analysis of 2 similarly designed phase 3, doubleblind, randomized, placebo controlled trials 4 week baseline/screening periods followed by 12 week treatment period Lubiprostone 8 mcg twice daily vs. placebo 18 years meeting Rome II criteria for IBS C Each study evaluated separately and as pooled analysis Lubiprostone n= 325 Placebo n= 180 Changes in abdominal pain and stool frequency analyzed as composite endpoints to match treatment responder definition by the FDA Consensus Guideline Bloating and stool frequency also evaluated CSBMs not evaluated because completeness of evacuation not assessed in one study Treatment emergent adverse effects recorded and evaluated for severity and relationship to treatment Drossman et al. Aliment Pharmcol Thera, 2009 Chang et al. Aliment Pharmacol Thera, 2016 Chang et al. Aliment Pharmacol Thera, 2016 Composite Endpoint FDA Response Criteria Improvement in Bloating Symptoms Adverse Effects Patients Achieving Response (%) * 1.5* 2.0* Baseline Abdominal Pain Score *P <0.01; P <0.05 Patients Achieving Response (%) * Baseline Bloating Score Adverse Event Placebo (N=387) Lubiprostone (N=779) Serious Adverse Event 1 1 Treatment related Serious Adverse Event Treatment Related Adverse Events Nausea 4 8 Diarrhea 4 6 Abdominal Distention 2 2 Study Discontinuation Due To Adverse Event 7 5 *One patient reported non cardiac related chest pain deemed possibly due to lubiprostone Pooled Placebo Pooled Lubiprostone Drossman et al. Aliment Pharmacol Thera,

8 IBS C Treatment Summary Drug Dose Place in Therapy Cost PEG Laxatives Fiber 17 grams daily with titration to effect Titrate to grams of psyllium daily Weak recommendations for 1 st line use based on low quality evidence Historical 1 st line agent lacking quality evidence for use Linaclotide 290 mcg daily Strong recommendation based on high quality evidence Use limited by cost Lubiprostone 8 mcg twice daily Moderate recommendation based on moderate quality evidence Use limited by cost Stimulant Laxatives Bisacodyl: 5 15 mg daily Senna: mg daily Commonly used 2 nd line agent lacking evidence for use in IBS $15/30 days $5/30 days $387/30 capsules $396/30 capsules $5/30 tablets Case Cont. MJ returns to clinic 4 months later Stopped eating fast foods and microwave dinners Now walks 3 days/week Trying to adhere to low FODMAP diet Watery stools 2 3 days/week Some improvement with lifestyle modifications Interested in pharmacologic therapy to treat IBS D symptoms IBS D Treatment Options IBS D Treatment Strategies Loperamide Inhibits peristalsis, prolongs transit time, and reduce fecal volume Alosetron (Lotronex ) 5 hydroxytryptamine 3 receptor antagonist modulates visceral afferent activity from the GI tract, decreasing colonic motility and secretion, and may improve abdominal pain Antispasmodics Thought to relax gut smooth muscle via anticholinergic effects or calcium channel blocking properties. Eluxadoline (Viberzi ) Mixed mu opioid receptor agonist, kappa opioid receptor agonist, and delta opioid receptor antagonist that acts locally to reduce pain and diarrhea FDA Consensus Guideline IBS D Abdominal Pain Intensity: weekly average of WAP score of 3 on a 0 10 point scale Weekly Responder: decrease in WAP score 30% from baseline Daily Responder: WAP score decrease 30% Stool Consistency: at least one stool with consistency of Type 6 or 7 on BSFS at least 2 days per week Weekly Responder: 50% reduction in days/week with at least one stool with BSFS type 6 or 7 compared with baseline Daily Responder: BSFS type <5 for all BMs that day or no BM Loperamide Often used first line in IBS D Reduces stool frequency, and increases stool consistency 2 mg 45 min before a meal on regularly scheduled basis Two RCTs in IBS D and IBS M found no benefit of loperamide over placebo for overall IBS symptoms Preferred to diphenoxylate or atropine for long term use ACG: insufficient evidence to recommend use Strong recommendation; very low quality evidence AGA: suggest using loperamide Conditional recommendation; very low quality evidence NICE: recommend as first choice anti motility agent Ford et al. Am J Gastroenterol, 2014 Weinberg et al. Gastroenterol,

9 Alosetron (Lotronex ) 0.5 mg twice daily x4 weeks May increase to 1 mg twice daily ACG: weak recommendation for use based on moderate quality evidence for women with IBS D AGA: suggest using alosetron to improve global symptoms Conditional recommendation; moderate evidence No guidance from NICE Guidelines Alosetron in IBS D Randomized, placebo controlled trial in women with severe IBS D Women 18 years with severe IBS D with at least 6 months of symptoms Rome II criteria Failed conventional therapy Discontinue any IBS medications 7 days prior to screening with exception of short acting anti diarrheals and antidepressants Lotronex.com/hcp/MOA Lotronex Package Insert Weinberg et al. Gastroenterol, 2014 Krause et al. Am J Gastroenterol, 2007 Endpoints Global Improvement Scale Primary: proportion of responders for IBS Global Improvement Scale at week 12 Responder reported moderate or substantial improvement to question: Compared to 3 months prior, are your IBS symptoms over the past 4 weeks substantially worse, moderately worse, slightly worse, no change, slightly improved, moderately improved, substantially improved Secondary Average rate of adequate relief of pain, discomfort, urgency, lower GI symptoms Proportion with normalized bowel patterns Safety: Adverse events of special interest monitored using specific algorithms Krause et al. Am J Gastroenterol, 2007 Responders (% with moderate or substantial improvement) Week 1 4 Week 5 8 Week 9 12 P <0.028 Week Placebo Alosetron 0.5 mg QD Alosetron 1 mg QD Alosetron 1 mg BID Adverse Effects Placebo (N=176) 0.5 mg QD (N=175) Alosetron 1 mg QD (N=172) 1 mg BID (N=176) Constipation 9 (5) 16 (9) 27 (16) 33 (19) Total Events Resolved w/ interruption Resolved w/o interruption Resolved, patient withdrew Resolution unknown Abdominal Pain 6 (3) 9 (5) 11 (6) 13 (7) Nausea 10 (6) 9 (5) 6 (3) 10 (6) Sinusitis 11 (6) 6 (3) 5 (3) 11 (6) Headaches 4 (2) 9 (5) 9 (5) 4 (2) Symptoms of Possible Ischemic Colitis Placebo (N=176) 0.5 mg QD (N=175) Alosetron 1 mg QD (N=172) 1 mg BID (N=176) Any Event 7 (4) 15 (9) 10 (6) 12 (7) Bloody diarrhea or 4 (2) 7 (4) 5 (3) 5 (3) rectal bleeding Worsening 1 (<1) 4 (2) 5 (3) 6 (3) abdominal pain Bloody diarrhea AND worsening pain 2 (1) 4 (2) 0 1 (<1) *1 out of the 44 patients with possible ischemic colitis actually diagnosed with ischemic colitis Krause et al. Am J Gastroenterol, 2007 Krause et al. Am J Gastroenterol,

10 Black Box Warning Ischemic colitis and serious complications of constipation resulting in Hospitalization Blood transfusion Surgery Death Indicated only for women with severe IBS D with chronic symptoms lasting 6 months not responding adequately to conventional therapy Discontinue immediately with constipation or symptoms of ischemic colitis Incidence of serious complications of constipation ~0.1% Incidence of ischemic colitis 0.2% over 3 months and 0.3% over 6 months Contraindications Chronic or severe constipation Intestinal obstruction, stricture, toxic megacolon, GI perforation and/or adhesions Ischemic colitis, impaired intestinal circulation, thrombophlebitis, or hypercoagulable states Crohn s disease or ulcerative colitis Diverticulitis History of hepatic impairment Concomitant use of fluvoxamine Lotronex Package Insert Lotronex REMS, 2016 Lotronex Package Insert Lotronex REMS, 2016 Antispasmodics May improve IBS symptoms by relaxing gut smooth muscle ACG: weak recommendation; low quality evidence AGA: suggests use of antispasmodics Conditional recommendation; low quality evidence NICE: consider alongside dietary and lifestyle modification Anticholinergic agents for post prandial cramping and loose stools Dicyclomine Hyoscyamine Peppermint oil possesses calcium channel blocking properties and may provide mild relief of symptoms ACG: weak recommendation; moderate quality evidence and low potential for adverse effects Ford et al. Am J Gastroenterol, 2014 Weinberg et al. Gastroenterol, 2014 Eluxadoline (Viberzi ) Agonizing mu opioid receptor: reduce GI transit Antagonizing delta opioid receptor: increased analgesic potency compared with pure mu agonist No guidance in current AGA or NICE guidelines 100mg twice daily in patients with a gallbladder 75 mg twice daily in patients without a gallbladder Viberzihcp.com Viberzi Package Insert Eluxadoline in IBS D 2 Phase 3 randomized, double blind, placebo controlled, parallel group, multicenter studies Pre treatment period of 4 weeks 26 week double blind treatment period 4 week post treatment period Patients years who met Rome III criteria for IBS D Average WAP >3 Average BSFS score >5.5 Average global symptom score >2 Received 75 mg or 100 mg or placebo tablets twice daily Endpoints Primary: proportion of patients with composite response at 12 and 26 weeks 30% reduction in WAP on 50% of days Stool consistency <5 on same days Secondary Pain relief Improvement in stool consistency Improvement in global symptoms score Adequate relief of IBS symptoms Change from baseline in IBS quality of life questionnaire Safety All adverse events Subjective Opiate Withdrawal Scale Lembo et al. NEJM, 2016 Lembo et al. NEJM,

11 Patients (%) Results Primary Efficacy End Point Week *P <0.05 **P <0.001 * * ** ** ** ** IBS 3001 IBS 3002 Pooled Data IBS Trial Placebo Eluxadoline 75 mg Eluxadoline 100 mg Patients (%) Primary Efficacy End Point Week ** * ** IBS 3001 IBS 3002 Pooled Data IBS Trial Lembo et al. NEJM, 2016 ** ** Adverse Effects 75 mg (N=807) Eluxadoline 100 mg (N=859) Combined (N=1666) Placebo N=808 All ADEs 486 (60.2) 500 (58.2) 986 (59.2) 450 (55.7) Pancreatitis 2 (0.2) 3 (0.3) 5 (0.3) 0 Sphincter of Oddi 1 (0.1) 7 (0.8) 8 (0.5) 0 Spasm Constipation 60 (7.4) 74 (8.6) 134 (8.0) 20 (2.5) Nausea 65 (8.1) 64 (7.5) 129 (7.7) 41 (5.1) Abdominal Pain 47 (5.8) 62 (7.2) 109 (6.5) 33 (4.1) Flatulence 21 (2.6) 27 (3.1) 48 (2.9) 13 (1.6) Anxiety 10 (1.2) 19 (2.2) 29 (1.7) 14 (1.7) *Spinchter of Oddi spasm occurred exclusively in patients without a gallbladder Lembo et al. NEJM, 2016 Subjective Opiate Withdrawal Scale Scale of 0 64 Higher score indicates more intense symptoms Median scores Eluxadoline 75 mg: 2 (range 0 54) Eluxadoline 100 mg: 3 (range 0 53) Placebo: 3 (range 0 56) Case Continued MJ is a 32 y/o female recently diagnosed with IBS D No inflammatory, infectious, or other concerning features identified Found inadequate relief with diet and lifestyle modifications What would you recommend as first line pharmacologic agent for MJ s IBS D symptoms? a) Linaclotide 290 mcg daily b) Eluxadoline 100 mg twice daily c) Loperamide 2 mg daily 45 minutes prior to a meal d) Alosetron 1 mg twice daily IBS D Treatment Summary Drug Dose Place in Therapy Cost Loperamide Alosetron 2 mg 45 min before a meal on regularly scheduled basis 0.5 mg twice daily May increase to 1 mg BID after 4 weeks if tolerated and inadequate response Mixed recommendations for use as 1 st line agent Weak recommendations for use as last line agent for women with refractory IBS D Antispasmodics Variable agents and doses Historical agent Poor recommendation for use based on low quality evidence Eluxadoline Gallbladder: 100 mg twice daily W/O Gallbladder: 75 mg twice daily No recommendations Approved after last guideline updates $105/100 capsules 0.5 mg: $780/30 tablets 1 mg: $1561/30 tablets Dicyclomine: $26/100 capsules Hyoscyamine: $85/100 tablets Peppermint Oil: $5 10/ 1 fl. oz. $1152/60 tablets Alternative Therapies Antidepressants Antibiotics Probiotics 11

12 Antidepressants TCAs Analgesic properties independent of mood improving effects Via anticholinergic properties slow transit time Use cautiously in patients with constipation 2015 meta analysis: subgroup TCA>SSRI in improving symptoms AGA Guidelines suggest using TCAs in patients with IBS Conditional recommendation; low quality evidence NICE Guidelines recommend as second line SSRIs AGA: suggest against using SSRIs for patients in IBS Conditional recommendation; low quality evidence NICE: recommend use only if TCAs ineffective ACG: weak recommendation for TCAs or SSRIs; high quality evidence Ford et al. Am J Gastroenterol, 2014 Weinberg et al. Gastroenterol, 2014 Antibiotics: Rifaximin Poorly absorbed, semi synthetic antibiotic that inhibits bacterial RNA synthesis by binding the beta subunit of DNAdependent RNA polymerase Activity against Gram positive, Gram negative, and anaerobic bacteria ACG Guidelines provide weak recommendation for use based on moderate quality of evidence AGA Guidelines suggest using rifaximin Conditional recommendation; moderate quality evidence No guidance provided in NICE Guidelines Ford et al. Am J Gastroenterol, 2014 Weinberg et al. Gastroenterol, 2014 Rifaximin in IBS Systematic literature search of Medline, EMBASE, Cochrane library, Web of Science, and PubMed to determine efficacy Included double blind, randomized trials comparing efficacy of rifaximin vs. placebo in patients with IBS defined by symptom based criteria including Manning, Kruis, Rome I III Primary Outcome: global improvement of symptoms Associated with improvement OR=1.57 (95%CI= ) P<0.001 NNT= 10.2 Secondary Outcome: bloating Associated with improvement OR=1.55 (95%CI= ) P<0.001 NNT= 10.1 Probiotics Recent meta analysis including 35 randomized controlled trials found improvement in overall global IBS symptoms with use of probiotics RR= 0.79 (95% CI ) NNT= 7 Data may not be reflective of true impact due to multiple formulations used in existing studies Higher quality studies demonstrate less treatment effect ACG guidelines recommend probiotics to improve global symptoms, bloating and flatulence Weak recommendation based on low quality evidence Insufficient and conflicting data regarding strains, preparations, and species to use No recommendations for or against use from AGA or NICE Menees et al. Am J Gastroenterol, 2012 Ford et al. Am J Gastroenterol, 2014 Probiotic Considerations Formulations Lactobacilli and bifidobacteria used most often in IBS Should contain several billion organisms to increase likelihood of gut colonization Store according to manufacturer specifications Avoid probiotics Immunocompromised Critically ill Patients with central venous catheters Separate from antibiotics by at least 2 hours Case Conclusion MJ returns to clinic and reports significant improvement in symptoms with use of loperamide Loose stools about once weekly Abdominal pain less frequent, but still bothersome Recurring depressive symptoms related to quality of life Continues to work on lifestyle and dietary modifications Which adjunct therapy may provide additional benefit for MJ? a) Amitriptyline b) Lactobacillus c) Rifaximin d) Sertraline Williams NT. AJHP,

13 Summary Pathophysiology remains unclear Diet and lifestyle modifications key Pharmacologic therapy dictated by IBS subtype Weigh risks and benefits of pharmacologic interventions Effective therapy varies between patients References Aziz I, Mumtaz S, Bholah H, Chowdhury FU, Sanders DS, Ford AC. High Prevalence of Bile Acid Diarrhea Among Patients With Diarrhea Predominant Irritable Bowel Syndrome Based on Rome III Criteria. Clin Gastroenterol Hepatol. 2015; 13(9): DOI: /j.cgh Camilleri M, Acosta A, Busciglio I, Boldingh A, Dyer RB, Zinsmeister AR, Lueke A, Gray A, Donato LJ. Effect of Colesevelam on Faecal Bile Acids and Bowel Functions in Diarrhoea Predominant Irritable Bowel Syndrome. Aliment Pharmacol Ther. 2015; 41(5): DOI: /apt Chang L, Chey WD, Drossman D, Losch Beridon T, Wang M, Lichtlen P, Mareya S. Effects of Baseline Abdominal Pain and Bloating on Response to Lubiprostone in Patients with Irritable Bowel Syndrome with Constipation. Aliment Pharmacol Ther (Sept 27). Epub ahead of print. DOI: /apt Chapman RW, Stanghellini V, Geraint M, Halphen M. Randomized Clinical Trial: Macrogol/PEG 3350 Plus Electrolytes for Treatment of Patients with Constipation Associated with Irritable Bowel Syndrome. Am J Gastroenterol. 2013;108: Chey WD, Kurlander J, Eswaran S. Irritable Bowel Syndrome A Clinical Review. JAMA. 2015;313(9): Chey WD, Lembo AJ, Lavins BJ, Shiff SJ, Kurtz CB, Currie MG, MacDougall JE, Jia XD, Shao JZ, Fitch DAA, Baird MF, Schneier HA, Johnston JM. Linaclotide for Irritable Bowel Syndrome With Constipation: A 26 Week Randomized, Double blind, Placebo Controlled Trial to Evaluate Efficacy and Safety. Am J Gastroenterol. 2012; 107: DOI: /ajg Davis M, Gamier P. New Options in Constipation Management. Curr Oncol Rep. 2015; 17:55. Dove LS, Lembo A, Randall CW, Fogel R, Andrae D, Davenport JM, Mcintyre G, Almenoff JS, Covington PS. Eluxadoline Benefits With Irritable Bowel Syndrome with Diarrhea in a Phase 2 Study. Gastroenterol. 2013; 145(2): Drossman DA, Chey WD, Johanson JF, Fass R, Scott C, Panas R, Ueno R. Clinical Trial: lubiprostone in patients with constipation associated irritable bowel syndrome results of two randomized, placebo controlled studies. Aliment Pharmacol Ther. 2009; 29(3): References Enck P, Aziz Q, Barbara G, Farmer A, Fukudo S, Mayer EA, Niesler B, Quigley EM, Rajilic Stojanovic M, Schemann M, Schwille Kiuntke J, Simren M, Zipfel S, Spiller RC. Irritable Bowel Syndrome. Nature Reviews Disease Primers. 2016; 2:1 24 Ford AC, Moayyedi P, Lacy BE, et al. Task Force on the Management of Functional Bowel Disorders. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol. 2014; 109(suppl1):S2 S26. Irritable Bowel Syndrome (IBS). Johns Hopkins Gastroenterology & Hepatology. Accessed Oct 10, Accessed from: A88E 44F9 900F 7E295C50D38B&GDL_DC_ID=D03119D7 57A A717 CF1E7426C8BA Krause R, Ameen V, Gordon SH, West M, Heath AT, Perschy T, Carter EG. A Randomized, Double Blind, Placebo Controlled Study to Assess Efficacy and Safety of 0.5 mg and 1 mg Alosetron in Women with Severe Diarrheapredominant IBS. Am J Gastroenterol. 2007; 102(8): Layer P, Stanghellini V. Linactolide for the Management of Irritable Bowel Syndrome With Constipation. Aliment Pharmacol Ther. 2014;39(4): Li F, Fu T, Tong WD, Liu BH, Li CX, Wu JS, Wang XF, Zhang AP. Lubiprostone is Effective in the Treatment of Chronic Idiopathic Constipation and Irritable Bowel Syndrome. Mayo Clinic Proceedings. 2016; 91(4): Lembo AJ, Lacy BE, Zuckerman MJ, Schey R, Dove LS, Andrae DA, Davenport JM, McIntyre G, Lopez R, Turner L, Covington PS. Eluxadoline for Irritable Bowel Syndrome with Diarrhea. NEJM. 2016; 374(3): Lotronex REMS Program. Sebela Pharmaceuticals, Inc. March _REMS_full.pdf Menees SB, Maneerattannaporn M, Kim HM, Chey WD. The Efficacy and Safety of Rifaximin for the Irritable Bowel Syndrome: A Systematic Review and Meta Analysis. Am J Gastroenterol. 2012; 107: Premier Medical Group. IBS and a Low FODMAP Diet. Accessed Oct 18, Accessed at: and a low fodmap diet/ Williams NT. Probiotics. AJHP. 2010; 67(6):