Management of the Refractory Functional GI Patient

Management of the Refractory Functional GI Patient Shanti Eswaran, MD Clinical Assistant Professor Division of Gastroenterology University of Michigan Ann Arbor, MI, USA

Functional Bowel Disease A good set of bowels is worth more to a man than any quantity of brains Henry Wheeler Shaw (1811-1888)

Functional GI Diseases FGIDs FBDs Globus Functional heartburn Esophageal hypersensitivity Functional dyspepsia Functional n/v Functional bloating IBS Sphincter of Oddi dysfunction Functional diarrhea Chronic constipation Functional abd pain Defecatory dysfunction

Irritable Bowel Syndrome Most common GI condition (10-15% of the population) More common in women More common in younger adults Comorbid conditions Idiopathic gastrointestinal disorder with no anatomic or histopathologic abnormality found on diagnostic testing No biomarker for diagnosis

Question 1: IBS is a diagnosis of exclusion A)True B)False

IBS Diagnosis of exclusion *42% of GIs think otherwise Why do providers continue to order tests in IBS, despite data that these tests are generally low yield? 1. Fear of missing real diagnosis Many other conditions can masquerade as IBS Time is on your side- IBS masqueraders are annoying but chronic conditions 2. Medical-legal issues 3. Patient reassurance negative diagnostic tests may be useful to allay patient concerns about serious illness

Irritable Bowel Syndrome Diagnosis is made on specific symptombased criteria and the exclusion of select organic diseases Rome IV CBC CRP TTG IgA +/- upper endoscopy/colonoscopy

Rome IV criteria for IBS Recurrent abdominal discomfort pain at least 3 days per month least 1 day per week in the last 3 months associated with 2 or more of the following: Improvement with related to defecation Onset Associated with a change in frequency of stool Onset Associated with a change in form of stool *Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis Drossman, et al. Gastroenterology. 2016

Question 2: Evidence-based treatments for IBS include all but A) Bran B) Rifaximin C) Nortriptyline D) Low FODMAP Diet E) Hypnosis

+ + Diet, lifestyle advice Positive diagnosis Explain, reassure Graded Treatment of IBS Psychological treatments Continuing care Improve functioning Follow-up visit Manage stress Pharmacotherapy Mild Severe Moderate

Lifestyle Advice Regular exercise Regular sleep Avoid caffeine Regular reasonablemeals Avoid knowndietary triggers Minimal etoh Consider dairy free trial

Impact of Physical Activity on IBS IBS-Severity Scoring System, IBS score 102 IBS pts by Rome II 12 wk intervention 20-60 moderate to vigorous activity 3-5 times/wk N = 38 N = 37 Johannesson E, et al. Am J Gastroenterol, 2011

Treatment Recommendation Quality of evidence IBS Treatment Options Treatment Benefits Most Common Adverse Events OVER THE COUNTER Psyllium Weak Moderate Best suited for IBS-C Bloating, gas PEG Weak Very Low Loperamide Strong Very low Beneficial for constipation but not global symptoms or pain in IBS-C Beneficial for diarrhea but not global symptoms or pain in IBS-D Bloating, cramping, diarrhea Constipation Probiotics Weak Low Possible benefits for global symptoms, bloating & gas as a class but unable to recommend specific probiotics Peppermint oil Weak Moderate Benefits for global symptoms & cramping Similar to placebo GERD, constipation Adapted from Chey, Kurlander, Eswaran JAMA 2015

Treatment Recommendation Quality of evidence Antidepressants Weak High Treatment Benefits TCAs & SSRIs Improve global symptoms & pain. Leverage side effects to choose TCAs for IBS-D patients & SSRIs for IBS-C patients Antispasmodics Weak Low Some drugs offer benefits for global symptoms and pain Linaclotide Strong High Improves global, abdominal & constipation symptoms in IBS-C Plecanatide Strong High Improves global, abdominal & constipation symptoms in IBS-C Lubiprostone Strong Moderate Improves global, abdominal & constipation symptoms in IBS-C Rifaximin Weak Moderate Improves global symptoms, pain, and bloating in non-constipated IBS patients Improves global symptoms in IBS-D patients Eluxadoline Alosteron Weak Moderate Other Therapies Psychological/ Behavioral Therapy Strong IBS Treatment Options Strong Improves global, abdominal & diarrhea symptoms in women with severe IBS-D Benefits for global IBS symptoms in all subgroups. Most Common Adverse Events Dry eyes/mouth, sedation, constipation or diarrhea Dry eyes/mouth, sedation, constipation Diarrhea Diarrhea Nausea, Diarrhea Similar to placebo Constipation, Acute pancreatitis Constipation, rare ischemic colitis Similar to placebo Diet Strong Moderate Low FODMAP, Gluten-Free Abdominal pain, bloating Difficulty with adherence Adapted from Chey, Kurlander, Eswaran JAMA 2015

Pharmacologic Treatments Options for IBS Bloating Probiotics Antibiotics Bloating / distension Abdominal pain / discomfort Abdominal pain /discomfort Antispasmodics Antidepressants TCAs / SSRIs Diarrhea Loperamide Alosetron Antibiotics Probiotics Eluxadoline Altered bowel function Constipation Ispaghula/psyllium Lubiprostone Osmotic laxatives Linaclotide Plecanatide

Question 3: Risk Factors for Refractory IBS Include All Except: A) Long duration of diagnosis B) Female gender C) Bowel disturbance (as opposed to pain) as predominant IBS symptom D) Co-morbid anxiety E) History of early life trauma Whitehead et al APT 2004

Refractory IBS Highly subjective Difficult Unpleasant Unrealistic Crazy Individuals who fail to improve on a variety of drug therapies or who have high healthcare utilization despite aggressive treatment

Refractory IBS Pain as predominant symptom Comorbid psychiatric diagnoses Trauma or abuse Refusing to accept the diagnosis Leads to cynicism regarding the healthcare system Provider burnout

IBS patients v IBS in the community College students (1988) Individuals with IBS who chose to be patients showed significant abnormalities on all areas of psychometric testing though GI symptoms were similar (except pain) Most patients with IBS do not seek care Drossman DA, et al. Gastroenterology 1988

Extraintestinal manifestations of IBS: Fibromyalgia comorbid disorders Dyspareunia/pelvic pain Back pain Headaches Urinary dysfunction/interstitial cystitis Associated with significantly more disability, psychopathology, and overall disease severity in both IBS and the comorbid disease Whitehead et al. Gastroenterology. 2002

Extraintestinal manifestations of IBS: comorbid disorders Common psychiatric disorders found in 50 94% of IBS patients Panic disorder Generalized anxiety disorder Major depressive disorder Somatoform disorders (less common) The presentation of "multiple problems" can be overwhelming and frustrating for the patient as well as the physician. Therapeutic nihilism Whitehead et al. Gastroenterology. 2002

Prevalence of Early Life Trauma in IBS and Healthy Controls Bradford et al, Clin Gastroenterol Hepatol. 10(4):385-90, 2012

IBS and Trauma Presence of an abuse history negatively impacts IBS disease severity Severity of abuse correlates to IBS severity Higher # EALs increases IBS symptoms and symptom severity Implications for being refractory to treatment State the rationale for inquiring about abuse Let the patient decide how detailed the answers are Determine whom else the patient has told about abuse Utilize mental health/faithbased resources to help patient cope Park et al Neurogastroenterol Motil. 2016

Conceptual Model for the Development of IBS Various types of stress can influence the permanent biasing of: Stress responsiveness Activation of the stress response Persistence of symptoms Mayer et al, Am J Physiol Gastrointest Liver Physiol 280: G519-524, 2001

Bidirectional Impact of the Brain-Gut Axis Psychological and physical stress interferes with the ability to down-regulate gut experiences. Grenham et al, Front Physiol, 2(94), 1-15, 2011

How do patients with IBS fare? Proportion of patients who report improvement in their IBS after 6 months of usual medical management 10-49% Clear need for supplemental interventions Reduce morbidity Reduce life impairment Reduce chronically high healthcare utilization Whitehead et al APT 2004

+ Psychological treatments Continuing care Improve functioning Follow-up visit Manage stress + Pharmaco therapy Diet, lifestyle advice Positive diagnosis Explain, reassure Graded Treatment of IBS Mild Severe Moderate

Effectiveness of Psychological Treatments Cognitive Behavioral Therapy Number Needed to Treat: 3 Gut-Directed Hypnosis Number Needed to Treat: 2 Rifaximin Number Needed to Treat: 10 Linaclotide Number Needed to Treat: 7 Slide information borrowed from Megan Riehl, PhD Menees, et al. Am J Gastroenterol. 107(1): 28-35; 2012 Yu & Rao. Therap Adv Gastroenterol. 7(5):193-205, 2014 Regueiro M, Greer J, Szigethy E. Gastroenterology,152(2):430-439, 2017

Cognitive Behavioral Therapy Structured form of psychotherapy Individual Web based Self administered 6-12 treatments Focus on the present situations in which symptoms occur rather than the patient s past history Based on the theory that maladaptive thoughts are the causes of psychological symptoms such as anxiety and depression, which in turn cause or exacerbate physical symptoms Most studied form of psychological treatment 30 RCTs IBS, non-cardiac chest pain, pediatric population Currently ongoing RCT Multicenter NIH funded 500 IBS patient Evaluating the role of self administered CBT v standard CBT Clinical efficacy Cost effectiveness

CBT and IBS Payne and Blanchard 34 subjects 8 weeks CBT v support group v wait list CBT: 67% reduction in composite bowel symptom score Support group: 31% reduction Wait list: 10% reduction Improvement was fully maintained at 3-month follow-up. Payne A, Blanchard EB J Consult Clin Psychol. 1995 Oct; 63(5):779-86

The GI Stress Cycle Worsening GI Symptom Initial GI Discomfort (diarrhea, stomach pain, etc) Sympathetic Arousal (HR, respiration, GI distress) Unhelpful Thoughts ( Oh no, here we go again ) Emotions (anxious, frustrated, angry)

Hypnosis Verbal intervention that utilizes a special mental state of enhanced receptivity to suggestion to facilitate therapeutic psychological and physiological changes. Suggestion: You pay less and less attention to unpleasant feelings inside you every day, as your bowel sensitivity steadily fades away Eye Fixation Passive Muscle Relaxation Deepening Suggestions Alert

Effectiveness and Durability of Hypnosis RCTs demonstrated sustained benefits from 3 months to 1 year post treatment Number Needed to Treat = 2.5 (95% CI, 1.5-7) Response rates >85% in refractory cases Continued improvements up to 3 years Maintenance at 5 years Miller et al., Aliment Pharmacol Ther. 41(9):844-55. 2015

Who needs to be referred? Moderate or severe symptoms after 3 to 6 months of medical management Case presentation suggests that stress or emotional symptoms are likely to be exacerbating GI symptoms or impairing coping with illness. Willing to accept the diagnosis and treatment Good insight Not good candidates: Poor insight Major psychiatric comorbidities Unmotivated AGA guidelines. Drossman et al, Gastroenterology, 2002

How to refer? Patients may be unaware of the influences of emotions and the brain on gastrointestinal functioning may not see psychological treatment as relevant to their GI problems. Introduce the role of psychological influences and psychological treatment early with FGID patients. Reassure the patient that the correct diagnosis has been made Establish a firm therapeutic alliance. Explain thoroughly the rationale for the psychological treatment Place emphasis on continuation of GI care

Antidepressant Action in IBS Antidepressant action Visceral analgesia Changes in motility Smooth muscle relaxation Adapted from Rome Foundation Functional GI Disorders Specialty Modules.

Antidepressants for IBS: Updated meta-analysis Persistent or Unimproved Symptoms 80 Placebo 64.9 63.7 Antidepressants 67.2 Patients (%) 43.9 RR=0.67 (95% CI=0.58-0.77) 1 43.3 RR=0.66 (95% CI=0.60-0.83) 45.5 RR=0.68 (95% CI=0.44-0.91) 0 TCAs + SSRIs 16 RCTs (n=1084) TCAs 10 RCTs (n=744) SSRIs 5 RCTs (n=356) RR=relative risk; SSRI=selective serotonin reuptake inhibitor; TCA=tricyclic antidepressant. Ford AC, et al. Am J Gastroenterol. 2014 Sep;109(9):1350-65

Do Antidepressants treat IBS, or co-existing depression? 4 RCTs screened for and excluded depressed patients 12 RCTs did not exclude depressed patients RR of symptoms persisting = 0.73 (95% CI=0.47-1.15) RR of symptoms persisting = 0.65 (95% CI=0.55-0.78) Ford AC, et al. 2014 AGJ

Antidepressants for IBS: Clinical Considerations Consider specific symptoms treated TCAs in IBS-D, SSRIs in IBS-C SSRI/SNRI for anxiety Consider side effect profiles - SSRIs may be better tolerated than TCAs Consider previous use of psychotropic agents Start with low dose 3 Titrate slowly (every 1-2 weeks) 3 Follow up to assess side effects, adherence, and efficacy 3 Poor response 3 Switch to different class antidepressant Combine treatments as augmentation Obtain psychiatry consultation Satisfactory response 3 Continue at minimum effective dose for 6 to 12 months Long-term therapy may be warranted for some patients SNRI=serotonin-norepinephrine reuptake inhibitor. 1. ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35. 2. Ford AC, et al. Gut. 2009;58:367-378. 3. Grover M, Drossman A. Curr Opin Pharmacol. 2008;8:715-723.

Diet as Treatment in IBS IBS patients are a heterogeneous group that are difficult to treat Limited number of drugs with poor efficacy Most patients are interested in the role of diet in IBS most perceive that their symptoms are at least partially related to specific foods/food intake Exclusion diets Low carb- little data Low fructose

Traditional Dietary Advice for IBS No standardized IBS diet! Avoid excess Caffeine, chocolate, alcohol Sorbitol Fatty or junk food Encourage Dietary fiber for hard stools Reasonable meal sizes Allow sufficient time for meals 20

What are FODMAPs? FODMAPS: fermentable oligo-, di-, and mono-saccharides and polyols Restricts the intake of foods high in FODMAPs Short chain carbs that are poorly absorbed by the small intestine Fruits with fructose exceeding glucose Apples, pears, watermelon Fructan containing vegetables (FOS) Onions, leeks, asparagus, artichokes Wheat based products (GOS) Bread, pasta, cereal, cake, cookies Sorbitol and lactose containing foods Raffinose containing foods (monosaccarides) Legumes, lentils, cabbage, brussels sprouts

FODMAP Fructose Polyols Lactose Fructans and Galactans High FODMAP food sources Alternative lower FODMAP food sources Apples, pears, watermelon, mango, cherries, honey, asparagus, fruit juices, dried fruits, highfructose corn syrup Citrus, berries, bananas, grapes, honeydew, cantaloupe, kiwifruit Sugar alcohols (sorbitol, maltitol, mannitol, xylitol, and isomalt), stone fruits, blackberries, apple, pear, avocado, mushrooms, cauliflower Sweeteners, such as sugar, glucose, other artificial sweeteners not ending in -ol (sucralose, aspartame are okay) Milk (cow, goat, sheep), yogurt, custard, ice cream, soft cheeses (ricotta, cottage) Lactose-free dairy products, rice milk, hard cheeses Wheat, rye, barley, garlic, onions, artichokes,, inulin, soy, leeks, shallots, legumes, lentils, chickpeas, cabbage, Brussels sprouts, broccoli, peas, fennel, beetroot, pistachio nuts, chicory Starches, such as rice, corn, potato, quinoa. Vegetables, such as winter squash, lettuce, spinach, cucumbers, bell peppers, green beans, tomato, eggplant, zucchini, pumpkin, turnip, parsnip, carrot

Osmotic Effects Eswaran. NGM. April 2017 Bohn et al Gastro 2015; Halmos et al Gastro 2014

Low FODMAP Plan Elimination phase Improvement of IBS symptoms? Cautious reintroduction phase 4 weeks Not all patients benefit Confusing to follow Requires RD instruction Requires a committed patient Little data on mechanism of action Will I get better? Which symptoms will get better?

Low FODMAP v Standard Diet in IBS: RCT 30 IBS patients 10 IBS-D 13 IBS-C 7 IBS-M Baseline 21 days study diet washout 21 days study diet All food was provided Small, all food provided, compared to placebo but all patients were able to tell which diet they were on Halmos Gastro 2014

FODMAPs in the US population Compare the efficacy of the low-fodmap diet to a diet based upon modified guidance from the National Institute for Health and Care Excellence (mnice) in US adults with IBS-D Dietitian guided mnice recommendations: Avoidance of trigger foods Small frequent meals Caffeine and alcohol in moderation Eswaran, Chey, et al, DDW 2016

Adequate Relief 60% 50% 40% 41% p=.3055 52% 30% 20% 10% 0% m-nice Low FODMAP In the last week, have you had adequate relief of your GI symptoms? Proportion of patients that answered Yes for 50% of weeks 3 and 4

Abdominal Pain 60% 50% p=.0083 51% 40% 30% 23% 20% 10% 0% m-nice 30% reduction in mean daily abdominal pain score for 2/4 weeks Low FODMAP

Bloating 60% 50% p=.0133 52% 40% 30% 26% 20% 10% 0% m-nice Low FODMAP 30% reduction in mean daily bloating score for 2/4 weeks

Overall IBS-QOL Scores Mean Value 80 70 60 50 40 p=.03 p <.0015 59.4 54.3 53.4 p<.0001 69.3 30 20 10 0 Baseline Week 4 Baseline Week 4 m-nice Low FODMAP

CBT Diet Improved Functioning Meds Follow up

Summary Rule out organic disease CBC, CRP, Celiac disease +/- endoscopy, +/- c diff Present IBS/functional disease early in the workup as a likely possibility There is mounting evidence to support selected lifestyle, dietary recommendations, psychotherapy for IBS Emphasis for refractory patients should be on improving functioning, not cure

Resources: To find therapists: CBT: www.abct.org www.academyofct.org Hypnosis: www.asch.net www.ibshypnosis.com The Complete Low-FODMAP Diet: A Revolutionary Plan for Managing IBS and Other Digestive Disorders Sue Shepherd PhD