SESSION 5 2:3pm 3:45pm Optimizing the Diagnosis, Treatment, and Management of Irritable Bowel Syndrome SPEAKERS Richard J. Saad, MD, MS Spencer Dorn, MD, MPH, MHA Presenter Disclosure Information The following relationships exist related to this presentation: Dr Saad has no financial relationships to disclose. Dr Dorn is an ad hoc consultants to Gerson Lehrman Group, Guidepoint Global and Coleman Research Group. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Learning Objectives Diagnose IBS and differentiate from other bowel disorders using established clinical guidelines Summarize the efficacy and safety of pharmacologic and nonpharmacologic treatment options for IBS Implement patient-specific methods for managing IBS symptoms and improving function and quality of life Irritable Bowel Syndrome: Making the Diagnosis Richard J. Saad, MD, MS Assistant Professor of Medicine Division of Gastroenterology & Hepatology University of Michigan 3 Irritable Bowel Syndrome (IBS) Diverse subgroup of functional bowel disorders Variable chronic gastrointestinal symptoms Abdominal discomfort, bloating, diarrhea, constipation, difficult passage of food or feces, passage of mucus, nausea Result in disordered gastrointestinal functioning Movement and processing of food/stool, sensory/motor function, secretory function, brain-gut interaction Lack a structural abnormality Lack a defining biomarker Rely on fulfillment of diagnostic clinical criteria IBS: Epidemiology Global prevalence of 11% 1 US prevalence of 1% to 15% 2 F:M of 1.5-2:1 Ratio greatest for constipation Most prevalent in those aged 25-54 years 3 Prevalence is inverse of socioeconomic status 4 1 Canavan C et al. Clinical Epidemiol. 214;4(6):71-8. 2 Saito YA et al. Am J Gastroenterol. 22;97(8):191-15. 3 Hungin AP et al. Aliment Pharmacol Ther. 25; 21(11):1365-75. 4 Minocha et al. Dig Dis Sci. 26;51(3):446-53.
IBS: Patient Impact Impairs quality of life Social, emotional, and physical dimensions Miss 1 activity/social event per week Willingness to give up 1 to 15 years of life for cure Impairs work Miss 8.5 to 21.6 days/year 12% stop working completely Cost to patient 15% to 43% buy OTC remedies 2/3 buy laxative, 1/3 more than 3 medications IBS: Impact on Health Care Outpatient 25% to 5% will see a primary care provider 3% of total direct health care costs ( $747- $7547/year) 2 to 3 visits/year During the initial year of diagnosis Average of 6 blood tests Average of 1 out-patient procedure Average of 1 radiological procedure Canavan C et al. Aliment Pharmacol Ther. 214;4(9):123-134. OTC=over the counter. Canavan C et al. Aliment Pharmacol Ther. 214;4(9):123-134. IBS: Impact on Health Care Inpatient Costs Based on National Inpatient Sample database 1997 21 Discharge diagnosis of IBS 11,433 12,842 Mean length of hospitalization 3.7 days 3.7 days Mean hospital charges (per hospitalization) $6,873 $21,153 Aggregate charge (national bill) $78.5 million $271 million Diagnostic Criteria for IBS: The Rome Criteria International working group of expert researchers and clinicians Diagnostic criteria created primarily for research purposes Most recent criteria published in 26 by Rome III Rome I (1992) Rome II (1999) Sethi S et al. Aliment Pharmacol Ther. 213;38(11-12):1338-1346. Rome III Criteria for IBS Recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with 2 or more of the following: Improvement with 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 Symptoms Supportive of IBS Abnormal stool frequency >3 BM/day or <3 BM/week Abnormal stool form lumpy/hard or loose/watery Fecal urgency Straining with defecation Sense of incomplete evacuation Passage of mucus Bloating Longstreth GF et al. Gastroenterology. 26;13(5):148-1491. Wilkins T, et al. Am Fam Physician. 212 Sep 1;86(5):419-26 BM=bowel movement.
A More Practical Clinical Definition for IBS: Abdominal pain/discomfort occurring in association with altered bowel habits for 12 or more weeks IBS Subtypes Irritable bowel syndrome with constipation (IBS-C) Irritable bowel syndrome with diarrhea (IBS- D) Irritable bowel syndrome with alternating constipation and diarrhea (IBS-M) ACG Task Force. Am J Gastroenterol. 29;14(S1)S1-S35. IBS Subtypes Are Based on Stool Consistency Percentage of hard or lumpy stools 1 75 5 25 IBS-C* IBS-U IBS-M IBS-D 25 5 75 1 Percentage of loose or watery stools Adapted from Longstreth GF et al. Gastroenterology. 26;13(5):148-1491. * Bristol Stool Form Scale 1-2 Bristol Stool Form Scale 6-7 IBS-M = IBS-mixed IBS-U = unclassified IBS Diagnosis - Overlap Between Chronic Constipation (CC) and IBS-C Chronic Constipation Abdominal Pain / Discomfort IBS With Constipation + D21 IBS vs CC Clinically: Diagnosis Overlap Between Functional Diarrhea and IBS-D IBS = abdominal discomfort present with or with constipation CC = abdominal discomfort occurs when constipation symptoms present - Abdominal Pain / Discomfort + Functional Diarrhea IBS With Diarrhea Adapted from Rome Foundation teaching slide D23
Paradigm Shift in the Diagnosis of IBS Historically a diagnosis of exclusion Now a diagnosis can be made based on fulfillment of symptom-based criteria and absence of alarm signs Diagnostic Studies to Consider in the Evaluation of IBS Symptoms Routine laboratory work CBC, CMP, ESR, CRP, TSH Antibody testing for celiac sprue Tissue transglutaminase Stool studies FOBT, O & P, C diff Hydrogen breath testing Glucose, lactulose, lactose, fructose Abdominal imaging X-ray, Ultrasound, CT, MRI Endoscopy Colonoscopy, EGD Pretest Probability of Organic Disease in IBS Pretest Probability in IBS (%) Prevalence in General Population (%) Colon cancer.51 4 6 Colitis/IBD.51.98.3 1.2 Thyroid disease 6 5 9 Lactase Deficiency 22 26 25 Celiac Disease 4.67.25.5 Lesions Yield of Colonoscopy in Non-C IBS The prevalence of structural abnormalities is not higher in IBS-M and IBS-D IBS Patients (n=466) N (%) Controls (n=451) N (%) P value Adenomas 36 (7.7) 118 (26.1) <.1 Hyperplastic polyps 39 (8.4) 52 (11.5) NS Colorectal adenocarcinoma (.) 1 (.2) NS Inflammatory bowel syndrome 2 (.4) (.) NS Microscopic colitis 7 (1.5) NA N/A NS=not significant. Cash BD et al. Am J Gastroeneterol. 22;97(11):2812-9 Chey WD et al. Am J Gastroenterol. 21;15(4):859-865. Evidence-based Testing in Clinical Practice Routine diagnostic testing not indicated Exception: serologic testing for celiac disease Directed testing in the setting of alarm features or failure of response to symptomdirected therapy Age-appropriate screening Brandt. Am J Gastroenterol. 22;97:S1-S26. Cash BD, Chey WD. Aliment Pharmacol Ther. 24;19(12):1235-1245. 1ACG Task Force. Am J Gastroenterol. 29; 14(S1):S1-S35. Alarm Features Age 5 Unintentional weight loss Family history GI malignancy Inflammatory bowel disease Celiac disease Severe (unrelenting) diarrhea Fevers, chills Travel to endemic area Nocturnal symptoms Blood in stool Anemia Lembo A, et al. N Engl J Med. 23;349:136-1368. Brandt LJ, et al. Am J Gastroenterol. 25;1(suppl 1):S5-S21. Cash BD, et al. Rev Gastroenterol Disord. 27;7:116-133. GI=gastrointestinal.
Optimizing the Diagnosis of IBS 1. Make the diagnosis! Based on presence of IBS-defining symptoms in absence of alarm features Only pursue directed testing IBS Conceptual Model Visceral Life Hypersensitivity Stress Coping Skills 2. Provide an explanation for symptoms Provides rationale for additional testing and treatment 3. Provide reassurance Post-Infectious Permeability Microbiome Motility Social Support Immune regulation Pathophysiology: For Your Patient Your bowels are overly sensitive to environmental stimuli Food Hormones Stress This results in bowel dysfunction Disturbed muscle function Altered secretory function Lower pain threshold Probability of Underlying Organic Disease Incidence Is Low! Cohort of 149 IBS patients (95% in primary care setting): only.7% developed organic disease over 3-year period 1 UK study (n=2956): 1% with colorectal tumor and.6% with IBD within 1 year 2 UK study found cumulative incidence of 3.7% for CD, IBD, and CRC 15 years after IBS diagnosis (compared with 1.7% in controls) 3 1 Yawn BP et al. Am J Manag Care. 21;7(6):585-592. 2 Garcia Rodriguez LA et al. Scand J Gastroenterol. 2;35(3):36-311. 3 Canavan C et al. PLoS One. 214;9(9):e16478. CD=celiac disease; CRC=colorectal cancer. Spencer Dorn, MD, MPH, MHA University of North Carolina School of Medicine Chapel Hill, North Carolina Patient-Provider relationship Lifestyle changes Diet, fiber, and probiotics CAM therapies Antispasmodics Antidepressants Psychological therapies Gut-specific IBS-D: Alosetron IBS-C: PEG, Lubiprostone, Linaclotide CAM, complementary and alternative medicine; IBS-C, irritable bowel syndrome with constipation; IBS-D, irritable bowel syndrome with diarrhea; PEG, polyethylene glycol.
Cornerstone of treatment Listen actively Determine reasons for visit Identify and respond to concerns and expectations Educate thoroughly Set realistic expectations Involve the patient in the treatment Positive physician-patient interaction reduces health care utilization and increases patient satisfaction Diary card symptom tracking can help identify exacerbating and alleviating factors and increase sense of control Moderate exercise for 2 to 6 minutes x 3 to 5 days/week improves IBS symptoms 11 Drossman DA et al. Gastroenterology. 22;123(6):218-2131.; Owens DM et al. Ann Intern Med. 1995;122(2):17-112. Dorn SD et al, Clin Gastroenterol Hepatol. 211;9(12):165-171. Johannesson E et al. Am J Gastroenterol. 211;16(5):915-922. Fermentable Oligo-, Di-, Monosaccharides And Polyols Among patients with IBS, diet is the #1 topic of interest 6% of subjects report that symptoms worsen after meals The act of eating as well as the specific foods consumed may be one of many factors that influences IBS Studying diet is quite challenging True food allergies are very rare General recommendations are possible, but diet should be tailored to the individual Excess Fructose Lactose Fructans Sorbitol Raffinose Honey, apples, pears, peaches, mangos, fruit juice, dried fruit Milk, ice cream, cheese, whey, curd Wheat (large amounts), rye (large amounts), onions, leeks, zucchini Apricots, peaches, artificial sweeteners and gums Lentils, cabbage, Brussels sprouts, asparagus, green beans, legumes Halpert A et al. Am J Gastroenterol. 27;12(9):1972-1982.; Simrén M et al. Digestion. 21;63(2):18-115.; Cremonini F,; Camilleri M. Gut. 23;52(5):619-621.; Dainese R et al. Am J Gastroenterol. 1999;94(7):1892-1897. Shepherd SJ, Gibson PR. J Am Diet Assoc. 26;16(1):1631-1639.; Gibson PR, Shepherd SJ. J Gastroenterol Hepatol. 21;25(2):252-258. RCTs N Fiber Response* Placebo RR of Unimproved Symptoms (95% CI) NNT (95%CI) Overall 12 591 48% 43%.87(.76-1.) 11 (5-1) Soluble 6 321 48% 36%.78 (.63-.96) 6 (3-5) Insoluble 5 221 46% 46% 1.2 (.82-1.27) *Improved or resolved symptoms. Probiotics:live or attenuated microorganisms that have beneficial effects in humans Meta-analysis of 35 RCTs (n=3452) determined: Probiotics are effective therapies for IBS (global symptoms, pain, bloating, and gas) (NNT=7) We found evidence to support the use of combinations of probiotics as a group, although notfor any of the different combinations studied individually. CI, confidence interval; NNT, number needed to treat; RCTs, randomized, controlled trials; RR, relative risk. Ford AC et al. BMJ. 28;337:a2313. Ford AC et al. Am J Gastroenterol. 214 Oct;19(1):1547-61.
Up to 5% of all patients with IBS use some sort of CAM Few CAM therapies have been rigorously evaluated for IBS: Peppermint Safe and moderately efficacious for pain Acupuncture Real and sham both more efficacious than placebo Smooth muscle relaxants with other anticholinergic effects Examples: dicyclomine, hyoscamine Meta-analysis of 22 RCTs comparing 12 different antispasmodics vs placebo (n=1778 patients) Significant heterogeneity among studies Symptoms persist in 39% of patients receiving antispasmodics vs 56% of placebo-treated patients (RR:.68; 95% CI:.57-.81) Appear most useful for abdominal pain Overall, these agents are cheap, widely available, and moderately efficacious for treating pain and bloating (and, possibly, urgency) Khanna R. et al. J Clin Gastroenterol. 214 Jul;48(6):55-12. Kaptchuk TJ et al. Plos One. 21 Dec 22;5(12). Ford AC et al. BMJ. 28;337:b1881. Tricyclic Antidepressants (TCAs): 9 studies (N=319 drug vs 256 control) Imipramine*, desipramine*, amitriptyline*, doxepin*; doses 1-15 mg Meta-analysis favors treatment Selective Serotonin Reuptake Inhibitors (SSRIs):5 studies (N=113 drug vs 117 control) Fluoxetine*, paroxetine*, citalopram*; dose 1-4 mg Meta-analysis favors treatment Putative mechanisms include: Central effects (antinociception, +/-anxiolysis and antidepressive) Peripheral effects (SSRIs reduce gut transit, TCAs are modestly anticholinergic) Anecdotally, it is essential to (a) discuss the rationale for these medications, (b) explain that patients may not see benefits for 4 to 6 weeks and that the dose may need to be adjusted *These agents are not currently US Food and Drug Administration approved for IBS. Ford AC et al. Gut. 29;58(3):367-378. RR NNT Trials N 95% CI 95% CI Cognitive behavioral 7 491.6 3 therapy.42-.87 2-7 Relaxation 5 234.82 training.63-1.8 Dynamic 2 273.6 3.5 psychotherapy.39-.93 2-25 Hypnotherapy 2 4.48 2.26-.87 1.5-7 Anecdotally, it is critical to (a) identify appropriate candidates and (b) explain the rationale for psychological therapy Ford AC et al. Gut. 29;58(3):367-378. Study N Female % Response: Alosetron, % 1. Camilleri M et al. Aliment Pharmacol Ther. 1999;13(9):1149-1159. 2. Camilleri M et al. Lancet. 2;355(929):135-14. 3. Camilleri M et al. Arch Intern Med. 21;161(14):1733-174. 4. Lembo T et al. Am J Gastroenterol. 21;96(9):2662-267. 5. Jones RH et al. Aliment Pharmacol Ther. 1999;13(11):1419-1427. Response: Placebo, % Therapeutic Gain, % Camilleri 1 37 53 6 33 27 Camilleri 2 647 1 41 29 12 Camilleri 3 626 1 43 26 17 Lembo 4 81 1 73 57 16 Jones 5 623 1 58 48 1 Female patients with chronic, severe IBS-Dwho failed other treatments Patient education regarding possible serious adverse effects of severe constipation or ischemic colitis.95 cases of ischemic colitis/1 patient-years.36 cases of severe constipation/1 patient-years If ischemic colitis occurs, it is usually within the first month of therapy Prescribing program mandated by US Food and Drug Administration Requires patient to sign attestation form
5 4.5 4 3.5 3 2.5 2 1.5 1.5 Placebo (n=71) PEG 335+E (n=68) # SBMs Pain Level SBMs, spontaneous bowel movements. Chapman RW et al. Am J Gastroenterol. 213;18(9):158-1515. PEG is an alcohol that is not absorbed through the gut lumen. It creates an osmotic gradient that drives water into the lumen 139 adults with IBS-C were randomized to placebo or PEG 335 plus electrolytes (PEG 335+E) During week 4 of treatment, PEG improved number of SBMs (P<.1), but not pain in IBS-C patients 5 Overall Responders (%) 25 *P=.1 17.9 Lubiprostone 8 µg bid n=78 1.1 Placebo n=387 Drossman DA et al. Aliment Pharmacol Ther. 29;29(3):329-341. 12-week treatment period Overall responder: Monthly responder for at least 2 of 3 months Monthly responder: At least moderate relief for 4/4 weeks or significant relief for 2/4 weeks Mean SBM Frequency per Month 8 7 6 5 4 3 2 1 Phase 3 Studies Randomized Withdrawal/Extension Studies Baseline 1 2 3 4 5 6 7 8 9 1 11 12 13 Month of Treatment P/L Group (n=179) Chey WD et al. Aliment Pharmacol Ther. 212;35(5):587-599. Change From Baseline -.25 -.5 -.75-1. -1.25-1.5 1 L/P/L Group (n=8) Abdominal Pain/Discomfort 2 3 4 5 6 7 8 9 1 11 12 13 Month of Treatment L/L Group (n=261) N=52 IBS-C patients who completed 12 or 16 weeks of a placebo-controlled phase 3 trial; patients enrolled in the extension study all received lubiprostone 8 µg bid. P, placebo L, lubiprostone % Adequate Relief: IBS Symptoms 8 6 4 2 Most common AE diarrhea (19.7% vs 2.5%) AE, adverse event. *P<.1 NNT=4.2 49.1 Lin 29 mcg N=41 Chey WD et al. Am J Gastroenterol. 212;17(11):172-1712. 25.1 Placebo N=43 Patient-Provider relationship Lifestyle changes Diet, fiber, and probiotics CAM therapies Antispasmodics Antidepressants Psychological therapies Gut-specific IBS-D: Alosetron IBS-C: PEG, Lubiprostone, Linaclotide