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Constipation Prevalence of IBS Irritable Bowel Syndrome: Diagnosis Past, Present, and Future IBS 12% IBS G. Nicholas Verne, M.D. Other GI 28% 15% IBD Professor and Division Director 14% Division of Gastroenterology, Hepatology, Nutrition All Other PC Peptic Other 20% Functional Diagnoses Liver 13% Department of Internal Medicine 88% 10% Ohio State University Columbus, OH Primary Care Gastroenterology Practice Practice Mitchell & Drossman, Gastroenterology, 1987 Prevalence of IBS in Quality-of-life impact of the US IBS vs other conditions Subscale score (100=good; 0=bad) 14 100 12 Male 90 10 Female 80 70 8 % 60 6 50 40 IBS 4 US General Population 30 Migraine 2 20 Asthma female (15-34) 10 GERD 0 0 15-34 35-44 >45 Physical Role Bodily General Vitality Social Role Mental Functioning Physical Functioning Health Ages in Years Pain Health Emotional Drossman et al., Dig Dis Sci, 1993 Frank et al, Clin Ther 2002 1 Medical Costs Stool Character- Associated With IBS Description • IBS results in an estimated $8 billion in direct medical costs annually • IBS sufferers incur 74% more direct healthcare costs than non-IBS sufferers • IBS patients have more physician visits for both GI and non-GI complaints Talley et al., Gastroenterology, 1995 IBS: Symptoms Prevalence by IBS subgroups Chronically recurring symptoms Survey respondents (%) 9 Abdominal pain 8 Overall 6.7 Females 9 Altered bowel function 5.6 5.6 Males 5.2 5.5 5.3 5.2 Alternator 4.7 3022 residents 3.5 Diarrhea Constipation surveyed in predominant predominant Minnesota 536 respondents 9 Incomplete evacuation 0 9 Urgency IBS- IBS- IBS- 9 Bloating constipation diarrhea alternating Talley et al, 1995 2 Rome I-II Criteria Rome III Criteria Visceral 1. At least 3 months of continuous 1. At least 12 weeks, which need or recurrent symptoms of not be consecutive, in the Hypersensitivity in IBS abdominal pain or discomfort that past 12 months of abdominal is: discomfort or pain that has 2 9 Relieved by defecation and/or of 3 features: Pain 9 Associated with a change in 9 Relieved by defecation; frequency of stool; and/or and/or Brain stem Ascending pain pathway 9 Associated with a change in Dorsal root ganglion consistency of stool 9 Onset associated with a change in frequency of 2. 2 or more of the following at least stool; and/or 25% of the time: Spinal 9 Onset associated with a 9 Altered stool frequency cord change in form 9 Altered stool form (appearance) of stool Viscera 9 Altered stool passage (straining, urgency, feeling of incomplete evacuation) 9 Passage of mucous; and/or 9 Bloating or feeling of abdominal distension Longstreth, Gastroenterology, 2006 Verne & Price, 2002 IBS-Pathophysiology CNS / ENS Visceral Pain Thresholds Stress affects Pain Clustered Autonomic GI function sensitivity contractions reactivity Pain produced by rectosigmoid balloon distension 60 Meals 3 cpm Visceral Post-infectious IBS Pain / motility motility hypersensitivity IBS 1950 19601970 1980 1990 2000 40 Mechanisms Brain-Gut 20 Interactions Normal Motility Pain Reporting % Myoelectrical Marker Inflammation 0 20 60 100 140 180 Visceral/Somatic Rectosigmoid balloon volume (mL) Hypersensitivity Whitehead et al., Dig Dis Sci, 1980 3 Distender Series ®/Barostat Visceral Stimulation Protocol Barostat Catheter/Balloon Somatic Hypersensitivity in IBS Patients • IBS patients also exhibit a number of extra- intestinal symptoms such as migraine headaches, back and muscle pain • Consistent with central hyperalgesic mechanism(s) • Recent studies have suggested that somatic hyperalgesia may also occur in IBS patients Verne & Price, 2002 4 Thermal Hyperalgesia Hot Water Immersion in IBS *P<0.001 * * Verne et al., Pain 2001. Mechanical Visual Viscerosomatic Analogue Scale Convergence Foot Anterolateral Colon Tract axon Price et al., Pain, 1994 Verne et al., Gut, 2006 5 Visceral Some Possible Mediators of Hypersensitivity:Pathophysiology Motility and Visceral Sensitivity • Triggers: chemical, environmental, physical, stress, inflammatory • Motility: • Visceral sensitivity: • Postulated mechanisms: - serotonin - serotonin 9hyperexcitability/activation of neurotransmitters - acetylcholine - tachykinins (sub P, CGRP) - nitric oxide - calcitonin gene-related 9modulation of nociceptive transmission (NMDA) - substance P peptide 9recruitment of silent nociceptors - vasoactive intestinal - neurokinin A 9loss of inhibitory modulation to dorsal horn peptide - enkephalins neurons - cholecystokinin 9neuroplasticity leading to chronic visceral hypersensitivity Mayer & Raybould, Gastroenterology, 1990; Kim and Camilleri, Am J Gastroenterol 2000 Mayer & Gebhart, Gastroenterology, 1994 Grider et al., Gastroenterology 1998 Sensitization Following Plasma 5-HT levels Peripheral Injury in IBS Mechanosensitive afferent 5-HT (nmol/l) 5-HT (nmol/l) Sensitized Controls (n=6) IBS patients (n=5) 1 1400 Meal 1400 Meal spinal 2 10 7 circuits 1200 3 1200 8 4 9 1000 5 1000 10 800 6 800 11 Dorsal root 9 ganglion 600 600 400 400 7 8 200 200 11 0 0 0 1.0 2.0 3.0 4.0 0 1.0 2.0 3.0 4.0 Peripheral Time (h after meal) Time (h after meal) Injury Bearcroft et al., Gut, 1998 6 Serotonin and EC cells Diagnostic Tests for IBS in Altered GI Motility If patient has typical features of IBS: Increased circulating 5-HT Diarrhea • Labs: 9CBC, electrolytes, LFTs, TSH • Stool studies: Increased number of EC cells Constipation in post-infectious IBS 9Occult blood, leukocytes, O & P, Giardia lamblia antigen • Endoscopy: Decreased number of EC cells in constipation 9Sigmoidoscopy ± air-contrast barium enema or colonoscopy if ≥ 50 yrs Bearcroft et al., Gut 1998 Spiller et al, Gut 2000 IBS - Pathophysiology “Red Flags” Input Integration Effect Additional diagnostic screening needed for Cognition atypical presentations such as: Affect • Anemia • Nocturnal symptoms of Sight Sound pain and abnormal bowel Smell • Fever function Somatosensory • Persistent diarrhea • Family history of GI cancer, • Rectal bleeding inflammatory bowel Motility disease, Viscerosensory Secretion Blood Flow • Severe constipation or celiac disease • Weight loss • New onset of symptoms in patients 50+ years of age 7 Case Presentation • 19 yo wf with hx “refractory IBS” • 12 year hx constipation, abdominal pain, and marked abdominal distension • Previous workup including endoscopy: negative • 3 weeks noted between spontaneous bowel movements • On exam, marked distension of abdomen is noted with decreased bowel sounds • KUB obtained: 8 Current Management of IBS Available Treatments • Establish a positive diagnosis for IBS • Reassure patient that there is no Antispasmodics Anticholinergic/ serious organic disease or alarming Pain Bloating Antiflatulents symptoms Antispasmodics TCAs/SSRIs • No “gold standard” treatment Altered • Existing therapies: Bowel Motility 9marginal efficacy Loperamide Calcium polycarbophil 9side effects Lactulose Cholestyramine 70% sorbitol Psyllium PEG solution 9target only 1 symptom Methylcellulose Psychological Therapy of Functional Gut Treatments for IBS Pain: A Unique Problem • Some patients with IBS may also benefit from: • Current treatment modalities are based on 9 Referral to a psychologist or psychiatrist unproven pathophysiological concepts 9 Hypnotherapy • Placebo response rates vary from 20-88 % 9 Biofeedback • Few therapies have ever been 9 Psychodynamic therapy conclusively been shown to be superior to 9 Stress management/relaxation placebo in well designed studies 9 Cognitive behavioral programs Drossman DA et al. The Functional GI Disorders, 2000. 9 Placebo Response Low Dose TCAs: Possible Rate in IBS Mechanisms of Analgesic Action 31 controlled treatment trials 1966-98, n= 2469 • Reuptake inhibition of NE and 5HT • Receptor antagonism of H1, 5HT-2, D2, • Overall range 17-84% muscarinic sites • Median 52 % • Mean 55.6 % • NMDA receptor antagonist • Range 17-40 % : 10 studies, n = 472 • Induction of glucocorticoid receptor • Range 41-60 %: 8 studies, n = 557 expression • Range 61-84 %: 13 studies, n = 1440 • Direct effect on peripheral afferent nerves Tricyclic Antidepressants Physiological and SSRIs Distribution of 5-HT • Used for pain CNS – 5% • Reserved for patients with severe or refractory symptoms 9Are effective for neuropathic pain GI tract – 95% • enterochromaffin cells 9Have central analgesic/anticholinergic effects • neuronal Drossman & Thompson, Ann Intern Med., 1992 Gershon, Aliment Pharmacol Ther.,1999 10 Serotonin (5-HT) Serotonin (5-HT) Receptors in the Gut Receptors in the Gut 5-HT3 5-HT4 • Currently 14 5-HT receptor or recognition Pharmacologic Action Antagonists Agonists sites identified: Accelerates UGI Transit + + • 5-HT , 5-HT , 5-HT , 5-HT2, 5-HT3, 5- Increased colonic motor - + 1A 1P 1C activity HT4 found in gut Slows colonic transit + - • 5-HT1: Inhibition of neurotransmitter Anti-emetic properties + ? release and increased smooth muscle contraction Analgesic + ? • 5-HT2: Contraction of gut smooth muscle Anxiolytic + ? Nodose Ganglion to Brain Serotonin Agents 5-HT 3 5-HT Aδ 5-HT4 3 5-HT3 Receptor Antagonists CGR Alosetron (Lotronex®) P Odansetron (Zofran®) 5-HT Distention Cilansetron Stimulation 5-HT4 Receptor Agonists EC Cells Cisapride (Propulsid®) ® Mast Cells Prucalopride (Resolor ) Tegaserod (Zelnorm®) 5-HT from EC cells activates 5-HT3 & 5-HT4 receptors on extrinsic afferents 11 ® Alosetron (Lotronex®)in IBS Alosetron (Lotronex ): Contraindications 9 Selective 5-HT3 receptor antagonist • Chronic or severe constipation 9 Enhances jejunal water/salt absorption • History of intestinal obstruction, adhesions, perforation, or toxic megacolon 9 Increases
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