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Treatment options in Irritable Bowel Syndrome

Treatment options in Irritable Bowel Syndrome. Phillis Ling MPH, DO. Definition and epidemiology. Revised Rome III diagnostic criteria include the following: Recurrent abd pain or discomfort at least 3 days per month in the last 3 months associated with 2 or more of the following:.

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Treatment options in Irritable Bowel Syndrome

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  1. Treatment options in Irritable Bowel Syndrome • Phillis Ling MPH, DO

  2. Definition and epidemiology • Revised Rome III diagnostic criteria include the following: Recurrent abd pain or discomfort at least 3 days per month in the last 3 months associated with 2 or more of the following:

  3. -improvement with defecation -Onset associated with a change in stool frequency -Onset associated with a change in stool form

  4. Most important step in the diagnosis is to listen, review symptoms in detail recognizing the key feature being the presence of abdominal pain or discomfort associated with bowel dysfunction -this separates IBS from functional constipation and functional diarrhea

  5. IBS affects up to 10%-20% of adolescents and adults. • Prevalence in women of 14.5% compared to 7.7% of men with a 2:1 (F:M) ratio • 40% to 60% of referrals to outpatient gastroenterology clinics.

  6. Pathophysiology • Visceral hypersensitivity • Abnormal gut motility • Genetics ( 2 fold increase in IBS in monozygotic twins, having a parent with IBS is an independent and stronger predictor of IBS than having a twin with disease)

  7. Psychosocial factors: heightened pain sensitivity to visceral stimulation of the brain-gut axis - Fibromyalgia( 49%pts have IBS), chronic fatigue syndrome (51%), chronic pelvic pain (50%), TMJ syndrome (64%)

  8. Post –infectious causes • Luminal irritation: small bowel bacterial overgrowth (SIBO), gas, ?food allergy

  9. Symptoms and treatment • Dietary triggers: caffeine,excess fatty foods, sorbitol, glucose, fructose, lactose, beans, uncooked broccoli, cabbage, cauliflower, carbonated drinks, certain spices • Dietary fiber: soluble (starches) vs insoluble (tough skin, peel seeds, pods) • soluble fiber is fermented in the proximal colon results in increased stool viscosity • Insoluble fiber binds water but more resistant to fermentation; increases stool bulk, decreases colonic transit time but can cause bloating, diarrhea, abd pain.

  10. AGA recommends 20-35g/day fiber;typical diet contains 11-13g/day - Bulking agents include metamucil,benefiber, citrucel,konsyl are considered soluble fiber, may be beneficial -metamucil –psyllium seed (ispaghula seed) 4/5RCTS improve ease of stool passage but no change in pain

  11. Antispasmodics (hyoscyamine, didydoline, glycopyrrolate) -Relax gut smooth muscle ; best given 30-60 minutes before meals if related to eating -insufficient data for recommendation

  12. Antidiarrheal Loperamide (IBS-D) opioid agonist inhibits intestinal secretion and peristalsis, slows intestinal transit, allow absorption of fluid and electrolytes • Minimal analgesia • Longer duration of action than diphenoxylate, less abuse potential, no anticholinergic agent added (eg atropine) • Generally safe and effective for treatment of diarrhea but needs monitoring in chronic patients to avoid megacolon

  13. Tricyclic antidepressants (TCAs) • Better than placebo at relieving global symptoms and abd pain • Used at a lower dose than in treating depression and anxiety (eg: nortryptiline 10mg daily, desipramine 50mg daily, amitryptiline 10-25mg daily)

  14. Secondary agents (nortryptiline, desipramine) preferred over tertiary agents (amitriptyline, imipramine) due to more favorable side effect profile • No evidence one more effective than another

  15. Selective serotonin reuptake inhibitor (SSRI) • May have beneficial effects on general well-being • No evidence one agent is better than another

  16. Serotonin-norepinephrine reuptake inhibitor (SNRI) such as duloxetine and venlafaxine • Effective in reducing pain in chronic pain such as fibromyalgia but • Data from RCT of their role in IBS lacking

  17. Serotonin (5hydroxytryptamine, 5HT) seems to be the most important neurotransmitter in the enteric nervous system in gut sensitization Serotonin receptor modulating drugs: Alosetron 5 HT3 receptor antagonist -used in IBS-D by antagonizing the release of serotonin to mucosal stimulation that results in increased intestinal secretion, motility and sensation

  18. Alosetron • Introduced in spring 2000; Placebo-controlled RCT at 1mg po bid for 12 weeks • Improved symptoms overall • Efficacy in women with IBS-D based on phase 2 trials • Complications from ileus, fecal impaction, ischemic colitis (latter prev 0.15% vs 0.06% in placebo group) • Reintroduced with strict guidelines in 2002 for IBS-D women with at least 6 months of symptoms not responsive to conventional treatment

  19. Tegaserod (initially approved in July 2002) Used in IBS-C by stimulating 5 HT4 receptors to increase gastric emptying, small bowel and colonic motility - 0.11% (13/11600 pts) increased cv events vs 0.01% ( 1/7031pts) - Reintroduced July 2007: restricted access for use in women 18 to 54 years with IBS-C or CC with unsatisfactory response to other treatment

  20. Alosetron and Tegaserod – Grade A AGA recommendations -evidence based on a minimum of 2 RCTs, p value <0.05; adequate sample size and appropriate methods

  21. Chloride channel activators (Lubiprostone) - acts on epithelial cells to increase intestinal fluid to promote spontaneous bowel movements • Drossman et al ( Gastro 2007) showed proportion of pts with symptom relief was significantly higher at dose of 8mcg po bid compared to placebo, in two 12 week phase 3 placebo-controlled randomized double blind trials • FDA approved at 24mcg po bid for CC

  22. Antibiotics and Probiotics Postinfectious (PI IBS) causes first suggested in the 1960s. • 90 % of people recover spontaneously following a bout of enteritis • 10 % develop PI IBS • Overall incidence of 4% to 36% of new onset IBS after an acute enteritis. • Symptoms can persist for years (6years) • Risk factors: Women, patients with anxiety, depression, severe or prolonged symptoms of gastroenteritis, absence of vomiting. • Salmonella infection results in the highest incidence approx 10%; other pathogens include Campylobacter, E Coli, Giardia, Shigella

  23. Mucosal inflammation develops as a response to initial bacterial infection • Low-grade inflammation is an abnormal reaction to the normal flora or response to changes in the intrinsic flora

  24. Rifaximin –luminal nonabsorbable (<0.4%) antibiotic • No clinically relevant antimicrobial resistance • ? Prevent traveler’s diarrhea to reduce new-onset IBS symptoms being assessed.

  25. Hypothesis that symptoms of IBS may result from abnormal fermentation assoc with small intestinal bowel overgrowth (SIBO) • Prevalence by lactulose breath test of 65 % to 84% in IBS patients • Rifaximin relieved global symptoms up to 10 weeks after discontinuation of therapy (Pimental et al) • Improve gas/bloating at lower dose • Need more study

  26. Other antibiotics • Neomycin -oral aminoglycoside that is systemically absorbed -neomycin 1g/day for 10 days improved IBS scores compared to placebo (N=111, p<0.05)

  27. Normalization of LBT with neomycin leads to decrease in IBS symptoms • Subanalysis on IBS –C pts(n=39) 20 received placebo and 19 received neomycin;global improvement seen, constipation improved • Methane producers receiving neomycin showed significantly improved constipation (p<0.05)

  28. Definition of probiotics: live organisms that, when ingested in adequate amounts, exert a health benefit on the host • ?inhibit visceral perception of pain • normalize epithelial barrier function • Reduce inflammation (reduce IL10/IL 12 ratio)

  29. One controlled pilot study of 77pts with IBS randomized to lactobacillus salivarius, Bifidobacterium infantis or placebo for eight weeks (O’ Mahony 2005) -those treated with Bifidobacterium showed greater reduction of symptoms throughout 8 week treatment period and some of the 4 week washout period

  30. Efficacy of B. infantis further studied in 362 women with IBS of any subtype (Whorwell, 2006) • 1X10 8 cfu/ml more effective

  31. Bifidobacterium infantis 35624 formulation showed statistical improvement in IBS symptoms • VSL#3 study inconclusive • At least 15 RCTs thus far • Occasional reports of endocarditis and abscesses receiving probiotics usually been secondary superinfections rather than primary

  32. PEG 3350 ( Grade A AGA recommendation) • Nonabsorbable nonmetabolized osmotic agent • Recent six month study suggested that PEG 3350 is effective over this period compared to placebo (52% vs 11%,P<0.001) • Concerns over long-term efficacy

  33. Other agents in development • Cilansetron similar to alosetron, a 5HT3 antagonist for abd pain/discomfort • Renzapride-a full 5-HT4 receptor agonist /5-HT 3 antagonist for IBS-C

  34. Renzapride • Pilot study in 17pts with IBS –C ;received placebo, renzapride 2mg po qd and renzapride 2mg po bid for 28 days • Improvement at 2mg po bid • Reduced abd pain, improved stool consistency, increased number of pain-free days • Well –tolerated by pts

  35. Linaclotide-agonist of human guanylate cyclase for IBS-C (phase 2) • Clonidine 0.1mg po bid alpha 2 agonist (phase 2/3) for IBS-D • Fedotizine, asimadoline- peripheral opioid agonists (phase 2) • Alvimopan opioid antagonist

  36. Dextofisopam-benzodiazepine receptor agonist (phase 2) for IBS-D and IBS-mixed • AT1-7505 5HT4 receptor agonist similar to cisapride • GW876008 CRF antagonist (phase 2) for IBS-D • Pindolol- beta blocker and 5HT antagonist (phase 2)

  37. Additional therapy • Cognitive –behavioral therapy • Cognitive-Change thinking patterns underlying somatization • Behavioral-modify behavior through relaxation, contingency ( reward healthy behavior) and assertion training • Hypnotherapy –improve symptoms, QOL

  38. Metanalysis of 17 RCTs of cog tx, beh tx,or both ( including hypnotherapy ) for IBS compared to control tx • Cognitive-behavioral tx more likely to have a reduction in GI symptoms • Estimated number sessions was two ( range of sessions typically 4 to 15 sessions)

  39. Psychotherapy • Herbal remedies (complementary alternative medication): no quality control in this area • Acupuncture: no improvement in quality of life compared to sham treatments for IBS

  40. conclusions • Holistic approach • Detailed history including diet, lifestyle • Recognition of pathophysiology in combination with pt’s psychosocial factors • Peripheral management target symptoms of constipation, diarrhea, bloating, pain • Ongoing study involving manipulating flora with probiotics and antibiotics to exert antibacterial, immune-modulating and anti-inflammatory effects • Central agents affect homeostatic afferent processing;may or may not improve individual IBS symptoms but tend to reduce global symptoms and improve well-being.

  41. Thank you for your attention.

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