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Irritable Bowel Syndrome: what are our treatment options?

Irritable Bowel Syndrome: what are our treatment options?. Sara Faber, MD January 19, 2011. Goals of discussion. Clinical context Epidemiology and diagnosis of IBS Review of treatment options for IBS

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Irritable Bowel Syndrome: what are our treatment options?

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  1. Irritable Bowel Syndrome: what are our treatment options? Sara Faber, MD January 19, 2011

  2. Goals of discussion Clinical context Epidemiology and diagnosis of IBS Review of treatment options for IBS Review of article: Rifaximin Therapy for Patients with Irritable Bowel Syndrome without Constipation. NEJM 2011; 364:22-32.

  3. How’s this for a chief complaint? • CC: “Can you give me a prescription for rifaximin?” • HPI: 20 yo F with h/o IBS. Diagnosed 1 y ago by physician friend of family. Evaluation involved extensive bloodwork, no scope. At presentation, had bloating and diarrhea. Now, pt c/o worsening bloating and diarrhea, 3-4 episodes daily. + mucus. No constipation. Symptoms unrelated to meals. Diarrhea interfering with college life.

  4. Patient history, continued… Meds: Previously was treated with “some pills” for her IBS. ROS: No weight loss, no nighttime pain, otherwise negative.  So, how do we answer her question?

  5. IBS – the basics • Definition: recurrent abdominal pain and disturbance in bowel habits in absence of organic cause. • Epidemiology: • Found in all patient population groups • More common in young women • Overall 2:1 female predominance in North America • Prevalence of 10-15%, though only 15% of these seek medical attention

  6. IBS: the cost to society • One study demonstrated that IBS is a risk factor for more frequent visits to physician (“high user of health care”) • 2nd most common cause of work absenteeism • 3.5 million annual doctor visits for IBS • Direct costs of 1.6 billion; indirect costs of 19.2 billion

  7. Diagnosing IBS • Manning criteria vs. Rome criteria • Both have undergone revision • Most recently, Rome criteria have been simplified to definition already presented • Four subtypes identified • IBS with constipation • IBS with diarrhea • Mixed IBS • Unsubtyped IBS

  8. Back to our patient… • Does she have IBS? • No red flag symptoms • Labs: CBC, chemistries, ESR normal. Celiac panel normal. Stool culture negative. Hemoccult negative. Refused scope. Diagnosed with IBS with diarrhea

  9. Approaching IBS treatment Most traditional therapies treat symptoms. Newer therapies are based on pathophysiologic theories.

  10. Non-pharmacologic therapies • Dietary modification • Increase fiber, minimize lactose • Efficacy of modifications has not been established, and food allg testing not recommended • Psychosocial interventions • Studies in UK ongoing: randomized controlled trial of mebeverine, methylcellulose, placebo and use of a self management cognitive behavioral therapy website. (BMC Gastroenterol. 2010 Nov 18;10:136.) • CBT may help with comorbidities.

  11. Other traditional pharmacologic therapies Bulking agents: psyllium Antispasmodics: hyoscine, dicyclomine Antidiarrheals: loperamide Agents to increase gut fluid secretion: lubiprostone, linaclotide

  12. Pathophysiology • No definitive pathway has been identified to explain IBS. • Therefore, likely multifactorial etiology. Studies have suggested: • IBS = serotonergic d/o? • IBS = inflammatory d/o? • IBS 2/2 bacterial overgrowth?

  13. IBS – a serotonergic disorder? • 5HT receptors found on smooth muscle, enteric neurons and enterocytes in the gut. • Studies suggest there may be 5HT excess in IBS c diarrhea, and 5HT insufficiency in IBS c constipation. • Treatment options: SSRIs, 5-HT3 antagonists and 5-HT4 agonists.

  14. IBS – an inflammatory disorder? • Studies have shown increased mast cells in GI tracts of patients with IBS. • Treatment options: • Steroids have not been shown to be effective. • Mesalamine undergoing investigation, but despite decreasing immune cells, did not seem to affect patient symptoms.

  15. IBS – 2/2 bacterial overgrowth? • Theory is that alterations in gut microbes leads to imbalance and symptoms of IBS. • No data for this b/s difficult to diagnose small intestinal bacterial overgrowth; small number of studies; studies use different definitions of overgrowth. • Treatment options: metronidazole, rifaximin

  16. So, how ‘bout that rifaximin? Pimental, et al. Rifaximin Therapy for Patients with Irritable Bowel Syndrome without Constipation. NEJM 2011; 364:22-32. Purpose: Evaluate if rifaximin (a minimally absorbed oral antibiotic), compared to placebo, offers significant relief of self-reported IBS symptoms.

  17. Study methods • Patients (Table 1, p 27) • Inclusion: • age >18 yr • dx of and current symptoms of IBS • daily pain of 2.5-4 out of 7-points (Likert scale with 0 = not at all and 6 = a very great deal) • consistency of stool >3.5 on 5 pt scale (i.e. loose) • Exclusion: constipation predominant IBS; on other therapies for IBS (full list p. 23)

  18. Demographic and Baseline Characteristics of the Modified Intention-to-Treat Population in the Two Studies. Pimentel M et al. N Engl J Med 2011;364:22-32

  19. Study methods • Study design (Fig 1, p 24) • Patients randomized to rifaximin or placebo x 14 days • Evaluated for 10 additional weeks for study endpoints

  20. Study design Pimentel M et al. N Engl J Med 2011;364:22-32

  21. Primary and secondary endpoints • Primary endpoint: “adequate relief” • Patients answered yes/no question: did they have adequate relief of “IBS symptoms”? • End point was adequate relief in: • At least 2 of 4 weeks in initial evaluation period (the month after getting treatment) • At last 2 of 4 weeks per month in months 1, 2, 3. • Proportion of patients who answered positively was assessed • Secondary endpoints • Adequate relief of bloating symptoms • Relief of abd pain and discomfort and loose stools (a composite end point): assessed daily • Safety measures

  22. Statistical Analysis • Modified intention to treat analysis: patients included even if they took just one dose, but all pts lost to follow up or pts who withdrew were excluded. • Missing data filled in with “last observation carried forward” method. • Assessed both binary data (yes/no questions) and continuous outcomes (scaled responses). • Ran 2 study groups simultaneously: TARGET1 and TARGET2: assessed data in individual groups as well as combined.

  23. Enrollment, Randomization, and Follow-up in the TARGET 1 and TARGET 2 Studies. Pimentel M et al. N Engl J Med 2011;364:22-32

  24. Results (combined groups)weeks 3-6 • Primary endpoint: • Adequate relief of IBS sxs for at least 2 of the first 4 weeks  40.7% of treatment group; 31.7% of placebo (P < 0.001) • Proportion of patients with response to treatment  40.2% in treatment group; 29.5% in placebo (P < 0.001) • Secondary endpoint: • Adequate relief of bloating for at least 2 of first 4 weeks  40.2% of treatment group; 30.3% of placebo (P < 0.001) • Proportion of pt with response  41.3% of treatment; 31.7% of placebo (P < 0.001) • Adequate relief of abd pain & loose stools: 44.3% in treatment group vs. 36.3% placebo (TARGET1)

  25. Results (combined groups)months 1-3 • “…more patients in the rifaximin group than in the placebo group in both studies had adequate relief of global IBS symptoms within the first month, with continued relief during the first 2 months and during all 3 months in both studies (P = 0.05 in TARGET 1, P = 0.005 in TARGET 2, and P < 0.001 in the two studies combined…)” • No significant benefit for bloating over 3 months

  26. Analyses of Primary, Key Secondary, and Other Secondary End Points. Pimentel M et al. N Engl J Med 2011;364:22-32

  27. Percentage of Patients with Adequate Relief of Global IBS Symptoms in the TARGET 1 and TARGET 2 Studies Combined. Pimentel M et al. N Engl J Med 2011;364:22-32

  28. Adverse Events during the 12-Week Study. Pimentel M et al. N Engl J Med 2011;364:22-32

  29. Limitations Modified ITT c missing data filled in Composite endpoints All endpoints were subjective scales Large benefit seen in placebo groups (~30% relief)

  30. Back to my patient… 20 yo F with IBS (with diarrhea, no constipation) who asks, “Can you give me a prescription for rifaximin?”

  31. References • Wald, A. Clinical manifestations and diagnosis of irritable bowel syndrome. Up-to-date. Revised 9/24/10. • Wald, A. Treatment of irritable bowel syndrome. Up-to-date. Revised 1/20/10. • Chang, JY et al. An update on irritable bowel syndrome: from diagnosis to emerging therapies. CurrOpin in Gastro 2011; 27:72-78. • Pimentel, M et al. Rifaximin Therapy for Patients with Irritable Bowel Syndrome without Constipation. NEJM 2011; 364:22-32.

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