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Antidepressants in Irritable Bowel Syndrome

Antidepressants in Irritable Bowel Syndrome. Alan Chiemprabha, M.D. Case Presentation. Mrs X is a 44 y.o.w.f with a PMHx significant for htn, tobacco abuse, anxiety, hyperlipidemia who presented to the OPD Medicine Clinic to establish a new PCP.

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Antidepressants in Irritable Bowel Syndrome

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  1. Antidepressants in Irritable Bowel Syndrome Alan Chiemprabha, M.D.

  2. Case Presentation • Mrs X is a 44 y.o.w.f with a PMHx significant for htn, tobacco abuse, anxiety, hyperlipidemia who presented to the OPD Medicine Clinic to establish a new PCP. • The patient has not seen a physician for several years and presents now because of worsening chronic, intermittent lower abdominal pain associated with three loose bowel movements each day for the last two months. • Fam Hx - negative for early CADz, cancer, gi dz • Soc HX - 1 ppd tob, no etoh, divorced, lives with 2 sons • Meds - xanax prn • ROS - poor sleep, depressed mood, occ crying spells, no weight loss/early satiety/bloody or melanotic stools/fevers/night sweats/night time abd pain/suicidal ideation. • Exam - normal vitals, mildly obese, unremarkable heent, cv, chest, abd, ext, pelvic, breast, rectal (heme -)

  3. A chronic noninflammatory disease characterized by abdominal pain, altered bowel habits consisting of diarrhea, constipation or both, bloating and disturbed defecation associated with significant disability and health care costs. More strict definitions include: Manning Criteria Rome Criteria Mild IBS (70%) - cared for by pcp; little or no functional impairment Moderate IBS (25%) - exacerbations disrupt daily activities Severe IBS (5%) - severe, unrelenting pain associated with Irritable Bowel Syndrome

  4. Manning criteria • Originally 15 symptoms were thought to be typical of IBS - 6 were found to be significantly more common in IBS. • Abdominal pain relieved by defecation • Looser stools with onset of pain • More frequent stools with onset of pain • Abdominal distention • Passage of mucus • Sensation of incomplete evacuation

  5. Rome Criteria • At least 3 weeks of continuous or recurrent symptoms of the following in the preceding 3 months: • Abdominal pain or discomfort relieved with defecation, or associated with a change in frequency of stool, or associated with a change in consistency of stool • Two or more of the following, at least on one fourth of the occasions or days: altered stool: frequency, form, passage, passage of mucous, or bloating or feeling of abdominal distention

  6. “Catfishin”

  7. affects 5-12% men affects 13-19% women U.S. incidence rate in non-whites unclear half present between the ages of 30 and 50 decreasing prevalence with increasing age (>60) symptoms wax and wane accounts for 3 million physician visits per year in the U.S. accounts for 12 percent of primary care visits and 25-50 percent of gastroenterology referrals IBS patients miss more work, utilize health care services more frequently, and incur higher healthcare costs on a yearly basis (primarily around the index year) Epidemiology/Health Care Burden

  8. Pathophysiology • Abnormal motility - no consensus; persons with IBS have increased motility in response to environmental or enteric stimuli. • Enhanced visceral sensitivity - to painful distentions, to normal intestinal function, increased somatic referral. • CNS Modulation - the brain-gut axis; link of higher cortical…visceral afferents…and visceral motor. • Psychosocial dysfunction - increased frequency of psychiatric diagnoses and abuse history in IBS patients.

  9. Diagnosis • Make a positive symptomatic diagnosis using the the Rome Criteria + absence of Red Flags/Alarm Sx • Talley et al.2 Manning criteria: sensitivity 58%; specificity 74% in discriminating IBS from organic gi disease. Manning criteria - less useful in clinical settings but is still useful in epidemiologic studies. • Vanner et al.1 Rome Criteria + absence of Red Flags: sensitivity 63%; specificity 100%. Validated in long-term outcome studies by Owens et al.20 • Perform routine diagnostic studies and risk stratify the patient for organic disease to determine of additional diagnostic studies are needed.

  10. Anorexia Malnutrition Weight Loss Progressive Pain Awakening Pain Sleeplessness secondary to pain Abnormal physical exam Large Volume Diarrhea Bloody Stools Nocturnal Diarrhea Greasy Stools Diagnosis cont’d: Red Flags

  11. Diagnosis cont’d • Initial diagnostics should include: CBC, Chemistry panel, LFT’s • Consider further diagnostics if symptoms persist despite the general treatment protocol. • For diarrhea-predominant subtypes: stool for quantitative volume, O&P, enteric pathogens, fecal fat, leukocytes, TSH, sigmoidoscopy and biopsy, small bowel biopsy. • For constipation-predominant subtypes: colonic transit studies to (verify presence and degree of constipation) and anorectal manometry.

  12. General Treatment Approach • 1. Good Patient-Physician Relationship • 2. Continued Education and Reassurance • 3. Dietary Modification • 4. Symptom Monitoring by Patient - mod • 5. Symptom Targeted Pharmacotherapy - mod • 6. Psychological Therapy - mod to sev • 7. Psychotropic Pharmacotherapy - mod to sev • 8. 5 HT 3 Antagonists and Newer Agents - mod to sev

  13. Symptom-Targeted Pharmacotherapy • For predominant Abdominal Pain and Bloating: levsin (an anticholinergic, hyoscyamine 0.125 mg tid), bentyl (an anticholinergic, dicyclomine 10-20 mg tid) and mebeverine (in Europe) to decrease sigmoid motility in response to meals. • For predominant Diarrhea: prn kaopectate and imodium (an opiod, loperamide 2-4mg tid) • For predominant Constipation: increase dietary fiber, metamucil (psyllium product), prn laxatives and stool softeners (avoid chronic use of stimulant laxatives).

  14. Psychological Therapy • Psychological therapy including: 1. Cognitive-behavioral treatment 2. Insight-oriented therapy 3. Relaxation/stress management treatment • Psychological therapy has been shown in RCT’s to reduce anxiety and decrease GI symptoms, mainly abdominal pain and diarrhea. • It seems to be most effective in those patients who relate their exacerbations of IBS to stressors, have typical IBS sx as opposed to chronic pain, and < 50 y.o.

  15. Easter Sunday ‘81

  16. Heefner et al.10 - Methods • Drug: Desipramine 150mg qhs 2 months • Methods: Double, Blind, Placebo Controlled, RCT • 44 pts with IBS randomized into 2 groups of 22, one receiving drug, the other placebo. Treatment lasted 2 mo. • Outcome measures: Patient-rated symptom scale for (0-3) depression, abdominal pain, bowel movement irregularities, interference with daily life, and the Zung-self rated depression scale.

  17. Heefner et al.10 - Results • 14/22 taking drug completed the study, 17/22 taking placebo completed the study (31/44). • Similar improvements in both drug and placebo groups for patient-rated depression, abdominal pain, and bowel movements. • Trend towards statistical significance in the Zung Self-Rating Depression Scale in pre and post drug group (not comparing drug to placebo). • Statistically sig improvement interference with daily life (p<0.05).

  18. Heefner et al.10 - Conclusions • Desipramine 150 mg qhs helps to significantly improve patient- perceived IBS-interference with daily life when compared to placebo but is not significantly different from placebo with regard to other patient-perceived symptoms of IBS.

  19. Steinhart et al.11 - Methods • Drug: Amitriptyline 50mg qhs 4 weeks • Double-blind, placebo-controlled, cross-over, RCT • 14 pts with IBS were randomized to 2 groups one beginning with Amitrip 50mg qhs, the other with placebo, and crossed over to the other treatment after a 2 wk washout period. Each treatment lasted 4 wks. • Outcome Measures: Pts and interviewers rated pt IBS severity on a 4 point scale (I-IV) 5 times during the study with these daily measures summed at the end of the study.

  20. Steinhart et al.11 - Results • Trend towards statistical significance (p=0.08) in the sum of daily symptom severity ratings when comparing drug to placebo. • Statistically significant improvement in the drug group when comparing the pretest daily symptom ratings and that of the group receiving the drug.

  21. Steinhart et al.11 - Conclusions • Treatment with Amitriptyline 50mg qhs showed a significant improvement (p=.0035) in the sum of daily symptom severity ratings when comparing the drug pretest group to the drug group but only a trend towards statistically significant improvement (p=0.08) in sums of daily symptom ratings when compared to placebo.

  22. Xmas ‘91

  23. Myren et al. 1982 12 - Methods • Drug: Trimipramine 50mg qd 4 weeks • Double-blind, placebo-controlled, RCT • 61 patients with IBS; 1 week washout then randomized to trimipramine or placebo for 4 weeks. • Outcome measures: Patient-rated scores registered by a physician on a 10cm analog scale before and after 28 days of treatment for obstruction, nausea, vomiting, belching, headache, sleeplessness, tiredness, anxiety, and depression.

  24. Myren et al. 1982 12 - Results • Significant reductions in complaint scores were seen for both trimipramine and placebo. • Statistically significant reduction in mucus in stool when comparing trimipramine pre-treatment to post-treatment (p<0.003). • “Significantly Higher” reductions in scores for vomiting, sleeplessness, and depression in the trimipramine group (no p value given). • No statistically significant differences given to distinguish trimipramine from placebo.

  25. Myren et al. 1982 12 - Conclusions • Trimipramine 50mg qd significantly decreases mucus in stools when compared to pretreatment. • Otherwise, trimipramine is not significantly different from placebo for obstruction, nausea, vomiting, belching, headache, sleeplessness, tiredness, anxiety, and depression.

  26. Myren et al. 1984 13 - Methods • Drug: Trimipramine 50mg qhs (A), 10mg qam + 40 mg qhs (B), 35 mg qhs (C), or 10 mg tid for 6 weeks (D), or placebo (E). • Double-blind, placebo-controlled, RCT • 428 pts randomized to five different groups (A-E) to one of the above dosings of trimipramine or placebo for 6 weeks. • Outcome measures: Pt-rated (1x/week) and physician-rated (before and at end of study) 10cm analog scale for abdominal pain, oppression, nausea, vomiting, acid eructions, headache, sleeplessness, tiredness, anxiety, depression, and mucus and blood in stool.

  27. Myren et al. 1984 13 - Results • Treatment groups A, B, and C had statistically significant reductions in analog scale values of abdominal pain, acid eructions, and nausea (A and B, p<0.010; C, p<0.05). A statistically significant improvement in the degree of depression (A-D) (p<0.01) and in “total effect of treatments” (p<0.05) occurred in the trimipramine groups when compared to placebo. No statistically significant differences were observed between the groups receiving different doses of trimipramine.

  28. Myren et al. 1984 13 - Conclusions • Trimipramine at doses of 35 mg qhs - 50 mg qhs for 6 weeks is significantly better than placebo at improving some IBS symptoms (abdominal pain, acid eructions, and nausea) (A and B, p<0.01; C, p<0.05). • Trimipramine at all study doses is significantly better than placebo in treating degree of depression scores (p<0.01) and “total effect of treatments” (p<0.05).

  29. Greenbaum et al.14 - Methods • Drugs: Desipramine titrated to 150mg qhs and atropine titrated to 1.2 mg qhs • Double-blind, placebo-controlled, cross-over RCT • 41 pts with IBS underwent a 4wk observation period followed by three 6 week test periods during which pts randomly assigned to receive one of the six possible sequences of the test agents.

  30. Greenbaum et al.14 - Methods Cont’d • Variables assessed biweekly with questionnaires were the following: # of bm’s/week, # of loose bm’s/week, pain index (0-6 scale), constipation (0-4 scale), diarrhea (0-4 scale), retrospective global assessment, desipramine levels. • Also, before the study and at the end of each test period pts were evaluated by two psychologists using the Hamilton Depression Rating Scale (to follow changes in depressive sx) and the Brief Psychiatric Rating Scale (to follow mental status).

  31. Greenbaum et al.14 - Results • 28 of 41 pts completed the study. 19 were diarrhea-predominant, 9 were constipation-predominant. • Diarrhea-predominant subgroup had a statistically significant reduction in the number of stools per week (p<0.02), pain index (p<0.0025), diarrhea (p<0.005), and (in the total group) improvement in the mean Brief Psychiatric Rating Scale compared to placebo (p<0.02). No differences in the # of loose stools/wk and HDRS. • Appeared to be a greater benefit in Retrospective Global Improvement with Desipramine (p=?).

  32. Greenbaum et al.14 - Results

  33. Greenbaum et al.14 - Results

  34. Greenbaum et al.14 - Conclusions • Desipramine titrated to 150mg qhs over a 6 week period is significantly better than placebo in the diarrhea-predominant subgroup at improving some IBS symptoms (pain, #stools/wk, diarrhea). • Appeared to have a greater beneficial effect on pt’s perception of global improvement. • There was no statistically significant difference between desipramine and placebo in depressive symptoms.

  35. Greenbaum et al.14 - Conclusions cont’d • In constipation-predominant pts the effect was unclear given the small N. • This study contrasts the results by Heefner et al. In which desipramine did not show a statistical difference in depressive sx, pain, and bm’s

  36. Tanum and Malt 15 - Methods • Drug: Mianserin titrated up to 120mg in 7wks then tapered to no pills by the end of the 8th week • 47 patients with FGD (functional gastrointestinal disorder including 60% IBS and 40% NUD) were left for randomization to drug and placebo groups after excluding for organic gi dz, renal, hepatic, respiratory, endocrine, rheumatic, cardiovascular, cerebrovascular, or psychiatric dz (including dementia, sz do, schizophrenia, mood/affective do, anxiety do, alc/drug abuse) and after a 1 wk washout period and 1wk single-blind placebo run-in period to exclude early placebo responders.

  37. Tanum and Malt 15 - Methods cont’d • Outcome Measures: Pts were assessed weekly the first 2 weeks then biweekly thereafter using 3 instruments: • 1. CGI - clinical global impression to assess changes in abdominal pain (7 to 1) in pts; performed by the primary investigator. • 2. VAS - visual analog scale; patient-rated pain (VAS-Pain) and 2 target symptoms associated with the abdominal pain (VAS-TSR1&2). • 3. DISS - Disability scale used to assess change in functional disability (0-10) for work, social, and family life.

  38. Tanum and Malt 15 - Results • 45/47 pts completed the study. Statistically significant improvements were seen for the mianserin group for all outcome variables (CGI, VAS-Pain, VAS-TSR, and DISS) at almost all time intervals. • For the placebo-treated patients the CGI, VAS-Pain, VAS-TSR, and DISS assessments remained almost unchanged from baseline. • There was no significant difference in response to treatment between IBS and NUD pts.

  39. Tanum and Malt 15 - Conclusions • Mianserin titrated to a dose of 120 mg qd in this study population showed a statistically significant improvement for all outcome variables at almost all time intervals for pain severity, pain symptoms, and measures of disability.

  40. Jackson et al.9 - Methods • Meta-Analysis of Functional Gastrointestinal Disorders (IBS and NUD) • Search of: • Medline (1966 to December 1998) • PsycLit (1974 to December 1998), and • EMBASE (1974 to December 1998) • Cochrane Library and Database • Federal Research in Progress

  41. Jackson et al.9 - Methods cont’d • Studies were screened for inclusion based on: randomization, placebo control, at least one group receiving an antidepressant, and measurable outcomes reported. • Studies were assessed for publication bias and heterogeneity. • 11 trials met all inclusion and exclusion criteria (8 for IBS and 3 for NUD)

  42. Jackson et al.9 - Results • For dichotomous outcome variables abdominal pain improvement or “response to treatment” the • Odds Ratio with therapy is 4.2 • Pooled Risk Difference is .32 • NNT 3.2 • For continuous outcome data since the studies did not use a common pain scale, pain scores were transformed to a standard meaure with antidepressant medication associated with an improvement of 0.9 SD units. • No publication bias found for either variable.

  43. Jackson et al.9 - Conclusions • Antidepressants reduce symptoms in Functional Gastrointestinal Disorder (both IBS and NUD). • For the dichotomous outcome of improvement in pain/symptoms the Odds Ratio = 4.2 • For the continuous outcome variable of abdominal pain scores a quantitative measure: the mean improvement or standardized mean difference for those receiving treatment compared to those not receiving treatment was 0.9 SD. • However...

  44. Jackson et al.9 - Results

  45. Secca ‘99

  46. Adverse Events • Heefner et al.- 3/8 drug, 1/5 placebo experienced -nausea, dizziness, palpitations, or pvc’s • Steinhart et al. - not discussed • Myren et al. 1982 - not discussed • Myren et al. 1984 - tiredness had trend towards statistical significance at 2 wks; not significant by end of study • Greenbaum et al. - 9 pts with anxiety, tremulousness, palpitations, sweating, xerostomia, and constipation. Dose reductions alleviated 6, 3 dropped from study. • Tanum et al. - 2 pts dropped out because of persistent sedation, vertigo, and “inner tension.”

  47. Take Home Points • Heefner et al. - desipramine helps with patient perceived quality of life but not with other IBS sx. • Steinhart et al. - amitriptyline shows a trend towards statistical significance with the sum of daily symptom severity ratings. • Myren et al. ‘82 - trimipramine has no clear benefit over placebo with regard to IBS sx with exception of mucus in stool. • Myren et al. ‘84 - trimipramine is significantly better than placebo at treating abdominal pain, acid eructions, nausea, depressive sx, and total effect of treatments.

  48. Take Home Points • Greenbaum et al. - Desipramine is significantly better than placebo at improving abdominal pain, # of stools/wk, and diarrhea. • Tanum et al. - Mianserin is significantly better than placebo at improving abdominal pain, symptoms associated with abdominal pain, and functional disability in a particular population of IBS pts. • Jackson et al. - Antidepressants appear to be useful in IBS for improvement in pain/symptoms and appear to improve pain to a significant degree

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