1. Managing IBS patients Dr Sameer Zar MBBS FRCP PhD Consultant Gastroenterologist Epsom & St Helier NHS Trust

2. Background  IBS affects 17 - 25% of general population  Approx. 50% IBS patients seek health care (predictors are age, female gender, abdominal pain, psychological distress)  IBS accounts for 30 – 50% referrals to gastroenterology clinics  Controversy whether IBS is a distinct disease entity or represents several different disease processes

3. 98% no change in diagnosis 88% have symptoms n=5952 1-8 years n=398 2-32 Years median ? years IBS - Prognosis

4. Genetics - IBS clusters in families OR 2.72, 95% CI 1.19-6.25 Pts relatives Spouses relatives Kalanatar et al. Gut 2003; 52: 1703-7

5. Pathophysiological model of IBS Psychosocial Factors Life stress Psychological state Coping Social support Physiology Motility Sensation Genetics Environment Bacterial Flora Food Hypersensitivity IBS Symptom experience Behaviour Outcome Medication Surgery visits Daily function QoL CNSENS Drossman DA et al, Gastroenterology 2002, 123:2108-2131

6. Diagnosis of IBS - Rome III Criteria Recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with 2 or more: Longstreth G., Gastroenterology 2006 Improvement with defecation Onset associated with change in form (appearance) of stool Onset associated with change in frequency of stool and/or Criteria fulfilled for the last 3 months with symptoms onset at least 6 months prior to diagnosis

10. Initial Evaluation Rome Recommendations Physical Examination Full blood count ESR Stool testing –Occult blood –O & P –M, C & S Sigmoidoscopy/ Colonoscopy Additional studies if needed IBS Diagnosis

13. Is screening for coeliac disease justified in IBS patients? Ig TTG negative but IgG or IgA AGA positive True positive 3 False positive 51 IgA TTG positive True positive 11 False positive 1 Sanders et al. Lancet 2001

15. Graded Treatment Response Symptom severity Severe Moderate Mild

16. Treatment Approach Effective Physician-Patient Interaction Attentive listening/Silence How long does a patient talk when asked an open question? How soon is the patient interrupted before he completes talking?

19. IBS Physician Patient Relationship Guidelines Identify concerns Explain basis for symptoms Reassure Cost effective evaluation Involve patient Provide Continuity Set realistic limits Drossman at al, Gastroenterology 1992;116;1008 Owens et al Annals of Int Med;1995:122;107

20. Treatment Approach Effective Physician-Patient Interaction Symptom Pattern –Diarrhoea Predominant –Constipation Predominant –Mixed/Alternating

21. Long Transit (e.g. 100 hrs) Short Transit (e.g. 10 hrs)

22. Rome III IBS Subtypes IBS-C IBS-M Type 1,2. IBS-U IBS-D Types 6,7 % BM Loose or watery 0 25 50 75 100 % BM Hard or Lumpy 100 75 50 25 0 25% of BM is the threshold for classification

23. Available IBS Treatments Abdominal Pain / discomfort Defecatory disorder Bloating Tegaserod Probiotics ?Antibiotics ?Exclusion diet Constipation Fibre Osmotic laxatives (Movicol) Tegaserod /Prucalapride Lubiprostone Biofeedback (Dyssynergia) Surgery (Colonic Inertia) Abdominal Pain Anticholinergics Antidepressants Alosetron (IBS-D) Tegaserod (IBS-C) Altered bowel function Diarrhoea Anticholinergics Loperamide/Diphenoxylate Probiotics Clonidine Cholestyramine Alosetron

24. IBS with Constipation (IBS-C)

25. Efficacy of Fibre in IBS Evidence for Ispaghula –6 studies, 321 patients –Significant effect on overall IBS symptoms –RR = 0.78; 95% CI = 0.63 to 0.96 –NNT = 6 (95% CI = 3 to 50) Recommendation –Bran has not been shown to be useful in IBS –Use in mild-moderate IBS –More effective in IBS-C –May need to start with lower dose (e.g. 1 tsp/day) and then increase as needed and tolerated Ford AC et al. BMJ 2008; 337;a2313

26. Lubiprostone in IBS-C Efficacy in clinical trials –Significantly higher overall response vs. placebo 1 –Grade 1B 2 What actually helps –Start at 8μg bid –Can increase to 24μg bid if needed –Take with meals to reduce nausea 1 Drossman DA, et al. Gastroenterology. 2007;132;2586-2587 2 ACG IBS Task Force, AM J Gastro 2009; 104 (S1); S1-S35 Pts achieving response (%)

27. Long-Term Effectiveness of PEG in Chronic Constipation % of patients Dipalma JA et al. Am J Gastroenterol. 2007

28. Laxatives in IBS Polyethylene glycol (PEG) –Improved stool frequency but not abdominal pain in IBS-C –Laxatives help constipation symptoms –Partially help bloating and pain/discomfort –Overuse can worsen symptoms ACG IBS Task Force, Am J Gastro 2009

29. Prucalopride in IBS Stimulates colonic activity and transit (5HT-4 receptor) Dose 2mg od (age 65) Women with chronic constipation Failed treatment at least two other types of laxatives and lifestyle changes for 6 months SE: abdominal pain, nausea, headache & diarrhoea Increase in bowel movements to 3 or more per week (Prucalopride 30% vs. placebo 11%, p<0.001 Nice Guidelines 2011

30. IBS with Diarrhoea (IBS-D)

31. Loperamide for IBS-D Efficacy in clinical trials –Not more effective than placebo at reducing pan, bloating, or global symptoms of IBS, but it is effective for the treatment of diarrhoea, reducing stool frequency, and improving stool consistency (Grade 2C) What actually helps –Use prn for episodic diarrhoea –Use proactively –Start with low dose to avoid constipation –Can use up to 2 tablets qid for more severe diarrhoea ACG IBS Task Force, Am J Gastro 2009

32. 5HT 3 Antagonists: Alosetron Clinical trial results 1 –8 studies, 4987 patients –RR symptom remain = 0.79 (95% CI 0.69 to 0.90) –NNT = 8 (95% CI = 5 to 17) Indication – women with severe IBS-D What really helps –Start with 0.5mg bid –Teach patient to titrate dose to avoid constipation and relieve pain and diarrhoea –Monitor for constipation and ischemic colitis 1 Ford AC et al. Am J Gastroenterol 2009

33. Other medications for IBS-D Antispasmodics Tricyclic antidepressants Rifaximin

34. Abdominal Bloating in IBS

35. Assess Factors Contributing to Bloating and Gas in IBS What goes in –Diet history and relationship to symptoms; food and symptom diary –Assess lactose and fructose intolerance –FODMAPs diet 1 What goes out –Slowed transit and altered gas handling –Need to treat constipation What they feel –Increased visceral perception 1 Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols; includes fructose, fructans, raffinose, polyols 1 Shepherd et al. Clin Gastroenterol Hep 2008

36. Overall Improvement of IBS with Rifaximin 10 Weeks Follow-up Pimentel M, et al. Ann Intern Med. 1006:145;557

37. Rifaximin in IBS –Patient selection: mild-moderate severity, bloating and gas, IBS-D and IBS-M –Breath tests may not predict treatment response –Use at least 1200mg/day x 10 days –Lack of data on lengthening duration of response and repeated treatment ACG IBS Task Force, Am J Gastro 2009

38. IBS – Luminal Microbial Environment Injurious Pro-inflammatory Bacteroides vulgatus Enterococcus faecalis E. coli (enteroadherent/ invasive) Protective Probiotics Lactobacilliyus sp. Bifidobacterium sp. Non-pathogenic E. coli Mild to Severe IBS

39. Probiotics Evidence –18 trials, 1650 patients 1 –RR symptoms remain = 0.71 (95% CI = 0.57 to 0.88) –NNT= 4 (95% CI = 3 to 12.5) –Only probiotic to demonstrate efficacy in appropriately designed RCTs in B infantis 35624 2 Recommendation –Patient selection: milder severity, bloating and gas symptoms –Not clear if one is better than other in clinical practice –Lack of quality data on available probiotics 1 Moayyedi P et al. Gut, Dec 2008 2 Brenner DM et al. Am J Gastroenterol. 2009

40. Selection of Patients for Antibacterial Therapy in IBS Does patient fit clinical profile of bacterial overgrowth: Postprandial abdominal discomfort, bloating and loose stools Antibiotic Maintenance with a probiotic Consider prokinetic to accelerate small bowel transit Repeat breath study, treat only if positive or Sustained response (>6months) Stool normalises or constipation Symptoms recur, previous test + ? H2 Breath Test

41. Food Hypersensitivity in IBS  20 – 65% of IBS patients attribute symptoms to adverse food reactions  Estimated prevalence of food hypersensitivity is 1.4 – 1.8% in general population Young et al, Lancet 1994; 343: 1127-30  Exclusion diets may be beneficial in IBS patients

42. Exclusion Diets in IBS NResponse rateDouble blind Jones et al 19822567%Yes Bentley et al 19831916%Yes Farah et al 19854927%No Petitpierre et al 19852420%No McKee et al 19874027.5No Nanda et al, 198920048%No

43. Food specific IgG4 antibodies in IBS Zar et al, AJG 2005

44. Effect of exclusion diet in IBS Zar et al. Scand J Gastroenterol 2005; 40(7): 800-7

45. IgG4 guided exclusion diet in IBS Atkinson et al, Gut 2004; 53: 1459-1464 10 lost to f/up 9 lost to f/up

46. Abdominal Pain in IBS

47. Antispasmodics in IBS Evidence –22 studies; 12 antispasmodics; 1778 patients –Overall symptoms improvement vs. placebo: 61% vs. 44% –RR symptoms remain = o.68 (95% CI = 0.57 to 0.81) –NNT = 5 (95 % CI = 4 to 9) Recommendation –Use in patients with intermittent symptoms –Can help decrease post-prandial pain –Use proactively, i.e. 30 min before meals –Chronic use can cause constipation, dry mouth, ?loss of response Ford AC et al. BMJ 2008

48. Rationale for Antidepressants Peripheral effects –Motility / secretion –Afferent Central pain modulatory effects Treatment of psychiatric co-morbidity (in higher doses) Moderate to Severe IBS-D

49. Rationale for Antidepressants Talk about these as ‘central pain modulators’ rather than antidepressants Moderate to Severe IBS-D

51. Antidepressant Receptor Site Effects NE5HTHistamineAch TCAs Amitryptyline+++ ++++ Doxepin+++++++++++ Desipramine+++ ++ Nortriptyline++++++ SSRIs Citalopram-++++-- Escitalopram-++++-- Fluoxetine-++++-- Paroxetine-++++-- Sertraline-++++-- SNRI’s Venlafaxine++ -- Duloxetine+++ --

52. Antidepressant Treatment TCASSRISNRI Potential Benefit Pain Depression ?Pain Depression, panic, anxiety, OCD Pain Depression Adverse events Sedation, hypotension, Constipation, dry mouth, arrhythmias, weight gain, sexual dysfunction Insomnia, Agitation, Diarrhoea, headaches, night sweats, weight loss, Sex dysfunction Nausea, Agitation, Dizziness, Sleep disturbance, Fatigue, Liver Dysfunction Efficacy for IBS GoodNot studiedGood?

53. Guidelines for Using Central Agents Desipramine (TCA) –Fair evidence of pain/diarrhoea benefit –Less sedation/constipation than Amitriptyline Duloxetine (SNRI) –Pain benefit –Not much effect on bowel function SSRIs –Anxiolytic –Can help constipation Buspirone –Anxiolytic –Augmentation treatment –Gastric accomodation Mirtazepine –For nausea and weight loss Quetiapine (Atypical antipsychotic) –For augmentation, sedation, extreme anxiety, sleep

54. Pain & Narcotic Vicious Cycle Pain & Narcotic Vicious Cycle Narcotics pain relief Delayed Transit Constipation / Ileus Distension Increased intestinal spasm / pain Increased intestinal spasm / pain Narcotics Nausea / Vomiting Nausea / Vomiting Withdrawal

55. Treatment Approach Effective Physician-Patient Interaction Symptom Pattern –Diarrhoea Predominant –Constipation Predominant –Mixed/Alternating Severity – Mild, Moderate, Severe

56. Graded Treatment Response Symptom severity Severe Moderate Mild

58. IBS - Clinical Spectrum MildModerateSevere Prevalence45 – 55%30-35%15-20% Practice type PrimarySpecialtyReferral Symptoms Constant -++++ Altered Gut Physiology ++++++ Psychosocial difficulties -++++ Healthcare use++++++

62. Benefits of Psychological Treatment High response rate (about 70%) Can benefit patients not responding to medical treatments Is additive to and possibly synergistic with medical treatments No side effects Benefits continue years after treatment ends Reduces health care costs

63. Limitations of Psychological Treatment Requires patient motivation –Needs to understand and accepts the process without stigma –Frequent visits –Home exercises –Treatment costs Requires trained therapist in community Therapist must be experienced working with with GI disorders Not widely available Usually requires ongoing medical treatment

64. Referral to Psychiatrist Treatable psychiatric disorder  Anxiety / panic  Major depression Poor adjustment to illness Psychosocial trauma affecting adjustment to illness  Major loss  Abuse Difficult therapeutic relationship  Borderline personality disorder  Factitious illness Treatable psychiatric disorder  Anxiety / panic  Major depression Poor adjustment to illness Psychosocial trauma affecting adjustment to illness  Major loss  Abuse Difficult therapeutic relationship  Borderline personality disorder  Factitious illness