1. Irritable Bowel Syndrome John McLaughlin Clinical Lecturer/Consultant Gastroenterologist Hope Hospital, Salford.

2. IBS What is (are?) IBS? Symptoms and diagnosis Aetiology Therapy and management

3. What is IBS? IBS is NOT a disease IBS is NOT a singular pathological entity IBS cannot have a single aetiology –but IBS is a useful term, coined to group patients with similar, medically unexplained symptoms IBS is difficult to manage, particularly pharmacologically

4. IBS: features IBS patients have symptoms characterised by –Unexplained abdominal pain –Disturbed bowel habit –Bloating No ‘red flags’: bleeding, weight loss, abdominal masses, malnutrition etc Clinical diagnosis here VERY SAFE <40-50 yrs By definition, conventional investigations are normal: colonoscopy, histology, blood tests, radiology

5. Current Diagnostic Criteria: Rome II 1999 At least 12 weeks or more (in last year) of abdominal pain or discomfort with 2 out of 3 of the following: –Relieved by defaecation –Associated with change in stool frequency >3/day or <3/week –Associated with change in stool form Also supported by passage of mucus, bloating, straining, urgency, sense of incomplete evacuation

6. Problems with Rome II PATIENT A Abdominal pain Urgent loose stool 3-4 times each morning Sense of incomplete evacuation PATIENT B Abdominal pain Strains to pass pellety stool every 3-4 days Bloating++ Can these very different patients really have the same disorder or common pathophysiology?

7. ‘Diarrhoea-predominant’ IBS –But when stools collected mean stool weight= 150g/day in ‘severe diarrhoea’ group –Diarrhoea is strictly >300g/day –More accurate to define as increased defaecatory frequency

8. NO! Seek and you shall find: –Functional Dyspepsia –Chronic Fatigue –Unexplained muscle pain (Fibromyalgia) –Temporomandibular dysfunction –Bladder symptoms –Gynaecological symptoms –Headaches –Backache –(All these body areas are normal too when investigated) Are symptoms confined to the bowel in IBS patients?

9. IBS symptoms are common 3-30% prevalence in unselected subjects 5% of all visits to GPs 25% of all visits to gastroenterologists Estimated 1% annual incidence No mortality from the disorder itself cf mortality from drugs, investigations, surgical procedures

10. IBS symptoms are common 3-30% prevalence in unselected subjects 5% of all visits to GPs 25% of all visits to gastroenterologists Estimated 1% annual incidence No mortality from the disorder itself cf mortality from drugs, investigations, procedures

11. Alosetron: 5-HT 3 antagonist (GSK) Approved February 9, 2000, and voluntarily withdrawn from the market November 28, 2000. -Women with diarrhoea-predominant IBS. By November 10, 2000, FDA had reviewed 70 cases of serious post-marketing adverse events –49 cases of ischaemic colitis –21 cases of severe constipation. –Of the 70 cases, 34 resulted in hospitalization without surgery, 10 resulted in surgical procedures, and three resulted in death. In some cases alosetron produced constipation serious enough to require surgery. ?1:350-700 risk of ischaemic colitis. Put back on the market June 7, 2002 with stricter criteria, patient-doctor agreement

12. Aetiology of FGD Aetiology of FGID ? Gut Hypersensitivity ? Gut Hypersensitivity ? Abnormal processing ? Abnormal processing Spinal Cord ? Hypervigilance ( ( ) ) Central Sensitisation ?motility disorder

13. Altered Motility?- probably not Evidence is inconsistent: maybe just epiphenomena of invasive study methods Stress induces colonic contractility in IBS and control subjects ‘Diarrhoea’-predominant –Prominent motility response to feeding –Some reports of accelerated transit and fast propagation of colonic contractions Constipation-predominant –Some reports of reduced propagation of colonic contractions

14. Where is the Problem ? ? ? Hypersensitive Gut ? Hypervigilant CNS?

16. Functional gut disorders ‘VISCERAL HYPERSENSITIVITY’ –Low thresholds to gut pain (eg inflating balloons in rectum, pain with lower volumes in ballon) –Perhaps reflects previous injury? Inflammation, infection, nerve fibre injury (TAH) –akin to secondary hyperalgesia eg after burns –However, problem may still lie in central connections: why the associated disorders if due to gut injury??

17. Post-infectious IBS Post Campylobacter best reported (Spiller) Persistent neuroimmune dysfunction Persistent subtle inflammation –eg mast cell infiltration; increased permeability Enteroendocrine cell hyperplasia –eg rectal 5-HT cells in rectum –Increased circulating 5-HT reported in females ……‘IBS’ common in ‘IBD’

18. Where is the Problem ? ? ? Hypersensitive Gut ? Hypervigilant CNS?

19. Hypervigilance Can alter sensory thresholds by focussing attention on any body area If in pain, convinced something’s wrong, subject will focus attention there Vicious circle of increasing symptoms could arise Anxiety/depression heightens this further

20. Prevalence of psychological problems Community IBS: no excess GP Hospital Cause of symptoms or driver to seek medical care? Psychological factors may worsen outcome –eg physical or sexual abuse reportedly

21. Relative risk of postinfectious IBS- both biological and psychological! Adverse life events in the previous year: x 2 Female sex: x 3.4 Hypochondriasis: x 2 All 3 factors: x 7 Bacterial factors : 1 in 10 of Campylobacter infected individuals developed post-infective IBS compared with just 1 out of 100 with Salmonella

22. ‘Biopsychosocial model’ Likely that components from each of these dimensions contribute to aetiology of IBS …. and other functional gut disorders

23. Therapeutic approach to IBS Need a better understanding of precise causes in mechanistically defined patient subgroups, not just ROME compliant trials –Peripheral/central origins Symptom-based approach: non-drug –Behavioural, psychological, hypnotherapy –Diet, exclusion Symptom-based approach: drugs –NB 20-70% placebo responses –Placebo benefits last 12 months or more

24. Therapeutic approach to IBS Positive diagnosis, rather than just failure to find something else Reassurance, minimal investigation Explanation ‘problem with the wiring rather than the plumbing’

25. Evidence for Therapy in IBS Fibre –Relieves constipation but worsens bloating Loperamide: empirically helpful Antispasmodics/anticholinergics –No good evidence –But may safely provide the placebo benefit

26. Evidence for Therapy in IBS Tricyclic antidepressants –Superior to placebo in meta-analysis SSRIs –No definite benefit from trials 5-HT 3 antagonist (alosetron) –12-17% benefit in female D-IBS 5-HT 4 agonist (tegasorod) –5-15% benefit in female C-IBS These need trials vs simple Rx not just placebo!

27. Evolving Therapy in IBS Novel agents in development –Antihypersensitivity Peripheral opioid antagonists Substance P, NMDA –Central pathways Corticotrophin releasing hormone antagonists –Motility CCK antagonists –Inflammation Steroids unhelpful in PI-IBS –Probiotics….

28. Summary and prospects IBS will remain a major cause of morbidity until its constituent causes are better understood As it has a social and experiential component, pharmacotherapy will largely be adjunctive at best Naïve studies with agents affecting visceral sensitivity are the best hope at present