Irritable Bowel Syndrome

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

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

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. 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++ Problems with Rome II 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. Are symptoms confined to the bowel in IBS patients? • 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)

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-HT3 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 FGID Aetiology of FGD ? Hypervigilance ? Hypervigilance ? Abnormal ( ? Abnormal ( processing processing ) ) ? Gut ? Gut Hypersensitivity Hypersensitivity Spinal Cord Spinal Cord 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. 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 Relative risk of postinfectious IBS- both biological and psychological!

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-HT3 antagonist (alosetron) • 12-17% benefit in female D-IBS • 5-HT4 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