Evolving Therapy in Irritable Bowel Syndrome (IBS)

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1 Evolving Therapy in Irritable Bowel Syndrome (IBS) Dr. Syed Mohammad Arif MBBS, FCPS (Medicine), MD (Gastro) Associate Professor Department of Medicine Dhaka Medical College

2 A good set of bowels is worth more to a man than any quantity of brains Josh Billings (Henry Wheeler Shaw)

3 There is nothing in life as underrated as a good bowel movement William D. Chey, MD 1960-?

4 IBS? An illness without a disease. No Anatomical or biological marker. A functional disorder affects mainly the bowel, the large intestine. relapsing GI problem Common Chronic Health Disorder.

5 First described in Introduction 50% of patients present <35 years old. 70% of sufferers are symptom free after 5 years. GPs will diagnose one new case per week. Point prevalence of patients per 2000 patients.

6 IBS Definition (Rome committee) A Functional Bowel Disorder in which abdominal pain is associated with defaecation or a change in bowel habit, and with features of disordered defecation and with distension. Rome classification def. Thompson et al. Gastroenterol Int. 1992;5:75-91

7 Evidence-Based Systematic Review on the Management of Irritable Bowel Syndrome by- American College of Gastroenterology Task Force on IBS

8 Pragmatic approach ACG defined IBS as abdominal pain or discomfort that occurs in association with altered bowel habits over a period of at least three months. AJG vol supplement 1, Jan 2009

9 Demographic predictors several predictorsgender, age, and socioeconomic status. 1.5 times more common in women than in men, pooled OR = 1.46; 95 % CI = ) (20 23) any age, more common 50 years? more common in lower socioeconomic groups similar in Whites and Blacks. key component of the Gulf-war syndrome 1991

11 IBS: Prevalence 13% US- 20% 17% UK-22% Ger- 12% China 23% Japan- 25% 9% 7-8% Aus13% Bangladesh 8.5% (strict criteria)* *Am J Gastroenterol 2001;96:

12 Prevalence of IBS

13 Presentation of IBS Abdominal pain- mostly in lower abdomen, chronic or recurrent, vary from person to person Altered bowel habit- constipation or diarrhea, or alternate diarrhoea & constipation- common.

14 Other Symptoms Gas and bloating Mucus with stool Belching, heart burn Abdominal fullness after meal Early satiety Non-GIT Increased urination pain during period

15 Associated Symptoms In people with IBS in hospital OPD. 25% have depression. 25% have anxiety. In one study 70% of women IBS sufferers have dyspareunia.

16 IBS subtypes IBS with constipation (IBS-C) hard stools > 25% time and loose stools <25% of the time IBS with diarrhoea (IBS-D) loose stools > 25% and hard stools <25% of the time. IBS-mixed (IBS-M)- one half unclassified (IBS-U)- (4%) Am J Gastroenterol 2005;100:

17 Pathophysiology Proposed mechanism- altered GIT motility, visceral hypersensitivity * Central neural dysregulation Abnormal psychological features Post-infectious IBS ENS (Enteric Nervous System) Abnormal Serotonin pathways Gut-Flora Mucosal alteration Immune activation and mucosal inflammation

18 IBS Pathophysiology Enhanced Perception Vagal Nuclei 5-HT Sympathetic Altered Motility Visceral Hypersensitivity Adapted from Camilleri and Choi. Aliment Pharmacol Ther. 1997;11:3.

19 ENS Intrinsic neural plexus of gut muscle Semiautonomous neural network with neurotransmitters. Brain of Colon, connected to CNS autonomic network Parasympathetic & sympathetic nerves CNS modulates by afferents & efferents Brain-Gut Axis

20 Brain-Gut Axis Dysfunction Processing of pain & contraction altered / abnormal In IBS altered interpretation of neurological messages from ENS (GIT) End Result- Increased pain sensitivity, Abnormal G I motility, Altered bowel habit

21 Post-Infectious IBS 6-17% in USA Does not appear specific to any particular organism Qualitative alteration in bacterial flora in small intestine Jejunal biopsy- Persistent low grade inflammation. Probiotics helps in recovery. Gut 2004;53: Curr Opin Gastroenterol Jan; 22(1): 13-7

22 Abnormal Brain Gut Axis Gut-Flora Change Well accepted. Why some people develop IBS, & others do not? No one really knows exactly! Dysentery, food poisoning, surgery, even pregnancy- insult to the Gut - Nerve endings retain a memory Nerves Remains Hypersensitive.

23 How to Diagnose IBS? No medical tests- positive for IBS, To do a positive diagnosis- Potential organic causes to be excluded clinically If symptoms fit well -published symptoms criteria of IBS- diagnosis is done positively Rome III Guideline- current standard criteria for diagnosis.

24 Positive diagnosis by symptom criteria- how confident? Symptoms alone are not specific for diagnosis Moreover, any functional GI disorder can exists with an organic disease There should be no alarm features

25 Alarm features of IBS abdominal pain, & or diarrhea-that awakens or interferes with sleep anaemia & weight loss rectal bleeding Family H/O Ca-colon, IBD, Coeliac Sprue minimum investigation to be done

The Positive Diagnosis of IBS: A Symptom-Based Approach Identify Current Primary Symptoms Abdominal pain / discomfort Bloating Constipation/Diarrhea Look for Red Flags Based on: History Physical exam

26 The Positive Diagnosis of IBS: A Symptom-Based Approach Identify Current Primary Symptoms Abdominal pain / discomfort Bloating Constipation/Diarrhea Look for Red Flags Based on: History Physical exam Laboratory tests Perform Selected Physical and Diagnostic Tests to Rule Out Organic Disease Make a Positive Diagnosis Adapted from Paterson et al. Can Med Assoc J. 1999;161:154. American Gastroenterological Association. Gastroenterology. 1997;112:2120.

Positive flexible sigmoidoscopy or colonoscopy (>50 years) Red Flags Adapted from a technical review.

27 Identify Red Flags History Unintentional weight loss Onset in older patient (>50 years) Family history of cancer or IBD Initial labs HGB WBC ESR Abnormal chemistry TSH Physical Abnormal exams Rectal bleeding / obstruction Positive flexible sigmoidoscopy or colonoscopy (>50 years) Red Flags Adapted from a technical review. Gastroenterology. 1997;112:2120. Paterson et al. Can Med Assoc J. 1999;161:154. Camilleri et al. Aliment Pharmacol Ther. 1997;11:3.

28 The balance of IBS diagnosis

29 Diagnostic Criteria Rome III Diagnostic criteria. Manning s Criteria.

30 Rome-III criteria Recurrent abdominal pain or discomfort three days per month in the last three months associated with 2 followings- 1. Improvement with defecation 2. Onset with change in frequency of stool 3. Onset associated with a change in form of stool *Criteria fulfilled for the past 3 months with symptom onset at least 6 months before diagnosis. Gastroenterology 2006;130:

31 Manning s Criteria Three or more features should have been present for at least 6 months: Pain relieved by defecation. Pain onset associated with more frequent stools. Looser stools with pain onset. Abdominal distension. Mucus in the stool. A feeling of incomplete evacuation after defecation.

32 Examination Results should be normal or non-specific. Abdomen and rectal examination. FBC, CRP. No consensus as to whether FOBs or sigmoidoscopy is needed.

33 Tests to be done Complete blood count, Stool for ova and parasites, Serum chemistries, Thyroid function studies, IBS-D and IBS-M (Routine serologic screening coeliac sprue) Tests vary on age, symptoms subtype, Family history

34 Other tests Alarm features Over the age of 50 years Colonoscopy X Typical IBS symptoms Low likelihood of uncovering organic disease Am J Gastroenterol 2002 ; 97 :

35 IBS: Evolving understanding 5-HT mediated visceral sensitivity and gut motility Brain-gut interaction Visceral hyperalgesia Abnormal motor function Drossman et al, 1999

36 IBS: Quality of life Comparison with other diseases Mean SF-36 score National normative value Diabetes type II IBS Clinical depression Wells et al, 1997

37 IBS: Negative impact on quality of life Mean IBSQOL score Theoretical normative value IBS Hahn et al, 1997

38 Reasons to Refer Age > 45 years at onset. Family history of bowel cancer. Failure of primary care management. Uncertainty of diagnosis. Abnormality on examination or investigation.

39 Urgent Referral Constant abdominal pain. Constant diarrhoea. Constant distension. Rectal bleeding. Weight loss or malaise.

40 Differential Diagnosis Inflammatory bowel disease. Cancer. Diverticulosis. Endometriosis. A positive diagnosis, based on Manning s criteria may provoke less anxiety than extensive tests.

41 Treatment of IBS Challenging job, no cure Patients concerns. Explanation. Same patient- varying symptoms No single approach to treat Multiple strategy required Non-consulters mild / other factors.

42 Treatment of IBS / cont d Consulters- Anxious / co-morbid psychopathological problem- e.g. depression, IBS Symptoms expressions Explored, Education, Reassurance given Initial Management

43 IBS: Patient's concerns What is IBS? DOCTOR Can it be treated? Do I have cancer? Where is the toilet? I can t talk to anyone about it I can't lead a normal life

44 Explanation Must offer a plausible reason for symptoms. Even if cause is unknown, patients require some explanation. Drawing a parallel with baby colic may help. Stress is currently a socially acceptable explanation for many symptoms in life.

45 Treatment of IBS / cont d Next steps Hardly any drug that resolves all symptoms To find most distressing symptoms To categorize (subtype) IBS Treatment depends on type & severity of symptoms

Abdominal pain / discomfort Antispasmodics

Alosetron, Tegaserod Brandt, AJG 2002;97:S7

Symptom-based medical treatment of IBS Constipation

pain / discomfort Bloating / distention Altered

Alosetron Ramosetrone Eluxadoline Bloating Dietary

46 Abdominal pain / discomfort Antispasmodics Peppermint oil Antidepressants TCAs / SSRIs Alosetron, Tegaserod Brandt, AJG 2002;97:S7 Drossman, Gastroenterology 2002;123;2108 Symptom-based medical treatment of IBS Constipation Fiber MOM solution Tegaserod Lubiprostone Abdominal pain / discomfort Bloating / distention Altered bowel function Diarrhea Loperamide Other opioids Alosetron Ramosetrone Eluxadoline Bloating Dietary measuresavoid chewing gums or carbonated bevarages Rifaximine Low FODMAP Peppermint oil

47 Treatment of IBS / cont d Predominant symptom- diarrhea Mild-moderate: Dietary change Anti-spasmodic / Loperamide Severe: TCA & or newer drugs

48 Treatment of IBS Predominant symptomconstipation Mild-moderate: Bulking agents Laxatives Tegaserod Lubiprostone Predominant symptom- pain Hyoscyamine, TCA, Alosetron, Tegaserod, Peppermint oil

49 Any Newer Therapy? Brain-Gut Axis abnormality & Gut-Flora Mucosal Interaction Newer avenue in IBS therapy

50 Newer Therapy Rifaximin: An antibiotic approved in May 2015 by the U.S. FDA for treatment of IBS with diarrhea (IBS- D) in adults. It relieves symptoms of bloating and diarrhea after a day course of treatment.

51 Neurological Message Modification ENS Many neurotransmitter, & receptors Important one is serotonin Abnormal Brain-Gut communication is signaled in ENS by 5 HT (1-7) receptors Newer drugs Atkinson W et al. Gastroenterology Jan; 130:34-43

52 Enteric Receptor-Subtypes Most experiences with 5HT 3 & 5HT 4 Intrinsic afferents- 5HT 3 receptors increases intestinal motility & secretions Antagonizing 5HT 3 decreases motility Similarly agonising 5HT 4 enhances GI motility

53 Enteric Receptor Active Agents Alosetron - 5 HT 3 antagonist slows small bowel & colonic transit effective in IBS-D, SAE, Ramosetron, a 5-HT 3 antagonist for IBS-D Tegaserod -5 HT 4 Partial agonist prokinetic effect in GIT, helps in IBS- C- withdrawn 5-HT4 receptor agonist Prucalopride- IBS-C

54 Newer drugs Lubiprostone: Locally acting chloride channel activator that enhances a chloride rich intestinal fluid secretion- used in IBS-C

55 Newer drugs IBS with Diarrhea (IBS-D) Eluxadoline : a new drug which acts on opioid receptors for the treatment of IBS with diarrhea (IBS-D) in adult men and women. In studies, eluxadoline was shown to reduce abdominal pain and improve stool consistency. The drug was FDA approved in May 2015.* *N Eng J Med Jan 2016

56 Newer drugs IBS-D Bile acid binders Colesevelam, a bile sequestrant, a medication in people with IBS-D Antidepressants (TCA, SSRI) Frequently used to treat patients with severe or refractory IBS symptoms and may have analgesic and neuro modulatory benefits in addition to their psychotropic effects Serotonin synthesis inhibitors LX-1031 is a tryptophan hydroxylase inhibitor that reduces local 5-HT synthesis and improvements in pain and stool consistency.

57 Newer drugs? IBS with Constipation (IBS-C) Linaclotide is in a class of medications called guanylate cyclase-c agonists. Used in adults aged 18 and older for IBS with constipation (IBS-C) and for chronic constipation (CC).

58 Drugs Being Studied Research is ongoing to find new medication for people with IBS. Probiotics are usually live bacteria. Some evidence supports a role in IBS for specific probiotics supplement formulations, mainly for symptoms of gas and bloating. Plecanatide and Elobixibat : Drugs for treatment of IBS with constipation currently in Phase 3 clinical trials.

59 Diet & IBS Dietary factors do not cause IBS Food intolerance is common, food allergy is rare. Dietary manipulation may help. Many foods are GI stimulant / irritant - Too large meal or high in fat, fried foods, coffee, caffeine, citrus fruits or alcohol Sweetener- candies, and gums cramping or diarrhea

60 Fibre Diet & IBS There are two main types of fibre: soluble fibre (which the body can digest) and insoluble fibre (which the body cannot digest). Foods that contain soluble fibre include: Oats, barley, rye, fruit such as bananas and apples Root vegetables such as carrots and potatoes Golden linseeds In IBS -C, increasing the amount of soluble fibre and the amount of water drink in diet can help.

61 Diet & IBS Foods that contain insoluble fibre include: Whole grain bread Bran Cereals Nuts and seeds (except golden linseeds) In IBS-D, insoluble fibre in diet will help to reduce diarrhoea.

62 Diet & IBS Low FODMAP diet Persistent or frequent bloating, a special diet called the low FODMAP diet can be effective. FODMAP stands for fermentable oligosaccharides, disaccharides, monosaccharides and polyols. Low FODMAP diet improves bloating.

63 Diet & IBS General eating tips IBS symptoms may also improve by: Regular meals and taking time when eating Not missing meals or leaving long gaps between eating Drinking at least eight cups of fluid a day particularly water and herbal tea Restricting tea and coffee intake Reducing the alcohol intake and fizzy drinks Reducing intake of resistant starch, Limiting fresh fruit to three portions a day. Avoiding sorbitol, an artificial sweetener found in sugarfree sweets, including chewing gum and drink.

64 Exercise Exercise helps to relieve the symptoms of IBS Walking, running or swimming, cycling or fast walking, at least 150 minutes of moderate-intensity aerobic activity, every week.

65 Psychological treatments Severe IBS patients( >12 months) require psychological treatments. Different types of psychological therapy: Psychotherapy Cognitive behavioral therapy (CBT) Hypnotherapy Complementary therapies: acupuncture and reflexology can help people with IBS.

66 Prognosis of IBS Life-Long condition Relapsing & remitting disorder Patients may have symptoms for some years (5-13 yrs), Not associated with any long term serious disease J Intern Med 1994;236:23 30 Aliment Pharmacol Ther2000;14: Br J Surg 2000;87:

67 Summary Common functional GI disorder World wide prevalence Chronic GI morbid disease Positive diagnosis - current approach Understanding of the pathophysiology - improving We may look forward to the effective newer therapies based on primary aetiology.

Irritable Bowel Syndrome (IBS)

Irritable Bowel Syndrome (IBS) Dr Rex J Polson 17 th January 2018 Overview Description of the condition Discussion of symptoms and investigations that may be required Discussion of management and treatment