Evolving Therapy in Irritable Bowel Syndrome (IBS)

Dr. Syed Mohammad Arif MBBS, FCPS (Medicine), MD (Gastro) Associate Professor Department of Medicine Dhaka Medical College

“A good set of bowels is worth more to a man than any quantity of brains”

Josh Billings (Henry Wheeler Shaw) 1818-1885

“There is nothing in life as underrated as a good bowel movement”

William D. Chey, MD 1960-?

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.

Introduction

• First described in 1771. • 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 40-50 patients per

2000 patients.

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

Evidence-Based Systematic Review on the Management of Irritable Bowel Syndrome by-

American College of

Gastroenterology Task Force on IBS

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. 104. supplement 1, Jan 2009

Demographic predictors

several predictors- gender, age, and socioeconomic status. 1.5 times more common in women than in men, pooled OR = 1.46; 95 % CI = 1.13 – 1.88) (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

US- 20%

9% 7-8% Aus13%

13%

Japan- 25%

UK-22% Ger- 12% 17%

IBS: Prevalence

Bangladesh 8.5% (strict criteria)* *Am J Gastroenterol 2001;96:1547–52.

China 23%

Prevalence of IBS

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.

Other Symptoms

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

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.

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;100:896–904.

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

IBS Pathophysiology

Adapted from Camilleri and Choi. Aliment Pharmacol Ther. 1997;11:3.

Enhanced Perception

Sympathetic

Vagal Nuclei

5-HT

Altered Motility

Visceral Hypersensitivity

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

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

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;53:1096–101. Curr Opin Gastroenterol. 2006 Jan; 22(1): 13-7

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.

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.

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

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

Adapted from Paterson et al. Can Med Assoc J. 1999;161:154. American Gastroenterological Association. Gastroenterology. 1997;112:2120.

Identify Current Primary Symptoms

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

Abdominal pain / discomfort Bloating Constipation/Diarrhea

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)

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.

Red Flags

The balance of IBS diagnosis

Diagnostic Criteria

Rome III Diagnostic criteria.

Manning’s Criteria.

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;130:1480–91.

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.

Examination

• Results should be normal or non-specific.

• Abdomen and rectal examination.

• FBC, CRP.

• No consensus as to whether FOBs or sigmoidoscopy is needed.

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

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 : 2812 – 9 .

IBS: Evolving understanding

1950 1960 1970 1980 1990 2000

Abnormal motor function

Visceral hyperalgesia

Brain-gut interaction

5-HT mediated visceral sensitivity and gut motility

Drossman et al, 1999

IBS: Quality of life Comparison with other diseases

30

40

50

60

70

80

90

Mean SF-36 score

National normative value

Diabetes type II

IBS

Clinical depression

Wells et al, 1997

IBS: Negative impact on quality of life

Theoretical normative value

Hahn et al, 1997

Mean IBSQOL

score

30

40

50

60 70

80

90

100

IBS

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.

Urgent Referral

• Constant abdominal pain.

• Constant diarrhoea.

• Constant distension.

• Rectal bleeding.

• Weight loss or malaise.

Differential Diagnosis

• Inflammatory bowel disease. • Cancer.

• Diverticulosis. • Endometriosis. • A positive diagnosis, based on Manning’s criteria may provoke less anxiety than extensive tests.

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.

Treatment of IBS / cont’d Consulters- • Anxious / co-morbid psychopathological

problem- e.g. depression, ⇓ • IBS Symptoms expressions Explored, Education, Reassurance given∗ ∗ Initial Management

DOCTOR

IBS: Patient's concerns

What is IBS?

Do I have cancer?

I can't lead a normal life

I can’t talk to anyone about it

Where is the toilet?

Can it be treated?

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.

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

Symptom-based medical treatment of IBS Diarrhea

Loperamide Other opioids Alosetron Ramosetrone Eluxadoline

Abdominal pain / discomfort Antispasmodics Peppermint oil Antidepressants

• TCAs / SSRIs • Alosetron, • Tegaserod

Constipation Fiber MOM solution Tegaserod Lubiprostone

Abdominal pain /

discomfort Bloating / distention

Altered bowel function

Brandt, AJG 2002;97:S7 Drossman, Gastroenterology 2002;123;2108

Bloating •Dietary measures- avoid chewing gums or carbonated bevarages •Rifaximine •Low FODMAP •Peppermint oil

Treatment of IBS / cont’d

Predominant symptom- diarrhea Mild-moderate: • Dietary change • Anti-spasmodic / Loperamide Severe: • TCA & or newer drugs

Treatment of IBS

Predominant symptom-constipation

Mild-moderate: • Bulking agents • Laxatives • Tegaserod • Lubiprostone

• Predominant symptom- pain

Hyoscyamine, TCA, Alosetron, Tegaserod, Peppermint oil

Any Newer Therapy ?

• Brain-Gut Axis abnormality & • Gut-Flora Mucosal Interaction ⇓ Newer avenue in IBS therapy

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 10–14 day course of treatment.

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. 2006 Jan; 130:34-43

Enteric Receptor-Subtypes

• Most experiences with 5HT3 & 5HT4

• Intrinsic afferents- 5HT3 receptors – increases intestinal motility & secretions

Antagonizing 5HT3 decreases motility

• Similarly agonising 5HT4 enhances GI motility

Enteric Receptor Active Agents

• Alosetron - 5 HT3 antagonist slows small bowel & colonic transit effective in IBS-D, SAE , Ramosetron, a 5-HT 3 antagonist for

IBS-D

• Tegaserod -5 HT4 Partial agonist prokinetic effect in GIT, helps in IBS-

C- withdrawn 5-HT4 receptor agonist Prucalopride-

IBS-C

Newer drugs

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

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

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.

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).

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.

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

Diet & IBS Fibre • 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.

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 .

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.

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 sugar-

free sweets, including chewing gum and drink.

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.

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.

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;14:23–34. Br J Surg 2000;87:1658–63.

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.