evolving therapy in irritable bowel syndrome...
TRANSCRIPT
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Evolving Therapy in Irritable Bowel Syndrome (IBS)
Dr. Syed Mohammad Arif MBBS, FCPS (Medicine), MD (Gastro) Associate Professor Department of Medicine Dhaka Medical College
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“A good set of bowels is worth more to a man than any quantity of brains”
Josh Billings (Henry Wheeler Shaw) 1818-1885
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“There is nothing in life as underrated as a good bowel movement”
William D. Chey, MD 1960-?
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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.
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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.
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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
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Evidence-Based Systematic Review on the Management of Irritable Bowel Syndrome by-
American College of
Gastroenterology Task Force on IBS
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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
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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
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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%
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Prevalence of IBS
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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.
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Other Symptoms
• Gas and bloating • Mucus with stool • Belching, heart burn • Abdominal fullness after meal • Early satiety Non-GIT • Increased urination • pain during period
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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.
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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.
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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
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IBS Pathophysiology
Adapted from Camilleri and Choi. Aliment Pharmacol Ther. 1997;11:3.
Enhanced Perception
Sympathetic
Vagal Nuclei
5-HT
Altered Motility
Visceral Hypersensitivity
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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
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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
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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
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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.
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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.
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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
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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
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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
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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
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The balance of IBS diagnosis
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Diagnostic Criteria
Rome III Diagnostic criteria.
Manning’s Criteria.
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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.
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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.
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Examination
• Results should be normal or non-specific.
• Abdomen and rectal examination.
• FBC, CRP.
• No consensus as to whether FOBs or sigmoidoscopy is needed.
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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
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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 .
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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
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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
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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
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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.
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Urgent Referral
• Constant abdominal pain.
• Constant diarrhoea.
• Constant distension.
• Rectal bleeding.
• Weight loss or malaise.
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Differential Diagnosis
• Inflammatory bowel disease. • Cancer.
• Diverticulosis. • Endometriosis. • A positive diagnosis, based on Manning’s criteria may provoke less anxiety than extensive tests.
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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.
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Treatment of IBS / cont’d Consulters- • Anxious / co-morbid psychopathological
problem- e.g. depression, ⇓ • IBS Symptoms expressions Explored, Education, Reassurance given∗ ∗ Initial Management
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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?
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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.
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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
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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
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Treatment of IBS / cont’d
Predominant symptom- diarrhea Mild-moderate: • Dietary change • Anti-spasmodic / Loperamide Severe: • TCA & or newer drugs
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Treatment of IBS
Predominant symptom-constipation
Mild-moderate: • Bulking agents • Laxatives • Tegaserod • Lubiprostone
• Predominant symptom- pain
Hyoscyamine, TCA, Alosetron, Tegaserod, Peppermint oil
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Any Newer Therapy ?
• Brain-Gut Axis abnormality & • Gut-Flora Mucosal Interaction ⇓ Newer avenue in IBS therapy
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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.
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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
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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
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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
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Newer drugs
• Lubiprostone: Locally acting chloride channel activator that enhances a chloride rich intestinal fluid secretion- used in IBS-C
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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
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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.
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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).
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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.
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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
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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.
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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 .
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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.
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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.
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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.
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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.
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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.
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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.
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