Irritable Bowel Syndrome (IBS) Role of Mebeverine

Dr. Leonardo Basa Dairy, Sp.PD, KGEH

Outline
IBS overview
International guideline IBS facts

IBS management Role of Mebeverine in IBS management

IBS Overview

INTRODUCTION
Patients with functional gastrointestinal disorders are commonly seen in daily practice. 12% of patient encounters in primary care practice and 41% of those in gastrointestinal practice. The first reported account of IBS was published by Powell in 1818. Irritable bowel syndrome (IBS) is a common disorder that affects a large intestine (colon), causes cramping, abdominal pain, bloating, diarrhea and constipation

INTRODUCTION
Irritable Bowel Syndrome (IBS) doesn't cause permanent damage the colon Irritable bowel syndrome is a chronic relapsing and remitting condition Other names, Mucous colitis, Spastic colitis, Nervous colon, Irritable colon The criteria for diagnosis have evolved from the Manning criteria in 1978 to the Rome I criteria in 1988, Rome II criteria in 1998, Rome III criteria in 2006

IBS Definition (Rome III Criteria)

Recurrent abdominal pain or discomfort for at least 3 days during the last 3 months associated With at least 2 of the following symptoms:

Improvement with bowel movement

Onset associated with changes in the frequency of bowel movements

Onset associated with changes in the form of stool

Gastroenterology 2006;130:1480-91

Manning Criteria

Gut 2007;56:17701798

IBS Definition
World Gastroenterology Organisation Global Guideline

Irritable bowel syndrome (IBS) is functional bowel disorder in which:

abdominal pain or discomfort is associated with defecation or a change in:
bowel habit bloating distension and disordered defecation (commonly associated features)

*In some languages, the words bloating and distension may be represented by the same term
World Gastroenterology Organization, 2009

EPIDEMIOLOGY
The prevalence of IBS ranges from 5-18 % In Europe and North America is estimated to be 1015%, in AsiaPacific region is increased (developing economies), Africa (Nigerian) based on the Rome II criteria found a 26.1% prevalence IBS is slightly more common in females IBS mainly occurs between the ages of 15 and 65. The first presentation of patients to a physician is usually in the 3050 year old age group

World map of IBS prevalence (20002004) based on the Rome II, III criteria, with figures for the Manning criteria in brackets where available.

IBS Classification
IBS with diarrhea (IBS-D):
Loose stools > 25% of the time and hard stools < 25% of the time Up to one-third of cases >> men

IBS with constipation (IBS-C):

Hard stools > 25% of the time and loose stools < 25% of the time Up to one-third of cases >> women

IBS with mixed bowel habits or cyclic pattern (IBS-M) :

Both hard and soft stools > 25% of the time One-third to one-half of cases

PATOFISIOLOGY
ALTERED BOWEL MOTILITY Abnormal timing & pattern of contractions w/ food or stress VISCERAL HYPERSENSITIVITY Abnormal excitability of neurons & pathways PSYCHOSOSIAL FACTORS May affect perceptions or central signal processing NEROTRANSMITTER IMBALANCE Increased serotonin levels? INFECTION / INFLAMATION Inflammatory cytokines may affect bowel sensitization

DIAGNOSTIC
Clinical history
It is important not only to consider the primary presenting symptoms, but also to identify precipitating factors and other associated gastrointestinal

Bloating ? Diarrhea

Dyspeptic symptoms

IBS Overlap of Symptom

Constipation
Abdominal pain / discomfort

Psychological assessment

Facts about IBS

IBS is not a psychiatric or psychological disorder
However, psychological factors may: play a role in the persistence & perceived severity of abdominal symptoms contribute to impairment in the quality of life & excessive use of health-care services
Physical examination
To detect possible organic causes

For these reasons, coexisting psychological conditions are common in referral centers and may include:
anxiety depression somatization hypochondriasis symptom-related fears

Symptom Patterns, Severity

Symptom Constipation Predominant Diarrhea Predominant Abdominal Pain Predominant

Severity Mild, can be ignored if the patient does not think about it Moderate, cannot be ignored but does not affect patient's lifestyle Severe/very severe, affects patient's lifestyle

Initial Assesment
Healthcare professionals should consider assessment for IBS if the person reports having had any of the following symptoms for at least 6 months:
A bdominal pain or discomfort B loating C hange in bowel habit.

NICE Guideline, 2008, IBS in Adults - Diagnosis and management of IBS in primary care

IBS diagnostic algorithm

FBC, full blood count; FOBT, fecal occult blood test; ESR, erythrocyte sedimentation rate.
* Where relevanti.e., when there is a high prevalence of celiac disease, parasitosis, and inflammatory bowel disease or lymphocytic colitis, respectively.

World Gastroenterology Organization, 2009

Alarm Symptom

DIFFERENTIAL DIAGNOSIS
Celiac sprue/ gluten enteropathy Lactose intolerance IBD (Crohn's disease, ulcerative colitis) Colorectal carcinoma Lymphocytic and collagenous colitis Acute diarrhea due to protozoa or bacteria Small-intestinal bacterial overgrowth (SIBO) Diverticulitis Endometriosis Pelvic inflammatory disease Ovarian cancer Comorbidity with other diseases

IBS Management
Rediscovering treatment approach

Stability IBS: percentage of IBS patients after 1 and 7 years from the first interview

Representative diagram of the stability over time of IBS: percentage of the patients reporting IBS after 1 and 7 years from the first interview
Gastroenterol Res Pract.;2012:936-960

How do clinicians manage IBS in real life?

What is our understanding of IBS? Multiple factors Multiple pathophysiological mechanisms Multiple symptoms intestinal, extra-intestinal A survey of English GPs 1 drug 98% 2 drugs 86% 3 drugs 47% 4 drugs 19%
IBS: the view from general practice. Thompson WG, EJGH 1997

Algorithm IBS Management

World Gastroenterology Organization, 2009

Management of IBS
Multi diciplinary approach No single treatment as beeing universally applicable to the management of IBS based on the predominant bothersome symptoms

Irritable Bowel - Management

Strong physician-patient relationship Education, reassurance Dietary Reduce EtOH, caffeine, fat (?????) Explore triggers Life stresses Foods Symptom-specific medications Pain predominant Diarrhea predominant Constipation predominant

Pharmacotherapy with predominant symptoms

1.

Abdominal Pain :
Antispasmodics :
Mebeverine, Cimetropium, Trimebutine . Hyoscine, Otilonium . Pinaverium

4. Constipation :
Bulking agent Probiotic : Bifidobacterium lactic Laxative: Lactulose Lubiprostone

Probiotik : Bifidobacterium lactic Paracetamol

2.

Bloating / distension
Probiotik : Bifidobacterium lactis, Bifidobacterium infantis Antibiotic : Rifaximin

5.

Psychologic treatment Anti Depressants:

Tricyclic antidepressant (TCA) Selective Serotonin Reuptake Inhibitor (SSRI) : Paroxetine, Citalopram

3.

Diarrhea :
Loperamide, Alosetron

Bothersome symptoms in IBS

41.984 thelephone interviews
Abdominal pain Bloating

Gas

Fatigue

Diarrhea

Constipation 0 20 40 60 80 100

Aliment Pharmacol Ther 2003;17:643-50

Correlation of Symptoms with Quality of Life in IBS

in 242 women in the general population (Rome I)

0.5

0.4

Correlation

0.3

0.2

0.1

Pain
Am J Gastroenterol 2006;101:124-132 Am J Gastroenterol 2000;95:999-1007

Gas

Q-TOT Bloating

Constipation

Diarrhea

Abdominal Pain in IBS is multifactorial

Psychological factors

Gut dysmotility
Brain-Gut axis

Visceral hypersensitivity

A combination of smooth muscle spasm, visceral hyperensitivity, and abnormalities of central pain processing may explain the abdominal pain that is an essential part of the symptom complex

Rationale of treatment of Abdominal Pain in IBS

Inhibit muscle contraction

Reduce activation of sensory pathways

Treat psychological associated factors

Role of Mebeverine In IBS Management

Anti-spasmodic agents
Anticholinergics/antimuscarinics
secretomotornerve ending

Dicyclomine Hyoscine Cimetropium bromide

Ca

++

SP

Direct smooth muscle relaxants Mebeverine Peppermint oil

ACh

Ca Ca
+ +

+ +

N KA
Ca
+ +

Ca-channel M

NK1
Ca
+ +

Na Ca
++

Na Ca
++

NK2
Ca
+ +

Ca

cation-channel
Ca
+ +

Ca
++

++

Ca Ca
+ +

Ca

Calcium channels blockers Otilonium bromide Pinaverium bromide

Smooth muscle cell

Ca

++

Ca
++

++

C a Ca

++

Efficacy of antispasmodics in IBS

Global improvement
21 RCT; Treatm. n=927; pla n=925

Pain improvement
11 RCT; Treatm. n=567; pla n=568

Mebeverine Cimetropium Trimebutine Otilonium Hyoscine Pinaverium TOTAL 0 1 2 3 4 5 6 7 OR: 2.13; P<0.00001
APT 2001;15:355-61

Mebeverine Trimebutine Otilonium Hyoscine Pinaverium Peppermint oil TOTAL

0 1 2 3 4 5 6 7 8

OR: 1.65; P<0.00004

META-ANALYSIS: EFFICACY OF ANTISPASMODICS

Treatment
Mebeverine
Kru Secco Tasman-Jones Subtotal (95% CI) 9/40 12/15 15/24 36/79 13/15 13/15 18/30 6/20 24/50 11/40 9/15 7/24 27/79 14/15 4/15 19/30 2/20 21/50

Control

Cimetropium
Piat Subtotal (95% CI)

Trimebutine
Flelding Moshal Subtotal (95% CI)

Otilonium
Baldi Barbier Battaglia Subtotal (95% CI) 7/15 16/36 76/160 99/211
106/182 106/182

2/15 7/36 53/165 62/216

104/178 104/178

Pain improvement

Hyoscine
Shafer Subtotal (95% CI)

Pinaverium
Delmont Subtotal (95% CI) 22/30 22/30 15/30 15/30

Poynard et al., 2001

Total (95% CI) 300/567 233/568 Chi-squared 23.62 (d.f.=10) P=0.01 Z=4.09 P=0.00004

Favours placebo

0.1

0.2

10 Favours treatment

Poynard, Aliment Pharmacol Ther 2001;15:355-361

Mebeverine - Mechanism of action

Inhibition muscle contraction at cellular level Increase in intracellular cAMP Stabilization of excitable membranes Weak anti-muscarinic activity

Independent of stimulus

Todays Ther Trends.1995;13(2):47-62

Efficacy of mebeverine on individual symptoms in IBS

**

***

Berthelot et al. 1981

Mebeverine
Mean symptoms score per month: mebeverine versus placebo

Proutet al. 1983

Tolerability MEBEVERINE
Generally very well tolerated % of patients without side effects NS between active arm and placebo arm Most side effects related to drugs with anticholinergic activity systemic effects (tachycardia, blurred vision, urinary retention)

Poynard, APT 1994;8:499

Drug
Mebeverine Pinaverium bromide

Adverse Reactions
0.86, p=0.80 0.78, p=0.73 0.73, p=0.19 0.66, p=0.43 0.50, p=0.07 0.33, p=0.29

Hyoscine Trimebutine
Cimetroprium bromide Octilium bromide Peppermint oil Dicyclomide bromide Total Homogeneity p=0.19
0.0
Poynard, APT 1994;8:499

0.22, p=0.02
0.21, p<0.01

0.50, p<0.01

0.1

0.3 0.6 1.0

2 3 4 Odds ratio

Summary
IBS is a chronic, relapsing and often life-long disorder, characterised by the presence of abdominal pain or discomfort, which maybe associated with defaecation and/or accompanied by bowel habit change Treatment should be multidiciplinary, including education, doctor-patient relationship, dietary modification, pharmacotherapy ( antispasmodics, bulking agents, antidiarrhea, antidepressant, probiotics, and psychological treatment) Mebeverine as one of antispasmodic which effective in the pharmacological treatment of IBS with good tolerability safety profile

IBS in developing countries

Neurogastroenterol Motil (2005) 17, 18

Irritable Bowel Syndrome (IBS) Role of Mebeverine

Dr. Leonardo Basa Dairy, Sp.PD, KGEH