Transcript Functional Dyspepsia

Future Perspectives in Gastroenterology
Functional Dyspepsia
Dyspepsia
Prevalence in industrialized countries
• worldwide 25% (7 - 41%)
• with heartburn: 40%
• without heartburn & IBS:10%
26%
7%
32%
14%
16%
27%
41%
13%
25%
Adapted from:
Locke, Bailliere‘s Clinical Gastroenterology 1998;12:435-41.
Defining Clinical Pathways for Dyspepsia …
…. discriminate Dyspepsia from GERD and IBS
Upper GI complaints
GERD
Dyspepsia
Lower GI complaints
Irritable Bowel Syndrome
(Functional) Dyspepsia, GERD, IBS
Discrimination by Symptoms limited by Overlap
Early Sateity
Meteorims
Vomiting
Functional
Dyspepsia
Nausea
Abdominal Pain
Constipation
Bloating
IBS
Diarrhoe
Epigastric Pain
GERD
Dysphagia
Heartburn
Distension
Belching
Regurgitation
Talley N. In: Modlin IM (ed.) From Gastrin to GERD: A Century of Acid Suppression.
Tylney Hall Lectures, Felsenstein CCCP; 8–9 April 2005
Defining Clinical Pathways for Dyspepsia …
Investigated versus Non-investigated Dyspepsia
Upper GI complaints
GERD
Dyspepsia
Non-investigated
Dyspepsia
Lower GI complaints
Irritable Bowel Syndrome
Investigated Dyspepsia
… had upper GI Endoscopy …
Defining Clinical Pathways for Dyspepsia …
Organic versus Functional Dyspepsia
Lower GI complaints
Upper GI complaints
GERD
Dyspepsia
Non-investigated
Dyspepsia
Irritable Bowel Syndrome
Investigated Dyspepsia
… normal upper GI Endoscopy
Organic Dyspepsia
Functional Dyspepsia
Dyspepsia
Main causes
Williams 1988
(n = 1386)
Stanghellini 1996
(n = 1057)
Heikkinen 1996
(n = 766)
Thomson 2003
(n = 1040)
% of patients with
diagnosis
60
50
40
30
20
10
0
Gastric
neoplasia
Peptic
ulcers
GERD
Functional
Dyspepsia
Functional Dyspepsia
Rome-III Criteria
Rome III:
 No evidence for structural disease
 One or more of:
- Bothersome postprandial fullness
- Early satiation
- Epigastric pain
- Epigastric burning
 2 Subgroups:
- Postprandial distress syndrome
- Epigastric pain syndrome
longer than 3
months,
at least 6 months
before diagnosis
Tack, Gastroenterology
2006;
130:1466-79.
Functional Dyspepsia
Rome-III Criteria versus Rome-II Criteria
Rome III:
 No evidence for structural disease
 One or more of:
- Bothersome postprandial fullness
- Early satiation
- Epigastric pain
- Epigastric burning
 2 Subgroups:
- Postprandial distress syndrome
- Epigastric pain syndrome
longer than 3
months,
at least 6 months
before diagnosis
Tack, Gastroenterology
2006;
130:1466-79.
Rome II:
 No evidence of organic disease
 Persistent or recurrent upper GI symptoms
 No relief by defecation or associated
with the onset of a change in stool behaviour
 2 Subgroups:
- Dysmotility-like dyspepsia
- Ulcer-like dyspepisa
At least 12 weeks
within the
preceeding
12 months.
Talley, Gut 1999; 45 Suppl
2:II37-II42.
Functional Dyspepsia – Rome-III Criteria
Subgroups – PDS and EPS
Postprandial Distress Syndrome (PDS)
Epigastric Pain Syndrome (EPS)
Must include one or both of the following:
Must include all of the following:
•Bothersome postprandial fullness,
occurring after ordinary sized meals, at
least several times per week*
•Early satiation that prevents finishing a
regular meal, at least several times per
week*
•Epigastric pain or burning (at least
moderate severity, at least once per
week)*
•Pain is intermittent*
•Not generalized or localized to other
abdominal or chest regions*
•Not relieved by defecation or passage
of flatus*
•Not fulfilling criteria for gallbladder
and sphincter of Oddi disorders*
Supportive criteria:
*longer than 3 months, at least 6
months before diagnosis
Tack, Gastroenterology 2006; 130:1466-79.
•Pain may be of a burning quality but
without a retrosternal component*
•Pain is commonly induced or
relieved by ingestion of a meal but
may occur while fasting*
•PDS syndrome may coexist
Functional Dyspepsia – Rome-III Criteria
Subgroups – PDS and EPS
Postprandial Distress Syndrome (PDS)
Epigastric Pain Syndrome (EPS)
Must include one or both of the following:
Must include all of the following:
•Bothersome postprandial fullness,
occurring after ordinary sized meals, at
least several times per week*
•Early satiation that prevents finishing a
regular meal, at least several times per
week*
•Epigastric pain or burning (at least
moderate severity, at least once per
week)*
•Pain is intermittent*
•Not generalized or localized to other
abdominal or chest regions*
•Not relieved by defecation or passage
of flatus*
•Not fulfilling criteria for gallbladder
and sphincter of Oddi disorders*
Supportive criteria:
•Upper abdominal bloating or postprandial
nausea or excessive belching can be
present*
•EPS may coexist
*longer than 3 months,
months before diagnosis
Tack, Gastroenterology 2006; 130:1466-79.
at least 6
Supportive criteria:
•Pain may be of a burning quality but
without a retrosternal component*
•Pain is commonly induced or
relieved by ingestion of a meal but
may occur while fasting*
•PDS syndrome may coexist
Functional Dyspepsia – Rome-III Criteria
Subgroups – PDS and EPS
Postprandial Distress Syndrome (PDS)
Epigastric Pain Syndrome (EPS)
Must include one or both of the following:
Must include all of the following:
•Bothersome postprandial fullness,
occurring after ordinary sized meals, at
least several times per week*
•Early satiation that prevents finishing a
regular meal, at least several times per
week*
•Epigastric pain or burning (at least
moderate severity, at least once per
week)*
•Pain is intermittent*
•Not generalized or localized to other
abdominal or chest regions*
•Not relieved by defecation or passage
of flatus*
•Not fulfilling criteria for gallbladder
and sphincter of Oddi disorders*
Supportive criteria:
•Upper abdominal bloating or postprandial
nausea or excessive belching can be
present*
•EPS may coexist
*longer than 3 months,
months before diagnosis
Tack, Gastroenterology 2006; 130:1466-79.
at least 6
Functional Dyspepsia – Rome-III Criteria
Subgroups – PDS and EPS
Postprandial Distress Syndrome (PDS)
Epigastric Pain Syndrome (EPS)
Must include one or both of the following:
Must include all of the following:
•Bothersome postprandial fullness,
occurring after ordinary sized meals, at
least several times per week*
•Early satiation that prevents finishing a
regular meal, at least several times per
week*
•Epigastric pain or burning (at least
moderate severity, at least once per
week)*
•Pain is intermittent*
•Not generalized or localized to other
abdominal or chest regions*
•Not relieved by defecation or passage
of flatus*
•Not fulfilling criteria for gallbladder
and sphincter of Oddi disorders*
Supportive criteria:
•Upper abdominal bloating or postprandial
nausea or excessive belching can be
present*
•EPS may coexist
*longer than 3 months,
months before diagnosis
Tack, Gastroenterology 2006; 130:1466-79.
at least 6
Supportive criteria:
•Pain may be of a burning quality but
without a retrosternal component*
•Pain is commonly induced or
relieved by ingestion of a meal but
may occur while fasting*
•PDS syndrome may coexist
Functional Dyspepsia
Exclusion diagnosis
Dyspeptic complaints
(not investigated dyspepsia)
-
remaining
uncertainty
diagnostic
effort
Anamnesis, physical examination, laboratory
(blood count, CRP, GOT, GPT, gGT, Krea,
Lipase), sonography
Upper endoscopy (duodenal
eosinophilia?)
Lower
endoscopy, CT/MRT, x-ray: stomachgut-passage/Sellink, ERCP, MRCP
Testing GI function:
-H2 breath tests: Lactose, Fructose
SIBO (Glucose)
-Gastric function: emptying, accommodation
-pH-metry, esophageal manometry
Functional Dyspepsia
modified: Guidelines of the German Society of Metabolic and Digestive Diseases
for the therapy of dyspepsia, Z Gastroenterologie 2001;39:937-56; Talley, DDW
Functional Dyspepsia
Pathomechanisms
Stress, Anxiety, Depression,
Sexual abuse, Sleep deprivation
Increased Visceral
Sensitivity
ANS Imbalance
Sensory inhibition
Inceased afferent
activity
Reduced Acid Clearance
Increased Acid Sensitivity
Low Grade
Inflammation
± HP Infection
Motor Activity
Accommodation
Altered Sensory & Motor Function
Functional Dyspepsia - Visceral Hypersensitivity
Hypersensitivity to mechanic Gastric Stimulation
Controls (n=10)
Volume of gastric
distension (ml)
Functional Dyspepsia (n=10)
700
* p < 0.05
600
500
400
300
200
*
*
100
0
Intragastric balloon
Mearin, Am J Gastroenterol 1999; 94:116-25.
Initial Sensation
Pain
Bradette, Dig Dis Sci 1991; 36:52.
Role of Acid in Functional Dyspepsia
Impaired Acid Clearance & Enhanced Sensitivity
Functional
Dyspepsia
Intragastric infusion
of 0.1 N HCl 5ml/min.
for 10 minutes
Healthy
controls
Complaints
50
80
Score (VAS)
Decrease of pH < 4 (%)
100
0
60
*
*
*
40
20
-50
0
duodenal
Bulb
proximal
Duodenum
Samsom, Gastroenterology 1999; 116:515-20.
before after
Infusion 1
before
after
Infusion 2
before
after
Infusion 3
Functional Dyspepsia - Visceral Hypersensitivity
Brain Imaging
Hypersensitive FD-Patients
- Activation of the lateral pain
system and frontal inferior gyri at
lower distention pressures
- none of the components of the
medial pain system are activated
Functional Dyspepsia - Visceral Hypersensitivity
Brain Imaging & pathophysiological Mechanisms
Hypersensitive FD-Patients
- Activation of the lateral pain
system and frontal inferior gyri at
lower distention pressures
- none of the components of the
medial pain system are activated
Lateral Pain System
Präfrontal Cortex (PFC)
Pain Memory, -Response
Interpretation
SI,SII Visceral
Perception
Thalamus
Anteriores Cingulum
(ACC) Attention, Anxiety,
Arousal
Insula
Visceral Perception
Dorsal Horn
Primary
Nociceptor
Mertz H, in Camilleri M, Spiller RC, Eds., IBS, Saunders 2002, p59.
Periaquaeductales
Grey
(PAG)
Pain
Inhibition
Localisation, Quality, Intensity
-Insula
-Periaquaeductal Grey (PAG)
-Primary somato-sensory Cortex
(SI)
-Secondary somato-sensory
Cortex (SII)
Medial Pain System
Affectivity (e.g. Anxiety, Attention)
-Anterior Cingulum (ACC) !
-Prefrontal Cortex (PFC)
Functional Dyspepsia
Pathomechanisms of Visceral Hypersensitivity ?
Altered brain processing of Nociceptive information
Disturbed descending Modulation of Perception
Neuroplastic Changes of
Sensory Pathways
Low Grade
Inflammation
± HP Infection
Increased mechanical &
chemical Sensitivity
Increase in mucosal mast cells
and / or inflammatory cells
Role of Motility in Functional Dyspepsia
Altered Accomodation & Emptying
Perzeption
Interdigestive
Accomodation
Tack J. et al., Current Gastroenterology Reports 2001, 3:503-508
Impaired fundic
accommodation
 redistribution of
food to antrum
Emptying
Disturbed Gastric Motility in Functional Dyspepsia
Options of investigation
•
Gastric emptying
• Scintigraphy
• C13 breath test
• fMRI
•
solid or liquid meals
solid and liquid meals
solid and/or liquid meals
Gastric accommodation
• Barostat
(invasive)
(radiation exposure)
• SPECT
(non invasive)
• fMRI
Impaired Accommodation in Functional Dyspepsia
Detection by Barostat
Pressure
(mmHg)
Functional
Dyspepsia
Healthy
Controls
30
20
Pressure/Volume
Curves at Food
Ingestion
10
0
50
100
150
Volume (ml)
Tack: Curr. Treat. Opt. Gastr. 2000;3:287-294.
200
Impaired Accommodation in Functional Dyspepsia
Detection by Barostat
Functional
Dyspepsia
Healthy
Controls
30
20
Pressure/Volume
Curves at Food
Ingestion
10
0
50
100
150
Volume (ml)
Tack: Curr. Treat. Opt. Gastr. 2000;3:287-294.
200
400
Rise of gastric volume pp (ml)
Pressure
(mmHg)
350
300
250
200
150
100
50
o
Patients Controls
Tack, Gastroenterology 1998; 115:1346-52.
Impaired Accommodation in Functional Dyspepsia
Detection by SPECT
Fasted Stomach
Postprandial Stomach
Schwizer W, et al. Gut 2002
Lunding et al.
Scan J Gastro 2006; 41: 1028
Impaired Accommodation in Functional Dyspepsia
Detection by SPECT
Healthy
Fasted Stomach
Functional Dyspepsia
Postprandial Stomach
Schwizer W, et al. Gut 2002
Proximal gastric
accomodation is
impaired
Kim et al Am J Gastro 2001; 96: 3099
Lunding et al.
Scan J Gastro 2006; 41: 1028
Impaired Accommodation in Functional Dyspepsia
Detection by SPECT
Healthy
Rapid initial
emptying of water:
a sign of impaired
accommodation ?
Fasted Stomach
Functional Dyspepsia
Postprandial Stomach
Schwizer W, et al. Gut 2002
Proximal gastric
accomodation is
impaired
Kim et al Am J Gastro 2001; 96: 3099
Lunding et al.
Scan J Gastro 2006; 41: 1028
Impaired Accommodation and altered Emptying
Detection by fMRI
Cumulative Change in Volume
of the proximal Stomach (ml)
Functional Dyspepsia (n=22)
Healthy Controls (n=15)
50
40
30
20
10
0
0
3
6
9
-10
12
15 Time
(min)
-20
Impaired postprandial
accommodation to a meal is
limited to the proximal stomach
Van der Voort, 2007; in preparation.
Impaired Accomodation and altered Emptying
Detection by fMRI –
‘One-Stop Shopping’
???
Cumulative Change in Volume
of the proximal Stomach (ml)
Functional Dyspepsia (n=22)
Healthy Controls (n=15)
50
40
Patients with one or more Alteration
of Accommodation or Emptying (%)
60
50
30
40
20
N = 22
Impaired accommodation of the
proximal stomach
Initially accelerated gastric emptying
Impaired relaxation of proximal stomach
& initially accelerated gastric emptying
30
Delayed overall gastric emptying
10
20
0
0
3
6
9
-10
12
15 Time
(min)
10
Impaired relaxation of proximal stomach
& initally accelerated gastric emptying
& delayed overall gastric emptying
Patients with pathological findings
0
-20
Impaired postprandial
accommodation to a meal is
limited to the proximal stomach
Van der Voort, 2007; in preparation.
More than 50% of patients have
one or more alteration in pp
relaxation, early or overall
gastric emptying
Functional Dyspepsia
Pathomechanisms of altered Motility ?
Stress, Anxiety, Depression,
Abuse, Sleep deprivation
Neuroplastic Changes of
Sensory Pathways
ANS Imbalance
Normal
Low Grade
Inflammation
± HP Infection
Accommodation
Emptying
Motor Activity
Electr. Activity
Functional Dyspepsia
Alteration of neurohumoral
duodeno-gastric feedback (CCK)
Treatment of Functional Dyspepsia
Basic Measures and Principles
•
The treatment of the patient starts with the positive
diagnosis (Cave: “…There is nothing wrong….“ ).
•
Education about the benignity of the disease
•
Dietetic consultation (Diary: trigger factors?)
•
Separate patients with FD from reflux disease!
•
Take advantage of the very high placebo effect:
„To act or not to act?“  Be proactive !
Improvement of symptoms
Treatment of Functional Dyspepsia
Placebo Effect
%Pat.
100
Placebo effect in therapeutic studies
(different time points)
Metaanalysis
75
50
25
0
2
3
4
Treatment week
Mearin, Am J Gastroenterol 1999; 94:116-25.
5
6
8
Mean
> 40 %
Treatment of Functional Dyspepsia
Lifestyle modifications
Recommendations
• Small frequent meals
• Stop smoking
But:
• Reduce alcohol
- Anecdotal reports only
- RCTs are missing
• Reduce caffeine
Feinle-Bisset, Am J Gastro 2004; 99:170-81;
Saad, Aliment Pharmacol Ther 2006; 24:475-92.
• Avoid irritating food
• Maintain an ideal weight
• Review medications
Drug therapy in Functional Dyspepsia
Groups of Compounds and Modes of Action
•
•
•
•
•
•
•
•
•
•
Acid inhibition
Cytoprotection
Antacids, H2-blocker, PPI
Sucralfate, PG analogues (misoprostol)
Prokinetics
Metoclopramide, Domperidone, (Cisapride)
H. pylori eradication
PPI + antibiotics, bismuth
Visceral analgetics
Opiate agonists, 5-HT3-R-antagonists
Antidepressants
Amitriptyline, Mianserin
Spasmolytics
Butylscopolamine
Antiemetics
Herbal medicine
Phenotiazine
Iberis amara, peppermint oil, caraway oil
Carminatives
Simethicone
Therapy of Functional
Dyspepsia
Acid Inhibition
Relative Risk Reduction in % [95% CI]
Drug Treatment of Functional Dyspepsia
Cochrane Meta-Analysis of 73 Studies
90
80
70
60
50
40
30
20
10
0
-10
-20
-30
-40
-50
Prokinetics
Bismuth
n = 19/3178 p.
n = 6/311 p.
*
*
PPI
*
n = 10/3347 p.
*
ns
H2-RA
n = 12/2183 p.
Antacids
n = 1/109 p.
ns
Sucralfate
n = 2/246 p.
Moayyedi p et al., Cochrane Database Syst Rev. 2007; Iss 3
90
80
70
60
50
40
30
20
10
0
-10
-20
-30
-40
-50
Therapy of Functional Dyspepsia with PPIs
Differences between Subgroups
n = 1248, FD, double blind, placebo-controlled
Ulcertype
50
* p < 0.05
*
Talley, Aliment Pharmacol Ther 1998; 12:1055-65.
Refluxtype
50
* p < 0.05
*
*
Omeprazole 20 mg
Free of symptoms in %
Omeprazole 10 mg
Free of symptoms in %
Free of symptoms in %
Placebo
Dysmotilitytype
50
Therapy of Functional Dyspepsia with PPIs
Differences between Subgroups
type
lcerU- PPIRefluxmore effectiveDysmotilitythan placebo (RRR
= 10.3%, NNT =
type
14.6) type
*
Talley, Aliment Pharmacol Ther 1998; 12:1055-65.
*
*
Free of symptoms in
%
* p < 0.05
%
- significant effect only in ulcer-like and reflux-like dyspepsia,
* p < 0.05
but not in dysmotility-like
& unspecified dyspepsia
50
50
50
Free of symptoms in
Free of symptoms in %
nMeta-Analysis
= 1248, FD, double blind, placebo-controlled
Wang, Clin Gastroenterol Hepatol 2007; 5: 178-85.
cebo
mg
Omeprazole 20 mg
Pla Omeprazole
- 7 studies, 10
3725
patients
Therapy of Functional
Dyspepsia
(Pro-)Kinetics
Therapy of Functional Dyspepsia with Prokinetics
Meta-analysis of 27 studies
Study
Van Ganse
Bekhti
De Loose De
Loose Van
Outryve
Van de Mierop
Creytens Milo
Deruyttere
Francois
Goethals
Hannon
Rosch Davis
De
Nutte
Hausken
Chung
Van Outryve
Kellow Wang
Al-Quorain
Champion
Champion
Yeoh
Yeoh
De Groot
Hansen
Kearney
Teixeira
Teixeira
Hallerback
Hallerback
Hallerback
Combined (95% CI)
Year
Effect Difference
1978
1979
1979
1979
1979
1979
1984
1984
1987
1987
1987
1987
1987
1988
1989
1992
1993
1993
1995
1995
1995
1997
1997
1997
1997
1997
1998
2000
2000
2000
2002
2002
2002
27 Studies, N=3435
-1844 Pat. received Drugs
-1591 Pat. received Placebo
6 Drugs:
Metoclopramide, Domperidone,
Trimebutine, Cisapride, Itopride,
Mosapride
The drugs have 30% excess
probability of producing a
response compared to placebo
-0.5 -0.25 0
.25 0.5 0.75
1
Hiyama, J Gastroenterol Hepatol 2007; 22:304-10.
Therapy of Functional Dyspepsia with Prokinetics
Targets, Agents and Clinical Efficacy
Mizuta et al., J Gastroenterol 2006; 41:1025–1040
Drug Treatment of Functional Dyspepsia
Prokinetics
Drug
Cisapride
Mechanism
5-HT4Agonist
Studies
+++
Comment
several but often small studies
( publication bias)
Cardiac arrhythmias !
Vitola, J Cardiovasc Electrophysiol 1998; 9:1109-13.
Domperidone:
> placebo In 10 of 11 studies
Domperidone
Metoclopramide
D2-Antagonist
++
Erythromycin
Motilin Agonist
+
Tegaserod
5-HT4-Agonist
+
first studies
Itopride
D2-Antagonist &
AChE - Blocker
+
Recent study failed to detect
effect on Dyspepsia Index
SSRI
(+)
Paroxetine
Effect in severe gastroparesis
Tack, Gastroenterology 1992; 103:72-9;
Maganti, Am J Gastro 2003; 98:259-63.
Talley, DDW 2007.
first studies
Drug Treatment of Functional Dyspepsia
Tegaserod – Current Experimental Data
Effects of Tegaserod on
Gastric Compliance
(Basal and pp Condition)
Influence of Tegaserod on
Gastric Accommodation
(Introduodenal Lipid)
Enhances accommodation in FD
Thusmhirn et al.,
Aliment Pharm Ther 2007; in press
Has no effect on gastric visceral sensation
Drug Treatment of Functional Dyspepsia
Tegaserod – Current Clinical Data
• Tegaserod improved Short Form Nepean Dyspepsia Index after 6 weeks treatment in patients with moderate to severe Functional Dyspepsia
Talley, DDW 2007.
• Difference between placebo and tegaserod in the more severe subgroup of
FD patients was more than 10%
Vekil, DDW 2007.
• Tegaserod improved daily activity impairment in FD patients with a more
pronounced effect in patients with more severe symptoms
Laine, DDW 2007.
• Tegaserod was also effective in patients with FD-heartburn overlap
Rodriguez-Stanley, DDW 2007.
• Tegaserod was well tolerated during 12 months‘ treatment with mild diarrhea
being an anticipated adverse event
Chey, DDW 2007.
IBS trials suggest cardiovascular side effects.
The future of tegaserod for this indication is vague.
% of patients
Drug Treatment of Functional Dyspepsia
Is Itopride effective in the treatment of FD?
Response Rate (wk 8)
70
*
*
p
<
0.05
*
60
*
50
40
30
20
10
0
Placebo
Holtmann,
N Engl J Med 2006;
354:832-40.
Itopride Itopride
50 mg 100 mg
3x/d
3x/d
Itopride
200 mg
3x/d
Drug Treatment of Functional Dyspepsia
Is Itopride effective in the treatment of FD?
Response rate
% of patients
70
60
* p < 0.05
*
*
Total gastric volume change
*
50
40
30
20
10
0
Placebo
Holtmann,
N Engl J Med 2006;
354:832-40.
Itopride Itopride
50 mg 100 mg
3x/d
3x/d
Itopride
200 mg
3x/d
Itopride failed to exert an effect on Nepean
Dyspepsia Index in FD (Phase III study)
Talley, DDW 2007.
No effects on:
-gastric emptying
-orocecal transit
-fasting gastric volume
-maximum tolerated volume
-aggregate symptom score
at nutrient drink challenge
Choung, Neurogastroenterol Motil 2007; 19:180–18
Therapy of Functional
Dyspepsia
Visceral Analgetics &
Antidepressants
Hypersensitivity in Functional GI Disorder
Targets of afferent nociceptive Pathways
Cortex
Spinal Cord
Descending inhibitory fibres
ANS. Input
2nd order neurons Dorsal
horn nucleus
Dorsal root ganglion Sensory
nerve endings in gut
Pain Perception
Pharmacological
Options
 opiates, Tricyclics
5HT3 antagonists
Clonidine
 opiates
5HT3 antagonists
Substance P CGRP
antagonists
NSAIDs
opiates
5HT3 antagonists
Therapy of Functional Dyspepsia - Antidepressants
Effects on abdominal pain
In favor of placebo
In favor of true
drugs
Tanum et al., 1996
Database:
• 13 studies (n=1717)
• Placebo-controlled
• randomized
Song et al., 1989
Arienti et al., 1994
Overall (95% CI)
McHardy et al., 1968
10
Standardized mean difference
Meta-Analysis of 4 placebo-controlled studies
with anxiolytics/antidepressants
0.55 (0.36-0.85)
0,1
Hojo, J Gastroenterol 2005; 40:1036-42.
Antinociceptive Treatment of Functional Dyspepsia
Visceral Analgetics
Drug
Mechanism
Fedotozine
Peripheral
k-Opiate-RAgonists
Proof
in studies
+/?
Comment
In 2 placebo-controlled
studies only low effect
Coffin, Aliment Pharmacol Ther 1996; 10:919-25;
Read, Gut 1997; 41:664-8.
A recent study did not show
any effect
Asimadoline
Choung, DDW 2007.
Ondansetron
Cilansetron
5-HT3Antagonists
Mianserin
5-HT2,- 5-HT3-,
2-Antagonist
(Antidepressant)
Sumatriptan
5-HT1-Agonist
?
+/?
No clinical studies
In 1 study (heterogen) better
than placebo
Tanum, Scand J Gastroenterol 1996; 31:318-25.
+/?
In 1 study significant
improvement of pp symptoms
Tack, Gut 2000; 46:468-73.
Drug treatment of FD with a 5-HT1-R-Agonist
Sumatriptan enhances gastric accommodation
Effect of the 5HT1-R-Agonist Sumatriptan
Rise of gastric volume pp (ml)
Rise of gastric volume pp (ml)
400
350
300
250
200
150
100
50
o
Patients
Controls
Tack, Gastroenterology 1998; 115:1346-52.
140
Accommodation
120
100
80
60
40
Symptoms
1050
Placebo
Food intake for
maximum satiety (kcal)
Basal conditions
900
750
600
450 Placebo
300
20
150
0
0
Sumatriptan
Sumatriptan
Treatment of Functional Dyspepsia with SSRIs
Paroxetin - beneficial effects on gastric function?
100
Cumulative Change in pp. Gastric Volume
50
time (min)
0
0
3
6
9
12
15
25
35
45
60
75
90
-50
-100
Patient
-150
Healthy controls n = 15
-200
Patient with Paroxetin
-250
Mönnikes et al; in preparation.
Therapy of
Functional Dyspepsia
H. pylori
Eradication
Helicobacter pylori in Functional Dyspepsia
Meta-analysis: Eradication vs. Placebo Eradication
• PPI treatment
• Dichotomous variables
• 17 studies, 3566 patients
• RRR: 10%
(CI = 6 - 14%)
• NNT = 14 : 1
(CI = 10 - 25%)
Moayyedi,
The Cochrane Library,
Issue 3, 2006.
H. pylori Eradication in Functional Dyspepsia
Complete Relieve of Symptoms after 1 Year
4 studies, 487 patients receiving eradication therapy, 491 placebo,
Symptoms/success of eradication after 12 months
Complete Relief of Symptoms in %
30
* p < 0.05
*
HP Eradication Rate in %
90
80
25
* p < 0.05
*
70
20
60
50
15
40
10
30
20
5
10
0
0
Eradication
Placebo
Treatment
Wang, DDW 2007.
Eradication
Treatment
Placebo
Therapy of Functional
Dyspepsia
Herbal Preparations &
Carminatives
Treatment of Functional Dyspepsia with STW 5
Clinical data
3 studies
STW 5 n = 138
Placebo n = 135
Reduction of GI symptoms
Melzer, Aliment Pharmacol Ther
2004; 20:1279-87.
Current Meta-analysis:
-Iberogast vs. Placebo
-4 Studies, n = 637
-Dyspesia score sig.
reduced in the STW 5
group
-NNT = 10
Holtmann, DDW 2007.
Rösch, Phytomedicine
2006; 13:114-21.
Herbal medicine in the treatment of FD
Effect of STW 5 on gastric motility
Iberogast
10 mN
Corpus
Antrum
20 mN
5 min
1 min
In vitro study
Iberogast
Hohenester, Neurogastroenterol & Motil 2004; 16:765-73.
Drug therapy of Functional Dyspepsia
Herbal medicine
Drug
Iberogast®
Iberis amara
+ 8 drug mixed
extract
Mechanism
spasmolytic &
toning
carminative?
antimicrobial?
Proof
in studies
+
Comment
2 published placebo-controlled
studies, 1 abstract
Buchert, Z Phytother 1994; 15:24-5; Madrich, Z
Gastro 2001; 39:511-7; v. Arnim, U Eur Gastro Week
2004, Prague, Abstract.
1 comparison with Cisapride
Rösch, Z Gastro 2002; 40:401-8.
Enteroplant®
Peppermint oil +
Caraway oil
Lipei®
Artichoke extract
spasmolytic
antimeteoristic
choleretic
spasmolytic
choleretic
Cholagogum F® choleretic
Celandine/Curcuma
2 placebo-controll. Studies
+/?
May, Aliment Pharmacol Ther 2000; 14:1671-7;
Micklefield, Phytother Res 2003; 17:135-40.
1 comp. with Cisapride
Madisch, Arzneimittelforschung 1999; 49:925-32.
+/?
+/?
1 placebo-controlled study
Holtmann, Aliment Pharmacol Ther 2003; 11-12;
1099-105.
1 placebo-controll. study
„biliary complaints“
Niederau, Med Klín (Munich) 1999; 94:425-30.
Drug therapy of Functional Dyspepsia – Carminatives
Simethicone has beneficial Effects
Symptom-Score
6
O‘ Brein Sum Score
normalized Deltas
16
Cisapride, 3x10mg
Placebo
N=185
12
8
4
Simethicon, 3 x 105 mg
Change of Symptom-Score
4
2
0
-2
-4
0
Base
line
2
3
8
Week
-6
Week 2
Week 4
Week 8
Holtmann, Aliment Pharmacol Ther 2002; 16:1641-8.
Therapy of Functional
Dyspepsia
Psychotherapy
Treatment of Functional Dyspepsia
Psychotherapy
Randomized,
controlled Tr.
Evidence Intervention
& Outcome criteria (different !
Haug et al. 1994
+
Bates et al. 1998
+
Hamilton et al. 2000
+/-
Calvert et al. 2002
Soo, The Cochrane Library, Issue 1, 2005;
Soo, The Cochrane Library 2007; CD003201.
+
• Kognitive Therapy
• Improvement of epigastric
symptoms at 1 year
• Psychosocial Suport by
Group Therapy
• Decrease in pain intensity and
frequency after 3 months
• Psycho-dynamic Therapy
• Decrease of Dyspepsia Score
after 3 (but not 12) Months
• Hypnotherapy
• Decrease of Dyspepsia Score
after 12 months
)
Psychotherapy in Functional Dyspepsia
Enhancing Coping Flexibility
Reduction of self-rated Dyspeptic Symptom Severity
Flexible Coping Psychotherapy (FCP) n = 33
Supportive Psychotherapy (SPP)
n = 31
Cheng, Psychosom Med 2007; 69:81-8.
Therapy of Functional
Dyspepsia
Drug Pipeline
Drug Pipeline for Therapy of Functional Dyspepsia
Drugs affecting Gastric Emptying
ATI-7505 (5-HT4-R Agonist)
-accelerated GE and increased colonic transit in healthy subjects (HS)
Camilleri, Neurogastroenterol Motil 2007; 19:30-8.
ABT-229 (Motilide)
-enhanced GE and stimulated antral motility in healthy subjects #
-failed to relieve symptoms in FD patients *
# Verhagen, Aliment Pharmacol Ther 1997; 11:1077-86; * Talley, Aliment Pharmacol Ther 2000; 14:1653-61.
Mitemcinal (= GM-611, Motilin Agonist)
-relieved gastroparesis symptoms in diabetic patients
McCallum, Aliment Pharmacol Ther 2007; 26:107-16.
Ghrelin (endogenous GHS)
-enhanced liquid emptying & decreased meal-related symptoms in idiopathic
gastroparesis
Tack, Aliment Pharmacol Ther 2005; 22:847-53.
Loxiglumide (CCK-A Antagonist)
-accelerated GE and increased antral motility in HS
Borovicka, Gut 1997; 41:500-4.
Botulinum Toxin
-Intrapyloric botulinum toxin sig. enhanced solid but not liquid GE and improved mealrelated symptoms in gastroparetic patients
Arts, Aliment Pharmacol Ther 2006; 24:661-7.
Drug Pipeline for Therapy of Functional Dyspepsia
Drugs targeting at Gastric Emptying
ATI-7505 (5-H T4-R Agonist)
- accelerated GE and increased colonic transit in healthy subjects (HS)
Camilleri,Neurogastroenterol Motil 2007; 19:30-8.
- Significant Effects in Functional Dyspepsia
stimulated have
antral motility
healthy subjects
# o relieve
symptoms
- enhanced GE
inand
general
notinbeen
proven
so far
ABT-229 (Mot ilide)
- failed tin FD patients *
# Verhagen, Aliment Pharmacol Ther 1997; 11:1077-86; * Talley, Aliment Pharmacol Ther 2000; 14:1653-61.
Motilin Agonist)
Mitemcinal (= GM-611,
- Improvement
of
Symptoms
in
Patients
- reliev ed gastroparesis symptoms in diabetic patients
, Aliment
Pharmacol
Ther 2007; 26:107-16.
McCallum
with
Gastroparesis
Ghrelin (endogenous GHS)
- enhanced liquid emptying & decreased meal-related symptoms in idiopathic aresis
ment Pharmacol Ther 2005; 22:847-53.
gastrop
Tack, Ali
 Test Gastric Emptying in Patients with
CCK-A Antagonist)
Functional
Dypepsia
Loxiglumide (rated GE and
increased antral motility
in HS
!
- accele
Borovicka, Gut 1997; 41:500-4.
Botulinum Toxin
- Intrapyloric botulinum toxin sig. enhanced solid but not liquid GE
and improved meal-related symptoms in gastroparetic patients
Arts, Aliment Pharmacol Ther 2006; 24:661-7.
Drug Pipeline for Therapy of Functional Dyspepsia
Drugs targeting at Visceral Hypersensitivity
Capsaicin (major component of red pepper, binds to vanilloid receptors)
-did not affect dyspeptic symptoms in patients with heartburn #
-Red pepper over a period of 5 weeks reduced the overall symptom score as
well as epigastric pain, fullness, and nausea in FD patients*
# Rodriguez-Stanley, Aliment Pharmacol Ther 2000; 14:129-34; * Bortolotti, Aliment Pharmacol Ther 2002; 16:1075-82.
Talnetant (Neurokinin 3-R Antagonist)
-reduced nociception associated with colorectal distention and stress-induced
hypersensitivity in rats
Fioramonti, Neurogastroenterol Motil 2003; 15:363-9.
Asimadoline (Peripheral k-Opiate-R-Agonists)
-no effect in functional dyspepsia
Choung, DDW 2007.
Clonidine (a2-adrenergic agonist & nitrergic control of smooth muscle)
-relaxes the stomach and reduces gastric sensation without inhibiting
accommodation or emptying in healthy volunteers.
Thumshirn, Gastroenterology 1999;116:573–585.
Drug Pipeline for Therapy of Functional Dyspepsia
Drugs targeting at Fundus Relaxation
Sildenafil (Phosphodiesterase-5 Inhibitor)
- increased fasting intragastric volume and volume of first perception;
induced a high postprandial relaxation and slowed liquid emtying
in healthy subjects
Sarnelli, AJP Gastrointest Liver Physiol 2004; 287:G988-G92.
Buspirone (5-HT-1a-R Agonist)
-enhanced gastric accomodation and improved symptoms in FD
Tack, Gastroenterology 1999; 116:A325.
R137696 (5-HT-1a-R Agonist)
-increased proximal stomach volume but did not affect distention-evoked
dyspeptic symptoms in healthy subjects
Boeckxstaens, Neurogastroenterol Motil 2006; 18:919-26.
338
(muscarinic M1 and M2 autoreceptors blocker  ACh release)
- enhances GI motility, gastric emptying and fundus relaxation
- ongoing international multicenter study
Ogishima,JPET 294:33–37,
Dyspepsia
Subgroups in the Population
Factor Analysis
Questionaire
 Population
Choung et al. Am J Gastroenterol 2007;102:1983–1989
Drug Therapy in Functional dyspepsia
Targeting Symptoms
Proton pump inhibitors
Spasmolytics
Pain
TCA
STW 5
Simethicone
Abdominal
bloating
(5-HT4-Agonists)
SSRIs
HP eradication
Early Satiety
Fullness
Metoclopramide
Nausea
Vomiting
Antiemetics
Thank you
Functional Dyspepsia
Management
Education, individual diet
Drug therapy necessary?
EPS: Antisecretory:
PPI
PDS: Prokinetic: Domperidone
Re-evaluation after 4 weeks
Failure:
Success: Stop of
medication
Change on alternative therapy
Success: Stop of
medication
Monitoring
Failure:
Clin. re-evaluation
Individual applicable therapy options a.o.:
• Antidepressants: Refractory symptoms, Constant Pain
• Eradication: Request of patient, NSARD therapy
• Herbal medicine: Postprandial Disstress Syndrome
• Psychotherapy: Refractory symptoms, QoL
Non-investigated Dyspepsia
Pathways of Patient Management
Age > 45 years
Alarm Symptoms
T Risk of
Malignancy
Endoscopy (EGD)
Biopsy for HP-Test
Age < 45 years; no NSRAs
No Alarm Symptoms
HP Prevalence
< 10%
HP Prevalence
> 10%
PPI empirical
Test & treat for HP
Test & treat for HP
PPI empirical
Endoscopy (EGD)
Endoscopy (EGD)
GERD: Comparison of symptoms and pH-metry
Typical symptoms are specific but not sensitive
Odynphagia
Pharyngeal Pain
Sickness
Belching
Upper
Abdominal Pain
Retrosternal
Retrosternal
Burning
Pain
Acid
Regurgitation
pH normal
pH pathol.
With excessive reflux:
also report non-typical
and extra-esophageal
symptoms
*
Heartburn
Klauser et al.,
Lancet 1990; 335:205-208
*
0%
patients
Patients with
typical symptoms
~ 50% have
nonexcessive
relux
100%
Dyspepsia, GERD, IBS
Discrimination by Symptoms limited by Overlap
n = 1059
unspezif.
Symptome
19%
Dyspepsie
14%
keine
Symptome
46%
Reflux
9%
RDS
12%
unspezif.
Symptome
18%
Reflux
10%
Dyspepsie
n = 146
RDS
16%
Dyspepsie
43%
Reizdarm
n = 130
unspezif.
Symptome
18%
Agreus et al. Gastroenterology 1995;109:671-80
keine
Symptome
12%
Dyspepsie
22%
Reflux
5%
keine
Symptome
6%
RDS
50%
Falk Symposium
Functional Dyspepsia
Hubert Mönnikes
Department of Medicine
Division Hepatology, Gastroenterology, and Endocrinology
Charité
Medical Faculty of Freie Universität & Humboldt-Universität, Berlin