Functional Dyspepsia Management in the Rome IV era · Functional Dyspepsia. Management in the Rome...
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Functional Dyspepsia Management in the Rome IV era Prof Tim Vanuytsel MD PhD Department of Gastroenterology, University Hospitals Leuven Translational Research Center for Gastrointestinal Disorders (TARGID) Leuven Intestinal Failure and Transplantation (LIFT) University of Leuven, Belgium
Transcript of Functional Dyspepsia Management in the Rome IV era · Functional Dyspepsia. Management in the Rome...
Functional DyspepsiaManagement in the Rome IV era
Prof Tim Vanuytsel MD PhD
Department of Gastroenterology, University Hospitals LeuvenTranslational Research Center for Gastrointestinal Disorders (TARGID)
Leuven Intestinal Failure and Transplantation (LIFT)University of Leuven, Belgium
Organic gastrointestinal disorders Conventional diagnostic means identify underlying disease
Organic vs. Functional
Organic gastrointestinal disorders Conventional diagnostic means identify underlying disease
Functional gastrointestinal disorders In up to 50% of patients seen by gastroenterologists, conventional
diagnostic means fail to explain the symptoms.
In these patients symptoms are thought to be caused by disturbances of gastrointestinal motility and sensitivity
Organic vs. Functional
Functional Gastrointestinal DisordersThe ROME Process
1984 20161988 1992 1996 2000 2004 2008 2012
Rome IIRome IManning
Kruis
FUNCTIONAL GASTRODUODENAL
DISORDERS
FUNCTIONAL BOWEL DISORDERS
FUNCTIONAL ANORECTAL DISORDERS
FUNCTIONAL ESOPHAGEAL DISORDERS
Functional Gastrointestinal DisordersThe ROME Process
•Functional dyspepsia;• Chronic nausea and vomiting disorders
• Belching disorders• Rumination syndrome
• Irritable bowel syndrome;• Functional bloating; • Functional constipation;• Functional diarrhoea
• Functional Chest Pain• Functional Heartburn• Reflux Hypersensitivity• Globus• Functional Dysphagia
• Faecal Incontinence Functional Anorectal Pain
• Functional Defaecation Disorder
Functional Dyspepsia
Uninvestigated dyspepsia
Dyspepsiasymptoms thought to originate from the stomach / duodenum
Functional dyspepsia Organic dyspepsia(ulcer, esophagitis, cancer, …)
70%
Routine Testing incl. endoscopy
Functional Dyspepsia
Functional Dyspepsia
Postprandial distress syndrome (PDS)
Meal-related symptoms (fullness, early satiation)
Epigastric pain syndrome (EPS)
Meal-unrelated symptoms(epigastric pain and burning)
Stanghellini et al. Gastroenterology 2016Mahadeva et al. Neurogastroenterol Motil 2016
Pathogenesis: Biopsychosocial Model
Drossman et al. Gut 1999Tanaka et al. J Neurogastroenterol Motil 2011
Dysregulated Brain-Gut Axis(bi-directional)
Impairedaccommodation
Delayed gastricemptying
Hypersensitivity togastric distention
45% 30% 35%
Pathogenesis: Biopsychosocial Model
Functional Dyspepsia
• History taking can be difficult in patients with functional dyspepsia.
• Comorbidity with GERD, IBS and other functional GI disorders is common.
• Misinterpretation and erroneous reporting of symptoms is common
• Sufficient clinic time is needed for FGID• Identify the most bothersome symptom or
symptom complex• Pictograms are helpful
Functional DyspepsiaCardinal Symptoms
Tack et al. Aliment Pharmacol Ther 2014
Fullness Early Satiation
Epigastric Burning Epigastric Pain
PDS
EPS
Functional DyspepsiaAssociated Symptoms
Tack et al. Aliment Pharmacol Ther 2014
Upper Abdominal Bloating Nausea
VomitingBelching
Functional DyspepsiaEndoscopy in Dyspepsia?
Broad definition Dyspepsia
Rome Criteria Dyspepsia
Ford et al. Clin Gastroenterol Hepatol 2010
N=5389
Functional DyspepsiaEndoscopy in Dyspepsia?
STARS I study: Primary care study in 17 countries2741 patients (18-70) fulfilling definition of functional dyspepsia (Rome II)
Cost of detecting 1 cancer:all: 118,000 euro (at 258 euro/endoscopy)>50 years: 43,000 euro
Vakil et al. Clin Gastroenterol Hepatol 2009
Functional DyspepsiaAlarm Features?
- Unintentional Weight Loss- Age > 55ys (35y in East Asia)- Dysphagia (especially if progressive) or Odynophagia- Persistent vomiting- Evidence of GI bleeding: melena, hematemesis, …- Iron-deficient Anemia- Family History of Gastric or Esophageal Cancer- Relevant abnormalities on physical examination
Stanghellini et al. Gastroenterology 2016
Functional DyspepsiaDiagnostic Evaluation
• H. pylori test and treat• PPI therapy• Prokinetic therapy (in PPI failures and 1st line in PDS)
Stanghellini et al. Gastroenterology 2016
Functional Dyspepsia
Functional Dyspepsia
Postprandial distress syndrome (PDS)
Meal-related symptoms (fullness, early satiation)
Epigastric pain syndrome (EPS)
Meal-unrelated symptoms(epigastric pain and burning)
Stanghellini et al. Gastroenterology 2016
Functional Dyspepsia
Functional Dyspepsia
Postprandial distress syndrome (PDS)
Epigastric pain syndrome (EPS)
PPI
H. Pylori test and treat
H. pylori eradication
Limitations:- Depends on the prevalence of HP- High NNT: 12.5- Therapeutic gain is late
(significance at 6-12 months)- Only tested in HP infected patients!
Most cost-effective treatment in FD
N=4,896 0.91 [0.88-0.94]
Moayeddi et al. Am J Gastroenterol 2017Mahadeva et al. Neurogastroenterol Motil 2016
Other Antibiotics: Rifaximin
Tan et al. Aliment Pharmacol Ther 2017
Global Dyspeptic Symptoms
P=0.02
P=0.1P=0.55*
95 Rome III FD (HP negative)Hong-Kong, secondary and tertiary careRifaximin 400mg tid vs. placebo for 14 days
Proton Pump Inhibitors
N=5,853 0.87 [0.82-0.94]
- NNT = 10- No need for dose escalation!- Aim for the lowest effective dose- Discontinue treatment if no effect in 4-8 wk- Differential effect in subgroups?
Moayeddi et al. Am J Gastroenterol 2017
ELF trial: 54 patients with functional dyspepsia4 wk treatment with lansoprazole 15mg vs. placebo
Suzuki et al. United European Gastroenterol J 2013
Proton Pump Inhibitors
Suzuki et al. United European Gastroenterol J 2013
PPIs work for epigastric pain/burning (EPS),but not for fullness and satiety (PDS).
54 patients with functional dyspepsia4 wk treatment with lansoprazole 15mg vs. placebo
Proton Pump Inhibitors
Functional Dyspepsia
Postprandial distress syndrome (PDS)
Epigastric pain syndrome (EPS)
Prokinetic drugs PPI
H. Pylori test and treat
1-2 months, standard dose
Treatment Algorithm
Prokinetics
- Mainly old, low-quality studiesMeta-analyses mainly rely on cisapride
- High risk of publication bias- Most products are not available in Europe/US
Metoclopramide: Extrapyramidal S/Domperidone: QTc prolongationClebopride: Extrapyramidal S/Alizapride: Extrapyramidal S/Itopride
PrucaloprideCinitaprideMosaprideRenzapride
Cisapride: QTc prolongation -> withdrawnTegaserod: cardiac ischemia -> withdrawn
N=8,788NNT = 6
0.92 [0.88-0.97]
Moayeddi et al. Am J Gastroenterol 2017
D2-
anta
goni
st5H
T4 a
goni
st
28
Holtmann et al. N Eng J Med 2006
ProkineticsItopride
29
Itopride 200 mg tid (n=136)
Itopride 100 mg tid (n=135)
Itopride 50 mg tid (n=135)
Placebo (n=142)
8 weeks 4 weeks
Follow-upScreening
Randomized study population
Treatment
Completers(n=474)
Screened patients(n=606)
Holtmann et al. N Eng J Med 2006
ProkineticsItopride
30
Holtmann et al. N Eng J Med 2006
Itopride vs placebo: p = 0.0065
Symptom ScoreLeeds Dyspepsia Questionnaire
Response RateSymptom Free or Marked Improvement
ProkineticsItopride
InhibitoryMotor Neuron
--
-NOVIP
+ +
Interneuron
Nicotinic receptor5-HT1-like receptor
Vagal efferent
CNS
Vagal afferent
Nutrients in the G.I. tract(oropharynx, stomach, duodenum)
ExcitatoryMotor Neuron
++
+ACh
+
5-HT1A receptorMuscarinic auto-receptor
5-HT4 receptor
cGMPACh
5-HT ?
Gastric Accommodation
-50
0
50
100
150
200
250
300
5 mg 10 mg 20mg 30mg 40mg
Buspirone dose
Mea
n vo
lum
e in
crea
se (m
l)
0
100
200
300
400
500
600
-30 -20 -10 0 10 20 30Time after drug administration (min)
Intr
a-ba
lloon
vol
ume
(ml)
Buspirone 5 mgBuspirone 10 mgBuspirone 20mgBuspirone 30mgBuspirone 40mg
Healthy volunteers, single oral dosesGastric Barostat
Van Oudenhove et al. Aliment Pharmacol Ther 2008
ProkineticsBuspirone (5HT1A agonist)
Tack et al. Clin Gastroenterol Hepatol 2012
17 FD patientsImproved PDS symptoms with buspirone 10mg t.i.d. (4 weeks, cross-over)
ProkineticsBuspirone (5HT1A agonist)
Dual Mechanism of Action:• Blocker of muscarinic auto-receptors• Blocks cholinesterase
• Accelerated gastric emptying• Increased accommodation
Matsushita et al. Neurogastroenterol Motil 2016
ProkineticsAcotiamide
FD-PDS (Rome III)Acotiamide 100mg t.i.d. vs. placebo
N=421
N=428
Japanese phase III study
Matsueda et al. Gut 2012
ProkineticsAcotiamide
Matsueda et al. Gut 2012
Overall Treatment Evaluation
Elimination of Fullness, Bloating and Early Satiety
Responder: improved or extremely improved
NNT=6
NNT=16
ProkineticsAcotiamide
Functional Dyspepsia
Postprandial distress syndrome (PDS)
Epigastric pain syndrome (EPS)
Prokinetic drugs PPI
H. Pylori test and treat
PPI (or combo?)
Neuromodulators
Treatment Algorithm
Drossman et al., Gastroenterology 2018
Neuromodulators (Antidepressants)
Augmentation
Neuromodulators
SulpirideLevosulpiride
Amitriptyline
SertralineEscitalopram
Venlafaxine
Ford et al. Gut 2017N=1,241NNT = 6
Neuromodulators: Amitriptyline
25mg od (2wk)> 50mg od
10mg od
Talley et al. Gastroenterology 2015
Neuromodulators: Amitriptyline
Talley et al. Gastroenterology 2015
Neuromodulators: Amitriptyline
Talley et al. Gastroenterology 2015
EPS
P=0.06
PDS
Amitriptyline is only useful to treat pain in patients with EPS, not in PDS.
Neuromodulators: Mirtazapine
N=34 FD (Rome III) patients with >10% weight loss and no psychiatric comorbidity.
Tack et al. Clin Gastroenterol Hepatol 2016
Neuromodulators: Mirtazapine
Tack et al. Clin Gastroenterol Hepatol 2016
NeuromodulatorsPsychotherapyNutritional Support
Experimental Treatment
Treatment Algorithm
Functional Dyspepsia
Postprandial distress syndrome (PDS)
Epigastric pain syndrome (EPS)
H. Pylori test and treat
Prokinetic drugs
PPI (or combo?)
Weight Loss: Mirtazapine Pain: Amitriptyline
PPI
