Transcript Dyspepsia

Functional Dyspepsia:
A Case-Based Approach
Case Study
• Christina is a 32-year-old woman referred
for the evaluation of a 1-year history of upper
gastrointestinal discomfort.
• She describes a daily, persistent ache or
discomfort that waxes and wanes.
– Occasional heartburn
• Eating seems to make the pain worse, and she feels
very full even after eating only a modest-sized meal.
• Her weight has remained stable for the past year.
Case Study
• Previously healthy female
– 2-3 glasses of wine/week; no tobacco
– High fiber diet
• PShx: Appendectomy (childhood)
• Meds: OCPs and occasional NSAIDS
– H2RAs tried x 1 month: no benefit
• Family Hx: Gallstones; IBS
• Physical exam: Epigastric tenderness o/w normal
Dyspepsia
Symptoms which are considered
to originate from the gastroduodenal region
Uninvestigated dyspepsia
Organic
dyspepsia
Endoscopy
30%
70%
Functional
dyspepsia
13
Dyspepsia:
Epidemiology and Burden of Illness
• 25% of the adult US population experiences
recurrent dyspepsia.
• Less than 50% of those with symptoms of
dyspepsia seek medical care.
• Dyspepsia accounts for up to 5% of all family
practice consultations.
• Dyspepsia has a significant impact on quality of
life.
Talley NJ et al. Gastroenterology. 1998;114: 582-595.
Tougas G et al. Am J Gastroenterol. 1999;94: 2845-2854.
The Economics of Dyspepsia
• It is estimated that 10% of all healthcare
expenditures in the United Kingdom go towards
treating dyspepsia.
• In the United States, direct costs (diagnostic
studies, emergency room visits, medications) and
indirect costs (absenteeism, presenteeism) for
dyspepsia amount to more than $2 billion/year.
Soo S et al. Cochrane Database Sys Rev. 2000;2;CD001960.
American Gastroenterological Association. The Burden of Gastrointestinal Diseases. 2001.
Organic vs Functional Dyspepsia
Dyspepsia
Identifiable cause for symptoms
• Peptic ulcer
• GERD (± esophagitis)
• Malignancy
• Pancreaticobiliary disease
• Medication
GERD, gastroesophageal reflux disease.
No identifiable explanation
• Unidentified pathophysiological
or microbiological abnormality
• Abnormal motor or sensory
function
– Altered gastric emptying
– Fundic dysaccommodation
– Gastroduodenal hypersensitivity
Tack J et al. Gastroenterology. 2006;130:1466-1479.
Proposed Pathophysiological Mechanisms
Involved in Functional Dyspepsia
Visceral
hypersensitivity
• abnormal
sensitivity to acid
Disrupted
gut–immune
interactions
Altered brain–
gut interactions
Functional
Dyspepsia
Genetic
factors
Abnormal
upper motor
+ reflex function:
•  Gastric emptying
• Dysaccommodation
Psychosocial
factors
Saad RJ et al. Aliment Pharmacol Ther. 2006;24:475-492.
Tack J et al. Gastroenterology. 2006;130:1466-1479.
GI Motility Disturbances in
Dyspepsia
Presenting symptoms
Dysfunction of
visceral afferents
Upper
abdominal pain
Postprandial abdominal
bloating
Nausea
Postprandial belching
Vomiting
Anorexia
Early satiety
Gastric
myoelectrical
dysrhythmias
Impaired fundic
accommodation
Delayed
gastric emptying
Antroduodenal
dyscoordination
Postprandial
antral hypomotility
Diagram adapted from Quigley EM. Aliment Pharmacol Ther. 2004;20:56-60.
Kellow JE. Med J Aust. 1992;157:385-388.
Options for
Uninvestigated Dyspepsia
Uninvestigated
dyspepsia
Test and treat
for H pylori
Empiric
therapy
Prompt EGD
• Age >45–50
• Warning signs
EGD, esophagogastroduodenoscopy.
Tack J et al. Gastroenterology. 1998;114:582-595.
Endoscopy in Uninvestigated
Dyspepsia
• In patients younger than 55 diagnosed with
dyspepsia, the incidence of gastroesophageal
malignancy was 1.06 per million
population/year.1
• Gastric cancer was present in less than 1 per
1000 patients with dyspeptic symptoms without
warning signs who underwent endoscopy.2
• No cases of gastric cancer were observed in
1886 patients with dyspepsia who underwent
endoscopy; 61% of these cases were functional
in nature (28% were acid related and 11% were
non-acid related).3
1. Gillen D. Am J Gastroenterol. 1999;94:2329-2330; 2. Breslin NP et al. Gut. 2000;46:93-97;
3. Froelich JW et al. Am J Gastroenterol. 2001;96:.
Initial Management of Uninvestigated
Dyspepsia: Pros and Cons of Immediate EGD
Advantages
• Provides
reassurance to
patient and doctor
• Allows targeted
therapy and the
potential for fewer
prescriptions
Disadvantages
• Expensive
• Invasive, with small
risk for complications
• Lack of infrastructure
to provide EGD to all
patients with
dyspepsia
Usefulness
• Patients with
symptom onset after
age 45 to 50 or with
alarm features
• Nonresponders to
initial test and treat,
empiric therapy, or
both
Cash BD et al. In: Hot Topics. 2003.
Initial Management of Uninvestigated
Dyspepsia: Pros and Cons of Test and Treat
Advantages
• Noninvasive
• Cure/symptomatic
benefit in those
with PUD
• Leads to similar
outcomes compared
with early EGD
• May reduce costs by
reducing endoscopy
workload and
medication use
Disadvantages
• Patients less satisfied
with test and treat
than with endoscopy
• May avert endoscopy in
only a minority of
patients
• Curing H pylori
improves symptoms
in <50% of patients
Usefulness
• Young patients without
alarm features in
regions in which gastric
cancer is rare
• Likely cost-effective
in areas of high
H pylori/ulcer
prevalence
• Effect on GERD?
PUD, peptic ulcer disease.
Cash BD et al. In: Hot Topics. 2003.
Initial Management of Uninvestigated
Dyspepsia: Pros and Cons of Empiric Therapy
Strategy
Advantages
Disadvantages
• OTC antacid
• Widely available
• OTC H2RA
or PPI
• Excellent safety
record
• Can rarely mask
serious disease
• Prescription
H2RA, PPI
• Inexpensive for
those with few
recurrences
• May only
postpone
investigation
• Can result in
chronic
medication use
• ? Potential for
AEs with longterm PPI use
OTC, over the counter; H2RA, histamine type-2
receptor antagonist; PPI, proton pump inhibitor.
Usefulness
• First onset of
dyspepsia of
short duration
• Young patients
with dyspepsia
without alarm
features
• Likely costeffective in
areas of low
H pylori/ulcer
prevalence
Cash BD et al. In: Hot Topics. 2003.
Uninvestigated Dyspepsia:
Summary
• One size does not fit all
• Factors favor the cost-effectiveness of empiric
antisecretory therapy over test and treat in many parts of
the United States.
– Decreasing H pylori and PUD prevalence
– Decreasing proportion of ulcers caused by H pylori
– Decreasing PPI costs
• The cost-effectiveness of combining empiric therapy and
test and treat deserves further study.
– High H pylori prevalence: test and treat and PPI for
–
nonresponders?
Low H pylori prevalence: PPI and test and treat for
responders?
Case Study
• Treated with PPI (once daily)
• Labs normal except for + H pylori
– Treated (triple therapy)
• Heartburn improved; epigastric pain worse
– Post-prandial nausea, bloating, constipation, lower
abdominal pain develop
• EGD performed: non-specific erythema
– Biopsies normal
• Diagnosed with Functional Dyspepsia
Rome III Criteria:
Functional Dyspepsia
Presence of one or more of the following symptoms,
thought to originate in the gastroduodenal region
Postprandial distress syndrome
(PDS): Meal-related FD
Bothersome
postprandial
fullness after
ordinary sized meals
Early satiety
that prevents
finishing a regular
sized meal
Epigastric pain syndrome (EPS)
Epigastric
pain
Epigastric
burning
No evidence of structural disease to
explain the symptoms and
*Symptoms
present for the past 3 months, with
onset at least 6 months before diagnosis
*New with Rome III criteria.
Tack J et al. Gastroenterology. 2006;130:1466-1479.
Overlap of GI motility and sensory
disorders
Discomfort
Belching
Heartburn
GERD
Regurgitation
IBS
Abdominal
pain
• Diagnosis can shift from
one disorder to another
over time
Dyspepsia
Bloating
Chronic
Constipation
(CC)
Constipation
Locke 3rd, et al. Neurogastroenterol Motil. 2005;17(1):29–34
Corazziari. Best Pract Res Clin Gastroenterol. 2004;18(4):613–31
Talley et al. Am J Gastroenterol. 2003;98(11):2454–9
Functional Dyspepsia:
Unclear Natural History
• 80% of patients have symptoms 18 to 24 months
after diagnosis.1
• 74% of patients have symptoms 12 to 24
months later.2
• In contrast, some studies have shown that
30% to 50% of patients experience resolution of
symptoms over the course of 12 to 24 months.3,4
1. Talley NJ et al. Am J Epidemiol. 1992;136:165-177.
2. Jones R et al. Br J Clin Pract. 1992;46:95-97.
3. Bonnevie O et al. Scand J Gastroenterol. 1982;17:1073-1076.
4. Sloth H et al. Scand J Gastroenterol. 1989;24:440-444.
Questions to Ask
• What is your most bothersome symptom?
• What other symptoms do you experience frequently?
• How do your symptoms affect your life?
• How do you explain your symptoms to family or
friends?
• Why do you think you developed these symptoms?
• What is your greatest concern about having
dyspepsia?
• What other concerns do you have about your
symptoms?
Case Study
• Desipramine begun (10 mg q.h.s.)
– Epigastric discomfort improved; no other changes
• RUQ ultrasound, celiac abs: normal
• Lactose free diet: no benefit
• Desipramine increased (50 mg q.h.s.)
– Groggy, constipation worse
• Metoclopramide started/desipramine stopped
– Nausea/bloating improve; constipation and
epigastric discomfort unchanged
• PEG started/ metoclopramide increased
Current Management of Functional
Dyspepsia
• Lifestyle changes
• H pylori eradication
• Antisecretory therapy
• Prokinetics
• Antinociceptive agents
• Psychological therapies
70%
Functional Dyspepsia
Treatment of Functional Dyspepsia:
Lifestyle Modifications
• No RCTs evaluate the role of diet or exercise.
• Smaller, more frequent meals may benefit
some patients.
• Low-fat diets may lessen symptoms in
some patients with FD.1,2
• Monitor medications, especially NSAIDs,
ASA products, iron, and antibiotics.
RCT, randomized-controlled trial; FD, functional
dyspepsia; ASA, acetylsalicylic acid.
1. Mullan A. Eur J Clin Nutr 1994;48:97-105.
2. Barbera RC et al. Eur J Gastroenterol Hepatol. 1995;7:1051-1057.
Cochrane Collaboration Meta-Analysis
of H pylori Cure for Functional Dyspepsia
• 12 RCTs (2903 patients)
• Mean response rate
– Placebo, 29% (range, 7%-51%)
– H pylori cure, 37% (range, 21%-62%)
• Relative risk of symptoms remaining
– 0.91 (95% CI, 0.86-0.95)
• NNT = 15 (95% CI, 10-28)
• Second meta-analysis of 10 RCTs in patients with FD
followed up for 1 year after treatment for H pylori did not
show any benefit in resolution of dyspepsia symptoms
compared with placebo.
NNT, number needed to treat.
Moayyedi P et al. Am J Gastroenterol. 2003;98:2621-2626.
Laine L et al. Ann Intern Med. 2001;134:361-369.
H pylori Eradication in Functional
Dyspepsia: The Bottom Line
• H pylori cure may offer benefit in a subset of
patients with FD.
– No reliable method exists to identify those likely to
respond.
– Overall benefits on a population basis are likely
to be small.
– If a chemopreventive benefit of H pylori cure for
gastric cancer can be demonstrated,1 the balance
will clearly favor treatment.
1Uemura
NEJM 2001
1. Uemura N. N Engl J Med. 2001;345:829-832.
Rationale for Antisecretory
Therapy in Functional Dyspepsia
• Overlap of GERD and dyspepsia symptoms
– Gastric acid secretion in patients with FD similar to that in
controls1
• Acid hypersensitivity
– Lowers threshold of mechanosensitive afferents2
– Increases nausea with duodenal acid infusion3
• Abnormal clearance from the duodenum3
– Decreases fasting clearance of exogenous acid
– Decreases fasting duodenal motor activity
1. Collen MJ. Dig Dis Sci. 1989;34:246-250.
2. Sansom MS et al. Gastroenterology. 1999;116:515.
3. Coffin B et al. Am J Physiol Gastrointest Liver Physiol. 2001;280:G904-G909.
H2RAs for Functional Dyspepsia
• Meta-analysis (2001)
• 22 RCTs in patients with nonulcer dyspepsia
• 14 studies, parallel group; 8 studies, crossover
• 15 of 22 studies found H2RA superior to placebo
at relieving epigastric pain but not global symptoms
of dyspepsia
• Significant design flaws in many studies, including
crossover design and inclusion of GERDpredominant patients
Redstone HA et al. Aliment Pharmacol Ther. 2001;15:1291-1299.
Cochrane Collaboration Meta-Analysis
of PPI Therapy for Functional Dyspepsia
• 7 RCTs (3031 patients)
• PPI for 2 to 8 weeks was superior to placebo
in relieving symptoms of nonulcer dyspepsia
• Relative risk of symptoms remaining
– 0.86 (95% CI, 0.80-0.93)
• NNT = 9 (95% CI, 6-26)
– Six RCTs (2032 patients) found no difference
between low-dose and standard-dose PPI for FD
Moayyedi P et al. Gut. 2003;52(suppl 1):A16.
Which Functional Dyspepsia Patients Are
Most Likely to Improve With PPI Therapy?
• Retrospective analysis of BOND and OPERA
studies (826 patients randomly assigned to
omeprazole 10 mg, 20 mg, or placebo)
• Treatment success defined as complete absence
of symptoms on last 3 days of week 4
• Predictors of success
– Fewer days with symptoms during week 1 of therapy
– Age older than 40
– Presence of heartburn
– Less bloating, epigastric pain, diarrhea
– Short duration of symptoms (<3 months)
Moayyedi P et al. Aliment Pharmacol Ther. 2003;18:117.
Emerging Therapies for Functional
Dyspepsia
• Antidepressants
• Serotonergic agents
• Dopaminergic agents
• CAM
– Cognitive/hypnotherapy
– Capsaicin
– Herbals
Prokinetic Agents for the
Treatment of Functional Dyspepsia
Physiological effects
Antiemetic
Gastric
emptying
Visceral
sensitivity
Gastric
antral
motility
Metoclopramide
Dopamine
antagonist
5-HT4 agonist

↑
↓
↑
Domperidone
Dopamine
antagonist

Tegaserod
5-HT4 agonist
↑
↑
↓
↓
↑
Levosulpiride
Dopamine
antagonist
5-HT4 agonist
↑
↓
↑
Agent
Primary
mode of action

Gastric
fundic
accommodation
↑
Saad RJ. Aliment Pharmacol Ther. 2006;24:475-492.
Antidepressants for Functional
Dyspepsia
• Reserved for moderate to severe symptoms
• Tricyclic antidepressants (TCAs)
– Visceral and somatic perception are altered with TCAs.1
– Study in 7 patients found that amitryptiline improved
–
symptoms but did not alter sensation of gastric distention.2
Meta-analysis in patients with FGIDs found improvement of
global symptoms (OR = 4.2; NNT = 3.2) and pain.3
• Selective serotonin reuptake inhibitors (SSRIs)
– Paroxetine did not alter perception of gastric distention but
–
did enhance gastric accommodation in healthy volunteers.4
No RCT findings have been published for FD.
FGID, functional gastrointestinal disorder.
1. Gorelick AB et al. Am J Physiol. 1998;275:G460-G466.
2. Mertz H. Am J Physiol. 1998;93:160-165.
3. Jackson JL et al. Am J Med. 2000;108:65-72.
4. Tack J et al. Am J Physiol. 2003;17:603-608.
Desipramine vs Placebo for
Moderate to Severe FGIDs
• Better response in patients with moderate symptoms
• Dose: 50-250 mg qhs
Desipramine
Placebo
(12 weeks)
P = 0.006
NNT = 4
100
Responses, %
P = 0.13
80
73
60
60
47
49
40
20
0
ITT n=201
PP n=153
Drossman DA et al. Gastroenterology. 2003;125:19-31.
Desipramine for FGID:
Moderate to Severe Adverse Effects
• 8-fold increase in study dropouts with TCA
• Multiple adverse effects common (mean, 3.5)
40
Desipramine (n = 135)
Patients, %
30
Placebo (n = 55)
26
20
20
16
11
13
13
8
10
2
0
Dry Mouth
Sleep
Constipation
Flush
Drossman DA et al. Gastroenterology. 2003;125:19-31.
Alosetron for Functional Dyspepsia
Total
Women
Men
*
60
Adequate Relief, %
50
46
40
40
40
39
51
49
54
43
39
42
43
40
30
20
10
0
Placebo n=66
*P < 0.05 compared with placebo.
0.5 mg n=59
1.0 mg n=67
2.0 mg n=65
Talley NJ et al. Aliment Pharmacol Ther. 2001;15:525-537.
Functional Dyspepsia:
5-HT4 Agonists
• Tegaserod improved preprandial and
postprandial gastric accommodation in healthy
volunteers.
• Global symptom improvement was noted in
women with FD on 6 mg bid tegaserod.2
• In patients with delayed gastric emptying and FD,
gastric emptying normalized in 80% of patients
receiving 6 mg tid tegaserod compared with 50%
receiving placebo (P < 0.058).3
1. Tack J et al. Gastroenterology. 2002;122:A453.
2. Tack J et al. Gastroenterology. 2002;122:A20.
3. Tougas G et al. Gastroenterology. 2003;124:A54.
Tegaserod in Functional Dyspepsia:
Days With Satisfactory Relief
D2302
50
50
P=0.0002
40
*
32.24
30
26.63
20
10
0
0
Placebo
(n=673)
Tegaserod
6 mg bid (n=680)
6.05% difference
Days With Satisfactory Relief (%)
Days With Satisfactory Relief, %
D2301
P=0.0662
40
30
29.36
31.87
20
10
0
Placebo
(n=652)
Tegaserod
6 mg bid (n=651)
3.16% difference
Talley NJ et al. Presented at: ACG. 2006.
Tegaserod Removed From The Market
• March 30, 2007- FDA and
0.12
Percent of patients with
cardiovascular events
Novartis removed tegaserod
from the market
• 13 patients treated with
tegaserod had cardiovascular
events
– 4 patients - heart attack (1
died)
– 6 patients - severe chest
pain/angina
– 3 patients - stroke
0.1
29 Randomized, controlled trials
of over 18,000 patients
13
0.08
0.06
0.04
0.02
1
0
Tegaserod
Placebo
N = 11,614
N = 7,031
http://www.fda.gov. Accessed April 2, 2007.
Itopride Hydrochloride Effects on
Gastric Motor and Sensory Function
• Dopamine D2 antagonist (similar to domperidone)
• Randomized, double-blind, placebo-controlled study
• Assessment of gastric function in 46 healthy persons
– Before and after 7 days of tid therapy
– No significant effects on gastric motor and sensory function
Placebo
Volume, mL
750
600
625
555
Itopride 100 mg
512
Itopride 200 mg
516
467
449
450
300
150
0
Total gastric volume (mL)
Proximal gastric volume (mL)
Choung RS et al. Am J Gastroenterol. 2006;101:S487.
Case Study
• Current tx: Omeprazole 20 mg q day,
metoclopramide 20 mg q ac, PEG 17 gm q day
– Nausea, bloating, heartburn improved
– Epigastric discomfort persists; now fatigued
• Domperidone 10 mg q.i.d. substituted for
metoclopramide; PPI and PEG continued
– Fatigue improves; epigastric pain persists
• Desipramine 25 mg q.h.s. reintroduced
– Epigastric pain tolerable
– Agrees to cognitive behavioral therapy evaluation
Complementary Medicine in the
United States
• Use of complementary medicine increased from 34%
to 42% (1990-1997).1
• Relaxation techniques (16%), herbal remedies (12%),
massage (11%) are its most common forms.1
• It is often used to treat chronic conditions.
– Back pain, anxiety, depression, headache
– IBS the most commonly treated GI problem2
– >20% alternative medicine use among IBS/FD patients3
• $21.2 billion in 1997
– $12.2 billion out of pocket
1. Eisenberg DM et al. JAMA. 1998;280:1569-1575.
2. Smart HL et al. Gut. 1986;27:826-828.
3. Koloski NA et al. Aliment Pharmacol Ther. 2003;17:841-851.
CBT vs Education for
Moderate to Severe FGID
CBT
100
P < 0.001
NNT=3
80
Responder rate, %
Education (12 weeks)
70
73
P < 0.001
NNT=3
60
40
37
41
20
0
ITT n=201
PP n=168
CBT, cognitive-behavioral therapy.
Drossman DA et al. Gastroenterology. 2003;125:19-31.
Hypnotherapy for
Functional Dyspepsia
*
100
HT, n = 26
Support and placebo, n=24
*
% Improvement
75
Medical, n = 29
*
73
*
59
50
43
41
33
*
42
34
25
10
11
0
End of Rx (16 wks)
*P < 0.05.
Hypnotherapy associated with less drug use
and fewer visits.
Long-term (56 wks)
QOL
Calvert EL et al. Gastroenterology. 2002;123:1778-1785.
Capsaicin for Functional Dyspepsia
Placebo, n = 15
5
Capsaicin, n = 15
Score
4
3
2
*
*
*
3
4
5
1
0
B
1
*P < 0.05.
One to two capsules red pepper powder q ac.
Epigastric pain and fullness relieved.
2
Time, weeks
Bortolotti M et al. Aliment Pharmacol Ther 2002;16:1075-1082.
Herbal Remedies for Functional
Dyspepsia: A Systematic Review
• 17 RCTs of herbal remedies are included in the
review (8 trials had a Jadad score >3).1
• Peppermint and caraway oil were the best-studied
herbal remedies.
– 4 RCTs show their benefits.
• Most studies were conducted with combinations
– Effective ingredient and quality control were unclear.
• Iberogast®, a combination of 9 herbs, relieved
symptoms compared with placebo in several
European studies.2
1. Thompson Coon J. Aliment Pharmacol Ther. 2002;16:1689-1699.
2. Gundermann KJ et al. Adv Ther. 2003;20:43-49.
Dyspepsia:
Novel Therapies
• Mianserin (tetracyclic antidepressant)
• Clonidine
• Sumatriptan/buspirone
• Paroxetine (SSRIs)
• Neurokinin antagonists
• Corticotrophin-releasing factor (CRF) antagonists
• Opioid antagonists
Medical Strategies for Functional
Dyspepsia
Therapeutic
intervention
Efficacy
Notes
H pylori eradication
36% vs 30% placebo; NNT 18 Meta-analysis of 13 RCTs
PPIs
33% vs 23% placebo; NNT 9
Meta-analysis of 8 RCTs
H2-receptor
antagonists
More effective than placebo
only for epigastric pain +
postprandial fullness
Meta-analysis of 11 RCTs
Antidepressants
– TCAs
73% vs 49% placebo; NNT 4.
Significant adverse effects
Single RCT only
Antacids
No better than placebo
1 RCT only
Bismuth salts
No better than placebo
Meta-analysis of 5 RCTs
Sucralfate
No better than placebo
Meta-analysis of 2 RCTs
Saad RJ. Aliment Pharmacol Ther. 2006;24:475-492.
Functional Dyspepsia Is…
Common
Treatable
Challenging
Functional
Dyspepsia
Chronic
Poorly understood
Controversial
Dyspepsia in Review
• Definition
• Epidemiology, natural history, and costs
• Underlying pathophysiology
• Diagnosis
• Treatment options
• Evidence to support current therapies
Functional Dyspepsia:
Diagnosis
• Thorough history and physical examination
• Evaluation for warning signs/features
– Unintentional weight loss, anemia, or dysphagia
– History of NSAID use
– Previous gastrointestinal bleeding or ulcer disease
– Recurrent vomiting
– Abnormal physical examination other than
epigastric pain
• High-prevalence or low-prevalence Helicobacter
pylori area?
NSAID, nonsteroidal antiinflammatory drug.
Functional Dyspepsia
Postprandial
distress syndrome
(PDS): Meal-related
FD
Epigastric pain
syndrome (EPS):
 Postprandial fullness,
 Pain or burning
after ordinary sized
meals, at least several
times per week, or
 Early satiation that
localized to the
epigastrium of at
least moderate
intensity
prevents finishing a
regular meal, at least
several times per week
Tack J et al. Gastroenterology. 2006;130:1466-1479.
H pylori Test and Treat: How, Who,
and What to Do With the Results
How to test for H pylori
• C-13 urea breath test
• Stool antigen test
Dyspepsia
(uninvestigated)
Age >55
or alarm features
EGD
If positive
• Initiate triple therapy
Age <55
No alarm features
H pylori prevalence
<10%
H pylori prevalence
>10%
Test and treat
H pylori
PPI trial
fails
fails
Test and treat
H pylori
fails
PPI trial
fails
Consider EGD
Talley NJ et al. Am J Gastroenterol. 2005;100:2324-2337.
Functional Dyspepsia: H pylori
Eradication
• A single-center study demonstrated
improvement in 21% of patients with H pylori
eradication (PPI + abx) compared with 7% with
PPI alone (P < 0.001).1
• Three multicenter RPCTs involving 759 patients
did not find any significant relief of dyspepsia
symptoms after H pylori eradication.2-4
RPCT, randomized placebo-controlled trial
1. McColl K et al. N Engl J Med. 1998;339:1869-1874.
2. Talley NJ et al. BMJ. 1999;318:833-837.
3. Talley NJ et al. N Engl J Med. 1999;341:1106-1111.
4. Froelich JW et al. Am J Gastro 2001; 96:_
Treatment of Dyspepsia (circa 1892)
• “Therapeutic measures may be divided into those
which attempt to replace in the digestive juices
important elements which are lacking…”
• “In the first group come hydrochloric acid and
ferments, which are so freely employed in
dyspepsia.”
• “Ewald recommend large doses of from 90-100
drops at intervals of 15 minutes after meals.”
Osler W. The Principles and Practice of Medicine. 1892.
Evidence for Prokinetic Therapies
• Metoclopramide – The most commonly used
prokinetic in the treatment of FD. A recent
meta-analysis failed to show any significant
benefit above placebo.1
• Cisapride – Seventeen studies were reviewed.
Earlier apparent favorable response might have
been attributed to publication bias. Recent review
of 17 studies did not show any significant benefit
compared with placebo.1,2
1. Abraham NS et al. Aliment Pharmacol Ther. 2004;19:631-641.
2. Soo S et al. Cochrane Database Sys Rev. 2000;2:CD001960.
Evidence for Prokinetic Therapies
• Domperidone – Eight studies were evaluated.
Many had severe design flaws. Recent metaanalysis showed a slight benefit at improving
symptoms compared with placebo.1
• Levosulpiride – A dopamine antagonist. Not
available in the United States. Recent study
showed benefit compared with cisapride, though
no placebo group was included.2
1. Veldhuyzen van Zanten SJO et al. Am J Gastroenterol. 2001;96:689-696.
2. Mearin F et al. Clin Gastroenterol Hepatol. 2004;2:301-308.
5-HT3 Antagonists for Functional
Dyspepsia
• 5-HT3 antagonists may alter visceral
perception.1
– Alosetron 1 mg bid did not alter perception of
gastric distention compared with placebo in healthy
volunteers.2
– Effects on visceral perception in FD patients have
not yet been reported.
• 5-HT3 antagonists may be beneficial for nausea.3
• Do 5-HT3 antagonists have effects on gastric
emptying?4
1Gershon
Rev Gastro Dis 2003;3:S25
2Zerbib APT 1994;8:403
1. Gershon
MD. Rev Gastroenterol Disord. 2003;3:S25-S34.
3Hasler,
2. Zerbib
F et al.Gastroenterol
Aliment Pharmacol
Ther. 1994; 8:403.
Chey
2003;125:1860
3.
Hasler WL et al. Gastroenterology. 2003;125:1860-1867.
4Akkermans
1988:29;1249
4. Gut
Akkermans
LM. Gut. 1988;29:1249-1252.
5-HT3 Antagonists for Functional
Dyspepsia
• In the only multicenter RPCT to date, 320 patients
with FD were randomly assigned to 3 doses of
alosetron or placebo for a 12-week trial period.
• Primary efficacy variable was adequate relief of
upper abdominal pain or discomfort.
• Fifty-five percent of patients receiving 1 mg bid
alosetron experienced adequate improvement
compared with 46% receiving placebo (P = 0.05). No
difference was observed in patients receiving 0.5 mg
bid or 2 mg bid alosetron.1
RPCT, randomized placebo-controlled trial
1. Talley NJ et al. Aliment Pharmacol Ther. 2001;15:525-537.
Effect of Tegaserod on Gastric Emptying,
Gastric Accommodation, and Small Bowel Transit
• In patients with dyspepsia and normal gastric emptying, tegaserod significantly
increased meal-induced gastric accommodation.1
Placebo
194
200
Time, min
150
Tegaserod 6 mg bid
137
†
*
116
128
100
50
0
Gastric emptying
T(1/2)
n = 40 (17 women).
Randomized, placebo-controlled, crossover study
*P < 0.008 vs placebo; †P < 0.002 vs placebo.
Small bowel transit
1. Tack J et al. Gastroenterology. 2005;128:A94.
2. Degen L et al. Neurogastroenterol Motil. 2005;17:821-826.
Interpersonal Psychotherapy for
Refractory Functional Dyspepsia
Total Symptom Score
16
14
PI therapy, n = 37
14.8
13.1
*
12
Symptomatic, n = 36
12.4
10.9
10
8.7
9.3
8
6
4
2
0
Entry
*P = 0.015.
Seven visits in 12 weeks.
Included patients with refluxlike symptoms.
End of Rx
1 yr FU
Hamilton J. Gastroenterology. 2000;119:661-669.
Functional Dyspepsia:
Summary
• Empiric antisecretory therapy is effective in a
•
•
•
•
•
subset of patients with FD.
Effective prokinetic therapy is eagerly awaited.
The benefits of H pylori cure in FD, if present
at all, are small.
Agents that affect accommodation or visceral
nociception may provide an alternative or may prove
complementary to acid suppression therapy.
Psychological therapies are effective in a subset of
FD patients.
Complementary strategies require further study.