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PRACTICAL THERAPEUTICS
Drugs 45 (6): 918-930, 1993
0012-6667/93/0006-091/$06,50/0
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DRU 1273
Functional Dyspepsia
Current Treatment Recommendations
Gerald Holtmann1 and Nicholas J, Talley2
1
2
Division of Gastroenterology, University of Essen, Essen, Federal Republic of Germany
Division of Gastroenterology and Internal Medicine, Mayo Clinic and Foundation,
Rochester, Minnesota, USA
Contents
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Summary
Summary
1. Prevalence and Definition of Dyspepsia
2. Pathophysiological Basis of Functional Dyspepsia
3. Classification of Functional Dyspeptic Symptoms
4. Drug Treatment of Functional Dyspepsia
4.1 Methodological Limitations of Trials
4.2 Randomised Controlled Trials in Function Dyspepsia
5. Principles of Management of Functional Dyspepsia
6. Conclusion
Symptoms of functional dyspepsia are frequent; the prevalence of dyspepsia (defined as pain
or discomfort centred in the upper abdomen) in the general population approaches 25%. By
definition, patients with functional dyspepsia do not have a structural'or biochemical explanation
for their symptoms. Disorders of function (e.g. delayed gastric emptying) are detectable in a
proportion of patients but remain poorly understood.
Nevertheless, the current rationale for drug treatment is based on altering pathophysiological
mechanisms which are believed to be associated with the development of symptoms. Although
the placebo response rates approach 60%, prokinetics, acid-suppressing agents and bismuth-containing compounds have been shown to be significantly better than placebo in reducing symp toms. Antacids are widely used, but no controlled study has been able to demonstrate a significant
benefit over placebo. The efficacy of sucralfate is uncertain.
Rational guidelines on which drug should be used for a given patient are lacking, although
approaches based on symptom profiles have been proposed; the duration of treatment needed to
achieve long-lasting relief of symptoms is also poorly defined. Identifying optimal treatment for
the individual patient, therefore, continues to be largely a trial and error process. Further re earch
efforts are needed to elucidate the pathophysiological basis of functional dyspepsia so that specific
therapy can be tailored to underlying pathophysiological disturbances.
Drug Treatment of Functional Dyspepsia
1. Prevalence and Definition of Dyspepsia
Dyspepsia is one of the most frequent health
conditions encountered in the general population.
Epidemiological studies have reported prevalence
rates that approach 25% annually if dyspepsia is
restricted to those who have recurrent upper abdominal symptoms, and heartburn alone is excluded (Talley el al. 1992). Nevertheless, most persons with dyspeptic symptoms do not seek medical
attention.
Functional (non-ulcer) dyspepsia is a heterogeneous disorder characterised by recurrent or chronic
abdominal pain or discomfort centred in the upper
abdomen. By definition, no organic disease such
as peptic ulceration, gastric cancer, chronic pancreatitis or gastroesophageal reflux disease (GORD
or GERD) can be identified as being responsible
for the symptoms. Patients with functional dyspepsia often have many symptoms, and hence it
has been suggested thai patients can be divided into
subgroups based on the symptoms that predominate (Colin-Jones el al. 1988; Drossman et al. 1990;
Talley el al. 199la).
2. Pathophysiological Basis of
Functional Dyspepsia
The pathophysiology of functional dyspepsia
continues to be very poorly understood; this topic
has been reviewed in detail recently (Holtmann &
Goebell 1992; Talley & Phillips 1988; Talley et al.
199la). Disturbances which may be associated with
the disorder include: (a) abnormal upper gastrointestinal motility and visceral perception that has
been postulated to account for postprandial distress, nausea, bloating and early satiety; and (b) increased sensitivity to gastric acid with or without
inflammation of the mucosa that may, in some
cases, account for upper abdominal pain.
Motility disturbances that have been observed
in some, but not all, patients with functional dyspepsia include delayed gastric emptying and postprandial antral hypomotility (Malagelada 1991).
Furthermore, some patienls wilh functional dyspepsia may have lower perception thresholds for
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stimuli originating from the stomach based on balloon distension studies compared with asymptomatic controls. However, the relevance of these observations in the generation of symptoms still needs
to.be determined (Talley & Phillips 1988).
The relationship between dyspeptic symptoms
and histological gastritis has remained controversial for years (Talley 1989). It is now accepted that
chronic gastritis is usually a result of infection with
Helicobacter pylori (Blaser 1990, 1992; Morris &
Nicholson 1987). In previous studies, the prevalence rate of infection with H. pylori in patients
with functional dyspepsia has approached 50%
(Tytgat et al. 1991). However, because this infection is also common in asymptomatic persons
(Dooley et al 1989), it remains unclear whether it
plays a pathogenic role in the development of
symptoms. Therefore, patients with dyspepsia and
only histological gastritis are still considered to have
functional dyspepsia (Talley et al. 199la).
3. Classification of Functional
Dyspeptic Symptoms
It is widely believed that patients with dyspepsia can be subdivided into subgroups based on the
symptoms that predominate, but this also continues to be controversial (Colin-Jones 1988; Talley
et al. 199la). Dyspepsia categories include 'ulcerlike', 'dysmotilily-Iike', 'reflux-like' and 'nonspecific' dyspepsia; it has been proposed that these
subgroups reflect entities with different pathophysiologies. These are shown in table I. However,
patients with true GORD are likely to account for
most cases of so-called reflux-like dyspepsia, and
such cases have probably often been included in
therapeutic trials of functional dyspepsia. It is well
known that patients with GORD respond to acidsuppressing measures which might at least partially
account for the apparent positive effect of certain
drugs in these studies. In general, we believe that
patients with symptomatic GORD should not be
given a label of functional dyspepsia.
Unfortunately, only a minority of patienls have
symptoms that fall into just one of the above mentioned categories; many patients have symptoms
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that fall into two or more groups (Talley et al. 1992).
There is also a substantial group of patients with
symptoms that do not fit into any of the criteria
shown in table I, and these are referred to as having nonspecific (or unspecified) dyspepsia. There
is, in addition, a considerable overlap of functional
dyspepsia with the symptoms of irritable bowel
syndrome (IBS), and this applies to each of the
symptom subgroups (Talley et al. 1992). Inclusion
of patients with IBS may account for the lack of
success of some of the therapeutic trials in functional dyspepsia.
4. Drug Treatment of Functional
Dyspepsia
Trials investigating drug therapy of patients with
functional dyspepsia are of interest not only because they may identify effective treatments, but
also because they may provide hints about the
underlying pathophysiological mechanisms.
4.1 Methodological Limitations of Trials
Many controlled and uncontrolled trials have
been carried out assessing the effects of different
drugs on the symptoms of functional dyspepsia. In
Drugs 45 (6) 1993
general, most of these studies have had substantial
methodological limitations (Talley 1991).
First of all, there has usually been no carefully
validated method utilised to assess improvement
of symptoms. In the trials published to date, some
studies have based improvement on a global assessment of symptoms only, but failed to take into
account individual symptoms, or vice versa. In addition, some studies have been based on the symptom assessment of the treating physician, while
others have relied on the patient's subjective assessment. Furthermore, most studies have failed to
carefully assess symptom subgroups (e.g. ulcer-like
or dysmotility-like), so the value of this classification is largely unknown. Unfortunately, quality
of life or life satisfaction has generally been ignored. The relevance of this outcome variable can
be illustrated by an example. An effective treatment that significantly reduces symptoms may on
the other hand negatively affect the quality of life
because the treatment has a major impact on lifestyle (e.g. frequent and inconvenient dosage schedule, or association with unpleasant side effects).
Data on the outcomes of treatment in relation to
cost (including costs of treatment, sick-leave days,
etc.) are also lacking (Bate & Richardson 1993).
Drug Treatment of Functional Dyspepsia
Almost all studies have avoided a follow-up
phase after completion of drug therapy, so the long
term treatment outlook remains essentially unknown. A large number of studies have also lacked
appropriate controls. In particular, a placebo group
remains absolutely essential because otherwise there
is no way of knowing the placebo responder rate,
which approaches 60% in some studies (Delattre et
al. 1985). A few experimental protocols have utilised multiple crossover designs where each patient
is treated sequentially with placebo or drug; thus,
each patient acts as his or her own control (Johannessen 1991), However, carryover effects from the
preceding treatment may be a major problem that
makes interpretation of such data difficult. Moreover, the generalisability of multiple 'n of 1' trials
is questionable (Lewis 1991).
Potential variability in the response rates in different populations have usually not been considered. In particular, if potent drugs are available as
over-the-counter (OTC) medications, the proportion of patients who have undergone previous empirical treatment might be large, and only those not
benefitting from medication (i.e. nonresponders)
may have been included in the trials. Moreover, if
patients are recruited only from tertiary care
centres, the response rate to a drug may be much
lower because these patients tend to comprise those
with intractable symptoms. Whether racial or geographical influences affect the outcome of treatment is virtually unknown. Another drawback of
numerous studies is the relatively small number of
patients included; this becomes particularly important when a high placebo response is observed,
because it may result in a considerable type II error
(i.e. an under-powered study).
4.2 Randomised Controlled Trials in
Functional Dyspepsia
The present review has evaluated all published
(primarily in peer reviewed journals), randomised,
double-blind, placebo controlled studies that were
identified by a Medline literature research for the
period 1979 to 1992. Furthermore, major review
articles (e.g. Dobrilla et al. 1989; Talley 1991;
Veld-
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huyzen van Zanten et al. 1989) were screened for
published drug trials in patients with functional
dyspepsia. Unpublished studies were not included
because their quality remains questionable in the
absence of careful peer review. Data from studies
that lacked a placebo control or were presented as
correspondence or abstracts are only reported where
their information was of particular interest.
4.2.1 Prokinetic Agents
Approximately 25 to 50% of patients with functional dyspepsia have objective evidence of gastroparesis, while less than 10% have small intestinal
dysmotility (Malagelada 1991). Furthermore, a
considerable proportion of patients with functional
dyspepsia have symptoms compatible with a disturbance of gastrointestinal motility, although the
correction between symptoms and motility derangements is weak (Malagelada 1991; Talley &
Phillips 1988). Nevertheless, prokinetic drugs have
been proposed as a rational treatment, particularly
for patients with dysmotility-like symptoms (Talley et al. 199la). Two classes of prokinetic drugs
are widely used, namely the dopaminergic receptor
blockers and cisapride.
Dopaminergic Receptor Blockers
Dopaminergic receptors are primarily located in
the proximal gastrointestinal tract; their blockade
has stimulatory effects on upper gastrointestinal
tract motility. Metoclppramide crosses the bloodbrain barrier and induces central antidopaminergic
effects in 20% of patients. Thus, the use of metoclopramide is limited by unwanted CNS effects such
as drowsiness, anxiety and extrapyramidal symptoms. These adverse effects are dose-related and
usually reversible after discontinuation of treatment. Another adverse event seen during treatment with metoclopramide is the development of
tardive dyskinesia which is rare, occurs predominantly in older patients, and is sometimes irreversible (Orme & Tallis 1984). Nevertheless, at
dosages commonly used in the treatment of patients
with functional dyspepsia, serious adverse effects,
especially in younger patients, are uncommon.
Based on the results of the available controlled
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Drugs 45 (6) 1993
trials, we conclude that metoclopramide is probably efficacious in improving symptoms of functional dyspepsia (De Loose 1979; Johnson 1971;
Perkel et al. 1979), but more data are needed.
Domperidone is a peripherally acting dopamine
antagonist (Champion 1988) that has now been extensively used in clinical practice; it does not cross
the blood-brain barrier. Similar to metoclopramide, domperidone stimulates oesophageal, gastric
and small intestinal motility (Weihrauch et al.
1979). In all but one study (Nagler & Miskovitz
1981), significant improvement of symptoms in
patients with functional dyspepsia has been observed (table II). Furthermore, in a study of 10 female patients with functional dyspepsia, Bradette
et al. (1991) showed that a fundic balloon elicited
symptoms at lower volumes during placebo compared with domperidone treatment, suggesting that
this drug may also alter visceral hypersensitivity.
While domperidone is better than placebo in treating patients with functional dvspepsia, it is probably no more efficacious than metoclopramide (De
Loose 1979).
Cisapride
Chemically related to metoclopramide is cisapride, a substituted piperdinyl benzamide. Cisapride facilitates cholinergic transmission in the
myenteric plexus (Tonini et al. 1989), and this effect is thought to be at least partially mediated by
the release of acetylcholine from postganglionic
nerve endings in the myenteric plexus (Schuurkes
et al. 1986). Whether this is a result of stimulation
of serotoninergic (5-hydroxytryptamine) 5-HT4 receptors, or inhibition of inhibitory afferents is still
unclear. Cisapride has been shown to increase lower
oesophageal sphincter tone, increase oesophageal
motility, and accelerate both gastric emptying and
small intestinal transit (Ceccatelli et al. 1988; Gilbert et al. 1987; Madsen 1990; Smout et al. 1985).
In clinical trials, 60 to 90% of patients with functional dyspepsia have had good to excellent global
symptomatic responses to this drug; this is generally superior to placebo, although the proportion
of placebo responses has been lower than expected
in most of the trials (table II). A meta-analysis re-
ported that prokinetic agents overall had a therapeutic success rate of approximately 50% over placebo (Dobrilla et al. 1989), although these pooled
estimates have been questioned by others (Talley
1991; Veldhuyzen van Zanten et al. 1989).
In contrast, despite a significant benefit in favour of cisapride compared with placebo after 2
weeks of treatment in dyspeptic patients with erosive prepyloric changes, this difference vanished
Drug Treatment of Functional Dyspepsia
during the re-evaluation after 4 weeks of treatment
(Hauskcn & Berstad 1992). Similarly, in a small
study of patients with recurrent right upper quadrant pain diagnosed as having the post-cholecystectomy syndrome (which in some cases appears
to overlap with functional dyspepsia), cisapride was
no more effective in relieving symptoms than placebo, despite the fact that the drug promoted biliary drainage (Farup et al. 1991).
Whether cisapride is superior to standard doses
of metoclopramide or domperidone remains controversial. Two studies (Corinaldesi ct al. 1987a;
Verhaegen et al. 1987) did not detect significant
differences, but one controlled study indicated that
cisapride improved symptoms in patients whose
symptoms did not improve after standard dosages
of domperidone or metoclopramide (Van Outyre
et al. 1990). However, further data are needed to
confirm this finding.
There is also debate whether or not combining
different prokinetics is of clinical value. Recently,
Tatsuta et al. (1992) compared the effects of cisapride alone with cisapride plus domperidone in
patients with dyspeptic symptoms and delayed gastric emptying. In this study, the combination of
cisapride and domperidone was more effective in
reducing symptoms versus cisapride alone, even
though only small numbers of patients were evaluated. Further studies are now required to clarify
these issues.
Other Prokinetic Agents
Clebopride is a substituted benzamide that may
also be a dopaminergic and serotoninergie antagonist. It has been compared with cisapride but not
placebo in patients with functional dyspepsia, but
it does not appear to offer any advantages over
other prokinetic drugs (Sabbatini et al. 1991).
Sulpiride, a dopaminergic antagonist, has been
shown in one trial to be superior to placebo (Hui
et al. 1986) but further data are lacking.
4.2.2 Antisecretory Drugs
A large proportion of patients with functional
dyspepsia have symptoms which traditionally have
been considered to reflect an acid-related disorder,
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namely ulcer-like dyspepsia. In addition, some
patients with functional dyspepsia do have histologically documented inflammation of the gastric
and duodenal mucosa, which it has been erroneously reasoned might heal if acid secretion were
reduced even temporarily. Therefore, drugs aimed
towards suppression of acid secretion have been
frequently tested.
Histamine H2-Receptor Antagonists
Results on the efficacy of histamine H2-receptor
antagonists, however, remain conflicting (table III).
Whereas about half of the trials found a significant
effect on dyspeptic symptoms, several studies were
unable to detect differences between H2-receptor
antagonists and placebo. The lack of a significant
effect in these latter studies may in part be explained by the relatively small sample sizes and
hence type II error. In addition, the heterogeneity
of the study populations may have influenced the
response to treatment.
A limited meta-analysis has suggested that there
is a 20% better therapeutic success rate with these
drugs compared with placebo (Dobrilla et al. 1989).
Both cimetidine (Johannessen et al. 1988, 1991,
1992) and ranitidine (Farup et al. 1991) have also
been tested in multiple crossover trials in patients
with functional dyspepsia. Results suggest that the
active drug is modestly superior to placebo, and
that those with ulcer-like dyspepsia or coexistent
symptomatic GORD are most likely to respond.
Pirenzepine
The benefit of the selective muscarinic blocking
agent pirenzepine remains controversial (Dal Monte
et al. 1982; Hradsky & Wikander 1982; Smith et
al. 1990;Talleyetal. 1986; Weberg & Berstad 1988).
We conclude that, when these studies are all considered, pirenzepine is probably inferior to H2-receptor antagonists in managing functional dyspepsia. Besides a type II error due to the relatively
small sample sizes in the negative studies, the substantially lower antisecretory potency of pirenzepine may help to explain these findings.
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Drugs 45 (6) 1993
toms not responding to conventional acid-suppressing measures, a brief trial of a proton pump
inhibitor may be justified.
Proton Pump Inhibitors
Proton pump inhibitors such as omeprazole have
been introduced for the treatment of acid-related
diseases in recent years. Clinical trials have commenced recently, but published data are not yet
available regarding the efficacy of these compounds in functional dyspepsia. Theoretically,
however, complete or near-complete inhibition of
acid secretion could be of value in some patients
with severe dyspeptic symptoms. On the other
hand, because functional dyspepsia is a benign disorder, the uncritical use of H+,K+-ATPase inhibitors in this disorder must remain questionable until the long term safety of this class of drugs has
been established in large populations. Nevertheless, in a limited number of patients with symp -
4.2.3 Sucralfate
Sucralfate stimulates mucosal prostaglandin
synthesis and has cytoprotective properties in experimental models, but has been tested in only two
completed placebo controlled trials in patients with
functional dyspepsia. One study (Kairaluoma et al.
1987) reported significant improvement of symptoms in 61 of 79 patients (77%) treated with sucralfate, compared with 40 of 72 (56%) in the placebo recipients. Interestingly, improvement of
symptoms was better when endoscopy did not reveal erosions or macroscopic evidence of inflammation of the gastric mucosa. However, the response to treatment was independent of the
histological grading of gastritis. Another study in
70 patients with functional dyspepsia who had erosions of the gastric and duodenal mucosa failed to
detect a significant benefit of sucralfale over placebo (Skoubo-Kristensen et al. 1989). After 6 and
12 weeks, 80 and 83% of sucralfate recipients, respectively, reported improvement or complete disappearance of symptoms, compared with 73 and
79%, respectively, of placebo-treated patients. The
lack of a significant difference may, therefore, be
because of the large placebo response rate. Alternatively, patients with erosions may represent a
group of patients who have different underlying
pathophysiological mechanisms than patients
without erosions.
In an open trial, sucralfate Ig four times daily
was compared with ranitidine 150mg twice daily
in 100 dyspeptic patients (Misra et al. 1992). Here,
global symptom improvement was significantly
better in patients treated with sucralfate versus
ranitidine (87 vs 64%) after four weeks. However,
as there was no placebo group and it was an unblinded study, the findings are questionable.
Sucralfate has also been compared with sulgicotide (sulglycotide), a sulphated glycopeptide that
forms a protective barrier on eroded mucosal surfaces and stimulates mucus release, in two small
double-blind, randomised trials (Barbara et al. 1990;
Drug Treatment of Functional Dyspepsia
Psilogenis et al. 1990). In both studies, symptoms
improved to a similar extent in the treated patients,
but again no placebo arm was included. Histological gastritis also similarly improved with both of
these drugs but H. pylori status remained unchanged.
4.2:4 Antacids
Antacids are frequently used, by patients with
functional dyspepsia. However, of the four randomised, placebo controlled studies that have been
reported to date (Gotthard et al. 1988; Nrrelund
et al. 1980; Nyrwn et al 1986: Weberg & Berstad
1988), all have failed to show a significant effect
of treatment, although there was improvement in
both active and placebo treatment groups.
One study compared an aluminum hydroxidecontaining antacid with sucralfate and placebo for
8 weeks in 45 patients with dyspepsia and who were
considered to have duodenogastric reflux-induced
bile gastritis, based on histology and scintigraphy
(Masci et al. 1989). While the histological features
improved to a greater degree during antacid treatment than with sucralfate or placebo, symptom responses were similar in all groups. However, the
power of the study was very limited and it was not
a blinded trial.
4.2.5 Treatment Aimed at Suppression and
Eradication of H. pylori
It is now accepted that chronic gastritis is usually caused by infection with H. pylori (Blaser 1990,
1992; Morris & Nicholson 1987; Talley 1989). In
previous studies, the prevalence rate of infection
with H. pylori in patients with functional dyspepsia
has approached 50% (Loffeld et al. 1988; Rokkas
et al. 1987), although infection is also common in
asymptomatic persons (Dooley et al. 1989). It has
nevertheless been postulated that H. pylori plays a
pathogenic role in functional dyspepsia in at least
a proportion of patients. If this holds true, symptoms should improve after eradication of H. pylori.
Several randomised placebo controlled trials on
the effects of bismuth-containing compounds have
reported improvement of symptoms following active treatment Clearance of H. pylori and histo-
925
logical improvement has also been associated with
a significant decrease in dyspeptic symptoms (Kang
et al. 1990; Lambert et al. 1987; Rokkas et al. 1988).
On the other hand, some trials have failed to detect
a significant effect of bismuth-containing drugs on
symptoms (Loffeld et al. 1989; McNulty et al. 1986).
However, the methodological limitations of all these
studies are considerable. Thus, improvement of
syptoms has often been observed even in patients
without H, pylori infection receiving active treatment, and in most patients eradication of H. pylori
was not successful (Chiba et al. 1992; Dill et al,
1990). Any beneficial effect of bismuth, therefore,
may be independent of the suppression or eradication of H. pylori. This is supported by observations from studies using antibiotics for suppression
of H. pylori, which have not demonstrated a significant effect on symptoms (Glupczynski et al.
1988; Holcombe et al. 1992; Morgan et al. 1988),
although the duration of treatment in some of these
trials was possibly too short Hailey and Newsom
(1984), in a small, randomised, placebo controlled,
multi-crossover study, found that bismuth salicylate (bismuth subsalicylate) tended to relieve more
episodes of dyspepsia and did so significantly faster
than placebo, but carryover effects and gastritis were
not evaluated.
Only one study has reported the relationship between eradication of H. pylori and symptoms
after 4 weeks of treatment. Symptoms improved
simi-larly in those patients in whom H. pylon
was or was not eradicated, but no placebo group
was in-cluded, and this was not a randomised trial
(Patch-ett et al. 1991). Recently, these authors have
also reported preliminary data suggesting that one
year after the end of eradication treatment, patients
with persistent H. pylori had persistent
symptoms, whereas patients without H. pylori
were
asymp-tomatic
(O'Morain
1992).
Randomised controlled trials are now urgently
needed to address this issue (Talley et al. 1991b).
In summary, the beneficial effect of eradication of
H. pylori for dyspeptic symptoms has not yet been
established; while bis-muth-containing agents
probably have beneficial effects on dyspeptic
symptoms, this might be in-dependent of effects
on H. pylori.
926
Drugs 45 (6) 1993
4.2.6 Other Agents
Several controlled and uncontrolled studies have
been performed to assess the efficacy of other drugs.
These include misoprostol (Hausken et al. 1990),
pancreatic supplements (Kleveland et al. 1990),
ursodeoxycholic acid (Pazzi et al. 1985; Tndury
1981), and antispasmodic drugs such as dicycloverine (dicyclomine) [Kagan et al. 1984; Stephens et
al. 1988] or trimebutine (Walters et al. 1980). So
far, these studies have not produced convincing
evidence that such treatment strategies are better
than placebo.
5. Principles of Management of
Functional Dyspepsia
If organic disease (e.g. peptic ulcer and oesophagitis) have been ruled out by endoscopy and
other appropriate testing, additional diagnostic
testing is unlikely to be positive. Reinvestigation
should be avoided in most cases unless there is a
change of symptoms suggesting the new onset of
organic disease (e.g. severe weight loss, pain radiating through to the back). Patients should be
strongly reassured about the absence of serious disease and should be informed about the nature of
the disorder. In managing patients with functional
dyspepsia, it is also useful to extract information
about factors that preceded the onset of symptoms
before drug treatment is considered. In particular,
patients should be carefully questioned with respect to medication use, including nonsteroidal antiinflammatory drugs stopping these may significantly improve symptoms, Patients should be advised to avoid specific foods that clearly aggravate
their symptoms (e.g. coffee, tea, alcohol). Obese
patients should also be urged to normalise their
weight, which is of particular help to patients who
also have GORD. It is important to realise that
some patients with functional dyspepsia are anxious, depressed or stressed, and these factors may
be the major reason why the patient has sought
counselling and treatment. Other patients have additional multisystem somatic symptoms, and display abnormal illness behaviour which may negatively affect management. A holistic approach alone
is sufficient to effectively manage a considerable
proportion of patients with functional dyspepsia.
An important issue when considering drug
treatment is the duration of symptoms. If symptoms have persisted for many years without affecting the quality of life, starting drug treatment
is often unnecessary. In contrast, if symptoms are
severely affecting quality of life, drug treatment
should be considered. However, only some patients
will respond, and many of those who do will have
a recurrence of symptoms soon after stopping
therapy. Thus, the optimal management of the
patient with functional dyspepsia must take into
account the intensity and duration of symptoms,
and the impact of symptoms on quality of life.
Numerous drugs are available to treat patients
with functional dyspepsia as described above (section 4.2). The decision to start a medication has to
keep in mind the potential risks of drug treatment;
the risk: benefit ratio must be extremely low, because functional dyspepsia is a disease without any
known mortality. The optimal duration of drug
treatment is unknown, because no controlled data
have evaluated the influence of duration of treatment on outcome. Until firm data are available,
treatment should be given for as short a period as
possible. It is common clinical practice to treat
patients until symptoms have resolved and then
discontinue medication. If symptoms do not respond after 2 to 4 weeks, then higher dosages or a
different drug, or rarely a combination of medications, may be helpful. Many patients with functional dyspepsia have recurring symptoms, so intermittent treatment is often sufficient to achieve
adequate control of the problem.
6. Conclusion
Functional dyspepsia is a disorder with an extremely high prevalence in the general population.
However, only a small proportion of subjects with
functional dyspepsia require drug treatment. Medical treatment achieves at least partial relief of
symptoms in the majority of patients. Because up
to 60% of patients have considerable improvement
of symptoms during placebo treatment (Talley &
Drug Treatment of Functional Dyspepsia
Phillips 1988), drugs which have not proven to be
efficacious in controlled trials may often seem to
be effective in relieving symptoms in clinical practice, which can be misleading. Still, we believe
it is reasonable to take advantage of the placebo
effect.
It remains a challenge to select patients who will
benefit from a particular medication and to determine the necessary duration of treatment. Because
of the methodological difficulties listed above, and
in particular the remarkable differences in the
characteristics of patients included in the various
trials, the clinical value of meta-analysis in this
particular field currently appears to be limited.
It is still widely believed that patients with dyspepsia can be subdivided into subgroups based on
the symptoms that predominate (Colin-Jones et al.
1988; Talley et al. 199la). However, there are no
convincing data indicating that such a symptomoriented classification identifies responders to a
particular type of treatment. Still, in clinical practice it is not unreasonable to use acid-suppressive
treatment or bismuth-containing drugs as first-line
treatment for patients with ulcer-like symptoms.
and prokinetic therapy for patients with dysmotility-like symptoms. Until the pathophysiological
basis of this disorder has been further elucidated,
empirical treatment will continue to dominate
clinical practice.
Acknowledgements
Supported in part by a grant from Deutsche Forschungsgemeinschaft, grant number Ho 1193/3-1 and by
the Mayo Foundation.
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