5.1 Introduction

Functional dyspepsia is the recommended term to denote dyspepsia for which no causal organic disease has been identified (see section 1.3). As it is a diagnosis of exclusion, clinical judgement must be exercised in the case of each patient to decide how much investigation is appropriate before the diagnosis may reasonably be applied. However, when taking these decisions, physicians should bear in mind that functional dyspepsia is more common than dyspepsia caused by underlying organic disease and that for most patients under 55 years of age, invasive investigation is not necessary before a working diagnosis of functional dyspepsia may be made.

Having made a diagnosis of functional dyspepsia, the clinician will wish to consider treatment options. Part of this consideration requires assessment of what has triggered the patient’s consultation: consultation with dyspepsia is more probable if the patient is anxious, depressed, stressed, has severe symptoms or is worried that the symptoms are signals of a life threatening illness.^{70, 71} Such concerns, if present, need to be addressed.

Not all patients with functional dyspepsia seek active treatment: for some, it may be sufficient to explain the condition and give reassurance that no serious disease has been found. For others, however, treatment may be warranted. Clinicians should remember that although by definition the causes and mechanisms responsible for functional dyspepsia symptoms are unknown, there is reason to believe that several different derangements of upper GI motor and sensory function may be implicated. This raises the possibility that symptom alleviation will need different treatments in different patients. Inevitably, clinical trials that have considered functional dyspepsia as a single entity and assessed the effect of one therapy do not address this possibility.

A working diagnosis of functional dyspepsia is likely to be appropriate for most patients with dyspepsia who have no alarm features and in whom initial investigations are negative. Repeated or increasingly invasive investigation in pursuit of an organic cause for the symptoms may be both futile and counter-productive.

5.2 Lifestyle advice

Eleven observational studies and surveys which consider functional dyspepsia and lifestyle factors were identified. Most of the published literature is based upon patients’ self-reported experiences, and is subject to the methodological criticisms associated with this type of data collection. One survey indicated that poor diet, stress and caffeine are perceived as the most common causes of GI symptoms.⁷² Another survey found that 80% of dyspeptic patients reported that avoidance of specific foods helped relieve dyspeptic symptoms.⁷³ Irregular eating patterns have been identified in functional dyspepsia, and this has been linked to stress, but causal effect is not clear.^{73, 74} A wide variety of food intolerances have been reported,⁷⁵ many of which patients are able to identify and self-treat without recourse to professional advice. Caffeine, alcohol and smoking have been reported as factors in the exacerbation of dyspeptic symptoms. ^{75, 76, 77} Other studies have found no association between these factors and dyspepsia.^{78, 79, 80}

There is no clear evidence to support a recommendation on the role of diet and lifestyle in the management of functional dyspepsia.

Patients with functional dyspepsia should be advised to stop smoking, and to exclude, or take only moderate amounts of alcohol and caffeine, in line with general healthy lifestyle recommendations.

If patients have adopted extreme dietary measures, they should be encouraged to follow a balanced diet to minimise the risk of nutritional deficiencies.

5.3 Psychological treatments

The correlation of psychosocial problems with functional dyspepsia suggests that psychosocial interventions may have a role in treatment.⁸¹ At the present time however there is no strong generalisable evidence on the benefit of this kind of intervention.⁸²

It is not possible to make a recommendation on the role of psychosocial interventions in the management of functional dyspepsia.

5.4 Pharmacological treatments

5.4.1 INTRODUCTION

Not all patients with functional dyspepsia require drug treatment. However, when prescription of medication is being contemplated, clinicians should appreciate that in functional dyspepsia, as in all other functional GI disorders, there is a substantial placebo response to therapy that constrains the interpretation of apparent treatment effectiveness in individual patients. No drug therapies have been found to have a high success rate in the treatment of functional dyspepsia though it should also be acknowledged that there is no scientific basis for supposing that all patients with functional dyspepsia should respond to the same pharmacological approach. Heterogeneity of presenting symptoms is evident in functional dyspepsia, heterogeneity of underlying mechanisms is suspected and there is some evidence suggesting different therapies may be effective for different patients. Conclusive evidence of this is lacking, however. The available information concerning drug therapy for functional dyspepsia all relates to relatively short term treatment periods and consequently drug treatment should usually be given on a short term basis only.

Medication is not necessary for all patients with functional dyspepsia. When medication is given, short term treatment, intermittent if necessary, is likely to be more appropriate than long term continuous therapy.

5.4.2 H. pylori ERADICATION

Four placebo controlled double blind RCTs compared effective eradication regimens to treatment regimens ineffective against H. pylori in patients with functional dyspepsia.^{83, 84, 85, 86} All four trials assessed symptoms using validated symptom scores at 12 months and excluded patients with confirmed peptic ulcer disease or oesophagitis at time of enrolment. Three of the four studies recruited patients with predominant symptoms of upper abdominal pain or discomfort (ROME II definition10).^{83, 84, 86} One study also included patients with predominant symptoms of heartburn, and this was the only trial to demonstrate a significant benefit for H. pylori.⁸⁵ A significant benefit remained after heartburn predominant patients were excluded (23% response compared to 10% in control group; p=0.02). This study was conducted in Glasgow and may therefore be most relevant to the Scottish population. Evidence level 1++

Three meta-analyses on the effect of H. pylori eradication on functional dyspepsia have differed in their conclusions.^{87, 88, 89} Evidence level 1++

The earliest review aggregated the results from the four studies quoted above and concluded that the results could not confirm or exclude benefit.⁸⁹ The most recent meta-analysis concluded that there is no significant benefit for eradication therapy based on the results from trials published up to December 1999.⁸⁸ Evidence level 1++

The largest meta-analysis was based on nine trials that evaluated symptoms in 2,541 patients at three to 12 months.^{87, 90} Trials published up to May 2000 were included in this meta-analysis although some of these were published in abstract form and authors provided further information. There was a significant (9%) reduction in the number of patients with functional dyspepsia remaining dyspeptic after eradication.^{87, 90} Evidence level 1++

On the basis of this last meta-analysis, 9% of functional dyspepsia patients who test positive for H. pylori benefit from eradication.^{87, 90} This effect can be described in terms of the number needed to treat (NNT) of 15 (ie 15 H. pylori positive functional dyspepsia patients will need to be given eradication therapy for benefit to be obtained in one).^{87, 90} Evidence level 1++

Overall because about 50% of patients with functional dyspepsia will be positive for H. pylori, eradication treatment will be symptomatically beneficial for slightly less than 5% of all functional dyspepsia patients. Evidence level 1++

H. pylori eradication therapy should be considered in the management of functional dyspepsia.

5.4.3 ACID SUPPRESSION

The true benefit of acid suppression therapy in functional dyspepsia can be difficult to quantify for the following reasons:

• few trials of medication have defined functional dyspepsia according to the Rome II definition¹⁰ and excluded patients with predominant symptoms of acid reflux
• there is a high placebo response to treatment.⁹¹ Evidence level 1+

Acid suppression therapy can be separated into histamine receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) and the results of treatment with either in functional dyspepsia are broadly similar. Evidence level 1+

One high quality RCT has shown a significant benefit from omeprazole over placebo of 10% (38% compared with 28%).⁹¹ This benefit increased in patient groups who had coexistent heartburn or epigastric pain, while no benefit was obvious in the patients with early satiety and nausea. A similar beneficial effect was demonstrated with H2RAs in patients with epigastric pain in trials using cimetidine⁹² and ranitidine.⁹³ There are no meaningful trials comparing the effects of PPIs and H2RAs. Evidence level 1++

Response to treatment has been associated with decreased health care costs and an improvement in health related quality of life. It has been suggested that patients who are more likely to gain longer term benefit may have an identifiable response after only one week of treatment.^{94, 95} Evidence level 1+

A small number of patients with functional dyspepsia (10%) may benefit from acid suppression therapy. A response is more likely in those with co-existent heartburn. Evidence level 1+

A trial of acid suppression therapy may be considered in the management of functional dyspepsia.

5.4.4 ANTACIDS

No evidence was identified on the efficacy of antacids in the management of functional dyspepsia.

5.4.5 PROKINETICS

Domperidone or metoclopramide are the prokinetic drugs still prescribed for patients with functional dyspepsia. They have different pharmacological properties from cisapride, the licence for which has been suspended in the UK.

Four meta-analyses of RCTs have explored the role of prokinetic pharmacological therapies in functional dyspepsia ^{96, 97, 98, 99} and three of them considered domperidone and metoclopramide.^{97, 98, 99} All three meta-analyses showed significant short term (2 to 12 weeks) improvement in global symptoms over placebo, but they included only a few trials and the combined number of patients covered in each meta-analysis is small. Since these trials are few in numbers, small scale and heterogeneous the positive results should be regarded with caution. Evidence level 1-

Although the trials of domperidone and metoclopramide showed significant improvement of global symptoms of dyspepsia over placebo in the short term, this positive effect may stem from bias due to the small number of patients involved in the trials.^{96, 97, 98, 99}

In view of the problems with the quality of the trials involved, the value of prokinetic drugs is uncertain. It is not possible to make a recommendation on the role of prokinetics in the management of functional dyspepsia.

5.4.6 CYTOPROTECTIVES

Cytoprotective agents include chelates and complexes, such as bismuth chelate and sucralfate and the prostaglandin analogue, misoprostol. Sucralfate acts by protecting the gastric mucosa, misoprostol has both antisecretory and protective properties.

• Chelates and complexes

Three RCTs were identified however only one study was considered methodologically sound and this study did not include a placebo group.¹⁰⁰ The two methodologically poor studies testing the efficacy of sucralfate produced conflicting results.^{101, 102} One study showed no effect against placebo¹⁰¹ whilst the other was suggestive of benefit but no placebo group was included in this study.¹⁰² Evidence level 1-

• Prostaglandin analogues

One study found no difference in efficacy between misoprostol and placebo but did identify increased side effects in the misoprostol treatment group.¹⁰³ Evidence level 1-

It is not possible to make a recommendation on the role of cytoprotectives in the management of functional dyspepsia.

5.4.7 ANTIDEPRESSANTS

A useful role for antidepressants in the management of idiopathic pain syndromes is often assumed. There is some evidence for the role of antidepressants in functional bowel disorders, but no clear evidence of benefit in functional dyspepsia.^{104, 105, 106}

It is not possible to make a recommendation on the role of antidepressants in the management of functional dyspepsia.

5.5 Informing patients

When a diagnosis of functional dyspepsia has been made, it may be helpful to explain to patients that:

• No disease or abnormality has been found and this should be taken as reassuring.
• Functional dyspepsia is very common and is not itself serious, though the discomfort, pain, distension and fullness which are perfectly genuine, are often unpleasant and bothersome.
• The definitive causes of functional dyspepsia are not known. It is known that, when compared with asymptomatic individuals, the stomach in many patients with functional dyspepsia empties more slowly after meals. There is also evidence of heightened visceral sensation in many functional dyspepsia patients who experience discomfort when the stomach is distended to a degree that does not cause discomfort in healthy subjects.
• Functional dyspepsia is not a condition caused by gastric hypersecretion: acid secretion is usually normal.
• Functional dyspepsia is not usually caused by stress, anxiety or depression but these factors may worsen the symptoms and diminish a patient’s ability to cope with them.
• Functional dyspepsia is not caused by sensitivity or allergy to dietary constituents. However functional dyspepsia sufferers, like everyone else, should avoid foods that upset them. This apart, no specific dietary pattern or restriction is required.
• Drug treatment is not very effective in functional dyspepsia but a minority of patients are helped by some medications.

5.6 Prognosis in functional dyspepsia

Little information is available that describes the long term outcome of patients with functional dyspepsia in the United Kingdom. In a study of Swedish patients with functional dyspepsia, about two thirds still had dyspeptic symptoms after ten years of follow up.¹⁰⁷ Many of them had undergone repeat GI investigations during the ten years, though new organic disease was rarely found. In common with other studies^{108, 109} many of these patients with functional dyspepsia exhibited symptoms that overlapped with those of irritable bowel syndrome. In a small proportion of patients, symptom profiles may actually change with time from the one condition to the other.¹¹⁰