Functional dyspepsia in adults

INTRODUCTION — 

Dyspepsia is a common symptom with an extensive differential diagnosis and a heterogeneous pathophysiology [1]. The prevalence of uninvestigated dyspepsia worldwide is up to 20 percent and varies according to the definition used [2,3]. Although dyspepsia can significantly impair quality of life, many individuals with dyspepsia do not seek medical attention [4]. The proportion of affected people who seek medical care ranges from 14 to 66 percent and varies by country and race/ethnicity [5].

Up to 80 percent of individuals with symptoms of dyspepsia have functional (idiopathic, nonulcer) dyspepsia. Many authorities regard it as a disorder of gut-brain interaction, similar to irritable bowel syndrome, globus, and other symptom-based gastrointestinal disorders [6]. This topic reviews the epidemiology, pathophysiology, diagnosis, and treatment of functional dyspepsia. The etiology, evaluation, and management of adults with uninvestigated dyspepsia are presented separately. (See "Approach to the adult with dyspepsia".)

EPIDEMIOLOGY AND PATHOPHYSIOLOGY

Prevalence — The prevalence of functional dyspepsia ranges from 5 to 16 percent worldwide [2,3]. A 2021 global epidemiology study involving over 73,000 adults in 33 countries identified a prevalence of 7.2 percent for functional dyspepsia [7]. Similarly, in a subsequent analysis of 44 studies including 256,915 participants from 40 countries, the pooled global prevalence of functional dyspepsia was 8.4 percent (95% CI 7.4-9.5 percent) [8]. Global prevalence declined slightly from 1990 to 2020 and varied depending on country, economic status, geographic region, and diagnostic criteria used.

Risk factors — Several factors are modestly associated with an increased risk of dyspepsia, including female sex, smoking, Helicobacter pylori infection, use of nonsteroidal anti-inflammatory agents, elevated body mass index, acute gastroenteritis, and specific psychiatric comorbidities.

●Acute gastroenteritis – The association between acute gastroenteritis and the subsequent development of functional dyspepsia is well established. The prevalence of postinfectious functional dyspepsia in adults is approximately 10 to 13 percent [9,10]. In a meta-analysis of six studies, individuals with an episode of acute gastroenteritis were more likely to develop functional dyspepsia after more than six months of follow-up than those without prior acute gastroenteritis (odds ratio 2.54, 95% CI 1.76-3.65) [9].

Specific clinical features may influence the likelihood of developing persistent functional dyspepsia after acute gastroenteritis. In one study, risk factors for the persistence of dyspepsia eight years after exposure to a waterborne outbreak of bacterial dysentery were female sex, smoking, premorbid irritable bowel syndrome (IBS), anxiety, depression, and >7 days of diarrhea or abdominal cramps during the acute illness [11].

●Psychologic conditions – Psychologic conditions that are associated with an increased risk of functional dyspepsia include generalized anxiety disorder, somatization, and major depression [12-15]. Individuals with a history of childhood abuse also have a higher prevalence of functional gastrointestinal disorders, including functional dyspepsia [16,17].

The relationship between anxiety and depression and functional dyspepsia appears bidirectional. Individuals with anxiety and depression at baseline have an increased risk of incident functional dyspepsia. Conversely, those with functional dyspepsia are more likely to develop subsequent anxiety and depression [1]. Anxiety symptoms may also affect the disease course of those with functional dyspepsia. In a prospective cohort study of 253 patients with functional dyspepsia, initial trait anxiety was independently associated with dyspepsia symptoms and quality of life at five-year follow-up [18].

Pathophysiology — The pathophysiology of functional dyspepsia is complicated and incompletely understood; potential mechanisms may differ between subtypes of functional dyspepsia (postprandial distress syndrome versus epigastric pain syndrome) [19] (see 'Diagnostic criteria' below). Potential mechanisms include the following [20]:

●Gastric emptying, accommodation, and vagal function – Functional dyspepsia has been associated with motility disorders, including delayed or accelerated gastric emptying, antral hypomotility, gastric dysrhythmias, impaired gastric accommodation in response to a meal, and abdominal vagal dysfunction [19,21-23]. The prevalence and severity of these findings vary among patients. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis".)

●Visceral hypersensitivity – Individuals with functional dyspepsia can also have visceral hypersensitivity independent of delayed gastric emptying [24]. Visceral hypersensitivity is characterized by a lowered pain threshold in the presence of normal gastric compliance. In a study of 270 individuals with functional dyspepsia, 37 percent had hypersensitivity to gastric distension [19]. Those with hypersensitivity reported higher symptom scores than normosensitive participants. Potential mechanisms of visceral hypersensitivity include mechanoreceptor dysfunction, aberrant processing of afferent input in the spinal cord or brain, and elevated plasma concentrations of enteral hormones [25,26].

●Gut-brain axis dysfunction – Gut-brain axis dysfunction may play a role in dyspepsia symptoms. Gut-brain axis communication occurs via the hypothalamic pituitary adrenal (HPA) axis and is modulated by alterations in the gut microbiome, gut epithelial cell barrier, immune function, and stress [1,27]. Magnetic resonance imaging of the brain shows functional abnormalities in areas that process afferent signals in persons with functional dyspepsia, especially those with the epigastric pain subtype [28].

In individuals with functional gastrointestinal disorders, mental stress can activate the amygdala and cause dysregulation of the HPA axis [29]. As an example, a history of adverse early life events was associated with HPA hyperresponsiveness to a visceral stressor in patients with IBS [30].

●Altered gut microbiome – Alterations in the upper gastrointestinal tract microbiome may lead to the development of dyspepsia and explain the association between acute gastroenteritis and the subsequent development of dyspepsia [11,31-34]. Conversely, the efficacy of H. pylori therapy in improving functional dyspepsia may be partly due to its impact on the gut microbiome [35,36].

●Duodenal inflammation and immune activation – Gastric and bile acids may cause low-grade inflammation that impairs mucosal integrity and results in abnormal gastrointestinal neuroregulation and symptoms of dyspepsia [37]. Abnormal populations of inflammatory cells have been detected in the duodenum of patients with functional dyspepsia, including increased eosinophils and mast cells and altered lymphocyte populations [38-42]. Conversely, the proton pump inhibitor pantoprazole reduces duodenal eosinophils, mast cells, mucosal permeability, and symptoms in patients with functional dyspepsia [43].

Inflammation may lead to disruption of the duodenal epithelial barrier [44]. This is supported by the observation of structural and functional abnormalities of epithelial cells and submucosal ganglia in the duodenum of patients with functional dyspepsia [45,46].

●H. pylori infection – Although some individuals with functional dyspepsia report symptom improvement after eradication of H. pylori [47], the role of H. pylori infection in the pathogenesis of functional dyspepsia remains unclear. (See "Helicobacter pylori: Epidemiology, pathophysiology, and overview of disease associations", section on 'Functional dyspepsia'.)

CLINICAL MANIFESTATIONS AND COMORBIDITIES

Symptoms — Patients with functional dyspepsia usually describe postprandial fullness, early satiety, bloating, and/or epigastric pain or burning. Symptoms may be severe enough to limit usual activities [48]. Postprandial fullness is the most intense symptom in patients with meal-induced symptoms [49]. Symptoms of epigastric burning are frequently confused with those of heartburn (ie, acid reflux) and require careful characterization to differentiate their location. Although some individuals may have nausea or vomiting, recurrent or persistent vomiting is not characteristic of functional dyspepsia and should prompt consideration of alternative diagnoses. (See "Approach to the adult with dyspepsia", section on 'Differential diagnosis'.)

Selected comorbidities — Several gastrointestinal disorders deserve special mention because they can be confused with functional dyspepsia and/or coexist with it. These include gastroesophageal reflux disease (GERD), gastroparesis, and irritable bowel syndrome (IBS). The clinical differentiation of these disorders from dyspepsia is discussed separately. (See "Approach to the adult with dyspepsia", section on 'Differential diagnosis'.)

●GERD – Functional dyspepsia and GERD frequently coexist, with studies suggesting that 9 to 75 percent of patients with functional dyspepsia also experience GERD symptoms [50].

●Gastroparesis – Functional dyspepsia and gastroparesis may be related disorders that exist along a spectrum. Abnormal gastric emptying is unstable over time, even in individuals with stable symptoms [51]. As an example, a prospective cohort of 944 tertiary care patients with chronic upper gastrointestinal symptoms used gastric emptying studies to classify participants as having gastroparesis or functional dyspepsia [51]. At 48-week follow-up, 42 percent of those who were initially classified as having gastroparesis had normal gastric emptying. Conversely, 37 percent of those who were initially classified as having functional dyspepsia had gastroparesis. Symptom severity and pathologic abnormalities on gastric biopsy did not significantly differ between those with gastroparesis and functional dyspepsia.

●IBS – More than 60 percent of patients with functional dyspepsia also have symptoms of IBS [52-54]. The overlap may be more likely when symptoms of either disorder are severe [55]. Compared with patients with IBS alone, patients with both IBS and functional dyspepsia had increased bloating and abdominal pain after a lactulose-nutrient challenge test [56].

EVALUATION AND DIAGNOSIS

Approach to evaluation — We suspect functional dyspepsia in individuals with a history of postprandial fullness, early satiety, or epigastric pain/burning. A clinical diagnosis of functional dyspepsia requires the fulfillment of symptom-based diagnostic criteria and an evaluation to exclude other causes of dyspepsia (algorithm 1). The evaluation of adults with dyspepsia is discussed separately. (See "Approach to the adult with dyspepsia", section on 'Initial evaluation' and "Approach to the adult with dyspepsia", section on 'Diagnostic approach'.)

Diagnostic criteria — Symptom-based criteria have been proposed to standardize the diagnosis of functional dyspepsia.

●Rome IV criteria – The Rome IV criteria define functional dyspepsia as the presence of one or more of the following symptoms: epigastric pain, epigastric burning, postprandial fullness, or early satiation and no evidence of structural disease (including at upper endoscopy) to explain the symptoms (table 1) [54]. The symptoms should have started at least six months before diagnosis and occurred during the last three months.

Individuals with these symptoms and a negative diagnostic evaluation likely have functional dyspepsia. Clinicians can presumptively diagnose functional dyspepsia even in individuals who do not explicitly meet the criteria for symptom frequency and duration.

●Functional dyspepsia subtypes – Rome IV criteria define two subtypes of functional dyspepsia (table 1):

•Postprandial distress syndrome – Postprandial distress syndrome is characterized by bothersome postprandial fullness and/or early satiation.

•Epigastric pain syndrome – Epigastric pain syndrome is characterized by bothersome epigastric pain or burning that is not exclusively postprandial.

Overlap between these subtypes is common [19,57]. As an example, in a survey of 551 respondents with functional dyspepsia, 61 percent had postprandial distress syndrome, 18 percent had epigastric pain syndrome, and 21 percent had symptoms of both conditions [3].

Differential diagnosis — The differential diagnosis of functional dyspepsia includes organic causes of dyspepsia and other conditions that cause epigastric or abdominal pain (table 2). Common organic causes of dyspepsia include peptic ulcer disease; medications, such as nonsteroidal anti-inflammatory drugs; and biliary pain. Gastric malignancy is a rare but life-threatening cause of dyspepsia in North America. These causes are discussed separately. (See "Approach to the adult with dyspepsia", section on 'Dyspepsia secondary to organic disease'.)

Other common disorders that can present with dyspepsia include gastroesophageal reflux disease, gastroparesis, irritable bowel syndrome, and cardiac ischemia. Clinical assessment, laboratory testing, and upper endoscopy differentiate these conditions from functional dyspepsia. The evaluation and differential diagnosis of dyspepsia are discussed separately. (See "Approach to the adult with dyspepsia".)

MANAGEMENT — 

The management of patients with functional dyspepsia is based predominantly on expert consensus and limited evidence from large, randomized trials (algorithm 2) [1,44,52,54,58]. Because many individuals will experience persistent symptoms despite initial pharmacotherapy, management success also depends on a strong therapeutic alliance and effective, empathic clinician communication [44,59,60]. Our approach to the management of functional dyspepsia is largely consistent with guidelines from the American College of Gastroenterology, Canadian Association of Gastroenterology, American Gastroenterological Association, and British Society of Gastroenterology [53,59,61].

Initial approach — We test all individuals with dyspepsia for H. pylori and select initial treatment based on the test results (algorithm 2). Testing for H. pylori should utilize a test that detects active infection (stool antigen assay, urea breath test, or biopsy performed at the time of upper endoscopy). Test selection depends primarily on whether the patient undergoes upper endoscopy. In these patients, we perform gastric biopsies to test for H. pylori. In patients who do not require an upper endoscopy or in whom biopsies were not performed during endoscopy, we perform noninvasive testing using a urea breath test or stool antigen assay. Testing strategies and biopsy techniques are discussed separately. (See "Indications and diagnostic tests for Helicobacter pylori infection in adults".)

Patients with H. pylori — We suggest treatment for H. pylori in individuals with dyspepsia who test positive for H. pylori infection [62]. Patients should receive an appropriate antibiotic regimen followed by retesting for H. pylori at least four weeks after completing antibiotics to confirm eradication. Selecting an antibiotic regimen, duration of treatment, and eradication testing are discussed separately. (See "Treatment of Helicobacter pylori infection in adults".)

In patients with functional dyspepsia, a strategy of "test and treat" for H. pylori is modestly more effective than placebo for symptom resolution. In a meta-analysis of 14 trials with 3903 participants, eradication therapy for H. pylori cured symptoms of functional dyspepsia more effectively than treatment with placebo or antisecretory therapy plus placebo antibiotics (relative risk [RR] of symptoms not being cured 0.91; 95% CI 0.89-0.94; number needed to treat [NNT] = 14) [63]. Compared with placebo or antisecretory therapy plus placebo antibiotics (16 studies; 4424 participants), H. pylori eradication therapy was also more efficacious for symptom improvement (RR of symptoms not improving 0.86; 95% CI 0.79-0.94; NNT = 7).

The rationale for H. pylori testing and treatment in the broader population of patients with uninvestigated dyspepsia is based upon the causative role of H. pylori in peptic ulcer disease and data from randomized trials that this strategy reduces dyspepsia symptoms. In a meta-analysis of two randomized trials of 563 H. pylori-infected patients with dyspepsia, H. pylori eradication therapy significantly reduced the likelihood of persistent symptoms, compared with placebo (RR 0.81; 95% CI 0.70-0.94; NNT = 7) [53,64].

H. pylori eradication may improve dyspepsia symptoms by altering acid secretion or modifying intestinal microbiota [65,66]. It may also prevent peptic ulcers associated with H. pylori. (See "Helicobacter pylori: Epidemiology, pathophysiology, and overview of disease associations", section on 'Functional dyspepsia' and "Helicobacter pylori: Epidemiology, pathophysiology, and overview of disease associations", section on 'Peptic ulcer disease (PUD)'.)

Patients without H. pylori

●PPI as preferred therapy – For individuals with a normal initial evaluation for dyspepsia who test negative for H. pylori or who remain symptomatic four weeks after eradication of H. pylori, we suggest treatment with a once-daily proton pump inhibitor (PPI) for four to eight weeks (algorithm 2) [67,68].

Both low- and standard-dose PPIs effectively treat dyspepsia symptoms [69]; high-dose (twice-daily) PPIs do not appear more effective than standard doses (table 3) [70]. (See "Antiulcer medications: Mechanism of action, pharmacology, and side effects", section on 'Antisecretory agents'.)

In patients whose symptoms improve with the PPI, we typically continue treatment for six months and then ask patients to taper and discontinue the PPI. Although long-term PPI therapy is generally safe, individuals with functional dyspepsia on chronic PPI therapy should try to discontinue PPIs every 6 to 12 months. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders", section on 'Discontinuing PPIs'.)

•Benefits compared with placebo – PPIs appear moderately effective for treating functional dyspepsia. Data supporting the use of PPIs come from randomized trials of individuals with functional dyspepsia and those with dyspepsia, most of whom likely had functional dyspepsia [53]. Representative studies include the following:

-In a systematic review of 18 trials of patients with functional dyspepsia, participants randomized to PPIs had a decreased risk of persistent dyspepsia symptoms, compared with those randomized to placebo (RR 0.88; 95% CI 0.82-0.94; NNT = 11) [69]. Low- and standard-dose PPIs were similarly efficacious.

-In a meta-analysis of six trials that included 2709 individuals with uninvestigated dyspepsia, those randomized to PPI therapy had a lower likelihood of persistent symptoms than those assigned to control medications (placebo or antacid therapy; 50 versus 73 percent; RR 0.75; 95% CI 0.64-0.88) [53].

PPIs may exert their beneficial effect by reducing duodenal eosinophils, mast cells, and mucosal permeability [43]. In individuals with functional dyspepsia, symptom improvement with PPIs may derive from elevated sensitivity to gastric acid in some individuals with dyspepsia or an overlap between or misdiagnosis of gastroesophageal reflux disease (GERD) and dyspepsia. (See 'Selected comorbidities' above and "Approach to the adult with dyspepsia", section on 'Gastroesophageal reflux disease'.)

•Benefits compared with H2RAs – PPIs may be more efficacious for dyspepsia than histamine 2 receptor antagonists (H2RAs) [71,72]. A systematic review of two trials found no significant difference between PPIs and H2RAs in reducing symptoms of functional dyspepsia (RR 0.88; 95% CI 0.74-1.04) [69]. However, most trials were of low quality, had significant between-study heterogeneity, and may have included individuals with GERD who had been misdiagnosed as having functional dyspepsia. A subsequent meta-analysis of seven trials in individuals treated empirically for dyspepsia reported similar results (RR 0.93 for persistent symptoms; 95% CI 0.76-1.16) [53].

●H2RAs as an alternative option – H2RAs are an alternative for patients who are unable to tolerate or prefer not to use PPI therapy. Although H2RAs are more efficacious than placebo, they may be less effective than PPIs for the management of functional dyspepsia. In a meta-analysis of 12 trials that included 2183 participants, H2RAs reduced symptoms compared with placebo (RR reduction 23 percent; 95% CI 8-35 percent; NNT = 7) [73]. However, the certainty of these results is limited because many of the studies included patients with GERD, which frequently overlaps with functional dyspepsia and may respond to H2RAs.

Subsequent approach

Neuromodulators — In patients with functional dyspepsia whose symptoms do not improve after eight weeks of PPI therapy, we initiate a trial of a low-dose neuromodulator, most commonly a tricyclic antidepressant (TCA) or the atypical antidepressant mirtazapine. We typically prefer a TCA because more robust evidence exists to support its efficacy for functional dyspepsia [74,75]. However, mirtazapine is an alternative for patients who are at risk for TCA-related side effects, such as cardiotoxicity (eg, QT interval prolongation) or orthostatic hypotension.

For patients with a partial response to a PPI, the TCA can be added to PPI therapy; otherwise, the PPI should be discontinued.

●TCAs – We begin with a low-dose TCA (eg, amitriptyline 10 mg, nortriptyline 10 mg, or desipramine 25 mg at night) and increase the dose at two- to three-week intervals. Many individuals respond to a dose of 20 to 30 mg. We typically do not exceed a dose of 50 mg because higher doses can cause daytime sedation and other anticholinergic side effects and may not be more effective than lower doses. The typical duration of a treatment trial is 8 to 12 weeks. If the patient responds, the TCA is continued for six months and then slowly tapered off. Patients with recurrent dyspepsia symptoms can resume the same medication.

Data supporting the efficacy of TCAs in functional dyspepsia include the following:

•In a trial of 292 participants with functional dyspepsia, more participants experienced adequate symptom relief with amitriptyline 50 mg daily than placebo (53 versus 40 percent) [76].

•In a network meta-analysis of pharmacotherapy for functional dyspepsia, TCAs ranked second for efficacy (RR 0.71 of remaining symptomatic; 95% CI 0.58-0.87) and first in analyses that included only trials at low risk of bias [77]. Most trials of TCAs studied patients who were refractory to other drugs analyzed in the network.

Low-dose TCAs may improve associated symptoms of insomnia and fibromyalgia in patients with functional dyspepsia [74]. Low-dose TCAs may also be useful in individuals with functional dyspepsia and concomitant irritable bowel syndrome because of their efficacy in treating both disorders [78]. (See "Treatment of irritable bowel syndrome in adults", section on 'Tricyclic antidepressants for persistent symptoms'.)

The mechanism of action of TCAs in functional dyspepsia is unknown. In one study, amitriptyline improved gastric accommodation and postprandial bloating and did not delay gastric emptying [75].

●Mirtazapine – Mirtazapine has also demonstrated benefit in the treatment of functional dyspepsia and may be especially useful in those with early satiety, postprandial fullness, or concomitant weight loss [79-81]. We usually begin with mirtazapine 15 mg one hour before bedtime and increase the dose; most patients need 30 to 45 mg nightly. Mirtazapine commonly causes somnolence; however, this side effect may improve after the first one to two weeks [79,80].

Small, randomized trials support the efficacy of mirtazapine for treating functional dyspepsia. Representative examples include the following:

•In a trial of 34 patients with >10 percent weight loss, mirtazapine 15 mg daily reduced global symptoms of dyspepsia, early satiation, and gastrointestinal-specific anxiety at eight weeks, compared with placebo. Participants receiving mirtazapine also reported weight gain and improved nutrient tolerance and quality of life [79].

•In a randomized trial of 60 participants with functional dyspepsia and >5 percent weight loss, mirtazapine 30 mg daily reduced dyspepsia and depression and resulted in more weight gain compared with paroxetine 20 mg daily or treatment with an acid inhibitor or prokinetic [80].

Studies suggest that mirtazapine may improve dyspepsia symptoms via a central mechanism of action [80,81].

●Trazodone – While some clinicians prefer trazodone over TCAs, few clinical data support its efficacy for functional dyspepsia.

Prokinetic agents — We reserve prokinetics for individuals in whom other therapies have failed. We typically start with metoclopramide 5 to 10 mg three times daily one-half an hour before meals and at night and limit the duration of treatment to four weeks. If symptoms recur, we repeat a course of therapy. Results of gastric emptying studies should not guide therapy because the relationship between gastric emptying and treatment efficacy has not been established.

Up to 30 percent of patients have side effects with prokinetic agents [53]. Although most adverse effects are mild and resolve with cessation of therapy, the risk of tardive dyskinesia increases with increasing patient age and the cumulative dose and duration of treatment. This underscores the importance of limiting the duration of treatment [53].

Prokinetic agents may improve symptoms of functional dyspepsia and are relatively well tolerated. In a meta-analysis of 29 trials of participants with functional dyspepsia, symptoms improved more frequently with prokinetics compared with placebo (40 versus 26 percent) [82]. However, prokinetics did not improve quality of life, and the quality of evidence was low. All agents except cisapride were well tolerated over the short term. No eligible studies assessed the efficacy of metoclopramide or domperidone, which are the only agents available in North America. Methodologic challenges in study design complicate the evaluation of prokinetics for treating functional dyspepsia [83]. These include a lack of validated endpoints, variable presence of delayed gastric emptying, and the frequent overlap of functional dyspepsia with GERD [23].

Additional evaluation of persistent symptoms — Patients with symptoms that persist despite trials of neuromodulator and prokinetic agents generally warrant additional evaluation (see "Approach to the adult with dyspepsia", section on 'Evaluation of persistent symptoms'). Evaluation should include an upper endoscopy if it was not previously performed. Patients with refractory functional dyspepsia who have persistent nausea and vomiting or risk factors for delayed gastric emptying (eg, diabetes mellitus) should also undergo a gastric emptying study to evaluate for gastroparesis. However, significant overlap exists between dyspepsia and gastroparesis [84,85], and treatment directed at accelerating gastric emptying in these patients may not improve symptoms. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis", section on 'Evaluation' and "Treatment of gastroparesis".)

THERAPIES WITH LIMITED OR UNCLEAR ROLE

●Psychotherapy – For individuals whose symptoms persist despite initial treatment, we encourage psychotherapy, especially for patients whose symptoms are exacerbated by psychosocial stressors or who are motivated to try psychotherapeutic interventions. Functional dyspepsia often coexists with mental health conditions, such as anxiety and depression, and limited evidence suggests that psychotherapy may benefit patients with functional dyspepsia. A systematic review of four trials of psychotherapeutic interventions (eg, relaxation therapy and hypnosis, psychodrama, and cognitive-behavioral therapy) suggested benefit in individuals with functional dyspepsia; however, methodologic deficiencies limit the certainty of these results [86]. Types of psychotherapy are discussed separately. (See "Overview of psychotherapies", section on 'Cognitive and behavioral therapies'.)

●Dietary modification – The efficacy of dietary interventions for managing functional dyspepsia is unclear [87]. The postprandial timing of symptoms suggests a role for dietary modification; however, studies have not identified specific foods that trigger functional dyspepsia [87]. Dietitians may help some patients through individualized approaches [88].

Data regarding the efficacy of a low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet are inconsistent. In a randomized trial of 105 participants, a low FODMAP diet was no more efficacious than traditional dietary advice for improving symptoms of functional dyspepsia [89]. An observational study of 50 individuals with functional dyspepsia found that a low FODMAP diet was associated with improved symptoms, compared with standard dietary advice [90]. Definitive evidence regarding the efficacy of dietary interventions awaits well-designed, randomized trials.

●Antiemetic agents – Patients with predominant postprandial nausea may benefit from a trial of other antiemetic agents, such as promethazine, prochlorperazine, or meclizine; however clinical trial data supporting their efficacy are lacking.

●Fundic relaxant drugs – Limited evidence suggests that relaxing the gastric fundus may improve early satiation and postprandial fullness. In a small randomized trial, buspirone (10 mg, three times daily for four weeks) increased gastric accommodation and reduced the overall dyspeptic symptom severity, compared with placebo [91]. A small observational study showed similar results [92].

●Antinociceptive agents – Antinociceptive agents, such as pregabalin, carbamazepine, or tramadol, may affect the central processing of pain and thereby decrease visceral hypersensitivity in patients with functional dyspepsia. In a post hoc data analysis of six randomized trials in participants with generalized anxiety disorder and prominent gastrointestinal symptoms, pregabalin reduced both anxiety and gastrointestinal symptoms more effectively than placebo [93]. Pregabalin also improved global symptoms and quality of life in patients with proton pump inhibitor-refractory dyspepsia but commonly caused dizziness [94]. We do not use tramadol or opioids to treat functional dyspepsia because of their side effects and addictive potential [60].

●Bioelectric neuromodulation – Bioelectric neuromodulation with auricular vagal nerve stimulation may improve symptoms of functional dyspepsia. In a trial of 300 Chinese patients with functional dyspepsia, auricular vagal nerve stimulation for 30 minutes twice daily reduced symptoms and improved quality of life, depression, and anxiety at four weeks, compared with sham stimulation [95]. Symptom improvement persisted for eight weeks after stopping stimulation, and adverse effects were minimal.

●Virtual reality – In a pilot study of participants meeting Rome IV criteria for functional dyspepsia, three-dimensional audiovisual programs administered at least daily for two weeks improved upper gastrointestinal symptoms, compared with sham intervention. Adverse effects were minor [96]. These findings need confirmation in larger trials.

●Complementary and alternative medicines – Complementary and alternative medicines with possible efficacy for treating functional dyspepsia include peppermint and caraway [97-99]. Data regarding the efficacy of these interventions include the following:

•A randomized trial of 315 patients with functional dyspepsia found marginal symptom improvement with STW5 at eight-week follow-up, compared with placebo [100]. STW5 is a European multiherbal preparation that contains peppermint and caraway. It may improve symptoms of functional dyspepsia by stimulating gastric fundic relaxation and antral motility [101].

•In a systematic review that included randomized trials of herbal and natural products, acupuncture, and homeopathy, peppermint oil and STW5 appeared to improve symptoms of dyspepsia [102]. Trials were generally of low quality, which limits the certainty of these findings.

•In a randomized trial of 95 patients with functional dyspepsia, a combination of L-menthol and caraway oil improved symptoms in the subset of participants with epigastric pain syndrome [103].

Acupuncture may also have efficacy in alleviating symptoms of functional dyspepsia. A meta-analysis of randomized trials suggested that acupuncture as an adjunct to conventional pharmacotherapy was superior to conventional pharmacotherapy alone in improving symptoms of functional dyspepsia [104].

Well-designed clinical trials are needed before recommending these products for the treatment of functional dyspepsia.

PROGNOSIS — 

Functional dyspepsia is a chronic disease that does not affect mortality. Symptoms vary in severity over time, and individuals may experience both asymptomatic periods and intermittent symptom relapses [52]. In two population-based studies, approximately 15 to 20 percent of individuals with functional dyspepsia had persistent symptoms and 40 to 52 percent had symptom resolution over a follow-up of 10 to 12 years [105]. In 30 to 35 percent of patients, dyspeptic symptoms diminished over time, and at subsequent time points, 30 to 35 percent of patients met criteria for another functional gastrointestinal disorder, such as irritable bowel syndrome [106].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dyspepsia".)

INFORMATION FOR PATIENTS — 

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Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Stomach ache and stomach upset (The Basics)")

●Beyond the Basics topics (see "Patient education: Upset stomach (functional dyspepsia) in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology and pathophysiology – The prevalence of functional dyspepsia is up to 16 percent worldwide. Its pathophysiology is likely multifactorial and involves dysregulation of the gut-brain axis. (See 'Epidemiology and pathophysiology' above.)

●Clinical manifestations

•Individuals with functional dyspepsia describe postprandial fullness, early satiety, and/or epigastric pain or burning. Patients may have nausea; however, persistent vomiting is infrequent and should alert the clinician to an alternative diagnosis. (See 'Symptoms' above and "Approach to the adult with dyspepsia", section on 'Initial evaluation'.)

•Functional dyspepsia may coexist with other gastrointestinal disorders, such as gastroesophageal reflux disease, gastroparesis, and irritable bowel syndrome. It is important to evaluate for and differentiate between these disorders in individuals with dyspepsia. (See 'Selected comorbidities' above and "Approach to the adult with dyspepsia", section on 'Differential diagnosis'.)

●Diagnosis – The clinical diagnosis of functional dyspepsia requires the fulfillment of symptom-based diagnostic criteria and an evaluation to exclude other causes of dyspepsia (algorithm 1 and table 1). (See 'Evaluation and diagnosis' above.)

●Evaluation – Evaluation of individuals with dyspepsia consists of a history, physical examination, laboratory studies, and endoscopic evaluation to exclude organic/structural disease underlying the symptoms. All individuals with dyspepsia should undergo testing for Helicobacter pylori infection (algorithm 1). (See "Approach to the adult with dyspepsia", section on 'Initial evaluation' and "Approach to the adult with dyspepsia", section on 'Diagnostic approach'.)

●Initial management

•In patients with functional dyspepsia and H. pylori infection, we suggest antibiotic treatment to eradicate the infection (Grade 2B). (See 'Patients with H. pylori' above and "Treatment of Helicobacter pylori infection in adults".)

•In patients with functional dyspepsia who test negative for H. pylori or who have persistent symptoms after eradication of H. pylori, we suggest treatment with a proton pump inhibitor (PPI) once daily for four to eight weeks (Grade 2A). (See 'Patients without H. pylori' above.)

●Subsequent management

•In patients with persistent symptoms after eight weeks of a PPI, we suggest a trial of a tricyclic antidepressant (TCA) (Grade 2C). We start a low dose (eg, amitriptyline 10 mg, nortriptyline 10 mg, or desipramine 25 mg at bedtime) and gradually increase the dose as tolerated. (See 'Neuromodulators' above.)

•In patients whose symptoms persist despite initial management and treatment with a TCA, we suggest a prokinetic agent (Grade 2C). We use metoclopramide 5 to 10 mg three times daily one-half an hour before meals and at night. We typically limit the treatment trial to four weeks because the risk of side effects, including tardive dyskinesia, increases with the cumulative dose and duration of treatment. (See 'Prokinetic agents' above.)

•We refer individuals with refractory symptoms to psychotherapy if their symptoms are associated with stressors. (See 'Therapies with limited or unclear role' above.)

●Prognosis – Functional dyspepsia is a chronic disease with varying symptoms over time; it does not increase mortality. (See 'Prognosis' above.)