Chapter 17. Functional (Nonulcer) Dyspepsia

• Dyspepsia is a common symptom having either an organic or a functional cause; distinguishing between the two can be a challenge.
• Clinical features of functional dyspepsia, gastroesophageal reflux disease, and gastrointestinal motility disorders overlap, making diagnosis difficult.
• Most patients with functional dyspepsia have normal esophagogastroduodenoscopy (EGD) findings.
• Endoscopy is indicated for patients with new-onset symptoms who are >55 years of age or have alarm features.
• Functional dyspepsia remains a diagnosis of exclusion.

This chapter outlines the evaluation and management of dyspepsia, with a primary focus on functional dyspepsia, also interchangeably called nonulcer dyspepsia. The term dyspepsia derives from the Greek "dys," meaning bad, and "pepsis," meaning digestion. Dyspepsia is a symptom, not a diagnosis. The term encompasses a broad spectrum of symptoms that include upper abdominal pain or discomfort, bloating, early satiety, postprandial fullness, nausea with or without vomiting, anorexia, symptoms of gastroesophageal reflux disease (GERD), regurgitation, and belching.

Classification

The multiple causes of dyspepsia can be classified as organic or functional. Among the organic causes are esophagitis, gastritis, peptic ulcer disease, benign esophageal strictures, upper gastrointestinal malignancies, chronic intestinal ischemia, and pancreaticobiliary disease. In addition, several medications can cause dyspeptic symptoms (Table 17–1). Most notable are nonsteroidal anti-inflammatory drugs (NSAIDs), which can cause mucosal injury leading to gastritis. Functional dyspepsia excludes all organic causes.

Previously, the Rome II criteria defined functional dyspepsia as pain centered in the upper abdomen in the setting of a normal endoscopy, with three main subtypes: ulcer-like, dysmotility-like, and unspecified (nonspecific). Recognizing that patients with functional dyspepsia may present with epigastric symptoms other than pain, the revised Rome III criteria in 2006 added bothersome postprandial fullness, early satiation, and epigastric burning to the diagnostic criteria (Table 17–2). Therefore, functional dyspepsia is now defined as "the presence of symptoms thought to originate from the gastroduodenal region, in the absence of any organic, systemic, or metabolic disease that is likely to explain the symptoms." In addition, the prior subtypes were revised to improve their clinical utility. Per Rome III criteria, functional dyspepsia symptoms fall into two main, distinctively defined disorders: postprandial distress syndrome and epigastric pain syndrome. Postprandial distress syndrome includes bloating, fullness, or early satiety with meals, while epigastric pain syndrome is defined by focal burning or pain localized to the epigastric region not relating to gallbladder or biliary causes. Postprandial distress syndrome and epigastric pain syndrome may coexist in patients with functional dyspepsia.

Epidemiology

Prior studies estimated that 20–30% of community patients report dyspeptic symptoms each year, with the majority believed to be related to functional dyspepsia. In prospective studies, the incidence of patients reporting dyspeptic symptoms for the first time is approximately 1% per year. It is believed that only about half of the patients with dyspeptic symptoms ultimately seek medical care, with severity of pain and anxiety being the significant predictive factors. Of patients who have not been worked up, 40% may have an organic cause for their dyspepsia. The prevalence of functional dyspepsia is about 12–15%.

Dyspepsia has led to sizeable health care burden, with new cases accounting for 5–7% of primary care office visits. Dyspeptic symptoms can account for up to 40–70% of gastrointestinal complaints in a general gastroenterology practice. The cost of treatment is substantial.

Organic dyspepsia can develop as a consequence of the varied disease processes mentioned in this chapter and described elsewhere in this text. The pathogenesis of functional dyspepsia is unclear. Factors that play a role in causation include altered visceral sensitivity, disturbances in motility, alterations in gastric accommodation, dietary factors, and psychosomatic factors. The role of Helicobacter pylori in the genesis of symptoms is controversial.

Altered Gastrointestinal Motility

Disturbances in gastrointestinal motility may be associated with dyspepsia symptoms and represent the underlying causative factor in functional dyspepsia. Motor disorders such as gastroesophageal reflux, gastroparesis, small bowel dysmotility, and biliary dyskinesia may cause dyspeptic symptoms. Disturbances in gastric emptying and gastrointestinal motor function occur in subgroups of patients with functional dyspepsia, and studies of these patients show female sex predominance. The prevalence of motility disorders has varied markedly between studies, likely due to subject selection criteria and study methodology. A meta-analysis of studies investigating functional dyspepsia and disturbed solid phase gastric emptying found 40% of patients with functional dyspepsia had slower emptying, and the pooled estimate of slowing was 1.5 times that of normal patients. On the other hand, a prospective study using a liquid test meal demonstrated that decreased maximum-tolerated meal volume and increased postprandial symptoms were associated with faster gastric emptying.

As mentioned, symptoms of GERD often overlap with dyspepsia symptoms. Poor visceral localization of symptoms can often cause a reflux event to be confused with other upper gastrointestinal sources of discomfort. A study of patients with diagnosis of functional dyspepsia per Rome III criteria revealed that almost one third had pathologic signs of acid reflux. In addition, both acid and nonacid reflux can cause symptoms. A report noted that patients with functional dyspepsia swallow air more frequently than controls; this finding was associated with an increase in nonacid reflux, which can also cause epigastric symptoms.

Altered Gastric Accommodation

Alterations in gastric accommodation or compliance have been hypothesized to be a cause of functional dyspepsia. During normal ingestion of food, the gastric fundus relaxes to "accommodate" the food particles. This accommodation is mediated by serotonin (5-HT1p) and nitric oxide via vagal inhibitory neurons of the enteric nervous system. The accommodation reflex may be impaired in as many as 40% of patients with functional dyspepsia, as demonstrated by gastric scintigraphy and ultrasound. Measurement of gastric pressure by a barostat, or a polyethylene balloon inflated in the stomach, connected to a pressure monitor has shown impaired meal-induced accommodation as well.

Visceral Hypersensitivity

While poor gastric compliance may result in dyspepsia symptoms, some patients may instead have normal gastric compliance but a lowered pain threshold. With visceral hypersensitivity or hyperalgesia, patients begin to experience pain or discomfort at a level of gastric distention normally not associated with symptoms in healthy individuals., resulting from increased sensory input to and from the stomach. Such enhanced perception is not limited to mechanical distention, but may also occur in response to temperature stress, acid exposure, chemical or nutrient stimuli, or hormones, such as cholecystokinin and glucagons-like peptide 1. In patients with visceral hypersensitivity, there may be altered central nervous system processing of these stimuli. Studies have demonstrated hypersensitivity to balloon distention in the stomach in as many as 50% of patients with functional dyspepsia. Compared with controls, patients with functional dyspepsia had a significantly lower threshold to both initial sensation of balloon distention and to sensation of pain. Some have suggested that such alteration in perception may be the main distinguishing factor between functional and organic dyspepsia. A similar mechanism of pathogenesis has also been proposed for irritable bowel syndrome.

Dietary Factors

Dietary factors may be a potential cause of symptoms in functional dyspepsia. Patients with functional dyspepsia appear to have altered eating patterns as well as food intolerances. They frequently report being able to tolerate only small quantities of food, with a high prevalence of snacking and low prevalence of eating large meals. Food intolerances are also high in prevalence among these patients. Fatty foods, in particular, have been linked to dyspepsia. Other intolerances with a reported prevalence greater than 40% include spices, alcohol, spicy foods, chocolate, peppers, citrus fruits, and fish. However, a recent epidemiologic study found no difference in total caloric, protein, fat, and carbohydrate intake between patients with dyspepsia and healthy controls. In particular, the percentages of protein, fat, and carbohydrate in their diet were also similar. In the same study, alcohol and nicotine use were not found to be risk factors for dyspepsia.

Food allergy has been cited as a possible mechanism for development of dyspeptic symptoms, especially postprandial symptoms. Some common food-specific immunoglobulin G antibody titers have been found to be elevated in functional dyspepsia patients compared to controls.

Helicobacter pylori Infection

The role of H pylori in functional dyspepsia is controversial, and no clear causal relationship has been established. This is true for both the symptom profile and pathophysiology of functional dyspepsia. Although some epidemiologic studies have suggested an association between H pylori infection and functional dyspepsia, others have not. The discrepancy may stem in part from differences in methodology and lack of adequate consideration of confounding factors such as past history of peptic ulcer disease and socioeconomic status. Controlled trials disagree about whether or not H pylori eradication is beneficial in functional dyspepsia, with roughly half of the trials showing improvement and the other half no improvement. A prior systematic review in the Annals of Internal Medicine on the benefit of eradicating H pylori in functional dyspepsia suggested no statistically significant effect, with an odds ratio (OR) for treatment success versus control of 1.29 (95% confidence interval [CI], 0.89–1.89; P = .18). However, the most recent update of a Cochrane Database review showed a small but statistically significant effect in curing symptoms (H pylori cure vs placebo, 36% vs 30%, respectively; relative risk reduction [RRR], 8%; 95% CI, 3–18%; number needed to treat [NNT] = 18). Despite the conflicting results, current guidelines by both major gastroenterological societies in the United States recommend eradication of H pylori in patients with functional dyspepsia.

Duodenal Eosinophilia

In recent years, some have hypothesized that duodenal eosinophilia may play a role in a subset of patients with functional dyspepsia. Several recent studies have shown significantly greater eosinophil counts in duodenal biopsies from patients with functional dyspepsia compared to those from healthy controls. These studies suggest that duodenal eosinophils may play a role in functional dyspepsia. However, eosinophilic infiltration has also been described in many different clinical scenarios, including healthy individuals. Therefore, the role of duodenal eosinophils in functional dyspepsia remains to be elucidated.

Psychological Factors

Psychosomatic and cognitive factors are important in the evaluation of patients with chronic dyspepsia. The psychiatric hypothesis holds that the symptoms of dyspepsia maybe due to depression, increased anxiety, or a somatization disorder. Epidemiologic studies suggest there is an association between functional dyspepsia and psychological disorders. Symptoms of neurosis, anxiety, hypochondriasis, and depression are more common in patients being evaluated for unexplained gastrointestinal complaints than in healthy controls. In addition, prior studies have demonstrated significant associations between dyspepsia symptoms and a history of abuse in childhood or adulthood. Comparisons of functional and organic dyspepsia have shown that patients with functional dyspepsia are less likely to have decreased stress or anxiety at 1-year follow-up after being reassured of having no serious disease. This suggests that functional dyspepsia symptoms are long-lasting, compared with those of organic dyspepsia, and that the emotional ties are strong.

Symptoms and Signs

The initial clinical evaluation should focus on symptom characteristics, onset, and chronicity. The clinician should try to interpret the symptoms in order to identify possible etiologies such as GERD, gallstones, medications side effects (particularly NSAIDs), chronic pancreatitis, diabetic gastroparesis, or obstruction. The patient should be asked about comorbidities, surgical history, family history of upper gastrointestinal malignancy, alcohol and tobacco use, dietary changes or allergies, stressful life events, and psychological factors.

In most cases, however, the clinical history is of limited use in distinguishing organic causes from functional dyspepsia. A large systematic review of the literature was performed to evaluate the effectiveness of diagnosing organic dyspepsia by clinical opinion versus computer models in patients referred for upper endoscopy. The computer models were based on patient demographics, risk factors, historical items, and symptoms. The study showed that neither clinical impression nor computer models were able to adequately distinguish organic from functional disease.

In a recent study, patients with peptic ulcer disease were compared with patients with functional dyspepsia in an age- and sex-matched study. Although the functional dyspepsia group reported more upper abdominal fullness and nausea and overall greater distress and anxiety, almost all the same symptoms were seen in both groups.

Therefore, it is the clinician's challenging task to separate patients who may have an organic disorder, and thus warrant further diagnostic testing, from patients who have functional dyspepsia, who are given empiric symptomatic treatment. The workup should be targeted to identify or rule out specific causes. Traditionally, high-risk patients have been identified by "alarm" features, which are listed in Table 17–3. However, the utility of these features in identifying the presence of upper gastrointestinal malignancy has been debated. A meta-analysis looking at the sensitivity and specificity of alarm features found a range of 0–80% and 40–98%, respectively. However, there was high heterogeneity between studies.

The physical examination may elicit abdominal tenderness. Although this finding is nonspecific, several features may shed lights on possible underlying etiologies. A positive Carnett sign, or focal tenderness that increases with abdominal wall contraction and palpation, suggests an etiology involving the abdominal wall musculature. Cutaneous dermatomal distribution of pain may suggest a thoracic polyradiculopathy. Thump tenderness over the right upper quadrant may suggest chronic cholecystitis. Most commonly, however, the physical examination is normal.

Diagnostic Evaluation

If a careful history and physical examination, along with judicious use of screening laboratory tests, does not lead to the diagnosis, then other studies with specific management strategies are recommended. Strategic algorithms have been suggested by the American Gastroenterology Association (Figures 17–1 and 17–2) and the American College of Gastroenterology.

There are several main strategies for new-onset dyspepsia, which include (1) empirical histamine-2 (H2)-receptor blocker therapy; (2) empirical proton pump inhibitor (PPI) therapy; (3) H pylori testing and treatment of positive cases, followed by acid suppression if the patient remains symptomatic; (4) early endoscopy; (5) early endoscopy with biopsy for H pylori and treatment, if positive; (6) acid suppression, followed by endoscopy and biopsy if the patient remains symptomatic; or (7) H pylori testing and treatment, if positive, followed by endoscopy if the patient remains symptomatic.

Several considerations, outlined below, should guide the selection of a strategy.

Esophagogastroduodenoscopy (EGD)

Patients who have not been previously worked up for dyspepsia should be scheduled for EGD if they demonstrate alarm features or are older than 55 years of age. Special consideration also should be given to patients whose country of origin is a region where stomach cancer is more prevalent (eg, Japan, China, and Chile). EGD is the gold standard for evaluating the upper gastrointestinal tract, as it can provide direct visualization and allows the endoscopist to obtain a biopsy specimen of the mucosa if needed. Thus, EGD has essentially replaced the upper gastrointestinal radiologic series as the diagnostic test of choice. Cost effectiveness of early endoscopy in patients older than 50 years of age has been studied in the United Kingdom, with findings of improvement in symptom scores, quality of life, and 48% reduction in use of PPIs. A recent study of 2741 dyspeptic patients without alarm features in the United States found a low prevalence of cancer (0.2%) and an age cut-off of 50 years old for early endoscopy to be adequate for detection of occult malignancy.

Patient's age is an important consideration with regard to endoscopy. The timing of upper endoscopy in younger patients (<55 years) is debatable. Patients who respond to the H pylori testing and treatment strategy, outlined below, can be managed without further investigation. In younger patients with continued symptoms despite this strategy, endoscopy usually adds little more to the diagnostic workup. Furthermore, the utility of endoscopy in reassuring patients with functional dyspepsia has been studied and has been deemed questionable as measured by anxiety and depression, which did not change before and after the procedure in these patients.

Helicobacter pylori Testing

For patients younger than 55 years of age and without alarm features, the clinician should first consider testing for H pylori and treating, if positive. The optimal test for H pylori is a 13C-urea breath test or stool antigen test. Helicobacter pylori is the main cause of peptic ulcer disease not associated with NSAID use, and it may be associated with functional dyspepsia in a small fraction of patients. Treatment usually consists of two antibiotics of different classes (eg, amoxicillin and clarithromycin), with a double dose of a PPI (eg, omeprazole, 40 mg twice daily). Many other regimens are available for use if the patient has a history of allergic reactions to a particular class or has previously failed one of the standard regimens (Table 17–4). If the patient is H pylori–negative, a trial of acid suppression is suggested; the most optimal approach to acid suppression is use of a PPI. As the prevalence of H pylori varies widely among different population, this strategy of H pylori test-and-treat followed by PPI trial is particularly recommended for patients from backgrounds with high prevalence of H pylori (>10%). On the other hand, empirical PPI therapy for 4–8 weeks before H pylori testing has been shown to be cost effective in patients with a low prevalence of H pylori (≤10%).

Other Studies

If a patient's symptoms are suggestive of biliary pain, an ultrasound of the abdomen should be obtained to evaluate the gallbladder for cholelithiasis or cholecystitis. Classic biliary colic is characterized by sudden onset of right upper quadrant pain that is constant, lasting 2–6 hours, associated with nausea, and worsened postprandially. Because of the visceral nature of the pain, it is poorly localizable. Patients with biliary-type pain with findings of gallstones should be considered for cholecystectomy. A quantitative cholescintigraphy scan with cholecystokinin challenge may suggest chronic cholecystitis as the diagnosis if the ejection fraction is less than 50%.

Abdominal computed tomography (CT) can also provide diagnostic clues in patients with chronic unexplained abdominal pain to the presence of chronic pancreatitis, pancreatic cystic lesions, or abdominal tumors such as carcinoid or gastrointestinal stromal tumors (GISTs). CT enterography can visualize the small bowel to aid in looking for undiagnosed Crohn disease or rare small bowel polyps or tumors.

A 24-hour pH test, using a catheter with multichannel intraluminal impedance, can demonstrate acid or nonacid reflux in patients with symptoms likely attributable to GERD. However, in most cases, empiric treatment with PPI therapy is more cost effective and practical. Gastric scintigraphy usually does not add much more information to the diagnostic picture. Although scintigraphy findings may be abnormal in up to 40–50% of cases, they do not help establish the diagnosis or provide therapeutic guidance.

The differential diagnosis of dyspepsia is broad. The findings from history and physical examination and judicious use of the diagnostic studies outlined in the preceding section can aid in distinguishing the various organic causes of dyspepsia from functional dyspepsia.

GERD and Nonerosive Reflux Disease

GERD and dyspepsia overlap frequently, often coexisting in the same patient. Thus, GERD should always be considered in the dyspeptic patient. If the symptoms are predominantly regurgitation, substernal burning, and acid taste, then GERD is more likely to be the cause than other etiologies. Formal reflux testing with a 24-hour pH study with esophageal impendence off antisecretory medications (eg, PPI) can demonstrate whether reflux, acid or nonacid, is present and identify the association between these reflux events and symptoms.

Peptic Ulcer Disease

About 15% of patients with dyspeptic symptoms have gastric or duodenal ulcers. Once diagnosed, the possible underlying causes of the ulcers should be investigated, as many risk factors for peptic ulcers may also lead to dyspepsia symptoms themselves, including the use of NSAIDs and the presence of H pylori infection.

Upper Gastrointestinal Malignancy

Less than 2% of dyspeptic patients have gastric cancer. Older patients carry a much higher risk, with 98% of cancers occurring in patients older than 50 years of age. Other risks for gastric cancer include H pylori infection, country of origin in an area endemic for gastric malignancy (Eastern Asia, the Andean regions of South America, and Eastern Europe), excessive salt and nitrate consumption, tobacco use, and family history of gastric cancer.

Chronic Intestinal Ischemia

Chronic intestinal ischemia (so-called intestinal angina) is characterized by chronic postprandial pain with marked weight loss due to mesenteric blood flow that is inadequate to the demands required by digestion. Typically the patient has a history of tobacco use or underlying atherosclerotic disease. A diagnosis may be made by magnetic resonance angiography or CT angiography.

Pancreaticobiliary Disease

The pain associated with chronic pancreatitis may be epigastric or localized to the central abdomen, classically with radiation to the mid back. Weight loss may occur. Pancreatic endocrine or exocrine insufficiency (eg, diabetes, steatorrhea) may or may not be present. Cholelithiasis usually is distinguishable from dyspepsia in being more localizable to the right upper quadrant.

Motility Disorders

Upper gastrointestinal motility disorders also overlap with dyspepsia. Many patients with functional dyspepsia have gastroparetic-type symptoms, which led to the Rome II classification of "dysmotility-like dyspepsia." This classification was of debatable clinical value, and has now been dropped from the Rome III criteria. Nonetheless, there is a preponderance of symptoms of bloating, early satiety, and nausea with vomiting in patients with functional dyspepsia. Causes of motility disturbance may include diabetic gastroparesis, chronic intestinal pseudo-obstruction, scleroderma, or postvagotomy syndromes.

Systemic Disorders

Dyspepsia may exist in a number of systemic disorders such as diabetes mellitus, coronary artery disease, thyroid disease, hyperparathyroidism, adrenal insufficiency, and collagen vascular diseases.

Infections

Gastric infections other than H pylori can cause dyspepsia. These include cytomegalovirus, tuberculosis, or fungal infections. Parasites to consider include Giardia lamblia and Strongyloides stercoralis. Small intestinal bacterial overgrowth is associated with nonspecific symptoms such as bloating, gassiness, and abdominal discomfort that may emulate dyspepsia and is increasingly identified. It is often associated with more lower gastrointestinal symptoms such as diarrhea that may distinguish it from classic dyspepsia. Diagnosis can be established by breath testing or a trial of antibiotics, if suspected.

Other Considerations

Other conditions to consider in the differential diagnosis include chronic gastric volvulus, infiltrative diseases (sarcoidosis, amyloidosis, eosinophilic gastroenteritis, Ménétrier disease), undiagnosed inflammatory bowel disease, celiac sprue, and idiopathic cause.

The treatment of organic dyspepsia is targeted to the cause. Specific treatment regimens for GERD, peptic ulcer disease, and other disorders that may cause dyspepsia can be found in their respective chapters in this book.

The treatment of functional dyspepsia primarily targets symptom relief. Studies have shown high placebo effect rates, and moderate success in response to PPIs, motility agents, and antidepressants. An effective physician-patient relationship is vital to treatment success.

General Measures

The physician-patient relationship is crucial to the treatment of functional dyspepsia. Earnest efforts to accurately assess the extent and chronicity of the patient's symptoms will engender trust and reassurance. Fears of having cancer or a life-threatening condition, anxiety levels, and stressful factors in the patient's life should be assessed and addressed early in the evaluation.

Reassuring patients that the cause of their symptoms is non–life threatening and not cancer related is often therapeutic in itself. Nevertheless, reviewing the workup and the differential diagnosis remains important, so that patients have an understanding of where they are in the treatment process. The diagnosis of functional dyspepsia should also be explained as a recognized clinical entity with the emphasis on the understood pathophysiology of the problem and perhaps, more importantly, what is not known about it.

Due to the chronicity of the problem, many patients have already tried different remedies to alleviate their symptoms. Often patients understand what works for them and what does not prior to the office visit, such as meal content and quantity, positional factors, and home remedies. It is important to recognize the variability of symptoms, exacerbators and alleviators, and response to treatment in patients with dyspeptic symptoms.

Lifestyle Modifications

No trials have been done to formally evaluate the efficacy of dietary or lifestyle modifications in functional dyspepsia. The current understanding of dietary contributors stems from observation in clinical settings or epidemiologic studies. Foods generally reported to cause symptoms include onions, peppers, citrus fruit, coffee, carbonated beverages, and spices. General dietary recommendations are to avoid fatty or heavily spiced foods and excessively large meals. Smaller, more frequent meals are beneficial in patients with GERD, impaired gastric accommodation, and delayed gastric emptying. Food allergies should be noted and avoided. A food diary can help identify triggers. A trial of dairy product avoidance may be helpful in identifying lactose intolerance, with a hydrogen breath test performed to formally make the diagnosis. Caffeine intake and alcohol should be minimized, although a recent epidemiologic study did not identify a link between alcohol and functional dyspepsia. Regular exercise and adequate restful sleep are also important and can be helpful in alleviating stress.

Pharmacotherapy

If reassurance and lifestyle changes do not alleviate symptoms, medications can be tried. However, drug therapy trials in functional dyspepsia have yielded conflicting results and conclusions, possibly owing to several factors. Placebo response rates are known to be high in functional dyspepsia, ranging from 32–85%. Studies are often limited by insufficient sample size, single-center trials, and variability in the definition of functional dyspepsia. Furthermore, enrollment of patients from tertiary referral centers into drug trials may not represent the general population in primary care. Patients with GERD may inadvertently be included in trials, which would bias response rates in antisecretory trials.

In addition to H pylori eradication therapy, the pharmacologic therapy for dyspepsia includes antisecretory agents, promotility agents, antidepressants and anxiolytics, and other classes of drugs.

Antisecretory Agents

PPIs have been extensively studied in several large, carefully designed, randomized controlled trials. A systematic review of eight studies with a total of 3293 patients who received PPI therapy for 2–8 weeks found a significant effect over placebo. PPI therapy relieved or eliminated symptoms in 33% of patients compared with 23% of those receiving placebo. The relative risk (RR) of remaining symptomatic on PPI versus placebo was significantly protective (RR = 0.86; 95% CI, 0.78–0.95; P = .003; NNT = 9).

Analysis of the subtypes of functional dyspepsia showed that patients with reflux-like and epigastric pain had a significant favorable response with PPI therapy, but those with dysmotility-type dyspepsia did not. Similarly, another meta-analysis of seven randomized placebo-controlled trials of PPIs with a total of 3725 patients found PPIs to be effective for patients with ulcer-like dyspepsia (RRR = 12.8%; 95% CI, 7.2–18.1%) and reflux-like dyspepsia (RRR = 19.7%; 95% CI, 1.8–34.3%), but not dysmotility-like dyspepsia and unspecified dyspepsia. As for H2-receptor blockers, the evidence supporting their use is generally modestly beneficial. Systematic reviews on H2-blockers versus placebo have shown improvement in epigastric pain, but not global symptoms.

Promotility Agents

Promotility agents are drugs that accelerate peristalsis by interacting with receptors for serotonin, acetylcholine, dopamine, and motilin (Table 17–5). The focus of drug development is now on serotonergic and dopaminergic drugs. Among the prokinetic agents available in the United States are metoclopramide and macrolide antibiotics, most commonly, erythromycin.

The use of these drugs has shown no clear relationship between pharmacologic enhancement of motility and improvement in symptoms of functional dyspepsia. Therefore, the benefit of prokinetics cannot be attributed solely to accelerated peristalsis. In fact, some drugs may actually worsen symptoms. An example is the negative influence that many drugs (eg, erythromycin and metoclopramide) have on postprandial fundic relaxation, or accommodation.

A systematic review of 14 randomized controlled trials reported prokinetics to be more effective than placebo in functional dyspepsia. However, the majority of the studies looked at cisapride, a serotonin 5-HT4 agonist and 5-HT3 antagonist that was taken off the market in the United States due to its association with adverse cardiac arrhythmia events. Another systematic review of 17 studies looked at cisapride and domperidone (also not available in the United States, again due to cardiac arrhythmia risk) and found both agents to be superior to placebo, but only by a global assessment of improvement by the investigator. Both agents are available through compassionate use protocols. A more recent systematic analysis of prokinetics showed that the effect over placebo was lost when only high-quality studies were included in the meta-analysis.

Metoclopramide was found to be more effective than placebo in two older studies. However, there are medicolegal concerns about long-term use of metoclopramide due to potential neurologic side effects, particularly movement disorders.

Among the more recently tested agents are tegaserod, a 5-HT4 agonist, and itopride, a dopaminergic antagonist. Neither drug is currently available in the United States. Tegaserod was previously approved for treatment of women with irritable bowel syndrome–predominant constipation and for men and women younger than 65 years with chronic constipation. It has been shown to increase gastric emptying and mildly improve symptoms in functional dyspepsia in phase III randomized controlled trials. However, in response to adverse events related to cardiac ischemia and stroke, tegaserod was removed from the market in early 2007. Itopride, which is available in Japan, is a dopaminergic antagonist that also acts as a weak muscarinic agonist. A recent phase II randomized controlled study of itopride versus placebo showed a dose-dependent improvement in the global assessment of patients with functional dyspepsia without significant differences in adverse events between treatment and placebo groups. The most frequent adverse events were abdominal pain, diarrhea, nausea, and constipation. A study of itopride in healthy subjects found that it reduces total postprandial volume without significantly accelerating gastric emptying or altering gastric motor or sensory function. This suggests that itopride, if efficacious in functional dyspepsia, is likely therapeutic in ways other than altering gastrointestinal motility. More recently, two phase III multicenter, randomized, double-blind, placebo-controlled studies have shown no benefit over placebo in a global patient assessment. Safety was comparable to placebo in these studies, with the rare occurrence of prolactin elevation in the patients receiving itopride (3.1% vs 0.2%).

Antidepressants and Anxiolytic Agents

The efficacy of antidepressants and anxiolytics is based largely on clinical observation and anecdotal data. Low-dose tricyclic antidepressants (TCAs), such as amitriptyline or desipramine, have been used in patients with various functional disorders, including functional dyspepsia and irritable bowel syndrome. Typically much lower doses (10–100 mg/day) are given for functional dyspepsia than for depression. As TCAs can slow gastric emptying due to their anticholinergic effect, they should be avoided in patients with gastroparesis–functional dyspepsia overlap syndrome. A high-quality randomized trial investigating the use of TCAs in treating functional gastrointestinal disorders (including irritable bowel syndrome and functional dyspepsia) showed that patients who could tolerate the therapy might show a benefit with desipramine over placebo (73% vs 49%, P = .0005, NNT = 4). However, 28% of patients dropped out because of adverse reactions, with the most commonly reported adverse effects being dry mouth, sleep disturbance, constipation, and confusion. The side effects are related to the anticholinergic activity of TCAs, and patients should be warned about the possible occurrence of these effects prior to use.

Use of selective serotonin reuptake inhibitors in functional dyspepsia has not been studied in randomized controlled trials. These drugs may be helpful in patients with concurrent depression.

Other Drugs

Antacids and bismuth have each been evaluated in a few trials for functional dyspepsia and have been consistently found to be no better than placebo. Sucralfate has been studied in several limited trials and found to be no more effective than placebo. Consequently, all of these agents play no major role in the treatment of functional dyspepsia.

Recommendations for Pharmacotherapy

To summarize, if, after providing reassurance and basic dietary and lifestyle interventions, symptoms persist, the clinician can consider a trial of pharmacologic agents. If H pylori testing yields a positive result, treatment is recommended with the understanding that eradication may or may not improve symptoms. Antisecretory medications can then be added, such as H2-blockers (ranitidine, 150 mg twice daily; cimetidine, 400 mg twice daily; or famotidine, 20 mg twice daily) or PPIs (omeprazole, 20 mg daily; esomeprazole, 40 mg daily; pantoprazole, 40 mg daily; lansoprazole, 30 mg daily; or rabeprazole, 20 mg daily). Antisecretory medications most likely benefit those with GERD symptoms or ulcer-like dyspepsia. If there is a response, a course of 2–6 weeks can be tried, with assessment of resolution of symptoms. If prokinetics are used, short courses of metoclopramide can be considered (5–10 mg prior to meals). Metoclopramide elixir is preferable to pill form. If symptoms are refractory and persist, low-dose TCAs (amitriptyline, imipramine, nortriptyline, or desipramine at 10–25 mg at bedtime) can be tried even in those without depression.

Psychological Therapy

Psychological therapy addresses the cognitive aspects of the pathophysiology of functional dyspepsia. Several modalities have been used, including cognitive-behavioral therapy, biofeedback, hypnotherapy, relaxation therapy, and insight-oriented psychotherapy. A systematic review of randomized controlled trials of psychological therapies found four eligible trials on applied relaxation therapy, psychodynamic psychotherapy, cognitive therapy, and hypnotherapy that all reported symptomatic improvement at 1 year. However, the studies were of small sample size and had other technical limitations to provide adequate evidence for efficacy.

Complementary and Alternative Medical Therapy

Nonprescription therapies have been tried in functional dyspepsia, often being self-prescribed. These therapies are not regulated by the U.S. Food and Drug Administration (FDA); therefore, standardization of purity and potency is not enforced. Safety and efficacy are also not regulated. Nevertheless, studies have been conducted with several of these agents. A systematic review of herbal remedies was published examining 17 studies that evaluated agents such as Angelica, artichoke, boldo, gentian, ginger, lemon balm, milk thistle, peppermint, and turmeric. Although the definitions of functional dyspepsia and study methodologies had significant heterogeneity, the symptom improvement scores ranged from 60% to 90% favoring treatment over placebo. Few adverse reactions were associated with the remedies, but formal safety reporting was not routinely available. Short-term use is likely safe.

The clinical course of functional dyspepsia has been evaluated in retrospective and prospective studies, with follow-up of 1.5–10 years for prospective studies and 5–27 years for retrospective studies. In general, a significant number of patients with functional dyspepsia became asymptomatic or improved overall after 1 to several years. History of GERD treatment during follow-up, prior history of peptic ulcer disease, use of aspirin, longer clinical history (>2 years), lower education, and psychological vulnerability were found to be associated with poorer prognosis in these studies. One study in Taiwan reported that patients with H pylori infection and functional dyspepsia were less likely to be symptom free at 2 years compared to those without H pylori (49% vs 58%).

This chapter is a revised version of the chapter by Dr. Victor S. Wang and Dr. Robert Burakoff that was in the previous edition of Current Diagnosis & Treatment: Gastroenterology, Hepatology, & Endoscopy.