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.
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.
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.
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.
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.
Peura DA, Gudmundson J, Siepman N, et al. Proton pump inhibitors: effective first-line treatment for management of dyspepsia. Dig Dis Sci.
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.
Table 17–5. Mechanism of Action of Promotility Agents. ||Download (.pdf)
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%).
Choung RS, Talley NJ, Peterson J, et al. A double-blind, randomized, placebo-controlled trial of itopride (100 and 200 mg three times daily) on gastric motor and sensory function in healthy volunteers. Neurogastroenterol Motil.
Hiyama T, Yoshihara M, Matsuo K, et al. Meta-analysis of the effects of prokinetic agents in patients with functional dyspepsia. J Gastroenterol Hepatol.
Holtmann G, Talley NJ, Liebregts T, et al. A placebo-controlled trial of itopride in functional dyspepsia. N Engl J Med.
Talley NJ, Tack J, Ptak T et al. Itopride in functional dyspepsia: results of two phase III multicenter, randomized, double-blind, placebo-controlled trials. Gut.
Vakil N, Laine L, Talley NJ, et al. Tegaserod
treatment for dysmotility-like functional dyspepsia: results of two randomized, controlled trials. Am J Gastroenterol
Veldhuyzen van Zanten SJ, Jones MJ, Verlinden M, et al. Efficacy of cisapride
in functional (nonulcer) dyspepsia: a meta-analysis. Am J Gastroenterol.
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.
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.
Van Zanten SV, Armstrong D, Chiba N, et al. Esomeprazole
40 mg once a day in patients with functional dyspepsia: the randomized placebo-controlled "ENTER" trial. Am J Gastroenterol.
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.
Thompson Coon J, Ernst E. Systematic review: herbal medicinal products for non-ulcer dyspepsia. Aliment Pharmacol Ther.