A wide variety of treatments have been used to manage FD including dietary and lifestyle modifications, H. pylori eradication, antacids, mucosal protectants, antisecretory agents, prokinetics, antidepressants, behavioural therapies as well as complementary and alternative medical (CAM) therapies (Tables 1 and 2). The fact that no single available therapy consistently provides relief to the majority of FD patients validates the heterogeneity of this disorder. Given this heterogeneity, it is difficult to generalize about the characteristics, which predict a greater or lesser response to therapy for this condition. Acknowledging this point, several authors have tried to identify predictors of response to therapy. A recent systematic review reported several characteristics of FD patients that negatively affect symptom remission including symptom duration exceeding 2 years, lower educational level, greater psychological vulnerability, coexistent H. pylori infection, use of aspirin, history of peptic ulcer disease and treatment for GERD.5 An earlier review of the literature reported limited evidence to suggest that older age, male sex, single marital status and more frequent occurrence of abdominal pain had a negative impact on the prognosis of FD, although these findings are more controversial.62 Recent evidence suggests that patients with overlapping FD and IBS report more severe symptoms and are more likely to exhibit visceral hypersensitivity in response to gastric distention.11 Another recent study found that patients with overlapping GERD symptoms and IBS reported more severe heartburn than those with GERD symptoms alone.63 These finding suggest that patients with multiple GI symptoms may represent a distinct subgroup with more severe symptoms, perhaps related to a more generalized disorder of altered visceral pain sensation. It is attractive to hypothesize that such patients may be more likely to respond to centrally acting therapies and less likely to respond to peripherally acting agents though this remains to be proven in clinical trials.
There are no trials which have formally evaluated the efficacy of various dietary or lifestyle modifications in patients with FD. Such treatment approaches have evolved from the observation that the symptoms of FD are frequently temporally related to the ingestion of food. A recent systematic review on this topic concluded that although a relationship between the ingestion of food and dyspeptic symptoms is frequently reported by FD patients, this relationship has not been formally assessed in careful clinical trials.64 This review reported that factors, such as food intolerances and eating patterns have only been anecdotally reported to play a role in the symptoms of FD. However, there is some, albeit limited, evidence that dietary fat ingestion is associated with dyspeptic symptoms.45, 65 Despite the lack of evidence, modifications similar to those recommended for GERD can be considered including smaller, more frequent meals; a low fat diet and avoidance of late evening meals. A food diary may be used to facilitate the identification of specific foods that trigger symptoms. Foods frequently reported to worsen dyspeptic symptoms include onions, peppers, citrus fruit, coffee, carbonated beverages and spices. Though not evidence-based, these recommendations are not associated with significant costs and unlikely to be associated with adverse outcomes.
H. pylori eradication
The role of H. pylori eradication in the treatment of FD remains controversial. Two recent trials concluded that H. pylori eradication improved quality of life66 and provided symptomatic benefit in FD.67 This is in contrast to other contemporary studies demonstrating no clear benefit compared with placebo or antisecretory agents.68–71 A recent analysis of two multicentre, multinational randomized-controlled trials (RCT) revealed no benefit to H. pylori eradication over placebo although a subgroup analysis revealed a significant benefit in reflux-like and ulcer-like dyspepsia as well as a benefit in those with healing of gastritis.72 In an effort to clarify the ambiguity that exists amongst clinical trials, several meta-analyses have been published also revealing discordant results.73–77 Three analyses concluded that a small yet statistically significant benefit existed with H. pylori eradication over placebo.73, 76, 77 One analysis revealed that no benefit existed74 and one revealed that insufficient evidence existed to make a determination.75 Further evaluation of these meta-analyses determined that only 11–38% of dyspeptics were symptom-free as a result of H. pylori eradication.78 The most recent update of the Cochrane database reported a small but statistically significant symptomatic benefit to curing H. pylori in patients with FD [H. pylori cure = 36% vs. placebo = 30%, relative risk reduction: 8%; 95% CI: 3–12%, number needed to treat (NNT) = 18].79 At present, it is reasonable to conclude that on a population basis, there appears to be a small but statistically significant benefit to H. pylori eradication in FD although the factors predicting a treatment response remain largely unknown.80 On a practical level, the clinician should understand that the prevalence of H. pylori is dropping or already low in many parts of the world and even when the organism is identified, the likelihood of achieving symptom improvement in FD patients following eradication therapy is likely to be <50%.
Proton pump inhibitors
Proton pump inhibitors (PPIs) have been evaluated in a number of large, well-designed RCTs. Based on the results of a meta-analysis, including eight studies and 3293 treated patients, PPI therapy given for 2–8 weeks was more effective in relieving or eliminating symptoms than placebo in patients with FD (33% and 23% response rates with PPI and placebo, respectively; relative risk of remaining symptomatic = 0.86, 95% CI: 0.78–0.95; NNT = 9).88 Though there was significant heterogeneity amongst the included trials, no asymmetry was found on a funnel plot decreasing concerns about publication bias. The risk ratio for remaining dyspeptic was similar between standard- and low-dose PPI regimens. Furthermore, patients with reflux-like symptoms and symptoms described with the words ‘burning’ or ‘sour’ are more likely to improve with PPI therapy. On the other hand, patients with symptoms suggestive of dysmotility, such as nausea and bloating are less likely to respond to PPIs.89 Additionally, the cost-effectiveness of PPI therapy for FD varies widely among different countries and is highly dependent upon the local cost of PPI therapy and whether therapy needs to be given continuously or only intermittently to control symptoms.80
The term prokinetic refers to a diverse group of medications that share the common characteristic of accelerating GI motility. Broadly speaking, these drugs exert their physiological actions through effects on a variety of neurotransmitter receptors including acetylcholine, dopamine, motilin and serotonin. Some examples of prokinetic drugs and their proposed mechanism of actions can be found in Table 3.
Table 3. Prokinetic agents122
|Agent||Primary mode(s) of action||Proposed physiological effects (foregut)|
| Metoclopramide||Dopamine-2-receptor antagonist Serotonin type 4 (5-HT4)-receptor agonist||Antiemetic effect Accelerates gastric emptying Decreases visceral sensitivity Increases gastric antral motility|
| Domperidone||Dopamine-2-receptor antagonist||Antiemetic effect Accelerates gastric emptying Decreases visceral sensitivity|
| Itopride||Dopamine-2-receptor antagonist Cholinesterase inhibitor||Antiemetic effect Accelerates gastric emptying|
| Levosulpiride||Dopamine-2-receptor antagonist Serotonin type 4 (5-HT4)-receptor agonist||Antiemetic effects Accelerated gastric emptying Decreases visceral sensitivity Increases gastric antral motility|
| Erythromycin ABT229||Motilin receptor agonist||Accelerates gastric emptying Reduces gastric fundic accommodation|
| Mosapride||Serotonin type 4 (5-HT4)-receptor agonist Serotonin type 3 (5-HT3)-receptor antagonist||Antiemetic effect Accelerated gastric emptying Increases gastric antral motility|
| Tegaserod||Partial serotonin type 4 (5-HT4) -receptor agonist||Accelerates gastric emptying Increases gastric antral motility Increases gastric fundic accommodation|
A fundamental question regarding the prokinetics is the mechanism/s by which they benefit symptoms. As has been mentioned, the relationship between accelerating gastric emptying and symptom improvement is tenuous. This point is perhaps best illustrated by the motilin receptor agonists, erythromycin and ABT-229. While these agents clearly accelerate gastric emptying, they often have little effect on and sometimes can actually worsen symptoms, particularly at higher doses.90, 91 It has been proposed that this disconnect may in part be related to the deleterious effects of these drugs on accommodation.90, 91 At present, it is safe to conclude that different classes of prokinetic agents benefit symptoms by mechanisms which may include but clearly extend beyond their effects on gastric emptying.
A recent systematic review reported that as a class, prokinetics appear to be more effective than placebo in the treatment of FD.84 Fourteen RCTs totalling 1053 patients were pooled demonstrating that prokinetics were twice as likely as placebo to improve dyspeptic symptoms. However, caution should be exercised in the interpretation of these results as the majority of the RCTs evaluated cisapride (a mixed 5-HT4 agonist and 5-HT3 antagonist that is no longer commercially available), the quality of many of these studies was marginal, heterogeneity existed amongst the included studies and a funnel plot suggested that publication bias may have influenced the results. Another meta-analysis pooling the results of 17 studies evaluating cisapride and four studies evaluating the dopaminergic antagonist, domperidone (not licensed in the US) revealed a marginal benefit compared with placebo based on the investigator's or patient's assessment of global symptoms.92 A more recent meta-analysis demonstrated that the observed benefit of prokinetics over placebo was lost when an the analysis was restricted to high quality studies.87
At present, the greatest activity appears to be focused on the development of serotonergic and dopaminergic drugs. Conflicting data currently exists on the efficacy of the mixed 5-HT4 agonist and 5-HT3 antagonist, mosapride.93–95 Tegaserod is a 5-HT4-receptor agonist that is currently approved for the treatment of women with the IBS and constipation and men and woman under the age of 65 years with chronic constipation. Tegaserod has been preliminarily shown to accelerate gastric emptying of solids in patients with FD and delayed gastric emptying.96–98 In a phase II RCT evaluating patients with FD, a dose of 6 mg t.d.s. normalized gastric emptying in 80% vs. 50% for placebo (P < 0.058).98 In a recent small trial, tegaserod 6 mg b.d. improved gastric accommodation after eating a meal in functional dyspeptics with normal gastric emptying.96 Phase III trials evaluating tegaserod in patients with FD are currently nearing completion in North America.
In a randomized trial, the dopaminergic antagonist, levosulpiride was as effective as cisapride in relieving symptoms in patients with dysmotility-like FD.99 Like another dopaminergic antagonist, domperidone, levosulpiride can be associated with breast tenderness and galactorrhea. This drug is available in some parts of the world but is currently not available in the US. A recent high quality phase II trial randomized 554 patients with FD to placebo or one of three doses of itopride, a dopaminergic antagonist with weak muscarinic agonist activity. Itopride significantly improved global dyspeptic symptoms and composite symptom score using the Leeds Dyspepsia Questionnaire. Overall, this drug was safe and well tolerated.100 However, a recent European phase III trial with itopride failed to meet its primary end point in confirming efficacy in the treatment of FD. A phase III trial in North America is currently ongoing with results pending. Further data analysis and the results of this ongoing trial should clarify what role itopride may play in patients with FD.
Antidepressants and antianxiety agents
Antidepressant and anxiolytic use in FD remains largely based on anecdotal data. A recent systematic review addressed antidepressant and antianxiety use in FD.101 Thirteen studies met the researcher's inclusion criteria with 11 demonstrating improvement in dyspeptic symptoms following treatment. Unfortunately, significant variability amongst the studies existed regarding the definition of FD, the measured outcomes, and the agent evaluated. Meta-analysis could only be performed on four of the trials (153 total subjects) demonstrating significant benefit of treatment with antianxiety drugs or antidepressants over placebo (relative risk: 0.55, 95% CI: 0.36–0.85).
The first high quality randomized trial comparing the efficacy of a tricyclic antidepressant or TCA (desipramine) to placebo in patients with functional gastrointestinal disorders (FGID) was recently published by Drossman et al.102 Most of the patients had IBS though some patients with other functional symptoms were also included. The intention-to-treat (ITT) analysis did not show a statistically significant improvement in a composite symptom scale between the desipramine and placebo groups (60% vs. 47%, P = 0.13). This was largely due to the 28% of patients who did not complete the trial related to adverse drug effects or non-compliance. When these patients were excluded from the analysis (per-protocol analysis), desipramine resulted in a statistically significant benefit compared with placebo (73% vs. 49%, P = 0.006, NNT = 4). From this data, we can conclude that many patients will not tolerate TCAs but those who can tolerate these medications are likely to experience symptomatic benefit. A post hoc analysis from this study suggested that many of the ‘adverse effects’ attributed to TCA therapy were present before the initiation of therapy and thus, may not actually have been caused by the TCA.103
In a small randomized trial of seven patients with FD, amitriptyline (50 mg qHS) was found to be more effective than placebo in improving symptoms.104 Most recently, Otaka et al. demonstrated the efficacy of amitriptyline in 14 FD patients who initially failed treatment with famotidine or mosapride reporting a response rate of 71%.95 Clinical benefit has not been found to correlate with changes in perception of gastric balloon distention, suggesting that the analgesic effects of TCAs are likely to be mediated centrally, perhaps through effects on the cortical processing of painful visceral sensations.105, 106
When the TCAs are used for FD patients, lower doses are typically necessary than when treating depression. For FGID, target doses for the TCAs range from 10 to 100 mg/day. Higher doses are necessary in the presence of comorbid psychological conditions like depression. These drugs are usually dosed in the evening to minimize problems related to their sedative effects. Patients should also be warned about the possibility of dry mouth and eyes as well as weight gain and constipation. Secondary amines, such as nortriptyline and desipramine may be better tolerated than the older tertiary amines (amitriptyline, imipramine). Unlike when used for depression, the clinical benefits of TCAs for functional disorders are often seen within 2 weeks of initiating therapy.
To date, there have been no randomized, placebo-controlled trials published in manuscript form which have evaluated selective serotonin reuptake inhibitors (SSRIs) for FD. Recent studies suggest that the SSRIs, paroxetine and sertraline, do not alter the sensation of gastric balloon distention107, 108 but may alter accommodation107 in healthy volunteers. Similarly, there is no data addressing the physiological or clinical effects of newer antidepressants, such as venlafaxine or mitazapine in patients with FD. Though it is clear that these agents are of benefit to comorbid depression and/or anxiety, it remains unclear whether they offer any benefit to GI symptoms associated with FD in the absence of concomitant psychiatric conditions. Because of the social stigma attached to their use and their narrow therapeutic window, it seems fair to suggest that antidepressants should be reserved for patients with persistent, moderate to severe symptoms who have failed to improve with the more conventional forms of medical therapy.
A variety of different psychotherapeutic modalities have been used to treat FGID including insight-oriented psychotherapy, relaxation and stress management training, cognitive-based behavioural therapy, biofeedback and hypnotherapy.109, 110 The best studied of these techniques is cognitive-behavioural therapy. This form of psychotherapy is designed to teach patients how to identify maladaptive behaviours and manage their responses to emotional and life stresses. Haug et al. randomized 100 patients with FD to cognitive psychotherapy or no therapy and found that the psychotherapy patients experienced significant improvement in symptoms, such as bloating, epigastric pain and nausea.111 Mine et al. randomized 198 FD patients to a combination of medical, psychiatric and psychotherapeutic treatments vs. medical therapy alone and found that multimodality therapy afforded significantly improved outcomes compared with medical therapy alone.112 Hamilton et al. sought to determine if brief psychodynamic-interpersonal psychotherapy was superior to reassurance alone. At the end of the therapy period, FD patients in the psychotherapy group had significant symptom reduction compared to the group treated with reassurance alone. A post hoc analysis at 1 year, removing patients with severe heartburn symptoms, indicated a potential benefit for the psychotherapy group.113 Another recent study in FD patients found that hypnotherapy yielded a greater improvement in symptoms as well as quality of life measures, reduced antidepressant medication and reduced consultation rates compared with supportive therapy or medical therapy.110
Though individual trials suggest clinical benefits, a recent systematic review concluded that there was insufficient evidence to support the efficacy of psychological therapies for FD.114 Despite this evidence-based conclusion, it does appear that addressing life stresses and improving coping mechanisms can be a useful adjunct to traditional therapies once organic GI disease has been excluded. Unfortunately, several factors make the implementation of psychological therapy challenging in clinical practice. In addition to overcoming the stigma of referring patients for psychological therapy and the failure of many insurance plans to cover this form of out-patient treatment, it can be difficult to find a mental health professional with the training and/or willingness to take on patients with a FGID.
Complementary and alternative medicine
A number of alternative treatment strategies to that of pharmaceuticals or psychological therapy have been employed in FD. A recent systematic review reported that at least 44 different herbal products have been recommended alone or in combination for the treatment of dyspeptic symptoms.115 This review included 17 RCTs, the largest number of studies having assessed peppermint and caraway in the treatment of FD. This analysis revealed symptom improvement in 60–95% of patients receiving herbal therapy vs. 30–55% in patients receiving placebo. Unfortunately, the baseline patient profiles in these trials were not always well defined and methods of symptom assessment were variable often relying on scoring systems lacking validation.
A more recent meta-analysis of the combination herbal remedy, STW 5 (Iberogast), pooled the data of three RCTs which included 273 FD patients. This meta-analysis found that STW 5 was superior to placebo at improving the most bothersome FD symptom reported by study participants (P = 0.001, odds ratio: 0.22, 95% CI: 0.11–0.41).116
Capsaicin, the active ingredient of red chilli pepper, has been evaluated in small clinical trials, which have yielded conflicting results. A RCT assessing capsaicin in 30 patients with FD demonstrated significant improvement in overall symptoms, epigastric pain, fullness and nausea compared with placebo.117 On the other hand, an earlier placebo-controlled crossover trial evaluating 11 patients with a primary complaint of heartburn and associated dyspepsia was unable to show significant improvements in postprandial dyspepsia scores with capsaicin.118 Interestingly, this study demonstrated worsening in immediate postprandial heartburn when capsaicin was ingested with a meal.
A RCT assessing artichoke leaf extract in 247 patients with FD demonstrated a significant improvement in both overall symptoms and disease-specific quality of life compared with placebo.119
Several issues regarding CAM therapies deserve mention. Available trials almost all suffer from significant methodological flaws making the results difficult to interpret. Further, because these agents are not regulated as pharmaceuticals, questions regarding agent purity and potency have been raised. Finally, though the short-term use appears relatively safe, the long-term safety of these agents has not been established.
A number of agents with antinociceptive properties are under investigation for the treatment of FD. κ-Opioid receptor agonists that may inhibit somatic and visceral pain pathways through their effects on peripheral opioid receptors, are being developed as a possible treatment for FD. One such agent, fedotozine, yielded promising preliminary results in the treatment of FD.120 Unfortunately, data from North America proved disappointing (unpublished data) and the development of this drug was halted. Another opioid agonist, asimadoline, has also shown some possible application for the treatment of dyspeptic symptoms.121
Other potential targets for emerging agents with possible effects on visceral sensation include purinoceptors, N-methyl-d-aspartate (NMDA) receptors, protease-activator receptors (PAR)-2, the vanilloid receptors, sodium-channel receptors and somatostatin receptors.122 The P2X purinoceptors are ligand-gated cation-channels located along pH-sensitive vagal and spinal afferent pathways.123 Although the role of these receptors in the generation of GI pain remains uncertain, antagonism of the P2X receptor suppressed inflammation-induced visceral pain in a mouse model.124
N-Methyl-d-aspartate receptors represent another class of ligand-mediated ion-channels expressed by afferent neurones in the enteric nervous system. NMDA receptors may play a role in visceral hypersensitivity, although the limited available evidence remains inconclusive. NMDA antagonism was initially shown to reduce the nociceptive response to colonic distention in a rat model.125 Paradoxically, the NMDA antagonist, dextromethorphan, increased the nociceptive response to gastric distention in small study involving nine healthy adults.126 This response has been ascribed to dextromethorphan's low affinity for the NMDA receptor. Future studies utilizing more selective NMDA receptor antagonists are eagerly awaited.
Protease-activator receptors consist of a family of four large G-protein-coupled receptors. Two of the receptor types, PAR-1 and PAR-2, have been found throughout the GI tract with a number of modulatory effects on mucosal and smooth muscle function.127 PAR-2 receptors have been identified on gastric mucosal sensory neurones in a rat model.128 Given their possible roles in the modulation of gastric motor and sensory function, PAR-2 agonists and antagonists may be potential candidates for the treatment of FD.
Vanilloid receptors are non-selective cation-channels located on afferent nerve endings that are activated by capsaicin, acid and temperature changes. Nerve fibres containing these vanilloid receptors have been identified in the mucosal and muscular layers of the gastric fundus and antrum in several animal models.129 Such receptors have therefore been postulated to play a role in gastric nociception.
Proton-gated sodium-channels also known as acid-sensing ion-channels have been found on primary afferent neurones. These channels have been suggested to play a role in the sensory responses of the gastroduodenal mucosa to acid exposure.130 Such a hypothesis remains to be tested in asymptomatic volunteers and dyspeptic patients.
Somatostatin is a neurotransmitter affecting GI motility, sensation and visceral sensation through six different G-protein-coupled receptors. The somatostatin analogue, octreotide, has been shown in several small studies to reduce the sensation of gastric fullness in healthy patients.131–133 The exact role of somatostatin receptors in FD requires further study.
Acting through alternative pathways, several additional agents including cholecystokinin (CCK) receptor antagonists,134 tachykinin receptor antagonists135 and corticotrophin-releasing factor (CRF) antagonists136 have been postulated to be potentially beneficial for FD. CCK is a neuropeptide released into the gut in response to the presence of intraluminal lipids. It is believed to mediate pain in the gut and known to inhibit gastric emptying through vagal afferent pathways.137, 138 CCK hyperresponsiveness or the interaction of CCK pathways with those of serotonergic pathways has been postulated to play a role in FD.139 Administration of the synthetic CCK analogue, CCK-8, has been shown to reproduce dyspeptic symptoms in 90% of a cohort of FD patients and the administration of a CCK antagonist, loxiglumide, was effective in controlling dyspeptic symptoms.139 A double-blind, placebo-controlled trial involving 12 FD patients demonstrated the ability of the CCK antagonist, dexloxiglumide, to prevent the dyspeptic symptoms produced by duodenal lipid infusion, reduce dyspeptic symptoms experienced by lipid infusion combined with gastric distention, and reduce sensitivity to distention.46
The tachykinins, substance P, neurokinin A and neurokinin B, exert their effects through their interaction with tachykinin receptors NK1, NK2 and NK3. The NK1 antagonist, aprepitant, has demonstrated antiemetic properties and is currently approved for the treatment of chemotherapy-induced nausea and vomiting.140, 141 NK1 antagonism has demonstrated antinociceptive effects in preclinical animal studies, although such findings have not been reproduced in humans.142 The precise role of NK3-receptor antagonism in gastro-vagal functions, gastric motility and nociception remain largely unknown.143
The hypothalamic-pituitary-adrenal (HPA) axis serves as the primary endocrine stress system in humans and provides an important interface between the brain and the gut-immune system. Activators of the HPA axis including physical and psychological stress have been suggested to play a role in FD. A recent study involving IBS patients found overactivation of the HPA axis with associated increases in proinflammatory cytokines.144 There is evolving evidence that CRF receptor antagonists may reduce stress-related alterations in upper gut function.145 CRF2-receptor antagonism has been shown to prevent CRF-induced alternations in gastric motility in a rat model.146 Further, animal studies have found that CRF1-receptor antagonism abolishes the gastric ileus that occurs immediately following celiotomy and caecal palpation.147 It is hoped that such preliminary findings may predict clinical applications for CRF antagonists in the treatment of FD.
Other serotonergic agents are also being investigated for their possible role in the treatment of FD. Preliminary work with the 5-HT1 agonist, sumatriptan, has stimulated interest in the development and evaluation of other 5-HT1 agonists for the treatment of FD.24, 34 In a dose ranging study involving women and men with FD who received placebo or three different doses of the 5-HT3-receptor antagonist alosetron, only women who received a dose of 1 mg b.d. achieved statistically significant improvements in adequate relief of their dyspeptic symptoms (54% vs. 43%, P < 0.05).148 In the US, this use of alosetron is restricted to women with severe IBS that has proven refractory to traditional treatments because of its association with occasional severe constipation and rare cases of ischaemic colitis. Other serotonergic agents which may offer benefit to FD include the 5-HT4 antagonists and 5-HT7 agonists.149