In daily clinical practice, proton pump inhibitors (PPIs ) and prokinetics are usually used as initial medications. Acid reduction therapy is commonly used as first-line medication mainly in cases of FD with epigastric pain while prokinetics are usually prescribed in cases of early satiety and postprandial fullness. A 3 weeks long randomized placebo controlled trial of the histamine-2 receptor antagonist (H2RA) famotidine conducted on a small group of children with FD has shown global improvement of symptoms but no beneficial effect on pain [130]. A pediatric trial compared four antisecretory agents (omeprazole, famotidine, ranitidine, cimetidine) for a period of 4 weeks in 169 children (age 2–16) diagnosed with functional dyspepsia [135]. The study showed that omeprazole was the most effective in achieving complete resolution of symptoms. Similar results were obtained in a study on adults with FD. One study showed that proton pump inhibitor (PPI) therapy was more effective than H2RA for FD [136]. A review of clinical trials in adult patients reported significant improvement in symptoms with PPI therapy [137]. These data suggests that empiric acid reduction for a limited period of time may be recommended in pediatric patients with FD.

Medications affecting visceral sensation are sometimes used to treat pediatric FD. Tricyclic antidepressants (TCAs) reduce nausea, abdominal pain, and delay gastric emptying. Amitriptyline is one of the more commonly used TCAs despite mixed results of efficacy in pediatric studies and the adverse effects related to anticholinergic and antihistaminic activity. An RCT of low-dose amitriptyline in children and adolescents with FAPDs identified high placebo effect (and high treatment effect) which made interpretation of medication efficacy difficult [138]. An earlier trial in pediatric IBS showed improved quality of life, but no clear improvement in abdominal pain [139]. A multicenter placebo controlled trial of amitriptyline in adults with FD showed modest, but significant improvement in symptoms [140]. The beneficial effect was similar to Saps et al. pediatric trial if calculated with intention to treat analysis (53 %), but the placebo effect was lower (40 %) than in the pediatric study. The study showed greater benefit in patients with pain predominant symptoms. Selective serotonin reuptake inhibitors (SSRI) were studied in a RCT of pediatric FAPDs, but did not show significant differences in symptom resolution [141]. The Talley et al. study of adult subjects with FD included an SSRI arm (escitalopram), and also did not show a benefit over placebo [140]. Prior studies of SSRIs in adults with FAPDs have shown efficacy equivalent to TCAs [142]. Given reports of cardiac dysrhythmia associated with TCA and SSRI use, it is reasonable to obtain baseline EKG to assess QT interval prior to initiation of therapy. While the use of TCAs and SSRIs is directed towards altered visceral sensitivity, their influence on gastrointestinal motility may affect symptom resolution. Two controlled studies on TCAs (nortriptyline, amitriptyline) found no benefit of these drugs in FD with delayed emptying [143]. Mirtazapine, an antidepressant with antagonism of H₁, α₂, 5HT_2c, and 5HT₃ receptors, was studied in a pilot RCT of adults with FD and weight loss [144]. Use of mirtazapine reduced dyspepsia symptom severity and improved quality of life, nutrient tolerance, and weight. An alternative strategy of targeting the specific nociceptor TRPV1 was attempted in adults with FD. A double blind, placebo controlled trial of red pepper powder in adults with FD showed initial, transient discomfort, but overall reduction on symptoms of pain and fullness [145].

Prokinetics as a class have shown mixed results in the treatment of FD in adults. A meta-analysis of prokinetics in 1844 adult FD patients found reduction in symptoms [146], but a separate study found no correlation between symptom improvement and gastric emptying rate [147]. Specific prokinetics may target 5HT, dopamine, or motilin receptors. Cisapride and other 5HT₄ receptor agonists improve gastric emptying and accommodation, and potentially alter visceral sensitivity. However, cisapride was withdrawn from the USA and European markets due to concern for fatal cardiac arrhythmias (although not clearly a concern in healthy children [148]). In adult trials, mosapride (5HT₄ agonist and 5HT₃ antagonist) demonstrated FD symptom improvement [149] although a meta-analysis could not support the effects of mosapride, possibly due to heterogeneity among study definitions and outcomes [150]. Cinitapride (5HT₄ receptor agonist, dopamine-2 receptor antagonist) reduced symptom severity as well as domperidone [151]. Domperidone and metoclopramide are dopamine antagonists used as prokinetic agents. Although metoclopramide is effective in FD, the potential for irreversible extrapyramidal adverse effects limits its use in pediatrics. Domperidone also improves FD symptoms in adult trials [152] and does not have similar risk of extrapyramidal adverse effects. However, due to its potential for adverse cardiac effects, in the USA it is only available for compassionate use as an investigational drug through the FDA. Erythromycin activates antral and small intestinal motilin receptors and decreases bloating with improved gastric emptying in adult FD patients, but does not alter postprandial symptoms [153]. Other motilin receptor agonists including camicinal are promising and improve gastric emptying, but efficacy to reduce FD symptoms is not yet established [154, 155]. Another prokinetic agent, acotiamide, improves gastric accommodation through acetylcholinesterase inhibition and shows promise in treatment of adult FD in ongoing trials [156–158]. Other novel prokinetics studied in gastroparesis (e.g., relamorelin, a ghrelin receptor agonist [159]) may in the future be studied in FD patients given the overlapping spectrum of symptoms and electromechanical dysfunction of the two disorders. Botulinum toxin A endoscopically injected in the pylorus safely reduced symptoms in pediatric patients with gastroparesis refractory to conventional therapy [160], and may be considered in a similar subgroup of refractory FD patients.

Gastric accommodation is an additional target of electromechanical dysfunction in FD. Cyproheptadine antagonizes 5HT_2a and 5HT_2b, histamine-1, and muscarinic receptors whose putative mechanism is improved gastric accommodation through fundic relaxation, although it may also have an effect by decreasing gastric hypersensitivity. It was found to be effective in a RCT of children with FAPDs [161], and provided symptom improvement in pediatric FD patients in an open-label trial, with few and mild adverse effects [131]. Buspirone, a 5HT_1a receptor agonist, improved accommodation in adults with FD and decreased symptom severity [162]. Other medications targeting the 5HT_1a receptor to improve accommodation include tandospirone and sumatriptan, but these have not as clearly reduced symptoms [163, 164]. Tegaserod, a 5-HT₄ agonist that was taken off of the market, was found to enhance gastric accommodation in adult patients with normal gastric emptying [165]. Ondansetron, a 5HT₃ antagonist, improved accommodation and reduced nausea in adults with FD, but mechanical and symptom effects were not seemingly associated [166].

Neuromodulation with gastric electrical stimulation significantly improved nausea and vomiting, and improved tolerance of nutritional intake in children with dyspepsia [167]. Gastric electric stimulation was also shown to improve quality of life and global health [168] in children with excellent long-term tolerance and few adverse effects [169]. Although the technology is currently in use only in few pediatric centers, it is a promising therapy for patients with refractory symptoms.

Pediatric FD patients with duodenal eosinophilia were demonstrated to have reduction of symptoms with histamine_1/2 antagonism or cromolyn, a mast cell stabilizer [170]. Of 21 patients who did not initially respond to ranitidine and hydroxyzine combination therapy, two were lost to follow-up and 17 clinically responded (complete or nearly complete resolution of pain) with the addition of cromolyn. Treatment of a similar cohort in a placebo-controlled crossover trial showed that children receiving montelukast, a leukotriene receptor antagonist, had a greater reduction in global pain than those on placebo without having any adverse effects [171]. However, symptom improvement does not seem to correlate to mucosal eosinophil density or activation, and the mechanisms of action are not yet determined [108].

There are several herbal preparations that have been purported to improve chronic abdominal pain. A multicenter placebo controlled trial of STW 5 (iberogast), an herbal compound with a mechanism of action that is not yet clearly understood, showed improvement of adult FD symptoms [172, 173]. An open label trial of iberogast also showed beneficial effects in pediatric patients with FAPDs [174]. Peppermint oil seems to affect various mechanisms involved with the pathophysiology of IBS. Two studies on adult volunteers have investigated the gastric sensorimotor aspects of peppermint oil. Papathanasopoulos et al. found that peppermint oil reduces intragastric pressure and proximal phasic contractility without affecting gastric tone, accommodation, visceral sensitivity, epigastric pain, or early satiety [175] while Inamori et al. found that peppermint oil enhances gastric emptying [176]. Studies in adults and children with IBS have shown a beneficial effect of peppermint oil on IBS symptoms [177]. Nigella sativa (black cumin) seed oil mixed with honey, added to standard treatment with famotidine, showed reduction of FD symptoms in an 8 week randomized controlled trial in adults [178]. Similarly, Pimpinella anisum (anise) supplementation reduced pain in adults with FD compared to controls [179]. Rikkunshito, a Japanese herbal preparation, was studied in a multicenter randomized clinical trial of FD adults and was shown to improve pain, accelerate gastric emptying, and improve accommodation possibly through serotonergic or ghrelin mediated pathways [180]. Although ginger is used to treat nausea and enhances gastric emptying, it did not improve symptoms in an adult FD trial [181]. Various phytotherapy compounds and plant extracts such as curcumin [182] have been used with different degrees of efficacy and evidence.

Therapies aimed at modifying psychosocial stress, catastrophizing behavior, and anxiety indirectly target visceral hypersensitivity and electromechanical dysfunction given the cross-talk between the gut, brain, and the environment. Importantly these therapies may be more effective in conjunction with medical therapy rather than in isolation [183]. Although sometimes difficult for patients and medical providers to access due to local absence of therapists or financial constraints, complementary therapies should be considered whenever possible. Over the last few years there have been several studies of gut directed hypnotherapy [184, 185] and cognitive behavioral therapy [186, 187] showing beneficial effect in children with FAPDs. Other complementary therapies with potential beneficial effects in the treatment of children with FAPDs are biofeedback assisted relaxation therapy [183], yoga [188], and acupuncture [189].