725479

research-article2017
TAJ0010.1177/2040622317725479Therapeutic Advances in Chronic DiseaseH Yamawaki, S Futagami

Therapeutic Advances in Chronic Disease Review

Management of functional dyspepsia: state

Ther Adv Chronic Dis

2018, Vol. 9(1) 23­–32

of the art and emerging therapies DOI: 10.1177/

https://doi.org/10.1177/2040622317725479
https://doi.org/10.1177/2040622317725479
2040622317725479

© The Author(s), 2017.

Reprints and permissions:
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Shuhei Agawa, Kazutoshi Higuchi, Yasuhiro Kodaka and Katsuhiko Iwakiri

Abstract:  Patients with functional dyspepsia, defined in the 2016 Rome IV criteria as
bothersome clinical dyspepsia symptoms, experience markedly reduced quality of life. Several
etiologies have been associated with the disorder. In the Rome IV criteria, the brain–gut axis
was acknowledged as an important factor in the etiology of functional gastrointestinal (GI)
disorders. The distinct subgroups of functional dyspepsia, epigastric pain syndrome (EPS) and
postprandial distress syndrome (PDS), are treated differently: acid secretion inhibitors are
recommended with patients with EPS, whereas prokinetic drugs as mosapride and acotiamide
are recommended for patients with PDS. A previous study has reported that proton pump
inhibitors (PPIs) and H2-blockers were equally effective in functional dyspepsia. A new drug,
acotiamide, a muscarinic antagonist and cholinesterase inhibitor, has been shown to improve
gastric motility in rodents and dogs, and to reduce PDS symptoms in patients in double-
blind multicenter studies. The pharmacological mechanisms of acotiamide remain unknown;
whether acotiamide alters gastric emptying and gastric accommodation in patients with
functional dyspepsia remains an open question. Other emerging treatment options include
Rikkunshito, a herbal medicine that improves gastric emptying through 5-hydroxytryptamine
(5-HT)2B-mediated pharmacological action, and tricyclic antidepressants (TCAs). Different
drugs are needed to accommodate the clinical symptoms and etiology in individual patients.

Keywords:  acid secretion inhibitors, acotiamide, functional dyspepsia, gastritis, mosapride

Received: 16 February 2017; revised manuscript accepted: 31 May 2017

Introduction Pathophysiology
Functional dyspepsia is a common disorder and Visceral hypersensitivity,5 impaired gastric
can markedly impair the patients’ quality of life. accommodation6 and impaired gastric emptying
Based on the Rome III classification criteria, the are commonly reported by patients with func-
Correspondence to:
main symptoms of functional dyspepsia consist of tional dyspepsia.7–9 Involvement of several other Seiji Futagami
bothersome postprandial fullness, early satiety, mechanisms has also been suggested, including Department of Internal
Medicine, Division of
epigastralgia, and epigastric burning.¹ In 2014, duodenal hypersensitivity to the luminal contents, Gastroenterology, Nippon
the guideline for functional dyspepsia patients small bowel dysmotility, psychological distur- Medical School, 1-1-5
Sendagi, Bunkyo-ku,
was also provided in Japan.² Functional dyspepsia bances,10 central nervous system disorders and Tokyo, 113-8602, Japan
is treated by two major categories of drugs: acid Helicobacter pylori infection.11,12 seiji.futagami@gmail.com
Hiroshi Yamawaki
inhibitors such as H2-receptor antagonists and Mako Wakabayashi
proton pump inhibitors (PPIs), and prokinetic H. pylori.  Recently, the H. pylori eradication ther- Noriko Sakasegawa
Shuhei Agawa
drugs that accelerate disturbed gastrointestinal apy was proposed as first-line treatment for H. Kazutoshi Higuchi
(GI) motility by modifying altered visceral sensi- pylori-infected dyspeptic patients,13 however, the Yasuhiro Kodaka
Katsuhiko Iwakiri
tivity. In 2016, Rome IV criteria defined that the main justification for H. pylori eradication in Department of Internal
diagnosis of functional dyspepsia required both- patients with functional dyspepsia may be related Medicine, Division of
Gastroenterology, Nihon
ersome clinical symptoms, and the brain–gut axis to other potential beneficial effects such as pre- Ika Daigaku, Bunkyo-ku,
was acknowledged as an important factor in the vention of gastric cancer and recurrence of gastric Tokyo, Japan
etiology of functional GI disorders.3,4 ulcer rather than symptomatic improvement.14

journals.sagepub.com/home/taj 23
Therapeutic Advances in Chronic Disease 9(1)
Although H. pylori infection may affect gastroduo-
denal motility and viscerosensory function, the
precise mechanism of its benefits in functional
dyspepsia is not clear.15–18 Therefore, although H.
pylori eradication does not have a direct beneficial
effect on of the symptoms of functional dyspepsia,
recent studies have reported that long-term H.
pylori eradication therapy improved the symptoms
of functional dyspepsia19 and according to the
Kyoto consensus meeting documents, symptoms
were cured from 6 months to 1 year after eradica-
tion therapy in functional dyspepsia patients with
H. pylori.13 Further studies will be needed to con-
firm the long-term effect of eradication therapy.20
Delayed gastric emptying.  Delayed gastric emptying
has been reported by gastric scintigraphy in a large
proportion (up to 45%) of dyspeptic patients,21
especially those with postprandial distress syndrome
(PDS). Other strategies to evaluate the speed of gas-
tric emptying include the paracetamol absorption
test which can measure the gastric emptying of liq-
uids, and the 13C breath test, which can measure the
gastric emptying of solids or liquids and can achieve
an accuracy comparable with gastric scintigraphy.22
We have previously reported that the Tmax value as
the point of maximum speed of gastric emptying for
a marker of gastric emptying in PDS patients was
significantly greater than in healthy volunteers.9 In
addition, we have also reported that nizatidine sig-
nificantly improved both gastric emptying and clini-
cal symptoms in functional dyspepsia patients with
impaired gastric emptying.23
Subtypes and targeted therapy
The functional dyspepsia subtypes, epigastric
pain syndrome (EPS) and PDS, require different
treatment; patients with EPS benefit from acid
secretion inhibitors, whereas patients with PDS
benefit from prokinetic drugs such as mosapride
and acotiamide.2 Other treatment options in EPS
include H2-blockers and PPIs.
Some patients with EPS have been reported to have
an intractable disease; these are likely to relate to the
various etiological factors contributing to functional
dyspepsia, which overlap with other diseases such as
irritable bowel syndrome (IBS), nonerosive reflux
disease (NERD) and pancreatic dysfunction.
Dietary and lifestyle modification
Dietary recommendations in functional dyspepsia
include eating smaller meals and avoiding high-fat
24 journals.sagepub.com/home/taj
meals which have been reported to aggravate clini-
cal symptoms such as nausea and abdominal pain
more than isocaloric high-carbohydrate meals.24
In our recent study,25 intake of dietary fat aggra-
vated clinical symptoms of dyspepsia in patients
attending the clinic.
Although Talley and colleagues reported that
smoking, alcohol, aspirin and the use of non-
steroidal anti-inflammatory drugs (NSAIDs) was
not associated with an increased risk of functional
dyspepsia in outpatients presenting for endos-
copy.26 However, in view of the Rome IV criteria
Stanghellini and colleagues recently recom-
mended that besides more frequent, smaller
meals and avoiding a high-fat diet, patients with
functional dyspepsia should avoid NSAID use,
coffee, alcohol, and smoking.4 Randomized con-
trolled trials (RCTs) and systematic studies are
warranted to confirm the efficiency of adjusting of
eating habits.
Standard drug treatments: anti-acid drugs
Several studies have reported that anti-acid ther-
apy and prokinetic agents are effective for certain
populations with functional dyspepsia.
H2-blocker therapy. H2-blockers (histamine H2
receptor antagonists) have been used as a first-
line therapeutic drug for functional dyspepsia. In
a 2012 review, Lacy and colleagues reported that
in 12 RCTs that compared H2-blockers with pla-
cebo in a total of 2183 participants, 54% had a
statistically significant improvement in dyspeptic
symptoms with H2-blocker therapy compared
with 40% in the placebo arm.27
PPI therapy.  Although PPIs also have been widely
used for the treatment of dyspeptic symptoms in
functional dyspepsia, evidence from RCTs sug-
gests that the efficacy of PPIs in functional dys-
pepsia is limited28–30 and may be confined to those
patients who have co-existing reflux symptoms.
The efficacy of PPIs fails against that of placebo
for nonacid-related symptoms.31–33
Comparison of PPI and H2-blocker therapy and
other treatments.  Generally, PPI treatment has
been reported to reduce basal gastric acid secre-
tion and gastrin-stimulated gastric acid secre-
tion levels compared with patients treated with
the H2-blocker H2RA. A comparison of PPI
therapy with H2-blocker therapy in nonulcer
dyspepsia showed a trend towards a better

outcome based on global dyspepsia cure with a
PPI, however, the difference was not statistically
significant.28 By contrast, Moayyedi and col-
leagues have reported that there were no differ-
ences in the effects of PPI and H2-blocker in
functional dyspepsia.2,34 In the CADET-HN
study, PPI treatment significantly improved
clinical symptoms compared with patients with
placebo and prokinetics.35
Standard drug treatments: prokinetic drugs
Previous studies have reported that metoclopra-
mide is not effective in functional dyspepsia.36,37
By contrast, a placebo-controlled trial reported a
beneficial effect of domperidone (10–20 mg three
times daily) with placebo.38
A recent meta-analysis concluded that itopride, a
D2 antagonist and acetylcholinesterase inhibitor,
improves the symptoms of early satiety and post-
prandial fullness.39 Moreover, itopride is more
effective than domperidone in improving post-
prandial fullness and early satiety.40–43
Standard drug treatments: antidepressants
Since refractory functional dyspepsia involves
psychiatric manifestations such as depression and
anxiety, many physicians prescribe antidepres-
sants for their patients. In Japan, according to the
guidelines for the treatment of functional dyspep-
sia, the first-line therapy includes PPIs or proki-
netics. For the treatment of refractory functional
dyspepsia,2 antidepressants such as tandospirone
are used as second-line drugs in clinical practice
in Japan. Koloski and colleagues have reported
that antidepressant treatment significantly
improves functional dyspepsia compared with
placebo.44,45
Tricyclic antidepressants. Lu and colleagues
reported in a systematic review that TCAs are
effective in the treatment of functional dyspepsia
symptoms.46 Other studies have reported that
TCAs are effective particularly for certain func-
tional dyspepsia patients with chronic pain.44,47
However, improvement of clinical symptoms of
functional dyspepsia treated with antidepressants
has been reported to be limited by Talley and col-
leagues.48 The disease subtype might have a role
in treatment efficacy. Talley and colleagues later
reported that patients with ulcer-like functional
dyspepsia who are on TCAs or amitriptyline are
journals.sagepub.com/home/taj 25
H Yamawaki, S Futagami et al.
more likely to report adequate symptom control
than are patients with dysmotility-like functional
dyspepsia.47
Serotonin-specific reuptake inhibitors (SSRIs) and
serotonin–norepinephrine reuptake inhibitors
(SNRIs).  In contrast with TCAs, no improvement
of clinical symptoms over placebo was seen in
patients taking escitalopram (an SSRI).46,49
Moreover, Van and colleagues reported no signifi-
cant improvements in symptom severity, anxiety
score, depression score and health-related quality
of life in patients receiving venlafaxine (an SNRI)
compared with placebo.49
Interestingly, according to a double-blind, pla-
cebo-controlled, multicenter study by Miwa and
colleagues, the 5-HT1A agonist, tandospirone,
improved abdominal symptoms such as upper
abdominal pain and abdominal discomfort at 4
weeks.50
To conclude, given the limited evidence for the
efficiency of antidepressants, further studies will
be needed to perform double-blind, multicenter
studies to determine the usefulness of antidepres-
sants for functional dyspepsia patients.
Acotiamide, a novel pharmacological treatment
The new drug, acotiamide, a muscarinic antago-
nist and cholinesterase inhibitor has been shown
to improve gastric motility and gastric emptying
in rodents and dogs (Table 1).51,52
Acotiamide monotherapy. Double-blind multi-
center studies have shown a significant improve-
ment in PDS symptoms such as postprandial
fullness, early satiety, upper abdominal bloating
in patients treated with acotiamide, as reported
by Matsueda and colleagues.53
In Japan, acotiamide for functional dyspepsia is
covered by insurance. Therefore, several Japanese
studies have reported acotiamide to be associated
with improvement of clinical symptoms in
patients with functional dyspepsia (Table 1),54–56
one of these was a long-term study.57 According
to our data, acotiamide treatment relatively
improved lower abdominal symptoms, although
this finding was not statistically significantly
(Table 1).58
Mechanisms of action. Although, as shown in
Table 1, many studies have reported
Therapeutic Advances in Chronic Disease 9(1)

Table 1.  Clinical symptoms and experiments for acotiamide usage.

Reference Subjects Clinical and experimental outcomes

Kawachi et al.52 Rat Gastric motility and gastric emptying by inhibiting
acetylcholinesterase activity
Seto et al.60 Restraint rat model Improvement of gastric emptying feeding inhibition
Matsueda et al.57 FD patients (Rome III) Improvement of elimination rate of postprandial fullness,
upper abdominal bloating and early satiety
Matsueda et al.54 FD patients (Rome III) Improvement of elimination rate for all three symptoms
(postprandial fullness, upper abdominal bloating, early satiety)
Ikeo et al.62 Guinea pig model Improvement of stress-induced gastric accommodation
Yamawaki et al.55 FD patients (Rome III) Improvement of PDS symptoms and impaired gastric emptying
Shinozaki et al.56 FD patients based on Improvement of PDS and EPS symptoms
the guidelines of JSGE
Yamawaki et al. FD patients (Rome III) Not significant improvement of constipation
[2014]58
Nagahama et al.63 Conscious dogs Enhancement of gastric antral motility in postprandial phase
Mayanagi et al.65 FD patients FD-related symptoms
Ogishima et al.61 Guinea pig Stimulation contraction of strips of stomach (facilitation of
ACh release)
Tack et al.59 FD patients Stimulation of gastric motility by inhibiting AChE activity
Matsunaga et al.51 Conscious dogs Improvement of PDS symptoms
ACh, acetylcholine; AChE, acetylcholine esterase; EPS, epigastric pain syndrome; FD, functional dyspepsia; PDS,
postprandial distress syndrome.

the relationship between gastric motility and
treatment with acotiamide,59–61 there are no
human data to clarify the pharmacological mech-
anisms of acotiamide. Thus, it is still an unsolved
issue whether acotiamide alters gastric emptying
and gastric accommodation in patients. Recently,
in a guinea pig model, Ikeo and colleagues
demonstrated that acotiamide improved stress-
induced impaired gastric accommodation,62 and
Nagahama and colleagues reported oral adminis-
tration of acotiamide to stimulate postprandial
gastroduodenal and colonic motor activities in
conscious dogs.63
Using the 13C-acetate breath test, we have
observed that acotiamide can improve functional
dyspepsia symptoms and ameliorate impaired
gastric emptying.55 In our study, we tried to clar-
ify whether acotiamide can improve gastric emp-
tying through upregulation of acylated ghrelin
and leptin levels in patients with functional dys-
pepsia. Interestingly, we addressed that the per-
centage of improvement of the acylated ghrelin/
total ghrelin levels in patients treated with acotia-
mide was significantly higher than in patients
treated with rabeprazole alone.55 Considering
previous reports that acylated ghrelin is associ-
ated with appetite and gastric emptying,64 acylated
ghrelin levels associated with acotiamide use may
underlie the symptom amelioration and restore
gastric emptying. Seto and colleagues have
reported that acotiamide exerted an impact on
the expression of genes related to the expression
of neuromedin U, known as a stress-related neu-
ropeptide.60 Acotiamide may thus act directly on
the gut and also indirectly through the brain–gut
axis, potentially via as the effects of ghrelin in the
central nervous system.60 Further research in ani-
mal models and in humans is still needed to clar-
ify whether acotiamide can affect both gastric
accommodation and gastric emptying and to elu-
cidate the pharmacological mechanisms of its
action.
Acotiamide as an add-on therapy.  We compared the
severity of PDS and EPS symptoms in patients
treated with acotiamide and rabeprazole combina-
tion therapy compared with rabeprazole monother-
apy (Table 1). In our results, acotiamide–rabeprazole
combination therapy significantly improved both

26 journals.sagepub.com/home/taj

Table 2.  Efficiency of acotiamide and rabeprazole combination therapy for clinical symptoms for 4 weeks.
Clinical symptoms Pre-treatment
Postprandial fullness 5.98 ± 0.68
Abdominal fullness 6.22 ± 0.64
Early satiety 6.18 ± 0.46
Epigastric pain 4.50 ± 0.76
Clinical symptoms assessed by visual analogue scale (VAS scale: 0–10; 0 = absent, and 10 = maximal) acotiamide and
rabeprazole combination therapy versus rabeprazole monotherapy.
PDS- and EPS-like symptoms compared with
rabeprazole monotherapy (Table 2). These results
suggest that combination therapy can stabilize both
of EPS and PDS symptoms.
Moreover, Mayanagi and colleagues have
reported a trend towards improved symptoms
with acotiamide–esomeprazole combination
therapy, although the finding was not statisti-
cally significant (Table 1).65 In patients with epi-
gastric pain, improvement of other symptoms
such as postprandial abdominal fullness may be
gradually abrogated by EPS symptoms and, the
patients’ quality of life may worsen. Since the
majority of patients with functional dyspepsia
have comorbid gastroesophageal reflux disease
(GERD) and IBS, combination therapy with
acotiamide and PPIs such as rabeprazole may be
considered for the treatment of functional dys-
pepsia patients.
Vonoprazan, a drug with potential for repurposing
to functional dyspepsia. In Japan, a new drug,
vonoprazan, a potassium-competitive acid blocker
(P-CAB) is used for the treatment of acid-related
disease such as reflux esophagitis and gastric
ulcers. Further studies will be needed as to
whether vonoprazan can efficiently manage func-
tional dyspepsia symptoms.
Rikkunshito: a Japanese herbal medicine treat-
ment.  In Japan, herbal medicine is very popular
and covered by national health insurance. Herbal
medicine is an empirical therapeutic drug with a
long history. Although it is used widely, scientific
evidence showing clinical benefits is scarce.
Rikkunshito is a well-known medicine in herbal
agents and is prepared from eight crude herbs:
Rhizoma Atractylodis lanceae, ginseng root, Pinellia
tuber, Poria sclerotium, jujube, satsuma mandarin
peel, licorice root, and ginger. In Japan,
journals.sagepub.com/home/taj 27
H Yamawaki, S Futagami et al.
Post-treatment Versus rabeprazole
3.44 ± 0.55 p = 0.018
3.82 ± 0.64 p = 0.040
4.06 ± 0.52 p = 0.041
2.98 + 0.51 p = 0.024
Rikkunshito is commonly used for dyspeptic
symptoms (Table 3).66
An RCT conducted in Japan showed improve-
ment of epigastric symptoms for dysmotility.67
In addition, Suzuki and colleagues reported
that Rikkunshito improved symptoms of epi-
gastric pain and postprandial fullness in func-
tional dyspepsia patients based on the Rome III
criteria in multicenter trials. However, they did
not acknowledge the significant improvement
of clinical symptoms in patients on placebo
(Table 3).68
Rikkunshito has been reported to improve gastric
emptying in patients with functional dyspepsia69
and to decrease other GI symptoms such as
abdominal pain, heartburn, and abdominal dis-
tension through the improvement impairment of
expansion of proximal stomach (Table 3).70
The effects of Rikkunshito are likely to be medi-
ated via the effect on ghrelin levels. Rikkunshito
has been shown to increases ghrelin levels in
Sprague–Dawley rats treated with cisplatin,67 and
several studies have evaluated its effects on ghre-
lin levels in human studies. Moreover, Rikkunshito
increased acylated ghrelin levels in the plasma
and regulated signs of GI dysmotility such as the
delay of gastric emptying in a Sprague–Dawley
rat model.71 In animal models, Rikkunshito accel-
erates gastric emptying through antagonism of
5-HT3 receptors (Table 3).72 Harada and col-
leagues reported Rikkunshito improved acylated
ghrelin levels and impaired gastric emptying in
the urocortin 1-induced stress models.73 They
suggested supplementation of exogenous acylated
ghrelin or enhancement of endogenous acylated
ghrelin secretion by the treatment of Rikkunshito
will be effective for amelioration of functional
dyspepsia symptoms because acylated ghrelin has
a strong efficiency of GI motility. In addition,
Therapeutic Advances in Chronic Disease 9(1)

Table 3.  Efficiency of Rikkunshito in improvement for clinical symptoms and animal models.

Reference Subjects Outcomes and mechanism

Tominaga Rat Improvement of gastric emptying via the
et al.72 antagonistic action of 5-HT3 receptor
Togawa et al.75 FD patients Desacylated ghrelin level
Harada et al.73 UCNI-induced stress Improvement of UCNI-induced delayed gastric
model emptying
Tatsuta et al.69 Chronic idiopathic Improvement of gastric emptying and clinical
dyspepsia symptoms
Suzuki et al.66,68 FD patients (Rome III) Potential efficacy for the relief of FD symptoms
Takeda et al.71 Cisplatin-treated rats Improvement of cisplatin induced GI dysfunction
by ghrelin release
Arai et al.76 FD patients Improvement of dyspeptic symptoms and the
increase of acylated ghrelin
Kusunoki FD patients Improvement of gastric emptying and motility
et al.70
Mondal et al.74 Suncus murinus Gastric relaxation
by the β-adrenergic pathway & - adrenergic pathway
5-HT, 5-hydroxytryptamine; FD, functional dyspepsia; GI, gastrointestinal; UCNI, urocortin 1.

Figure 1.  Flowchart of the treatment of FD patients. FD, functional dyspepsia; H2RA, histamine type-2
receptor antagonist; Hp, Helicobacter pylori; PPI, proton pump inhibitor.

Mondal and colleagues have also reported that
Rikkunshito affected gastric relaxation in a Suncus
murinus model.74
In one study, Rikkunshito improved symptoms of
functional dyspepsia through the elevation of
deacylated ghrelin levels in H. pylori-negative
patients, and the levels of deacylated ghrelin cor-
related with the efficacy of Rikkunshito.75 In
another study that did not control for H. pylori
status, Rikkunshito also ameliorated dyspeptic
symptoms and increased acylated ghrelin levels.76
Rikkunshito has been suggested to improve
gastric emptying through 5-HT2B-mediated

28 journals.sagepub.com/home/taj

pharmacological action.67 Takeda and colleagues
also speculated that the improved gastric motility
in association with Rikkunshito use is mediated
through ghrelin activity as a GI function control-
ling peptide.
Patient-tailored treatment
Functional dyspepsia is diagnosed on the basis of
clinical symptoms and patient’s medical history;
endoscopy can exclude organic diseases such as
gastric ulcer and gastric cancer. The first-line
therapy for patients with EPS-type functional
dyspepsia includes anti-acid therapy such as PPIs,
H2-blockers and vonoprazan. First-line treatment
of PDS-type functional dyspepsia includes proki-
netic drugs such as itopride, metoclopramide and
acotiamide. If these treatments and combined
therapies are ineffective, functional dyspepsia
should be considered as treatment-resistant, and
patients should be treated with second-line thera-
pies such as antidepressants or a herbal medicine
such as Rikkunshito (Figure 1).
Conclusion
Choosing the correct treatment for functional
dyspepsia is difficult, and even though the preva-
lence of functional dyspepsia is increasing, phar-
macological therapeutic options remain limited.
Development of new drugs to treat the disorder
is, therefore, a priority.
Conflict of interest statement
The author(s) declared no potential conflicts of
interest with respect to the research, authorship,
and/or publication of this article.
Funding
The author(s) disclosed receipt of the following
financial support for the research, authorship,
and/or publication of this article: This work was
supported in part by grants from the Ministry of
Education, Culture, and Science and from the
Ministry of Health, Japan.
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