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com
ScienceDirect
New developments in the treatment of gastroparesis
and functional dyspepsia
Jan Tack1 and Michael Camilleri2
Functional dyspepsia (FD) and gastroparesis are frequent
causes of upper gastrointestinal symptoms such as
postprandial fullness, early satiation, epigastric pain or burning,
upper abdominal bloating, bothersome belching, nausea and
vomiting. The underlying pathophysiological mechanisms are
heterogeneous and involved mechanisms such as abnormal
gastric motility (accommodation, emptying), visceral
hypersensitivity, low grade mucosal inflammation and cellular
changes in enteric nerves, muscle or interstitial cells of Cajal.
Patient-reported outcomes for evaluating treatment efficacy in
these conditions were recently developed and validated.
Prokinetic agents, which enhance gastric motility, are used for
treating both gastroparesis and FD. In FD, besides acid
suppressive therapy and Helicobacter pylori eradication,
neuromodulators and drugs that enhance gastric
accommodation can be applied. In gastroparesis, anti-emetics
may also provide symptom relief. Novel approaches under
evaluation in these conditions are the fundus relaxing agents
acotiamide and buspirone and the antidepressant mirtazapine
in FD. For gastroparesis, recently studied agents include the
prokinetic ghrelin agonist relamorelin, the prokinetic
serotonergic agents velusetrag and prucalopride, the anti-
emetic aprepitant and per-endoscopic pyloric myotomy
procedures.
Addresses
1
TARGID, University Hospital, Leuven, Belgium
2
Mayo Clinic, Rochester, MN, USA
Corresponding author: Tack, Jan (jan.tack@kuleuven.be)
Current Opinion in Pharmacology 2018, 43:111–117
This review comes from a themed issue on Gastrointestinal
Edited by Giovanni Sarnelli and Jan Tack
https://doi.org/10.1016/j.coph.2018.08.015
1471-4892/ã 2018 Published by Elsevier Ltd.
Introduction
Functional and motility disorders of the stomach are
commonly encountered in gastroenterology clinical prac-
tice [1,2]. Patients present with upper gastrointestinal
symptoms such as postprandial fullness, early satiation,
epigastric pain or burning, upper abdominal bloating,
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bothersome belching, nausea and vomiting, and routine
diagnostic work-up for underlying structural or metabolic
disease, such as endoscopy, blood tests and radiological
examination often fail to identify a cause for the
symptoms.
Functional dyspepsia (FD) is considered a heterogeneous
condition: postprandial distress syndrome (PDS), charac-
terized by meal-related symptoms such as postprandial
fullness and early satiation, and epigastric pain syndrome
(EPS), characterized by meal-unrelated symptoms such
as epigastric pain or burning [1,2].
In patients with persisting symptoms, assessment of
motility is often the next step, most commonly measure-
ment of gastric emptying. When this is delayed, the
patient is considered as having gastroparesis, a syndrome
characterized by upper gastrointestinal symptoms includ-
ing nausea or vomiting, and delayed gastric emptying in
the absence of mechanical obstruction [3,4]. Gastropar-
esis occurs in several clinical settings, particularly as a
complication of diabetes mellitus, upper gastrointestinal
surgery, neurological disease, collagen vascular disorders,
viral infections, drugs, etc. In the majority of cases no
underlying cause is found and gastroparesis is termed
idiopathic [3,4]. This review summarizes current patho-
physiological concepts and recent progress in the treat-
ment of functional dyspepsia and gastroparesis.
Pathophysiological concepts: disordered
motility, visceral hypersensitivity and mucosal
alterations
Pathophysiological mechanisms in FD
The pathophysiology of FD is most likely heterogeneous,
with different underlying mechanisms contributing to
somewhat more specific diverse symptom patterns
[1,2] (Figure 1). Impaired gastric accommodation to a
meal, delayed gastric emptying and hypersensitivity to
gastric distention are the mechanisms classically impli-
cated in PDS [5]. Impaired gastric accommodation to a
meal is present in up to 50% of FD patients, is associated
with early satiation and weight loss, and may result in
redistribution of the meal to the distal stomach and more
rapid gastric emptying [5,6]. Visceral hypersensitivity is
present in approximately one third of FD patients and is
associated with higher intensity ratings of all epigastric
symptoms, including pain [5,7]. Visceral hypersensitivity
is supported by functional brain imaging studies or lack of
anti-nociceptive in response to gastric signals and by co-
morbid psychosocial disorders such as anxiety, depression
Current Opinion in Pharmacology 2018, 43:111–117
112 Gastrointestinal
Figure 1
1
2
7
Neuromodulators
Fundus relaxants
3 6.
Gastroprokinetics
4
Endoscopic myotomy
5
Pathophysiological mechanisms serving as (potential) therapeutic targets in functional dyspepsia and gastroparesis.
and somatization [8,9,10]. Delayed gastric emptying
occurs in up to one third of FD patients and, in some
series, has been associated with postprandial fullness,
nausea and vomiting [4,5,11].
More recently, impaired duodenal mucosal integrity, with
low-grade mucosal inflammation characterized by eosin-
ophils and mast cells, has been reported as a putative
pathophysiological mechanism in FD [1,5,12,13], con-
ceivably associated with changes in upper gastrointestinal
microbiota [14,15].
Mechanisms in gastroparesis
Cellular mechanisms
Several studies have documented loss of interstitial cells of
Cajal (ICC) and fibrosis of the muscular layers in severe
cases of diabetic gastroparesis [16,17]. Similar findings have
been reported in idiopathic gastroparesis patients, but
inflammatory cell infiltration around myenteric neurons
and neuronal loss have also been implicated [16,17]. The
triggers leading to ICC or neuronal loss are incompletely
understood. Animal models of type 1 diabetes have impli-
cated a phenotypical switch from anti-inflammatory or
alternatively activated M2 macrophages to pro-inflamma-
tory M1 or classically activated macrophages [18]. While
some human observations are consistent with such a mech-
anism [19], other data from patients with idiopathic gastro-
paresis do not support the reduction in ICCs or M2 macro-
phages, and in contrast provided evidence of reduced
electrically-coupled fibroblast like cells that are positive
for PDGFRa with no reduction in M2 macrophages [20].
Current Opinion in Pharmacology 2018, 43:111–117
Anti-emetics
1. Anxiety, depression, somatization
2. Central mechanisms of visceral
hypersensitivity
3. Peripheral mechanisms of hypersensitivity to
gastric distention
4. Impaired gastric accommodation
5. Delayed gastric emptying
Low-grade duodenal inflammation
7. Nausea/vomiting center
Current Opinion in Pharmacology
Pathophysiology
In diabetic and idiopathic gastroparesis, the correlation of
symptoms with the delay in gastric emptying is the subject
of continuing debate, with recent analysis showing the best
correlations are found in studies that use optimally mea-
sured gastric emptying for at least 3 hours by scintigraphy or
breath test [21]. Similar to FD, mechanisms such as
impaired accommodation and visceral hypersensitivity also
contribute in patients with gastroparesis [22,23].
Diagnostic considerations in patients with
upper GI symptoms
Gastroparesis may result from iatrogenic causes, including
bariatric and other gastric surgery and, more commonly,
from medications. The two most relevant drug classes are
all opioids and anti-diabetic medications such as pramlin-
tide and GLP-1 agonists (e.g. exenatide and liraglutide),
but not dipeptidyl peptidase IV inhibitors such as vilda-
gliptin and sitagliptin.
After excluding obstruction or significant mucosal dis-
eases, getting the right diagnosis for the patient’s symptoms
is an essential first step, especially because classical
symptoms of gastroparesis may result from impaired
gastric accommodation. Among 1287 patients presenting
to a tertiary care center with upper gastrointestinal symp-
toms, there was an approximately equal proportion
(25%) with delayed gastric emptying, impaired gastric
accommodation, a combination of both, or absence of
both [6]. This is consistent with a broader spectrum of
gastric neuromuscular dysfunctions that may present with
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 Treatment of gastroparesis and functional dyspepsia Tack and Camilleri 113
prominent symptoms such as early satiety and postpran-
dial fullness. This reflects the overlap of ‘gastroparesis’
with functional dyspepsia.
Impaired gastric accommodation may be recognized with
validated methods where available (SPECT and MRI), or
with screening tests such as the size of the proximal
stomach on the gastric scintigraphy scan taken immedi-
ately after radiolabeled meal ingestion, or by means of a
water load or nutrient drink test [24–29].
Endpoints for clinical trials
Functional dyspepsia
To date, there is a paucity of validated patient-reported
outcome (PRO) measures to evaluate treatment efficacy
in FD. The Leuven Postprandial Distress Scale for PDS
was validated in 2016 [30]. The content validity and
psychometric performance of a new PRO, the Functional
Dyspepsia Symptom Diary, was recently reported [31].
Next validation steps, including test–retest reliability,
sensitivity to change and determination of the minimal
clinically important difference are needed to establish
this diary as a PRO for FD studies.
Gastroparesis
There is substantial progress validating PROs for gastro-
paresis. With recent psychometric validation and respon-
siveness of two PROs in gastroparesis: the American
Neurogastroenterology and Motility Society (ANMS)
Gastroparesis Cardinal Symptom Index (GCSI) daily
diary and the Diabetic Gastroparesis Symptom Severity
Diary; these are used in ongoing clinical trials presented
to regulatory authorities [32,33].
Treatment approaches
Functional dyspepsia
Current therapeutic approaches
Guidelines recommend eradication in patients with
upper GI symptoms and negative endoscopy who are
Helicobacter pylori infected, although the therapeutic
effect is limited in size and delayed [34]. Acid suppres-
sion using PPI therapy is the traditional first-line therapy
in FD, although this may be most effective for EPS and
overlapping GERD [34,35]. Meta-analysis confirms effi-
cacy of prokinetics as a group, but very few agents are
widely available and the design and quality of studies are
extremely heterogeneous [34]. Domperidone is available
in many countries outside the United States of America,
and while there is low-quality evidence of efficacy, the
drug has been associated with QT prolongation [34].
Other prokinetics, available in selected countries include
clebopride, cinitapride, mosapride, tegaserod and ito-
pride. The evidence for their efficacy is often limited
or lacking and there may be risk for adverse events such as
pseudo-parkinsonism with drugs that have dopamine
antagonistic effects in the brain, such as clebopride or
cinitapride [36]. Although newer prokinetics have
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become available, the focus in the past years has been
on gastroparesis (see below) not FD.
Drugs that enhance accommodation
Impaired accommodation is the most commonly docu-
mented motor abnormality in FD. The anxiolytic 5-
HT1A agonist buspirone was tested in 17 patients: there
were improved FD symptoms with enhancement of
gastric accommodation without effects on anxiety to
explain symptomatic benefit. PDS symptoms and espe-
cially early satiation benefitted most from buspirone
10 mg t.i.d. treatment [37]. A multi-center 4-week study
of tandospirone, another 5-HT1A agonist, in 144 FD
patients demonstrated alleviation of epigastric pain and
discomfort, independent of changes in anxiety and
depression levels [38].
Acotiamide is a mixed presynaptic muscarinic auto-recep-
tor inhibitor and a cholinesterase inhibitor, that enhanced
both gastric contractility and accommodation in preclini-
cal models [38]. In extensive phase 2 studies in Europe,
Japan and the U.S.A., PDS symptoms were the most
responsive symptoms with 100 mg t.i.d. the optimal dose
[39]. A 4-week phase 3 study in FD patients in Japan
showed superiority of acotiamide over placebo for PDS
symptoms (early satiation, postprandial fullness, upper
abdominal bloating); acotiamide was well tolerated [40]
and safe in a one-year open label study in 207 FD patients
[41]. Mechanistic placebo-controlled studies, including
an and a scintigraphy study in 50 FD patients, showed
that acotiamide enhances gastric accommodation (in
ultrasound study in 34 FD patients) and gastric emptying
(by scintigraphy in 50 FD patients) [42,43].
Neuromodulators
In a study conducted in patients with functional dyspep-
sia, amitriptyline (tricyclic antidepressant) improved
symptoms in patients who did not have delayed gastric
emptying, and it modestly improved sleep quality. The
typical doses is 25 mg/day [44,45]. Nortryptiline was not
superior to placebo for relief of symptoms in gastroparesis
[46].
In a systematic review and meta-analysis, psychotropics
provide superior benefit to placebo in FD, particularly
tricyclic antidepressants and older antipsychotics (like
sulpiride and levosulpiride, which also have dopamine-
2 antagonistic properties) [44]. The largest neuromodu-
lator trial included 292 FD patients randomized to
8 weeks treatment with placebo, amitriptyline or escita-
lopram. Escitalopram showed no benefit while amitripty-
line improved symptoms only in the subgroup with
epigastric pain (EPS-like subgroup) or those with normal
gastric emptying [46]. It modestly improved sleep quality
[47]. The treatment response to amitriptyline was not
influenced by genetic variants in the GNb3 (825C>T) or
the serotonin reuptake transporter (5-HTT LPR genetic
Current Opinion in Pharmacology 2018, 43:111–117
114 Gastrointestinal
variants) genes, and the therapeutic effect was not
explained by effects on gastric motility, nutrient volume
tolerance or psychosocial co-morbidity [47–49].
Mirtazapine, an antidepressant with activity on diverse
neurotransmitter receptors, was efficacious in non-
depressed and non-anxious FD patients with major
weight loss [50]. In addition to increased body weight,
mirtazapine improved overall symptoms, early satiation
nausea, and nutrient volume tolerance. In a mechanistic
healthy volunteers study, mirtazapine did not signifi-
cantly affect gastric sensorimotor functions suggesting a
predominantly central mode of action [51].
Targeting gut microbiota in FD
Probiotic containing products are popular as self-manage-
ment or prescribed treatment for bowel symptoms, and
there are now early data on upper GI symptoms. In a 4-
week controlled study, 100 healthy Japanese adults with
upper gastrointestinal symptoms were randomized to
daily ingestion of a fermented milk with or without
Bifidobacterium bifidum YIT10347. The intervention did
not alter gastric emptying rate but improved postprandial
discomfort and epigastric pain, but also bowel symptoms
such as diarrhea and flatulence, making it unclear whether
symptomatic benefit can be attributed to the upper
gastrointestinal effects [52]. Another study from Japan
randomized FD patients to 12 weeks treatment with
Lactobacillus gasseri OLL2716 or placebo, with a tendency
of better symptom improvement and a higher rate of
symptom elimination (17 versus 35%, p = 0.048) in the
active group [53]. In a study from Hong Kong, H. pylori
negative FD patients were randomized to rifaximin
400 mg or placebo t.i.d. for 2 weeks and followed up
for 8 weeks. Rifaximin was well tolerated and superior
to placebo in providing adequate relief (78% versus 52%,
P = 0.02). Most responsive symptoms seemed to be belch-
ing and postprandial fullness/bloating [54]. The mecha-
nism and site of action of rifaximin in this indication
remain to be established.
Gastroparesis
Prokinetics
Both ghrelin and motilin enhance gastric emptying rate,
and agonists at the respective receptors have been devel-
oped for treatment of gastroparesis [55]. Relamorelin, an
injectable ghrelin receptor agonist (10 ug s.c. once or
twice daily), was evaluated in a placebo-controlled phase
2 study in 204 patients with diabetic gastroparesis (88%
type 2). In a pre-specified analysis in patients with active
vomiting (n = 119), twice-daily relamorelin significantly
enhanced gastric emptying and improved symptoms of
vomiting, nausea, abdominal pain, bloating, and early
satiety compared to placebo [56].
Relamorelin (10, 30 or 100 ug s.c. twice daily), was evalu-
ated in a2b study in 393 patients with diabetic
Current Opinion in Pharmacology 2018, 43:111–117
gastroparesis and active vomiting symptoms (90% type
2DM). Relamorelin significantly improved symptoms of
nausea, abdominal pain, postprandial fullness, and bloat-
ing over placebo, and also enhanced gastric emptying.
Elevated glycemia occurred dose-dependently in 15% of
patients treated with relamorelin [57].
In placebo-controlled, double-blind, randomized mecha-
nistic studies in healthy volunteers, relamorelin 30 ug s.c.
significantly enhanced the frequency of normal ampli-
tude antral contractions, without reducing gastric volumes
and nutrient volume tolerance [58] suggesting the gastro-
prokinetic effect is unlikely to interfere with gastric
accommodation. Relamorelin is currently being tested
in phase 3 trials in diabetic gastroparesis.
Prucalopride (1–2 mg/day), a 5-HT4 receptor agonist, is
approved in most countries (other than USA) for the
treatment of chronic constipation [59]. The drug accel-
erates gastric emptying and was shown in a preliminary
report to enhance gastric emptying and to relieve symp-
toms in 28 patients with idiopathic gastroparesis [60].
Velusetrag, another 5-HT4 receptor agonist, showed
symptom improvement and enhanced gastric emptying
at 5 mg dose in a 3-dose phase 2b study compared to
placebo in 232 patients with idiopathic or diabetic gastro-
paresis [61].
Anti-emetics
Aprepitant, a selective neurokinin-1 receptor antagonist
used in the treatment of chemotherapy induced nausea
and vomiting, was evaluated in a 4-week placebo-con-
trolled study in 126 patients with chronic nausea and
vomiting caused by ‘gastroparesis-like syndrome’ [62].
All patients had at least moderate symptoms of chronic
nausea and vomiting; other characteristics of the patient
cohort were delayed gastric emptying in 57%, diabetes in
29% and narcotic use in 8%. Aprepitant had no significant
effect over placebo on the primary outcome variable,
reduction in nausea with at least 25 mm on a 100 mm
VAS scale (46 versus 40%). However, aprepitant showed
significant improvement in overall, nausea and vomiting
symptom severity measured by the GCSI, but also was
associated with more frequent adverse events. Baseline
clinical characteristics did not affect the response. Sepa-
rately, effects of aprepitant on gastric sensorimotor func-
tion were evaluated in a placebo-controlled study in
24 healthy subjects. Aprepitant did not alter gastric emp-
tying, but increased gastric volumes and gastric accom-
modation and tended to increase gastric nutrient volume
tolerance [63].
In 33 gastroparesis patients seen in an emergency depart-
ment with vomiting, patients were randomized to stan-
dard treatment with or without haloperidol 5 mg i.v.
Those treated with haloperidol had significantly lower
scores for pain and nausea one hour after administration,
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 Treatment of gastroparesis and functional dyspepsia Tack and Camilleri 115
and no adverse events were reported [64]. Prolonged
usage of haloperidol or related drugs, such as chlorproma-
zine, needs to be evaluated.
Metoclopramide use is associated with a black box warn-
ing due to induction of extrapyramidal symptoms. In a
multi-center 4-week placebo-controlled trial, a new for-
mulation of metoclopramide as nasal spray 10 mg t.i.d.
was studied in 285 diabetic patients (82.5% type 2 DM)
with gastroparesis-like symptoms. Female patients had
significantly greater symptom relief (measured by GCSI)
to metoclopramide than placebo nasal spray [65]. Meto-
clopramide was generally well tolerated, although dys-
geusia, headache and dizziness occurred more frequently
than with placebo. As this trial did not require delayed
gastric emptying in history or at baseline, it remains
unclear whether the patients had gastroparesis, and fur-
ther studies with the nasal spray formulation need to
appraise risks of extrapyramidal and other CNS adverse
events.
Gastric electrical stimulation
A systematic review and meta-analysis evaluated
13 cohort series supporting evidence of benefit but 5 con-
trolled trials failed to show benefit. In addition, meta-
regression analysis showed a strong correlation between
baseline symptom severity scores and magnitude of
improvement, suggesting regression to the mean was a
major contributor to the perceived benefit [66].
Pyloric procedures
Several uncontrolled case series reported favorable
response to intra-pyloric injection of botulinum toxin
[67], but two sham-controlled trials did not support effi-
cacy of pyloric botulinum toxin injection in gastroparesis
[68,69]. Nevertheless, based on the assumption that
increased pyloric resistance contributes to the pathogen-
esis of gastroparesis, pyloric balloon distentions, intrapy-
loric botulinum toxin injections and surgical pyloroplas-
ties have been performed in gastroparesis patients [70]
and more recently, gastric peroral endoscopic myotomy
(G-POEM) has been developed as a novel treatment
approach. Case series to date suggest potential efficacy,
and a preliminary report of a systematic review and meta-
analysis was presented in support of G-POEM [71].
Summary
Research on FD and gastroparesis continues to explore
pathophysiological mechanisms and novel treatment
approaches. In FD, the research focus has shifted to
the potential of loss of mucosal integrity, low-grade
inflammation and potentially changes in microbiota in
the duodenum as emerging areas of interest. In gastro-
paresis, the role of macrophages in the loss of interstitial
cells of Cajal as a mechanism of disease is an ongoing hot
topic. We anticipate continued advances in novel treat-
ment approaches including new prokinetic agents
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(acotiamide, relamorelin), anti-emetics, psychotropics
including tricyclic agents for pain and therapies targeting
the pylorus. Jan Tack is supported by a Methusalem grant
from Leuven University.
Conflict of interest statement
Jan Tack has given Scientific advice to AlfaWassermann,
Allergan, Christian Hansen, Danone, Grünenthal, Iron-
wood, Neutec, Shire, Takeda, Theravance, Tsumura,
Zealand and Zeria pharmaceuticals and has served on
the Speaker bureau for Abbott, Allergan, Janssen, Shire,
Takeda and Zeria Michael Camilleri has given advice to
Allergan and Takeda, with no personal remuneration, and
has received research support from Allergan/Rhythm and
from Takeda.
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