INVITED REVIEW
Functional Nausea in Children

Katja Kovacic and yCarlo Di Lorenzo
ABSTRACT
Chronic nausea is a highly prevalent, bothersome, and difficult-to-treat
symptom among adolescents. When chronic nausea presents as the predomi-
nant symptom and is not associated with any underlying disease, it may be
considered a functional gastrointestinal disorder and named ‘‘functional
nausea.’’ The clinical features of functional nausea and its association with
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comorbid conditions provide clues to the underlying pathophysiological
mechanisms. These may include gastrointestinal motor and sensory disturb-
ances, autonomic imbalance, altered central nervous system pathways, or a
combination of these. This review summarizes the current knowledge on
mechanisms and treatment strategies for chronic, functional nausea in children.
Key Words: chronic nausea, cyclic vomiting syndrome, functional
gastrointestinal disorders, migraines
(JPGN 2016;62: 365–371)
C hronic nausea is a frequent complaint encountered by
pediatric gastroenterologists. It is usually described as an
unpleasant and painless sensation of imminent vomiting. It tends to
cluster with several functional gastrointestinal disorders (FGIDs)
but may also present as a primary symptom, not associated with any
demonstrable underlying disease (1). As such, it is often termed
‘‘functional nausea’’ because of the lack of diagnostic biomarkers.
The adult Rome III criteria define chronic idiopathic nausea as
occurring several times per week, typically not associated with
vomiting and without an organic cause (2). The current pediatric
Rome III criteria do not yet recognize a category for chronic nausea
despite its high prevalence in adolescents, but the Rome IV
pediatric committee is considering adding ‘‘functional nausea’’
to the next iteration of the criteria.
A recent study reported a 53% prevalence of chronic nausea
in children with pain-associated FGIDs (3). Notably, more frequent
nausea was associated with impaired social and school functioning.
Functional nausea can be highly distressing but given its subjective
nature, the absence of evidence-based guidelines for a diagnostic
workup, and the lack of proven effective treatments, it is often
neglected by medical providers. Other, more episodic FGIDs, such
as abdominal migraines and cyclic vomiting syndrome (CVS), are
also highly associated with nausea and may evolve into debilitating,
Received September 18, 2015; accepted December 8, 2015.
From the Department of Pediatrics, Division of Gastroenterology,
Hepatology, and Nutrition, Center for Pediatric Neurogastroenterology,
Motility, and Autonomic Disorders, Medical College of Wisconsin,
Milwaukee, and the yDivision of Pediatric Gastroenterology, Hepatol-
ogy, and Nutrition, Nationwide Children’s Hospital, Columbus, OH.
Address correspondence and reprint requests to Katja Kovacic, MD,
Division of Gastroenterology, Hepatology, and Nutrition, Medical
College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI
53226 (e-mail: kkovacic@mcw.edu).
The authors report no conflicts of interest.
Copyright # 2016 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0000000000001076
JPGN  Volume 62, Number 3, March 2016
Copyright 2016 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
What Is Known
 Functional nausea is common in children with func-
tional bowel disorders.
 Gastric motor disturbances including gastric empty-
ing and accommodation abnormalities commonly
present with nausea.
 Plausible mechanisms involve complex vagal neural
circuits and higher brain regions such as the limbic
system.
 Altered sensations and visceral hypersensitivity
likely play a role but mechanisms remain unclear.
What Is New
 Nauseous patients experience many comorbidi-

ties, greater symptom severity, and psychosocial
disability.
Migraines, cyclic vomiting syndrome, and autonomic
dysfunction appear closely linked to functional
nausea.
 Treatment is mainly empiric or aimed at comorbid
features.
daily chronic nausea. Nausea is also a common manifestation of
many acute and chronic medical conditions, drug or toxin effects,
gastrointestinal (GI) motility disorders, motion, autonomic or cen-
tral nervous system (CNS) pathology, and emotional arousal and
anxiety. Despite this broad prevalence, surprisingly little is known
about the pathophysiology underlying chronic nausea. This review
summarizes the current concepts and knowledge regarding the
clinical features, possible mechanisms, and available treatments
for functional nausea in children.
CLINICAL FEATURES
Genetic vulnerability and psychosocial susceptibility are
cardinal features of several FGIDs. The biopsychosocial model
for FGIDs represents a broadly accepted term that encompasses
interactions among genetic, environmental, physiologic, and psy-
chosocial factors. Patients with chronic nausea share many features
and comorbidities with other FGIDs including chronic pain, fatigue,
headaches, sleep disturbances, anxiety, and family history of
FGIDs. There is, however, increasing evidence that nauseated
patients experience more severe symptoms. A study comparing
patients with primary (likely ‘‘functional’’) chronic nausea to those
with nausea associated with functional abdominal pain found that
these comorbidities are prevalent in both groups but are present
at an even higher rate in those with primary nausea (1). This
same study found that chronic nausea is more common in white
adolescent girls and that 70% experienced anxiety. A large,
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 Kovacic and Di Lorenzo
prospective study of children with functional abdominal pain found
a 45% prevalence of nausea and noted the presence of more severe
GI and somatic symptoms, depression, low self-esteem, disability,
and family stress in subjects with nausea (4). Long-term nausea was
also linked to greater disability, anxiety, and depression. Persistent
nausea in adult patients with migraines is also more common in
white girls and linked to greater pain, disability, and depression.
Many of these features appear to be closely linked to an altered
brain-gut axis and heightened visceral sensitivity, akin to the
broadly accepted concept of FGIDs that is based on abnormal
processing of afferent signals, altered microbiota, and heightened
reactivity to both noxious and physiologic visceral signals.
PSYCHOLOGICAL COMORBIDITY
Psychological factors are known to influence digestive
symptom perception and coping strategies in FGIDs. Chronic GI
distress may also influence pathways that process sensations of
discomfort and nausea, leading to amplified perception. In irritable
bowel syndrome (IBS) there is evidence that both physical and
mental stress may increase proinflammatory cytokines through the
autonomic nervous system and hypothalamic-pituitary-adrenal axis
(5). A large community-based survey in adults found that anxiety
significantly increased the risks of nausea (6). Anxiety appears
more prevalent in adolescents with chronic nausea and nausea is
associated with long-term psychological distress and disability
(1,4). A study in adolescents with chronic nausea linked nausea
to social disability and worse school functioning (3). A morning
surge in cortisol production has been associated with anxiety
disorders and may explain the common clinical presentation of
morning nausea in adolescents, who then slowly tend improve later
in the day (3,7). It is unclear from these studies whether psycho-
logical distress is a primary or secondary manifestation of chronic
nausea in children. The disabling nature of the symptoms coupled
with frequent diagnostic uncertainty and lack of effective therapies
may account for a higher mental distress in this population.
NAUSEA AND EMETIC PATHWAYS
Nausea is historically viewed as a prodrome of emesis or as a
low-grade activation of the emetic pathway (8). The main pathways
of emesis include activation of the area postrema by circulating
Anxiety
Motion
Cerebral cortex
thalamus
limbic system
Vestibular nucleus
cerebellum
Hypothalamus
NTS
Vagal efferents
Area postrema
Blood borne
toxins and hormones
FIGURE 1. Postulated brain-gut pathways in the generation of nausea. CCK ¼ cholecystokinin; HT ¼ hydroxytryptamine; NTS ¼ nucleus tractus
solitarius.
366
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JPGN  Volume 62, Number 3, March 2016
emetogenic substances and hormones, vestibular pathways, CNS
activation, and signals through abdominal vagal afferent chemo-
and mechanoreceptors (1,9). The latter responds to changes in
tension and contractility of the gastric wall and may underlie the
sensations of functional dyspepsia, including nausea and postpran-
dial fullness (10). Signals from chemoreceptors responding to
substances (eg, serotonin, cholecystokinin, substance P) released
from enteroendocrine cells are carried by vagal afferent nerve fibers
to higher brain centers (Fig. 1) (11). The blockage of these signals
by serotonin (5-HT3) antagonists accounts for some of the effec-
tiveness of these drugs in vomiting induced by chemotherapy,
toxins, and viruses. Yet, there is limited evidence to support the
classic emetic pathways as the model for functional nausea (8,12).
Chronic functional nausea and chemotherapy-induced nausea do
not respond particularly well to standard antiemetic therapies such
as 5-HT3 antagonists (5). These clinical observations coupled with
recent neuroimaging studies point to a broader network of higher
cortical centers involved in the generation of functional nausea (13).
CENTRAL MECHANISMS
There is growing evidence that apparently distinct emetic
pathways converge to the brainstem nucleus tractus solitarius
(NTS) and from there to higher cortical regions where they evoke
the sensation of nausea. The limbic system also has inputs to the NTS
and is a plausible path to how nausea and vomiting signals influence
the autonomic nervous system. The NTS is not just a simple brainstem
relay center. It receives descending modulation signals from higher
cortical regions (hypothalamus, vestibular, and limbic systems) and is
modulated by gut hormones and various afferent inputs (8). Afferent
signals carried by the vagus nerve relay a vast amount of sensory
information from the GI tract to the brainstem dorsal vagal complex
(NTS, area postrema, and dorsal motor nucleus of the vagus) (14).
There is ample support for a major role of the vagal neurocircuitry in
the generation of nausea and vomiting. Activation of mechano- and
chemoreceptors in the GI tract initiate vagovagal reflexes (sensory
and motor vagal fibers) that carry signals to and from the CNS.
Furthermore, the integrity of the abdominal vagus nerve appears
essential for initiation of emesis (14).
A study using functional magnetic resonance imaging
evaluated the involvement of the limbic brain structures in
ANS Vagal afferents
(CCK, HT Substance P)
Accommodation
hyperalgesia
Nausea Gastric
dysrhythmias
Gastric
ANS
emptying
Hypersensitivity to
duodenal acid/lipids Constipation
“Cologastric break”
Low-grade
inflammation
Immune activation
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 JPGN  Volume 62, Number 3, March 2016
experimentally induced nausea (motion induced) (13). In that study,
transition to strong nausea caused phasic activation mainly in
brainstem and limbic brain regions known to process stress,
emotion, and fear conditioning (amygdala, ventral putamen, and
dorsal pons/locus coeruleus). Once strong nausea was experienced,
there was, however, a ‘‘sustained’’ activation in a broader network
of interoceptive, limbic, somatosensory, and cognitive regions.
There are also data indicating the presence of altered white matter
microstructure in individuals susceptible to motion-induced nausea
(15). These studies suggest that nausea is a multidimensional state
involving several higher brain structures. It is, however, unclear
whether the data based on motion-induced nausea translate to other
mechanisms of nausea.
GI pain and emetic signals transmitted to the CNS may be
amplified or attenuated depending on environment, emotions, and
internal perceptions specific to each individual. The limbic system
appears to play a key role in regulating these signals. Thus, a
complex interconnected neurocircuitry appears involved in the
input signals for nausea.
AUTONOMIC DYSFUNCTION AND MIGRAINES
The sensation of nausea is associated with physiologic corre-
lates of autonomic outflow such as diaphoresis, salivation, palpita-
tions, pallor, and stomach awareness. Multiple studies have shown
evidence for autonomic dysregulation in several FGIDs, IBS being
the most commonly studied condition (16,17). Heart rate variability
studies in motion-induced nausea also suggest altered sympathovagal
balance. Although some studies are conflicting and methodologies
differ, there is evidence for gradual sympathetic activation with
increased nausea and decreased parasympathetic tone during nausea
(18,19). Autonomic dysfunction is also well described in clinical
studies of FGIDs with chronic nausea as a frequent complaint (20,21).
In a small study, Sullivan et al described significant associations
between orthostatic intolerance and chronic GI complaints, including
nausea, and GI symptom improvement with treatment of orthostasis
(22). Retrospective data on adolescents with chronic idiopathic
nausea also noted a high cooccurrence of dizziness, fatigue,
migraines, and postural tachycardia syndrome (1).
CVS is another disorder with features of autonomic dysregu-
lation and reported autonomic abnormalities (23). It is thought to
represent a migraine variant and often evolves into either true
migraines or a chronic, debilitating nausea. These overlapping
features suggest the possibility of a primary disorder of autonomic
function in some children presenting with chronic nausea with or
without other functional bowel complaints and autonomic symptoms.
The latter may include dizziness, lightheadedness, syncope, chronic
fatigue, mental clouding, anxiety, headaches upon sitting/standing,
and more worrisome symptoms such as palpitations and shortness
of breath. Autonomic imbalance should thus always be considered in
the differential diagnosis of patients with chronic nausea.
Autonomic abnormalities are commonly found in patients
with migraine headaches, and there is a migraine subcategory termed
syncopal migraine (24). Nausea is also a cardinal feature and part of
the diagnostic criteria for migraine headaches (25). The complex
pathophysiology of migraines involves inappropriate activation of
the trigeminocervical pain system, possibly mediated by the brain-
stem (26). Nausea is highly associated with pain during migraine
attacks, but it is also a feature of the migraine prodrome, suggesting
that nausea also occur independent of pain (27). A recent neuroima-
ging study with positron emission tomography scans in migraine
patients with nausea showed activation of central medullary brain
structures including the NTS, dorsal motor nucleus of the vagus, and
the nucleus ambiguous in addition to the periaqueductal grey (28).
These same nuclei were not activated in patients with migraine
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Chronic Nausea
without nausea. Another large survey of patients with migraine
reported that frequent, persistent (>2 years) nausea is common in
migraineurs and carries twice the risk of progression to chronic
migraine compared with migraineurs without nausea (11). Nausea
in tension-type headaches is also a predictor of chronic migraines in a
population-based study (29). These observations support the concept
of centrally driven nausea in patients with comorbid migraines.
GASTRIC EMPTYING ABNORMALITIES
Nausea is one of the cardinal symptoms associated with
delayed gastric emptying. Unfortunately, nausea and other symp-
toms of gastroparesis (vomiting, early satiety, postprandial fullness,
bloating, and abdominal discomfort) are nonspecific and overlap
with other FGIDs such as functional dyspepsia. A large study in
adults with gastroparesis reported nausea as the most common
(84%) and often the most bothersome symptom, but nausea was
equally prevalent in subjects with normal gastric emptying (30). In a
smaller study of children with delayed compared with normal 4-
hour gastric emptying of a solid meal, nausea was the only symptom
linked to delayed gastric emptying (31). A larger, retrospective
study in children with gastroparesis based on 2-hour gastric empty-
ing scans found nausea to be the third most common symptom (after
vomiting and abdominal pain) (32). In younger children, there is
some evidence that vomiting is the most common clinical feature,
whereas older children with gastroparesis have more predominant
nausea and abdominal pain (33).
Nausea as a result of functional dyspepsia may be difficult to
differentiate from that associated with gastroparesis as the clinical
presentation is similar. Furthermore, an estimated 25% to 50% of
patients with functional dyspepsia have delayed gastric emptying,
and there is controversy whether these conditions are part of the same
spectrum of disorders (34,35). Nausea can also be a presentation of
rapid gastric emptying, which presents with symptoms overlapping
with gastroparesis. Two studies in adults with ‘‘symptoms of delayed
gastric emptying’’ reported rapid gastric emptying in 11% and 28% of
patients (36,37). Rapid gastric emptying is also described in adult
patients with CVS (38) and in autonomic dysfunction, with the
majority (80%) of individuals experiencing nausea (39).
Constipation may represent another plausible link between
nausea and gastric emptying abnormalities. Clinically, it is com-
monly recognized that constipated children have concurrent nausea
and dyspeptic symptoms. A Brazilian study demonstrated an associ-
ation between childhood functional fecal retention and delayed
gastric emptying based on liquid gastric emptying scans (40).
Another study of children with dyspepsia showed an association
between constipation and delayed gastric emptying based on ultra-
sound measurements of gastric emptying time (41). In this study,
laxative therapy improved both gastric emptying time and dyspeptic
symptoms. A ‘‘cologastric brake,’’ whereby colorectal impaction
stimulates reflex inhibition of gastric motor activity, is a
postulated mechanism.
OTHER GASTRIC AND DUODENAL
ABNORMALITIES
Postprandial nausea is one of the classic features of func-
tional dyspepsia. Concurrent symptoms of postprandial fullness,
early satiety, and meal-induced epigastric discomfort suggest that
the nausea may originate from gastric accommodation abnormal-
ities. The gastric accommodation reflex consists of relaxation of the
proximal stomach to accept food without an increase in gastric
pressure. Impaired proximal stomach function in response to food
ingestion is well documented through electronic barostat studies in
adults with functional dyspepsia (42). Abnormal distribution of the
gastric contents in the distal stomach is also described (43). Apart
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 Kovacic and Di Lorenzo
from gastric emptying abnormalities, there is evidence that both
structural and functional duodenal abnormalities exist in patients with
dyspepsia (35). Postprandial nausea appears to occur both during
gastric and duodenal transit of food, suggesting that the mechanism
may not solely involve poor stomach compliance (44). Other plaus-
ible mechanisms include gastric and duodenal hypersensitivity to
mechanical distention but also sensitivity to duodenal acid and
lipids as well as mucosal inflammation (35). Duodenal hypersensi-
tivity to acid has been correlated with sensation of nausea in patients
with dyspepsia (45). Lee et al (46) have demonstrated increased
duodenal acid exposure during daytime and postprandially in patients
with prominent nausea. The role of hypersensitivity to gastric dis-
tention is also well established in functional dyspepsia and may be a
factor in the sensation of nausea (47). There is increasing evidence
of low-grade inflammation with increased mast cell counts and
eosinophilia in functional bowel disorders such as IBS and func-
ional dyspepsia (48). Duodenal eosinophilia has been linked to
dyspeptic symptoms in children, with nausea being the most common
symptom (49). The mechanisms may involve immunological altera-
tions with release of mediators that increase excitability of enteric
nerves and resulting hypersensitivity to distention (50,51).
Finally, gastric myoelectrical disturbances are abnormalities
in the normal 3 cycles per minute slow wave activity of the stomach.
Gastric dysrhythmias have been recorded by electrogastrography in
subjects with autonomic dysfunction, gastroparesis, and unexplained
nausea and vomiting (52–54). Diagnostic usefulness is, however,
limited because of inconsistent correlation among electrogastro-
graphy disturbances, symptoms, and gastric emptying rates (55).
DIAGNOSIS
Based on clinical experience and retrospective data, there is
little role for extensive diagnostic evaluations in patients with
features of functional, chronic nausea (1). A thorough clinical
history and assessment of nausea characteristics such as timing,
frequency, relation to meals, and concurrent GI symptoms (pain,
bloating, postprandial fullness, early satiety, heartburn, concurrent
vomiting, stooling pattern) are essential. It is equally important to
assess comorbid symptoms such as autonomic disturbances,
migraine headaches, sleep problems, chronic fatigue, and psycho-
logical distress. A family history of functional disorders or
migraines may be supportive of functional nausea rather than
organic conditions. Alarm features such as weight loss, neurological
symptoms, severe morning vomiting/headaches, and bilious or
bloody emesis should prompt further workup. Pregnancy always
needs consideration in postpubertal girls. Allergic and inflamma-
tory conditions, celiac disease, and peptic or Helicobacter pylori
mucosal diseases deserve consideration in patients with chronic
nausea if supported by other clinical symptoms or personal/family
history. It is important to note that in the absence of clinical red
flags, endoscopy has low yield in the evaluation of patients with
chronic nausea. Nearly all (98%) of endoscopies were normal in a
larger cohort of children with chronic nausea (1). A 4-hour nuclear
medicine gastric emptying study may be justified, especially when
symptoms persists hours after meal ingestion. Comorbid symptoms
and clinical features should closely guide diagnostic workup.
TREATMENT
There are no published treatment trials on chronic nausea to
guide therapy. Treatment of functional nausea is challenging and
generally based on empiric strategies. Retrospective data suggest
little benefit of classical antiemetics such as 5-HT3 antagonists
(ondansetron) (1). Alternative therapies such as ginger, STW5, and
peppermint oil may have some efficacy for meal-related nausea. In
a systematic review, ginger 1 g daily was found more effective than
368
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JPGN  Volume 62, Number 3, March 2016
placebo for a wide variety of causes of nausea and vomiting,
including pregnancy, postoperative, and motion-induced nausea
(56). STW5 is an herbal supplement with proven efficacy in clinical
trials for functional upper GI symptoms including nausea (57). This
supplement is not yet approved for use in the United States.
Peppermint oil has shown efficacy in children with IBS (58) and
although never studied in nausea, children with nausea and dys-
peptic features may benefit from it.
Like in many other functional disorders, an interdisciplinary
approach addressing psychosocial burden is likely to represent the
most effective intervention. Educating family on the role of stress in
functional disorders, using simple analogies to explain brain-gut
connections and establishing a trustworthy relation will facilitate
treatment. After careful medical history and assessment, providing
reassurance and nonpharmacological alternatives that are unlikely
to be associated with adverse effects is often well received by
families. Early involvement of a psychologist and emphasis on
coping strategies and maintaining functioning with continued
school attendance is a primary goal. Cognitive behavioral therapy,
biofeedback, and relaxation strategies may be of great benefit.
Dietary guidance with a focus on low fat, liquid calories and more
frequent meals may help those experiencing postprandial nausea
even in the absence of gastroparesis. There is evidence that stimu-
lation of the wrist acupuncture point P6 is as effective as medi-
cations in preventing postoperative nausea and vomiting (59).
Based on the same principle, there are now several commercially
available devices that are marketed for nausea of pregnancy or
motion sickness, which may also provide benefit to adolescents
with chronic functional nausea.
Medications
Psychotropic medications such as tricyclic antidepressants
(TCAs) and selective serotonin reuptake inhibitors may be reserved
for more refractory symptoms but are frequently used in FGIDs
(Table 1). Amitriptyline is perhaps the most commonly used TCA
for a variety of FGIDs including IBS, functional abdominal pain,
abdominal migraine, and CVS. It is also a primary prophylactic
migraine drug (60) with both antimigraine and visceral analgesic
functions. Given the plausible relations of chronic nausea with these
disorders, empiric therapy with TCAs is often trialed. Retrospective
data in children with chronic nausea indicate that nearly half have
good response (>50% improvement) to amitriptyline at a mean
dose of 50 mg nightly (1). Other migraine therapies such as beta-
blockers and anti-epileptics, including topiramate and levetirace-
tam, have shown efficacy in related disorders such as CVS (61,62)
and may prove beneficial in nausea as well.
If clinical history reveals symptoms of autonomic imbalance,
nausea may be approached with several lifestyle measures. These
include aggressively increasing hydration and salt intake, regular
sleep and exercise, and carefully addressing comorbid symptom
burden. The addition of a low-dose mineralocorticoid (fludrocorti-
sone) may improve nausea as documented by Fortunato et al in 2
studies (63,64).
Cyproheptadine is another drug commonly used for FGIDs
and migraine prophylaxis (65,66). Cyproheptadine has antiseroto-
nergic and antihistamine effects and is postulated to improve gastric
accommodation in patients with functional dyspepsia (67). It also
stimulates appetite and therefore may help many patients with
chronic, meal-related nausea with dyspeptic features and weight
loss. Given the possible role of immune alterations and mast cell
activation, other antihistamine therapies may be effective. Limited
pediatric data suggest efficacy of montelukast (a leukotriene recep-
tor antagonist) in children with dyspepsia (68). Buspirone is an
anxiolytic shown to reduce symptoms in adults with dyspepsia by
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 TABLE 1. Drug therapies commonly used for FGIDs and possibly efficacious for functional nausea JPGN 

Class Drug Mechanism of action Adverse effects Indications/comments

Alternative therapies Ginger Unknown, possible 5-HT3 antagonism Heartburn, abdominal cramps Functional dyspepsia, nausea, morning sickness,

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sea sickness, CINV
STW5 (Iberogast) Unknown, possible improved gastric fundic Abdominal cramps, dizziness Herbal combination preparation, functional
relaxation dyspepsia, IBS
Peppermint oil Possible Ca2þ channel and 5-HT3 antagonism Heartburn, flushing, headaches Plant-derived, presumed antispasmodic, IBS,
functional dyspepsia
Antiemetics Ondansetron 5-HT3 antagonist Headache, QTc prolongation CINV, post-operatively, CVS
Promethazine D2-Antagonist and H1 antagonist Somnolence, tardive dyskinesia, CINV, motion/morning sickness,
anti-cholinergic effects postoperatively, migraines
Prochlorperazine D2-antagonist Migraines, CINV, postoperatively
TCAs Amitriptyline Serotonin and norepinephrine reuptake inhibitor, QTc prolongation, sedation, weight gain, IBS-D, chronic nausea, anxiety, migraines, and
antagonism of several 5-HT, NMDA and anticholinergic effects, nightmares, CVS. Start with low dose, titrate to effect.
a1-adrenergic receptors postural hypotension Consider EKG for QTc prolongation.
Volume 62, Number 3, March 2016

Imipramine and nortriptyline less constipating

Nortriptyline
Imipramine
Doxepin
SSRIs Citalopram Selective serotonin reuptake inhibitor Suicidal ideation, akathisia, nausea, Anxiety/depression, IBS, functional dyspepsia
vomiting, sexual dysfunction
Fluoxetine
Paroxetine
Anxiolytics Buspirone Presumed 5-HT1A and 5-HT2 agonist Dizziness, headache, somnolence, tremors Functional dyspepsia, small trial in adults
Tetracyclic antidepressant Mirtazapine 5-HT2, 5-HT3, H1- and a2-adrenergic antagonist Somnolence, weight gain, orthostatic Gastroparesis, anxiety
hypotension, constipation
Antimigraine Cyproheptadine 5-HT2A and H1-antagonist Somnolence, weight gain, restlessness, anti- Migraine, CVS prevention
cholinergic effects
Propranolol Nonselective beta-adrenergic blocker Bradycardia, hypotension, fatigue, insomnia, CVS and migraine prevention, contraindicated in
constipation asthma and diabetes
Topiramate Unknown, anticonvulsant Weight loss, somnolence, mental clouding Limited data in CVS, migraine prevention
Levetiracetam Anticonvulsant Somnolence, headache Limited data in CVS
Prokinetics Erythromycin Macrolide antibiotic, motilin receptor agonist QTc prolongation, torsades, seizures, Prokinetic, tachyphylaxis common with long-
abdominal pain term use
Metoclopramide D2-Antagonist, 5-HT4 agonist Irritability, dystonic and extrapyramidal Chronic use may result in tardive dyskinesia
reactions
Domperidone D2-Antagonist Headaches, serious cardiac effects Gastroparesis, need FDA exemption
Mineralocorticoid Fludrocortisone Mineralocorticoid Swelling, hypertension, headache, Autonomic dysfunction
hypokalemia
NK-1 receptor antagonist Aprepitant NK-1 antagonist Fatigue, dizziness, diarrhea CINV, gastroparesis
Cannabinoids Dronabinol CB1, CB2-receptor agonist Disorientation, hallucinations, paranoia, CINV, schedule III controlled substances
vertigo, addiction
Nabilone CB1-receptor agonist

Many of these drugs are indicated for comorbid features and used off-label for gastrointestinal symptoms. TCAs, SSRIs, and tetracyclic antidepressants have an FDA black box suicide warning.
Anticholinergic effects include dry mouth, constipation, urinary retention, blurred vision, and so on. CINV ¼ chemotherapy-induced nausea and vomiting; CVS ¼ cyclic vomiting syndrome; FDA ¼ Food
and Drug Administration; IBS ¼ irritable bowel syndrome; SSRI ¼ selective serotonin reuptake inhibitor; TCA ¼ tricyclic antidepressant.
Chronic Nausea

369

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 Kovacic and Di Lorenzo
improving gastric accommodation as measured by barostat studies
(69). Although proton-pump inhibitors are often trialed in patients
with dyspeptic features and postprandial symptoms, there is no
available data to support their use in functional nausea.
Prokinetics may improve symptoms of nausea if there is
evidence of delayed gastric emptying. Dopamine-2 receptor
antagonists such as metoclopramide and domperidone were mainstay
treatments for gastroparesis in the past. Their use has, however, been
limited more recently because of the potential for serious adverse
effects. Domperidone is currently available only in the United States
through Food and Drug Administration exemption. Erythromycin is a
motilin receptor agonist with potent prokinetic activity. Long-term
use may be limited because of the common development of tachy-
phylaxis. Furthermore, erythromycin may induce pain as it increases
gastric tone (70). Case reports of refractory nausea because of
gastroparesis suggest that agents such as mirtazapine (antiserotoner-
gic, antihistamine properties) and the neurokinin-1 receptor antagon-
ist aprepitant have potential efficacy for nausea (71,72). When nausea
is associated with gastroparesis, endoscopic injection of botulinum
toxin in the pylorus may be beneficial (73).
Cannabinoids have been studied extensively for nausea and
vomiting associated with chemotherapy (74), but their use is still
controversial because of the potential for abuse. Many states in the
United States now, however, permit medical use of cannabis (75).
Synthetic cannabinoids such as dronabinol and nabilone may have
efficacy for refractory nausea but are mainly recommended for
chemotherapy-induced nausea and vomiting and appetite stimu-
lation (76).
Finally, there is increasing evidence that gastric neuromodu-
lation with intraabdominal implantation of gastric pacemaker
improves drug-refractory gastroparesis and refractory nausea and
vomiting of unclear etiology. Although gastric emptying is not
always improved, symptom response rates between 50% and 70%
are reported (77–79). Various mechanisms including central, auto-
nomic, and/or enteric have been proposed. More long-term data are
needed to determine the effectiveness and target population for GI
neuromodulation in children.
CONCLUSIONS
Nausea is a highly prevalent, yet poorly characterized symp-
tom. The pathophysiology of functional nausea may be multi-
factorial but likely involves autonomic, central, and GI pathways
coupled with psychological comorbidity. Because of the lack of
objective biomarkers and effective therapies, the burden of disease
remains high. Future studies should attempt to characterize patients
with chronic functional nausea through both clinical and patho-
physiologic phenotyping. As underlying mechanisms are complex
and poorly understood, further studies are needed to find more
targeted and effective therapies.
Acknowledgment: The authors thank Scott Stoll for
the illustration.
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