618131

research-article2015
TAG0010.1177/1756283X15618131Therapeutic Advances in GastroenterologyP Singh, SS Yoon

Therapeutic Advances in Gastroenterology Review

Nausea: a review of pathophysiology

Ther Adv Gastroenterol

2016, Vol. 9(1) 98­–112

and therapeutics DOI: 10.1177/

1756283X15618131

© The Author(s), 2015.

Reprints and permissions:
Prashant Singh, Sonia S. Yoon and Braden Kuo http://www.sagepub.co.uk/
journalsPermissions.nav

Abstract:  The sensation of nausea is a common occurrence with diverse causes and a
significant disease burden. Nausea is considered to function as a protective mechanism,
warning the organism to avoid potential toxic ingestion. Less adaptive circumstances are also
associated with nausea, including post-operative nausea, chemotherapy-induced nausea,
and motion sickness. A common definition of nausea identifies the symptom as a precursor
to the act of vomiting. The interaction, though present, does not appear to be a simple
relationship. Nausea is unfortunately the ‘neglected symptom’, with current accepted therapy
generally directed at improving gastrointestinal motility or acting to relieve emesis. Improved
understanding of the pathophysiological basis of nausea has important implications for
exploiting novel mechanisms or developing novel therapies for nausea relief.

Keywords:  autonomic nervous system, central nervous system, diagnostics, nausea,

neuroendocrine, pathogenesis, therapeutics, vomiting

Introduction addition, as nausea often coexists with vomit- Correspondence to:

Braden Kuo, MD
Nausea is a commonly encountered symptom with ing, epidemiologic data on nausea alone is Massachusetts General
a broad list of possible causes (Table 1). It has sparse. An estimated cost of $4–16 billion to the Hospital – GI Unit, 55 Fruit
Street, Blake 4, Boston,
been defined as an ‘unpleasant painless subjective US economy has been suggested being attribut- MA 02114, USA
feeling that one will imminently vomit’ [Hasler and able to nausea and vomiting [Thomas, 2000]. bkuo@partners.org
Prashant Singh, MD
Chey, 2003]. While nausea and vomiting are often Aside from the economic impact, the psycho- Division of
thought to exist on a temporal continuum, this is logical toll is also a significant factor [Thomas, Gastroenterology,
Department of Medicine,
not always the case. There are situations when 2000]. Massachusetts General
severe nausea may be present without emesis and Hospital, Boston, MA, USA
less frequently, when emesis may be present with- In population studies, more than 50% of adults Sonia S. Yoon, MD
Division of
out preceding nausea. Most individuals report that reported at least one episode of nausea, and more Gastroenterology, Weill
nausea is more common, more disabling, feels than 30% of adults reported one episode of vom- Cornell Medical College,
New York, NY, USA
worse and lasts longer than vomiting [Stern et al. iting within the preceding 12 months, with
2011]. Despite this, there is a clear understanding women reporting more episodes of nausea than
of the mechanisms underlying nausea; much of men [Rub, 1992]. In a large population based
which is about nausea concomitant with emesis. study of 62651 individuals, 12.5% of the indi-
With this in mind, the aim of this review is to viduals reported nausea as ‘minor or major com-
examine current knowledge to understand the plaint’ in the last 12 months with the prevalence
pathophysiological basis of nausea, review the of nausea being three times higher in women
diagnosis and management, and consider the evi- than in men. [Haug et al. 2002]. Similar results
dence for traditional and novel therapies. have been reported in other epidemiological
studies [Walker et al. 1992]. In addition, race has
also been shown to be associated with differential
Epidemiology rates of the experience of nausea with White/
Nausea is by definition a subjective sensation African-Americans experiencing less nausea than
which poses an inherent limitation in accurately Asian/Asian-American subjects [Stern et  al.
assessing the resultant economic burden. In 1993, 1996]

98 http://tag.sagepub.com
 P Singh, SS Yoon et al.

Table 1.  Common causes of nausea.

Medications and toxic etiologies Disorders of the gut and peritoneum
Cancer chemotherapy Mechanical obstruction
Analgesics   Gastric outlet obstruction
Cardiovascular medications   Small bowel obstruction
 Digoxin Functional gastrointestinal disorders
 Antiarrhythmics   Functional dyspepsia
 Antihypertensives   Chronic idiopathic nausea
  β-Blockers   Cyclic Vomiting Syndrome
  Calcium-channel antagonists   Idiopathic vomiting
Hormonal preparations/therapies  
  Oral antidiabetics   Non-ulcer dyspepsia
  Oral contraceptives   Irritable bowel syndrome
Antibiotics/antivirals Organic gastrointestinal disorders
 Erythromycin   Pancreatic adenocarcinoma
 Tetracycline   Peptic ulcer disease
  Sulfonamides  Cholecystitis
  Antituberculous drugs  Pancreatitis
  Acyclovir  Hepatitis
Gastrointestinal medications   Crohn’s disease
 Sulfasalazine Neuromuscular disorders of the gastrointestinal tract
 Azathioprine  Gastroperesis
Nicotine   Post-operative nausea and vomiting
CNS active   Chronic intestinal pseudo-obstruction
Narcotics CNS causes
Antiparkinsonian drugs Migraine
Anticonvulsants Increased intracranial pressure
   Malignancy
Radiation therapy  Hemorrhage
   Infarction
Ethanol abuse  Abscess
   Meningitis
Infectious causes Congenital malformation
 Gastroenteritis Hydrocephalus
  Otitis media Pseudotumor cerebri
Acute intermittent porphyria Seizure disorders
  Demyelinating disorders
Miscellaneous causes Psychiatric disease
Cardiac disease Psychogenic vomiting
Myocardial infarction Anxiety disorders
Congestive heart failure Depression
Radiofrequency ablation Pain
Starvation Eating disorders
  Labyrinthine disorders
  Motion sickness
  Labyrinthitis
  Tumors
  Meniere’s disease
  Iatrogenic
  Endocrinological and metabolic causes
  Pregnancy
  Other endocrine and metabolic
  Uremia
  Diabetic ketoacidosis
  Hyperparathyroidism
  Hypoparathyroidism
  Hyperthyroidism
  Addison’s disease

http://tag.sagepub.com 99
Therapeutic Advances in Gastroenterology 9(1)

Figure 1.  Pathogenesis of nausea.

Central and peripheral pathways involved in pathogenesis of nausea. Afferent information from various stimuli are relayed
to nucleus tractus solitarius via four pathways: vestibular and cerebellar, cerebral cortex and limbic system, area postrema
and gastrointestinal tract via vagus nerve.*
*Once any of these neural pathways are activated, it culminates into sensation of nausea with or without vomiting. The
efferent information from nucleus tractus solitarius is also responsible for activation of autonomic nervous response via
vagal pathways. Nausea is also associated with gastric dysrhythmia and release of vasopressin. However, the cause–effect
relationship of this triad is not very well understood and warrants further studying.

Chronic, unexplained nausea alone or with vom-
iting occurs less commonly but is associated with
significant comorbidity and poses a therapeutic
challenge to providers [Pasricha et al. 2011]. The
exact prevalence of chronic idiopathic nausea or
functional vomiting is not well studied and popu-
lation-based studies are needed to estimate the
disease burden.
Pathophysiology
The underlying mechanisms involved in nausea
are complex and encompass psychological states,
the central nervous system, autonomic nervous
system, gastric dysrhythmias, and the endocrine
system (Figure 1).
In order to understand the pathophysiology
underlying nausea, it is important to introduce the
concept of the dynamic threshold [Stern, 2002]. It
is proposed that each individual has a threshold
for nausea that changes minute by minute. At any
given moment, the threshold depends on the
interaction of certain inherent factors of the indi-
vidual with the more changeable psychological
states of anxiety, anticipation, expectation and
adaptation [Stern, 2002]. This dynamic interac-
tion likely explains the inter- and intra-individual
variability that is typically encountered in the face
of a nauseogenic stimulus [Stern, 2002].
Stimuli giving rise to nausea and vomiting origi-
nate from visceral, vestibular, and chemoreceptor

100 http://tag.sagepub.com

trigger zone inputs which are mediated by seroto-
nin/dopamine, histamine/acetylcholine and sero-
tonin/dopamine, respectively. These relationships
serve as the basis on which current pharmacologi-
cal therapy for nausea and vomiting is recom-
mended [Chepyala and Olden, 2008].
Central nervous system
Despite the prevalence and importance of nausea,
surprisingly little is known regarding the central
mechanisms underlying this sensation [Kowalski
et al. 2006; Napadow et al. 2013]. The neurocir-
cuitry involved in emesis is better characterized.
Associated autonomic changes which occur dur-
ing nausea and emesis (e.g. salivation, sweating)
are coordinated at the level of the medulla oblon-
gata [Hornby, 2001]. Chemosensitive receptors
detect the presence of emetic agents in the blood
and this information is relayed via the area pos-
trema to the nucleus tractus solitarius (NTS)
[Hornby, 2001]. Abdominal vagal afferents which
detect gastric tone and contents also project to
the NTS [Hornby, 2001]. Neurons from the
NTS then project to a central-pattern generator
which coordinates the various actions involved in
the act of emesis in addition to directly projecting
to neurons in the ventral medulla and hypothala-
mus, from which higher brain areas can be
reached [Hornby, 2001].
Many studies have suggested that the cerberal
cortex is also involved in pathways of nausea
[Miller, 1999; Napadow et  al. 2013]. Recent
investigations using functional magnetic reso-
nance imaging techniques in healthy adults have
shown that the medial prefrontal cortex and the
pregenual anterior cingulate cortex, areas of the
brain involved in higher cognitive function and
emotion, are positively correlated with an increase
in heart rate during nausea, suggesting the impor-
tance of cognitive and emotional centers in mod-
ulating the parasympathetic to sympathetic shift
associated with nausea [Kim et al. 2011; Napadow
et  al. 2013]. Napadow and colleagues studied
humans predisposed to motion sickness and sug-
gested that nauseogenic stimulus causes activa-
tion of amygdala, putamen and locus ceruleus
which translates into fear conditioning and emo-
tional triggering. This ultimately leads to the sen-
sation of strong nausea [Napadow et  al. 2013].
This is followed by continued, sustained activa-
tion in cortical areas such as insula, anterior cin-
gulated cortex, nucleus accumbens, orbitofrontal,
somatosensory and prefrontal cortex. These areas
http://tag.sagepub.com 101
P Singh, SS Yoon et al.
are involved in the interoceptive, limbic, soma-
tosensory and cognitive network which alerts the
suffering individual of the changes in interocep-
tive signaling so that appropriate autonomic and
motor responses are initiated in a timely manner
[Napadow et  al. 2013]. Many of these areas
involved in the nausea circuit specifically anterior
cingulate cortex, insular cortex, nucleus accum-
bens and amygdala are known to be involved in
processing of acute as well as chronic painful
stimulus [Borsook et al. 2010; Doan et al. 2015].
Furthermore, the medial prefrontal cortex, which
appears to be much more involved in chronic pain
than acute pain perception, was also found to be
a part of the nausea circuit [Baliki et  al. 2006;
Hashmi et al. 2013]. It is plausible that the brain
perceives peripheral noxious stimuli through sim-
ilar pathways, which in some cases lead to chronic
pain and in others to chronic nausea.
Understanding the central mechanisms of nau-
sea, especially chronic unexplained nausea will be
important for the development of therapies in the
treatment of chronic nausea.
Autonomic nervous system
Characteristic physiological changes (sweating,
pallor, salivation, increase in blood pressure,
tachycardia, cutaneous vasoconstriction,
decreased gastrointestinal motility) occurring
before vomiting are mediated by the autonomic
nervous system (ANS) and are well described
[Horn, 2008]. Afferent signaling arises from vagal
inputs, reflecting mechanical or chemical stimuli
[Horn, 2008, 2014]. Several studies have now
shown that increasing nausea perception is asso-
ciated with decreased parasympathetic and
increased sympathetic modulation which
accounts for majority of abovementioned symp-
toms [Muth, 2006; LaCount et al. 2011]. In addi-
tion, LaCount and colleagues have shown that
bursts of cardiovagal modulation precedes transi-
tion to a higher level of nausea, perhaps by
prompting interoceptive re-evaluation by the sub-
ject culminating in rating nausea at a higher level
[LaCount et  al. 2011]. This autonomic outflow
during nausea is likely modulated by the central
nervous system (CNS). While some areas of the
brain, such as insula appear to be modulating
both sympathetic as well as parasympathetic
response, there also appears to be a divergent
central control for autonomic response of nausea
[Sclocco et al. 2014]. Thus, ANS outflow and the
CNS network controlling it could be determinant
of overall nausea intensity, and understanding
Therapeutic Advances in Gastroenterology 9(1)
them in more detail could be of therapeutic
importance.
Endocrine. Several hormones have been studied
in the pathogenesis of nausea with the most
important being vasopressin. Increase in vaso-
pressin secretion in various emetogenic situations
is clear evidence that the rise in vasopressin level
precedes emesis, indicating that this rise does not
appear in response to volume depletion or hyper-
osmolarity. [Fisher et  al. 1982; Feldman et  al.
1988; Koch et  al. 1990; Koch, 1997]. Studies
have also reported a positive correlation between
serum vasopressin level and nausea intensity
[Page et al. 1990; Caras et al. 1997]. However, the
cause–effect relationship between nausea and
vasopressin is still not clear. Although some stud-
ies have shown that supra-physiological levels of
vasopressin can induce gastric dysrhythmias and
nausea whether this happens under normal physi-
ological circumstances is not clear [Caras et  al.
1997; Kim et al, 1997]. The precise temporal rela-
tionship between vasopressin, gastric dysrhyth-
mias and nausea should be studied in order to
give us insight into pathogenesis of acute and
chronic nausea syndromes. In addition to vaso-
pressin, corticotropin-releasing factor (CRF) has
been established as brain–gut mediator in foregut
function and can stimulate inhibitory motor
nerves in the dorsal motor nucleus of the vagus,
causing delayed gastric emptying and nausea
[Taché, 1999].
Gastric dysrhythmias
The stomach is a neuromuscular organ, the
myoelectrical activity of which can be measured
by a number of techniques including electrogas-
trography. Normal gastric myoelectrical activity
reflects the balance of the intrinsic pacemaker
activity of the stomach, smooth muscle, the
enteric nervous system, the ANS and hormone
levels [Koch, 1997]. Activity frequency slower
than the intrinsic rate is termed bradygastria; a
faster frequency is termed tachygastria. There are
numerous studies demonstrating the relationship
of nausea with the onset of dysrhythmias in indi-
viduals with motion sickness, pregnant females,
drug-induced nausea and gastroparesis [Xu et al.
1993; Hasler et  al. 1995; Coleski and Hasler,
2009; Koch, 2014]. Xu and colleagues have
shown that in individuals experiencing vection-
induced nausea, experienced tachygastria a few
minutes beforehand, suggesting a relationship
between gastric dysrhythmias and nausea [Xu
102 http://tag.sagepub.com
et al. 1993]. Interestingly, medications and inter-
ventions that promote normalization of myoelec-
trical activity from tachygastria decrease nausea,
and conversely, stimuli that decrease normal
myoelectrical activity and increase dysrhythmias
promote the sensation of nausea [Koch, 2014].
Whether activation of sympathetic nervous sys-
tem precedes onset of gastric dysrhythmias or vice
versa is not clear and needs to be studied in future
[Muth, 2006; Koch, 2014]. High amplitude, ret-
rograde persistaltic contractions of small intestine
from the distal to the proximal part on antroduo-
denal manometry has been shown to precede
vomiting episodes [Thompson and Malagelada,
1982]. However, the causal relationship between
gastric dysrhythmias or small intestinal dysmotil-
ity and nausea is not well established.
Diagnosis
Detailed history and physical exam forms the cor-
nerstone of evaluating patients with the chief
complaint of nausea. History and physical exam
help to rule out the nongastrointestinal causes of
nausea such as CNS, endocrinological and psy-
chiatric diagnoses, which might be the primary
cause or could be a contributing factor (Table 1)
[Hasler and Chey, 2003]. The mainstay of diag-
nostic evaluation of the patient with nausea and
vomiting is correcting any symptom consequences
(electrolyte abnormalities, dehydration, malnutri-
tion), identifying the cause of the symptoms and
initiating targeted therapy, and lastly, if no cause
is found, initiating therapy directed at suppress-
ing the symptoms [Hasler and Chey, 2003].
There are no well-designed, controlled trials to
guide diagnostic evaluation in patients with acute
or chronic nausea. Basic blood work, including
electrolytes, liver function tests, pancreatic
enzymes and pregnancy test (wherever applica-
ble) should be performed to help establish etiol-
ogy. If mechanical obstruction is suggested by
clinical presentation, radiological investigations
such as abdominal X-ray and abdominal CT scan
are typically the first-line investigations [Hasler
and Chey, 2003]. If mucosal diseases such as
ulcer or mass are suspected, esophagogastroduo-
denoscopy remains the most sensitive and specific
investigation to study the esophageal, gastric and
duodenal mucosa. If needed, small bowel mucosa
can be studied by small bowel follow through and
enteroclysis.
Scintigraphic measures of solid phase gastric
emptying (such as 99mTc-sulfur colloid in egg) are

commonly used to evaluate gastric motion func-
tion in suspected gastroparesis [Camilleri et  al.
2013]. Following the test for four instead of two
hours has been shown to improve accuracy in
diagnosing gastroparesis [Tougas et  al. 2000].
One should remember that these studies do not
establish cause–effect relationship in patients with
nausea. Their utility is further limited by the find-
ing that symptoms are not well correlated with
abnormalities of gastric emptying and medica-
tions to improve motility have been shown to
improve symptoms without changing emptying
delay [Hasler and Chey, 2003]. In general, most
providers would advocate an empirical trial of
antiemetic or prokinetic medications prior to spe-
cialized testing [Hasler and Chey, 2003].
Moreover, many of these patients need to be on
antiemetics to be able to tolerate these tests.
However, many of these agents, specifically pro-
kinetics, can alter gut motility. Thus, it is impor-
tant to interpret the results in the context of being
on or off medication. Investigations such as cuta-
neous electrogastrography and antroduodenal
manometry to study gastric motor functions are
not widely available, are expensive and their role
in the diagnostic algorithm of patients with
chronic nausea is not well established [Hasler and
Chey, 2003; Parkman et al. 2003]. A reduction or
decrease of expected postprandial electrogastric
amplitude has been shown to correlate with
delayed gastric emptying [Chen et  al. 1996;
Parkman et  al. 2003]. Similarly, postprandial
antral hypomotility on atroduodenal manometry
is a common finding in patients with unexplained
nausea, as well as gastroparesis, and could be
used if other tests for gastric motility are normal
in a patient with persistent symptoms despite
empirical treatment [Kerlin, 1989; Thumshirn
et  al. 1997; Quigley et  al. 2001]. It aids in the
diagnosis of motor disorders in such cases but
when normal, helps to rule out dysmotility as a
cause of nausea.
Patients with unexplained chronic nausea (even
after thorough investigation including normal
gastric emptying studies) pose a diagnostic
dilemma and they remain indistinguishable from
those with documented gastric delay with respect
to demographics, stability of symptoms over time,
healthcare utilization and health-related quality
of life [Pasricha et al. 2011]. In the absence of an
identifiable cause, Rome III criteria for functional
gastroduodenal disorders can be utilized to diag-
nose functional disorders related to nausea and
vomiting, including chronic idiopathic nausea,
http://tag.sagepub.com 103
P Singh, SS Yoon et al.
functional vomiting, cyclical vomiting syndrome
and rumination syndrome. Pasricha and col-
leagues showed that current Rome III diagnostic
criteria may be inadequate for differentiating this
group of patients, with significant overlap of diag-
noses; many patients met diagnostic criteria for
functional dyspepsia, irritable bowel syndrome
and chronic idiopathic nausea/functional vomit-
ing [Pasricha et al. 2011]. Further refinement will
be guided by evolving experience and knowledge
of this specific group of patients.
Management
A distinction should be made with respect to
management of acute versus chronic symptoms as
they are likely entirely different entities and
response to therapeutics differ between the two.
There is a paucity of literature evaluating the
pharmacological therapy of chronic, unexplained
nausea [Quigley et al. 2001]. This is likely related
to the fact that most clinically encountered epi-
sodes of nausea and vomiting are typically short
lived and self-limited [Quigley et al. 2001]. Most
of the literature is focused on those clinical situa-
tions where the risk of nausea and vomiting is
high, such as in pregnancy, the post-operative
time period, post chemotherapy, and post radia-
tion [Quigley et al. 2001]. It is important to real-
ize the inconsistent effect on the relief of nausea
compared with vomiting, with nausea being more
resistant to interventions. This finding likely
reflects the different physiology of these two dis-
tinct symptoms [Quigley et  al. 2001]. Effect of
various antiemetics on different types of nausea,
e.g. benzodiazepines for anticipatory nausea and
serotonin antagonists for chemotherapy-induced
nausea again highlights the complex pathophysi-
ology of nausea.
Current medical therapy generally falls into two cat-
egories: agents directed at suppressing nausea and
preventing vomiting (antiemetic) which typically act
centrally, and agents directed at modulating gastro-
intestinal motility (prokinetic). Commonly utilized
antiemetics are listed (Table 2).
Serotonin 5-HT3 antagonists such as granisetron
and ondansetron have utility in post-operative
vomiting, post-radiation therapy, and in prevent-
ing chemotherapy-related emesis [Hasler and
Chey, 2003]. Their mechanism of action is medi-
ated primarily though central 5-HT3 receptor
blockade (mainly in the chemoreceptor trigger
zone) and peripheral blockade of 5-HT3 receptors
Therapeutic Advances in Gastroenterology 9(1)

Table 2.  Common antiemetic agents.

Medications Typical dosage Side effects Route of administration

Anticholinergics  
 Scopolamine 0.3–0.6 mg q24 hours Tachycardia, confusion, dry mouth, SL, IV, IM, transdermal
constipation, urinary retention, blurred vision
Antihistamines  
 Meclizine 25–50 mg q24 hours Drowsiness, confusion, blurred vision, Oral
 Diphenhydramine 25–50 mg q6–8 hours constipation, urinary retention Oral, IM, IV
 Cinnarizine 25–75 mg q8 hours Oral
 Cyclizine 25–50 mg q4–6 hours Oral
 Hydroxyzine 25–100 mg q6–8 hours Oral, IM
Phenothiazines  
 Prochlorperazine 5–10 mg q6–8 hours Extrapyramidal side effects, tardive Oral, IM, IV, rectal
 Promethazine 12.5 –25 mg q4–6 hours dyskinesias, neuroleptic malignant syndrome, Oral, IM, IV, rectal
 Chlorpromazine 10–25 mg q4–6 hours hyperprolactinemia, QT prolongation Oral, IM, IV
Perphenazine 4–8 mg q8–12 hours Oral
Benzamides  
 Metoclopramide 10–20 mg q6–8 hours Sedation Oral, IM, IV
 Domperidone 10 mg q8–24 hours Anxiety Oral
Mood disturbances
Sleep disruption
Dystonic reactions
Tardive dyskinesia
Galactorrhea
Sexual dysfunction
5-HT3 antagonists  
 Ondansetron 4–8 mg q4–8 hours Headache, fatigue, Oral, IV
 Granisetron 1–2 mg q24 hours malaise, constipation Oral, IV, transdermal
 Palonosetron 0.075–0.25 mg q24 IV
hours
Cannabinoids  
 Dronabinol 2.5–10 mg q6–8 hours Palpitations, tachycardia, vasodilation/ Oral
 Nabilone 1–2 mg q8–12 hours facial flushing, euphoria, abnormal thinking, Oral
dizziness, paranoia, depersonalization,
hallucinations, visual changes
Benzodiazepines  
 Lorazepam 0.5–2 mg Ataxia, cognitive dysfunction, depression, Oral, SL, IM, IV
 Alprazolam 0.25–1 mg dizziness, drowsiness, dysarthria, fatigue, Oral
irritability, memory impairment, sedation
Corticosteroids  
 Dexamethasone 4–8 mg q4–6 hours Emotional instability, acne, bruising, Oral, IM, IV
hyperglycemia, adrenal suppression,
Cushing’s syndrome
Butyrophenones  
 Droperidol 0.625–1.25 mg q24hours QTc prolongation, orthostatic hypotension, IM, IV
extrapyramidal symptoms, CNS effects
NK-1 Receptor  
Antagonists
 Aprepitant 80–125 mg q24 hours Fatigue, constipation, hiccups Oral
SL, sublingual; IV, intravenous; IM, intramuscular; CNS, central nervous system.

on intestinal vagal and spinal afferent nerves [Bodis has increased despite the introduction of potent
et al. 1994; Hornby, 2001; Chepyala and Olden, 5-HT3 antagonists [Roscoe et al. 2000, 2000]. Its
2008]. Their effect in relieving nausea is less robust utility in other forms of nausea, such as gastropare-
and prevalence of chemotherapy-induced nausea sis and functional vomiting, is not well studied and

104 http://tag.sagepub.com

it has not been shown to be superior to metaclo-
pramide or promethazine in a double-blinded ran-
domized controlled trial in controlling nausea
symptoms in adults visiting the emergency depart-
ment. [Hasler and Chey, 2003; Barrett et al. 2011;
Camilleri et al. 2013]
Antihistamines have a therapeutic role in motion
sickness and labrynthitis and exert their antiemetic
action through central anticholinergic (M1 recep-
tor) and antihistamine (H1 receptor) effects
[Flake et  al. 2004; Chepyala and Olden, 2008].
These drugs suppress labyrinthine and vestibular
stimulation and that of the chemoreceptor zone
in the brainstem [Flake et al. 2004; Chepyala and
Olden, 2008].
Anticholinergic agents act centrally via the mus-
carinic receptors and block the pathway from the
inner ear to the brainstem and the ‘vomiting
center’ [Golding and Stott, 1997; Chepyala and
Olden, 2008]. Scopolamine is the most widely
used anticholinergic and is administered as a
transdermal patch for both prophylaxis and treat-
ment of motion sickness, but its use in other
forms of nausea are not well established [Quigley
et  al. 2001]. Selective M3 and M5 antagonist
(Zamifenacin) appears to be equally effective
implicating these two receptor subtypes [Golding
and Stott, 1997; Chepyala and Olden, 2008].
Phenothiazines are antidopaminergic agents
which act via nonselective inhibition of mainly
D2 and D3 receptors in the region of the area
postrema, but also muscarinic and H1 receptors
[Sanger and Andrews, 2006; Chepyala and
Olden, 2008]. They have demonstrated efficacy
in treating nausea related to migraine, motion
sickness and vertigo, as well as post-operative and
post-chemotherapy nausea and vomiting [Quigley
et  al. 2001]. The butyrophenone, droperidol, is
only available as a restricted use drug by the FDA,
primarily due to its effects on QT prolongation.
Its efficacy is well documented in post-operative
and chemotherapy-associated nausea and vomit-
ing and like phenothiazines, the mechanism of
action is primarily via antidopaminergic activity
in the chemoreceptor zone [Quigley et  al. 2001;
Chepyala and Olden, 2008].
Cannabinoids have been investigated in chemo-
therapy-related nausea and vomiting [Herman
et al, 1979]. They are thought to act primarily via
the cannabinoid receptor (CB1) in the ‘vomiting
center’ of the medulla and the area subpostrema
http://tag.sagepub.com 105
P Singh, SS Yoon et al.
of the NTS, although potential to modulate
5-HT3 activation in nodose ganglions and sub-
stance P release in the spinal cord could also con-
tribute to their antiemesic activity [Sanger and
Andrews, 2006; Chepyala and Olden, 2008].
Like many of the other antiemetic agents, the ant-
inausea effect of cannabinoids is not as well estab-
lished as their antiemetic effect [Sanger and
Andrews, 2006].
Benzodiazepines have been investigated as
adjunctive therapy in post-operative nausea and
small reports have shown that its use reduces
anticipatory nausea associated with chemother-
apy [Hasler and Chey, 2003; Rodola, 2006]. It is
postulated that the antiemetic mechanism of
action involves dopamine in the chemoreceptor
trigger zone [Di Florio and Goucke, 1993;
Takada et  al. 1993; Rodola, 2006]. Its primary
mode of action is via its sedative, anxiolytic, and
amnestic properties in reducing the anticipatory
component of nausea [Cooper and Gent, 2002;
Chepyala and Olden, 2008].
Corticosteroids are often used concomitantly
with 5-HT3 antagonists and other agents for
acute, as well as delayed chemotherapy-induced
nausea and vomiting. They have also been shown
to have efficacy equivalent to ondansetron and
droperidol in post-operative nausea [Apfel et  al.
2004]. The mechanism of action is unclear but
most likely involves its effect on prostaglandin
formation and inflammation [Sanger and
Andrews, 2006; Chepyala and Olden, 2008].
The role of tachykinin peptides such as substance
P in the vomiting reflex has been exploited thera-
peutically, with aprepitant, an antagonist of the
tachykinin receptor NK1. Aprepitant is FDA
approved for the prevention of both acute, as well
as delayed chemotherapy-induced nausea and
vomiting and has been showed to potentiate the
effects of 5-HT3 receptor antagonists and corti-
costeroids [Madsen and Fuglsang, 2008; Curran
and Robinson, 2009; Roila et  al. 2010]. Case
reports have demonstrated the use of aprepitant
in the treatment of gastroparesis-associated nau-
sea and vomiting with no demonstrated change in
gastric emptying [Chong and Dhatariya, 2009;
Fahler et al. 2012]. Formal investigation into the
efficacy of aprepitant in the treatment of chronic,
refractory nausea and vomiting is needed.
Prokinetic medications are listed (Table 3) and
include agents that act primarily as a prokinetic
Therapeutic Advances in Gastroenterology 9(1)

Table 3.  Prokinetic agents.

Agent Typical Dosage Side Effects Route of administration

Metoclopramide 10–20 mg q6–8 hours Sedation Oral, IM, IV
Anxiety
Mood disturbances
Sleep disruption
Dystonic reactions
Tardive dyskinesia
Galactorrhea
Sexual dysfunction
Domperidone 10mg q8–24 hours Galactorrhea/gynecomastia Oral
Sexual dysfunction
Erythromycin 250–500mg q8 hours Nausea and vomiting Oral, IV
Diarrhea
IV, intravenous; IM, intramuscular.

(e.g. erythromycin) versus those that have both
prokinetic and antiemetic properties (e.g. meto-
clopramide). Erythromycin exerts its effects via
activation of motilin receptors present on gut
smooth muscle, possibly leading to modulation of
vagal nerve pathways involved in emesis [Javid
et  al, 2013]. At low doses of 50–100 mg before
meals, it has been shown to be efficacious in con-
trolling nausea and vomiting in patients with
delayed gastric emptying. However, when used as
antibiotic at higher doses (250–500 mg, 2–4 times
a day), it induces nausea, possibly with vomiting
[Javid et  al. 2013]. At higher concentrations it
probably promotes nausea by contracting the gas-
tric fundus and thus inducing gastric dysrythmias
and prolonged, nonpropulsive hypermotility of
the antrum [Tack et al. 1992; Bruley des Varannes
et al. 1995; Coulie et al. 1998; Javid et al. 2013].
Recently, ghrelin has been shown to increase gas-
tric emptying in patients with diabetic gastropare-
sis [Murray et al. 2005]. It has also been shown to
control nausea in ferrets exposed to cisplatin; but
its effect on nausea in humans is not yet studied
[Rudd et  al. 2006]. However, it is important to
realize that nausea likely has both peripheral and
central components, and the prokinetic mecha-
nism of action is likely restricted to the periphery.
Metoclopramide and domperidone are benza-
mides with potent antiemetic and prokinetic
properties. Their mechanism of action is complex
and involves vagal and central 5-HT3 and D2
receptor antagonism with prokinetic properties
via gut dopamine receptor antagonism and
5-HT4-receptor agonist activity. They are differ-
entiated by the fact that domperidone does not
cross blood–brain barrier and is thus free of
extrapyramidal side effects which are common
with metaclopramide. Domperidone is not avail-
able in the US but metaclopramide is manufac-
tured for both oral and parenteral use. These
drugs have been shown to be efficacious in post-
chemotherapy vomiting and gastroparesis.
Clinically, the use of prokinetic agents is unfortu-
nately limited by numerous side effects, some of
which may be irreversible.
Novel therapies
Novel and nontraditional medical therapies for
nausea and vomiting have been studied (Table 4),
and include low-dose antidepressants such as
tricyclic antidepressants (TCAs). Retrospective
studies have showed moderate symptom reduc-
tion in patients with chronic nausea and vomit-
ing including cyclical vomiting syndrome in both
diabetic and non-diabetic population; however,
given lack of good prospective studies, their use
is typically reserved for those with moderate to
severe or refractory symptoms [Prakash et  al.
1998; Prakash and Clouse, 1999; Namin et  al.
2007; Sawhney et  al. 2007]. In a retrospective
study of 37 patients with chronic functional nau-
sea, 51% patients had a complete response and
an additional 33% had at least moderate symp-
toms reduction with low dose TCAs [Prakash
et  al. 1998]. TCAs such as amitriptyline have
been shown to have some benefit in functional
upper gastrointestinal symptoms such as painful
dyspepsia in patients who do not have prolonged
gastric emptying [Talley et  al. 2015]. This is
likely true for other symptoms such as chronic
nausea where TCAs are likely to benefit only
those patients without delayed gastric
emptying.

106 http://tag.sagepub.com
 P Singh, SS Yoon et al.

Table 4.  Novel and non-traditional therapies for nausea.

Agent Mechanism of action Typical dosage Side effects Route of

administration
Tricyclic Antihistaminic and 10–100 mg/day is Constipation, gastric Oral
antidepressants muscarinic activity the common range emptying delay,
Amitriptyline for most of these agitation, sedation
Nortriptyline
Doxepin
Desipramine
Imipramine
Gabapentin Mitigation of calcium 300–900 mg thrice Clumsiness, Oral
currents and daily somnolence
tachykinin in areas For sensitive
such as the area patients, consider
postrema starting at between
12.5 to 25 mg daily
Olanzapine Targets dopaminergic 5–10 mg/day Somnolence, Oral
(D1, D2, D3 and D4), postural
serotonergic (5- hypotension,
HT2A, 5-HT2C, 5-HT3, dizziness, dyspepsia,
5-HT6), histaminic restlessness, weight
and muscarinic gain and rarely
receptor extrapyramidal
symptoms

Gabapentin, a γ-aminobutyric acid analog has demonstrated symptomatic improvement after

been shown to be efficacious in preventing post-
operative nausea and vomiting in multiple rand-
omized controlled trials. (Guttuso, 2014) There
is also some use of gabapentin in preventing acute
and delayed chemotherapy-associated nausea and
vomiting, hyperemesis gravidarum, and life-
threatening refractory emesis following posterior
fossa surgery [Guttuso et  al. 2003, 2005; Ajori
et  al. 2012; Guttuso, 2014]. It is suggested that
the mechanism of action involves mitigation of
calcium currents in areas such as area postrema
[Guttuso et  al, 2003; Guttuso, 2014]. Future
studies should explore its use in patients with
chronic functional nausea vomiting.
Olanzapine is a known antagonist for dopamine
and serotonin receptors. Clinical trials have dem-
onstrated the efficacy of olanzapine in the control
of both acute and delayed chemotherapy induced
nausea and vomiting [Passik et  al 2004; Navari
et al. 2005, 2013]. In animal studies, olanzapine
has been shown to be effective for the control of
narcotic-induced nausea and sleep disturbance
associated with chronic pain [Torigoe et al. 2012].
Gastric electrical stimulation (GES) is a tech-
nique used for refractory gastroparesis. A recent
analysis of a large series at one institution
GES but a need for additional surgical proce-
dures and complications after GES implant
[Keller et  al. 2013]. Symptomatic improvement
achieved by GES in patients with gastroparesis is
best explained by activation of vagal afferent
pathways to influence CNS control mechanisms
for nausea and vomiting, accompanied by
enhanced vagal efferent autonomic function and
decreased gastric sensitivity to volume distention
which enhances postprandial gastric accommoda-
tion [McCallum et  al. 2010]. GES with short
pulses can improve gastroparesis symptoms such
as nausea and vomiting and GES with long pulses
has been shown to improve gastric motility [Lei
and Chen, 2009]. Evidence for the efficacy of
GES in patients without demonstrated gastric-
emptying delay (such as patients with functional
dyspepsia and chronic, refractory, idiopathic nau-
sea and vomiting) is evolving [Lu et al. 2013].
With respect to dietary recommendations in the
management of nausea and vomiting, a low-fat,
low-fiber diet with small frequent meals is typi-
cally recommended if patients are able to tolerate
oral intake. A short-term liquid diet in extreme
cases of patients not tolerating a solid diet is also
routinely recommended [Hasler and Chey,
2003]. For patients with chronic, unexplained

http://tag.sagepub.com 107
Therapeutic Advances in Gastroenterology 9(1)
symptoms, dietary recommendations typically
follow those routinely recommended for patients
with documented gastric emptying delay,
although there are no large, well-designed trials
evaluating this strategy.
Dietary manipulation and supplements have also
been investigated for the management of nausea
and vomiting. Ginger is a herbal supplement that
has been shown to have some efficacy in small
studies to reduce severity of post-operative nausea
and vomiting, morning sickness and motion sick-
ness [Ernst and Pittler, 2000; Keating and Chez,
2002]. Studies involving the use of ginger in pre-
vention of chemotherapy-induced nausea and
vomiting are conflicting and do not support its use
[Navari, 2013]. Its mechanism of action is largely
unknown but improvements in gastric motility,
anti-5-hydroxytryptamine activity and central
antiemetic effects have been postulated [Navari,
2013]. Rieber and colleagues investigated human
subjects, looking at the effect of acute tryptophan
depletion when subjected to a rotational proce-
dure intended to induce nausea and found that it
increased [Rieber et al. 2010]. Interestingly, acute
tryptophan depletion was also shown to slow gas-
tric emptying time in females [van Nieuwenhoven
et  al. 2004]. These findings suggest a potential
role of diet and supplements in modulating the
sensation of pain and nausea, which would be
important to pursue with further research.
Alternative and complementary approaches to
the management of nausea and vomiting include
hypnosis, acupressure and acupuncture. In a sys-
tematic review, P6 acupoint stimulation signifi-
cantly reduced nausea, vomiting and the need for
rescue medications in the post-operative setting
[Lee and Fan, 2009]. Another randomized con-
trolled trial involving 63 subjects with post-surgi-
cal gastroparesis showed that P6-acupoint
stimulation was superior to metaclopramide in
achieving complete recovery rate [Sun et  al.
2010]. Marchioro and colleagues have also shown
efficacy of hypnosis in preventing chemotherapy-
induced anticipatory nausea and vomiting in 16
patients [Marchioro et al. 2000].
In summary, acute nausea (e.g. related to chemo-
therapy) is easier to control than chronic unex-
plained nausea. Antiemetics such as
antihistaminics, antidopaminergics and 5-HT3
antagonists are often the first-line agents used for
common causes of acute nausea. Other agents
such as steroids and aprepitant are most
108 http://tag.sagepub.com
commonly used for acute and delayed phase of
chemotherapy-induced nausea. Benzodiazepines
are best suited for the anticipatory component of
post-operative or chemotherapy-induced nausea.
Chronic nausea is much more difficult to control
and poses a therapeutic challenge for most health
care providers. As discussed above, the central
pathways of chronic nausea are very close to
chronic neuropathic pain and thus therapeutic
options are also directed towards the same. The
first line therapeutic options for these patients are
neuromodulators such as TCAs, olanzapine,
gabapentin and possibly cannabinoids and benzo-
diazepines. However, if a patient is found to have
delayed gastric emptying, prokinetics are the
agents of choice. For patients with chronic nau-
sea, we recommend starting with the lowest pos-
sible dose of antinausea agents and titrating
slowly, as most of these types of patient are sensi-
tive to triggers such as food and medications,
which could worsen their symptoms.
Conclusions and future directions
In a recent comprehensive publication, nausea is
defined as ‘an unpleasant sensation of a protec-
tive mechanism elicited by the interaction of
inherent factors and changeable psychological
states’ [Stern et  al. 2011]. This definition con-
cisely encompasses our current understanding of
the interaction of diverse systems with the psy-
chological milieu in nausea. Clinically, patients
with chronic and refractory symptoms in the
absence of an identifiable cause pose a significant
challenge and should be the focus of clinical
investigation. Determining the burden of disease
by developing disease-specific quality of life ques-
tionnaires is also necessary.
Evolving understanding of the central as well as
peripheral pathophysiology underlying nausea will
be crucial for the development of novel treatment
options, whether they are new agents, novel uses of
older agents, or combination therapies. For now,
atypical agents such as TCAs, olanzapine, gabap-
entin, alternative therapies such as acupuncture
and hypnosis, and the potential role of dietary
modification hold significant promise for the future
and should be studied rigorously in clinical trials.
Funding
This research received no specific grant from any
funding agency in the public, commercial, or not-
for-profit sectors.

Conflict of interest statement
Dr Braden Kuo has received fees for serving as a
consultant for Takeda, Furiex Pharmaceuticals
and Genova Diagnostics, and received research
funding from Furiex Pharmaceuticals.
References
Ajori, L., Nazari, L., Mazloomfard, M. and Amiri, Z.
(2012) Effects of gabapentin on postoperative pain,
nausea and vomiting after abdominal hysterectomy:
a double blind randomized clinical trial. Arch Gynecol
Obstet 285: 677–682.
Apfel, C., Korttila, K., Abdalla, M., Kerger, H.,
Turan, A., Vedder, I. et al. (2004) A factorial trial of
six interventions for the prevention of postoperative
nausea and vomiting. N Engl J Med 350: 2441–2451.
Baliki, M., Chialvo, D., Geha, P., Levy, R., Harden,
R., Parrish, T. et al. (2006) Chronic pain and the
emotional brain: specific brain activity associated with
spontaneous fluctuations of intensity of chronic back
pain. J Neurosci 26: 12165–12173.
Barrett, T., DiPersio, D., Jenkins, C., Jack,
M., McCoin, N., Storrow, A. et al. (2011) A
randomized, placebo-controlled trial of ondansetron,
metoclopramide, and promethazine in adults. Am J
Emerg Med 29: 247–255.
Bodis, S., Alexander, E. III, Kooy, H. and Loeffler,
J. (1994) The prevention of radiosurgery induced
nausea and vomiting by ondansetron: evidence
of a direct effect on the central nervous system
chemoreceptor trigger zone. Surg Neurol 42: 249–252.
Borsook, D., Sava, S. and Becerra, L. The pain
imaging revolution: advancing pain into the 21st
century. (2010) Neuroscientist 16:171–185.
Bruley des Varannes, S., Parys, V., Ropert, A.,
Chayvialle, J., Rozé, C. and Galmiche, J. (1995)
Erythromycin enhances fasting and postprandial
proximal gastric tone in humans. Gastroenterology 109:
32–39.
Camilleri, M., Parkman, H., Shafi, M., Abell,
T. and Gerson, L. (2013) American College of
Gastroenterology. Clinical guideline: management of
gastroparesis. Am J Gastroenterol 108: 18–37.
Caras, S., Soykan, I., Beverly, V., Lin, Z. and
McCallum, R. (1997) The effect of intravenous
vasopressin on gastric myoelectrical activity in human
subjects. Neurogastroenterol Motil 9: 151–156.
Chen, J., Lin, Z., Pan, J. and McCallum, R. (1996)
Abnormal gastric myoelectrical activity and delayed
gastric emptying in patients with symptoms suggestive
of gastroparesis. Dig Dis Sci 41: 1538–1545.
Chepyala, P. and Olden, K. (2008) Nausea and
vomiting. Curr Treat Options Gastroenterol 11:
135–144.
http://tag.sagepub.com 109
P Singh, SS Yoon et al.
Chong, K. and Dhatariya, K. (2009) A case of
severe, refractory diabetic gastroparesis managed by
prolonged use of aprepitant. Nat Rev Endocrinol 5:
285–288.
Coleski, R. and Hasler, W. (2009) Coupling and
propagation of normal and dysrhythmic gastric slow
waves during acute hyperglycaemia in healthy humans.
Neurogastroenterology and motility 21: 492–499.
Cooper, R. and Gent, P. (2002) An overview of
chemotherapy-induced emesis highlighting the role
of lorazepam as adjuvant therapy. Int J Palliat Nurs 8:
331–335.
Coulie, B., Tack, J., Peeters, T. and Janssens, J.
(1998) Involvement of two different pathways in the
motor effects of erythromycin on the gastric antrum in
humans. Gut 43: 395–400.
Curran, M. and Robinson, D. (2009) Aprepitant:
a review of its use in the prevention of nausea and
vomiting. Drugs 69: 1853–1878.
Di Florio, T. and Goucke, R. (1993) Reduction
of dopamine release and postoperative emesis by
benzodiazepines. Br J Anaesth 71: 325.
Doan, L., Manders, T. and Wang, J. (2015)
Neuroplasticity underlying the comorbidity of pain
and depression. Neural Plast 2015: 504691.
Ernst, E. and Pittler, M. (2000) Efficacy of ginger
for nausea and vomiting: a systematic review of
randomized clinical trials. Br J Anaesth 84: 367–371.
Fahler, J., Wall, G. and Leman, B. (2012)
Gastroparesis-associated refractory nausea treated
with aprepitant. Ann Pharmacother 46: e38.
Feldman, M., Samson, W. and O’Dorisio, T.
(1988) Apomorphine-induced nausea in humans:
release of vasopressin and pancreatic polypeptide.
Gastroenterology 95: 721–726.
Fisher, R., Rentschler, R., Nelson, J., Godfrey, T. and
Wilbur, D. (1982) Elevation of plasma antidiuretic
hormones (ADH) associated with chemotherapy-
induced emesis in man. Cancer Treat Rep 66: 25–29
Flak, Z., Scalley, R. and Bailey, A. (2004) Practical
selection of antiemetics. Am Fam Physician 69:
1169–1174.
Golding, J. and Stott, J. (1997) Comparison of the
effects of a selective muscarinic receptor antagonist
and hyoscine (scopolamine) on motion sickness, skin
conductance and heart rate. Br J Clin Pharmacol 43:
633–637.
Guttuso, T. Jr (2014) Gabapentin’s anti-nausea
and anti-emetic effects: a review. Exp Brain Res 232:
2535–2539.
Guttuso, T. Jr, Roscoe, J. and Griggs, J. (2003) Effect
of gabapentin on nausea induced by chemotherapy in
patients with breast cancer. Lancet 361: 1703–1705.
Therapeutic Advances in Gastroenterology 9(1)
Guttuso, T. Jr, Vitticore, P. and Holloway, R. (2005)
Responsiveness of life-threatening refractory emesis
to gabapentin-scopolamine therapy following
posterior fossa surgery. Case report. J Neurosurg 102:
547–549.
Hashmi, J., Baliki, M., Huang, L., Baria, A., Torbey,
S., Hermann, K. et al. (2013) Shape-shifting pain:
chronification of back pain shifts brain representation
from nociceptive to emotional circuits. Brain 136:
2751–2768.
Hasler, W. and Chey, W. (2003) Nausea and
vomiting. Gastroenterology 125: 1860–1867.
Hasler, W., Soudah, H., Dulai, G. and Owyang,
C. (1995) Mediation of hyperglycemia-evoked
gastric slow-wave dysrhythmias by endogenous
prostaglandins. Gastroenterology 108: 727–736.
Haug, T., Mykletun, A. and Dahl, A. (2002) The
prevalence of nausea in the community: psychological,
social and somatic factors. Gen Hosp Psychiatry 24:
81–86.
Herman, T., Einhorn, L., Jones, S., Nagy, C.,
Chester, A., Dean, J. et al. (1979) Superiority of
nabilone over prochlorperazine as an antiemetic in
patients receiving cancer chemotherapy. N Engl J Med
300: 1295–1297.
Horn, C. (2008) Why is the neurobiology of nausea
and vomiting so important? Appetite 50: 430–434.
Horn, C. (2014) The medical implications of
gastrointestinal vagal afferent pathways in nausea and
vomiting. Curr Pharm Des 20: 2703–2712.
Hornby, P. (2001) Central neurocircuitry associated
with emesis. Am J Med 111:106S–112S.
Javid, F., Bulmer, D., Broad, J., Aziz, Q., Dukes,
G., Sanger, G. et al. (2013) Anti-emetic and emetic
effects of erythromycin in Suncus murinus: role of
vagal nerve activation, gastric motility stimulation and
motilin receptors. Eur J Pharmacol 699:48–54.
Keating, A. and Chez, R. (2002) Ginger syrup as
an antiemetic in early pregnancy. Altern Ther Health
Med.8: 89–91.
Keller, D., Parkman, H., Boucek, D., Sankineni,
A., Meilahn, J., Gaughan, J. et al. (2013) Surgical
Outcomes After Gastric Electric Stimulator Placement
for Refractory Gastroparesis. J Gastrointest Surg 17:
620–626
Kerlin, P. (1989) Postprandial antral hypomotility in
patients with idiopathic nausea and vomiting. Gut 30:
54–59.
Kim, J., Napadow, V., Kuo, B. and Barbieri, R.
(2011) A combined HRV-fMRI approach to assess
cortical control of cardiovagal modulation by motion
sickness. Conf Proc IEEE Eng Med Biol Soc 2011:
2825–2828.
110 http://tag.sagepub.com
Kim, M., Chey, W., Owyang, C. and Hasler, W.
(1997) Role of plasma vasopressin as a mediator of
nausea and gastric slow-wave dysrhythmias in motion
sickness. Am J Physiol 272: G853–G862.
Koch, K. (1997) A noxious trio: nausea, gastric
dysrhythmias and vasopressin. Neurogastroenterol Motil
9:141–142.
Koch, K. (2014) Gastric dysrhythmias: a potential
objective measure of nausea. Exp Brain Res 232:
2553–2561.
Koch, K., Summy-Long, J., Bingaman, S., Sperry,
N. and Stern, R. (1990) Vasopressin and oxytocin
responses to illusory self-motion and nausea in man
J Clin Endocrinol Metab 71:1269–1275.
Kowalski, A., Rapps, N. and Enck, P. (2006)
Functional cortical imaging of nausea and vomiting: a
possible approach. Auton Neurosci 129: 28–35.
LaCount, L., Barbieri, R., Park, K., Kim, J.,
Brown, E., Kuo, B. et al. (2011) Static and dynamic
autonomic response with increasing nausea
perception. Aviat Space Environ Med 82: 424.
Lee, A. and Fan, L. (2009) Stimulation of the wrist
acupuncture point P6 for preventing postoperative
nausea and vomiting. Cochrane Database Syst Rev
CD003281.
Lei, Y. and Chen, J. (2009) Effects of dual-pulse
gastric electrical stimulation on gastric tone and
compliance in dogs. Dig Liver Dis 41: 277–282.
Lu, P., Teich, S., Di Lorenzo, C., Skaggs, B., Alhajj,
M. and Mousa, H. (2013) Improvement of quality of
life and symptoms after gastric electrical stimulation in
children with functional dyspepsia. Neurogastroenterol
Motil 25: 567–e456.
Madsen, J. and Fuglsang, S. (2008) A randomized,
placebo-controlled, crossover, double-blind trial
of the NK1-receptor antagonist aprepitant on
gastrointestinal motor function in healthy humans.
Aliment Pharmacol Ther 27: 609–615.
Marchioro, G., Azzarello, G., Viviani, F., Barbato, F.,
Pavanetto, M., Rosetti, F. et al. (2000) Hypnosis in
the treatment of anticipatory nausea and vomiting in
patients receiving cancer chemotherapy. Oncology 59:
100–104.
McCallum, R., Dusing, R., Sarosiek, I., Cocjin,
J., Forster, J. and Lin, Z. (2010) Mechanisms of
symptomatic improvement after gastric electrical
stimulation in gastroparetic patients. Neurogastroenterol
Motil 22: 161–167.
Miller, A. (1999) Central mechanisms of vomiting.
Dig Dis Sci 44: 39S–43S.
Murray, C., Martin, N., Patterson, M., Taylor, S.,
Ghatei, M., Kamm, M. et al. (2005) Ghrelin enhances
gastric emptying in diabetic gastroparesis: a double

blind, placebo-controlled, crossover study. Gut 54:
1693–1698.
Muth, E. (2006) Motion and space sickness: intestinal
and autonomic correlates. Auton Neurosci 129: 58–66.
Namin, F., Patel, J., Lin, Z., Sarosiek, I., Foran, P.,
Esmaeili, P. et al. (2007) Clinical, psychiatric and
manometric profile of cyclic vomiting syndrome
in adults and response to tricyclic therapy.
Neurogastroenterol Motil 19: 196–202.
Napadow, V., Sheehan, J., Kim, J., Lacount, L., Park,
K., Kaptchuk, T. et al. (2013) The brain circuitry
underlying the temporal evolution of nausea in
humans. Cereb Cortex 23: 806–813.
Navari, R. (2013) Management of chemotherapy-
induced nausea and vomiting: focus on newer agents
and new uses for older agents. Drugs 73: 249–262.
Navari, R., Einhorn, L., Passik, S., Loehrer, P. Sr,
Johnson, C., Mayer, M. et al. (2005) A phase II trial
of olanzapine for the prevention of chemotherapy-
induced nausea and vomiting: a Hoosier Oncology
Group study. Support Care Cancer 13: 529–534.
Page, S., Peterson, D., Crosby, S., Ang, V., White,
A., Jenkins, J. et al. (1990) The responses of arginine
vasopressin and adrenocorticotrophin to nausea
induced by ipecacuanha. Clin Endocrinol (Oxf) 33:
761–770.
Parkman, H., Hasler, W., Barnett, J. and Eaker, E.
for the American Motility Society Clinical GI Motility
Testing Task Force (2003) Electrogastrography:
a document prepared by the gastric section of the
American Motility Society Clinical GI Motility Testing
Task Force. Neurogastroenterol Motil 15:89–102
Pasricha, P., Colvin, R., Yates, K., Hasler, W.,
Abell, T. and Unalp-Arida, A. (2011) Characteristics
of patients with chronic unexplained nausea
and vomiting and normal gastric emptying. Clin
Gastroenterol Hepatol 9: 567–576.
Passik, S., Navari, R., Jung, S., Nagy, C., Vinson, J.,
Kirsh, K. et al. (2004) A phase I trial of olanzapine
(Zyprexa) for the prevention of delayed emesis in
cancer patients: a Hoosier Oncology Group study.
Cancer Invest 22: 383–388.
Prakash, C. and Clouse, R. (1999) Cyclic vomiting
syndrome in adults: clinical features and response
to tricyclic antidepressants. Am J Gastroenterol 94:
2855–2860
Prakash, C., Lustman, P., Freedland, K. and Clouse,
R. (1998) Tricyclic antidepressants for functional
nausea and vomiting: clinical outcome in 37 patients.
Dig Dis Sci 43: 1951–1956.
Quigley, E., Hasler, W. and Parkman, H. (2001)
AGA technical review on nausea and vomiting.
Gastroenterology 120: 263–286.
http://tag.sagepub.com 111
P Singh, SS Yoon et al.
Rieber, N., Mischler, D., Schumacher, V., Muth,
E., Bischoff, S., Klosterhalfen, S. et al. (2010) Acute
tryptophan depletion increases experimental nausea
but also induces hunger in healthy female subjects.
Neurogastroenterol Motil 22: 752–757.
Rodola, F. (2006) Midazolam as an anti-emetic. Eur
Rev Med Pharmacol Sci 10: 121–126.
Roila, F., Herrstedt, J., Aapro, M., Gralla, R.,
Einhorn, L., Ballatori, E. et al. (2010) Guideline
update for MASCC and ESMO in the prevention of
chemotherapy- and radiotherapy-induced nausea and
vomiting: results of the Perugia consensus conference.
Ann Oncol 5: v232–v243.
Roscoe, J., Hickok, J. and Morrow, G. (2000) Patient
expectations as predictor of chemotherapy-induced
nausea. Ann Behav Med 22: 121–126.
Roscoe, J., Morrow, G., Hickok, J. and Stern, R.
(2000) Nausea and vomiting remain a significant
clinical problem: trends over time in controlling
chemotherapy-induced nausea and vomiting in 1413
patients treated in community clinical practices.
J Pain Symptom Manag 20: 113–121.
Rub, R., Andrews, P. and Whitehead, S. (1992)
Vomiting—incidence, causes, ageing and sex. In
Bianchi, A, Grelot, L., Miller, A. and King, G. (eds),
Mechanisms and Control of Emesis, Montrouge: John
Libbey Eurotext.
Rudd, J., Ngan, M., Wai, M., King, A., Witherington,
J., Andrews, P. et al. (2006) Anti-emetic activity of
ghrelin in ferrets exposed to the cytotoxic anti-cancer
agent cisplatin. Neurosci Lett 392: 79–83.
Sanger, G. and Andrews, P. (2006) Treatment of
nausea and vomiting: gaps in our knowledge. Auton
Neurosci 129: 3–16.
Sawhney, M., Prakash, C., Lustman, P. and Clouse,
R. (2007) Tricyclic antidepressants for chronic
vomiting in diabetic patients. Dig Dis Sci 52: 418–424.
Sclocco, R., Kim, J., Garcia, R., Sheehan, J., Beissner,
F., Bianchi, A. et al. (2014) Brain circuitry supporting
multi-organ autonomic outflow in response to nausea.
Cereb Cortex Aug 12. pii: bhu172.
Stern, R. (2002) The psychophysiology of nausea.
Acta Biol Hung 53: 589–599.
Stern, R., Hu, S., LeBlanc, R. and Koch, K. (1993)
Chinese hyper-susceptibility to vection-induced motion
sickness. Aviat Space Environ Med 64: 827–830.
Stern, R., Hu, S., Uijtdehaage, S., Muth, E., Xu, L.
and Koch, K. (1996) Asian hypersusceptibility to
motion sickness. Human Heredity 46: 7–14.
Stern, R., Koch, K. and Andrews, P. (2011) Nausea:
mechanisms and management. New York: Oxford
University Press.
Therapeutic Advances in Gastroenterology 9(1)
Sun, B., Luo, M., Wu, S., Chen, X. and Wu, M.
(2010) Acupuncture versus metoclopramide in
treatment of postoperative gastroparesis syndrome in
abdominal surgical patients: a randomized-controlled
trial. Zhong Xi Yi Jie He Xue Bao 8: 641–644.
Taché, Y. (1999) Cyclic vomiting syndrome: the
corticotropin-releasing-factor hypothesis. Dig Dis Sci
44: 79S–86S.
Tack, J., Janssens, J., Vantrappen, G., Peeters, T.,
Annese, V., Depoortere, I. et al. (1992) Effect of
erythromycin on gastric motility in controls and in
diabetic gastroparesis. Gastroenterology 103: 72–79.
Takada, K., Murai, T., Kanayama, T. and
Koshikawa, N. (1993) Effects of midazolam and
flunitrazepam on the release of dopamine from rat
striatum measured by in vivo microdialysis. Br J
Anaesthesia 70: 181–185.
Talley, N., Locke, G., Saito, Y., Almazar, A., Bouras,
E., Howden, C. et al. (2015) Effect of Amitriptyline
and Escitalopram on Functional Dyspepsia: A
Multicenter, Randomized Controlled Study.
Gastroenterology 149: 340–349.e2.
Thomas, C. (2000) The economic impact of nausea and
vomiting. In Blum, R., Heinrichs, W. and Herxheimer,
A. (eds), Nausea and Vomiting. London: Whurr.
Visit SAGE journals online
http://tag.sagepub.com
Thompson, D. and Malagelada, J. (1982) Vomiting
SAGE journals and the small intestine. Dig Dis Sci 27: 1121–1125.
112 http://tag.sagepub.com
Thumshirn, M., Bruninga, K. and Camilleri, M.
(1997) Simplifying the evaluation of postprandial
antral motor function in patients with suspected
gastroparesis. Am J Gastroenterol 92: 1496–1500.
Torigoe, K., Nakahara, K., Rahmadi, M., Yoshizawa,
K., Horiuchi, H., Hirayama, S. et al. (2012)
Usefulness of olanzapine as an adjunct to opioid
treatment and for the treatment of neuropathic pain.
Anesthesiology 116: 159–169.
Tougas, G., Eaker, E., Abell, T., Abrahamsson,
H., Boivin, M., Chen, J. et al. (2000) Assessment of
gastric emptying using a low fat meal: establishment
of international control values. Am J Gastroenterol 95:
1456–1462.
Van Nieuwenhoven, M., Valks, S., Sobczak, S.,
Riedel, W. and Brummer, R. (2004) Acute tryptophan
depletion slows gastric emptying in females. Br J Nutr
91: 351–355.
Walker, E., Katon, W., Jemelka, R. and Roy–Bryne,
P. (1992) Comorbidity of gastrointestinal complaints,
depression, and anxiety in the Epidemiologic
Catchment Area (ECA) Study. Am J Med 92:
26S–30S.
Xu, L., Koch, K., Summy–Long, J., Stern, R.,
Seaton, J., Harrison, T. et al. (1993) Hypothalamic
and gastric myoelectrical responses during vection-
induced nausea in healthy Chinese subjects. Am J
Physiol 265: E578–E584.