Vol. 115 No.

5 May 2013

Review and recommendations for the prevention, management,

and treatment of postoperative and postdischarge nausea and
vomiting
Danielle Cruthirds, PhD,a Pamela J. Sims, PharmD, PhD,a and Patrick J. Louis, DDS, MDb
Samford University and University of Alabama, Birmingham, Alabama

Patients have rated severe nausea to be worse than postoperative pain. The overall incidence of postoperative
nausea and vomiting (PONV) is 25%-30% and can lead to delayed discharge and unanticipated hospital admission. After
outpatient surgery, the overall incidence of postdischarge nausea has been reported to be 17% and of vomiting 8%, higher
than nausea and vomiting reported during the procedure or recovery. Patients who experienced postdischarge nausea and
vomiting (PDNV) were unable to resume normal daily activities as quickly. This paper addresses the frequency,
pathophysiology and patient perception of PONV and PDNV and reviews antiemetics and adjunctive medications used for
the prevention, management, and treatment of PONV and PDNV. For each, the indication, mechanism of action, adverse
effects, drug interactions, and implications for oral surgery and outpatient sedation are provided. Because many antiemetics
are available for prevention, management, and treatment of PONV and PDNV, optimal medication choices are important for
each procedure and patient. (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;115:601-611)

Patients have rated severe nausea to be worse than
postoperative pain.1 The overall incidence of postoper-
ative nausea and vomiting (PONV) has been reported to
be 25%-30% and can lead to delayed discharge and
unanticipated hospital admission.2 After outpatient sur-
gical procedures, the overall incidence of postdischarge
nausea has been reported to be 17% (range 0%-55%)
and of postdischarge vomiting 8% (0%-16%), which
are higher than nausea and vomiting reported during the
procedure or recovery in the office.1,3,4 Patients who
experienced postdischarge nausea and vomiting
(PDNV) were not able to resume their normal daily
activities as quickly as those who did not.4 The present
paper examines the frequency of PONV and PDNV, the
pathophysiology of nausea and vomiting, and how
PONV and PDNV are perceived by patients, reviews
antiemetics and adjunctive medications, and discusses
current therapies in the prevention, management, and
treatment of PONV and PDNV.
PATHOPHYSIOLOGY OF POSTOPERATIVE
NAUSEA AND VOMITING
A 20%-30% incidence of PONV can be expected with
the use of intravenous sedation and general anesthesia
for oral and maxillofacial surgery procedures.5-7 By
a
Department of Pharmaceutical, Social, and Administrative Sciences,
McWhorter School of Pharmacy, Samford University.
b
Department of Oral and Maxillofacial Surgery, University of Ala-
bama.
Received for publication Apr 23, 2012; returned for revision Aug 26,
2012; accepted for publication Sep 18, 2012.
© 2013 Elsevier Inc. All rights reserved.
2212-4403/$ - see front matter
http://dx.doi.org/10.1016/j.oooo.2012.09.088
definition, nausea is described as a subjectively un-
pleasant sensation associated with awareness of the
urge to vomit, and vomiting is described as the forceful
expulsion of upper gastrointestinal contents via the
mouth brought about by the powerful sustained con-
traction of the abdominal muscles.8 Both nausea and
vomiting are responses to certain stimuli. These stimuli
can include olfactory, visual, vestibular, and psycho-
genic sources. Factors that trigger PONV include stim-
uli before, during, and after the operative procedure.9
The mechanisms leading to nausea are for the most
part unclear. They are thought to be the result of the
disruption of the normal contraction-relaxation pattern
of the stomach caused by a response to stimuli in the
higher brain centers.10,11 Associated changes include
gastrointestinal (GI) motility, GI relaxation, duodenal
retroperistalsis, decreased gastric acid secretion, in-
creased salivation, pallor, tachycardia, feelings of hot
and cold, and diaphoresis.10,11
The vomiting reflex appears to originate in the
emetic or vomiting center located in the medulla. There
are multiple sensory inputs involved in this reflex,
Statement of Clinical Relevance
Antiemetics have important and potentially serious
effects when used in combination with local anes-
thesia, conscious sedation, or other postoperative
medications. This comprehensive review seeks to
improve clinicians’ knowledge regarding postoper-
ative and postdischarge nausea and vomiting to
inform and guide treatment.

601
ORAL AND MAXILLOFACIAL SURGERY
602 Cruthirds, Sims, and Louis
including the vagus nerve (cranial nerve X), the ves-
tibular nerve (cranial nerve VIII), the limbic system,
and the chemoreceptor trigger zone (CRTZ).9 The va-
gus nerve relays sensory input, primarily thru serotonin,
from the mechanoreceptors and chemoreceptors in the
GI tract, respiratory tract, and cardiovascular system.
The vestibular nerve relays input from the auditory
labyrinth, with the primary neurotransmitters being his-
tamine and acetylcholine. The limbic system appears to
play a role in the learned response of anticipatory
nausea and vomiting.12 The CRTZ is exposed to blood
and cerebrospinal fluid and, therefore, can react to
substances in the blood. Several neurotransmitters and
neuromodulators trigger this area, including serotonin,
dopamine, histamine, acetylcholine, substance P, and
adrenaline.13 The CRTZ identifies harmful substances
and relays this to the vomiting center (VC). The VC
then activates the efferent motor pathways initiating the
vomiting response.10,14 Metabolic factors that are me-
diated by the vomiting center and CRTZ include ure-
mia, diabetes mellitus (hypo- or hyperglycemia), elec-
trolyte disturbances (sodium, potassium), hormonal
imbalances (estrogen, progesterone), and pregnancy.
Sensory stimulation includes tactile stimulation of the
posterior pharynx as well as stretching, inflammation,
or injury to the airway. The vomiting cascade is com-
plex and includes multiple steps. The cascade continues
until the stimulus is no longer present.10
NAUSEA AND VOMITING AFTER OFFICE-
BASED ANESTHESIA
In recent years, office-based anesthesia has been used
more frequently as well as being applicable to more
complex cases. Complications associated with office-
based anesthesia include vomiting during induction
(0.1%) or in the recovery room (0.3%), laryngospasm
or bronchospasm (0.3%), cardiac arrhythmias (0.1%),
syncope (0.1%), prolonged recovery (0.2%), and pe-
ripheral vascular injury (0.1%).16
Although the rates of these complications are low,
patients rate severe nausea as worse than postoperative
pain.1 This specific complication can delay discharge
and is one of the leading causes of unexpected hospital
admission after planned ambulatory surgery.17 A 2002
review showed an incidence of 17% for nausea (range
0%-55%) and 8% for vomiting (range 0%-16%) after
outpatient surgery.15 Of those that did not experience
PONV while in the hospital, almost one-half experi-
enced it on day 1-3 after procedure. This further com-
plicates the management of PONV because its occur-
rence is usually not witnessed by the care team.15 Many
surgeons continue to view PONV as a minor compli-
cation that poses little threat to the patient.18 In con-
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May 2013
trast, patients view this complication as being more
debilitating than the operation itself.15
ANTIEMETICS IN ORAL AND
MAXILLOFACIAL SURGERY
Activation of the VC or the sensation of nausea may
result from the stimulation of the CRTZ, the vestibular
apparatus, visceral afferent inputs, and cortical inputs.
At least 3 nerves and 7 neurotransmitters are involved,
making prophylaxis and treatment complex.19 An im-
portant stimulus for PONV in oral or maxillofacial
surgery is the effect of swallowed blood in the stom-
ach.19 Blood in the stomach is one of the strongest
peripheral-acting emetogenic stimuli and is difficult to
treat by antiemetic medication alone.20,21 Perioperative
suctioning of the oral cavity to remove secretions and
blood before the patient swallows is important. Two
procedures commonly performed by Oral and Maxill-
ofacial Surgeons during a surgery conducted under
general anesthesia that help decrease blood from the
oral cavity entering the stomach include placement of
an oropharyngeal pack and placement of a nasogastric
tube to suction the stomach contents at the completion
of surgery. Accumulation of blood in the stomach often
results in nausea and vomiting and must be removed to
obtain complete relief.20,21
There are currently 2 schools of thought regarding
the management of PONV: prophylactic antiemetic
treatment and symptomatic treatment.18 Complications
such as aspiration of vomitus and asphyxia have often
been cited to justify use of prophylaxis. In general,
universal prophylaxis is not warranted.22,23 Nonphar-
macologic strategies to reduce the baseline risk should
first be considered.19 Reducing or avoiding opioids in
patients that are at high risk for nausea and vomiting is
an important strategy.19 Opioids can increase the risk of
PONV through several mechanisms: direct stimulation
of the area postrema, decrease in GI motility with
prolongation of gastric emptying time, and sensitization
of the otic and vestibular areas to motion.2,9 Patient
movement after surgery with stimulation of endolymph
in the inner ear appears to increase the frequency of
opioid-induced emesis.2 Patients receiving very large
doses of opioids during general anesthesia have a lower
incidence of PONV compared with patients undergoing
outpatient surgery who receive significantly lower
doses of opioids.24 More frequent changes in body
position that occur in the ambulatory patient increase
the frequency of opioid-induced emesis.2,24 PONV in
outpatients often occurs after movement from chair to
standing, after ambulation, or during the car ride
home.25 These dose-related effects may last for up to 6
hours after opioid administration.25 Nitrous oxide
(N2O) can cause PONV by direct central nervous sys-
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Volume 115, Number 5
tem (CNS) stimulation of the VC and interaction with
opioid receptors, and by stimulation of the sympathetic
nervous system and peripheral pathways. When N2O is
combined with opioids, the incidence of PONV has
been shown to increase in high risk patients.1,9,15,16 A
multimodal analgesic regimen should be used to mini-
mize opioid dose requirements.9,15,16
Because only 25%-30% of surgical patients experi-
ence PONV, not all patients require antiemetic prophy-
laxis.15 Patient-, anesthesia-, and surgery-related risk
factors for PONV should be evaluated to identify pa-
tients who may benefit from prophylactic antiemetics.19
RISK FACTORS
The easiest and most effective mode of determining a
patient’s risk of PONV is to determine their individual
patient risk assessment score. Apfel et al. recently de-
veloped a simplified risk-scoring system that appears to
be predictive for PONV. The score consists of 4 pre-
dictors: female gender, history of motion sickness
and/or PONV, nonsmoking, and use of postoperative
opioids. When 0, 1, 2, 3, or 4 of these risk factors were
present, the incidence of PONV was 10%, 21%, 39%,
61%, and 79%, respectively. Patient risk of PONV can
manifest from three main factors: preoperative, intra-
operative, and postoperative.9,15,18,26,27
Preoperative factors
Age. In adults, there is a correlation between increas-
ing age and decreasing incidence of PONV. PONV is
more common in children after the age of 3 years, with
a peak incidence in the 11–14-year-old age group.9
Gender. Until puberty, the incidence of PONV ap-
pears to be equal between male and female patients.
After puberty, female patients are 2-3 times more likely
to experience PONV, with incidences also being more
severe.9
Hormonal balance. For female patients, procedures
that occur closer to the menstrual cycle have an in-
creased risk of PONV.9
Weight. Morbidly obese patients (⬎2 times their
ideal body weight) have a higher incidence of PONV
after long procedures (⬎3 h) than nonobese patients.
This is thought to be related to the longer time required
to clear anesthetics from the body because of the affin-
ity of adipose tissue for the agents used in anesthesia.9
Gastric contents. A full stomach increases the risk of
nausea and vomiting during both induction and recov-
ery.9 Aspiration of gastric contents is an important
concern.28 Solid food increases the risk of PONV by
distending the gut and by the release of GI hormones
that can sensitize the vomiting reflex.29 It is appropriate
to fast from intake of clear liquids ⱖ2 hours before
elective procedures requiring moderate sedation, deep
REVIEW ARTICLE
Cruthirds, Sims, and Louis 603
sedation, or general anesthesia.30 It is appropriate to
fast from intake of a light meal or nonhuman milk ⱖ6
hours before elective procedures requiring general an-
esthesia, regional anesthesia, or sedation/analgesia.30
The American Society of Anesthesiologists Task Force
notes that intake of fried or fatty foods or meat may
prolong gastric emptying time. Additional fasting time
(e.g., ⱖ8 h) is needed in such cases.30 Both the amount
and the type of food ingested must be considered when
determining an appropriate fasting period.30
Prior history. There is a 3-fold increase in the inci-
dence of PONV in patients who have a history of
PONV or motion sickness.9
Intraoperative factors
Type of operation. Surgery of the mouth, throat, ton-
sils and adenoids carry a higher than normal risk due to
the swallowing of blood which is a strong stimulus for
vomiting.9
Duration of operation. The greater the duration of
the operation, the higher the risk of PONV. This is due
to the increased amount of anesthesia required as well
as the increased clearance time of the various agents
used for anesthesia.9
Type of anesthesia. The type of anesthesia used has
a definite influence on the risk of PONV. The following
scheme can be utilized: general anesthesia ⬎ regional
blocks. Opioids carry the highest risk for PONV. Spe-
cifically, opioids used for premedication carry a greater
risk than benzodiazepine use. In addition, etomidate,
methohexitone, ketamine and thiopentone carry a
higher risk than propofol use.9
Postoperative factors
Pain. Postoperative pain is a major cause of PONV.
Intravenous (IV)–administered opiates have been
shown to relieve both pain and nausea in patients who
have pain with nausea.9
Hypotension. Orthostatic hypotension secondary to
dehydration may further contribute to PONV. Opioid
analgesics, owing to their vasodilating effects, and phe-
nothiazine antiemetics, owing to their blockade of
␣-adrenergic receptors in the peripheral vasculature,
can contribute to this hypotension.9
Dehydration. Children are particularly susceptible to
PONV contributed to by dehydration.9
Opioid analgesia. Opioids given for analgesia have a
strong emetic effect.9
Oral intake.9
TRADITIONAL ANTIEMETIC INTERVENTIONS
The different classes of antiemetic agents commonly
used for PONV include anticholinergics, antihista-
mines, phenothiazines, sedatives/anxiolytics, butyro-
ORAL AND MAXILLOFACIAL SURGERY
604 Cruthirds, Sims, and Louis
phenones, dopamine antagonists, serotonin receptor an-
tagonists, and corticosteroids, alone or in combination.
Drugs that may be effective prophylactic medication
for PONV may be ineffective for the treatment of active
vomiting. The various antiemetic medications currently
available exhibit different binding affinities for and act
at different emetic neuroreceptors in the area postrema,
CRTZ, nucleus of the solitary tract, and VC. Therefore,
no single antiemetic medication has been 100% effec-
tive for all patients. Although it is best to begin with a
single agent in nausea that is difficult to control or treat,
combination therapy has been proven to be more effi-
cacious than monotherapy. In the case of combination
therapy, drugs from different classes should be chosen
to optimize effects.1,2,9,15,16,19,26,31
Anticholinergics
Anticholinergic drugs block the action of acetylcholine
on the parasympathetic nervous system. Most anticho-
linergic drugs interact with muscarinic cholinergic re-
ceptors in the brain, secretory glands, heart, and smooth
muscle and are also called antimuscarinic agents.32
Belladonna alkaloids (atropine, scopolamine) are well
absorbed from the GI tract, whereas quaternary anti-
cholinergics (glycopyrolate) are poorly absorbed when
administered orally.33 Parasympathetic response is ab-
sent or decreased depending on the number of receptors
blocked by anticholinergic drugs and the underlying
degree of parasympathetic activity. Because cholin-
ergic muscarinic receptors are widely distributed in the
body, anticholinergic drugs produce effects in a variety
of locations, including the CNS, heart, smooth muscle,
secretory glands, and eye.2 Some anticholinergics are
administered before surgery to help in relaxation and to
decrease secretions such as saliva.2,9,15,26,31
Dimenhydrinate (Dramamine) is a commonly used
anticholinergic in the treatment of motion sickness.
Benefit is due to the high concentration of H1 and
muscarinic cholinergic receptors in the vestibular sys-
tem. Use is contraindicated in children under the age of
2 years.34
Scopolamine can be given the preceding evening or
just before surgery.9,31 It is a tropane alkaloid drug with
muscarinic antagonist effects.2,31 Specifically, it is a
competitive antagonist of M1 receptors. Scopolamine
displays long-term activity of up to 72 hours.2,35
Anticholinergics are more effective in treating mo-
tion sickness than PONV.2 If anticholinergic agents are
used perioperatively to reduce saliva, they may assist in
reducing postoperative vomiting more than nausea.2 If
used concurrently with opioids, such as morphine, that
possess emetic properties of a longer duration than the
antiemetic properties of scopolamine, delayed PONV
may occur.2 To assist with the delayed PONV, the
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May 2013
application of the transdermal delivery system (TDS) of
scopolamine the night before surgery provides drug
administration for up to 3 days.2 The potential disad-
vantages of the use of anticholinergics include sedation,
blurred vision, mydriasis, dry mouth, memory loss,
urinary retention, hallucinations, confusion, and disori-
entation.26,31 These effects can be additive with the an-
ticholinergic effects of the opioids.2,16 The sedative
effects of an anticholinergic agent such as scopolamine
may be beneficial in enhancing sedation during the
procedure.24
Indications in sedation. The recommended dose of
scopolamine for PONV prevention is 0.3-0.6 mg intra-
muscular (IM), IV, or subcutaneous. Scopolamine has
also been used as a 1.5 mg TDS that is placed behind
the ear and usually left in place for 1-3 days. In 2010,
Apfel published a systematic review and meta-analysis
on the use of scopolamine TDS.36 Scopolamine TDS
was associated with a significantly reduced risk for
PONV during the first 24 hours after the start of anes-
thesia and was effective compared with placebo in the
prevention of PONV when treatment was initiated the
night before (early application) or on the day of surgery
(late application).36 However, scopolamine TDS was
associated with a higher prevalence of visual distur-
bances at 24-48 hours compared with placebo.36 Owing
to the low incidence of adverse events and no signifi-
cant increase in recovery time, the scopolamine TDS is
recommended alone or in combination with other drugs
such as ondansetron for prevention of PONV.37 In
addition, it has the added benefit of enhancing sedation
and decreasing salivation.
Antihistamines
Hydroxyzine (Vistaril, Atarax) is a diphenylethane
derivative categorized as a first-generation pipera-
zine.24,38 It is an H1 receptor inverse agonist with
sedative, antiemetic, anticholinergic, and bronchodilat-
ing properties.24,38,39 The duration of action is 4-6
hours, with minimal circulatory and/or respiratory de-
pressant effects.38,39 In doses up to 1.5 mg/kg, IV
hydroxyzine caused no decrease but rather a significant
increase in PaO2 and no increase in PaCO2 and/or pH
for up to 60 minutes after administration.40 The seda-
tive, antisialogogic, and antiemetic effects of hy-
droxyzine make it a good premedication when given in
combination with opioids to supplement their analgesic
effect.39 Hydroxyzine is further beneficial in that it
lacks both antagonism and synergy with benzodiaz-
epines and scopolamine, allowing either of the two
agents to be used simultaneously or later in the proce-
dure as needed. IM hydroxyzine (100 mg) was shown
to decrease the incidence of PONV more effectively
than IM droperidol (2.5 mg).39 When given orally, it is
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Volume 115, Number 5
rapidly absorbed, with an onset of action of 30 minutes
and the peak concentration and maximal clinical effec-
tiveness in 2 hours.24,38 Hydroxyzine is metabolized in
the liver to the active metabolite cetrizine.33,38 The
half-life of hydroxyzine is ⬃16 hours and is prolonged
with age.38 Administration in the elderly differs from
administration in younger patients with consideration
given to possible reduced elimination. When adminis-
tered concurrently with other sedative drugs, such as
opioids, the dose should be reduced.33
Indications in sedation. Hydroxyzine can be used for
longer procedures in oral sedation as a single agent or
in combination with benzodiazepines and/or opioids. It
can also be used as a premedication or to prolong the
duration of sedation and reduce PONV during intrave-
nous sedation techniques. There is currently no IV
preparation, so it must be administered via an oral or
IM route. Use in oral sedation in combination with
midazolam has been shown to be more efficacious than
midazolam alone.41
Cyclizine, primarily used for motion sickness,33 has
effectiveness similar to promethazine in preventing and
treating PONV caused by opioids.2 Its primary mech-
anism of action is not completely understood, but it
may have direct effects on the labyrinthine apparatus
and the CRTZ.33 It exerts a central anticholinergic
action.38 The overall incidence of adverse effects is less
frequent with cyclizine compared with the phenothia-
zine antiemetics, and excess sedation is the most fre-
quent adverse effect of cyclizine.42,43
Indications in sedation. Cyclizine is available as an
over-the-counter preparation in an oral form and typi-
cally is not used in oral and parental sedation tech-
niques. Because the drug is not available in a parenteral
form, this prevents its use in parenteral sedation tech-
niques. It can be used to potentiate sedation and to
prevent or manage PONV.
Dopamine receptor antagonists
The phenothiazines (promethazine, prochlorperazine),
benzamides (metoclopramide, trimethobenzamide),
and butyrophenones (droperidol) are strong D2 antag-
onists.2
Phenothiazines encompass the largest of the 5 main
classes of neuroleptic antipsychotic drugs. Phenothia-
zines are classified into 3 groups that differ regarding
the substituent on nitrogen. These include aliphatic
compounds, which contain acyclic groups, piperidines,
which contain piperidine-derived groups, and pipera-
zines, which contain piperazine-derived groups.38 His-
torically, phenothiazines (promethazine, prochlorpera-
zine) have been among the most widely used antiemetic
medications.2 The phenothiazines exert a direct D2
receptor blocking effect in the CRTZ, with moderate
REVIEW ARTICLE
Cruthirds, Sims, and Louis 605
antihistaminic and anticholinergic actions, and are es-
pecially effective in countering the effects of opioids on
the CRTZ.2 They have no effect on gastric emptying.44
These drugs have ␣-adrenergic blocking activity and
can cause profound hypotension when epinephrine is
administered.45
Promethazine (Phenergan) is an aliphatic phenothia-
zine sometimes used at induction of anesthesia.33 Pro-
methazine is an effective prophylactic antiemetic with
more sedation and a more prolonged recovery period
than prochlorperazine.2,26 It is a first-generation H1
receptor antagonist competitively blocking histamine
H1 receptors without blocking the secretion of hista-
mine.38 Promethazine also acts as a moderate musca-
rinic acethylcholine antagonist.38 It displays strong se-
dation and moderate to strong extrapyramidal side
effects with moderate autonomic effects.38 Prometha-
zine has a half-life of 16-19 hours.46 In April 2006, the
U.S. Food and Drug Administration (FDA) alerted pre-
scribers that promethazine should not be used for chil-
dren ⬍2 years old, because of the potential for fatal
respiratory depression. The FDA further stated that
caution should also be exercised when administering
promethazine in any form to pediatric patients ⱖ2 years
old.33,47 In addition, in 2009 the FDA required a boxed
warning for promethazine injection to better communi-
cate the risks of severe tissue injury associated with IV
administration of this drug.33,48
Indication in sedation. Promethazine has both strong
antiemetic and sedative effects. It is available in oral
and parenteral preparations and can be used as an
adjunct medication in oral and parenteral sedation tech-
niques. It can also be used to decrease the incidence and
improve the management of PONV. It is not recom-
mended in pediatric patients ⬍2 years old and should
be used with caution in sedation techniques in any age
group, especially pediatric and geriatric patients. Ow-
ing to the potential for adverse events, the drug should
be used with caution as a prophylactic agent in a patient
consider at high risk for PONV. When it is used to treat
PONV, studies have shown that a dose of 6.25 mg in
the adult is as effective as higher doses.49,50 In patients
who have failed PONV prophylaxis with ondansetron,
the use of promethazine was significantly more effec-
tive than a repeated dose of ondansetron for the treat-
ment of established PONV.49
Prochlorperazine (Compazine) is a piperazine phe-
nothiazine which blocks D2 receptors. After IM injec-
tion, antiemetic action is evident within 30-60 minutes
and lasts for 3-4 hours.51 Oral administration results in
a slower onset of action but a longer duration of action
(6 h).51 It is effective for low to moderate nausea and
can be administered both before and after surgery.2
Prochlorperazine displays weak autonomic effects and
ORAL AND MAXILLOFACIAL SURGERY
606 Cruthirds, Sims, and Louis
moderate sedation. It has a higher incidence of extrapy-
ramidal symptoms (EPS), including akathesia (motor
restlessness), acute dystonia (spasmodic contractures
producing trismis, torticollis, opisthotonos, and oculo-
gyric crisis), pseudoparkinsonism, and tardive dyskine-
sia.33,42,43,52,53 Higher doses of this drug display in-
creased effectiveness, but use is dose limiting because
of side effects, which can include hypotension, restless-
ness, and sedation.33 Hypersensitivities to this drug can
occur, and there is cross-reactivity with other drugs in
this class.54
Indication in sedation. Prochlorperazine is available
in oral, rectal suppository, and injectable dosage forms
and is generally not used in sedation techniques, owing
to the potential for adverse side effects.
Anticholinergic adverse effects of the phenothiazines
include dry mouth, urinary retention, tachycardia and
drowsiness.2 Furthermore, the phenothiazines block
␣-adrenergic receptors causing hypotension.33 When
combined with opioids, the sedative, anticholinergic
and hypotensive effects of phenothiazines are at least
additive if not synergistic with the sedating, respiratory
depressant, anticholinergic and vasodilating effects of
opioid analgesics.2
Because phenothiazines block ␣-adrenergic recep-
tors (␣-blockers),33 they can prevent the vasoconstric-
tion desired from the agents commonly found in com-
bination with local anesthetics used in dental
procedures.45 The vasoconstrictors are present to con-
fine the local anesthetic to the region around the site of
injection, which reduces systemic effects and prolongs
the duration of action. In addition, the vasoconstrictor
reduces bleeding. As a result of the phenothiazine-
induced ␣-adrenergic blockade, the ␤-adrenergic ef-
fects of the vasoconstrictors predominate, resulting in
the potential for hypotension and reflex tachycardia.45
Furthermore, the phenothiazine reversal of vasocon-
striction can reduce the duration of effect of the local
anesthetic.45
Benzamides
Metoclopramide (Reglan) serves as an antiemetic ow-
ing to antagonism of D2 receptors in the CRTZ in the
CNS, the GI tract, and area postrema VCs.55 This
prevents nausea and vomiting triggered by most stim-
uli. It also possesses mixed 5-HT3 receptor antagonism
and 5-HT4 receptor agonism.55 At higher doses, 5-HT3
antagonist activity may contribute to its antiemetic ac-
tivity. Metoclopramide is unrelated to the phenothia-
zines and has no antihistaminic properties. As an anti-
emetic, metoclopramide is not overly effective. It is
normally reserved for patients at low emetic risk. Its
most common use is in adjunct therapy with opioids to
prevent PONV that results from opioid use.56,57 It in-
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May 2013
creases lower esophageal sphincter tone and promotes
gastric emptying, which may prevent the delayed gas-
tric emptying caused by opioid analgesics.55-57 Meto-
clopramide has a short duration of action (1-2 h) and
therefore may not be effective for PONV when admin-
istered before a procedure.33,56 However, it promotes
gastric emptying during the procedure, which reduces
the potential for accumulation of swallowed blood in
the stomach.33,56,57 To provide adequate plasma con-
centrations for antiemetic effectiveness, metoclopra-
mide is best administered at the end of surgery, and it
has a better antiemetic efficacy in the immediate post-
operative period when administered to patients taking
opioids for postoperative pain.2 Metoclopramide can be
given IV or IM near the end of surgery and by mouth
every 4-6 hours as needed.2 An oral disintegrating
tablet (ODT) is available. This dosage form dissolves
on the tongue and has a faster onset of action than the
oral swallowed tablet.33 Metoclopramide has relatively
few adverse effects when used in low doses and does
not affect hemodynamic stability.58 Metoclopramide
has a number of important drug interactions, so a com-
plete medication list should be reviewed before admin-
istration.33,55,59
Indication in sedation. Metoclopramide can be used
as a premedication to prevent PONV. Owing to its short
duration of action, it may be best used for short proce-
dures or near the end of longer procedures.2 As an
alternative, the ODT form can be used as an adjunctive
medication in the management of PONV. Some studies
have shown that ondansetron has a better effect than
metoclopramide for preventing PONV.60,61
Trimethobenzamide (Tigan), is considered to be a
substituted benzamide similar to metoclopramide and
thus is a dopamine antagonist with possible weak
5-HT3 effects.62 Trimethobenzamide is thought to have
effects on the CRTZ, although its specific mechanism
of action is unknown.33 Side effects can include drows-
iness, dizziness, headache, diarrhea, muscle cramps,
and blurred vision.33 Trimethobenzamide can be given
orally or by IM injection and has a mean half-life of 7-9
hours.33 Dose adjustment should be considered in the
elderly as well as those with renal impairment.63
Indication in sedation. Trimethobenzamide is avail-
able in an oral and a parenteral preparation. There is
very little published on this drug for the management of
PONV, and much of that literature is old.64-67 This
makes it difficult to draw definite conclusions with
modern outpatient anesthetic techniques. Some recent
studies show that it may be useful when managing
patients with movement disorders.68 Owing to few side
effects, it may be a good choice in the prevention and
management of PONV. This may be particularly useful
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Volume 115, Number 5
as an alternative to promethazine in the elderly and
patients with Parkinson disease.68
Butyrophenones
The butyrophenone droperidol has a pharmacologic and
antiemetic profile similar to phenothiazines.2 Droperidol
is a strong D2 receptor antagonist that acts at the CRTZ
and area postrema.2 The onset of antiemetic action for
droperidol is slower than that of prochlorperazine, but the
duration of effect is longer (as long as 24 h after admin-
istration).58 Droperidol is an ␣-blocker, with adverse ef-
fects of hypotension, an anticholinergic, with adverse ef-
fects of sedation, and a dopamine antagonist, with adverse
EPS.2 Furthermore, droperidol can cause QT interval pro-
longation. Droperidol should be used with caution as an
antiemetic for management of PONV.69
Indication in sedation. In the outpatient setting, care
must be taken in the choice of antiemetics. Owing to
reported side effects, droperidol is used with caution for
the management or prevention of PONV in the office-
based setting. Its use, however, has been shown to be
efficacious. In a study that combined 5-HT3 receptor
antagonists with droperidol or dexamethasone for
PONV, there was no difference in antiemetic efficacy
between the 2 combinations. The incidence of com-
monly reported side effects was also similar in the 2
combination groups.70 In a placebo-controlled study,
ondansetron (4 mg), droperidol (0.625 mg), and dro-
peridol (1.25 mg) were compared in 2,061 adult surgi-
cal outpatients at high risk for PONV. Droperidol was
more effective than either ondansetron or droperidol in
the 0 –24-hour period. There were no significant differ-
ences among the treatment groups in the total number
of patients reporting ⱖ1 adverse event. Headache was
the most frequent neurologic complication, and its in-
cidence was significantly lower in the droperidol
groups compared with the ondansetron group. There
were no significant differences among the treatment
groups regarding the incidence of hypotension, seda-
tion, or agitation/anxiety.71 Although droperidol is a
cheaper alternative, ondansetron has been shown to
prevent vomiting more effectively in children.19
As with phenothiazines, droperidol blocks ␣-adren-
ergic receptors (␣-blocker),33 and can prevent the va-
soconstriction desired from the agents commonly found
in combination with local anesthetics used in dental
procedures.45 As stated above, vasoconstrictors are
present to confine the local anesthetic to the region
around the site of injection, which reduces systemic
effects and prolongs the duration of action. In addition,
the vasoconstrictor reduces bleeding. As a result of the
droperidol-induced ␣-adrenergic blockade, the ␤-ad-
renergic effects of the vasoconstrictors will predomi-
nate, resulting in the potential for hypotension and
REVIEW ARTICLE
Cruthirds, Sims, and Louis 607
reflex tachycardia.45 Furthermore, the droperidol rever-
sal of vasoconstriction can reduce the duration of effect
of the local anesthetic.25
Serotonin receptor antagonists
The serotonin 5-HT3 receptor is highly specific and
selective for nausea and vomiting.2,72 5-HT3 receptor
antagonists alone or in combination with other agents
are the most commonly used protocols for PONV.26
These agents selectively block 5-HT3 receptors in the
periphery and brain (CRTZ).19 Stimulation of the
5-HT3 receptors has been shown to initiate the vomiting
reflex.19 Peripheral 5-HT3 receptors are located in vagal
nerve terminals, which are linked to the VC via the
nucleus tractus solitaries.19 These drugs can block the
initiation of the vomiting reflex caused by emetogenic
stimuli.19 The antivomiting effect is greater than the
antinausea effect with this class of drugs. They com-
pare favorably with other antiemetics.2,26
Although initially developed for the treatment of
chemotherapy- and radiotherapy-induced nausea and
vomiting, ondansetron (Zofran) was the first 5-HT3
receptor antagonist evaluated and approved for
PONV.5 Ondansetron administered at a dose of 4 mg
IV at the end of surgery was found to be effective in
preventing PONV and preventing opioid-induced
PONV.26,73-78 Although other 5-HT3 receptor antago-
nists are available, including dolasetron, ondansetron
has the lowest adverse effect profile.2 Compared with
phenothiazines, sedation and EPS are not typically
seen.2 The cost of 5-HT3 receptor antagonists is higher
than that of phenothiazines, but the safety profile is
much better and the adverse effect profile much lower.6
Unlike phenothiazines, the 5-HT3 receptor antagonists
do not reduce the effectiveness of vasoconstrictors used
with local anesthesia or cause the associated drug in-
teractions.2 As a result, they are cost-effective for pro-
phylaxis in high-risk patients. Use of these agents has
been shown to result in a relative risk reduction of
20%-30% and to improve the control of nausea and
vomiting into the second and third days after surgery.19
Efficacy is similar to droperidol or dexamethasone for
the prevention of vomiting in adults, and their favorable
side effect profile has made them a popular choice for
adults and children.2 Although of less importance with
ondansetron than other 5-HT3 receptor antagonists,
ondansetron may be less effective in patients with in-
creased cytochrome P450 2D6 activity owing to in-
creased metabolism of the drug; therefore, for these
patients, doses may need to be higher.19 Ondansetron is
available as an oral tablet, ODT, or oral film and for IV
administration. The IV route of administration (ROA)
requires smaller doses than the oral (swallowed) ROA
because the IV ROA bypasses the liver and the first
ORAL AND MAXILLOFACIAL SURGERY OOOO
608 Cruthirds, Sims, and Louis May 2013

Table I. Primary indication and important dental considerations of antiemetics

Class Primary indication Important dental considerations
Anticholinergics Motion sickness, vertigo Xerostomia, additive anticholinergic effects with opioids
Dimenhydrinate (Dramamine) Paradoxic reactions
Scopolamine
Antihistamines
Hydroxyzine (Vistaril, Atarax) Anxiolytic Safest agent for prevention of anxiety-associated nausea and vomiting
Cyclizine Vertigo Xerostomia; additive anticholinergic effects with opioids
Phenothiazines Nausea and vomiting High incidence of adverse drug effects, hypotension, and respiratory
depression, additive with opioids; risk of extrapyramidal side
effects; caution in patients with dystonia; block desired effect of
vasoconstrictors used in local anesthesia
Promethazine (Phenergan) More sedating, longer acting
Prochlorperazine (Compazine)
Butyrophenones Nausea and vomiting Similar to phenothiazines; risk of QT interval prolongation
Droperidol Can be used with caution
Benzamides Few adverse side effects
Metoclopramide (Reglan) Gastric-emptying agent
Trimethobenzamide (Tigan) Nausea and vomiting Least expensive and safest agent for preventing and treating nausea
and vomiting
Serotonin receptor antagonists (5-HT3 Nausea and vomiting
receptor antagonists)
Ondansetron (Zofran) Most expensive, most effective and safest agent for preventing and
treating nausea and vomiting

pass effect.33 ODTs or films are excellent options for
nauseated patients, because these dosage forms are
designed to disintegrate and dissolve rapidly in the oral
cavity where they are at least partially absorbed. Ab-
sorption in the oral cavity prevents exposure of drug to
the stomach which prevents the potential loss of drug
available for absorption into circulation caused by vom-
iting and also prevents exposure of the (orally ab-
sorbed) drug to the first pass effect.19 Therefore, doses
of ODTs should be initially lower than doses of oral
(swallowed) tablets. All 5-HT3 receptor antagonists
have similar side effects, which include headache, con-
stipation, and dizziness.31
Indication in sedation. Because of few side effects
and little or no sedation, ondansetron is a good first
choice in the management and prevention of PONV.
Studies, however, show that repeated dosing may not
improve efficacy and that combination therapy is more
effective.79,80
ADJUNCTIVE INTERVENTIONS
Corticosteroids. Dexamethasone is a long-acting po-
tent glucocorticoid and antiinflammatory. It is used
perioperatively to reduce swelling.26,81 The lowest pos-
sible dose of steroids should be used to avoid side
effects. Common side effects include gastrointestinal
irritation, psychiatric disturbances, hypertension, fluid
and sodium retention, increased intraocular pressure,
and allergic reactions.33 Use is contraindicated in cases
of severe hypertension, uncontrolled diabetes mellitus,
glaucoma, and osteoporosis.33 Corticosteroids have
been shown to be teratogenic.33 In children undergoing
a tonsillectomy, there is higher incidence of late re-
bleeding.82 Dexamethasone has been shown to decrease
PONV after the use of sedation and anesthesia.70 Be-
cause it is commonly used by oral and maxillofacial
surgeons to decrease postoperative swelling, it may
also be a good choice to help prevent PONV.83
Benzodiazepines. Benzodiazepines (i.e., alprazolam,
diazepam, lorazepam, triazolam, midazolam) used for
sedation may decrease the incidence of PONV by de-
creasing the plasma levels of catecholamines. Benzo-
diazepines enhance the effect of the neurotransmitter
GABA, which results in sedative and anxiolytic ef-
fects.84 Benzodiazepines are often given before surgery
to relieve anxiety.84 In children, lorazepam has been
shown to produce a similar antiemetic effect but less
postoperative agitation compared with droperidol.85 IV
midazolam has been found to be effective in preventing
vomiting after tonsillectomy in children.86 Hypnotic doses
of benzodiazepines do not affect respiration in normal
adult subjects but may in children and those with hepatic
dysfunction, such as alcoholics.84 Furthermore, hypnotic
doses may worsen sleep-related breathing disorders by
adversely affecting control of the upper airway muscles or
by decreasing ventilatory response to CO2, which may
cause hypoventilation and hypoxemia in patients with
COPD and sleep apnea.84,87 At higher doses, benzodiaz-
epines depress alveolar ventilation as a result of a decrease
in hypoxic rather than hypercapnic drive.
Propofol. Propofol is a potent hypnotic agent used in
deep sedation and general anesthesia techniques. It has
excellent antiemetic properties and can be used with a
benzodiazepine for deep sedation in patients with a
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Volume 115, Number 5
Table II. Choosing the best antiemetic
Goal Antiemetic
Reduce nausea caused by Metoclopramide 5-10 mg 30 min before procedure; may
swallowing blood repeat in 4-8 h if needed; ODT
effective in 10-15 min
Reduce nausea caused by Hydroxyzine 50-100 mg 30 min before procedure
anxiety
Prevent or treat nausea Trimethobenzamide 300 mg every 6-8 h as needed
Prevent or treat nausea Ondansetron 8 mg every 8 h as needed: ODT: 4 mg
and vomiting every 8 h as needed
ODT, Oral disintegrating tablet.
strong history of PONV as an alternative to techniques
that use inhalational agents and opioids.88,89
CURRENT THERAPIES
In outpatient oral and maxillofacial surgery, strategies to
reduce PONV and PDNV should be considered, espe-
cially in high-risk patients. Before surgery, patients that
are identified as high risk for PONV should be treated
prophylactically. Patients with a history of PONV or se-
vere motion sickness should receive prophylactic treat-
ment which could include the use of scopolamine TDS,
hydroxyzine, trimethobenzamide, and/or ondansetron be-
fore surgery. The use of the scopolamine patch has been
shown to be effective prophylactically in patients with a
history of PONV, with a particular benefit in patients who
experience PONV and PDNV with movement or for
whom opioid-induced PONV is delayed.25 When used
preoperatively, both scopolamine and hydroxyzine have
the advantage of enhancing sedation.2 Trimethobenz-
amide is relatively inexpensive and has a low incidence of
adverse effects. Both ondansetron and metoclopramide
have been shown to be more effective in preventing
PONV when administered at the end of surgery.2 In
addition, metoclopramide may aid in GI emptying and
decrease PONV related to the swallowing of blood. Dur-
ing surgery, medications that have antiemetic properties
and are used during sedation and anesthesia include ben-
zodiazepines, propofol, and dexamethasone.2 If there are
no contraindications, these drugs should be considered.
The use of opioids should be minimized in high-risk
patients. Four milligrams of ondansetron administered IV
has been determined to be the optimally effective dose for
the treatment of opioid-induced PONV. Owing to their
side effects, promethazine and droperidol should be used
with caution in adults and older children and is contrain-
dicated in patients under the age of 2 years.
After surgery, individuals in whom ondansetron fails
should be reassessed and a different agent used for
rescue therapy.
Although there are many antiemetics available, some
have significant side effects. Knowledge of the phar-
macology and the side effects of these drugs should
REVIEW ARTICLE
Cruthirds, Sims, and Louis 609
Dosing Dental considerations
Do not use in patients with Parkinson
disease
Some sedation
More expensive; ODT faster onset of action
and an excellent option when can not
tolerate swallowed tablet
guide the clinician in choosing the proper antiemetic
(Tables I and II).
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Reprint requests:
Pamela J. Sims, PharmD, PhD
Professor, Department of Pharmaceutical, Social, and
Administrative Sciences
McWhorter School of Pharmacy
Samford University
800 Lakeshore Drive,
Birmingham, AL 35229
pjsims@samford.edu