ORIGINALPART
VERTIGO AND MOTION SICKNESS. ARTICLE
Vertigo and motion sickness. Part II:
Pharmacologic treatment
Timothy P. Zajonc, MD; Peter S. Roland, MD
Editors note
Vertigo and motion sickness. Part I: Vestibular anatomy
and physiology, appeared in the September 2005 issue
of ENT Journal, pp. 581-4.
Abstract
Vertigo is a sensation of movement when no movement is
actually occurring. It is often accompanied by visceral
autonomicsymptomsincludingpallor,diaphoresis,nausea,
and vomiting. Vertigo is similar to motion sickness in that
both may be caused by vestibular stimulation that does not
matchaninternalmodelofexpectedenvironmentalstimuli.
Indeed, a functioning vestibular system is necessary for
the perception of motion sickness. For this reason, many
of the same drugs are used to treat both conditions. The
investigation of drugs that treat motion sickness helps
to discover medications that may treat vertigo caused
by disease of the vestibular system. In this article, we
discuss the pharmacologic agents that are now available
for the treatment of vertigo and those agents that are still
under study.
Introduction
The efficacy of medications used to treat vertigo often can
be inferred from their usefulness in treating motion sick-
ness. This is especially true when the medication being
evaluated is a vestibular suppressant. Additional objective
data concerning a drugs efficacy can be gained from (1)
large clinical studies of patients who experience similar
environmental challenges, (2) evaluation of laboratory-
induced motion sickness, (3) electronystagmography, and
(4) animal studies.
Clinical trials. Interest in studying treatments for mo-
tion sickness increased during World War II when large
numbersoftroopswerebeingtransportedbysea.Transport
From ENT Associates, Johnson City, Tenn. (Dr. Zajonc), and the Depart-
ment of OtolaryngologyHead and Neck Surgery, University of
Texas Southwestern Medical Center at Dallas (Dr. Roland).
Reprint requests: Peter S. Roland, MD, Professor and Chairman, De-
partment of OtolaryngologyHead and Neck Surgery, University
of Texas Southwestern Medical Center, 5323 Harry Hines Blvd.,
Dallas, TX 75390-9035. Phone: (214) 648-3102; fax: (214) 648-
2246; e-mail: peter.roland@utsouthwestern.edu
Volume 85, Number 1 25
II: PHARMACOLOGIC TREATMENT
ships provided a good setting for early studies compar-
ing efficacy. Research continued, and in a notably large
study published in 1980, Hargreaves reported the results
of a double-blind, placebo-controlled evaluation of cin-
narizine for the prophylaxis of seasickness.1 In that study,
335 volunteers were given either cinnarizine or placebo
during voyages of 5 to 7 days. Symptoms were evaluated
by questionnaire, and the results indicated a statistically
significant reduction in the incidence of seasickness in
the active-treatment group. Similar studies are still being
performed.
Rotation testing. Probably the most widely used method
of objectively evaluating an antivertiginous drugs efficacy
in the laboratory involves inducing motion sickness in
a controlled fashion. Subjects are placed in a chair and
rotated about a vertical axis. Subjects are then asked to
perform a defined series of head motions out of the plane
of motion over a set period of time. The number of head
movements that can be accomplished before vomiting or
severe nausea occurs or prior to the subjects request to
stoptherotationbecomesanobjectivemeasureoftolerance
to motion sickness-inducing stimuli. Each subject can be
used as his or her own control, which allows researchers to
individualize the rate of rotation. More susceptible subjects
are then able to participate at a slower, more comfortable
rotational velocity without compromising the integrity of
the study.2
Caloricstimulation.Electronystagmographycanbeused
to test a drugs ability to suppress vestibular activity. In a
study comparing the antihistamine dimenhydrinate with
placebo, Barber et al examined changes in the frequency,
duration,andvelocityoftheslowcomponentofnystagmus.3
They found that measurement of the velocity of the slow
component was the most useful indicator of suppressed
vestibular function.
Animal models. A number of animal models for the
study of motion sickness have been used over the years.
Researchersonceexpressedsomeconcernabouttheuseof
caninemodelsinearlystudiesbecausedogsdidnotrespond
toscopolamine,whilehumansexperienceastrongreaction;
however,subsequenttrialssuggestedthattheproblemwith
these earlier studies might have simply been inadequate
dosing. Feline models are very useful because we have
 ZAJONC, ROLAND
accumulated a wealth of neuroanatomic, neurochemical,
and neurophysiologic information on cats. Rat models are
unique in that these animals do not vomit in response to
coriolis stimulation, but they do demonstrate observable
behavioral changes such as pica (eating nonnutritive sub-
stances such as kaolin). Rats are generally easier to handle
than larger animals, and they require less stimulation time
than do dogs and cats.4 Squirrel monkeys are the only pri-
matescommonlyusedinanimalstudiesofmotionsickness.
They are highly susceptible to motion sickness induced
by coriolis stimulation, and their response to anti-motion
sickness drugs is similar to that of humans.5
In this article, we review the different classes of drugs
that are used to treat motion sickness and vertigo. We
discuss the agents that are now available (table 1) and
those that are still under investigation (table 2). (In part
I of this article, we discussed the essential anatomy and
physiology of the vestibular system and the associated
vomiting reflex.6)
Benzodiazepines
Diazepam. Sekitani et al first reported on the suppressant
activity of diazepam in the medial vestibular nuclei of cats.7
Theyusedmicroelectrodestorecordthespontaneousfiring
rates of neurons in the medial vestibular nucleus. They
foundthatdiazepam0.4mg/kgexertedstrongsuppressant
activity and reduced the firing frequency by nearly 75%.
They also found that a dosage as low as 0.1 mg/kg had
similar suppressant activity. Both of the -aminobutyric
acid (GABA) receptorsGABA A and GABA Bhave
been found in the vestibular nuclei, but benzodiazepines
are active only at the GABA A receptors. These receptors
are believed to mediate diazepams vestibular suppressant
activity.7
Diazepam has been tested specifically for the prevention
of motion sickness in humans. McClure et al alternated
oral administration of diazepam 5 mg, dimenhydrinate 50
mg, and placebo in a group of normal subjects; subjects
were also tested after receiving no treatment.8 Results
were determined according to the length of time that had
passed between administration and exposure to motion
stimuli. Motion stimuli were provided by rotation and
head-tilt maneuvers, and treatment efficacy was measured
by analyzing the number of maneuvers tolerated and the
recordings of skin sweat sensors. The greatest effect was
observedwhenpatientstookdiazepamordimenhydrinate
120 minutes prior to the onset of the stimuli, which was the
longest interval studied. Clinically, doses of diazepam as
small as 2 mg can be effective in controlling vertigo.
Lorazepam. Intravenous lorazepam is used to treat acute
vestibular vertigo in some emergency departments. Marill
et al compared lorazepam 2 mg IV with dimenhydrinate 50
mg IV and found that lorazepam provided better control
of symptoms.9
26 ENT-Ear, Nose & Throat Journal January 2006
Clonazepam. Clonazepam, which has marked antiepi-
lepticproperties,wasreportedtocontrolsymptomsinmost
patients in a study of migraine-related vertigo.10 Because
the drug takes 4 hours to reach peak plasma levels, it is
not used orally for acute vertigo.
Alprazolam. The properties of alprazolam, a short-
acting benzodiazepine, are similar to those of diazepam.
However, short-acting benzodiazepines carry a greater
risk for abuse and withdrawal symptoms. Benzodiazepines
also have generalized central nervous system effects, and
they are sedating.
Care should also be taken to avoid benzodiazepine over-
dose, which can result in respiratory depression, especially
in elderly individuals.
Antihistamines
The histamine-1 (H1) blockers have long been used to
prevent motion sickness. It has been argued that their an-
tivertiginous efficacy is not the result of the H1 effects but
rather the result of their central anticholinergic actions.11
Wood et al compared antihistamines to phenothiazines,
anticholinergics, sympathomimetics, and various combi-
nations.12 Subjects were evaluated (1) in a slow-rotation
room, (2) during aerobatic maneuvers, (3) at sea, and (4)
during zero-gravity parabolic flight. Results were based
on the duration of stimulus that was tolerated. The authors
concludedthatantihistaminesasagroupareinthemoderate
range of effectiveness for the treatment of motion sickness.
Most of these agents are sufficient for treating motion sick-
ness induced by civilian travel, but antihistamines are not as
useful in severe conditions or in highly sensitive patients.
(Combinations of a sympathomimetic and scopolamine or
promethazine were most effective.)
Ethanolamines. Two of the most studied anti-motion
sickness drugs are diphenhydramine and dimenhydri-
nate. Wood and Graybiel included these two medications
in their evaluation of the relative efficacy of 16 anti-
motion sickness drugs.2 This study involved the laboratory
assessment of human subjects who performed head-tilt
maneuvers during rotation about a vertical axis. Efficacy
was judged by the number of head tilts that were toler-
ated. Dimenhydrinate 50 mg proved to be more effective
than meclizine 50 mg. In addition, Muth et al found that
dimenhydrinatereducedincreasesingastricmotilityduring
motion sickness-inducing stimuli.13
Ethylenediamines and alkylamines. Ethylenediamines
(e.g., tripelennamine) have H1 antagonistic effects, but they
donotdemonstratestrongcentraleffects.Alkylamines(e.g.,
chlorpheniramine) are effective at low doses in preventing
motion sickness, but they do have strong central effects
and therefore produce marked drowsiness.
Piperazines. Meclizine, cyclizine, and buclizine are long-
acting antihistamines. They also produce light sedation.
Meclizine, the best known of these, is commonly used for
 VERTIGO AND MOTION SICKNESS. PART II: PHARMACOLOGIC TREATMENT

Table 1. Selected medications approved in the U.S. for motion sickness and vertigo

Drug MS AV CV Action Dosage Precaution

Benzodiazepines
Diazepam + + + GABA A-mediated Oral: 2, 5, or 10 mg Sedation; avoid in patients
inhibition in the bid to qid; w/pulmonary insufficiency,
vestibular nuclei Slow IV: 5 to 10 mg q4h sleep apnea, or liver or
kidney disease; addiction
is possible

Lorazepam + + Same as diazepam Oral: 1 to 2 mg tid; Same as diazepam

IM/slow IV: 2 mg

Clonazepam + + Same as diazepam Oral: 0.5 mg tid; Same as diazepam

Antihistamines
Diphenhydramine + + H1 blockade; Oral: 25 to 50 mg Sedation
anticholinergic effects q4h to q6h;
IM/IV: 10 to 50 mg qid

Dimenhydrinate + + Same as Oral: 50 mg q4h to q6h Sedation

diphenhydramine IM/IV: 25 to 50 mg
q4h to q6h

Meclizine + + Same as Oral: 25 to 50 mg Sedation

diphenhydramine qd to qid

Cyclizine + + Same as Oral: 50 mg q4h to q6h Sedation; may aggravate

diphenhydramine severe heart failure

Promethazine ++ H1 blockade; strong Oral: 25 mg q6h; Sedation; use w/caution in

anticholinergic effects suppository: 50 mg q12h patients w/renal failure
IM: 25 mg q4h to q6h

Anticholinergics
Scopolamine + + M1, M2, and M3 blockade; Oral: 0.6 mg q4h Sedation, dry mouth,
M3 blockade is likely transdermal: 1.5-mg blurred vision, acute angle
most important patch delivers glaucoma, dermatitis,
1.0 mg q3d possible withdrawal
symptoms; rare psychosis
reported

Scopolamine/ ++ Same as scopolamine Oral: 0.6 mg/25 mg q6h Hypertension, anxiety,

ephedrine* alone plus adrenergic arrhythmia; use w/caution
and dopaminergic in patients w/hyperthyroid-
effects ism, diabetes, or glaucoma

Scopolamine/ ++ Same as scopolamine/ Oral: 0.6 mg/5 to 10 mg Same as scopolamine/

d-amphetamine* ephedrine q6h ephedrine

Neuroleptics
Droperidol/fentanyl + ? Antiadrenergic and IM/slow IV: droperidol Hypotension, respiratory
antidopaminergic effects; 2.5 to 5 mg/fentanyl depression; use w/caution
analgesia w/fentanyl 50 g/ml q12h in patients w/liver or kidney
disease

* Both adrenergics are effective as monotherapies.

Key: MS = motion sickness; AV = acute vertigo; CV = chronic vertigo.

Volume 85, Number 1 27

 ZAJONC, ROLAND

Table 2. Selected investigational medications and agents not approved in the U.S.

Drug MS Vertigo Suspected drug action

Anticholinergics
Idaverine M1 and M2 receptor blockade

Zamifenacin + M3 and m5 receptor blockade

Anticonvulsant
Phenytoin + Stabilization of neuronal membranes in CNS

Calcium antagonists
Flunarizine + + Labyrinth suppression, possibly at the level of the vestibular hair
cells

Cinnarizine + + Same as flunarizine

Nimodipine + Same as flunarizine; possible CNS modulation

Nifedipine + Unknown

Tricyclic antidepressant
Doxepin + Strong H1 antagonist, adrenergic, and anticholinergic effects;
weak dopaminergic effect

Serotonergics
8-OH-DPAT ++ 5-HT1A agonist effects, probably in the vestibular nuclei

DOI 5-HT2 agonist effects

Imipramine/fluoxetine + (A) Increase in concentration of serotonin in synapses

Ondansetron 5-HT3 receptor blockade, likely in the area postrema

(chemoreceptor trigger zone)

Others
GR203040 + (AH) NK1 receptor blockade

LY233053 + (A) NMDA blockade in the vestibular nuclei and the final common
pathway for vomiting

ORG 2766 + (A) Suppression, possibly in the vestibular nuclei

Key: MS = motion sickness; CNS = central nervous system; 8-OH-DPAT = 8-hydroxy-2-(di-n-propylamino)tetralin; DOI = 1-(2,5-dimethoxy-4-
iodophenyl)-2-aminopropane; A = in animals; AH = in animals and humans; NMDA = n-methyl-d-aspartate.

the prevention of motion sickness in civilian environments. Meclizinewasgiven2hourspriortotestingandtransdermal

In addition to the finding that meclizine 50 mg was less
effective than dimenhydrinate 50 mg,2 meclizine has been
found to be less effective than transdermal scopolamine. In
a placebo-controlled study, Dahl et al exposed 36 subjects
to a ship-motion simulator after they had received either
oral meclizine 25 mg or a transdermal scopolamine patch.14
scopolamine was given 12 hours prior to testing. Subjects
were graded on a 5-point nausea scale, with 0 representing
no symptoms and 5 representing vomiting. Subjects who
wore the scopolamine patch had significantly lower scores
than either the meclizine or placebo subjects; meclizine
was significantly more effective than placebo.

28 ENT-Ear, Nose & Throat Journal January 2006

 VERTIGO AND MOTION SICKNESS. PART II: PHARMACOLOGIC TREATMENT
Cinnarizine is a piperazine that exerts calcium channel
blocking effects. It has been used in Europe for many
years, but there is concern regarding its central side effects.
(Cinnarizine is discussed in more detail in the section on
Calcium antagonists.)
Piperidines. The best known piperidine is terfenadine.
Although it has been removed from the market, one hu-
man study by Kohl et al demonstrated that a single large
(300 mg) dose of terfenadine increased to a statistically
significant degree the number of head movements toler-
ated by subjects during rotation.15 Because terfenadine
does not cross the blood-brain barrier, this finding raised
the possibility that motion sickness might be treatable by
blocking only peripheral receptors. However, structures
suchastheareapostrema,medianeminence,portionsofthe
hypothalamus, and other circumventricular organs that lie
outside the blood-brain barrier play an integral role in the
vomiting reflex.Therefore the effectiveness of terfenadine
may well be attributable to its central sites of action.
Astemizole, another highly selective H1 inhibitor
with little central nervous system penetration, has also
been reported to be effective in the treatment of chronic
vertigo.16,17 In a prospective study, Jackson and Turner
evaluated 38 patients with chronic vertigo who exhibited
repeatablespontaneousorpositionalnystagmus.17Patients
with Mnires disease were excluded from the study.
Patients were given 5, 10, or 20 mg/day of astemizole for
13 weeks. Patients were evaluated by electronystagmog-
raphy. A positive response was defined as a 50% reduc-
tion in the number of nystagmus beats recorded during a
body-positioning protocol. Patients were also evaluated
by a subjective symptom questionnaire. This study re-
vealed that although some patients showed no objective
or subjective changes, 73% did improve. Responses were
demonstrated after 2 to 4 weeks of therapy, and the return
of symptoms was delayed by 2 weeks or more after the
drug was discontinued.
In another human study, Kohl et al tested 20 subjects
after they had taken oral astemizole 30 mg/day for 1 week.18
Although subjects were found to have therapeutic blood
levelsofastemizole,thedrugdemonstratednoeffectiveness
against motion sickness-inducing stimuli. These subjects
also exhibited no change in their vestibuloocular reflex.
Phenothiazines. The phenothiazines were first explored
for their usefulness in treating psychoses. They also have
antiemetic properties, but most drugs in this group are only
slightly effective against motion sickness, promethazine
being a notable exception.
Promethazineexertsstrongantihistamineproperties,and
it is more effective than any antihistamine in preventing
vertigo.Promethazinealsohasthestrongestanticholinergic
activity of all the phenothiazines. Wood and Graybiel re-
ported that oral promethazine 25 mg was only slightly less
effective in preventing motion sickness than scopolamine
Volume 85, Number 1 29
0.6 mg.2 Intramuscular promethazine 25 mg was shown to
increase the number of head movements tolerated by 78%,
although this was less than the 91% reduction seen with
scopolamine 0.2 mg.19 However, promethazines duration
of action is 12 hours, versus 4 hours for scopolamine.19
Promethazine hastens adaptation to motion sickness-
inducing stimuli, as Lackner and Graybiel demonstrated
in a controlled human head-tilt experiment.20Three groups
of subjects were given either placebo or promethazine 50
mg orally prior to testing sessions. The sessions were held
2 days apart to allow for habituation. Patients in one of the
twopromethazinegroupswereallowedtoperformasmany
head movements as possible, while those in the other pro-
methazine group were forced to match the number of head
movements performed by those in the placebo group. At
the final session, all groups received placebo only. Analysis
of the results revealed statistically significant increases in
the number of head movements performed by all groups.
However, the group given promethazine and allowed to
perform as many head movements as possible showed the
greatestimprovement.Thepromethazinegroupinwhichthe
numberofheadmovementswasrestricteddidnobetterthan
the placebo group. These findings suggest that if subjects
increasetheirexposuretomotionsickness-inducingstimuli,
promethazine may actually help to increase adaptation.
Promethazine does exert significant sedating properties
and the 25-mg dose can impair functional performance,
but the sedative effect can be circumvented by adding 10
mgofamphetamine/dextroamphetamine(d-amphetamine).
Larger doses of promethazine degrade performance to
such an extent that sedation cannot be prevented by add-
ing amphetamine.21 (As discussed later in this article,
d-amphetamine exerts antivertiginous effects of its own.)
Prochlorperazine,anotherphenothiazine,demonstrates
H1blockadeandithassignificantanticholinergicproperties.
It also has a 40-fold greater antidopaminergic effect than
does promethazine, and it is an effective antiemetic. Pro-
chlorperazinedoeshavesomeanti-motionsicknesseffects,
but it ranks well below scopolamine and the antihistamines
in this regard. For example, not only was prochlorperazine
5 mg shown to be less effective than meclizine in prevent-
ing motion sickness, tripling the dose actually decreased
the number of head tilts tolerated.2
Chlorpromazine has no anti-motion sickness efficacy,
even though it is quite effective against chemically induced
nausea.22
Anticholinergics
Anticholinergic medications act on muscarinic receptors.
(There are five known structural subtypes of muscarinic
receptors, designated m1 through m5. The capitalized des-
ignations M1, M2, and M3 represent pharmacologic defi-
nitions, which are based on the actions of various drugs
that bind muscarinic receptors selectively.) One study
 ZAJONC, ROLAND
involving bovine brain tissue found that the highest den-
sities of muscarinic receptors were in the area postrema
and the vagal nuclear complex.23 Intermediate densities
were found in the parvicellular reticular formation, and
the lowest concentration of receptors was found in the
vestibular nuclei.
Scopolamine. Scopolamine is believed to bind well
to all types of muscarinic receptors. In their study of 16
agents, Wood and Graybiel found that oral scopolamine
was the most effective single agent in preventing vertigo.2
They also evaluated scopolamine in combination with two
other adrenergic medications that were found to have anti-
motion sickness activity of their own; scopolamine had
an additive effect when combined with ephedrine and a
synergistic effect when combined with amphetamine.2 In
fact, the combination of scopolamine and amphetamine
proved to be the most effective of all medications alone or
in combination. Operational performance has been shown
to decrease with doses of scopolamine of 0.8 mg or more.
However, the addition of d-amphetamine 5 mg with sco-
polamine 1.0 mg prevented a decrease in performance.21
Although scopolamine is effective, adaptation to new
environmental stimuli can be delayed. This was demon-
strated in one clinical study of 51 sailors who worked in
rough seas over a period of 7 days.24 Upon embarking on
their voyage, the subjects were given either transdermal
scopolamine or transdermal placebo and instructed to
wear the patch for 3 days. Initially, vomiting did occur less
often in the scopolamine group. But on day 6, 3 days after
removal of all patches, vomiting occurred in 23% of the
scopolamine group but in none of the placebo controls.
Thescopolaminetransdermaltherapeuticsystemdelivers
a continuous 1-mg total dose over 3 days; thereafter, a new
patch may be applied. The effectiveness of transdermal
scopolamine has been proven to be similar to that of oral
scopolamine.25 Its autonomic side effects include reduced
salivationandblurredvisionfromreducedaccommodation.
The most common side effect is dry mouth, which has been
reported in 30 to 50% of patients. Blurred vision commonly
occurs with continued use. In a study of 12 subjects, Parrot
monitoredvisualacuityduringtheplacementofsequential
patches.26 Blurred vision occurred in 1 subject upon place-
ment of a second patch, 4 subjects experienced blurred
vision with a third patch, and 6 reported blurred vision
with a fourth. Central nervous system side effects include
decreased alertness, impaired attention, and difficulty re-
memberingnewinformation.Addictionandpsychosishave
alsobeenreportedwiththeuseoftransdermalscopolamine
for 1 month or longer.25,27,28 Reports of addiction relate to
patients inability to discontinue medication because of
severe withdrawal symptoms, such as nausea, vomiting,
headache, and disequilibrium.28Transdermal scopolamine
has also been documented to cause acute angle-closure
glaucoma, and therefore it should not be used in patients
30 ENT-Ear, Nose & Throat Journal January 2006
suspected of having glaucoma.29 Contact dermatitis may
occur in 10% of patients after 1 month or more of use; this
rate may rise to more than 30% among patients who use
transdermal scopolamine for 1 year or longer.30
Buccal administration of 1 mg of scopolamine in a sus-
tained-release hydroxypropylmethylcellulose vehicle was
shown to reduce vomiting during parabolic flights by 50%
and to reduce nausea scores by approximately 31%.31
Glycopyrrolate. Glycopyrrolate is commonly used to
decreasecopioussecretionsandtopreventtraction-induced
vagal inhibitory cardiac reflexes. Storper et al tested gly-
copyrrolate for efficacy in treating vertigo in 37 patients
with Mnires disease.32 Of this group, 22 patients were
given oral glycopyrrolate 2 mg twice a day. Compared with
the remaining 15 patients who had not received glycopyr-
rolate, the study group had a significantly greater reduction
in Dizziness Handicap Inventory scores.
Idaverine. Idaverine, which is not approved in the United
States, is believed to be a selective M1 and M2 antagonist
with a significantly lower affinity for M3 receptors. Lucot
et al investigated its efficacy in preventing motion sick-
ness by comparing it with scopolamine in a cat model.33
They found that idaverine exerted no protective effects;
in fact, larger doses actually induced emesis. This finding
suggests that the M3 receptor may be responsible for the
anti-motion sickness effects of scopolamine.
Zamifenacin. Zamifenacin is a new selective anticho-
linergic under investigation. This agent binds selectively
to M3 and m5 receptor subtypes, and it has been shown
to be as efficacious as scopolamine in preventing motion
sickness.34 This suggests that the M3 receptor, the m5
receptor, or both may be responsible for scopolamines
anti-motion sickness effect. Further research may or may
not determine that the use of zamifenacin or other selective
anticholinergics can effectively control motion sickness
and vertigo with fewer side effects.
Neuroleptics
Neuroleptics are known for their antipsychotic properties.
Two major groups of neuroleptics are the phenothiazines
and the butyrophenones. (The phenothiazines are dis-
cussed in more detail in the earlier section on Antihis-
tamines.)
The butyrophenones are essentially derivatives of halo-
peridol. Droperidol is used almost exclusively in anesthesia
because of its strong sedating properties and antiemetic
effects. Droperidol has antiadrenergic and antidopaminer-
gic effects. It is believed that its antinausea effects may be
attributable to the blocking of dopamine receptors in the
area postrema. A fixed-dose combination of droperidol 2.5
mg/ml and fentanyl 50 g/ml is commercially available.
Dowdy et al performed caloric tests prior to and 1 week
after administration of a single dose of droperidol/fentanyl
andobservedacompletesuppressionofcaloricnystagmus
 VERTIGO AND MOTION SICKNESS. PART II: PHARMACOLOGIC TREATMENT

in 8 of 9 subjects.35 Subjects who received either droperidol
alone or fentanyl alone demonstrated an absence of or only
a slight reduction in caloric responses.
Droperidol has been proven useful, either alone or in
combination with fentanyl, in clinical studies of treatments
for acute vertiginous episodes brought on by Mnires
disease.36,37 Gates reported his personal experience with
droperidol/fentanyl for the control of vertigo in 12 patients
with Mnires disease.36 He found that 58% of these pa-
tients achieved long-term control of their vertigo during
a follow-up of 2 to 8 years. The mechanism for any pro-
posed long-term effects of droperidol/fentanyl is not clear.
Currently, droperidol/fentanyl is being used in emergency
departments for the control of acute peripheral vertigo;
good results have been reported by Irving et al.38
Johnson et al evaluated droperidol alone for the control
of peripheral vertigo.37 Twelve patients with acute vertigo
secondary to Mnires disease were given either placebo
or droperidol 5 mg intramuscularly. Patients in the active-
treatmentgroupexperiencedaresolutionofsymptomswith-
in 60 minutes, whereas the controls remained unchanged.
The controls were then put on droperidol, and their vertigo
resolved, as well. The usual droperidol dose for adults is
2.5 to 5 mg intramuscularly or intravenously. Monitoring
of vital signs and respiratory support are necessary dur-
ing administration in view of the drugs risk for causing
hypotension and respiratory depression. Benadryl 25 to 50
mg can also be given prior to droperidol administration to
help prevent extrapyramidal side effects.39
A highly selective dopamine-2 (D2) receptor antagonist,
l-sulpiride, is under investigation. In squirrel monkeys,
l-sulpiride has been found to exert strong anti-motion sick-
nesseffectsandnoextrapyramidalsideeffectsatthedosing
levels studied. Miller and Brizzee compared l-sulpiride
with domperidone, a peripherally acting D2 antagonist.40
Domperidone demonstrated no ability to prevent motion
sickness.Becausedomperidonewouldhavebeenavailable
to the area postrema (outside the blood-brain barrier), it is
likely that the anti-motion sickness effects of l-sulpiride
occur outside the area postrema. This conjecture supports
the hypothesis that although the area postrema is part of
the chemoreceptor trigger zone, it is not associated with
the production and control of motion sickness.

11th International WorkshopLaser Voice Surgery and Voice Care

Friday April 7 & Saturday April 8, 2006
PARIS FRANCE

Chairman: Jean ABITBOL, M.D.

Co-Chairmen: Robert T. SATALOFF, M.D., D.M.A.; Michal BENNINGER, M.D.; Harvey TUCKER, M.D.

TOPICS
Benign lesions of the vocal folds Neurolaryngology & laryngo-pharyngeal reflux
Laser vs. cold instruments Cutting edge in Laryngology and Voice Science

With the International Faculty

ABITBOL PATRICK, M.D. (France) ELIDAN JOSEF, M.D. (Israel) MERATI ALBERT, M.D. (USA)
ACCORDI MAURIZIO, M.D. (Italy) FORD CHARLES, M.D. (U.S.A.) MURRY THOMAS, Ph.D. (U.S.A.)
ALTMAN KEN, M.D. (U.S.A.) FRIEDRICH GERHARD, M.D. (Austria) PAPASPYROU SPYROS, M.D. (Greece)
ANDREA MARIO, M.D. (Portugal) GARDNER GLENDON, M.D. (U.S.A.) REMACLE MARC, M.D. (Belgium)
AVIV JONATHAN, M.D. (U.S.A) GIOVANNI ANTOINE, M.D. (France) RICCI-MACCARINI ANDREA., M.D. (Italy)
BEHLAU MARA, Ph.D. (Brazil) HIRANO SHIGERU, M.D. (Japan) RUBIN JOHN, M.D. (U.K.)
BLESS DIANA, Ph.D. (U.S.A.) IZDEBSKI KRZYSZTOF, Ph.D. (U.S.A.) SHAPSHAY STANLEY, M.D.(U.S.A.)
CASTRO ALBERT, M.D. (France) KOROVIN GWEN, M.D. (U.S.A.) THIBEAULT SUSAN, M.D. (U.S.A.)
CHABOLLE FREDERIC, M.D. (France) LACCOURREYE OLLIVIER, M.D. (France) TIMSIT CLAUDE, M.D. (France)
CHARRIER JEAN-BAPTISTE, M.D. (France) LACAU SAINT GUILY JEAN, M.D. (France) ULOZA VIRGILUS, M.D. (Lithuania)
CREVIER-BUCHMAN LISE, M.D., Ph.D. (France) LICHTENBERGER GYRGY, M.D. (Hungary) WOO PEAK, M.D. (U.S.A.)
CRUMLEY ROGER, M.D. (U.S.A.) MAIMARAN J. JACQUES, M.D. (France) WOODSON GAYLE, M.D. (U.S.A.)
DAVIES GARFIELD, M.D. (U.K.) MARAGOS NICOLAS, M.D. (U.S.A.) YLITALO RIITTA, M.D., Ph.D. (Sweden)
DEDO HERBERT, M.D.(U.S.A.) MARIE JEAN-PAUL, M.D., Ph.D. (France) ZERAT LAURENT, M.D. ( France)

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Volume 85, Number 1 31

 ZAJONC, ROLAND
Anticonvulsants
Phenytoin acts diffusely upon the central nervous sys-
tem to stabilize neuronal membranes. It is believed to
stabilize the threshold against hyperexcitability caused
by excessive stimulation while leaving normal neuronal
activity essentially unaffected.41,42 The neural mismatch
produced by motion sickness can be viewed as a source
of excessive stimulation. Chelen et al investigated the
usefulness of phenytoin in preventing motion sickness in
7 healthy male volunteers using a rotation and head-tilt
protocol.42 Subjects were treated with a loading dose of 1
to 1.4 grams of phenytoin during the 20 hours preceding
the study, and their blood was tested to measure thera-
peutic levels. The authors discovered that phenytoin was
associated with an 11-fold longer duration of tolerance
to exposure than placebo. This duration of tolerance was
4-fold greater than that associated with a scopolamine/
d-amphetamine combination. Chelen et al made no spe-
cific recommendation to use phenytoin to prevent motion
sickness, but they alluded to larger ongoing trials that they
were conducting. In another study, Stern et al showed
that phenytoin decreased gastric motility in response to
motion sickness-inducing stimuli.43
Calcium antagonists
Calcium ions are present in the endolymph. In response
to movement of the endolymph, calcium ions flow into
the cells of the crista ampullaris. This triggers an action
potential that is propagated centrally. It is postulated that
calcium channel blockers inhibit the flow of calcium from
the endolymph into the cells of the crista ampullaris.44
Flunarizine. Flunarizine is one calcium channel blocker
that has been found to be a powerful peripherally acting
labyrinth suppressant. At both 10 and 30 mg, it has been
found to be more effective in reducing caloric responses
than is prochlorperazine 5 mg.44 Additionally, flunarizine
reduces vestibuloocular reflex gain in harmonic accelera-
tion tests, and it is clinically useful in preventing motion
sickness and vertigo.45,46
Cinnarizine. Cinnarizine is similar to flunarizine, but
it is less potent. The usual dose of cinnarizine is 30 mg
orally 2 hours prior to motion sickness-inducing stimuli.
During prolonged exposure to stimuli, cinnarizine can be
continued at 15 mg three times daily. Children aged 5 to
12 years can be treated with one-half the adult dose. In a
slow-rotation study, cinnarizine was shown to increase the
number of rotations tolerated before the development of
motion sickness.47 Cinnarizine has also been proven effec-
tive in placebo-controlled studies of seasickness.1,48
In a study of saccadic eye movements after ingestion
of either flunarizine or cinnarizine in 10 subjects, Shupak
et al found that peak saccadic velocity was significantly
lower in the flunarizine group.49 (Saccadic velocity is
related to a group of burst neurons in the brainstem.) The
32 ENT-Ear, Nose & Throat Journal January 2006
subjects who took cinnarizine demonstrated only a trend
toward reduction in peak saccadic velocity. This finding
suggests the possibility that calcium antagonists exert
central effects.
Flunarizine and cinnarizine have been used in Europe,
but not widely elsewhere in the world. Neither drug is
selective for a particular calcium channel subtype. They
therefore exert their effects throughout the central ner-
vous system. Potential side effects include weight gain,
depression, sedation, and even parkinsonian symptoms.
Flunarizine has a long half-life, and steady-state plasma
levels are not reached for 2 months. Residual concentra-
tions are detectable for up to 4 months after cessation of
therapy.45,50,51
Nimodipine. Nimodipine is a highly lipophilic agent that
readily crosses the blood-perilymph barrier. It is approved
in the U.S. for the reduction of cerebrovasospasm following
subarachnoidhemorrhage.Inaretrospectivestudy,Lassen
et al reported that nimodipine was given to 12 patients with
Mnires disease who had failed to respond to first-line
medical management with diet restrictions and a diuretic
(and, on occasion, a vestibular suppressant).52 The authors
found that vertigo had been controlled in 67% of these
patients. The duration of treatment and follow-up in this
study ranged from 5 to 27 months; patients who had failed
treatment did so within 6 months. In addition to blocking
calcium influx into vestibular hair cells, nimodipines
antivertiginous effects might be attributable to its central
modulation of signals secondary to peripheral vestibular
irritation. The recommended dosage for nimodipine is 30
mg twice a day.39,52
Nifedipine. During a double-blind study of nifedipines
antihypertensive effects, Marley and Joy serendipitously
discovered that nifedipine alleviated a single patients
motion sickness.53
Sympathomimetics
The anti-motion sickness efficacy of d-amphetamine alone
wasfoundtobeequaltothemidrangeefficacyoftheantihis-
tamines in the comparison study byWood and Graybiel.2 In
a squirrel monkey study, d-amphetamine was also effective
against motion sickness when the animals were exposed
to a combination of vertical oscillations and horizontal
rotation.5 The mechanism of action of amphetamine, a
noradrenaline releaser, in preventing motion sickness is
unclear. Its effects were once believed to be produced by
an increase in noradrenergic activity in the brainstem,
but this hypothesis is now being questioned. This theory
was weakened by the results of an animal study in which
Takeda et al measured the turnover of catecholamines in
ratbrainstemsduringadouble-rotationprotocol;although
methamphetamine 5 mg/kg prevented pica, no increase in
brainstem catecholamines was observed.54
Another theory holds that the anti-motion sickness ef-
 VERTIGO AND MOTION SICKNESS. PART II: PHARMACOLOGIC TREATMENT
fects of amphetamine are attributable to the enhancement
of selective dopaminergic stimulation.55 This hypothesis
is supported by the fact that both methylphenidate (a
nonamphetamine-like stimulant that enhances dopami-
nergic transmission but not norepinephrine transmission)
and d-amphetamine have anti-motion sickness effects.
These drugs may exert their anti-motion sickness effects
via their similar enhancement of dopaminergic transmis-
sion.55,56 Additionally, the anti-motion sickness effects of
the l-isomer of d-amphetamine are weaker than those of
d-amphetamine; the weaker dopaminergic effects of the
l-isomer might explain its lack of efficacy.55,57
Ephedrine 25 mg in combination with scopolamine can
be used to lessen the performance degradation caused by
sedation. Use of this combination also takes advantage of
the synergistic activity of the two medications. Ephedrine
25 mg can also be used in combination with promethazine
25 to 50 mg.
Tricyclic antidepressants
Two of the tricyclic antidepressants that have been investi-
gated for anti-motion sickness effects are imipramine and
doxepin. (Owing to its ability to inhibit serotonin uptake,
imipramine is discussed later in the section on New ho-
rizons in the subsection on Serotonergic agonists and
antagonists.)
Doxepin exerts strong H1 antagonistic effects, and it
has adrenergic and anticholinergic effects, as well. One
human study demonstrated that doxepin is as effective as
the combination of scopolamine and amphetamine for the
prevention of motion sickness.58 Subjects were exposed
to rotation with head-tilt maneuvers daily for 5 consecu-
tive days. Results were based on the number of head tilts
that were tolerated. Both treatment groups demonstrated
increasing tolerance to coriolis stimulation daily (no sta-
tistically significant difference), suggesting that therapy
facilitated adaptation, and both regimens were signifi-
cantly superior to placebo. However, doxepin does have
substantialsedating properties as well as other undesirable
anticholinergic side effects. Doxepin also has a strong
potential for adverse interactions with other drugs.
New horizons
Serotonergic agonists and antagonists. Serotonin (5-
hydroxytryptophan [5-HT]) is an indole amine found
throughout the body. Its effects are mediated via 5-HT
receptors. The 5-HT1, 5-HT2, 5-HT3, 5-HT4, and 5-HT5
receptors have been identified in vivo. Additional 5-HT1
and 5-HT2 receptor subclasses have been identified and
characterized, as well.59
The 5-HT1A receptors are probably present in the ves-
tibular nuclei and elsewhere in the emetic pathway.60 In
cats, 5-HT1A receptor agonists such as 8-hydroxy-2-(di-
n-propylamino)tetralin (8-OH-DPAT) have been shown
Volume 85, Number 1 33
to prevent vomiting elicited by both motion-induced and
chemical-induced nausea.61-63
Biver et al studied the distribution of 5-HT2 receptors in
human brain tissue via positron-emission tomography.64 A
radiotracer specific for 5-HT2 receptors revealed a primar-
ily cortical distribution; these receptors were found to a
lesser extent in the basal ganglia and cerebellum. A 5-HT2
agonist1-(2,5-dimethoxy-4-iodophenyl)-2-aminopro-
pane (DOI)has been shown to block emesis induced by
motion and cisplatin in an animal model.65,66
The 5-HT3 receptors are present in high densities in
both the central and peripheral nervous systems. They are
found in the area postrema, nucleus of the tractus solitarius,
cerebral cortex, spinal cord, and visceral autonomic and
sensory nerves.67 The 5-HT3 receptor antagonists (e.g.,
ondansetron) are used extensively for the control of post-
operative nausea and vomiting. Stott et al demonstrated
thattheirantinauseaeffectdoesnotpreventmotion-induced
vomiting.68
Selective serotonin reuptake inhibitors (SSRIs) work by
increasing synaptic concentrations of serotonin. Imipra-
mine (a tricyclic antidepressant with strong serotonergic
properties) and fluoxetine (an SSRI) have been tested in
the animal model Suncus murinus.66 Both agents exhibited
dose-dependent effectiveness in preventing motion sick-
ness. Their usefulness in humans is not yet clear.
Neurokinin receptors. Neurokinin type 1 (NK1) receptors
are naturally bound by substance P, and they are involved
in a variety of processes, including smooth muscle relax-
ationorcontraction,neuronaldepolarization,andexocrine
gland secretion. Substance P is a peptide neurotransmitter
that is localized to many neuronal structures. Substance
P is believed to play a role in the transmission of sensory
information, particularly that associated with noxious
stimuli, from the periphery to central structures. Some NK1
receptor antagonists have been shown to have strong anti-
emetic properties. One of the most selective NK1 receptor
antagonists, GR203040, has demonstrated effectiveness
against motion-induced emesis in animal models.69 It
should be noted that although this drug is highly selective
for NK1 receptors, it has some affinity for H1 receptors.70 In
human studies, however, NK1 receptor antagonists alone
and in combination with the 5-HT3 receptor antagonist
ondansetron have proven to be no more effective than
placebo in the treatment of motion-induced nausea in
humans.71 The fact that NK1 receptor antagonists have
demonstrated effectiveness in preventing chemotherapy-
induced nausea but not motion sickness-induced nausea
suggests that there is a different mechanism of action for
motion-induced nausea.
Miscellaneous agents. N-methyl-d-aspartate (NMDA)
antagonists have been evaluated in animal models in an
effort to find a drug that will serve as a broad-spectrum
antiemetic.TheselectivecompetitiveantagonistLY233053
 ZAJONC, ROLAND
has been shown to act in this capacity by blocking both
motion- and chemical-induced emesis in cats.72 The sites
of action appear to be both the vestibular nuclei and later
in the final common pathway for vomiting.
Animal studies have also shown that short adrenocor-
ticotrophic hormone (ACTH) fragments relieve vertigo
symptoms and accelerate their disappearance.51,73,74 The
site of action of one fragment, ORG 2766, appears to be
in the vestibular nucleus complex itself.
Ineffective agents include ginger root and acetylleucine.
Ginger root (Zingiber officinale) has been found to have
no effect on motion sickness in rotary-chair tests and only
a very mild effect on tachygastria in motion sickness.75
Acetylleucine, which has been used in France since 1957,
has no clinical trials to support its use; neither does the
Ginkgo biloba extract EGb 761.51
Selecting a medication
It is possible to predict the clinical usefulness of some
medicationsbyreferringtotheneurophysiologicmodelfor
vertigo and motion sickness. For example, if a vestibular
suppressant is successful for treating motion sickness, it will
likely be useful for treating vertigo, as well. It is also impor-
tant to consider a medications onset of action. A drug with
a rapid onset of action is required to treat acute vestibular
vertigo or ongoing motion sickness, whereas a slow-acting
medication is appropriate for chronic vertigo.
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