THERAPY IN PRACTICE
CNS Drugs 2003; 17 (2): 85-100
1172-7047/03/0002-0085/$30.00/0
© Adis International Limited. All rights reserved.
Pharmacological Treatment of Vertigo
Timothy C. Hain and Mohammed Uddin
Departments of Neurology, Otolaryngology and Physical Therapy and Human Movement
Sciences, Northwestern University, Chicago, Illinois, USA
Contents
Abstract
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Physiology of Vertigo . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Neurochemistry of Vertigo . . . . . . . . . . . . . . . . . . . . . . . .
3. Drugs Used in the Treatment of Vertigo . . . . . . . . . . . . . . . . .
3.1 Vestibular Suppressants . . . . . . . . . . . . . . . . . . . . . . .
3.1.1 Anticholinergics . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.2 Antihistamines . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.3 Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . .
3.1.4 Calcium Channel Antagonists . . . . . . . . . . . . . . . .
3.2 Antiemetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3 Agents That Affect the Rate of Compensation . . . . . . . . . .
3.4 Agents of Uncertain Efficacy and Mechanism . . . . . . . . . .
4. Drug Treatment of Individual Conditions . . . . . . . . . . . . . . . .
4.1 Benign Paroxysmal Positional Vertigo . . . . . . . . . . . . . . .
4.2 Ménière’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.1 Episodic Treatment . . . . . . . . . . . . . . . . . . . . . . .
4.2.2 Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3 Vestibular Neuritis . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4 Bilateral Vestibular Paresis . . . . . . . . . . . . . . . . . . . . . .
4.5 Central Vertigo . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6 Psychogenic Vertigo . . . . . . . . . . . . . . . . . . . . . . . . .
4.7 Treatment of Undetermined and Ill-Defined Causes of Vertigo
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abstract
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This review discusses the physiology and pharmacological treatment of vertigo and related disorders. Classes of medications useful in the treatment of vertigo include anticholinergics, antihistamines, benzodiazepines, calcium channel
antagonists and dopamine receptor antagonists. These medications often have
multiple actions. They may modify the intensity of symptoms (e.g. vestibular
suppressants) or they may affect the underlying disease process (e.g. calcium
channel antagonists in the case of vestibular migraine). Most of these agents,
particularly those that are sedating, also have a potential to modulate the rate of
compensation for vestibular damage. This consideration has become more relevant in recent years, as vestibular rehabilitation physical therapy is now often
recommended in an attempt to promote compensation. Accordingly, therapy of
vertigo is optimised when the prescriber has detailed knowledge of the pharma-
86
Hain & Uddin
cology of medications being administered as well as the precise actions being
sought.
There are four broad causes of vertigo, for which specific regimens of drug
therapy can be tailored. Otological vertigo includes disorders of the inner ear such
as Ménière’s disease, vestibular neuritis, benign paroxysmal positional vertigo
(BPPV) and bilateral vestibular paresis. In both Ménière’s disease and vestibular
neuritis, vestibular suppressants such as anticholinergics and benzodiazepines are
used. In Ménière’s disease, salt restriction and diuretics are used in an attempt to
prevent flare-ups. In vestibular neuritis, only brief use of vestibular suppressants
is now recommended. Drug treatments are not presently recommended for BPPV
and bilateral vestibular paresis, but physical therapy treatment can be very useful
in both. Central vertigo includes entities such as vertigo associated with migraine
and certain strokes. Prophylactic agents (L-channel calcium channel antagonists,
tricyclic antidepressants, β-blockers) are the mainstay of treatment for migraineassociated vertigo. In individuals with stroke or other structural lesions of the
brainstem or cerebellum, an eclectic approach incorporating trials of vestibular
suppressants and physical therapy is recommended. Psychogenic vertigo occurs
in association with disorders such as panic disorder, anxiety disorder and agoraphobia. Benzodiazepines are the most useful agents here. Undetermined and illdefined causes of vertigo make up a large remainder of diagnoses. An empirical
approach to these patients incorporating trials of medications of general utility,
such as benzodiazepines, as well as trials of medication withdrawal when appropriate, physical therapy and psychiatric consultation is suggested.
1. Physiology of Vertigo
Vertigo is the illusion of rotational motion.
Most vertigo with definable cause is otological,
caused by dysfunction of the rotational velocity
sensors of the inner ear, the semicircular canals.
For consideration of other types of vertigo, it is
helpful to consider how the brain processes motion
signals. In the normal situation, individuals continuously process three types of sensory input: vestibular (inner ear), visual and somatosensory. These
three streams of information are combined in the
central vestibular apparatus to form an estimate of
orientation and motion of the head and body. Physiological and pathological vertigo is caused by
asymmetrical input into the central vestibular apparatus or asymmetrical central processing.[1]
Accordingly, possible sources of vertigo include all possible combinations of sensory disturbances related to motion as well as malfunction of
the central vestibular apparatus. Practically, however, because the visual and somatosensory senses
mainly produce position-coded signals, vertigo is
© Adis International Limited. All rights reserved.
only rarely a consequence of visual or somatosensory malfunction. An example of ‘visual vertigo’
might be vertigo associated with an oculomotor
disturbance accompanied by nystagmus. Nevertheless, the common varieties of visual disturbance,
diminished vision, double vision or disorders of the
accommodation system usually do not create vertigo. Similarly, vertigo is only occasionally associated with somatosensory dysfunction, as in cervical vertigo. Central vertigo is more frequent than
nonvestibular sensory vertigo but still uncommon
compared with otological vertigo, as is discussed
in more detail in section 4.
When planning treatment, the symptom of vertigo should be differentiated from motion sickness,
which is the malaise and nausea that may follow
real or illusory sensations of motion. Motion sickness can be caused by a mismatch of sensory signals as well as malfunction of central structures
involved in comparison between senses encoding
motion. Vertigo and motion sickness are not synonymous. For example, carnival rides frequently
CNS Drugs 2003; 17 (2)
Treatment of Vertigo
elicit illusory rotational sensations, but motion
sickness can often be avoided. Also, the symptoms
of motion sickness usually persist longer and tend
to be more disturbing than the inciting vertigo.
Again, although normal individuals experiencing
similar sensory disturbances reliably experience
vertigo, susceptibility to motion sickness varies remarkably. In addition, the pharmacological management of vertigo and motion sickness are clearly
distinct.[2,3]
Finally, when planning treatment, recovery and
compensation must also be considered. Every vestibular stimulus, whether the result of natural motion or disease, has the potential to initiate a process
of compensatory adaptation. The pharmacological
management of compensation is distinct from that
of vertigo and motion sickness and, in fact, agents
that relieve vertigo or motion sickness often block
compensation. There are two key concepts regarding compensation that need to be considered when
planning therapy of vertigo. First, promotion of
central compensation is desirable during the process of recovery from persistent vestibular imbalance, such as after a severe bout of vestibular neuritis (see section 4.3). Second, prevention of
unneeded and counterproductive compensation
may be desirable after a transient vestibular imbalance, such as might be caused by Ménière’s disease (see section 4.2).
2. Neurochemistry of Vertigo
There are at least six neurotransmitters of the
vestibular system involved in the three-neuron arc
between the vestibular hair cells and oculomotor
nuclei that drives the vestibulo-ocular reflex (see
table I). There are also a host of other neurotransmitters that modulate function or are involved in a
more minor way.
Glutamate (and aspartate) is an excitatory transmitter at all three neurons in the arc.[4,5] Alphaamino-3-hydroxy-5-methylisoxazole-4-proprionic
acid (AMPA)–type glutamate receptors are thought
to mediate synaptic transmission, as they do in most
regions of the CNS. N-methyl-D-aspartate (NMDA)–
type glutamate receptors appear to contribute to
© Adis International Limited. All rights reserved.
87
both maintenance of resting discharge of central
vestibular neurons as well as possibly long-term
modulation of synaptic transmission in the central
vestibular structures.[5]
Acetylcholine is both a peripheral and central
agonist affecting muscarinic receptors. However,
peripherally acetylcholine appears only to be involved in the brainstem efferent–hair cell synapse,
which has an uncertain functional significance.
Acetylcholine appears to function centrally as an
excitatory neurotransmitter. Both nicotinic and
muscarinic cholinergic receptors have been demonstrated in all vestibular nuclei with the highest
density within the medial vestibular nuclei.[5] Local injection of cholinergic agonists into the vestibular nuclei induces a postural syndrome in intact
animals that closely resembles the postural syndrome following hemilabyrinthectomy. Acetylcholine is involved with compensation. In animals
that have compensated for vestibular deficits, systemic injection of cholinomimetics induces the reappearance of postural asymmetries.[6] Of five subtypes of acetylcholine receptors presently known,
receptors found in the pons and medulla, presumably those involved with dizziness, are almost exclusively of the muscarinic M2 subtype.[7]
γ-Aminobutyric acid (GABA) is thought to be
the inhibitory neurotransmitter for the commissures in the medial vestibular nucleus as well as
being the inhibitory neurotransmitter between the
cerebellar Purkinje cells and lateral vestibular nucleus.[8] Stimulation of the two types of GABA
receptors, GABAA and GABAB, have similar inhibitory effects on vestibular pathways.[9] Specific
Table I. Neurotransmitters of the vestibular system
Neurotransmitter
Peripheral role
Central role
Glutamate
Excitatory
Excitatory
Acetylcholine
Excitatory for efferent synapse Excitatory
GABA
Unclear
Inhibitory
Dopamine
Excitatory
Noradrenaline
(norepinephrine)
Modulator
Histamine
Unclear
GABA = γ-aminobutyric acid.
CNS Drugs 2003; 17 (2)
88
GABAB agonists, such as baclofen, decrease the
duration of vestibular responses in animal models.[10] GABA is also the inhibitory neurotransmitter for the vertical vestibulo-ocular system, whereas
glycine serves for the horizontal vestibulo-ocular
system.[11]
The mechanisms of action of several other neurotransmitters known to be important targets in the
pharmacological management of vertigo are less
well understood. Histamine is found diffusely in
central vestibular structures. Histamine does not
appear to be a neurotransmitter in the peripheral
vestibular system.[12] Centrally acting antihistamines modulate symptoms of motion sickness.[2]
Stimulation of histamine H1 and H2 receptors excites central medial vestibular nucleus neurons.[4,5]
H3 is an autoreceptor that inhibits histamine release.
Noradrenaline (norepinephrine) modulates the intensity of central reactions to vestibular stimulation[13] and facilitates compensation. Centrally acting adrenergic drugs such as amphetamine and
ephedrine have a prophylactic effect against motion sickness.[13] Dopamine may accelerate vestibular compensation to unilateral labyrinthectomy,
and dopamine blockers may delay recovery.[14]
The neurochemistry of emesis overlaps in part
with the neurochemistry of vertigo and motion
sickness. Acetylcholine and histamine are excitatory neurotransmitters involved in the central
control of emesis.[3] GABA receptor agonists inhibit central emesis reflexes as well as cortical
pathways involved in anticipatory vomiting. Dopamine is more important in emesis than vertigo as it
is an excitatory central neurotransmitter in the chemoreceptor trigger zone and vomiting centre and
is involved peripherally in modulating gut motility. Serotonin is also important in emesis but plays
little or no role in vertigo and a minor role in motion sickness.[15,16] Selective agents that block the
serotonin 5-HT3 receptor subtype reduce nausea
and emesis through a combined action on central
reflexes and peripheral receptors.[17]
© Adis International Limited. All rights reserved.
Hain & Uddin
3. Drugs Used in the Treatment
of Vertigo
Vestibular suppressant and antiemetic drugs are
the mainstay of treatment of vertigo.
3.1 Vestibular Suppressants
Vestibular suppressants are drugs that reduce
nystagmus evoked by a vestibular imbalance. Conventional vestibular suppressants consist of three
major drug groups: the anticholinergics, the antihistamines and the benzodiazepines (see table II).
We will also discuss use of calcium channel antagonists for vestibular suppression, although their
use for this purpose currently is not accepted universally.
3.1.1 Anticholinergics
Anticholinergics are central vestibular suppressants that suppress firing in vestibular nucleus neurons of animals[18] and reduce the velocity of vestibular nystagmus in humans.[19-22] In spite of a
study suggesting effectiveness of glycopyrrolonium
bromide (glycopyrrolate) in Ménière’s disease,[23]
as acetylcholine is not a peripheral neurotransmitter in vestibular afferents it seems unlikely that anticholinergics that have no central action are useful
for vestibular suppression.
Anticholinergics are also useful for managing
motion sickness. Scopolamine, for example, increases motion tolerance.[13] Agents with central
anticholinergic effects are most important, because
anticholinergic drugs that do not cross the bloodbrain barrier are ineffective in controlling motion
sickness.[2] Unlike antihistamines, which are discussed is section 3.1.2, pure anticholinergics are
ineffective for motion sickness if administered after symptoms have already appeared.
All anticholinergics conventionally used in the
management of vertigo or motion sickness have
prominent adverse effects, often including a dry
mouth, dilated pupils and sedation. Scopolamine
and atropine are nonspecific muscarinic receptor
antagonists.[7] It is to be hoped that agents selective
for vestibular subtypes of muscarinic receptors
will eventually be developed or discovered among
CNS Drugs 2003; 17 (2)
Treatment of Vertigo
89
Table II. Vestibular suppressants, arranged in order of preference from most to least commonly used (oral doses unless otherwise stated)
Drug
Dosea
Meclozine
Oral tablets 12.5–50mg every 4-6h Antihistamine, anticholinergic
or chewable tablets 25mg tid
Sedating, precaution in prostatic enlargement
Clonazepam
0.5mg bid
Benzodiazepine
Mildly sedating, drug dependency
Scopolamine
0.5mg patch every 3 days
Anticholinergic
Topical allergy, precaution in glaucoma,
tachyarrhythmia, prostatic enlargement
Dimenhydrinate
50mg every 4–6h
Antihistamine, anticholinergic
Sedating, precaution in prostatic enlargement
Diazepam
2–10mg (one dose) given acutely
orally, IM or IV or 2mg orally bid
Benzodiazepine
Sedating, respiratory depressant, drug
dependency, precaution in glaucoma
Lorazepam
0.5mg bid
Benzodiazepine
Mildly sedating, drug dependency
a
Pharmacological class
Adverse reactions
Doses are all those used routinely for adults and generally will not be appropriate for children.
bid = twice daily; IM = intramuscularly; IV = intravenously; tid = three times daily.
our currently available pharmacopoeia, as these
agents may provide vestibular suppression with
fewer adverse effects.
The transdermal preparation of scopolamine
deserves some special comment. The transdermal
delivery method has a great advantage in that it
bypasses the stomach, making it effective in situations where gastric absorption may be erratic. The
main problem is skin irritation, which usually precludes long-term usage. Anticholinergic adverse
effects such as dry mouth and blurred vision also
limit use. Occasional patients become dependent
on scopolamine patches and develop withdrawal
symptoms (usually nausea and vertigo) when it is
discontinued.[24]
3.1.2 Antihistamines
All the antihistamines in general use for control
of vertigo also have substantial anticholinergic activity, and it seems likely that most or all of their
vestibular suppressant effect derives from their anticholinergic action. It is well accepted, however,
that centrally acting antihistamines can prevent
motion sickness and reduce the severity of its
symptoms even if taken after the onset of symptoms.[2] Antihistamines that do not cross the bloodbrain barrier are not used to treat vertigo. Little is
known about the effect of drugs that affect histamine on vestibular compensation.
In small doses, benzodiazepines are extremely useful for management of vertigo. They are also useful
in prevention of motion sickness.[27] Habituation,
impaired memory and increased risk of falling are
the main problems. Although it has been suggested
that benzodiazepine treatment might impair compensation for vestibular lesions, experimental data
have not borne this out.[28]
Lorazepam is a particularly useful agent because of its effectiveness and simple kinetics. Lorazepam has no active metabolites. Habituation, the
biggest problem,[29] can be avoided by keeping the
dose to 0.5mg twice a day or less. Lorazepam can
also be taken sublingually (1mg) for an acute attack of vertigo. For brief bouts of vertigo, such as
are typically found in Ménière’s disease, lorazepam usually can be discontinued after a few days.
Low doses of diazepam (2mg twice a day) can be
used similarly. Relatively little information is
available about habituation potential and efficacy
of clonazepam, but it appears as effective as a vestibular suppressant as lorazepam.[30] It is also usually prescribed in a dose of 0.5mg twice a day. The
authors prefer to avoid use of alprazolam for vestibular suppression because of the potential for a
difficult withdrawal syndrome. Long-acting benzodiazepines are usually not helpful for relief of
vertigo.
3.1.4 Calcium Channel Antagonists
3.1.3 Benzodiazepines
Benzodiazepine drugs are GABA modulators, acting centrally to suppress vestibular responses.[25,26]
© Adis International Limited. All rights reserved.
Calcium channel antagonists may have utility
in the treatment of dizziness. Two examples of this
group, flunarizine and cinnarizine, are popular
CNS Drugs 2003; 17 (2)
90
Hain & Uddin
antivertiginous agents outside of the USA.[31,32]
Nimodipine has recently been reported as possibly
effective in Ménière’s disease[33] as well as in alleviating peripheral vertigo.[34]
There are several reasons why calcium channel
antagonists might be of help in the management of
vertigo. Some calcium channel antagonists have
been shown to be vestibular suppressants.[31,35]
Vestibular dark cells also contain calcium channels, suggesting the possibility that calcium channel antagonists might change ion concentration in
endolymph.[36] Practically, some calcium channel
antagonists, such as verapamil, have strong constipating effects, which may be helpful in managing
diarrhoea caused by vestibular imbalance. Calcium channel antagonists also often have anticholinergic and/or antihistaminic activity.[37] Finally,
calcium channel antagonists may be effective in
‘vestibular Ménière’s’, as individuals with this diagnosis have a high prevalence of migraine,[38] for
which calcium channel antagonists are often effective.[39]
positories are commonly used in outpatients who
are unable to absorb oral agents because of gastric
atony or vomiting. Sublingual administration is
also useful. Injectables are used in the emergency
room or inpatient settings.
Some antihistamines commonly used as vestibular suppressants have significant antiemetic properties (e.g. meclozine). When an oral agent is appropriate, meclozine is generally the first to be
used, because it rarely causes adverse effects any
more severe than drowsiness. A combination of an
antihistamine (doxylamine) and pyridoxine (vitamin B6) is presently marketed for nausea associated with pregnancy.
Phenothiazines, such as prochlorperazine and
promethazine, are effective antiemetics, probably
because of their dopamine receptor antagonist activity, but they also act at other sites. For example,
promethazine is also an H1 and muscarinic receptor
antagonist. Because these drugs can induce significant adverse effects, such as dystonia, they are
considered second-line drugs whose use should be
brief and cautious. Dopamine antagonists such as
the phenothiazines also have the potential to slow
vestibular compensation.[14]
Drugs that speed gastric emptying, such as
metoclopramide, a dopamine antagonist, and powdered ginger root may be helpful in managing emesis.[40] Although metoclopramide is a potent cen-
3.2 Antiemetics
Table III lists the drugs that are commonly used
for control of nausea in patients with vertigo. The
choice of agent depends on consideration of the
route of administration and the adverse effect profile. The oral agents are used for mild nausea. SupTable III. Antiemetics for use in vertigo, arranged in alphabetical order
Drug
Usual adult dosea
Pharmacological class
Adverse reactions
Granisetron
1mg orally or IV
Serotonin 5-HT3 antagonist
Headache
Meclozine
12.5 or 25mg orally every 4–6h or tid;
25mg chewable tablet tid
Antihistamine, anticholinergic
Sedating, precautions in
glaucoma, prostate enlargement
Metoclopramide
10mg orally tid or 10mg IM
Dopamine antagonist, stimulates
upper gastrointestinal motility
Restlessness or drowsiness,
extrapyramidal
Ondansetron
4mg orally or IV
Serotonin 5-HT3 antagonist
Headache, diarrhoea, fever
Prochlorperazine
5 or 10mg IM or orally every 6–8h or
25mg rectally every 12h
Phenothiazine
Sedating, extrapyramidal
Promethazine
25mg orally every 6–8h, 25mg rectally
every 12h or 12.5mg IM every 6–8h
Antihistamine
Sedating, extrapyramidal
Thiethylperazine
10mg orally or IM up to tid
Phenothiazine
Sedating, extrapyramidal
Trimethobenzamide
250mg orally tid, 200mg IM tid or 200mg
rectally tid
Similar to phenothiazine
Sedating, extrapyramidal
a
Doses are all those used routinely for adults and generally will not be appropriate for children.
IM = intramuscularly; IV = intravenously; tid = three times daily.
© Adis International Limited. All rights reserved.
CNS Drugs 2003; 17 (2)
Treatment of Vertigo
tral antiemetic, it is ineffective in preventing motion sickness.[41] Domperidone, a peripherally acting
dopamine D2 receptor antagonist, has antiemetic
activity as a result of peripheral gastrokinetic action as well as central action on the chemoreceptor
trigger zone. It has similar efficacy to metoclopramide combined with a more favourable safety profile.[42] It is not available in the USA. All of these
medications, being dopamine antagonists, probably slow vestibular compensation.
5-HT3 antagonists such as ondansetron are
highly effective antiemetics that are also sometimes effective in vestibular disorders that manifest with nausea, including some central disorders.[43] These agents do not appear to be helpful
in preventing motion sickness.[15] The high cost of
these agents currently limits their usefulness.
3.3 Agents That Affect the Rate
of Compensation
Although the manipulation of compensation ordinarily is not considered in clinical practice, it
seems reasonable to do so in the interest of improving patient outcomes. If a patient has a permanent
vestibular lesion, for instance an acoustic neuroma
or a persistent vestibular neuritis, it may be desirable to accelerate central compensation. On the
other hand, one might wish to retard compensation
in individuals with a transient vestibular lesion,
such as is often caused by Ménière’s syndrome, as
‘recovery’ nystagmus can be part of the clinical
picture.[44,45]
At this writing, there are few data regarding the
effect on clinical outcomes of pharmacological
agents that alter vestibular compensation.[46] Many
drugs used to treat vertigo are reported to affect the
rate of compensation to vestibular lesions in animal models.[46] Drugs that accelerate compensation are mainly stimulants, and drugs that retard
compensation are mainly sedatives. Most, if not
all, vestibular suppressants retard compensation.
Dopamine agonists accelerate compensation, and
antagonists slow compensation.[14] Adrenergic agonists such as ephedrine and amphetamines occasionally are used in combination with vestibular
© Adis International Limited. All rights reserved.
91
suppressants.[13] Although they are most often
used to counteract the sedative effects of vestibular
suppressants, these stimulants may also help by
promoting vestibular compensation. Amphetamines
have been shown to speed recovery of motor function in stroke.[47] Calcium channel antagonists such
as verapamil also may enhance compensation.[46]
It seems likely that antihypertensive agents, which
act through adrenergic blocking or depleting, may
slow vestibular compensation.
3.4 Agents of Uncertain Efficacy
and Mechanism
Many substances, procedures and devices have
been promoted as effective treatments of vertigo,
and many of these have no clear proof of efficacy.
The tendency to attribute curative properties to a
bewildering number of medications and procedures has been particularly evident in the treatment
of Ménière’s disease.[48,49] It seems likely that
most of these agents have minor or no pharmacological efficacy, but they may function as placebos.
An intriguing member of this group is betahistine. Whereas the antihistamines used in treating
vertigo are usually centrally acting H1 receptor antagonists that are also muscarinic blockers (e.g.
meclozine), betahistine is an H1 receptor agonist
and H3 receptor antagonist.[50] It has been suggested that betahistine decouples the negative
feedback loop controlling histamine release, resulting in central facilitation of histaminergic
neurotransmission in the brain.[51] In therapeutic
doses, administration of betahistine is associated
with reduction in the gain of the vestibulo-ocular
reflex.[51,52] In addition, betahistine increases
blood flow to the inner ear.[53] It has also been suggested that betahistine may accelerate compensation.[54] In the USA, however, as of 2002, the US
FDA does not recognise betahistine as an effective
medication. A recent review concluded that there
was insufficient evidence to say whether or not
betahistine had an effect in Ménière’s disease.[55]
Ginkgo biloba is promoted for the treatment of
Alzheimer’s disease, sexual dysfunction, depresCNS Drugs 2003; 17 (2)
92
Hain & Uddin
sion, headache, claudication, vertigo and tinnitus.[56] Ginkgo biloba may reduce the viscosity of
the blood (literally blood thinning), and it also may
be an antioxidant. A recent study suggests that
Ginkgo biloba is similar in efficacy for vertigo as
betahistine.[57] Like Ginkgo biloba, Vertigoheel, a
homeopathic remedy, has recently been compared
with betahistine and found to be equivalent.[58]
Baclofen and amantadine, both centrally acting
agents used generally in conditions unrelated to
vertigo, are sometimes advocated for vertigo. Baclofen is most commonly used in patients in whom
the diagnosis of microvascular compression of the
eighth nerve is being considered. Amantadine is
used in an attempt to promote compensation in individuals with brain injury.[59] As amantadine is a
dopamine agonist, it seems possible that it might
be useful. No formal studies of efficacy of these
drugs for treatment of vertigo and related conditions are yet available.
4. Drug Treatment of
Individual Conditions
4.1 Benign Paroxysmal Positional Vertigo
Benign paroxysmal positional vertigo (BPPV)
is the single most common type of vertigo, accounting for roughly 20% of all vertigo cases.[60]
BPPV is diagnosed by combining a history of positional vertigo with a typical nystagmus pattern
that appears on positional testing. It is currently
thought that BPPV is caused by the presence of free
otoconia or ‘canaliths’ within the semicircular canals, dislodged from the otolith organs by trauma,
infection or degeneration (see figure 1). The debris
moves to the lowest part of the posterior canal with
changes in head position and causes vertigo and
nystagmus as it tumbles. Symptoms can be very
intense, but fortunately they are brief, since dizziness occurs only while the debris shifts position.
Physical treatments based on manipulation of
the head are the most effective treatment for
BPPV.[61] Drugs are not nearly as helpful for BPPV
as are physical treatments, but antiemetics can be
helpful in patients whose vertiginous spells are fol© Adis International Limited. All rights reserved.
lowed by nausea. Meclozine may also be an effective adjunct to the specific exercises for this condition. In this situation, meclozine is taken prior to
the home exercise in an attempt to prevent motion
sickness and nausea. Ondansetron can be very
helpful in preventing emesis associated with diagnostic or therapeutic manoeuvres. In this situation,
an oral or sublingual dose of 4–8mg is given 30
minutes prior to the manoeuvre. Vestibular suppressants that have little antiemetic activity (e.g. diazepam, lorazepam) are generally unable to reduce
day-to-day symptoms of BPPV to acceptable levels.
Some patients with BPPV are conditioned by
the reliable appearance of vertigo with particular
positions and develop a phobia related to sleeping
on their back or on one side. The phobia can persist
for years after the inner ear condition has resolved.
This entity is called ‘phobic postural vertigo’. Phobic postural vertigo is best treated with exercises,
such as the Brandt-Daroff exercises,[62] that are
desensitising rather than with vestibular suppressant medications. Benzodiazepines can be helpful
in individuals with phobic postural vertigo who
Posterior
semicircular
canal
Utricle
Vestibule
Cupulolithiasis, debris
attached to cupula
Canalithiasis, debris
in posterior canal
Fig. 1. Canalithiasis mechanism of benign paroxysmal positional
vertigo (reproduced with permission from Dr T. Hain).
CNS Drugs 2003; 17 (2)
Treatment of Vertigo
93
otherwise might refuse to participate in the desensitisation procedures.
Endolymphatic sac
4.2 Ménière’s Disease
Ménière’s disease is the second most common
cause of vertigo of otological origin. It is classically attributed to dilation and periodic rupture of
the endolymphatic compartment of the inner ear
(see figure 2). The pathognomonic symptoms include fluctuating hearing, roaring tinnitus, aural
fullness and tinnitus.[63]
Endolymphatic duct
Utricle
Saccule
Stapes
4.2.1 Episodic Treatment
For the episodic vertigo that is common in
Ménière’s syndrome, vestibular suppressants with
or without an antiemetic (table II and table III) are
used to treat the acute attack, and no medications
are used in the interim. These agents do nothing to
correct the vestibular imbalance that causes the
symptoms, but they suppress the manifestations of
the imbalance (vertigo and nausea). Meclozine, diazepam, lorazepam and clonazepam are the most
useful suppressant agents for mild attacks (see table II for doses). Intramuscular promethazine or
prochlorperazine and intravenous diazepam are
used in the emergency department or inpatient setting for treatment of severe attacks. Otherwise,
nausea is managed with sublingual or suppository
preparations. However, these are rarely required
because most patients have some warning involving a change in hearing or aural sensation and can
take meclozine or a similar preparation before the
full-blown attack appears.
4.2.2 Prophylaxis
There is no consensus on prophylaxis of
Ménière’s syndrome,[62,64] and simply treating the
symptoms is considered acceptable. No matter
what prophylactic treatment is used, remission
eventually occurs in 60–80% of cases.[48,49] Because of the great variability in the course of
Ménière’s disease, to have adequate power a clinical trial requires very large numbers, and very few
of these have been performed.
However, it is common practice to advise dietary salt restriction (1–2g salt diet) and use of a mild
© Adis International Limited. All rights reserved.
Fig. 2. Engorged endolymphatic compartment of the inner ear in
Ménière’s disease (reproduced with permission from Northwestern
University, Chicago, IL, USA).
diuretic such as hydrochlorothiazide/triamterene
(Dyazide®1 or Maxide®), as it is felt that this regimen may reduce the frequency of attacks. It should
be noted that Dyazide® may cause significant hyponatraemia, especially in the elderly and in those
who are already salt restricted; in this situation, one
may wish to use an every-other-day dose schedule
and/or monitor serum electrolytes. The Maxide®
form of the drug is scored and can be broken in half.
In patients who cannot tolerate hydrochlorothiazide/
triamterene, diuretics that inhibit carbonic anhydrase, such as acetazolamide or methazolamide,
are occasionally helpful. Spironolactone may be
used in women with perimenstrual flare-ups. Calcium channel antagonists such as verapamil may
also be helpful, although very few formal studies
of efficacy are available.[33]
Patients are also encouraged to avoid caffeine
and stop smoking. Daily use of vestibular suppressants, as a prophylactic treatment, is generally discouraged out of concern that they may impair vestibular compensation. Some authors recommend a
1 Use of tradenames is for product identification only and
does not imply endorsement.
CNS Drugs 2003; 17 (2)
94
Hain & Uddin
brief course of corticosteroids, especially if a surgical treatment is being considered.[65]
4.3 Vestibular Neuritis
Vestibular neuritis is a monophasic, self-limited
condition that presents with vertigo, nausea, ataxia
and nystagmus.[66] These symptoms are brought
about by an acute imbalance in vestibular tone
combined with directionally asymmetrical response to head rotation. Vestibular neuritis is thought
to be caused by a viral infection of the vestibular
portion of the eighth cranial nerve. Mumps and
various types of herpes viruses are possible infectious agents.
A peculiar aspect of this condition is that hearing is not impaired; the viral infection is hypothesised to selectively affect vestibular fibres of the
eighth nerve, sparing the neighbouring fibres carrying cochlear information. When hearing is also
affected, the syndrome is termed ‘labyrinthitis’.
Similar presentations can arise from noninfectious
aetiologies, such as vascular compromise.
Evidence suggests that almost all patients with
vestibular neuritis have satisfactory resolution of
their symptoms as a result of a combination of recovery of function and central compensation.[66]
Severe distress associated with constant vertigo,
nausea and malaise usually lasts 2 or 3 days. Many
patients are ready to return to their regular activities after a week, and it is likely that in these instances there has been only a transient and incomplete vestibular lesion. However, a substantial
proportion of patients may take as long as 2 months
to improve. On subsequent testing, this group often
is demonstrated to have a continued unilateral paralysis of vestibular function.
Unfortunately, it is not possible to predict
whether a patient will have a transient vestibular
imbalance and recover quickly or a permanent loss
of function associated with a poorer prognosis. The
implication for treatment is that if a permanent vestibular imbalance is made more tolerable by a vestibular suppressant medication or if central compensation is partially blocked by a benzodiazepine
or agent with dopamine receptor blocking activity,
© Adis International Limited. All rights reserved.
the patient may not recover as rapidly as otherwise.
Even bedrest may be poorly conceived, since animal studies have shown that immobilisation delays
recovery from experimental vestibular lesions.[67]
Thus, the treatment strategy for vestibular neuritis involves use of as few medications as possible
and encouraging activity as much as is practical. In
the first few days of the illness, patients usually
severely restrict their activities, as rapid head
movements and activities such as sitting up or turning over in bed may cause increased vertigo. Vestibular suppressants and antiemetics are commonly
used at this point, prescribed as suppositories if
necessary. By the third day, it is usually possible
to greatly reduce usage of vestibular suppressants,
and the patient should be encouraged to increase
activity as tolerated.
Most patients recover completely within 2
months. Those that do not usually have a significant fixed vestibular paresis combined with central
dysfunction that slows their compensation. For example, patients with alcoholic cerebellar degeneration or individuals of advanced age may recover
much more slowly.[68,69] Such patients can benefit
from a programme of physical therapy incorporating gait training and visual-vestibular exercises.
Surgical treatment is not indicated for vestibular
neuritis.
4.4 Bilateral Vestibular Paresis
Bilateral vestibular paresis presents with oscillopsia, ataxia and mild vertigo.[70] Typically, patients have recently been treated for a serious infection, most often osteomyelitis or peritonitis.
The infection is treated for several weeks with an
ototoxic antibacterial (of which gentamicin is the
most commonly encountered). The symptoms of
bilateral vestibular paresis, ataxia and oscillopsia
manifest themselves when the patient recovers
from their infection and tries to walk.
When examined, these patients can read the vision chart with their head still but lose at least four
lines of acuity when their head is gently oscillated
from side to side. They are unable to stand in the
tandem Romberg position (heel to toe, arms crossed)
CNS Drugs 2003; 17 (2)
Treatment of Vertigo
with eyes closed for 6 seconds. Hearing is generally little affected. Rotatory chair testing is the best
way to confirm this diagnostic impression.
The long-term prognosis of patients with ototoxicity is only fair. A lengthy exposure to an
aminoglycoside antibacterial such as gentamicin
can cause a loss of vestibular hair cells.[71] As there
is no mechanism for hair cell regeneration in humans, the loss is permanent. Nevertheless, unless
there is a superimposed cerebellar lesion, substantial recovery is the rule. Most patients return to
productive work within 1–2 years of exposure, although they continue to have impaired balance in
situations where other senses are not informative,
such as in the dark or while walking on an uneven
surface. Recovery is felt to be a result of a combination of CNS plasticity and sensory substitution.[72]
It is important to note that medications that reduce symptoms of other forms of otological vertigo, such as the vestibular suppressants and most
antiemetics, generally make symptoms worse in
bilateral vestibular paresis. Vestibular suppressants must be eliminated in the management of this
condition. It is also prudent to avoid medications
with potential vestibular suppressant activity, such
as calcium channel antagonists, and those that
have central anticholinergic adverse effects (e.g.
many of the tricyclic antidepressants). Patients
should be warned to avoid subsequent exposure to
ototoxic drugs, especially gentamicin and loop diuretics (e.g. furosemide, bumetanide and ethacrynic
acid). If a loop diuretic is necessary, bumetanide is
the least ototoxic.[73] These patients should also be
advised to avoid loud noises, as they are likely to
be more vulnerable to noise-induced hearing loss
than the general population. Theoretically, in individuals with some remaining vestibular function,
medications that promote central plasticity might
be helpful in treating bilateral vestibular paresis,
and those that retard compensation, such as dopamine antagonists, would slow or prevent recovery.
Bilateral vestibular paresis often responds well
to physical therapy. No surgical treatment is cur© Adis International Limited. All rights reserved.
95
rently available for bilateral vestibular loss. Prosthetic devices are presently being developed.
4.5 Central Vertigo
Vertigo caused by CNS dysfunction, or ‘central
vertigo’, is unusual. In the emergency room setting
or otolaryngology clinic, a central cause of vertigo
is identified in less than 5% of cases. Even in neurology settings, central vertigo typically accounts
for only about 20% of diagnoses in patients complaining of vertigo.[74] Central vertigo is largely
caused by vascular disorders. In the authors’ experience, vertigo associated with migraine, stroke or
transient ischaemia accounts for the majority of
cases of central vertigo. A large number of individual miscellaneous neurological disorders, such as
seizures, multiple sclerosis, posterior fossa tumours and the Arnold-Chiari malformation, make
up the remainder.
In central vertigo, a prolonged duration of
symptoms is common. Although patients with peripheral vestibular imbalance typically recover
within days to months, patients with central vertigo may continue to be distressed by ataxia, nausea and the illusion of motion for years. Presumably, the persistence of symptoms in patients with
central vertigo reflects a defect in the central mechanisms that usually compensate for vestibular lesions.
A combination of headache and vertigo is a
common presentation, particularly in women in
their mid-30s. In most instances, these symptoms
are caused by vertebrobasilar migraine, and a prophylactic drug should be tried. [75] A sustainedrelease preparation of verapamil 120mg is often
effective.[39] If the patient does not tolerate verapamil (constipation is the most common problem),
a trial of amitriptyline can be made. When treating
vertigo, amitriptyline is favoured over the newer
selective serotonin reuptake inhibitor (SSRI) family of antidepressant medications because of its anticholinergic and antihistamine activity. Pizotifen,
an antihistamine with a chemical structure similar
to the tricyclic antidepressants, can also be effective.[76] β-Blockers form the third line of treatment,
CNS Drugs 2003; 17 (2)
96
Hain & Uddin
but do not have the vestibular suppressant effects
of verapamil and amitriptyline.[77] Valproic acid
can be used for migraine prophylaxis, but adverse
effects, including weight gain and hair loss, limits
its usefulness.[77] Some authors have suggested
that acetazolamide therapy may also be effective
in this situation, but its significant adverse effects
limit its usefulness.[78]
Another common presentation of central vertigo is in patients with a known central lesion, for
whom the goal is to reduce symptoms of vertigo or
ataxia. Benzodiazepines such as lorazepam, clonazepam and diazepam are frequently helpful (see
table II for doses), but one must be wary of habituation and physical dependence.[79] Meclozine
taken in a dose of 25mg twice daily is occasionally
successful. Dopamine blockers such as prochlorperazine can be tried. The antiemetic ondansetron
may be helpful when central vertigo does not respond to the usual agents.[80] Similarly, occasional
patients with oculomotor signs localising to the
vestibulocerebellum are helped by acetazolamide
therapy.[81]
Carbamazepine or oxcarbazepine, in doses appropriate for neuralgia or epilepsy, can be tried in
patients having vertigo combined with an abnormal EEG or brief episodic symptoms, ‘quick spins’,
that have not responded to other medications.
Gabapentin, a glutamate blocker, may also be used
in this situation.[82] Baclofen is used similarly. In
this situation, also called ‘vestibular paroxysmia’,
one might be treating epilepsy, microvascular
compression of the eighth nerve, irritation of the
vestibular nerve caused by a neurotrophic virus,
postsurgical vestibular neuralgia or intrinsic brainstem lesions.[83] Gabapentin is also generally useful as a suppressor of nystagmus.[82]
Physical therapy emphasising effective use of
appliances such as canes, walkers and footwear is
often useful.
4.6 Psychogenic Vertigo
Psychogenic vertigo is vertigo that is caused by
an independently diagnosable psychiatric problem
such as anxiety, depression, somatisation or malin© Adis International Limited. All rights reserved.
gering. Psychiatric-associated vertigo is the coexistence of an organic vertigo with an independently diagnosable psychiatric condition, such
as anxiety, which might be comorbid or reactive.
Often ‘dizziness’ is a more appropriate term to use
in this situation than ‘vertigo’, as these patients
may not be able to define their symptoms in terms
of an inappropriate movement of the environment,
but rather use terms such as ‘light-headed’ or
‘woozy’.
Because of inadequacies of our diagnostic methodology, it is difficult to determine the proportion
of these patients in the ‘dizzy’ population as it presents to the clinician or at large in the population.
Some authors indicate that as many as 50% of all
patients with dizziness have a ‘functional’ source
of complaints.[84] However, this large percentage
results from an algorithm where patients with no
findings on testing were assigned this diagnosis.
This process is obviously fraught with peril, given
that patients for whom the diagnostic process may
have failed are placed in the same category as those
who do indeed have a psychological origin of symptoms. In the first author’s practice, only about 5%
of patients are assigned the ‘psychogenic’ diagnosis. A high proportion of patients with chronic (organic) vertigo develop secondary reactive psychiatric complications such as panic disorder and
depression, which are important to treat on their
own merits.
Treatment is based on the psychiatric diagnosis.
Anxiety and panic are the most common diagnoses, and benzodiazepines are the mainstay of treatment. As considerably larger doses of these medications are needed for anxiety than for vestibular
suppression, and because it is likely that these patients will need long-term treatment, psychiatric
referral can be very useful in these cases. SSRIs
can also be used, but they are less useful. Although
they have an advantage over the benzodiazepines
in that they are not habituating, SSRIs are not as
reliable as the benzodiazepines for management of
anxiety, and they can also contribute to nausea and
ataxia.[85,86]
CNS Drugs 2003; 17 (2)
Treatment of Vertigo
Depression is an extremely unusual cause of
vertigo. When it is very clear that depression is
significant, one of the SSRI family, such as sertraline, may be used. These agents can result in some
minor nausea as well as increase anxiety, and for
this reason should be used with caution.[87,88] Almost all antidepressants increase ataxia.[89,90]
Somatisation syndrome and malingering are
also commonly encountered in patients with a potentially disabling but subjective symptom such as
dizziness. No drug treatments are available for either diagnosis. In these situations, the clinician’s
goal is to reduce inappropriate expense and use of
healthcare resources.
4.7 Treatment of Undetermined and
Ill-Defined Causes of Vertigo
Regardless of whether one is practising in the
emergency room, otolaryngology clinic, neurology clinic or a general medical setting, variants of
unlocalisable diagnoses such as ‘unknown diagnosis’, ‘vasovagal’ syncope, ‘hyperventilation syndrome’, ‘post-traumatic vertigo’ and ‘nonspecific’
dizziness are the most common single ‘cause’ of
dizziness reported. Between 38 and 52% of diagnoses fall in this category across many series.[74,84,91,92] The unifying feature of these diagnoses is the lack of abnormality on otological and
neurological examinations.
Treatment is necessarily empirical in vertigo of
undetermined origin. In the first author’s practice,
we ask the patient to log their symptoms on a calendar. Next, for patients already taking medication, we withdraw drugs that could affect the vestibular system, recording symptoms over 2 or more
weeks. This strategy may identify individuals with
ataxia caused by medication. One must be very
careful in this situation not to eliminate a medication critical to the patient’s well being. For example, when one withdraws an antihypertensive such
as a calcium channel antagonist that has vasodilator properties, angina may be precipitated.
Several drugs are then tried. If the patient does
not respond to daily meclozine, this may be replaced by a small dose of clonazepam or lorazepam.
© Adis International Limited. All rights reserved.
97
It is generally difficult to exclude mild Ménière’s
disease, and salt restriction and a diuretic such as
hydrochlorothiazide/triamterene may be tried. A trial
of migraine prophylaxis with sustained-release
verapamil (120mg of a sustained-release preparation each morning) is sometimes helpful in patients
with dizziness and headaches or patients with the
diagnosis of ‘vestibular Ménière’s’. Carbamazepine or oxcarbazepine is tried for the symptom of
‘quick spins’ alluded to in section 4.5. Gabapentin
is also a reasonable drug to try empirically for central vertigo.
Patients who do not respond to the above regimens are followed at 3- to 6-month intervals and
undergo yearly audiometric screenings. This is important, as occasionally the symptoms of individuals
with small acoustic neuromas or early Ménière’s
disease will evolve into an identifiable clinical presentation. It is often helpful to re-examine patients
quickly when there is an acute flare of symptoms,
as in this way one can sometimes diagnose intermittent conditions that can have normal intercurrent examinations, such as BPPV and Ménière’s
disease.
5. Conclusion
Vertigo is caused by several broad categories of
illness. The most common forms of otological vertigo are BPPV, Ménière’s disease, vestibular neuritis and ototoxicity. Treatment of these disorders
may be very effective but depends critically on attaining the correct diagnosis. Central vertigo has a
poorer prognosis than otological vertigo, and the
approach to treatment is largely empirical. Psychogenic vertigo is difficult to diagnose, and the treatment approach critically depends on the diagnosis.
Psychiatric referral will be needed in many of these
cases. The treatment of patients with dizziness of
unknown cause is also empirical. An organised and
methodical approach to management of these patients is essential to maximise patient satisfaction.
CNS Drugs 2003; 17 (2)
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Hain & Uddin
Acknowledgements
The authors have provided no information on sources of
funding or on conflicts of interest directly relevant to the
content of this review/study.
20.
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Correspondence and offprints: Dr Timothy C. Hain, Departments of Neurology, Otolaryngology and Physical Therapy/
Human Movement Science, Northwestern University, 645
N. Michigan, Suite 1100, Chicago, IL 60611, USA.
E-mail: t-hain@northwestern.edu
CNS Drugs 2003; 17 (2)