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Otoneurología 2014:
comprendiendomejor los trastornos vestibulares
SUPLEMENTO
original
Actual.Med.
2014; 99: (791). Supl. 37-60
avoided with gradually increasing doses. Laboratory testing is
recommendabletomonitor liverfunction.Rarely,valproatecauses
agranulocytosis, thrombocytopenia or pancreatitis. Valproate is
contraindicated in patients with liver disease, and it should be
avoided by women of childbearing age; it is contraindicated in
pregnancybecauseof risk spinabifidaandothermalformations.
Valproate is approved in the European Union for the
treatmentofepilepsyandbipolardisorder, and insomeEuropean
countries,amongwhichSpain isnot included, topreventmigraine
headaches.
Topiramate and valproate significantly reduce migraine
frequency and increase the proportion of responders compared
with placebo, topiramate has a slight but significant advantage
over valproate (24,25). The two anticonvulsants are classified
as medications with established efficacy (level A) in migraine
prevention (26,27). Gabapentine, oxcarbazepine, vigabatrin and
lamotrigineare ineffective,whereas thereareno controlled trials
withpregabalin inmigraineprophylaxis (28, 29).
Variousauthorshavestudiedtheeffectivenessoftopiramate
inVM. CarmonaandSettecase, ina small open trialwithpatients
with migraine-vertigo and auditory symptoms, found that crisis
disappeared inall patientsandauditorysymptomsstabilized (30).
Gode et al. in an observational prospective study showed that
topiramatewas effective in reducingboth the frequency and the
severityof vertigoepisodes andmigraineattacks (31).
Inone small clinical trial valproatewas effective in reducing
migraine attacks although it did show no effect on vestibular
symptoms neither in rotatory chair test (32). On the contrary, in
another studywithvalproicacid theauthorsobservedadecrease
in the frequency of both headache and vestibular symptoms,
although it does not cause any statisticallymeaningful change in
ENGfindings (33).
Although lamotrigine is considered ineffective in migraine
prophylaxis, someauthors have reportedpositive results onaura
symptoms. Bisdorff have pointed out that anticonvulsantswhich
areeffective in treatingauraappear toexhibitmorepotential for
treatingVM (34). A retrospective study inpatientswithmigraine
related vertigo with lamotrigine in increasing doses, proved a
significant reduction in vertigo frequency but not in headache
frequency (35).
Clonazepam,abenzodiazepinewithantiepilepticproperties,
was judged as possibly ineffective for episodic migraine
prevention (36). It has been used inVM in various observational
studies although it isdifficult toevaluate itsefficacy sinceanxiety
is a comorbid condition (17, 21).
Antidepressants
Amitriptyline, a tricyclicantidepressant, has longbeenused
inmigraine prophylaxis. Its activity as antidepressant appears to
berelatedto inhibitionofserotoninandnorepinephrinereuptake,
and it couldbealsoaputativemechanismof action inmigraine.
Dry mouth, nasal congestion, constipation, urinary
retention, blurred vision and confusion are all anticholinergic
side effects, while orthostatic hypotension is attributable to
antagonism of α
1
adrenoceptors, and sedation and weight gain
to blockade of H
1
-histamine receptors. Antihypertensive drugs,
suchasbeta-blockers,mayaggravate theorthostatichypotension
causedbyamitriptyline.
Amitriptyline and venlafaxine are considered a second
choice drug (level B) for migraine prophylaxis according to the
European Federation of Neurological Societies (EFNS), and
American Academy of Neurology (AAN) - American Headache
Society (AHA) guidelines (26,27). Nonetheless, the Canadian
Headache Society guideline classified amitriptyline as strong
recommendation and high quality evidence, and it is considered
afirst choicedrug (36).
Amitriptyline has been reported in VM by some authors
in descriptive studies (17,21). Nortriptyline has been also used
successfully in VM patients in retrospective studies (17,18,19).
Occasionally selective serotonin reuptake inhibitors have
been used in the prophylaxis of VM (17,37). Neither of these
antidepressants has been tested as a single medication in
randomized clinical trials.
It is important to keep in mind that dosage in VM is
considerably lower than thoseused for depression.
Beta-blockingdrugs
Beta-blockers act antagonizing the effects of endogenous
cathecolamines at β-adrenoceptors by competitive binding to
these receptors. Beta-blockers differ in their affinities for β
1
and
β
2
receptors. Propranolol, timolol andnadolol are nonselective β
antagonists while atenolol, bisoprolol, metoprolol and nebivolol
are β
1
selective antagonists, also known as cardioselective since
β
1
receptors are locatedmainly in the heart. Although themajor
indications of beta-blockers are hypertension, ischemic heart
disease, heart failureandarrhythmias, theyarealsoapproved for
other purposes including migraine prophylaxis. The mechanism
of action in this indication isunknown.
Common adverse effects of β-adrenergic blocking drugs
are bradycardia, orthostatic hypotension, fatigue, erectile
dysfunction. Beta-blockers are contraindicated in patients with
asthma due to the risk of bronchoconstriction. They also should
be used with caution in patients with type 2 diabetes mellitus
with riskof hypoglycemia.
Metoprolol, propranolol and timolol are the beta blockers
with highest strength of evidence of efficacy (level A); atenolol
and nadolol are probably effective (level B) whereas nebivolol
is considered as possibly effective (level C) according to the
classification of the AAN /AHS (26). Metoprolol can be used in
pregnancy.
At present, no randomized clinical trials haveevaluated the
efficacy of beta-blockers in VM as a single treatment. Various
studies describe the use of propranol, metoprolol or atenolol in
VMpatients, but the authors report global outcomeof groups of
patients treatedwith several pharmacological groups (17,18,21).
It is worth noting that a prospective, randomized, placebo-
controlled multicenter study is currently being conducted by
Strupp to investigate the prophylactic action of metoprolol on
attack frequency inVM (PROVEMIG) (38).
Calcium channel antagonists
Calciumantagonistsactbyblockadeofvoltage-gatedL-typed
Ca
2+
channels in cardiac, skeletal and smooth muscle. Calcium
channel-blocking drugs are used primarily as antihypertensive
agents and in the treatment of angina pectoris. Moreover,
nimodipine and nicardipine are considered cerebral vasodilators
due to their affinity for cerebral blood vessels. Cinnarizine and
flunarizineareH
1
antihistamines. Themechanismor siteof action
of calcium channel antagonists inmigraine is uncertain. Various
hypotheses have been considered: blocking of 5-HT release,
interferingwithneurovascular inflammationor cortical spreading
depression, inhibition of CGRP release, enhancing of analgesic
effect. Four types of calcium channels have been reported in
neurons: L, T, N, P/QandR.
Flunarizine in Europe and verapamil in USA are the most
common drugs of this group used in migraine prevention. The
main side effects of flunarizine areweigh gain and somnolence,
but it also inducedparkinsonism. These risks areminimizedwith
a lowdose (5mg).
Flunarizine has been shown to be effective in migraine
prophylaxis inseveral studies.EFNSguidelineclassifiedflunarizine
with level A (27). There is not sufficient evidence to support
the use of verapamile, nifedipine and nimodipine for migraine
prophylaxis (26).
Flunarizinewas used for benign recurrent vertigo in several
old studies. Recently, Lepcha et al. has carried out a randomized
controlled clinical trial toevaluate theeffectivenessof flunarizine
in the prophylaxis of VM (39). Flunarizine plus betahistine and
vestibularexercises significantly reduce the frequencyand severity
of vestibular episodes as compared with only betahistine and
vestibular exercises. Currently, there are no studies on efficacy in
