Eur Arch Otorhinolaryngol
DOI 10.1007/s00405-013-2786-4
OTOLOGY
Flunarizine in the prophylaxis of migrainous vertigo:
a randomized controlled trial
Anjali Lepcha Sophia Amalanathan
Ann Mary Augustine Amit Kumar Tyagi
Achamma Balraj
Received: 11 July 2013 / Accepted: 16 October 2013
Springer-Verlag Berlin Heidelberg 2013
Abstract Migrainous vertigo is a common cause of diz-
ziness presenting to an otorhinolaryngology/otoneurology
clinic. Although it causes a substantial burden to the
individual and society there are no randomized controlled
trails on prophylactic medication for this condition. Flu-
narizine, a calcium channel blocker has been used effec-
tively in both migraine and vestibular conditions. This
randomized control trial was undertaken in a tertiary aca-
demic referral center to evaluate the efficacy of flunarizine
in patients with migrainous vertigo when compared to non-
specific vestibular treatment of betahistine and vestibular
exercises. The effect of flunarizine on two particularly
disabling symptoms of vertigo and headache was studied.
A total of 48 patients who were diagnosed with definitive
migrainous vertigo completed the study of 12 weeks
duration. Patients in arm A received 10-mg flunarizine
daily along with betahistine 16 mg and paracetamol 1 gm
during episodes, and arm B received only betahistine and
paracetamol during episodes. Symptom scores were noted
at the start of the study and at the end of 12 weeks. Ana-
lysis of the frequency of vertiginous episodes showed a
significant difference between arm A and arm B
(p = 0.010) and improvement in severity of vertigo
between the two groups (p = 0.046). Headache frequency
and severity did not improve to a significant degree in arm
A as compared to arm B. The main side effects were
weight gain and somnolence and this was not significantly
A. Lepcha (&)
A. M. Augustine
A. K. Tyagi
A. Balraj
Department of ENT, Unit IV, Christian Medical College and
Hospital, Vellore 632004, Tamilnadu, India
e-mail: anjalilepcha@yahoo.com
S. Amalanathan
Department of ENT, Indira Gandhi Medical College and
Research Institute, Puducherry 605609, India
different between the two groups. Flunarizine (10 mg) is
effective in patients with migrainous vertigo who suffer
from considerable vestibular symptoms.
Keywords Flunarizine
Migrainous vertigo

Episodic recurrent vertigo
Migraine disorder

Prophylaxis
Introduction
Patients with migraine often complain of dizziness or
vertigo during or in between attacks. Various terminologies
have evolved to describe this condition such as migraine-
associated vertigo, migraine-related vestibulopathy, ves-
tibular migraine, or migrainous vertigo [14].
Migrainous vertigo (MV) can be defined as a vestibular
syndrome caused by migraine that can present as sponta-
neous or positional vertigo lasting seconds to days,
accompanied by migrainous symptoms [1]. Like migraine,
MV is a diagnosis by exclusion and cannot be diagnosed by
specific tests. An operational clinical criterion (definite and
probable) has been proposed based on the IHS classifica-
tion of headaches [1]. Various authors have emphasized the
migrainous origin of episodic vertigo that can occur even in
the absence of headache [1, 5, 6]. Vestibular migraine has
been recognized as a separate entity from migraine with
brainstem aura (earlier basilar migraine) only recently. A
new set of diagnostic criterion has been proposed jointly by
the Committee for Classification of Vestibular Disorders of
the Barany Society and the Migraine Classification Sub-
committee of the International Headache Society (IHS) [7].
A diagnosis of vestibular migraine is considered in the
presence of vestibular symptoms of any type, history of
migraine and a temporal association between the two, all
123

other causes of vestibular symptoms having been ruled out
[8].
Vestibular symptoms in MV can be quite debilitating,
but the current evidence for both acute and prophylactic
treatment consists of a few studies on the successful use of
prophylactic anti-migraine medications [9]. Earlier studies
have been non-randomized trials in the western population
[10]. Flunarizine is a selective calcium channel blocker
indicated as a maintenance treatment for classical and
common migraine [1113]. The side effects of flunarizine
are minimal and infrequent, and good compliance has been
reported because it is taken as a once a day dose. The main
side effects of weight gain and drowsiness are similar to
propranolol, another drug with proven efficacy used in
migraine prophylaxis [14, 15]. Although extrapyramidal
side effects have been reported earlier in calcium channel
blockers (CCB) including flunarizine, more recent studies
have not shown an association between parkinsonism and
CCB [16, 17]. The efficacy of flunarizine in migraine
headache prophylaxis has been confirmed in both open and
controlled trials [18].
A search of English literature showed no randomized
controlled studies evaluating the effectiveness of flunari-
zine with respect to MV. Hence, the purpose of this study
was to evaluate the effectiveness of flunarizine in the
prophylaxis of MV in a cohort of patients.
Materials and methods
This study was carried out in the audiovestibular clinic at
our tertiary care referral hospital after obtaining clearance
from the institutional review board and ethical committees
and done in accordance with the ethical standards laid
down in the 1964 Declaration of Helsinki. Patients who
attended this clinic between July 2010 to August 2011 with
complaints of headache and vertigo were assessed using a
structured, pretested questionnaire (Appendix). This improvement of symptoms. For reporting improvement of
self-reported questionnaire was used to obtain information
about the type and duration of headache, aura if present and
vestibular symptoms. It also assessed the severity and
frequency of headache and vertigo: the two most disabling
symptoms of MV. A numbering system was used, based on
patients perception of frequency and severity of headache
and vertigo symptoms. The patient chose 1 score out of 6
scores for frequency of symptoms. High-frequency scores
were 14 (where score 1was[5 episodes/week, 2 was 34/
week, 3 was 1/week, 4 was 23/month,) low-frequency
scores were 56 (where 5 was 23/3 months, 6 was \2/
3 months.) For reporting severity of symptoms, the patient
chose 1 out of 5 scores. 1 was extremely mild symptoms, 2
was mild, 3 was moderately severe, 4 was severe and 5 was
extremely severe.
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Eur Arch Otorhinolaryngol
Ear, nose, throat and neurotological examination was
done followed by specific audiovestibular investigations
and imaging when required. Fifty-two consecutive patients
between the age of 18 and 75 who were diagnosed as MV
based on the Neuhauser et al. [1] criteria were enrolled in
this study after they gave an informed written consent.
Patients with associated benign paroxysmal positional
vertigo, Menieres disease, chronic discharging ear, past
history of ear surgery, profound hearing loss, stroke,
intracranial tumors or those on calcium channel blockers
for hypertension were excluded from the study.
On the assumption that specific prophylactic treatment
for migraine would reduce symptoms by 80 % and that
symptomatic treatment in the control arm would reduce
symptoms by 40 %, an estimated 24 patients per arm
would be required to provide a result with a 95 % confi-
dence interval for a power of 80 %. Informed consent was
obtained from all patients prior to their recruitment.
Patients were subsequently block randomized (blocks of 4)
into two treatment arms, A and B using computer-gener-
ated random numbers. Allocation of patients into the two
arms was done by the primary investigator based on the
computer-generated numbers. Initial evaluation and fol-
low-up of these patients were done by clinicians working in
the unit including the primary investigator.
Patients in treatment arm A received 10-mg flunarizine,
once daily at bed time. Betahistine 16 mg thrice a day for 48 h
was given with the onset of a vertiginous attack, and para-
cetamol 1 g was taken for acute attacks of headaches. Patients
in treatment arm B received symptomatic treatment with
betahistine and paracetamol like in arm A. Both groups were
instructed to carry out active vestibular exercises. All patients
were reviewed at the end of 12 weeks and their symptoms of
vertigo and headache were reassessed using another ques-
tionnaire. Patients were not shown their previous scores and
asked to mark based on recall of symptoms in the preceding
12 weeks. An additional score was added to evaluate the
severity of symptoms the patients chose 1 out of 5 scores.
Little improvement scores were 02, marked improvement
scores were 3 and 4 where 0 was no improvement, 1 was mild
improvement, 2 was moderate improvement, 3 was excellent
improvement and 4 was completely asymptomatic. Any
adverse effects were also noted.
The results were analysed using SPSS version 16.0.
Tests of significance were done using Fishers exact test
and Chi-square test.
Results
The demographic profile of the subjects enrolled is given in
Table 1, and age and sex distribution of subjects is given in
Eur Arch Otorhinolaryngol

Table 1 Demographic profile of patients in the study age of onset of MV irrespective of gender was 32 years of
Frequency Percentage
age. Figure 1 shows the frequency of associated symptoms
such as visual, olfactory, motor and sensory aura that
Sex occurred along with the MV attacks. Visual aura (experi-
Male 18 34.6 enced in 85.4 % of patients) was the commonest associated
Female 34 65.4 symptom followed by other associated symptoms such as
Total 52 100 phonophobia (75 % of patients) and photophobia (68.8 %
Age of patients), numbness and tingling (31.5 % of patients).
B24 years 12 23.1 Olfactory aura described as a distortion/perceiving strange
2534 years 23 44.2 odors preceding or accompanying an attack was present in
C35 years 17 32.7 20.8 % of patients. Tinnitus was an accompanying symp-
Total 52 100.0 tom in 19 % of patients and a similar number had fluctu-
ating hearing levels during attacks. Decreased levels of
vigilance (described by patients as being sleepy/foggy and
Table 2 Age and sex distribution of subjects in the treatment arm unclear headed) were experienced by 41.6 % and motor
and control arm
weakness by 18.8 % of patients. Dizziness with headaches
Treatment arm Control arm Total p value was experienced by 79 % of patients and 66 % had asso-
(Arm A) (Arm B) ciated imbalance during attacks.
Sex Headache lasted less than an hour in 18 (34.6 %)
Male 10 8 18 0.77 patients and in 17 (32.7 %), it lasted more than 24 h.
Female 16 18 34 Headaches of at least moderate to severe intensity were
Total 26 26 52 reported in 77 % of subjects.
Age
Of the 52 patients initially enrolled, 48 completed the
B24 years 6 6 12 0.28
study. One patient from Arm A and three patients from Arm
2534 years 14 9 23
B were lost to follow-up even after numerous attempts were
made to contact them both via telephone as well as by post.
C35years 6 11 17
Therefore, 25 patients in Arm A completed the study and 23
Total 26 26 52
in Arm B. Table 3 shows vertigo and headache symptoms at
3 months of follow-up in the treatment and control arms.
Table 2. There was no statistical difference between the Analysis of the difference in frequency between the epi-
two groups in terms of sex distribution (p = 0.770, Chi- sodes of vertigo before and after treatment in both arms
square test) and age distribution (Chi-square test, showed significant improvement in Arm A compared to
p = 0.28). All 52 patients studied had headache and ver- Arm B (p = 0.010, Fishers exact test). There was an
tigo. There were 23 patients (44 %) between 25 and improvement in the severity of vertigo after treatment in
34 years, and 65 % of subjects were females. The mean arm A compared to Arm B (p = 0.046, Fishers exact test).

Fig. 1 Frequency of various 90

Percentage of patients

associated symptoms that occur

80
during a typical attack
70
60
50
40
30
20
10
0

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Table 3 Comparison of vertigo and headache characteristics post Discussion

treatment in the treatment and control arms
A B p value Migrainous vertigo is not a rare entity and its prevalence
has been reported as 7 % in a dizziness clinic group and
Vertigo frequency 9 % in a migraine clinic group [1]. It is difficult to
High frequencya 3 11 14 0.010 determine the prevalence of MV mainly because the entity
Low frequencya 22 12 34 by itself is an evolving concept, and internationally
Total 25 23 48 approved diagnostic criteria were published only in 2012
Improvement in vertigo severity [8]. The criteria used in this study were proposed by
Little improvementb 3 9 12 0.046 Neuhauser et al. [1]. Definite MV accounted for only a
b
Marked improvement 22 14 36 third of migraineurs with a history of vestibular vertigo. In
Total 25 23 48 general, the prevalence of MV was higher among women
Headache frequency and highest in the reproductive age group. The demo-
High frequencya 8 10 18 0.38 graphic profile of our patients (Table 1) are similar to
Low frequencya 17 13 30 other studies [19]. At the age of onset of migraine
Total 25 23 48 symptoms, the severity of headache was more and this had
Improvement in headache severity attenuated over time when compared to that of vertigo
Little improvementb 6 10 16 0.22 which had become more severe. This type of pattern in the
Marked improvementb 19 13 32 natural course of the disease has been mentioned earlier
Total 25 23 48 [20]. Absence or attenuation of migrainous headache
A is the treatment arm and B is the control arm
during vertiginous attacks may be due to an interaction of
a
High frequency (scores 14), low frequency (scores 56) where
vestibular and trigeminal mechanisms [21]. We found that
score 1 is [5 episodes/week, 2 is 34/week, 3 is 1/week, 4 is 23/ 52.6 % of patients who described their vestibular symp-
month, 5 is 23/3 months, 6 is \2/3 months toms as severe also experienced photophobia, phonopho-
b
Little improvement (scores 02), marked improvement (scores 3, 4) bia, visual and other sensory and motor auras. These
where 0 is no improvement, 1 is mild improvement, 2 is moderate phenomena may be of diagnostic importance as they may
improvement, 3 is excellent improvement and 4 is asymptomatic
represent the only apparent association between vertigo
and migraine. Auditory symptoms and sensorineural
Follow-up of both arms in terms of frequency and
hearing loss in MV are less frequent when compared to
severity of headache attacks of the study group is shown in
vestibular symptoms [22]. The duration of vertigo attacks
Table 3. Arm A with the flunarizine prophylaxis had better
was shorter when compared to that of headaches which
outcomes at follow-up at 3 months, but the differences
tend to last longer; however, the frequency and severity of
were not significant.
the vertigo spells were comparable to that of the headache.
Side effects Out of the 48 who completed the study, 8
Vestibular symptoms in MV were manifest as light-
complained of side effects. 6 (24 %) of the flunarizine
headedness, dizziness, unsteadiness and also spinning type
group had side effects and 2 (9 %) in the control group. In
of vertigo.
five subjects somnolence was noted, four of who were from
Although MV is a common cause of dizziness in
arm A and one from arm B. Three complained of weight
patients, there are very few studies that deal with the
gain, of which two were in arm A and one in arm B. One
prophylactic treatment of this entity. MV may respond to
subject from the flunarizine group who had weight gain
the same medications used to treat migraine headaches, but
also complained of acne. These side effects were not sig-
there is limited data on this [23]. A small randomized trial
nificant enough for the subjects to stop the study mid-way.
using zolmitriptan for aborting attacks in these patients
A comparison of side effects did not show any significant
showed inconclusive results due to the limited power of the
difference between the two groups (p = 0.248, Fishers
study [10]. Acetazolamide has been reported to improve
exact test), Table 4.
symptoms in familial migraine with vertigo and tremor
[24]. It has also been found to be useful in MV in familial
Table 4 Comparison of side effects between the groups hemiplegic migraine [25]. Retrospective studies on patients
One or more No adverse Total p value who fit the criteria for MV have shown varying levels of
adverse effects effects benefit with drugs such as beta blockers, calcium channel
Arm A 6 19 25 0.248
blockers, tricyclic antidepressants, cyproheptadine, anti-
Arm B 2 21 23
convulsants and benzodiazepines. These have been used
Total 8 40 48
either singly or in various combinations; pharmacological
therapy has also been used in association with dietary

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changes, lifestyle modifications and avoidance of triggers
[9, 2630].
Betahistine, a H1 receptor agonist and H3 receptor
antagonist, has been found efficacious in the treatment of
vestibular vertigo [31]. Vestibular rehabilitation therapy
has also been shown to be beneficial in patients with
migraine-associated dizziness irrespective of the etiology
[32]. These two modalities of treatment are widely used in
the management of vestibular disorders.
Flunarizine, a calcium channel antagonist, has been used
with some success in the treatment of both migraine and
vertigo. Experimental and clinical trials have shown
encouraging effects on vestibular disorders in the past [33,
34]. Some of these disorders could have included MV, as
the definition of this entity is still evolving. Flunarizine has
been shown to objectively reduce vertigo symptoms in
vestibular neuritis [35]. It has been used with good results
in the treatment of migraine prophylaxis in both in adult
and childhood migraines [11, 12, 18, 3639].
The mechanism of action of flunarizine in migraine
prophylaxis is still controversial. It has been suggested
that blockage of sodium and calcium channels by flu-
narizine could help explain its ability to control cortical
excitability in migraine which is essentially considered a
channelopathy [40]. Li et al. [41] have stated that flu-
narizine helps to prevent cerebral mitochondrial injury in
cortical spreading depression in both hypoxic and norm-
oxic conditions.
Majid Fotuhi et al. in their review article have suggested
that the treatment response should be evaluated after
3 months with [50 % reduction in attack frequency being
a realistic goal [9].
Overall, all patients in the group treated with flunari-
zine improved after 3 months and this was assessed with
regards to the specific crippling symptoms of vertigo and
headache. Accompanying symptoms and aura were
described during the start of the study as part of disease
evaluation, but the effects of treatment on these were not
studied. While the improvement of vertigo symptoms
were statistically significant, this was not so in case of
headache symptoms. Although headache symptoms
improved, the difference was not statistically significant.
One possible explanation is a reporting bias in our study,
as this study was done among patients who presented to
an audiovestibular clinic with primary complaints of
vertigo. The results from this study show that in patients
with MV treated with flunarizine, betahistine and ves-
tibular exercises there is significant improvement in ver-
tigo control when compared to those who only received
betahistine and vestibular exercises. More randomized
double-blind controlled trials are needed to study com-
binations of flunarizine with other antimigrainous drugs
in MV.
Conclusion
Flunarizine (10 mg) is a useful drug in patients with MV,
especially in those who have significant morbidity due to
their vestibular symptoms. Severity and frequency of
headache in MV are reduced to a less significant extent by
Flunarizine. Compliance is good and side effects are
minimal. We recommend the use of flunarizine as a first
line of treatment in patients who suffer from MV and in
whom vestibular complaints are considerable.
Acknowledgments The authors would like to gratefully acknowl-
edge the contributions of Professor Vinohar Balraj and Ms. Visali in
the statistical analysis of this article. This study was supported by
funding from the Fluid Research Grants, CMC Research, Vellore.
Conflict of interest The authors declare that they have no conflicts
of interest.
Appendix
This questionnaire was based on a similar one used for a
previous study of vestibular deficits among clinically
defined subgroups of patients with both migraine and
vertigo attending tertiary referral neuro-otology clinics.
(By AB under the guidance of Dr Ros Davis and Prof
Goadsby in National hospital for Neurology and Neuro-
surgery, Queens Square, London, submitted as partial
fulfilment of the requirements for MSc. in Audiological
Medicine, University College London.)
References
1. Neuhauser H, Leopold M, von Brevern M et al (2001) The
interrelations of migraine, vertigo, and migrainous vertigo.
Neurology 56:436441
2. Dieterich M, Brandt T (1999) Episodic vertigo related to
migraine (90 cases): vestibular migraine? J Neurol 246:883892
3. Cutrer FM, Baloh RW (1992) Migraine-associated Dizziness.
Headache J Head Face Pain 32:300304. doi:10.1111/j.1526-
4610.1992.hed3206300.x
4. Cass SP, Furman JM, Ankerstjerne JKP et al (1997) Migraine-
related vestibulopathy. Ann Otol Rhinol Laryngol 106:182189
5. Slater R (1979) Benign recurrent vertigo. J Neurol Neurosurg
Psychiatry 42:363367
6. Oh AK, Lee H, Jen JC et al (2001) Familial benign recurrent
vertigo. Am J Med Genet 100:287291
7. Headache Classification Committee of the International Head-
ache Society (IHS) (2013) The international classification of
headache disorders, 3rd edition (beta version). Cephalalgia
33:629808. doi:10.1177/0333102413485658
8. Lempert T, Olesen J, Furman J et al (2012) Vestibular migraine:
diagnostic criteria. J Vestib Res 22:167172. doi:10.3233/VES-
2012-0453
9. Fotuhi M, Glaun B, Quan SY, Sofare T (2009) Vestibular
migraine: a critical review of treatment trials. J Neurol 256:711
716. doi:10.1007/s00415-009-5050-5
123

10. Neuhauser H, Radtke A, von Brevern M, Lempert T (2003)
Zolmitriptan for treatment of migrainous vertigo: a pilot ran-
domized placebo-controlled trial. Neurology 60:882883
11. Schmidt R, Oestreich W (1991) Flunarizine in migraine pro-
phylaxis: the clinical experience. J Cardiovasc Pharmacol
18(Suppl 8):S21S26
12. Martnez-Lage JM (1988) Flunarizine (Sibelium) in the prophy-
laxis of migraine. An open, long-term, multicenter trial. Cepha-
lalgia Int J Headache 8(Suppl 8):1520
13. Kim H, Byun SH, Kim JS et al (2013) Comparison of flunarizine
and topiramate for the prophylaxis of pediatric migraines. Eur J
Paediatr Neurol 17:4549. doi:10.1016/j.ejpn.2012.10.001
14. Diener HC, Matias-Guiu J, Hartung E et al (2002) Efficacy and
tolerability in migraine prophylaxis of flunarizine in reduced
doses: a comparison with propranolol 160 mg daily. Cephalalgia
Int J Headache 22:209221
15. Gawel MJ, Kreeft J, Nelson RF et al (1992) Comparison of the
efficacy and safety of flunarizine to propranolol in the prophy-
laxis of migraine. Can J Neurol Sci 19:340345
16. Simon KC, Gao X, Chen H et al (2010) Calcium channel blocker
use and risk of Parkinsons disease. Mov Disord 25:18181822.
doi:10.1002/mds.23191
17. Ton TGN, Heckbert SR, Longstreth WT Jr et al (2007) Calcium
channel blockers and beta-blockers in relation to Parkinsons
disease. Parkinsonism Relat Disord 13:165169. doi:10.1016/j.
parkreldis.2006.08.011
18. Lucetti C, Nuti A, Pavese N et al (1998) Flunarizine in migraine
prophylaxis: predictive factors for a positive response. Cepha-
lalgia Int J Headache 18:349352
19. Neuhauser H, Lempert T (2009) Vestibular migraine. Neurol Clin
27:379391. doi:10.1016/j.ncl.2008.11.004
20. Johnson GD (1998) Medical management of migraine-related
dizziness and vertigo. Laryngoscope 108:128
21. Kolev O (1990) How caloric vestibular irritation influences
migraine attacks. Cephalalgia Int J Headache 10:167169
22. Vitkovic J, Paine M, Rance G (2008) Neuro-otological findings in
patients with migraine- and nonmigraine-related dizziness. Au-
diol Neurootol 13:113122. doi:10.1159/000111783
23. The International Classification of Headache Disorders: 2nd
edition (2004) Cephalalgia Int J Headache 24(Suppl 1):9160
24. Baloh RW, Foster CA, Yue Q, Nelson SF (1996) Familial migraine
with vertigo and essential tremor. Neurology 46:458460
25. Magis D, Boon E, Coppola G et al (2012) A novel CACNA1A
mutation results in episodic ataxia with migrainous features
without headache. Cephalalgia Int J Headache 32:11471149.
doi:10.1177/0333102412459572
26. Waterston J (2004) Chronic migrainous vertigo. J Clin Neurosci
11:384388. doi:10.1016/j.jocn.2003.08.008
123
Eur Arch Otorhinolaryngol
27. Reploeg MD, Goebel JA (2002) Migraine-associated dizziness:
patient characteristics and management options. Otol Neurotol
23:364371
28. Maione A (2006) Migraine-related vertigo: diagnostic criteria and
prophylactic treatment. Laryngoscope 116:17821786. doi:10.
1097/01.mlg.0000231302.77922.c5
29. Celiker A, Bir LS, Ardic N (2007) Effects of valproate on ves-
tibular symptoms and electronystagmographic findings in
migraine patients. Clin Neuropharmacol 30:213217. doi:10.
1097/wnf.0b013e31803bb3ee
30. Bisdorff AR (2011) Management of vestibular migraine. Ther
Adv Neurol Disord 4:183191. doi:10.1177/1756285611401647
31. Della Pepa C, Guidetti G, Eandi M (2006) Betahistine in the
treatment of vertiginous syndromes: a meta-analysis. Acta
Otorhinolaryngol Ital 26:208215
32. Gottshall KR, Moore RJ, Hoffer ME (2005) Vestibular rehabili-
tation for migraine-associated dizziness. Int Tinnitus J 11:8184
33. Olesen J (1990) Calcium antagonists in migraine and vertigo.
Possible mechanisms of action and review of clinical trials. Eur
Neurol 30(Suppl 2):3134 discussion 3941
34. Schmidt R, Oestreich W (1991) Flunarizine in the treatment of
vestibular vertigo: experimental and clinical data. J Cardiovasc
Pharmacol 18(Suppl 8):S27S30
35. Corvera J, Corvera-Behar G, Lapilover V, Ysunza A (2002)
Objective evaluation of the effect of flunarizine on vestibular
neuritis. Otol Neurotol 23:933937
36. Toldo I, De Carlo D, Bolzonella B et al (2012) The pharmaco-
logical treatment of migraine in children and adolescents: an
overview. Expert Rev Neurother 12:11331142. doi:10.1586/ern.
12.104
37. Schurks M, Diener H-C, Goadsby P (2008) Update on the pro-
phylaxis of migraine. Curr Treat Options Neurol 10:2029
38. Peer Mohamed B, Goadsby PJ, Prabhakar P (2012) Safety and
efficacy of flunarizine in childhood migraine: 11 years experi-
ence, with emphasis on its effect in hemiplegic migraine. Dev
Med Child Neurol 54:274277. doi:10.1111/j.1469-8749.2011.
04154.x
39. Evers S (2008) Treatment of migraine with prophylactic drugs.
Expert Opin Pharmacother 9:25652573. doi:10.1517/14656566.
9.15.2565
40. Ye Q, Yan L-Y, Xue L-J et al (2011) Flunarizine blocks voltage-
gated Na(?) and Ca(2?) currents in cultured rat cortical neurons:
a possible locus of action in the prevention of migraine. Neurosci
Lett 487:394399. doi:10.1016/j.neulet.2010.10.064
41. Li F, Qiu E, Dong Z et al (2011) Protection of flunarizine on
cerebral mitochondria injury induced by cortical spreading
depression under hypoxic conditions. J Headache Pain 12:4753.
doi:10.1007/s10194-011-0300-1