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Betahistine treatment in managing vertigo and improving vestibular

compensation: Clarification

Article in Journal of Vestibular Research · November 2013

DOI: 10.3233/VES-130496 · Source: PubMed

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Journal of Vestibular Research 23 (2013) 139–151 139
DOI 10.3233/VES-130496
IOS Press

Betahistine treatment in managing vertigo

and improving vestibular compensation:
Clarification
Michel Lacour∗
UMR 7420, CNRS/Université Aix-Marseille, Marseille, France

Received 15 November 2012

Accepted 30 August 2013

Abstract. Betahistine dihydrochloride (betahistine) is currently used in the management of vertigo and vestibular pathologies
with different aetiologies. The main goal of this review is to clarify the mechanisms of action of this drug, responsible for the
symptomatic relief of vertigo and the improvement of vestibular compensation. The review starts with a brief summary recalling
the role of histamine as a neuromodulator/neurotransmitter in the control of the vestibular functions, and the role of the his-
taminergic system in vestibular compensation. Then are presented data recorded in animal models demonstrating that betahistine
efficacy can be explained by mechanisms targeting the histamine receptors (HRs) at three different levels: the vascular tree, with
an increase of cochlear and vestibular blood flow involving the H1R; the central nervous system, with an increase of histamine
turnover implicating the H3R, and the peripheral labyrinth, with a decrease of vestibular input implying the H3R/H4R. Clinical
data from vestibular loss patients show the impact of betahistine treatment for the long-term control of vertigo, improvement of
balance and quality of life that can be explained by these mechanisms of action. However, two conditions, at least, are required
for reaching the betahistine therapeutic effect: the dose and the duration of treatment. Experimental and clinical data supporting
these requirements are exposed in the last part of this review.

Keywords: Vertigo, vestibular compensation, histamine receptors, betahistine

1. Introduction ogy of vestibular system disorders has been recently

reviewed and, according to the up-dated knowledge on
The vestibular lesion model is considered since a the primary mechanisms of action of the drugs, sub-
long time as a good experimental approach for inves- stances acting on the vestibular system can have effects
tigating neuroplasticity in the central nervous system on either voltage-gated ion channels or neurotransmit-
(CNS) and CNS recovery after stroke or injury (see 44 ters and neuromodulator receptors [74]. The latter class
and 71 for reviews). It has been also used to determine of pharmacological treatments includes drugs acting
the efficacy of therapeutic options for the symptomatic on excitatory amino acid, acetylcholine, GABA, amine
treatment of vestibular diseases as well as the improve- and histamine receptors.
ment of functional recovery after vestibular loss, that
1.1. Histamine and vestibualr compensation:
is, for both rehabilitation and pharmacological treat-
Background
ment of vestibular deficits [41]. The neuropharmacol-
Antihistaminics are the most commonly used in
∗ Correspondingauthor: Michel Lacour, 21 Impasse des Vertus,
the medical treatment of vertigo, but they cause im-
13710 FUVEAU, France. Tel.: +33 612 471 247; E-mail: michel. portant sedation detrimental for the recovery process,
[email protected]. which limits therefore their administration to the first

ISSN 0957-4271/13/$27.50 
c 2013 – IOS Press and the authors. All rights reserved
140 M. Lacour / Vertigo, vestibular compensation, and betahistine

few days after an acute vestibular loss. In contrast, been reported. Microiontophoretic application of his-
histaminics like betahistine dihydrochloride, a struc- tamine in the VN decreased the spontaneous firing rate
tural analog of histamine, have no sedative effects and of VN cells [34]. It induced inhibition in 78% and 68%
are commonly used for the treatment of Menière’s of neurons in the medial and lateral VN, respectively,
disease [13] and patients with vertiginous syndromes while a facilitation effect was observed in 9% and 27%
of peripheral origin. This paper reviews the current of neurons in these respective nuclei [39]. However,
knowledge on the main mechanisms of action of be- iontophoresis of the VN with histamine H1 antago-
tahistine obtained from data collected in animal mod- nists (diphenhydramine) led to similar inhibitory ef-
els of peripheral vestibular lesion, and it highlights fects on both the spontaneous and evoked firing rate
what are the requirements for reaching the therapeutic of vestibular neurons [67]. Several experimental and/or
effect with this drug in vestibular loss patients. methodological factors may explain this apparent dis-
crepancy found in the in vivo studies: the type of
1.1.1. The histaminergic system and vestibular preparation (decerebrate or anesthetized) and of VN
functions (summary) (medial, lateral), as well as the very nature of the
Histaminergic neurons are exclusively located in the VN cells (type I/type II neurons, facilitatory/inhibitory
tuberomammillary (TM) nuclei of the posterior hy- neurons). . . In addition, the excitatory effect of his-
pothalamus [62]. Their histaminergic nerve endings tamine could be explained by a decreased GABA re-
project diffusely through the whole brain, onto vari- lease. Indeed, histamine has been found to inhibit
ous nervous structures including the vestibular nuclei GABA release via H3 heteroreceptors located on non-
(VN) complexes in both rats and cats [40,59,79]. His- histaminergic nerve terminals, including GABAergic
tamine distribution in the brain parallels that of its fibers (reviewed in [11]), and the commissural projec-
synthesizing enzyme, histidine decarboxylase (HDC: tion between the VN complexes on both sides is me-
cf [69]). Four histaminergic receptors (HRs) have been diated predominantly by inhibitory GABAergic neu-
identified and designated as H1 , H2 , H3 and H4 Rs. rons, with additional polysynaptic pathways involv-
They are located at postsynaptic terminals for the H1 ing excitatory commissural neurons that activate con-
and H2 receptors, at presynaptic sites on histaminergic tralateral GABA or glycinergic inhibitory (type II) in-
and nonhistaminergic nerve terminals for the H3 au- terneurons [53]. Moreover, histaminergic modulation
toreceptors and heteroreceptors, respectively. All these of GABA release has been observed in the VN of nor-
types of HRs are also diffusely and heterogeneously mal and labyrinthectomized rats [6]. The Fig. 1 is a
distributed throughout the CNS, except for the H4 Rs simplified schematic drawing of the possible effects
typically found outside the CNS [29,51]. The stan- of histamine, histamine agonists and histamine antag-
dard agonist (α-methylhistamine) and antagonist (thi- onists on the firing rate of vestibular type I cell in the
operamide) of the H3 autoreceptors regulate the syn- vestibular nuclei.
thesis and release of histamine, down-regulation and Taken together, the excitatory effect of histamine on
up-regulation of histamine turnover being observed the central vestibular neurons seems predominant, as
with H3 Rs agonists and antagonists, respectively (Ta- illustrated by the behavioral effects of histamine re-
ble 1). ceptor ligand infusion into the VN. Using chronically
Stimulation and blockade of the H3 Rs located at implanted osmotic micropumps, a stereotyped postural
presynaptic sites on histamine afferent fibers reach- and ocular motor syndrome similar to that observed af-
ing the VN complexes inhibits and increases histamine ter acute unilateral loss of the vestibular input, was re-
turnover and release, respectively. Histamine-induced produced in the guinea pig after unilateral infusion of
modulation of the activity of the VN cells has been selective histamine H2 antagonists (cimetidine) or H3
reported in vivo and in vitro. In vitro, histamine de- agonists (α-methylhistamine) [70,89]. Conversely, H2
polarized the rat medial VN neurons, an effect that agonists and H3 antagonists caused mirror-images of
was mediated through H1 [33] and H2 [61,70,88] his- the vestibular syndrome.
tamine receptors. Similar findings were recently found There is strong evidence now that the central his-
in the rat inferior VN neuron [60] and whole-cell taminergic system is involved in the regulation of
patch recordings showed histamine excitation of the vestibular functions (reviewed in [42,62]), and the
rat lateral VN neurons mediated through H2 recep- vestibulo-hypothalamic loop very likely plays a signif-
tors [91]. In vivo, both inhibitory and facilitatory ac- icant role in this process. Indeed, vestibular stimula-
tions on the cat medial and lateral VN neurons have tion using either warm caloric water [30] or 2 g hyper-
 M. Lacour / Vertigo, vestibular compensation, and betahistine 141

Table 1
The four classes of histamine receptors and their main agonists and antagonists
Agonists Antagonists
H1 2-Thiazolyl-ethylamine 2-methylhistamine Diphenhydramine promethazine meclizine
H2 Impromidine dimaprit Cimetidine ranitidine zolantidine
H3 α-methylhistamine Betahistine thioperamide
H4 4-Methyhistamine Thioperamide JNJ 7777120

Fig. 1. Simplified schematic drawing illustrating how the vestibular nuclei cells can be neuromodulated by histamine, histamine agonists and
histamine antagonists. Type I cells in the vestibular nuclei complex (VN) on one side (left or right) receive excitatory influences from primary
vestibular afferents of the same side (left VN). These type I neurons have excitatory effects on GABAergic interneurons (type II cells) which in-
hibit the resting discharge of the type I cells on the opposite side by means of the inhibitory vestibular commissural system. All kinds of histamine
receptors (H1, H2, H3) are found in the VN; they are located either post-synaptically on the type I neurons (H1 and H2) or pre-synaptically
both on histaminergic nerve terminals originating from the tuberomammillary nuclei (TM) of the posterior hypothalamus (H3 autoreceptors),
and on non-histaminergic nerve terminals (H3 heteroreceptors) like the GABAergic nerve fibres of the commissural system. Histamine release
in the VN (light green arrows and symbols), or infusion of the VN with histamine agonists of the H1 and H2 receptors (dark green symbols),
induce a neuro-modulation of the type I vestibular target cells. Histamine antagonists (orange symbols) block the H3 autoreceptors located on
histaminergic nerve terminals, thus increasing histamine turnover and release of histamine in the VN (excitatory effect on the type I cells), which
in turn inhibits the release of GABA via the H3 heteroreceptors (desinhibition of the type I cells).

gravity [87] up-regulated histamine release from the order perceptual deficits ([7] for a review), and it is ag-
hypothalamus. In addition, the histaminergic system is gravated by neurovegetative disorders (nausea, vomit-
also involved in vestibular autonomic responses [32]. ing). The vestibular syndrome is usually categorized
into static deficits, which are continuously present in
stationary subjects, and dynamic deficits which are
1.1.2. The histaminergic system and vestibular observed during head or body motion in space. The
compensation (summary) vestibular syndrome ameliorates over time in a pro-
Many experimental data support the view that the cess described in the literature as “vestibular compen-
histaminergic system is implicated in the process of be- sation” ([16,44,71] for reviews). The static symptoms
havioral recovery occurring after unilateral damage of of spontaneous nystagmus, ocular tilt reaction, vertigo,
the peripheral vestibular system. A typical vestibular and change in perception of subjective visual vertical
syndrome is observed in most of the species acutely af- resolve progressively over the first months, whereas
ter a unilateral vestibular loss. This syndrome involves the dynamic symptoms like vestibulo-ocular reflex
successive levels of damage, from basic reflex prob- asymmetry and postural instability remain poorly com-
lems like ocular motor or postural problems to higher pensated [15,41]. There is a general agreement today
142 M. Lacour / Vertigo, vestibular compensation, and betahistine

UNILATERAL VESTIBULAR LOSS

OCULOMOTOR POSTURAL PERCEPTIVE

SYNDROME SYNDROME SYNDROME

STATIC DEFICITS DYNAMIC DEFICITS

Complete Compensation Incomplete Compensation

PHARMACOLOGICAL
TREATMENTS
Vestibular Nuclei Whole Brain
Brain Orchestration Brain Orchestration
of Neurobiological of Behavioral
Melodies Melodies
VESTIBULAR
REHABILITATION

Rebalance of the VN Substitutions

neuronal activity New Strategies

Fig. 2. Compensation of the static and dynamic vestibular deficits: the brain orchestration of neurobiological and behavioural melodies. Didactic
diagram showing how the brain compensates differently the static and the dynamic deficits constituting the ocular motor, the postural and the
perceptive syndromes (the neurovegetative syndrome is not shown). The curved arrows indicate the primary action of drug or rehabilitation:
pharmacological treatments act mainly at the vestibular nuclei (VN) level and modulate the orchestration of the neurobiological signatures
induced by VN deafferentation, while vestibular rehabilitation can change the orchestration of the behavioural strategies elaborated by the whole
brain.

for considering the static symptoms as the result of the orchestration of behavioral melodies. These concepts
neural imbalance between the VN complexes activity and their clinical relevance are illustrated in the Fig. 2.
on both sides, and their recovery as the result of a rebal- It is shown that both pharmacological treatments and
ance in the average neural activity over time. Indeed, vestibular rehabilitation can modify the whole brain
electrophysiological recordings of the VN activity in orchestration. Indeed, the VN are a major target for
unilateral labyrinthectomized guinea pigs [65,66,72, drugs, which can slow down or accelerate the recovery
73] and unilateral vestibular neurectomized cats [90] of the static vestibular deficits, while vestibular reha-
showed a strong asymmetry in the spontaneous fir- bilitation procedures can help the patients to use sen-
ing discharge of the VN neurons, with ipsilateral shut- sory substitution processes, consisting in the potenti-
down and unchanged activity on the contralateral side. ation of remaining sensory inputs, and/or to elaborate
Rebalance of the VN neurons activity was achieved the best behavioral strategy supplying their dynamic
in both species with different time constants, and con- deficits.
sisted in the restoration of a near normal spontaneous The neurobiological signatures found in the VN on
discharge in the ipsilateral deafferented VN. As a rule, the lesion side (sometimes bilaterally) include the up-
VN neuronal rebalance was always concomitant of the regulation of immediate early genes (genetic signa-
disappearance of the behavioral static symptoms. In ture) and neurotrophines (neurotrophic signature), as-
contrast, the recovery of the dynamic symptoms im- troglial reaction and neurogenesis (structural signa-
plies the whole brain, which uses sensory substitution ture), up-regulation of the cholinergic, GABAergic and
processes and elaborates new behavioral strategies that histaminergic systems (neurochemical signature), in-
mimick the lost vestibular functions [15,41,45]. crease of the markers of stress (neurohormonal signa-
We have showed that the complete compensation of ture), of tumor necrosis factor α (neuroinflammatory
the static deficits was due to plastic events in the VN, signature), and of cytochrome oxydase (metabolic sig-
which can be seen as the expression of a deafferenta- nature). Interestingly, we have demonstrated that the
tion code [43], that is, the coordinated interplay of mul- orchestration of these brain signatures was dependent
tiple plasticity mechanisms acting with precise tim- on the nature of the VN deafferentation (total ver-
ings. This deafferentation code is made of reactive sig- sus partial, acute versus progressive, structural versus
natures I have proposed to compare to the brain orches- functional), that is, on the vestibular aetiology [18,47].
tration of neurobiological melodies. By analogy, the re- There may be an almost totally silent orchestration in
covery of the dynamic deficits may be seen as the brain the case of a very slow and progressive loss of vestibu-
 M. Lacour / Vertigo, vestibular compensation, and betahistine 143

lar inputs (normal ageing, for instance) while all the effect would involve H1 receptors, presynaptic H3 het-
signatures are played in the case of a sudden, acute and eroreceptors, and autonomic α2 -receptors, at least in
total loss of vestibular inputs. Older people or bad com- the guinea pig inner ear. More recently, Ihler et al. [31]
pensated vestibular loss patients may have a deficit in confirmed the increase of blood flow in cochlear cap-
the expression of these plasticity mechanisms. illaries after betahistine administration using intravi-
The neurochemical signature observed in animal tal fluorescence microscopy in guinea pigs in vivo. Be-
models of vestibular lesion involves strong changes in tahistine could also regulate the vestibular blood flow
the histaminergic system. Using in situ hybridization in the posterior semi-circular ampulla, as observed in
method in unilateral vestibular neurectomized (UVN) the guinea pig by Dziadziola et al. [20]. Assuming
cats, we have demonstrated a long lasting increased that endolymphatic hydrops is the pathophysiologi-
expression of the mRNA coding for histidine decar- cal basis of Menière’s disease, due to over-production
boxylase (HDC), the enzyme synthesizing histamine, or under-absorption of the endolymph, an increased
in the ipsilateral tuberomammillary nucleus [43,84]. In cochlear/vestibular blood flow would produce vasodi-
UVN cats treated with thioperamide, a pure antagonist latation and increased permeability at the peripheral
of the H3 receptor, or with betahistine, a less powerful labyrinth level, an important factor for the treatment of
H3 receptor antagonist, the HDC mRNA up-regulation vertigo. In addition, this vascular effect could have a
was increased bilaterally, and the vestibular symptoms beneficial role centrally, at the VN level, helping the
(spontaneous nystagmus, posture and locomotor bal- VN cells on the lesion side to increase their metabolic
ance) were more rapidly recovered compared to un- activity and, therefore, to improve the balance between
treated UVN cats [84]. These results show clearly a the two sides.
close correlation between changes in histamine levels In the same period, investigations of the sponta-
and the time-course of vestibular compensation. They neous and evoked resting discharge of ampullar recep-
also emphasize the potential role of drugs acting on the tors were measured in isolated preparations of the frog
histamine receptors in vestibular pathology. posterior semi-circular canal during perilymphatic ad-
ministration of betahistine [8,9,12]. The resting dis-
charge was decreased with drug concentration as low
2. Mechanisms of action of betahistine as 10−7 mol/L whereas inhibition of the evoked activ-
ity was obtained at doses as high as 10−2 mol/L. Be-
Betahistine dihydrochloride (betahistine) is a his- tahistine could act on the basolateral membranes of the
tamine-like drug working as both partial histamine H1 sensory cells, dark cells and/or afferent nerve termi-
Rs agonist and more potent histamine H3 Rs antago- nals, and might involve histamine H3 Rs in the periph-
nist [3,86]. The histamine H3 Rs display a constitu- eral vestibular system. Soto et al. [75] showed that be-
tive activity, and it was demonstrated with recombinant tahistine produced a postsynaptic inhibition on the ex-
rat and human histamine H3 Rs that ligands previously citability of the primary afferent neurons in the vestibu-
identified as antagonists should be reclassified into in- lar endorgans. More recent in vitro studies investi-
verse agonists. The recent study of Ghabou et al. [27] gated the firing discharge of primary vestibular neu-
showed that betahistine acted in vivo as a partial in- rons in the rat [17]. They demonstrated that 1) both H3
verse agonist to enhance histamine neuron activity. and H4 Rs are co-expressed in all vestibular neurons
in the Scarpa’s ganglion, and 2) highly selective H4
2.1. Experimental data in animal models Rs antagonists reversibly decreased the depolarization-
evoked firing in a concentration dependent manner
The first reports on the role of betahistine in vestibu- and, at millimolar concentration, they completely abol-
lar compensation pointed, many years ago, to vascular ished the neuronal discharge without affecting the rest-
effects in the inner ear. Systemic administration of be- ing membrane potential. In contrast, the H3 Rs an-
tahistine induced an increase in cochlear blood flow in tagonist betahistine induced a firing inhibition at ele-
guinea pigs and other experimental animals [54]. Fur- vated concentrations together with a depolarizing ef-
ther experiments in the rat [48] and guinea pig [49] in- fect. The authors suggested that betahistine worked
ner ear using laser doppler flowmetry and different lig- through combined H3 /H4 Rs effects, with firing in-
ands of the histamine receptors showed an increased hibition mediated by the H4 Rs and depolarization by
cochlear blood flow resulting primarily from vasodi- the H3 Rs. Such high concentrations, associated with
latation of the anterior inferior cerebellar artery. This long-lasting depolarization, could have detrimental ef-
144 M. Lacour / Vertigo, vestibular compensation, and betahistine

BETAHISTINE: Mechanisms of action

Central Nervous System Vascular Tree Peripheral Labyrinth

HISTAMINE HISTAMINE
HISTAMINE
H3 R H3 R INVERSE AGONIST
H1 R AGONIST
INVERSE AGONIST H4 R ANTAGONIST

INCREASED DECREASE IN
REBALANCING BRAIN
COCHLEAR VESTIBULAR
VN ACTIVTY AROUSAL
BLOOD FLOW INPUT

FASTER
FUNCTIONAL RECOVERY

Fig. 3. Mechanisms of action of betahistine. Schematic diagram illustrating the main mechanisms of action of betahistine responsible for the
faster functional recovery after acute unilateral vestibular loss. Data collected in animal models of vestibular loss demonstrated effects at the CNS
(cat model), the vascular tree (rat and guinea pig models), and the peripheral labyrinth (frog and rat models) levels. VN: vestibular nuclei.

fects to the vestibular cell but, fortunately, they are not and antagonists reducing and enhancing histamine re-
found in physiological conditions. lease, respectively [2,4,26].
Few data are available regarding the role of be- Taken together, the data collected in animal mod-
tahistine in the recovery process after vestibular loss els demonstrate that the clinical action of betahistine
in animal models. We have been the first to demon- can be attributed to different mechanisms acting on dif-
strate that oral administration of betahistine at high ferent targets (Fig. 3): 1) an increased blood flow in
daily doses of 50 mg/kg or 100 mg/kg strongly accel- the vestibular system, due to the H1 Rs agonist prop-
erated the time-course of recovery in UVN cats [81]. erty of betahistine, 2) an increased histamine turnover
As compared with untreated cats that fully recovered and enhanced histamine release in the CNS, a process
their static postural control and dynamic equilibrium implying the H3 Rs antagonist (or H3 Rs inverse ag-
function in 6 weeks, the betahistine-treated cats recov- onist) property of betahistine. The histamine-induced
ered within 3 weeks (cf Table 2). Similar data were influences at the level of the secondary vestibular neu-
found in UVN cats treated with thioperamide: the time rons might help to rebalance more quickly the neu-
constant of the recovery process for horizontal spon- ronal activity of the VN complexes on both sides, and
taneous nystagmus, posture function and locomotor 3) a possibly inhibitory influence exerted at the level of
balance recovery was reduced by 50% [84]. Our re- the peripheral end organs and primary vestibular neu-
sults have been confirmed in unilateral labyrinthec- rons through combined H3 /H4 Rs effects. In addition,
tomized rats receiving various H3 Rs antagonist com- betahistine-induced up-regulation of histamine induces
pounds, including betahistine and thioperamide [58]. a general brain arousal favoring sensorimotor activ-
Betahistine interaction with the histaminergic system ity (opposite effect compared to vestibulo-depressant
was also investigated in healthy cats by quantifying drugs), described as a crucial factor for functional re-
HDC mRNA using in situ hybridization, histamine im- covery after a vestibular loss. Finally, the H3 Rs seem
munoreactivity changes, and by binding analyses to to be the main target responsible for the clinical ac-
H3 Rs using an histamine H3 Rs agonist ([3 H] N - tion of betahistine, as revealed by electrophysiological
α-methylhistamine) and radioautography methods [80, studies.
82]. Results showed that treatment with betahistine in-
creased histamine synthesis through blockade of the 2.2. Clinical data in vestibular loss patients
histamine H3 autoreceptors. They confirmed the oppo-
site effects of different histamine H3 Rs ligands on his- There are different treatment strategies for patients
tamine turnover in rat brain slices, the H3 Rs agonists with recurrent vertigo, dizziness and instability of
 M. Lacour / Vertigo, vestibular compensation, and betahistine 145

Subjective Visual Vertical (Deg)

14
NUMBER of ATTACKS (/month)

12

10 BETAHISTINE 48 mg tid 10 PLACEBO

8 8 BETAHISTINE 48 mg

6 6
* *
4
* 4
* *
2 * 2

0 0

0 3 6 9 12 7 30 90
TIME (Months) TIME (Days)

A B
1400
BODY SWAY (Power Index %)
6

1000
PLACEBO PLACEBO
HEAD TILT (Deg)

4 BETAHISTINE 48 mg BETAHISTINE 48 mg
600
*
2
*
* *
200

0 0

7 30 90 7 30 90
TIME (Days) TIME (Days)
C D
D
Fig. 4. A–D: Betahistine improvement of vertigo and vestibular compensation. A: Histograms showing the decrease of the frequency of vertigo
attacks per month in Menière’s disease patients (N = 62) under betahistine treatment at the daily dose of 48 mg tid, compared to the mean
number of attacks per month during the three months preceding the treatment (modified from [78]) (*: significant differences at p < 0.01). B-D:
Histograms showing the acceleration of the recovery of the static vestibular deficits in Menière’s patients (N = 8) under betahistine treatment
at the daily dose of 48 mg (filled histograms) compared to placebo controls (N = 8; open histograms), for subjective visual vertical (B), head
orientation in space (C) and body sway (D) (modified from [64]). *: significant differences at p < 0.01 with respect to the placebo group or the
data preceding the treatment.

vestibular origin, but agents acting on the histamin- management of vestibular syndromes in MD compared
ergic system are drugs of choice for the treatment of to calcium channel blockers (flunarizine, cinnarizine)
symptoms of vertigo [63]. In a review of 152 publi- or other drugs (Ginkgo biloba), and as effective as cin-
cations dealing with medical treatment for MD over narizine in non-MD vestibular patients (cf [74]).
20 years, only betahistine and diuretics have proven ef- The clinical efficacy of betahistine in the treatment
ficacy in double-blind trials for the long-term control of recurrent vertigo has been evidenced in many stud-
of vertigo [13]. Betahistine is the most often used in ies [10,21,55]. Most of them have been focused on sub-
European Countries, Latina America and Canada, par- jective scales with vertigo as the main symptom [46],
ticularly for Menière’s disease (MD). It is not officially and/or on questionnaires on self-evaluation of qual-
approved in the United States but many vestibular pa- ity of life [1,23,55–57]. Indeed, the unpredictable and
tients get the drug in Mexico or Canada. MD is the sudden attacks of vertigo are the main disabling prob-
second most common cause of peripheral vestibular lem in MD, impairing quality of life and leading
vertigo characterized by recurrent spontaneous attacks to secondary psychiatric problems (anxiety, fear, de-
of vertigo, tinnitus, fluctuating hearing loss, and aural pression, . . . ). Compared with placebo, these studies
fullness. If the underlying cause of MD remains still showed that betahistine was effective in reducing the
unknown, there is a general agreement to consider the frequency, severity and duration of vertigo and asso-
endolymphatic hydrops as the pathological process. ciated neurovegetative symptoms, as well as in im-
Betahistine was reported to be the most effective in the proving the patients’ quality of life, even though data
146 M. Lacour / Vertigo, vestibular compensation, and betahistine

A Cochlear Blood
Cochlear blood flowFlow
B tele-methylhistamine
50 *
value value

* *
1,5

40
basal

%%
Changes in %

1,4
from basal

in in
fold changefrom

1,3

Changes
25

Changes
change

20 1,2
peak

1,1
fold

1,0
0,0001 0,001 0,01 0,1 1 10
dosage [mg/kg b. w.] (treatment group) 0.3 3 30
betahistine treatment (mg/kg b.w.) betahistine treatment (mg/kg)
A B

C HDC mRNA Expression * *

400%
(TMN)
%(TMN)

* * * * *
50 mg
in %

10 mg 3 W
3M
ChangesIN

200%
CHANGES

10 mg 50 mg
2 mg 5 mg 5 mg
3W 1W BASAL
3M 2M 3M
2 mg 2 mg 5 mg LEVEL
1W 3W 3W
LOW DOSES LOW DOSES HIGH DOSES HIGH DOSES
SHORT TIME LONG TIME SHORT TIME LONG TIME

betahistine treatment
C
Fig. 5. A-C: Dose – and duration-dependent effects of betahistine treatment on cochlear blood flow, turnover of histamine and histamine
catabolism. A: Changes (peak fold, in %) of cochlear blood flow after administration of different doses of betahistine ranging from 0.001 mg/kg
of body weight to 1 mg/kg b.w. in the guinea pig in vivo (modified from [31]) (*: p < 0.01). B: Changes (in %) of tele-methylhistamine after
acute administration of betahistine at doses of 0.3, 3 or 30 mg/kg in the mice (modified from [27]) (*: p < 0.01). C: Changes (in %) of HDC
mRNA expression in the tuberomammillary nuclei (TM) of the cat after betahistine treatment with doses ranging from 2 mg/kg (low dose) per
day to 100 mg/kg (high dose) per day for treatment durations ranging from short periods (1 week) to long periods (3 months)(modified from [83])
(*: p < 0.001). These three studies demonstrate dose-effects of betahistine on the increase of cochlear blood flow (A), the increase of histamine
turnover (C), and the increased amount of the first metabolite of histamine (B). In addition, betahistine treatment duration-dependent effects on
histamine turnover are seen (C).

from meta-analyses were sometimes conflicting [35, reported in patients with disabling MD receiving be-
36,77]. In an open, non-masked trial, Strupp et al. [78] tahistine treatment [14]. Long-term administration of
reported a significant reduction in the number of at- betahistine was also reported useful to reduce tinni-
tacks per month in a total population of 112 patients tus in a retrospective data from patients with vestibu-
with MD (Fig. 4A). Similar results were reported by lar dysfunction [25], to normalize postural stability of
Ganança et al. [24] in a randomized, open-label study patients with benign paroxysmal positional vertigo af-
of 120 patients with well-established MD, the most ter repositioning Epley’s maneuver [76], and to reduce
improvement being seen within the first 12 weeks vertigo spells in patients with unilateral vestibular neu-
of treatment. The long-term prophylactic betahistine ritis [68]. Moreover, betahistine treatment has addi-
treatment of attacks of vertigo in MD has been con- tional benefits to vestibular rehabilitation on disabil-
firmed by Strupp et al. [78]. In addition, prevention of ity, balance, and postural stability in patients with uni-
vestibular neurectomy and improvement of vestibular lateral disorders [37], and combination of betahistine
compensation after vestibular neurectomy have been and vestibular rehabilitation was recommended for im-
 M. Lacour / Vertigo, vestibular compensation, and betahistine 147

Table 2
proving both postural stability and quality of life in a Betahistine improvement of vestibular compensation in an animal
case report of a patient with acute unilateral vestibular model (cat) and in unilateral vestibular loss patients (Menière’s dis-
loss [28]. ease patients) Full recovery under betahistine treatment was com-
Only a few studies used well-controlled paradigms pared to that recorded under placebo conditions. Unilateral vestibu-
lar neurectomized cats were submitted to betahistine daily doses of
and measures in the laboratory to specify the role of 50 mg/kg till complete postural recovery. Menière’s disease patients
betahistine, particularly on vestibular compensation, underwent a curative unilateral vestibular neurectomy and received
in humans. An effect of betahistine on the vestibulo- betahistine at the daily dose of 48 mg (24 mg bid) from 3 days up to
ocular reflex was reported for paroxysmal vertigo pa- 3 months after UVN
tients [38]. We have been the first to investigate be- Cat model Meniere’s patients
Full recovery Full recovery
tahistine therapy in patients who underwent a total
Placebo 6–7 Weeks 3 Mouths
unilateral vestibular deafferentation (vestibular neurec- Betahistine 3 Weeks 1 Month
tomy) as surgical treatment for MD [64]. In this ran-
domized, double-blind, placebo-controlled study, we As far as the animal models are concerned, the ef-
investigated the time course of vestibular compensa- fects of betahistine on both cochlear microcirculation
tion using up-to-date data analyses and a broad spec- and histamine synthesis and release were correlated
trum of vestibular-induced changes: postural disorders to dosages. In a recent in vivo investigation in guinea
(body sway and head orientation), oculomotor disor- pigs, Ihler et al. [31] demonstrated a dose-dependent
ders (spontaneous nystagmus and ocular cyclotorsion), effect of betahistine on cochlear stria vascularis blood
deviation of the subjective visual vertical (SVV), and flow. They described a sigmoid correlation between in-
self-evaluation of postural stability (questionnaires). crease in blood flow and dosages, the lowest dosage
Results showed that betahistine reduced the time to (0.001 mg/kg body weight) having the same effect
recovery for most of the static postural, oculomotor, as placebo, the highest (1.0 mg/kg b.w.) inducing the
and perceptive symptoms, as well as for the patients’ maximal increase in blood flow, while intermediate
self-evaluation of stability, compared to the placebo dosages (0.01 and 0.1 mg/kg b.w.) produced interme-
group (Fig. 4B–D). Time to recovery was reduced by diate increases (Fig. 5A). Interestingly, the effects of
2 months for postural stability, by 3 months for the the dosage range of betahistine on cochlear micro-
SVV and head orientation, and was effective as early circulation corresponded well to clinically used sin-
as 4 days after treatment administration (cf Table 2). In gle dosages to treat MD (16 mg three times daily or
addition, the effects remained during the whole com- 24 mg twice daily: [24]; 24 mg bid: [64]). Assum-
pensation period tested (up to 3 months). These data ing that improved effects of higher doses of betahis-
confirmed the strong acceleration of the recovery pro- tine in the treatment of MD might be due to a corre-
cess we had previously demonstrated in UVN cats un- sponding cochlear blood flow increase, one could ex-
der betahistine treatment [80]. They emphasize the role pect a similar correlation between dosages and ver-
of betahistine at CNS targets, and indirectly corrobo- tigo spells on the long term. In a comparison of high
rate the notion that the drug reduces the asymmetrical (48 mg tid) versus lower (16 mg or 24 mg tid) dosages
functioning of the vestibular system at the VN level. of betahistine in MD patients, Strupp et al. [78] re-
ported a significant reduction in the number of vertigo
attacks in both groups in their follow-up evaluation at
3. Requirements for reaching the betahistine 6 and 12 months. But the mean reduction was higher
therapeutic effect in the high dosage group compared to the low dosage
group, and the longer the treatment, the greater the
Experimental studies in animal models of vestibu- difference between the two groups. Confirmation that
lar loss and clinical investigations in vestibular loss high dosage of betahistine and long-term treatment are
patients demonstrated clearly that two conditions, at more effective than low dosage and short-term treat-
least, are required for reaching the betahistine thera- ment has been provided by Lezins et al. [50]. Taken
peutic effect: the dose and the duration of treatment. together, the results demonstrate that management of
These two factors, dose and duration, were found cru- vertigo with betahistine may be strongly affected by
cial in experimental analyses focused on the major dose- and duration-dependent effects.
mechanisms underlying the vestibular compensation Similar conclusions had been drawn previously re-
process, and in clinically relevant measures of the fre- garding the time course of the behavioral recovery
quency of attacks of vertigo per month in MD patients. after vestibular loss. Two different kinds of studies
148 M. Lacour / Vertigo, vestibular compensation, and betahistine

in cats and mice have investigated the betahistine- regulation of the histamine neuron activity. This is a
induced changes of the histaminergic system. These key process in central vestibular compensation very
changes have been analyzed by quantifying either the likely involved in therapeutics. However, betahistine
expression of HDC mRNA ([83]; cat) or the level of action on pre-synaptic H3 heteroreceptors located
tele-methylhistamine ([27]; mice). They were focused on non histaminergic neurons regulating vestibular
therefore on the enzyme synthesizing histamine (cat functions cannot be excluded [5,52]. The histamine-
model) or on the first metabolite of histamine (mouse induced modulation of GABA release after acute uni-
model). Using different groups of healthy cats receiv- lateral vestibular loss could be a very early mechanism
ing daily betahistine doses of 2, 5, 10 or 50 mg/kg dur- of vestibular compensation [19].
ing 1 week, 3 weeks, 2 months or 3 months, we showed Finally, prophylactic treatment of MD with betahis-
that the basal expression of HDC mRNA remained un- tine seems an effective way to reduce increased en-
changed in those groups receiving low doses (2 and dolymphatic pressure and hydrops. It is also an effec-
5 mg/kg) for short time periods (1 or 3 weeks). By tive way to shorten considerably the vestibular com-
contrast, the basal level was significantly higher com- pensation process. Comparison of the behavioral re-
pared to controls in the groups of cats receiving low covery profiles in our cat model and in MD patients
doses for long periods (2 or 3 months: twofold higher) submitted to betahistine treatment shows similar accel-
and those receiving high doses (10 and 50 mg/kg) for erations of functional recovery with time benefits of 1
short periods (1 or 3 weeks: twofold to fourfold higher) and 2 months, respectively, compared to placebo con-
(Fig. 5C). If we know the dose-response curve of be- trols (Table 2). These effects are highly dependent on
tahistine on HDC mRNA in unlesioned cats, the dose- the dose and duration of treatment, two factors that
response curve in lesioned animals remains unknown. could explain some contradictory results of available
Its ED50 may be lower than in controls since imbal- trials in the literature.
anced vestibular activity resulting from vestibular loss
activates histamine neurons [84,85]; and the effect of
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