European Annals of Otorhinolaryngology, Head and Neck diseases (2012) 129, 65—68

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ORIGINAL ARTICLE

A protective effect of 5-HT3 antagonist against

vestibular deficit? Metoclopramide versus
ondansetron at the early stage of vestibular neuritis:
A pilot study
F. Venail a,∗,b,c, R. Biboulet a, M. Mondain a,b,c, A. Uziel a,b,c

a
Service ORL, département otologie et otoneurologie, hôpital Gui-de-Chauliac, CHRU, 80, avenue Augustin-Fliche,
34295 Montpellier cedex 5, France
b
Université Montpellier sud de France, 163, rue Auguste-Broussonnet, 34090 Montpellier, France
c
Inserm U1051, institut des neurosciences de Montpellier, hôpital Saint-Eloi, BP 74103, 80, avenue Augustin.-Fliche,
34091 Montpellier cedex 05, France

KEYWORDS Summary
5-HT3 antagonist; Objectives: Ondansetron is an antiemetic 5-HT3 receptor antagonist with proven efficacy in
Vestibular neuritis; central balance disorder. A pilot study investigated impact on acute unilateral vestibular neu-
Neuroprotection ritis.
Patients and methods: A randomized clinical trial included 20 vestibular neuritis patients.
Subjects received methylprednisolone-valacyclovir, associated to 5 days’ metoclopramide
(30 mg/d; group M, n = 10) or ondansetron (8 mg/d; group O, n = 10). Assessment was based
on early and 1 month videonystagmography, duration of hospital stay and time to first indepen-
dent walking. Blinded intention-to-treat analysis used univariate (Student test) and multivariate
(linear logistic regression) analysis.
Results: Early caloric vestibular deficit was significantly lower in group O than group M (56.53%
versus 84.38%; P = 0.03). Vestibular preponderance did not differ between groups (8.2◦ /s in O
versus 10.34◦ /s in M). At 1 month, trends were observed for vestibular deficit (43% in O versus
63.4% in M; P = 0.07) and preponderance (1.67◦ /s in O versus 1.74◦ /s in M; P = 0.4). Hospital
stay and time to first independent walking were significantly shorter in O (2.88 versus 4.5 days
(P = 0.03); and 1.25 versus 2.25 days (P = 0.001), respectively).
Conclusion: Early treatment with ondansetron associated to corticosteroids and antiviral treat-
ment reduced vestibular deficit in acute-phase vestibular neuritis as compared to reference
histamine H1 receptor antagonists. The treatment did not affect central compensation. Ben-
efit includes improved tolerance of vertigo syndrome and reduced hospital stay. These results
should be confirmed on a larger series, particularly to determine the mechanism of action of
5-HT3 antagonists on vestibular function.
© 2012 Elsevier Masson SAS. All rights reserved.
∗ Corresponding author. Tel.: +33 6 13 42 52 37.
E-mail address: frederic.venail@inserm.fr (F. Venail).

1879-7296/$ – see front matter © 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.anorl.2011.10.006
66 F. Venail et al.

Introduction

The physiopathology of vestibular neuritis is poorly under-

stood; viral infection and/or microcirculation disorder are
currently the main hypotheses [1]. Whatever the mecha-
nism, it induces neuronal dysfunction in Scarpa’s ganglion
or the brainstem [2].
The usual antiemetics prescribed to treat the associ-
ated vegetative signs are histamine H1 receptor antagonists.
Apart from their antiemetic effect, these receptors have
been shown to be present on and affect the function of
vestibular neurons [3]. H1 antagonists may thus play a role
in vestibular function as such [4].
More recently, other antiemetics, serotonin 5-HT3 recep-
tor antagonists, were used in nausea and vomiting, being
more effective than H1 antagonists. In animals, 5-HT3 recep-
tors are expressed in the neurons of Scarpa’s ganglion and
medial brainstem vestibular nuclei [5]. We therefore sought
to investigate their as yet undetermined role in regulating Figure 1 Inclusion flowchart.
vestibular physiology.
Given the proven efficacy of 5-HT3 receptors in post-
traumatic neuroprotection [6], the present pilot study Results
focused on the preventive effect of a 5-HT3 antagonist,
ondansetron, on vestibular deficit in acute-phase vestibular After checking inclusion criteria, 10 patients were included
neuritis. in either arm and 14 were excluded (seven for interval to
treatment more than 48 hours, five for central signs on VNG,
and two for unilateral deficit less than 25%) (Fig. 1).
Patients and methods Mean age in group M was 48 years 9 months (range:
31—75 years) and in group O 61 years 4 months (range:
43—88 years) (P = 0.05 on Student test).
An open-label, randomized comparative study was con-
Mean early vestibular deficit was greater in group M than
ducted within the ENT department of the Montpellier
group O (84.38 ± 20.57% versus 56.53 ± 27.78%; P = 0.049
(France) University Hospital Center from September 2007 to
on Student test; Fig. 2). Mean early preponderance was
December 2008. The study drugs were already authorized for
10.34 ± 4.26◦ /s and 8.2 ± 5.63◦ /s (P = 0.40 on Student test)
the indication in question; local ethics committee approval
in groups M and O respectively (Fig. 2).
was obtained.
First unassisted walking was earlier in group O than
All cases (n = 34) of suspected vestibular neuritis with
group M (1.25 ± 0.52 versus 2.25 ± 0.89 days; P = 0.01on Stu-
onset at least 48 hours before initiation of treatment were
dent test; Fig. 3). Mean hospital stay was 4.5 ± 1.48 and
included. In case of misdiagnosis corrected on videonystag-
2.88 ± 1.17 days (P = 0.03 on Student test) in groups M and O
mography (VNG: central signs or less than 25% deficit) or
respectively (Fig. 3).
imaging within 48 hours of initiation of treatment, the sub-
Assessment at 1 month found a mean vestibular deficit
ject was excluded from analysis.
of 63.4 ± 34.30% in group M and 43 ± 31.25% in group O
All patients received methylprednisolone-valacyclovir,
(non-significant on Student t test: P = 0.07; Fig. 2), and
associated blindedly to 5 days’ metoclopramide (30 mg/d)
mean preponderance of 1.74 ± 0.60◦ /s and 1.67 ± 0.63◦ /s
or ondansetron (8 mg/d). Assessment was based on early
(P = 0.40, Student t test), respectively (Fig. 2).
(24—48 hours after symptom onset) and 1 month VNG, ana-
Multivariate analysis on linear logistic regression showed
lyzing vestibular deficit in terms of slow horizontal phase
early vestibular deficit to correlate with early prepon-
speed (◦ /s) and directional preponderance (◦ /s) on caloric
derance (P = 0.004) and treatment group (P = 0.03). The
testing.
age difference between treatment groups did not account
Duration of hospital stay and time to first unassisted
for the difference in early vestibular deficit. One-month
walking were also recorded.
vestibular deficit correlated with the early value (P = 0.009),
At end of treatment, the two groups were compared
but not with treatment group or age. Hospital stay cor-
for: patient age, early and 1 month post-onset percentage
related with age and treatment group (P = 0.01 each), but
vestibular deficit on the caloric test calibrated according to
not with early vestibular deficit: advanced age and meto-
de Jonckees, early and 1 month post-onset directional pre-
clopramide treatment were associated with longer hospital
ponderance on caloric test (◦ /s), date of first walking and
stay.
date of discharge home.
Statistical analysis comprised univariate analysis (Stu-
dent test) plus multivariate analysis on stepwise logistic Discussion
regression, with a threshold of 0.15 at each step. The sig-
nificance threshold was systematically set at 5% (Systat 10.2 These results indicate that ondansetron, administered early
software, SYSTAT Inc.). in association with corticosteroid and antiviral therapy, was
A protective effect of 5-HT3 antagonist against vestibular deficit? 67

Figure 2 Early and 1 month mean vestibular deficit and directional preponderance. Left column: caloric deficit (above) and
directional preponderance (below) on early examination in the metoclopramide and ondansetron groups; right column: the same
variables at 1 month. The only significant difference (P < 0.05) was for early caloric deficit.

Figure 3 Date of first unassisted walking and mean hospital stay in the metoclopramide and ondansetron groups. Both time to
first unassisted walking and total hospital stay were shorter in the ondansetron group (P < 0.05).

more effective than associated metoclopramide in reducing
hospital stay in vestibular neuritis patients.
The explanation of this effect is two-fold. On one hand,
it may lie in improved tolerance for the vegetative signs
(nausea and vomiting) associated with vertigo, against which
ondansetron is more effective than metoclopramide [7].
On the other hand, ondansetron may also act on the
early vestibular deficit found on the first VNG examina-
tion.
Early vestibular deficit was lower in group O than group
M. The 5-HT3 antagonist effect of ondansetron may play a
role in vestibular synapse neuromodulation, limiting possi-
ble excitotoxicity secondary to excessive glutamate release,
as seen in the cochlea following acoustic trauma and in
the vestibule following aminoside [8,9] or AMPA receptor
antagonist treatment [10].
It has been shown in stroke models that 5-HT3 receptors
play a role in aggravating post-infarction toxic lesions [6];
as they are expressed in animals in Scarpa’s ganglion neu-
rons and medial brainstem vestibular nuclei [5], the question
arises as to their role in vestibular physiology.
These receptors are very probably activated under
physiological conditions, given their presence in the area
postrema and solitary tract, which are areas involved in the
nausea-vomiting reflex [11] and which project toward the
vestibular nuclei [12,13]. Their role, however, can hardly be
more than one of modulation, since clinical use of 5-HT3
antagonists induces neither vertigo nor astasia.
These arguments are particularly supported by several
reports of the interest of ondansetron in the treatment of
vertigo and astasia following cerebral trauma and brainstem
damage related to multiple sclerosis [14,15].
68
For neuroprotective purposes, very early application is
probably needed for a clinical effect to be induced. Here
lies the main limitation of the present study. There was a
group difference in early vestibular deficit: but, when this
was measured, the patients were already receiving meto-
clopramide or ondansetron, and it is impossible to know,
for obvious reasons of examination tolerance, whether the
two groups had comparable deficits before initiation of
treatment. Only a larger series could answer this ques-
tion.
At all events, ondansetron does not impair the capa-
city for central compensation, as seen in the absence of any
difference in directional preponderance between the two
groups, with scores less than 2◦ /s in both.
The medium-term effect of ondansetron is harder to
assess. While there was a notable, if non-significant, group
difference at 1 month, this seemed purely related to early
deficit values: if the early deficit was indeed related to
treatment, it may be supposed that ondansetron, by its
acute-phase effect, limits the worsening or promotes reco-
very of the early deficit.
These hypotheses thus remain to be confirmed, and dose-
response studies on larger series and animal models of
acute vestibular deficit will be needed to determine the
action mechanism of 5-HT3 antagonists in vestibular neu-
ritis.
Conclusion
The results of the present pilot study suggest that
ondansetron administered in the acute-phase of vestibu-
lar neuritis in association with corticosteroid and antiviral
therapy reduces vestibular deficit and hospital stay in com-
parison with reference anti-H1 antiemetic treatment in the
same association. Specificity and action mechanism, how-
ever, remain unknown and should be explored in animal
models and a larger series in order to determine whether
the present findings can be generalized in the management
of this pathology.
Disclosure of interest
The authors declare that they have no conflicts of interest
concerning this article.
F. Venail et al.
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