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Administration of the Combination
Clonazepam-Deanxit as Treatment for Tinnitus
*Olivier Meeus, †Dirk De Ridder, and *Paul Van de Heyning
*University Department of Otorhinolaryngology and Head and Neck Surgery, and ÞNeurosurgery, Brain
Research Center Antwerp for Innovative & Interdisciplinary Neuromodulation (BRAI2N), Antwerp University
Hospital (UZA), University of Antwerp, Antwerp, Belgium
Hypothesis: Present study investigates the combination of
Deanxit and clonazepam (Rivotril) intake for relief of tinnitus
complaints, respecting a double-blind placebo-controlled approach for Deanxit in a crossover setup.
Background: Although several pharmacologic treatmentsV
including antidepressants, prostaglandins, and aminobutyric
acid (GABA)Yactive drugsVwere already presented as promising in tinnitus treatment, no drug has yet been approved by
the Food and Drug Administration and European Medicine
Agency for the treatment of tinnitus.
Methods: Patients were randomly assigned to patient group A
or patient group B in a double-blind way. Patient group A first
received 3 weeks of Deanxit, followed by 1 week of washout
and 3 weeks of placebo. Treatment was given in opposite order
to subjects from Patient group B. All patients received a daily
treatment consisting of clonazepam 1 mg once daily, starting on
Day 1.
Results: Significant tinnitus reduction was seen after intake of
the combination clonazepam-Deanxit, whereas no differences
in tinnitus could be demonstrated after the administration of
clonazepam-placebo. This was true for all patients according to
the following parameters: time patients are annoyed by the
tinnitus ( p = 0.026) and the visual analogue scale for tinnitus
annoyance ( p = 0.024).
Conclusion: Although tinnitus reduction was recorded as modest, this article provides valuable data demonstrating a placebocontrolled tinnitus reduction after clonazepam and Deanxit
intake. Key Words: ClonazepamVDeanxitVFlupentixolV
MelitracenVTinnitus.
Otol Neurotol 00:00Y00, 2011.
Tinnitus can be defined as the perception of noise in
the absence of an external sound. In developed countries,
up to 30% of individuals report tinnitus at some point
in their lives, with 10% to 15% of individuals experiencing tinnitus significantly enough to require medical
evaluation (1).
To date, tinnitus therapies have been shown to only
marginally decrease tinnitus complaints in selected groups
of patients. Several studies involving medication that
modulates neurotransmitter systems in the brain demonstrated beneficial results in some tinnitus patients (2,3).
However, these significant effects could always be questioned because of methodologic issues (2,4,5).
Antidepressant medication, such as selective serotonin
reuptake inhibitors, does not seem to benefit tinnitus
patients, whereas tricyclic antidepressant drugs might
yield a small improvement in tinnitus (4).
GABA-ergic drugs also have been investigated in the
treatment of tinnitus, and clonazepam has been shown to
decrease tinnitus complaints in a retrospective review by
Gananca et al. (6).
Dopamine agonists and antagonists have been tried
as well. Piribedil, a dopaminergic drug with affinity to
D39D29D1 receptors (7) yielded no significant improvement of Tinnitus Handicap Inventory and visual analogue
scale score compared with placebo in a recent study (8).
On the other hand, sulpiride, a D2 antagonist did influence
tinnitus perception (9).
Deanxit is a drug combination of flupentixol and
melitracen, thereby combining possible tricyclic antidepressant beneficial effects with dopamine D1 and D2
blocking properties, which might benefit patients as well.
Based on the fact that tinnitus likely results from
mechanisms involving multiple neurotransmitter systems, a combination of drugs interfering with multiple
Address correspondence and reprint requests to Olivier Meeus, M.D.,
Ph.D., University Department of Otorhinolaryngology and Head and
Neck Surgery, Antwerp University Hospital (UZA), University of
Antwerp, Wilrijkstraat 10, B-2650 Edegem-Antwerp, Belgium; E-mail:
[email protected]
This study was performed with a grant from the Tinnitus Research
Initiative.
1
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2
O. MEEUS ET AL.
neurotransmitter systems might result in better effects
than drugs acting on a single receptor.
The present study investigates the combination of
Deanxit and clonazepam (Rivotril) intake for relief of
tinnitus complaints. To rule out the antidepressant properties of this therapy, and given the fact that antidepressants are known to work only after a few weeks,
Deanxit treatment was administered for a total of only
3 weeks.
We hereby respect the double-blind placebo-controlled
approach for Deanxit in a crossover design, permitting
each patient to act as his own control. Multiple questionnaires were used to assess the multidimensional
aspects of the self-perceived tinnitus complaints.
MATERIALS AND METHODS
The protocol (8/64/260) was approved by the Ethical Committee of the Antwerp University Hospital. Informed consent
was obtained from all patients.
Study Design
Prospective double-blind, randomized, placebo-controlled
crossover study investigating the additional effect of Deanxit
(flupentixol 0.5 mg + melitracen 10 mg) on clonazepam (Rivotril)
1 mg. Deanxit combines the neuroleptic flupentixol (0.5 mg) and
the tricyclic antidepressant melitracen (10 mg). Clonazepam is
a benzodiazepine with GABA-A-agonist properties.
Patients were randomly assigned to patient group A or patient
group B in a double-blinded way. Patient group A first received
3 weeks of Deanxit, followed by 1 week of washout and 3 weeks
of placebo. Treatment was given in opposite order to subjects
from patient group B (Fig. 1).
Given the demonstrated efficacy of clonazepam in a retrospective review for treatment of tinnitus complaints (6), all
patients received a daily treatment consisting of clonazepam 1
mg once daily, starting on Day 1.
FIG. 1.
TABLE 1.
Inclusion and exclusion criteria
Inclusion criteria:
Primary complaints of chronic tinnitus (93 mo)
Pure tone, narrow band noise of polyphonic tinnitus
Unilateral or bilateral tinnitus
Age, 918 yr
Patient able to cooperate
Normal magnetic resonance imaging pontine angle
Exclusion criteria:
Depression: Beck Depression Inventory II 9 21
Pulsatile tinnitus
Pregnancy or breast-feeding
Epilepsy
Somatic tinnitus
Ménière’s disease
Otosclerosis
Middle ear pathology
Specific contraindications for Deanxit
Parkinson disease
Recovery from myocardial infarction
Known conducting disturbances bundle of His
Known untreated glaucoma
Intake of monoamine oxidase inhibitors less than 15 days ago
Specific contraindications for Clonazepam
Hypersensibility benzodiazepine
Severe chronic respiratory disorders
Severe liver insufficiency
Acute closed angle glaucoma
Alcoholism/drug addiction
Given the elimination half-time of melitracen (19 h) and
flupentixol (35 h), a washout time of 5 times this elimination
half-time (5 35 h = 175 h È 7 d) was respected between both
blocks of 3 weeks of therapy.
Patients
All patients presented to our Multidisciplinary Tinnitus Clinic
with primary complaints of chronic tinnitus. All patients
underwent thorough ENT clinical examination with otoscopy
Study setup.
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CLONAZEPAMYDEANXIT AS TREATMENT FOR TINNITUS
TABLE 2.
Tinnitus characteristics pretreatment, postplacebo, and post-Deanxit according to study groups
Pretreatment
Mean
(standard deviation)
Patients group A
(n = 13; 10S 39)
Tinnitus pitch (kHz)
t\Tinnitus loudness (dBSL)
6.2 (3.7)
8.4 (7)
Total score
Emotional and cognitive
Auditory disturbance
Intrusivness
Sleep disturbance
Somatization
42.2
19.7
6.7
10.4
3.3
2.1
(15.4)
(8)
(4.1)
(2.6)
(3)
(2.1)
Total score
Attention
Social
Emotional
19.8
5.8
8.2
5.8
(8.8)
(2.6)
(4.9)
(2.6)
8.5 (5.5)
VAS-W
VAS-M
VAS-A
%TimeAW
%TimeAN
Patients group B
(n = 15; 15S)
Tinnitus pitch (kHz)
Tinnitus loudness (dBSL)
58.8
52.5
60.9
69.2
67.7
(23)
(17.9)
(20)
(20.2)
(24.9)
4.5 (2.8)
7.5 (6.4)
Total score
Emotional and cognitive
Auditory disturbance
Intrusivness
Sleep disturbance
Somatization
46.8
22.1
6.4
11.9
3.5
2.9
(9.1)
(5.8)
(2.2)
(2.4)
(2.2)
(1.8)
Total score
Attention
Social
Emotional
18.9
4.9
7.7
6.3
(6.7)
(1.9)
(3)
(2.9)
8.2 (7.5)
VAS-W
VAS-M
VAS-A
%TimeAW
%TimeAN
Dropout patients
(n = 7; 6S 19)
3
67
59.1
62.9
69
73
Audiometry
Tinnitus pitch (kHz)
3.5
Tinnitus loudness (dBSL)
11.3
(16)
(20.5)
(17.1)
(22.4)
(22.8)
Total score
Emotional and cognitive
Auditory disturbance
Intrusivness
Sleep disturbance
Somatization
38.4
18.9
5.4
10.1
3.4
0.6
(14.1)
(8.5)
(3.7)
(4.4)
(2.4)
(1.1)
Total score
Attention
Social
Emotional
14.1
4.6
5.1
4.4
(6.5)
(2.4)
(3.1)
(2.8)
(2.3)
(11.9)
7.3 (5.3)
VAS-W
VAS-M
VAS-A
%TimeAW
%TimeAN
77.6
72.9
73.4
63
63
(19.7)
(19.5)
(20.6)
(33.5)
(33.5)
Postplacebo
Range
Mean
(standard deviation)
Audiometry
(0.3Y12.5)
5.2 (2.8)
(0Y20)
8.5 (7.2)
Tinnitus Questionnaire
(24Y74)
43.5 (13.7)
(7Y35)
19 (7.2)
(0Y13)
7.2 (4)
(7Y16)
10.7 (3.2)
(0Y8)
4.2 (2.4)
(0Y6)
2.5 (2)
Hyperacusis Questionnaire
(4Y34)
21.4 (9.1)
(0Y10)
6.3 (2.1)
(2Y18)
8.1 (4.5)
(2Y11)
7 (3)
Beck Depression Inventory
(1Y19)
11.4 (6.7)
Visual Analogue Scales
(22Y98)
60.8 (18)
(23Y92)
54.4 (19.3)
(37Y95)
59.2 (19.2)
(20Y100)
72.5 (24.5)
(20Y100)
68.3 (26.2)
Audiometry
(0.5Y8)
4.1 (2.6)
(0Y25)
8 (6.8)
Tinnitus Questionnaire
(31Y61)
38.9 (12)
(15Y37)
17.9 (6)
(2Y10)
5.7 (3.9)
(7Y15)
10.7 (2.8)
(0Y7)
1.8 (1.9)
(0Y6)
1.9 (1.7)
Hyperacusis Questionnaire
(4Y30)
19.3 (7.1)
(1Y8)
4.9 (2.2)
(1Y11)
8.3 (3.7)
(2Y11)
6.2 (2.5)
Beck Depression Inventory
(0Y20)
8.5 (6.2)
Visual Analogue Scales
(38Y95)
60.1 (23)
(29Y96)
50.4 (25.8)
(30Y85)
49.7 (24.1)
(10Y100)
65 (27.6)
(40Y100)
68.7 (30.4)
n=3
(1Y8)
6 (2.8)
(0Y30)
22.5 (24.7)
Tinnitus Questionnaire
(15Y59)
47 (4.2)
(6Y32)
22.5 (3.5)
(0Y10)
7 (2.8)
(5Y16)
13 (1.4)
(0Y7)
2.5 (0.7)
(0Y3)
2 (2.8)
Hyperacusis Questionnaire
(0Y19)
22.5 (6.4)
(0Y7)
7.5 (0.7)
(0Y9)
7 (0)
(0Y8)
8 (5.7)
Beck Depression Inventory
(0Y13)
10.5 (0.7)
Visual Analogue Scales
(53Y99)
89 (1.4)
(50Y99)
93 (1.4)
(47Y99)
90.5 (3.5)
(25Y100)
95 (7.1)
(25Y100)
90 (14.1)
Post-Deanxit
Range
Mean
(standard deviation)
Range
(0.5Y8)
(0Y30)
4.8 (3)
7.3 (4.9)
(0.3Y8)
(1Y15)
(24Y72)
(6Y32)
(0Y13)
(3Y14)
(0Y8)
(0Y6)
40.8 (14.3)
17.8 (8.2)
7.1 (3.4)
10.8 (2.7)
2.9 (2.3)
1.9 (1.4)
(24Y78)
(6Y38)
(1Y14)
(5Y15)
(0Y8)
(0Y4)
(7Y36)
(3Y10)
(1Y15)
(3Y12)
21.6 (8.6)
6.5 (2.3)
8.5 (5)
6.6 (2.5)
(6Y38)
(2Y10)
(1Y18)
(3Y10)
(0Y23)
10.5 (7.6)
(0Y29)
(37Y94)
(26Y96)
(32Y98)
(30Y100)
(20Y100)
59.5 (18.4)
50.9 (17.2)
49.5 (24.6)
72.5 (21.8)
65.4 (27.9)
(32Y90)
(20Y77)
(9Y81)
(30Y100)
(10Y100)
(0.5Y8)
(0Y20)
3.8 (2.6)
7.5 (7)
(0.5Y8)
(0Y20)
(13Y57)
(5Y29)
(0Y11)
(3Y16)
(0Y5)
(0Y5)
35.8 (11.7)
16.7 (6.2)
5.3 (3.4)
9.5 (2.4)
2.7 (2.7)
1.7 (1.6)
(11Y58)
(3Y28)
(0Y11)
(3Y14)
(0Y8)
(0Y5)
(9Y34)
(2Y10)
(2Y14)
(3Y11)
17.1 (6.3)
4.7 (2)
7.4 (2.9)
5 (2.5)
(2Y26)
(1Y8)
(1Y12)
(0Y9)
(0Y21)
9.1 (6.5)
(0Y24)
(21Y93)
(11Y95)
(15Y95)
(10Y100)
(10Y100)
(4Y8)
(5Y40)
67.3 (17.2)
53.9 (20.9)
55.4 (19.7)
63.2 (25.4)
58.6 (25.7)
n=4
3 (1.4)
6.5 (2.1)
(28Y92)
(20Y90)
(17Y94)
(15Y100)
(10Y100)
(2Y4)
(5Y8)
(44Y50)
(20Y25)
(5Y9)
(12Y14)
(2Y3)
(0Y4)
42 (2.8)
19 (1.4)
7.5 (3.5)
11 (1.4)
2.5 (0.7)
2 (2.8)
(40Y44)
(18Y20)
(5Y10)
(10Y12)
(2Y3)
(0Y4)
(18Y27)
(7Y8)
(7Y7)
(4Y12)
23 (7.1)
7 (2.8)
8.5 (3.5)
7.5 (0.7)
(18Y28)
(5Y9)
(6Y11)
(7Y8)
(10Y11)
6.5 (6.4)
(2Y11)
(88Y90)
(92Y94)
(88Y93)
(90Y100)
(80Y100)
75 (25.5)
74 (29.7)
83 (14.1)
85 (7.1)
70 (28.3)
(57Y93)
(53Y95)
(73Y93)
(80Y90)
(50Y90)
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O. MEEUS ET AL.
and audiometric evaluation. Inclusion and exclusion criteria
are listed in Table 1. Thirty-five consecutive patients started
the study protocol. After a dropout of 7 subjects, 28 patients
(25 men and 3 women; mean age, 55.4 yr; SD, 9.1) were
included in the study protocol. Mean age and range (years) were
as follows: dropout patients, 48.3 (20Y74); patient group A, 57.9
(46Y66); and patient group B, 53.2 (33Y72). Tinnitus characteristics are shown in Table 2.
Tinnitus Measurement Tools
Visual Analogue Scale
Before the study (‘‘pre’’), patients had to score 3 visual
analogue scale (VAS) scales (ranging from 0 to 100) quantifying
the self-perceived tinnitus: 1, worst tinnitus loudness (VAS-W);
2, mean tinnitus loudness (VAS-M); and 3, mean tinnitus
annoyance (VAS-A). Patients were instructed that 0 represented
‘‘absent/not annoying tinnitus,’’ whereas 100 corresponded to
‘‘extremely loud/extremely annoying tinnitus, could not get any
worse.’’ They were instructed always to rate their tinnitus as
they had perceived it during the previous 24 hours. Additionally,
patients were asked to answer the following questions on 2
separate VAS ranging from 0 to 100: 1, What percent of the
waking time have you been aware of the tinnitus during the
previous 24 h? (%TimeAW) 2, What percent of the waking time
have you been annoyed by the tinnitus during the previous 24 h?
(%TimeAN). These same VAS were scored after the first
treatment (post 1) and after the second treatment (post 2).
Questionnaires
The questionnaires presented to the patients consisted of the
Dutch version of the Tinnitus Questionnaire (TQ) (10Y12), the
Beck Depression Inventory (BDI-II) (13), and the Hyperacusis
Questionnaire (HQ) (14,15). For all questionnaires, higher
scores indicate more severe complaints.
Categorical Scale
After the first and the second treatment, a categorical scale
was additionally used to assess whether the tinnitus had changed
compared with the pretherapeutic level. Following statements
concerning the change in tinnitus complaints were specified to
the patients: 1, severe improvement; 2, moderate improvement;
3, slight improvement; 4, unchanged; 5, slight worsening; 6,
moderate worsening; and 7, severe worsening.
At the end of the study, patients were additionally asked
which period of treatment hadVin their own opinionVprovided
the best symptom reduction (Treatment 1 or Treatment 2).
FIG. 2.
Audiometry
Pure Tone Auditory Thresholds
Pure tone audiometry was performed before treatment using
the ‘‘up 5Ydown 10’’ method at 0.125, 0.25, 0.5, 1, 2, 3, 4, 6,
and 8 kHz.
Tinnitus Analysis
Tinnitus loudness and pitch were assessed at times ‘‘pre,’’
‘‘post 1,’’ and ‘‘post 2’’ contralateral to the tinnitus ear in unilateral tinnitus patients and contralateral to the worst tinnitus ear
in bilateral tinnitus patients. Computation of the tinnitus loudness (dBSL) was achieved by subtracting the absolute tinnitus
loudness (dBHL) by the auditory threshold at that frequency.
Statistical Analysis
Differences in pretreatment characteristics were assessed
between groups A and B and dropouts using a 1-way analysis of
variance.
To prevent the clonazepam intake from jeopardizing the comparison between treatment outcomes after Deanxit or placebo,
the group assignment (A or B) was added as factor in the general
model of repeated measures. This taken into consideration, both
outcomes of Treatments 1 and 2 could be compared with the
tinnitus assessments before the study (‘‘pre’’).
This furthermore allowed us to use the ‘‘pre’’ assessments to
compare both results of Therapies 1 and 2.
In case sphericity was not assumed by Mauchly’s Test of
Sphericity, the Greenhouse-Geisser value was used for the tests
of within-subjects effects. If appropriate, post hoc pairwise
comparisons were performed with Bonferroni correction for
multiple comparisons so that a significance level of alpha = 0.05
could be adopted in every analysis.
The randomization key was only revealed to the patients after
6 weeks of therapy and full completion of all study outcome
measurements.
RESULTS
Of the 35 included patients, 28 finished the complete
study protocol, resulting in a 20% dropout. Although
extrapyramidal syndromes and tardive dyskinesia are
known side effects of Deanxit, they were not observed in
our study population. Results on audiometry are represented in Figure 2.
Mean air conduction thresholds are shown separately for right and left ears as measured on pure tone audiometry.
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CLONAZEPAMYDEANXIT AS TREATMENT FOR TINNITUS
A 1-way analysis of variance demonstrated no differences in pretreatment characteristics between groups A
and B and dropouts ( p 9 0.05).
A significant difference in the percent of waking time
annoyed by the tinnitus (%TimeAN) was found when
5
results were compared between pretherapeutic results
(‘‘pre’’), results after Deanxit intake (‘‘Deanxit’’)
and results after placebo intake (‘‘placebo’’) ( p = 0.014).
This was true independent of the study group to which
patients had been assigned ( p = 0.251). Pairwise
FIG. 3. A and B, Individual results before and after therapy. %TimeAN represents the response on a VAS regarding the question: ‘‘What
percent of the waking time have you been annoyed by the tinnitus during the previous 24 hours?’’ Significantly lower scores were found for
%TimeANDeanxit compared with %TimeANpre (MD, 10.3; p = 0.026). VAS-A represents the mean tinnitus annoyance as scored on a VAS
ranging from 0 to 100. Patients were instructed that 0 represented ‘‘not annoying tinnitus,’’ whereas 100 corresponded to ‘‘extremely
annoying tinnitus, could not get any worse.’’ Significantly lower scores were found for VAS-ADeanxit compared with VAS-Apre (MD, 9.5;
p = 0.024).
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6
O. MEEUS ET AL.
comparisons allowed to identify significantly lower
scores for %TimeANDeanxit compared with %TimeANpre
(mean difference [MD] = 10.3; p = 0.026). %TimeANDeanxit was also significantly lower than %TimeANplacebo (MD, 7.5; p = 0.037) (Fig. 3). However, no
significant difference was found between %TimeANplacebo and %TimeANpre.
A significant difference in mean tinnitus annoyance
(VAS-A) was found between ‘‘pre,’’ ‘‘Deanxit,’’ and
‘‘placebo’’ ( p = 0.031). This was again independent of
the study group to which the patients had been assigned
( p = 0.099).
Pairwise comparisons showed this effect to be significant between VAS-ADeanxit and VAS-Apre (MD, 9.5;
p = 0.024).
A significant difference in somatization was found
between ‘‘pre,’’ ‘‘Deanxit,’’ and ‘‘placebo’’ (p = 0.037).
This effect was, however, dependent of the study group
to which patients had been assigned ( p = 0.026).
Paired T test were performed separately for groups A
and B and demonstrated significant differences only in
patients who had received Deanxit in the second period.
In these patients, significantly lower scores were revealed
for somatizationDeanxit compared with somatizationpre
(MD, 1.2; p = 0.001). Moreover, somatizationplacebo
was significantly lower compared with somatizationpre
(MD, 1.0; p = 0.002).
A significant difference in the total score of the TQ
was found between ‘‘pre,’’ ‘‘Deanxit,’’ and ‘‘placebo’’
FIG. 4.
( p = 0.016). This effect was again dependent of the study
group to which patients had been assigned ( p = 0.034).
Paired T test were therefore again performed and, for
a second time, demonstrated significant differences only
in patients who had received Deanxit in the second period. In these patients, significantly lower scores were
revealed for TQDeanxit compared with TQpre (MD, 11.0;
p = 0.000). Moreover, TQplacebo was significantly lower
compared with TQpre (MD, 7.9; p = 0.001).
No other significant differences were found between
scores at ‘‘pre,’’ ‘‘Deanxit,’’ or ‘‘placebo’’ when comparisons were performed on the other tinnitus measurements or audiometry.
Only 3 of 28 patients reported tinnitus improvement
after Deanxit without any tinnitus improvement after
placebo (Fig. 4).
Because tinnitus improvement also could be expected
resulting from clonazepam intake together with the study
medication, some tinnitus reduction also could be expected in the period of placebo treatment. We therefore
evaluated in which period of treatment patients had received Deanxit or placebo and which of these 2 treatment
periods had been reported by the patients as having resulted in the best tinnitus reduction. Of 28 patients, 10
patients designated the period in which they had received
Deanxit as having resulted in better tinnitus relief than the
period in which placebo had been administered (Table 3).
Nine patients responded not to have experienced any difference between both periods of treatment, and 9 patients
Responses to the question ‘‘How did the tinnitus change after therapy compared with the pretherapeutic state?’’.
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CLONAZEPAMYDEANXIT AS TREATMENT FOR TINNITUS
TABLE 3. Comparison between the treatment period
reported by the patients as having resulted in the best tinnitus
reduction and the treatment period in which Deanxit was
administered instead of placebo
Which period of treatment
has, in your opinion,
provided the best
tinnitus relief?
Period Period
No
1
2
difference Total
Period in which
Treatment 1
Deanxit was
Treatment 2
administered instead
of placebo
Total
4
6
3
6
6
3
13
15
10
9
9
28
designated the period with placebo as having resulted in
better tinnitus relief.
DISCUSSION
Several pharmacologic treatments including antidepressants, prostaglandins, and aminobutyric acid
(GABA)Yactive drugs have been proposed as promising
in tinnitus treatment (2,3). However, no drug has yet
been approved by the Food and Drug Administration
and European Medicine Agency for the treatment of
tinnitus (2,3).
Tinnitus is believed to result from a reorganization
involving various circuits of the lemniscal and extralemniscal pathways in the brain (16). Nevertheless, it is
not yet known exactly which population of neurons in the
cerebral cortex and subcortical structures are critically
involved in the tinnitus generation (17). Which neurotransmitter systems are involved is equally unknown.
Based on the principles of agonism and synergism, a
therapy interacting with more than 1 receptor site could
therefore result in more tinnitus reduction compared with
a therapy involving only 1 action mechanism.
In the present study, a significant decrease in tinnitus
perception was obtained after administration of a combination of clonazepam 1 mg and Deanxit, which combines flupentixol 0.5 mg (antipsychotic) and melitracen
10 mg (tricyclic antidepressant). This tinnitus decrease
was, however, not present when clonazepam was administered alone with placebo. The tinnitus reduction could
therefore have resulted either from the administration of
Deanxit alone or from the administration of the combination Deanxit-clonazepam.
Melitracen
Given the composition of Deanxit, the tinnitus reduction in the present study could therefore have merely
resulted from the administration of the tricyclic antidepressant melitracen. As mentioned before, previous
studies investigating the use of tricyclic antidepressants lacked convincing evidence for efficacy because of
7
the absence of a double-blind placebo-controlled setting,
whereas in other cases, they only demonstrated significant effects in selected patient groups (5). This latter was
confirmed in a review by Robinson (18) and Salvi et al.
(19) in which antidepressants were shown to work best
for tinnitus patients with more severe tinnitus, who are
depressed or anxious or who are treated for a longer time
with an adequate dose of medication. This suggests that
the effect of antidepressant medication results from improving the associated comorbidity in tinnitus patients
with possible secondary tinnitus improvement. Doubleblind placebo-controlled studies investigating the tricyclic antidepressants nortriptyline (20), the selective
serotonin reuptake inhibitor paroxetine (21), and sertraline (22), demonstrated a reduction in depression, strain,
annoyance, and even tinnitus loudness in subgroups of
tinnitus patients. No such subgroups could be determined
in this study population. This can partially be due to the
fact that the scores on the BDI-II were already relatively
low before therapy in our study population.
Nevertheless, an effect based solely on the antidepressant properties of melitracen is unlikely in this
study because antidepressants are known to work best
after a few weeks. Accordingly, a previous study reported
a placebo-controlled tinnitus reduction after a 16-week
intake of sertraline (22), whereas another article described
some reduction in tinnitus perception after 4 weeks of
treatment with paroxetine (21).
A 3-week administration of melitracen might therefore
not have been sufficient to improve tinnitus complaints
based on its antidepressant properties alone. Moreover,
no differences in BDI-II scores could be demonstrated
after the 3 weeks of melitracen administration. Finally,
with a BDI-II score of more than 21 set as exclusion
criterion, patients with depressive symptoms were even
excluded from this study, again arguing against the idea
that the measured tinnitus reduction solely resulted from
decreased depressive symptoms.
Flupentixol
In line with previous studies demonstrating tinnitus
reduction after therapy with the combination of the antipsychotic sulpiride (D2 antagonist of dopamine receptor) and hydroxyzine (a subcortical sedative) (23) or the
combination of sulpiride with melatonine (a pineal substance with antidopaminergic action) (9), one also could
assume the tinnitus reduction in the present study to result from the administration of the antipsychotic flupentixol, which is known to decrease both D1 (activation
of adenylate cyclase) and D2 (inhibition of adenylate
cyclase) activity (24). Given the fact that the dopaminergic pathway was previously proposed as a structure
involved in the functional neuroanatomy of tinnitus perception (25), tinnitus reduction could indeed have resulted from an antidopaminergic mechanisms.
Clonazepam
Clonazepam is known to enhance the inhibitory effect
of GABA by binding to a specific regulatory site on the
Otology & Neurotology, Vol. 00, No. 00, 2011
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8
O. MEEUS ET AL.
GABA-A receptor enhancing GABAergic inhibition of
neural firing. Additionally, clonazepam decreases the
consumption of 5-HT (serotonin) by neurons and binds
tightly to central-type benzodiazepine receptors. GABA is
broadly represented in the central auditory pathway and
features major inhibitory properties. Given the hypothesis
that tinnitus results from a loss in central GABA-mediated
lateral inhibition (26), a decrease in tinnitus sensation is
therefore to be expected after GABA increase.
A study investigating the combined intake of clonazepam and a GABA agonist (gabapentin) in 30 patients
finally enrolled 21 patients responding well to an initial
dose and thereby reported a significant tinnitus reduction
in 19 patients (63.3%) (27). Another study compared the
intake of clonazepam (Group 1), clonazepam and gabapentin (Group 2), and placebo (Group 3) (28) and demonstrated a significant tinnitus reduction in Groups 1 and
2 compared with placebo. However, no additional tinnitus reduction could be demonstrated between clonazepam alone or in combination with gabapentin. The
absence of tinnitus reduction after gabapentin was confirmed in another study including 30 tinnitus patients
receiving 4 weeks of gabapentin (29) and in a study
investigating a 5-week gabapentin treatment in 52 tinnitus
patients (30).
The beneficial effects of clonazepam in the symptomatic treatment of patients with cochleovestibular disorders
were again pointed out in a retrospective survey with 32%
of the patients reporting tinnitus improvement (6). Nevertheless, no control group was included in that study.
Based on the categorical scale in the present study,
12 (42.9%) of 28 patients reported at least a slight
tinnitus improvement after intake of the combination
clonazepam-placebo. This is in line with the 30% to 40%
placebo response rate published previously (5). This
response rate is nevertheless lower than expected, given
the previously mentioned studies acclaiming the tinnitusreducing properties of clonazepam.
Although no significant tinnitus reduction was obtained in the present study using clonazepam alone, the
addition of Deanxit did result in tinnitus relief. This is
in line with another study in which a combination of
drugs acting on different action sites (dopamine antagonist and subcortical sedative) resulted in increased tinnitus improvement (23).
A study investigating the GABA transaminase inhibitor
vigabatrin demonstrated elimination of tinnitus in an animal model, but the serious side effects have prevented its
clinical use (31). In line with previous findings, a combination of low-dose vigabatrin with a drug acting on another
activation site could possibly reduce tinnitus without the
side effects reported with high-dose vigabatrin.
Combination Deanxit-Clonazepam
SignificantValthough modestVtherapeutic results
were obtained after clonazepam-Deanxit intake according
to the VAS for mean tinnitus annoyance (VAS-A), the
tinnitus questionnaire (TQ), the somatization dimension
of the TQ, and the percentage of time that patients feel
annoyed by the tinnitus (%TimeAN) in the present study.
In contrast, no results were seen independent of the study
groups after clonazepam-placebo intake.
Because clonazepam has been proposed as an adjunct
for the medical treatment of depression, accelerating the
response to conventional antidepressants and augmenting their efficacy and preventing relapses (32Y34), clonazepam could possibly have exerted an augmenting
effect on the antidepressant effect of melitracen. However, because the BDI-II depression scale was not significantly improved after the treatment, it is unlikely that
this is the mechanism explaining the tinnitus improvement in this study.
Clonazepam also potentates the cataleptic effect of
neuroleptics (35). This might be related to the antidopaminergic action of clonazepam (36), strengthening
the action of flupentixol. Furthermore, adding clonazepam might be useful to prevent or treat the potential side
effects of flupentixol, that is, tardive dyskinesias, when
foreseeing the long-term use of the drug (37).
When asked which period of treatment had resulted in
better improvement of the tinnitus complaints, patients
did not systematically point out the period in which they
had received Deanxit. Up to 32% even indicated the
period in which placebo was given as having resulted in
better results, whereas another 32% experienced no difference between both treatment periods. This discrepancy
between study results could suggest that the combination
of clonazepam-Deanxit indeed reduced tinnitus complaints, even if this was not confirmed by the responses
on the categorical scale for tinnitus change after therapy.
We can therefore suggest a tinnitus improvement at a
clinically irrelevant level, not tangible by the patients.
The effects on tinnitus perception were minimal but
statistically significant in a prospective double-blind,
randomized placebo-controlled crossover study. In our
opinion, further investigations are therefore needed to
elucidate the exact mechanism of the beneficial effect of
this polypharmacologic treatment and to improve its
effects. Comparative studies using Deanxit (flupentixol
and melitracen) as monotherapy, flupentixol plus clonazepam, and melitracen plus clonazepam in a double-blind
placebo-controlled setting are needed to fine tune the
therapy and to understand its beneficial effects. As discussed previously, the doses possibly have to be adjusted,
the population size enlarged, and/or the duration of the
therapy prolonged.
Furthermore, a study involving a larger study populations can underline whether the differences found
for the TQ and the Somatization dimension still remain
and whether they indeed depend on the order in which
Deanxit or placebo treatment was administered. A possible explanation for this phenomenon would be the
need of an uploaded concentration of clonazepam before
Deanxit could induce a measurable influence on these 2
tinnitus dimensions.
The intention to conduct such investigations should,
however, be considered along with the side effects that
can be expected with this medication. Most importantly,
Otology & Neurotology, Vol. 00, No. 00, 2011
Copyright © 2011 Otology & Neurotology, Inc. Unauthorized reproduction of this article is prohibited.
CLONAZEPAMYDEANXIT AS TREATMENT FOR TINNITUS
flupentixol is known to possibly induce tardive dyskinesia with limited spontaneous reversibility, even if applied
in low dosage (38). Adding clonazepam, which is used to
treat tardive dyskinesias (37) might be preventive because
no tardive dyskinesias were noted in this study.
Finally, the size of our study population was characterized by a relatively high dropout rate, similar to the
17% dropout rate observed in a previous article investigating the effects of sertraline on tinnitus (22). All
dropout patients were contacted after not showing up at
the study evaluation moments. Various reasons for quitting the study were mentioned, including ‘‘I forgot it,’’
‘‘I went on a holiday and forgot pills at home,’’ and
‘‘I did not feel any improvement, so I quit the study.’’ The
latter was mentioned by 2 subjects, one of which had
received placebo and the other had received Deanxit.
Both patients quit the study during Treatment 1. Because
only patients completing the study protocol were included
in our statistical analysis, no intention-to-treat values can
be deduced from our results.
CONCLUSION
A modest, although statistically significant, placebocontrolled tinnitus reduction could be obtained after
Deanxit-clonazepam intake, whereas no reduction could
be demonstrated after clonazepam-placebo intake. This
suggests better tinnitus relief when drugs acting on multiple neurotransmitter systems are combined. Further
investigation is mandatory to reveal and improve the
underlying action mechanisms responsible for this tinnitus improvement.
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