Otology & Neurotology 32:701Y709 2011, Otology & Neurotology, Inc.

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 Neurosurgery, 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 32:701Y709, 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).

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: oliviermeeus@uza.be This study was performed with a grant from the Tinnitus Research Initiative.

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 701

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O. MEEUS ET AL.
TABLE 1. Inclusion and exclusion criteria

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.

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 ` Menieres 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 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

FIG. 1.

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) Total score Emotional and cognitive Auditory disturbance Intrusivness Sleep disturbance Somatization Total score Attention Social Emotional 6.2 (3.7) 8.4 (7) 42.2 19.7 6.7 10.4 3.3 2.1 19.8 5.8 8.2 5.8 (15.4) (8) (4.1) (2.6) (3) (2.1) (8.8) (2.6) (4.9) (2.6)

703

Postplacebo Range Mean (standard deviation) Range

(0.5Y8) (0Y30) (24Y72) (6Y32) (0Y13) (3Y14) (0Y8) (0Y6) (7Y36) (3Y10) (1Y15) (3Y12) (0Y23) (37Y94) (26Y96) (32Y98) (30Y100) (20Y100) (0.5Y8) (0Y20) (13Y57) (5Y29) (0Y11) (3Y16) (0Y5) (0Y5) (9Y34) (2Y10) (2Y14) (3Y11) (0Y21) (21Y93) (11Y95) (15Y95) (10Y100) (10Y100) (4Y8) (5Y40) (44Y50) (20Y25) (5Y9) (12Y14) (2Y3) (0Y4) (18Y27) (7Y8) (7Y7) (4Y12) (10Y11) (88Y90) (92Y94) (88Y93) (90Y100) (80Y100)

Post-Deanxit Mean (standard deviation)

4.8 (3) 7.3 (4.9) 40.8 (14.3) 17.8 (8.2) 7.1 (3.4) 10.8 (2.7) 2.9 (2.3) 1.9 (1.4) 21.6 (8.6) 6.5 (2.3) 8.5 (5) 6.6 (2.5) 10.5 (7.6) 59.5 (18.4) 50.9 (17.2) 49.5 (24.6) 72.5 (21.8) 65.4 (27.9) 3.8 (2.6) 7.5 (7) 35.8 (11.7) 16.7 (6.2) 5.3 (3.4) 9.5 (2.4) 2.7 (2.7) 1.7 (1.6) 17.1 (6.3) 4.7 (2) 7.4 (2.9) 5 (2.5) 9.1 (6.5) 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) 42 (2.8) 19 (1.4) 7.5 (3.5) 11 (1.4) 2.5 (0.7) 2 (2.8) 23 (7.1) 7 (2.8) 8.5 (3.5) 7.5 (0.7) 6.5 (6.4) 75 (25.5) 74 (29.7) 83 (14.1) 85 (7.1) 70 (28.3)

Range
(0.3Y8) (1Y15) (24Y78) (6Y38) (1Y14) (5Y15) (0Y8) (0Y4) (6Y38) (2Y10) (1Y18) (3Y10) (0Y29) (32Y90) (20Y77) (9Y81) (30Y100) (10Y100) (0.5Y8) (0Y20) (11Y58) (3Y28) (0Y11) (3Y14) (0Y8) (0Y5) (2Y26) (1Y8) (1Y12) (0Y9) (0Y24) (28Y92) (20Y90) (17Y94) (15Y100) (10Y100) (2Y4) (5Y8) (40Y44) (18Y20) (5Y10) (10Y12) (2Y3) (0Y4) (18Y28) (5Y9) (6Y11) (7Y8) (2Y11) (57Y93) (53Y95) (73Y93) (80Y90) (50Y90)

8.5 (5.5) VAS-W VAS-M VAS-A %TimeAW %TimeAN Patients group B (n = 15; 15S) Tinnitus pitch (kHz) Tinnitus loudness (dBSL) Total score Emotional and cognitive Auditory disturbance Intrusivness Sleep disturbance Somatization Total score Attention Social Emotional 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) 46.8 22.1 6.4 11.9 3.5 2.9 18.9 4.9 7.7 6.3 (9.1) (5.8) (2.2) (2.4) (2.2) (1.8) (6.7) (1.9) (3) (2.9)

8.2 (7.5) 67 59.1 62.9 69 73 Audiometry Tinnitus pitch (kHz) 3.5 Tinnitus loudness (dBSL) 11.3 Total score Emotional and cognitive Auditory disturbance Intrusivness Sleep disturbance Somatization Total score Attention Social Emotional 38.4 18.9 5.4 10.1 3.4 0.6 14.1 4.6 5.1 4.4 VAS-W VAS-M VAS-A %TimeAW %TimeAN (16) (20.5) (17.1) (22.4) (22.8) (2.3) (11.9) (14.1) (8.5) (3.7) (4.4) (2.4) (1.1) (6.5) (2.4) (3.1) (2.8)

Dropout patients (n = 7; 6S 19)

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)

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)

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O. MEEUS ET AL. 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.

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 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.

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).

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 Mauchlys 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.

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).

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.

FIG. 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

705

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). Otology & Neurotology, Vol. 32, No. 4, 2011

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O. MEEUS ET AL. ( 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

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.

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 10 3 6 9 6 3 9 13 15 28

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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

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
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O. MEEUS ET AL. 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,

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
Otology & Neurotology, Vol. 32, No. 4, 2011

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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. REFERENCES
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