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Introduction
Tinnitus is the phantom perception of sound resulting from abnormal/false activity within the auditory nervous system without any corresponding mechanical or vibratory activity from the cochlea and is not related to any external sound stimuli [1]. One-third of the global population experiences tinnitus at least once in their lifetime [2], and approximately 1%-5% of individuals with tinnitus experience serious psychosocial complications that may require medication. Furthermore, recent studies have reported that patients with tinnitus are likely to have comorbid psychological disorders, including anxiety and depression, and show a high prevalence of depression [3-6]. In addition, the severity of tinnitus is positively correlated with anxiety and depression levels [7].
Tinnitus is a chronic illness that has no cure. Treatments such as tinnitus retraining therapy, cognitive behavioral therapy, transcranial magnetic stimulation, electrical stimulation, and the use of masking devices and white noise machines have been studied. However, there is no definitive cure for tinnitus [8]. The management of tinnitus requires a multidisciplinary approach depending on the symptoms and comorbid conditions of patients with tinnitus [9,10]. Currently, there are no FDA-approved drugs for the treatment of tinnitus [11]. However, clinical studies are underway to evaluate the efficacy of N-methyld-aspartate and dopamine D2 antagonists, selective serotonin reuptake inhibitors, and γ-aminobutyric acid agonists [12]. Previous studies have suggested that patients with severe depression may experience improvements in tinnitus after treatment with antidepressants such as nortriptyline or sertraline [13].
Several studies have investigated the use of benzodiazepines for tinnitus treatment. Some studies have shown that clonazepam is effective for tinnitus. Clonazepam, which is sold under the brand name Rivotril, is a benzodiazepine medication that is used to prevent and treat tinnitus, seizures, panic disorder, anxiety, and movement disorders [14-16]. It increases activity of GABA, and potentiate the inhibitory neurotransmission in the brain cortex. The effect of clonazepam begins within 1 h and lasts for 6-12 h. The typical side effects of clonazepam include sedation, motor impairment, and confusion. The intermittent side effects of clonazepam include irritation, psychomotor agitation, dizziness, hallucinations, memory loss, and headaches [17]. Regarding long-term use, side effects such as tolerance, dependence, and withdrawal symptoms may occur [18,19]. Clonazepam is a very basic drug that is widely used around the world and is also commonly used for tinnitus [20].
When clonazepam is used for tinnitus, it can easily cause various side effects [21]; therefore, it is important to determine the dose of the drug for each individual. In addition, optional use is recommended after the symptoms of tinnitus have been controlled. Many studies claim that clonazepam effectively alleviates tinnitus [16], but its effects on sleep quality and depression have not been discussed.
In this study, we aimed to determine whether clonazepam at a lower dose than that used in other studies is effective in treating chronic tinnitus lasting more than 3 months. This paper will perform a comparative analysis of questionnaire scores before and after 3 months of clonazepam administration by using the Tinnitus Handicap Inventory (THI), Beck Depression Inventory (BDI), and Pittsburgh Sleep Quality Index (PSQI), which are questionnaires that can assess the conditions of patients with tinnitus.
Subjects and Methods
Subjects
A total of 527 patients with tinnitus who visited a tertiary hospital in 2019-2021, underwent hearing and tinnitus tests, and completed a tinnitus questionnaire were considered for the study. The exclusion criteria were acute sudden hearing loss; Meniere’s disease; brain tumor, including internal auditory canal schwannoma and muscular/vascular tinnitus. In addition, patients who needed hearing aids because of definite severe-to-profound hearing loss or asymmetric hearing loss and those who refused to participate in the study were excluded. The study was conducted on 150 patients who agreed to the tinnitus treatment, completed a questionnaire, and were followed up. A final analysis was performed on 76 patients who completed the questionnaire before and after treatment with clonazepam (Fig. 1).
Treatment protocol
This study was conducted prospectively. Rivotril (Roche Inc., Morgantown, WV, USA) was to be taken as one-half to one pill (0.25-0.5 mg) before going to bed and preferably every day for the first month. Basically, 0.25 mg was taken, and 0.5 mg was taken if patients complained of severe tinnitus discomfort or sleep problems. In the second and third month, it can be taken optionally, only when the patient has trouble sleeping or severe tinnitus. This was performed to reduce the addiction caused by the drug and to establish a recommendation for effective use under autonomous management. The importance of ideal sleep hygiene was emphasized in patients during the treatment period for tinnitus. After taking Rivotril, it is recommended to lie down and sleep immediately without using TV, radio, cell phones, or smartphones. It is recommended to have a warm shower before going to bed. Habits such as avoiding extreme exercise 3 h before sleep, avoiding caffeine-containing and stimulating food, and drinking warm milk were encouraged.
This prospective cohort study aims to analyze the results of the THI, BDI, and PSQI questionnaire surveys before and after clonazepam usage. At the first visit, a tinnitus survey and questionnaire were administered, and tympanic membrane examination, pure tone audiometry (PTA), and tinnitogram were performed for all patients. The Institutional Review Board approved this study (Korea University College of Medicine IRB ED15142-2019).
The THI was administered to the patients to evaluate the severity of tinnitus. The Korean version of THI measures the effect of tinnitus on daily life, and its reliability and validity have been proven in a previous study [22]. It contains 25 items under the following subscales: functional subscale (11 items), emotional subscale (9 items), and catastrophic subscale (5 items). Each question is rated as zero (none), two (sometimes), or four (always). The total score is calculated in the range of 0-100.
The Korean version of BDI was used to evaluate the severity of depressive symptoms. It comprises 21 questions that include the emotional, cognitive, motive, and physiological areas of depression. Each question is rated on a scale of 0 to 3 depending on the degree of symptoms, and the total score is calculated from a range of 0 to 63. A previous study found that a BDI score of 16 or above for male and 17 or above for female was indicative of depression [23].
The Korean version of PSQI was used to assess sleep quality. It comprises 19 items that measure subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medication, and daytime function. Each question is rated on a scale of 0 to 3 depending on the degree of symptoms, and the total score is calculated from a range of 0 to 21. A total score of five or above indicates poor sleep quality.
Statistical analysis
All values are presented as mean±standard deviation using SPSS 21.0 (IBM Corp., Armonk, NY, USA). A paired sample t-test was used to compare the changes in THI, BDI, and PSQI scores before and after medication use. Multiple data were analyzed using the analysis of variance. Correlation analysis was used to examine the correlation between THI/BDI and THI/PSQI. Multiple regression analysis was used to confirm the correlation between post-THI and pre-THI and BDI. A p-value less than 0.05 was considered statistically significant.
Results
Demographics of tinnitus patients
A total of 38 males and 38 females from the enrolled patients were analyzed in this study, and the average age was 57.2±9.01 years. The right and left PTA threshold levels were 30.4±20.67 dB HL and 31.7±17.06 dB HL, respectively. Before treatment, the THI score was 44.3±23.4, the BDI score was 7.96±2.36, and the PSQI score was 6.85±4.68. After treatment, the THI score was 33.6±17.1, the BDI score was 7.38±2.25, and the PSQI score was 4.04±3.20.
The initial THI score before treatment was not associated with age (p=0.914). In addition, the right and left PTA hearing outcomes were not correlated with the initial THI scores, thus showing that age and intensity of bothersome tinnitus were not significantly related (p=0.101 and 0.549, respectively) (Table 1).
Fig. 2A describes the results of THI, which showed a statistically significant improvement from 44.3 before treatment to 33.6 after treatment (75.8%, p<0.0001). Fig. 2B describes the results of BDI, which showed no significant improvement from 7.96 before treatment to 7.38 after treatment (92.7%, p=0.1231). Fig. 2C shows the results of PSQI, which showed a statistically significant improvement from 6.85 before treatment to 4.04 after treatment (58.0%, p<0.001).
In general, tinnitus symptoms were closely related to depression and sleep quality. THI and BDI showed a significant positive correlation (r=0.639, p=0.0027), and the relationship between THI and PSQI was the same (r=0.812, p<0.0001). On the basis of multiple regression analysis, the BDI and PSQI scores were found to be significantly related to the pre-treatment THI scores by 0.006 and <0.001, respectively. The initial THI score was calculated as pre-THI=-6.299+2.884× pre-BDI+2.832×pre-PSQI. In addition, the change in THI after treatment could be predicted using the pre-treatment of THI and PSQI, which was calculated as post-THI=0.7673 +0.6947×pre-THI+0.3572×pre-PSQI (Table 1).
Fig. 3 shows the changes in THI before and after clonazepam treatment for tinnitus. The THI items that could be improved by clonazepam were items 1, 5, 6, 7, 8, 12, 13, 14, 20, 24, and 25. Feelings of hopelessness, complaints, and irritability regarding tinnitus were also reduced. In particular, sleep quality improved at night. Work, household chores, and enjoyment of life, all of which were interrupted by tinnitus, improved. Unstable mood and fatigue caused by tinnitus were also reduced. In addition, tinnitus became less severe in stressful situations. When comparing the improvement score, question 7 (i.e., “Do you have difficulties falling asleep because of your tinnitus?”) was found to have the most improvements. This result was the same as that in the PSQI scores related to sleep. However, question 21 (i.e., “Do you feel depressed because of your tinnitus?”) showed little difference before and after treatment. Therefore, the changes in BDI before and after treatment were the same as the result that was not significant.
Discussion
Clonazepam can improve various symptoms of tinnitus, particularly when used effectively and can improve sleep quality. The score obtained by THI, which is a tinnitus questionnaire, was significantly correlated with the scores obtained by BDI, which is a measure of depression, and PSQI, which is a measure of sleep quality. However, clonazepam did not significantly improve depression.
Many studies have investigated the use of benzodiazepine drugs for the treatment of tinnitus (Table 2), particularly alprazolam or clonazepam. The effectiveness of alprazolam varies among studies. Johnson, et al. [25] showed that alprazolam improved the tinnitus of 13 out of 17 patients. However, Jalali, et al. [27] showed that alprazolam did not improve tinnitus. Unlike alprazolam, clonazepam was shown to be effective in most studies. Lectenberg and Shulman [24] showed that 18 of 26 tinnitus cases improved when clonazepam 0.5-3 mg was used. Ganança, et al. [21] showed that when using clonazepam 0.5-1.0 mg for 60-180 days, 32% of patients with tinnitus showed improvements. Bahmad, et al. [26] showed that clonazepam 0.5-2 mg improved the visual analog scale (VAS) score for tinnitus. Recently, Han, et al. [28] showed that 61% of the mean THI and VAS scores and 74% of tinnitus loudness improved when using clonazepam 0.5-2 mg for 5 weeks. Although clonazepam was effective in treating tinnitus, there were also side effects; a common side effect during the study was drowsiness, headache, and sedation.
Unlike previous studies, the current study used a low dose of clonazepam (0.25-0.5 mg) for 1 month and optionally for the next 2 months and showed improvements in tinnitus. Second, during the treatment of tinnitus using clonazepam, the THI, BDI, and PSQI scores were measured, and changes in depression and sleep disturbance were studied. In addition, the pre-THI and post-THI scores were calculated by correlating the pre-BDI and pre-PSQI scores. It is also valuable to roughly predict the post-THI score on the basis of the pre-THI and pre-PSQI scores. Therefore, it can be inferred that not only drugs but also education on sleep hygiene can be helpful in the treatment of tinnitus.
Limitation of this study was that other medications especially hypnotics and anxiolytics, and comorbidities including psychologic disorders were not considered in the current study. However, when using benzodiazepine for the treatment of tinnitus, it is important to select and use the minimum dose without side effects personally and to inform the patient that the drug will be gradually discontinued as symptoms improve.
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