Abstract
We investigated the effect of amitriptyline, a tricyclic antidepressant, on patients with subjective tinnitus. The study group consisted of 37 adult patients admitted to the Ear, Nose, and Throat and Audiology Department of Hacettepe University. The amitriptyline group consisted of 20 patients and the placebo group consisted of 17 patients. All of the patients were evaluated using a questionnaire, audiologic evaluation, high-frequency audiometry, impedancemetric tests, auditory brainstem response, tinnitus frequency, and loudness matching assessed by audiometric methods at the beginning and end of the study. The patients in the amitriptyline group received 50 mg/day amitriptyline in the first week and 100 mg/day for the following 5 weeks. In the placebo group, the patients received tablets consisting of lactose starch for 6 weeks, with a dosage of 1 tablet/day. The subjective complaints of the patients in the amitriptyline group decreased, and the "present" symptoms resulted in fewer complaints. The severity of tinnitus decreased in the amitriptyline group by means of subjective and audiometric methods. In the placebo group, no significant change was observed. The success of treatment was 95% in the amitriptyline group and 12% in the placebo group. Amitriptyline therapy was concluded to be effective.
Key words: amitriptyline, tinnitus, tricyclic antidepressants
Sommaire
Nous avons investigue les effets de l'amitriptyline, un antidepresseur tricyclique sur des patients avec acouphene subjectif. Le groupe d'etude est forme de 37 patients vus au departement d'ORL et d'audiologie de l'universite Haceteppe en Turquie. Vingt patients font partie du groupe amitriptyline et 17 du groupe placebo. Tous les patients ont ete evalues par questionnaire, evaluation audiologique incluant l'audiometrie de haute-frequence, l'impedancemetrie, les potentiels evoques du tronc cerebral, le pairage de la frequence, et de l'intensite de Vacouphene par methode audiometrique, autant au debut qu'a la fin du traitement. Les patients de ce groupe ont requ 50 mg/jour d'amitriptyline pour la premiere semaine et 100 mg/jour pour les 5 semaines suivantes. Les plaintes subjectives des patients traites ont diminue et les symptomes actuels ont cause moins de plaintes. La severite de I'acouphene telle que mesuree par les methodes subjectives et audiometriques a diminue dans le groupe traite A l'amitriptyline. Le succes du traitement est de 95% dans le groupe traite et 12% dans le groupe placebo. Nous concluons donc que l'amitriptyline est efficace. Tinnitus is the sensation of sound in the ear or in the head without an external stimulus.1 Tinnitus is observed in 33% of the general population at different degrees, but 2% of the patients present with more severe forms.2 Tinnitus is perceived as a pure-tone simple sound in approximately 25% of patients, but it may include the more diversified sounds such as steam escaping, ringing, or buzzing.1
The majority of sufferers are between the ages of 40 and 80 years.1 Although some studies have indicated that males and females are equally affected,1,3 other studies suggest a slight male predominance (46.5% female, 53.3% male).4 Most commonly, tinnitus is seen in association with hearing loss.5 Hearing is within normal limits in 8% of patients with tinnitus.6 In those exposed to noise, tinnitus is observed in 6.6%.5
In the medical treatment of tinnitus, many different drugs have been used. These are local anaesthetics,1,7,8 vitamins,',5 anticonvulsants,'-10 tranquilizers,8',10 barbiturates,8 calcium channel blockers,8,10 muscle relaxants,8,10 and antihistaminics.10 Antidepressant drugs have also been used in the treatment of tinnitus (trimipramine,11 and nortriptyline12,is).
The pharmacologic effects of tricyclic antidepressants act on various neurotransmitter receptors and endorphin pathways.ll By inhibiting the postsynaptic uptake of norepinephrine and serotonin, tricyclic antidepressants increase the noradrenergic and serotonergic effects in the brain.14 Tricyclic antidepressants are postulated to decrease the cochlear potential by stimulating the adrenergic perilabyrinthine network.1,8,11 Tricyclic antidepressants also appear to have anticholinergic and antihistaminic effects. Their anticholinergic action leads to decreased production of endolymph,8,11 and their antihistaminic action causes vasoconstriction of the cochlear artery.11
In this prospective and single-blind study, the amitriptyline and placebo groups were randomly selected. We evaluated the effect of amitriptyline, a tricyclic antidepressant, on patients with subjective tinnitus.
Materials and Methods
The patients in the study group were selected from patients who attended the Ear, Nose, and Throat Department of Hacettepe University's Faculty of Medicine with the primary complaint of subjective tinnitus during June 1993 and July 1994. None of the patients had a history of acute acoustic trauma, Meniere's disease in an acute attack period, hypertension, glaucoma, or retrocochlear pathology. There were 37 patients with subjective tinnitus. Twenty were randomly included in the amitriptyline group and 17 in the placebo group. Both the amitriptyline and placebo groups had no experience of depression.
In the amitriptyline group, the patients' ages ranged from 18 to 64 (mean 40.8 11.9). Ten (50%) of the patients were female, and 10 (50%) were male. In the placebo group, the patients' ages ranged from 21 to 57 (mean 36.9 11.8). There were 6 (35%) female and 11 (65%) male patients in this group.
All patients included in the study were evaluated with a history, physical examination, and an otolaryngologic examination. Patients were screened with electrocardiography, and patients with cardiac pathology were excluded from the study. Using a questionnaire based on the questionnaire of the American Tinnitus Association (ATA),4 the subjective complaints of the patients were investigated. The patients were asked to grade the severity of their complaints on a 10-point scale, with 1 being very mild and 10 being very severe.
All patients were evaluated with a 0.125- to 8-kHz audiologic examination (using an AC-5 Audiometer and TDH-39 MX 41/AR earphone); 10-, 12-, 14-, 16-, and 18-kHz high-frequency audiometry (using Interacoustics AS 10 HF Audiometer and Koss HV-IA earphone); and impedancemetric tests (using Interacoustics AZ-7 impedancemeter). American National Standards Institute (ANSI-1969) standards were used.ls Tinnitus frequency and intensity matching were done.
All patients were evaluated using auditory brainstem response (ABR). Early latencies, auditory potentials seen 10 msec after the auditory impulse, were studied. Wave I, III, and V and I-III, III-V, and I-V interpeak latencies were evaluated. Cox's16 normal limits were used.
In the amitriptyline group, 20 patients were given 25-mg tablets of amitriptyline. They received 50 mg of amitriptyline at night for the first week and 100 mg for the following 5 weeks. In the placebo group, 17 patients were given lactose-starch tablets indistinguishable from amitriptyline tablets at night for 6 weeks.
The study was performed as single blind. The patients did not know to which group they had been assigned. After 6 weeks, the questionnaire, audiologic examination, high-frequency audiometry, impedancemetric tests, ABR, tinnitus frequency, and intensity matching were repeated.
In statistical analysis, the SPSS program was used.
Results
The data about the duration, character, and localization of tinnitus and subjective complaints of patients were obtained by the questionnaire. In the amitriptyline group, six patients had symptoms for less than 1 year, five for 1 to 2 years, six for 2 to 5 years, and one for 10 to 20 years. In the placebo group, four patients had symptoms for less than 1 year, six for 1 to 2 years, and six for 2 to 5 years.
For the amitriptyline group, in the pretreatment period, the right ear was involved in six and the left ear in seven patients, whereas the sound was bilateral in seven patients. In the post-treatment period, the right ear was involved in seven and the left in nine patients, whereas the sound was bilateral in three patients. In the placebo group, in the pre- and post-treatment periods, the right ear was involved in four and the left ear in seven patients, whereas the sound was bilateral in six patients.
The subjective complaints of the majority of patients in the amitriptyline group were decreased at the end of the study, and the present complaints caused less disturbance. In the placebo group, the subjective complaints did not differ. According to the questionnaire, 95% of the patients in the amitriptyline group and 12% of the patients in the placebo group said that their tinnitus had decreased at the end of the study.
The subjective tinnitus ratings of the amitriptyline and placebo groups are depicted in Table 1. These changes were found to be statistically significant in the amitriptyline group (p < .05) but were not significant in the placebo group (p > .05).
The ABR results of the amitriptyline and placebo groups are shown in Table 2. The conventional audiologic evaluation, high-frequency audiometry, impedancemetric tests, and results of the ABR tetra demonstrated no statistically significant change in both groups post-treatment.
There was no statistically significant change of tinnitus frequency in both groups. In the amitriptyline group, tinnitus frequency switched to higher or lower frequencies, but in statistical evaluation, no significant change was found.
The tinnitus intensity levels found by audiometric matching in the amitriptyline and placebo groups are given in Table 3. These changes were found to be statistically significant in the right and left ears in the amitriptyline group and in the left ear in the placebo group (p < .05).
Discussion
Subjective tinnitus is a complex symptom for both the patient and the clinician. The main goal of the management is to eliminate unwanted head noise completely, which is not always possible.
Tricyclic antidepressants have been used in the management of subjective tinnitus. In the present study, amitriptyline, a tricyclic antidepressant, was used in patients with a primary complaint of tinnitus. Patients were given amitriptyline for 6 weeks, 50 mg/day for the first week and 100 mg/day for the following 5 weeks. No major side effects were seen except for mild sedation and dryness of the mouth, lasting for 1 to 2 weeks.
In the questionnaire, patients were asked about their subjective complaints pre- and post-treatment. After the treatment, 95% of the amitriptyline group felt that they had benefitted, whereas only 12% of the patients receiving a placebo benefitted.
In our study, the audiologic results did not demonstrate any significant change. Subjective tinnitus ratings reduced significantly with amitriptyline treatment. In the ATA questionnaire, subjective tinnitus ratings were 4 to 6 over 10, which is similar to our study.' In our study, it was noted that amitriptyline treatment reduced the audiologic tinnitus severity level significantly without an effect on the ABR.
After the treatment, the frequency of tinnitus not infrequently changed to higher or lower frequency, but these changes were not statistically significant. This was probably owing to the heterogeneity of the tinnitus matches among the patients.
In other Studies, different tricyclic antidepressants have been investigated. Dobie at al. 12 used 100 mg/day of nortriptyline in adult patients with tinnitus for 6 weeks. In this study, the audiologic results also did not demonstrate a significant change. Tinnitus severity decreased by 43% in the nortriptyline group and 30% in the placebo group. Overall, 67% of their study group and 40% of the placebo group were pleased with the treatment.
Sullivan et al.13 studied the effects of nortriptyline in disabled tinnitus patients with major depression. Nortriptyline, 100 mg/day, was taken for a 6-week period. In this study, there was a 10-dB decrease in tinnitus severity with nortriptyline treatment. The severity of depression decreased on average by 65%.
Mihail et al.11 used another tricyclic antidepressant, trimipramine, in patients with subjective tinnitus. In this double-blind study, trimipramine, 150 mg/day, was given for 6 weeks, after which followed a rest period of 4 weeks and then another 6 weeks of treatment. Subjective tinnitus ratings were 4.3 in the trimipramine group and 4.0 in the placebo group on a 1 to 7 scale in the pretreatment period. Trimipramine was found to improve wave morphology in some patients, but it had no consistent effect on interwave latencies. The researchers thought that trimipramine may not have been effective. However, the placebo effect played a significant role in the results.
The ABR is especially helpful for the evaluation of retrocochlear pathologies in patients with tinnitus. One study demonstrated that wave I and III latencies were longer in female patients with tinnitus.17 Auditory brainstem response results are typically within normal limits in patients with tinnitus whose hearing is normal.6 Wave V latency has been reported the shorter than normal limits in patients with high-frequency hearing loss and tinnitus.18
In our study, we used a large dose of the tricyclic antidepressant amitriptyline. It was noted that in patients with subjective tinnitus, amitriptyline therapy was found to be 95% successful in decreasing tinnitus at the end of the study, whereas placebo therapy demonstrated a success rate of 12%. In the amitriptyline group, subjective tinnitus ratings and the audiologic tinnitus severity level were decreased significantly. There was no significant change in the audiologic examination and ABR results. In the amitriptyline group, subjective complaints related to tinnitus were reduced after the treatment period, and the "present" symptoms were reduced after amitriptyline treatment. Conversely, in the placebo group, it was observed that the complaints continued to be about the same.
Reduction of the conduction of tinnitus, inhibition of afferent fibres from the organ of Corti and fibres of the olivocochlear bundle, and the general antidepressant effect were the possible mechanisms of action in patients receiving amitriptyline. The patients, who were informed about the possible side effects of amitriptyline, adjusted well to the treatment in both groups. Therefore, amitriptyline therapy may have affected the high benefit rate in the amitriptyline group.
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Nuray Bayar, MD, Bilgehan Boke, PhD, Ergin Turan, MD, and Erol Belgin, PhD
Received 17/07/00. Received revised 18/01/01. Accepted for publication 06/02/01.
Nuray Bayar: Ear, Nose, and Throat Department, Faculty of Medicine, Kirikkale University, Kirikkale, Turkey; Bilgehan Boke, Ergin Turan, and Erol Belgin: Ear, Nose, and Throat Department, Faculty of Medicine, Hacettepe University, Turkey.
Address reprint requests to: Dr. Nuray Bayar, Kuzgun Sok. Orkide Apt. No: 50/13, 06540 Asagi Ayranci, Ankara, Turkey.
Copyright Decker Periodicals, Inc. Sep/Oct 2001