Otol Neurotol 2003 Jan;24(1):86-89

The Role of Zinc in the Treatment of Tinnitus

H. Nedim Arda, Umit Tuncel, Ozgur Akdogin and Levant Ozluoglu -
Dept. of Ear, Nose and Throat, Head and Neck Surgery, Ankara Human Research and Education Hospital, Ankara, Turkey

Objective: This study was designed to investigate the role of zinc administration in treatment of tinnitus.

Study Design: Randomized, prospective, placebo-controlled study.

Setting: Patients with tinnitus were admitted to the Ear, Nose and Throat Clinic of the authors' hospital.

Patients: Patients with tinnitus with no known pathologic conditions of the ear, nose and throat; the mean age of patients receiving zinc was 51.2 years and that of 13 patients given placebo was 55 years.

Intervention: Blood zinc levels were measured. Frequency was detected by audiometry and loudness of tinnitus was screened by tinnitus match test. A questionnaire that scored tinnitus subjectively between 0 and 7 was given to patients before zinc treatment. After 2 months of treatment (zinc 50 mg daily to zinc group, placebo pill containing starch to placebo group), all of the tests were performed again. There was no difference in age, sex, duration of tinnitus and affected ears between the patients treated with zinc and those treated with placebo. Blood zinc levels were lower than normal in 31% of patients before treatment.

Main Outcome Measures: A decrease in tinnitus loudness by at least 10 dB was accepted as clinically favorable progress. A decrease of more than 1 point in subjective tinnitus scoring was accepted as valid.

Results: Clinically favorable progress was detected in 46.4% of patients given zinc. Although this decrease was not statistically significant, the severity of subjective tinnitus decreased in 82% of the patients receiving zinc. The mean of subjective tinnitus decreased from 5.25 to 2.82 (P<0.001). However, the decrease in severity of the tinnitus was not significant in patients receiving placebo.

Conclusion: It can be concluded that patients with tinnitus may have low blood zinc levels (31%) and clinical and subjective improvement can be achieved by oral zinc medication. However, it remains to be seen whether the longer duration of treatment has more significant results.

Tinnitus is one of the most common hearing disturbances, affecting 17% of all populations and 33% of the elderly . Although there are many drugs suggested by many authors in the literature, none has been approved by the U.S. Food and Drug Administration . The use of agents claimed to increase blood flow depends on the theory that ischemia in the end organ or central nervous system causes tinnitus.

Zinc is a trace element, which is present in minute quantities in living cells but plays an important role in body metabolism. Indeed, it is an essential nutrient for proper functioning of the immune system. Specific and nonspecific immune responses are impaired, and consequently susceptibility to bacterial, viral, and fungal infections increases as a result of zinc deficiency . Zinc is also protective against reactive oxygen species (ROS) such as copper and manganese (Cu-Zn superoxide dismutase [SOD] MnSOD) . Zinc deficiency may affect cognitive development with alterations in attention, activity, neuropsychologic behavior, and motor development, although this is not well understood. Zinc appears to be essential for neurogenesis, neuronal migration, and synaptogenesis, and its deficiency is thought to interfere with neurotransmission and in turn neuropsychologic behavior . Zinc is widely distributed in the central nervous system. It acts as a synaptic modulator and plays a role in neuronal death under pathologic conditions. Zinc is also present in the synapses of the auditory system . This placebo-controlled study was undertaken to investigate whether zinc is useful in the treatment of tinnitus.

MATERIALS AND METHODS

This study included 41 patients with tinnitus seen at our Ear, Nose and Throat clinics between April 2000 and May 2001. The patients ages ranged from 21 to 74 years of age (mean age 51.2 years in the placebo group and 55 years in the zinc group). There were 28 patients in the zinc group, of whom 16 were women (57.1%) and 12 were men (42.9%). There were 13 patients in the placebo group, of whom 8 were women (69.2%) and 4 were men (30.8%).

At first, 50 patients (30 in the zinc group, 20 in the placebo group) were planned to be included in this study in a random assignment, but 2 patients in the zinc group and 7 patients in the placebo group were noncompliant in taking their pills. As a result, a total of 41 patients (28 in the zinc group, 13 in the placebo group) were included in the study. The patients in the zinc group were divided into two groups; 10 patients (35.2%) with a zinc level of 70 µg/dl or less and 18 patients (64.8%) with a zinc level greater than 70 µg/dl.

A typical otologic and audiologic examination was carried out in all patients. The inclusion criteria were that patients had no pathologic conditions of the ear, nose, and throat that might be responsible for tinnitus, such as venous hum, vascular neoplasm, arteriovenous fistula, intracranial hypertension, and vascular tumors, or any metabolic, neurologic, or psychiatric diseases. Patients were also asked whether they had acoustic trauma and vascular diseases, took ototoxic drugs, or had undergone surgical procedures.

Audiology and high-frequency audiology were performed in all patients before and after treatment. High-frequency audiologic examination was done using a soundproof chamber clinical audiometer, AC 40, with the standard of Industrial Acoustic Company and KOSS HV/PRO Digital Headphones. The evaluation of the hearing test results was based on the mean pure tone levels (dB at 500 Hz + dB at 2000 Hz/3) at low frequencies (125 Hz to 1kHz) . The mean hearing threshold values were calculated at 10 to 18 kHz using high-frequency audiometry (Table 1).

Tinnitus match tests were performed, and loudness was determined before and after the treatment. Measurement of tinnitus loudness was done after the detection of accurate pure tone. The patients were asked to compare the given stimulus with tinnitus. Frequency and amplitude were investigated from 1000 Hz to higher frequencies at the same tone until detection of tinnitus frequency (pitch match frequency). A multi-frequency module of audiometry was used, and tinnitus frequency was obtained. When necessary, narrow band noise was used. After the detection of frequency, the given stimulus was compared with tinnitus loudness at increases of 1 dB (loudness matching/loudness match: dB SL).

Also, the patients were asked to determine subjective tinnitus loudness before and after the treatment by answering a series of seven question with a total possible score of 0 to 7 (Table 2) . They were also asked whether the sounds were low or high frequency and whether the tinnitus was intermittent or continuous. The patients were told that if they heard a sound like wind, breeze, flowing water, buzz, rustle or cicada, then it was low frequency, and if they heard a sound like a high-pitched voice, metallic tinkle, signal, or twitter, then it was a high frequency . The onset of tinnitus was also determined.

Zinc levels were also determined before and after the treatment, and 28 patients in the zinc group were given 50 mg zinc per day for 2 months (Zinco 220, 50 mg). Thirteen patients in the placebo group were given one starch tablet daily for 2 months. Zinc levels were determined in undiluted serum by flame atomic absorption spectrometry, using a matrix-matched (12% glycerol) standard curve . Normal zinc levels vary between 70 and 150 µg/dl.

There was no significant difference between the treatment groups in the side/laterality of the tinnitus, the subjective frequency category of the tinnitus, or the prevalence of intermittent versus continuous tinnitus (Tables 3 and 4), nor were the mean durations of the tinnitus significantly different.

Students T test was used to compare blood zinc levels between the zinc and placebo groups and between the groups with 70 µg/dl or less and greater than 70 µg/dl. The Mann-Whitney U test was used for difference and percentage of the groups, and the paired T test was used to evaluate whether zinc administration increased the blood zinc level in the groups.

RESULTS

In the zinc group, the 10 patients (35.2%) with a zinc level of 70 µg/dl or less had a mean zinc level of 67.4 µg/dl before the treatment. After 2 months treatment, the mean zinc level increased to 92.8 µg/dl (P=0.01). The 18 patients with a zinc level greater than 70 µg/dl had a mean zinc level of 89.0 µg/dl, which increased to 97.56 µg/dl (P=0.001). Zinc levels increased significantly in both groups (Table 5).

In the placebo group, 3 patients had blood zinc levels lower and 10 had levels higher than 70 µg/dl. There was no statistically significant change of blood zinc level in the placebo group after treatment (Table 5).

In the zinc group, mean frequency was 5.31 kHz, and loudness was 52.57 dB before treatment. Frequency decreased to 5.02 kHz and loudness to 49.91 dB after treatment, but these decreases were not statistically significant. A decrease in frequency and decrease in loudness of 10 dB or more was considered clinical improvement. Accordingly, in 13 patients (46.4%), loudness decreased by more than 10 dB, so the patients were considered to have improved clinically.

In the placebo group, the patients had an average frequency of 5.88 kHz and an average objective loudness of 63.27 dB before treatment. The administration of starch tablets did not alter those parameters statistically (Table 6).

The subjective symptoms of patients were scored from 0 to 7 (Table 2). The T test was used for evaluation of differences within groups. Subjective symptoms were observed to improve significantly in the zinc group (P<0.001) but did not show a significant improvement in the placebo group (Table 6).

Patients were asked about subjective symptoms before and after treatment. Of 28 patients given zinc, 23 (82%) noted improvement in symptoms, 4 patients reported no change, and 1 patient reported worsening symptoms. The decrease of subjective tinnitus scoring is statistically significant. Of 13 patients given placebo, 4 (22%) reported improvement in subjective symptoms. There was a significant improvement in subjective symptoms in the zinc group compared to the placebo group (P<0.05) (Table 6). As for the correlation between all parameters, there was a positive correlation between subjective symptoms and tinnitus loudness (r=0.34, P<0.05).

It is known that high dozes of zinc will lead to low levels of copper and in turn anemia . It may also cause gastric disturbances and diarrhea. However, in this study there was no change in the hemograms of patients; only 2 patients in the zinc group had mild gastric disturbance, and there were no side effects in the placebo group.

DISCUSSION

The pathophysiology of tinnitus is not clear; however, it is believed that tinnitus usually results from an anatomic of functional change. We think that zinc has a role in the pathophysiology of tinnitus, although there is little information about it. Zinc is present in the cochlea, especially the stria vascularis, in the form of Cu/Zn SOD and trace elements . A raised plasma concentration of zinc may cause an increase in Cu/Zn SOD activity because zinc and copper, both of which are trace elements, are responsible for Cu/Zn SOD stability and activity . Endogenous Cu/Zn SOD and Zn may both protect the cochlear structure against ROS damage and contribute to the maintenance of integrity and activity of Na,K-ATPase.

To our knowledge, there are few studies on and association between tinnitus and zinc level, and the results of the studies are conflicting. Paaske et al., in a placebo-controlled study, found that only 1 in 48 patients had a low level of zinc and that only 2 patients had a clinical improvement . Gersdorff et al. reported an association between tinnitus and a low serum level of zinc: 68.7% of 115 patients with tinnitus had hypozincemia . Shambaugh reported an improvement in tinnitus and hypozincemia after treatment with zinc . In a study of 27 patients with tinnitus and hypozincemia, Gersdorff et al. reported that 4 patients (15%) showed a good improvement and 10 patients (37%) a less improvement after the administration of zinc . Ochi et al. observed a significant decrease in the serum zinc levels of patients with tinnitus compared with patients in a control group . All these findings suggest that zinc is useful in at least some patients with tinnitus. Also, the measurement of serum zinc levels allows the identification of patients with tinnitus and this increases the overall efficacy of treatment. In this study, 37.7% of patients in the zinc group had low levels of zinc before the administration of zinc, and the zinc level increased significantly after treatment (P<0.01); 13 patients (46.4%) showed a clinical improvement; and 82% of patients given zinc experienced an improvement in subjective symptoms, with a statistical significance (P<0.001). As far as we know, no study has reported a significant improvement in subjective symptoms.

It is agreed that the frequency of tinnitus is usually more than 2 kHz, that it peaks at 3 to 4 kHz, and that tinnitus is present at 4 kHz. In this study, the finding of a 5 kHz frequency can be explained by the efficient use of high-frequency audiometry.

Although tinnitus loudness seems to be subjective, it is the most important objective criterion that is practically measurable. Tinnitus score, through a subjective criterion, is also important in that it reflects the degree of discomfort.

In this preliminary study, it can be concluded that hypozincemia is frequent in patients with tinnitus and there is some preliminary evidence that administration of zinc for 8 weeks appears to have a beneficial effect in some patients with tinnitus.

CONCLUSION

In this placebo controlled study, we observed that some of the patients with tinnitus had a low level of zinc. But regardless of blood zinc level being normal or low, the administration of zinc improved not only blood zinc level but also clinical disease. We think that zinc affected ROS, and thus clinical improvement was provided. However, further studies are needed for more convincing evidence on the role of zinc in the treatment of tinnitus.

Subjective improvement was more significant in the zinc group than in the placebo group. One should remember that patients with tinnitus, especially the elderly, may be administered zinc as well as other drugs. Improvement of tinnitus and even of hearing may increase significantly if zinc is given for 6 months or more. In addition, patients should be monitored for a long time to detect recurrences of tinnitus. In this study, the patients are still being followed up.

REFERENCES

1. Jastreboff P, Gray WC, Mattox DE, Tinnitus and hyperacusis In: Cummins CW, ed, Otolaryngology Head Neck Surgery. 3rd ed. St. Louis: Mosby-Year Book, 1998.
2. Parnes SM, Current concepts in the clinical management of patients with tinnitus, Eur Arch Otorhinolaryngol 1997;254:406-9.
3. Wellinghausen N, Immunobiology of gestational zinc deficiency, Br J Nutr 2001;85:81-6.
4. Speich M, Pincan A, Ballereau F. Minerals, trace elements and related biologic variables in athletes and during physical activity, Clin Chem Acta 2001;312:1-11.
5. Bhatnager S, Taneja S, Zinc and cognitive development, Br J Nutr 2001;85:139-45.
6. Zirpel L, Parks TN, Zinc inhibition of group 1 mediated calcium homeostasis in auditory neurons, J Assoc Res Otolaryngol 2001;2:180-7.
7. Stach BA, Clinical audiology: an introduction, San Diego: Singular Publishing Co., 1998.
8. Ohsaki K, Ueno M, Zheng HX, et al. Evaluation of tinnitus patients by multidrug treatment, Auris Nasus Larynx 1998;25:149-54.
9. Crinnioe CL, McCart GM, Microparnitol for tinnitus, Ann Pharmacolog 1995;29:782-4.
10. Pakarek RS, Beisel WR, Bartelloni PJ, et al, Determination of serum zinc concentrations in normal adult subjects by atomic absorption spectrophotometry, Am J Clinical Pathol 1972;57:506-10.
11. Shambaugh ED, Zinc: the neglected nutrient, Am J Otol 1989;10:156-60.
12. Rarey KE, Yao X, Localization of Cu/Zn-SOD and Mn-SOD in the rat cochlea, Acta Otolaryngol 1996;116:833-5.
13. Akeil E, Tug T, Doseyan Z, Antioxidant enzyme activities and trace element concentration in ischemia-reperfusion, Biol Trace Elem Res 2000;76:13-7.
14. Paaske BP, Pederme CB, Kjems G, et al, Zinc in the management of tinnitus; placebo-controlled trial, Ann Otol Rhinol Laryngol 1991;100:647-9.
15. Gersdorff M, Robillard T, Steni F, et al, A clinical correlation between hypozincemia and tinnitus, Arch Oto rhinolaryngol 1987;244:190-3.
16. Shambaugh GE Jr, Zinc for tinnitus, imbalance, and hearing loss in the elderly, Am J Otol 1986;7:476-7.
17. Gersdorff M, Robillard T. Steni F, et al, Epreve surcharge au sulfan de zinc chez des patients souffrani d'acouphenes associa a hypozincemia, Acta Otorhinolaryngol Belg 1987;41:498-505.
18. Ochi K, Okashi T, Kinoshita H, et al, The serum zinc level in patients with tinnitus and the effect of zinc treatment, Nippon Jibunkoka Gakkai Kaiho 1997;100:915-9.