Volume 32, Issue 1 , Pages 19-23, January 2011
Simvastatin and Ginkgo biloba in the treatment of subacute tinnitus: a retrospective study of 94 patients
Article Outline
- Abstract
- 1. Introduction
- 2. Patients and methods
- 3. Results
- 4. Discussion
- 5. Conclusion
- References
- Copyright
Abstract
Objectives
Studies suggest that hypercholesterolemia promotes the development of inner ear disorders such as tinnitus. However, the underlying pathomechanisms are still not clearly defined.
Methods
A retrospective study was performed to assess whether a reduction of serum cholesterol by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors may result in a relief of subacute tinnitus. Remission rates of 58 patients were investigated after 4 months of treatment with simvastatin (40 mg). Results were compared to treatment with Ginkgo biloba (120 mg; n = 36) as control group. Differences between tinnitus score at the day of first treatment and after 4 months were used as main outcome measure.
Results
After treatment with simvastatin or G biloba, tinnitus score decreased from 41.3 ± 10.4 to 37.4 ± 17.3 and from 44.7 ± 11.2 to 41.2 ± 8.7, respectively. However, independently of the treatment regimen, differences of tinnitus scores were considered not significant.
Conclusions
After administration of simvastatin over 4 months, this retrospective study has shown no significant efficacy in treatment of subacute tinnitus. For a more conclusive answer, further prospective, double-blind, and placebo-controlled studies with a larger number of patients are needed.
1. Introduction
The onset of tinnitus is often associated with a dysfunction of the outer hair cells (OHCs) of the cochlea. However, the underlying pathomechanisms are still obscure and a matter of debate. Similar to other inner ear disorders such as sudden sensorineural hearing loss, disturbances of cochlear microcirculation are one of the most frequently discussed reasons. Cochlear blood flow is sensitive to changes and even limited impairment of perfusion leads to an immediate dysfunction of the organ of Corti [1]. Animal models and clinical evidence show a negative effect of hyperlipidemia on hearing function [2]. High serum low-density lipoprotein (LDL) and low high-density lipoprotein (HDL) are commonly accepted as major vascular risk factors, not only for large vessels. Histochemical studies of hypercholesterolemic animals disclosed a vacuolar degeneration of the capillary vessels at the stria vascularis [3] and patches of amorphous material in strial marginal cells and in OHCs [4]. Apart from its well-known role in the development of atherosclerosis and in the increase of blood viscosity, cholesterol can impair cochlear microcirculation by diminishing the release of the potent vasodilator nitric oxide (NO) from endothelial cells [5]. A second possible mechanism of hearing impairment by high serum cholesterol is a direct action at the OHC membrane. Isolated OHCs show diminished motility when incubated with a cholesterol-enriched medium, probably due to a loss of flexibility caused by integration of cholesterol molecules into the lateral wall membrane [6], [7]. Immediately lowering serum LDL by means of apheresis accordingly increases cochlear blood flow without additional hemodilution and has been proven to be effective in treatment of idiopathic sudden sensorineural hearing loss. Interestingly, a minor (1.8 dB) but significant improvement of hearing threshold at the contralateral, healthy ear was also observed in the study [8].
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are highly effective at lowering serum cholesterol levels. They are among the most widely used classes of drugs worldwide for their potential in prevention of vascular diseases such as myocardial infarction and stroke [9]. Apart from their effectiveness in prevention of occlusion of big- and medium-sized vessels, statins act on the endothelium of small vessels. Inhibition of HMG reductase induces activation of endothelial NO synthase and consecutive vasodilatation [5], [10], [11], [12] and thus improves microcirculation. Furthermore, statins reduce plasma viscosity and might improve cochlear microcirculation [13]. Therefore, the question arose if patients with continuing tinnitus also may benefit from lowering plasma LDL levels by the HMG-CoA reductase inhibitor simvastatin. As tinnitus is a disease with a high emotional contribution, the use of a validated questionnaire assessing the impact of tinnitus on the individual and a comparison to another common treatment that has been proven without any efficacy compared to placebo were necessary to investigate this question.
Over all, no significant benefit of treatment with statins on the outcome of tinnitus was observed when compared to patients who received G biloba.
2. Patients and methods
In a retrospective study, remission rates of 58 patients with subacute tinnitus and slightly increased LDL cholesterol were investigated after 4 months of treatment with 40 mg of simvastatin. Because previous studies revealed that treatment of tinnitus with Ginkgo biloba extract is not more effective than placebo [14], [15], 36 patients after treatment with G biloba extract (120 mg/d) for 4 months served as control group. Patients were treated within the ENT Department of the University of Munich between January 2004 and August 2008. Patients aged between 18 to 80 years and with uni- or bilateral tinnitus tinnitus between 2 and 12 months were enrolled in the study. These patients had serum LDL cholesterol between 130 and 160 mg/dL without any history of cardiocirculatory disease or more than one further risk factor such as hypertension, diabetes, positive family history, smoking, HDL cholesterol lower than 40 mg/dL or age (female > 55 years, male > 45 years). Tinnitus was evaluated using a standardized questionnaire designed by Goebel and Hiller. This questionnaire is a validated and published [16] tool of measurement for the patient's perception of tinnitus. Patients were eligible if tinnitus score was 30 to 60 (moderate to severe intensity). Audiometric testing included pure-tone audiometry (frequencies 125, 250, 500, 1000, 2000, 3000, 4000, 6000, and 8000 Hz) in accordance with ISO 7029, tympanometry, stapedius reflex measurements, and the German speech intelligibility (Freiburger Sprachtest). The sound level in decibels at which 50% of the recorded digits were recognized corresponds to perception of speech. Further masking and matching of tinnitus were performed. Because subacute tinnitus of 12 months duration very probably did not escape from the auditory pathway yet, tinnitus was defined as cochlear tinnitus if masking level was not more than 15 dB above hearing threshold. Laboratory tests were done at the Department of Clinical Chemistry of the University of Munich with standard methods including total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and lipoprotein (a).
Patients were excluded from the investigation if they had previously been treated for tinnitus; had objective or retrocochlear tinnitus; other disorders of the inner ear with known cause; Menière's disease; subacute, conductive, psychogenic hearing loss; or were under treatment with HMG-CoA reductase inhibitors or Ginkgo or had been treated before. Patients were excluded from treatment with simvastatin if there were contraindications to the use such as active liver disease, cholostasis, persisting elevation of serum transaminases or myopathy, or if they were under treatment with drugs known to critically interact with atorvastatin such as immunosuppressive substances, fibrates, or nicotinic acid.
2.1. Interventions, main outcome measures, statistical analysis
We aimed to answer the question, if lowering elevated serum cholesterol levels by administration of simvastatin may result in a relief of subacute tinnitus. Therefore, in this retrospective study, tinnitus score and audiometric testing were evaluated in 58 patients after treatment with simvastatin (40 mg/d) for a period of 4 months. The outcome was compared to a control group consisting of 36 patients after treatment with G biloba extract (120 mg/d) for 4 months. Tinnitus score, audiometric and laboratory testing were performed as described above before treatment and after 4 months.
Differences between tinnitus score on the day of first treatment and after 4 months were used as main outcome measure. Patients were assigned to severity groups having the following criteria: tinnitus score 0–30, mildly ill; tinnitus score 31–46, moderately ill; tinnitus score 47–59, markedly ill; tinnitus score 60–84, severely ill. After treatment, data were analyzed in regard of improvement and worsening within the groups. Differences in loudness and frequency of tinnitus (masking and matching) after 4 months and the development of hearing thresholds (pure tone audiometry at frequencies of 3, 4, 6, and 8 kHz) after 4 months were used as secondary outcome measures. Statistical analysis was performed using SPSS software (version 12.0). The paired t test was used for the comparison in the individual group and ANOVA for the comparison of the different groups. A P value of α ≤ .05 was judged significant.
3. Results
Patients met the inclusion criteria in 94 cases, whereas 58 patients had been treated with simvastatin (40 mg) and 36 patients with G biloba (120 mg). Table 1 shows the participants' baseline characteristics. Tinnitus score, age, and blood pressure did not differ significantly between the groups.
Table 1. Patients' baseline characteristics
| Simvastatin (n = 58) | G biloba (n = 36) | |
|---|---|---|
| Characteristics | ||
| Sex | ||
 Male | n = 32 | n = 22 |
| Female | n = 26 | n = 14 |
| Age (y) | 49.45 ± 10.31 | 51.51 ± 13.65 |
| Body mass index (kg/m2) | 25.47 ± 3.24 | 23.67 ± 2.73 |
| Blood pressure (mm Hg) | ||
| Systolic | 131.43 ± 15.32 | 137.67 ± 18.79 |
| Diastolic | 86.32 ± 9.51 | 82.47 ± 13.69 |
| Tinnitus score | 41.3 ± 10.4 | 44.7 ± 11.2 |
| total cholesterol (mg/dL) | 243.00 ± 34.01 | 239.00 ± 29.12 |
| HDL cholesterol (mg/dL) | 56.92 ± 17.96 | 61.34 ± 11.31 |
| LDL cholesterol (mg/dL) | 158.67 ± 24.80 | 159.15 ± 23.01 |
After 4 months, laboratory testing of the simvastatin group revealed significantly lower total cholesterol and LDL cholesterol (both P < .01) compared to the onset point and to G biloba–medicated patients. After the treatment with simvastatin, LDL decreased from 158.67 ± 24.80 to 88.00 ± 23.95 mg/dL and total cholesterol decreased from 243.00 ± 34.01 to 195.08 ± 31.45 mg/dL. Tinnitus score showed no significant differences compared to the beginning of therapy and to G biloba group. After 4 months, tinnitus score decreased from 41.3 ± 10.4 to 37.4 ± 17.3 (Fig. 1). Comparing severity groups, 46% reported an improvement, whereas 21% worsened (Fig. 2). Before treatment, 0 patients were assigned to mildly ill, 40 to moderately ill, and 18 to markedly ill. After 4 months, 3 patients were assigned to mildly ill, 45 to moderately ill, and 10 to markedly ill. Neither pure tone thresholds nor speech perception showed significant differences after 4 months.
Fig. 1.
Tinnitus scores of all 3 groups after 4 months. Tinnitus score showed no significant differences compared to the beginning of therapy and to the other groups.
Fig. 2.
Improvement and worsening of tinnitus classified in severity groups. Tinnitus score, 0–30 mildly ill; tinnitus score, 31–46 moderately ill; tinnitus score, 47–59 markedly ill; tinnitus score 60–84, severely ill.
Patients treated with G biloba for 4 months had no significant differences in laboratory tests, as compared to the study onset point. Total cholesterol (239.00 ± 29.12 to 246.00 ± 34.36 mg/dL) and LDL cholesterol (159.15 ± 23.01 to 153.48 ± 28.65 mg/dL) were significantly (P < .01) higher than in the simvastatin group. Tinnitus score has not changed as compared to the beginning of therapy. Tinnitus score decreased from 44.7 ± 11.2 to 41.2 ± 8.7; however, differences did not reach significance. Patients reported an improvement into a lower severity group in 34%, whereas 17% worsened (Fig. 1, Fig. 2). Before treatment, 0 patients were assigned to mildly ill, 30 to moderately ill, and 6 to markedly ill. After 4 months, 5 patients were assigned to mildly ill, 31 to moderately ill, and 2 to markedly ill. Neither pure tone thresholds nor speech perception showed significant differences after 4 months.
4. Discussion
Both experimental and clinical data suggest that elevated serum cholesterol might be a cofactor in the development of hearing disorders. In many cases, the onset of tinnitus is assumed to be a result of an OHC dysfunction and subacute tinnitus of 12-month duration may not have escaped from the auditory pathway yet. Thus, at least some of the possibly negative impacts of high serum cholesterol on the inner ear should be counteracted quickly, when cholesterol levels are lowered. Integration of cholesterol in the lateral wall of OHCs with a consecutive loss of membrane flexibility [6] and diminished motility can only occur while cholesterol levels are high and should normalize as soon as lower cholesterol levels are reached. Cholesterol uptake in endothelial cells depresses the production of NO [5], which acts as a potent vasodilator in the regulation of cochlear microcirculation. Apart from lowering cholesterol levels, simvastatin was shown to directly promote endothelial NO synthase activation [5]. Furthermore, statins improve hemorheologic parameters by diminishing plasma viscosity [13]. Both effects should be capable of improving cochlear microcirculation acutely. Because simvastatin very effectively lower elevated serum cholesterol, it seemed possible that it might exhibit a positive effect on tinnitus. Lowering of total and LDL cholesterol in the simvastatin-treated group was highly significant and in the range known from other studies with statins [9]. Therefore, compliance must have been satisfactory. Nevertheless, primary outcome measure tinnitus score showed no significant differences after 4 months. Despite a tendency toward relief by simvastatin, no statistically significant improvement was observed when considering the overall outcome. However, concerning severity groups the patients clearly redistributed in novel disease strength. The results of the present study are in accordance with results of a study for the treatment of presbyacusis with atorvastatin. These authors also reported no significant changes of tinnitus after treatment with atorvastatin over 13 months [17] using the standardized questionnaire designed by Goebel and Hiller [16]. In line with our results, a tendency toward a relief of tinnitus through atorvastatin intake was observable as a continuous improvement of the tinnitus score from 38.3 to 34.8 after 7 and 27.6 after 13 months was obvious compared to the fairly stable score under placebo (23.6 to 24.8 after 7 and 26.8 after 13 months). However, the number of patients with tinnitus was very small (9 in the atorvastatin group, 13 in the placebo group).
To further compare the outcome of simvastatin treatment, 36 patients were provided with G biloba extract and served as placebo group. G biloba was used as control because double-blind, placebo-controlled trials [14], [15] investigating the effect of G biloba in treatment of tinnitus found no significant differences between G biloba– and placebo-treated groups. These studies comprised large cohorts (1121 and 66 patients) and used a validated questionnaire similar to the questionnaire used herein. In the present study, no significant differences between simvastatin and the placebo group was observable after 4 months of treatment. Thus, the effect of statins on tinnitus was clinically not relevant and in the range of placebo treatment. This may be due to the fact that tinnitus is of multifactorial origin and that the dysfunction of OHCs may play a role only in the beginning, whereas in subacute and chronic tinnitus, extraauditory components (prefrontal region, limbic system) get more and more important being not accessible for cholesterol-lowering therapy. Therefore, multimodal therapy concepts including progressive muscle relaxation according to Jacobson, physiotherapy, educative seminars, training of selective attention, and the change of judgment, attitude, and behavior toward tinnitus provide a bundle of strategies that significantly reduce the emotional and cognitive distress of patients who have subacute and chronic tinnitus.
5. Conclusion
In our study, simvastatin administered daily for 4 months had no effect on the subjective tinnitus. It is still possible that the benefits of lowered serum cholesterol take longer to act on tinnitus. This type of therapeutic approach to combat subjective tinnitus should be further investigated in double-blind, placebo-controlled studies with a larger number of patients.
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PII: S0196-0709(09)00209-9
doi:10.1016/j.amjoto.2009.09.004
© 2011 Elsevier Inc. All rights reserved.
Volume 32, Issue 1 , Pages 19-23, January 2011
