Ginkgo Biloba for Tinnitus

E. Ernst & C. Stevinson

A number of uncontrolled (e.g .4-8 ) or controlled but non-randomised clinical trials (e.g .9 , 10 , 11) suggest that the regular medication with ginkgo biloba is effective in the treatment of tinnitus. As such trials are open to bias and tend to over-estimate the effect size, 12 this systematic review was aimed at summarising all randomised controlled trials on this subject.

Methods

Computerized literature searches were performed to identify all randomised controlled trials of ginkgo biloba for tinnitus. Databases included Medline, Embase, and the Cochrane Library (all from their respective institution to June 1998). The search items used were ginkgo biloba, gingko, ginkgo, tinnitus, and hearing disorders. In addition, manufacturers of ginkgo biloba preparations were asked to contribute published and unpublished material. Our own extensive files were also searched for relevant publications. The bibliographies of the studies and reviews thus retrieved were scanned for further relevant publications. There were no restrictions on the language of publication.

Trials were included if performed on patients with tinnitus treated with ginkgo biloba and compared to placebo or another active medication in the control arm. Studies not performed on ginkgo biloba mono-therapy or those using homeopathic dilutions of ginkgo biloba [e.g .11 ] were excluded. Trials performed on patients whose primary complaint was not tinnitus (e.g. cerebral insufficiency 13 or sudden loss of hearing 14 , 15 were also rejected. Data extraction was performed in a standardized, predefined fashion. Trial outcomes and methodological quality were independently assessed by both authors using a standard scoring system to measure the likelihood of bias .16 Discrepancies in the evaluation of individual trials were resolved by discussion.

Results

Five trials fulfilled the above criteria and were included in this review. Key data from these studies are summarized in Table 1.

Meyer headed a team of 10 French ear, nose and throat specialists to conduct a multicentre trial with two parallel groups 17 and 103 tinnitus patients were included. Patients were excluded if they had had infections or surgery or had suffered from acute diseases of the ears. Patients were treated with 4 ml of a ginkgo biloba extract per day for 1-3 months or with a placebo. Therapeutic success was evaluated by a severity score of tinnitus symptoms. The results suggest that the ginkgo biloba treated group experienced greater and faster improvement of symptoms. This trial lacks a clear description of essential methodological details. It does not report any drop-outs and the criteria for evaluation are not clearly defined.

The same author conducted a pseudo-randomised multicentre trial of 259 patients with tinnitus for at least 1 year .18 Patients received either 3x 3 ml daily of ginkgo biloba extract or almitrine-raubasine or nicergoline to be taken as normally recommended for a minimum period of 1 month. The number of patients whose symptoms greatly improved or disappeared according to a specialist’s evaluation was significantly greater in the ginkgo group than the others. Patients on ginkgo also reported a significantly greater reduction in the severity and discomfort of symptoms and speed at which symptoms disappeared. Some important methodological details are missing from the report of this trial, such as whether the patients and evaluators were blinded and how long treatments lasted. Furthermore, patients were allocated to groups according to the day of the week of the first consultation, so were not properly randomised with the groups having unequal numbers of patients.

Holgers et al. from Sweden performed a study with several unusual design features .19 They admitted 80 patients with persistent severe tinnitus into an uncontrolled investigation where all patients received 2 x 14.6 mg daily of ginkgo biloba (Seredrin®). The 20 patients who seemed to respond positively were recruited for a subsequent cross-over double-blind randomised controlled trials versus placebo with a 1-week washout period in-between. The primary endpoint was patient preference. There was no difference in numbers of patients preferring ginkgo biloba over placebo compared to those making the opposite choice. This study is original and well conducted; however, it suffers from a small sample size in the controlled phase. Moreover, according to today’s knowledge, ginkgo biloba was under-dosed which could account for the negative result.

Morgenstern and Bierman published a trial including 99 patients with chronic tinnitus .20 All patients were initially treated with 3 x 1 placebo tablets per day for 2 weeks (run-in phase). Subsequently they were randomised to receive either active medication (3 x 40 mg ginkgo biloba extract) or placebo for 12 weeks. The audiometrically determined loudness of the tinnitus in the worse affected ear was the primary endpoint. The results show that the loudness of sounds was on average reduced significantly more in the actively treated group compared to placebo.

Juretzek reported an (as yet) unpublished trial to us.21 All 60 patients with chronic tinnitus were treated (for 10 days) with daily injections of 200 mg ginkgo-biloba extract Egb 761. Subsequently they were randomised to receive either 2 x 80 mg oral extract or placebo for 3 months. The primary endpoint was the loudness of the tinnitus sounds in the worse affected ear. In the initial uncontrolled phase there was a reduction of 8.5 dB on average. In the randomised phase there was a further improvement in the actively treated group which was significant in comparison to the results obtained with placebo.

Discussion

Randomised controlled trials of ginkgo biloba for tinnitus proved to be quite scarce. Five such studies were identified for this review and collectively, the results suggest that extracts of ginkgo biloba are effective in treating tinnitus. Only one study 19 produced a negative result and that may have been related to the dose being suboptimal (2 x 14.6 mg extract per day). All other studies used much higher doses (120-160 mg extract per day).

The studies were also heterogeneous in other respects. Endpoints included a rating from the patient of severity of tinnitus or preferred treatment, an evaluation from a specialist and the loudness of tinnitus measured by an audiometer. Four different ginkgo biloba products were used, taken as either tablets, drops or by injection and daily doses were different in each trial. Patients in all trials were described as having chronic or persistent tinnitus but few studies defined criteria for inclusion. The cause or source of tinnitus may have differed within studies as well as between them. The duration of treatment also varied between trials.

Trials were assessed for their methodological quality using the instrument devised by Jadad et al .16 to measure the likelihood of bias. The three critical factors are the description of randomization, blinding, and withdrawals. The most recent study included in the review 21 could not be assessed as so far it has only been published as an extended abstract. One trial 20 received a perfect score and another 19 was scored highly. The other two trials 17 , 18 had lower marks with the former one scoring zero. These scores may to some extent reflect the quality of the paper rather than the trial design, but from the information available, it is not possible to exclude the possibility of bias affecting the results of some trials.

With one exception, the randomised controlled trials in this review were placebo-controlled. Patients taking ginkgo biloba improved significantly more than those on placebo in three of the trials. The lack of difference between ginkgo biloba and placebo in the other placebo-controlled trial 19 has already been discussed with regard to under-dosing patients. In the remaining study which compared ginkgo with two products of the same therapeutic class but with different mechanisms of action, ginkgo biloba produced significantly better results than the other treatments.

If one accepts that ginkgo biloba is an effective treatment for tinnitus, the question arises as to how it works. The pharmacological profile of ginkgo biloba is complex. Its main constituents are ginkgolides and bilobalides, both terpenoids and a range of flavonoids .16 Ginkgo biloba has been shown to have anti-ischaemic, anti-oedema, anti-hypoxic, radical-scavenging and metabolic actions .22, 23 In addition, it increases disturbed microcirculatory blood flow through increasing the fluidity of blood .24, 25 The relative importance of these actions in the clinical effects of ginkgo biloba in tinnitus is uncertain at present. A common cause of the symptoms of tinnitus could be a deficiency of blood supply to the inner ear. It is conceivable that most of the above-mentioned pharmacological actions of ginkgo biloba contribute to its clinical effectiveness for this indication.

Overall, the results of these trials are favourable to gingko biloba as a treatment for tinnitus, but a firm conclusion about its efficacy is not possible. At present, the body of evidence is small. More trials are needed to test the therapeutic value of gingko biloba for relieving tinnitus. Furthermore, it is important that such trials are methodologically rigorous and consistent in terms of the endpoints being measured, the doses used and the classification of patients.

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