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BMJ 2001;322:73 ( 13 January )
Papers
Effectiveness of Ginkgo biloba in treating tinnitus: double blind, placebo
controlled trial
Shelley Drew, research associate, Ewart Davies, senior lecturer.
Pharmacology Department, Division of Neuroscience, University of Birmingham,
Birmingham B15 2TT
Correspondence to: S Drew [EMAIL PROTECTED]
Abstract
Top
Abstract
Introduction
Participants and methods
Results
Discussion
References
Objective: To determine whether Ginkgo biloba is effective in treating
tinnitus.
Design: Double blind, placebo controlled trial using postal questionnaires.
Participants: 1121 healthy people aged between 18 and 70 years with tinnitus
that was comparatively stable; 978 participants were matched (489 pairs).
Intervention: 12 weeks' treatment with either 50 mg Ginkgo biloba extract LI
1370 three times daily or placebo.
Main outcome measures: Participants' assessment of tinnitus before, during,
and after treatment. Questionnaires included items assessing perception of
how loud and how troublesome tinnitus was. Changes in loudness were rated on
a six point scale. Changes in how troublesome were rated on a five point
scale.
Results: There were no significant differences in primary or secondary
outcome measures between the groups. 34 of 360 participants receiving active
treatment reported that their tinnitus was less troublesome after 12 weeks
of treatment compared with 35 of 360 participants who took placebo.
Conclusions: 50 mg Ginkgo biloba extract LI 1370 given 3 times daily for 12
weeks is no more effective than placebo in treating tinnitus.
Introduction
Top
Abstract
Introduction
Participants and methods
Results
Discussion
References
Tinnitus, or "ringing in the ears," is a common condition recognised as a
problem by about 10% of the population and considered a major problem by
about 0.5%.1 There are no effective pharmacological treatments for tinnitus.
Because tinnitus is considered to have a number of underlying causes, it is
unlikely that a single treatment will be effective for all patients.
Therefore, trials of treatments for tinnitus need to be capable of
identifying treatments that may help only a subgroup of those with tinnitus.
Such trials should be well controlled and include large numbers of patients.
Previous trials have failed to meet these criteria and have produced
inconsistent and ambiguous results.2
Extracts from the Ginkgo biloba tree have been used in Chinese medicine for
thousands of years. Recently, however, Ginkgo biloba extracts have become
commonly available in health food stores throughout the United Kingdom;
Ginkgo biloba is one of the top 10 selling herbs in health food stores in
the United States.3 High quality, standardised extracts from the leaves of
the tree have been shown to have significant therapeutic effect on the
symptoms of cerebral insufficiency, including memory disturbances and other
cognitive deficits such as tinnitus. 4 5 In Germany and several other
European countries Ginkgo biloba is registered as a drug and is among the
top five most commonly prescribed medications: more than five million
prescriptions were written in Germany in 1998.6 In Germany, Ginkgo biloba
extracts must meet the requirements of the 1994 German Commission E
monograph which specifies what the extract must contain.7 This ensures that
extracts that are prescribed are almost identical to those which have been
shown to be effective in clinical trials. Extracts sold in the United
Kingdom, however, are not classed as drugs and so are not required to
conform to the standards of those that have been shown to be effective.
Thus, there is a large variety of extracts available.
Determining whether Ginkgo biloba is effective in treating tinnitus is
hindered by the lack of evidence. Prospective studies carried out to
determine whether it is effective in treating tinnitus without accompanying
symptoms of cerebral insufficiency have provided inconsistent results.2 None
the less, Ginkgo biloba is frequently suggested as a possible treatment for
tinnitus in the press, and many people with tinnitus are using a variety of
products on the basis of limited evidence.
In this study a standardised extract of Ginkgo biloba (LI 1370, Lichtwer
Pharma, Berlin, Germany) was used in a large, controlled trial to determine
whether it is effective in treating tinnitus. This is one of the most
popular brands sold in the United Kingdom, and the extract conforms to the
requirements of the German Commission E monograph.
Participants and methods
Top
Abstract
Introduction
Participants and methods
Results
Discussion
References
Participants
Participants were recruited through advertisements in the national press in
the United Kingdom and the British Tinnitus Association's publication,
Quiet. Altogether, 1121 participants were selected from the original 8667
applicants and matched when possible. The criteria for creating matched
pairs were that participants had to be the same sex, be similar ages (10
years difference), and the duration of tinnitus had to be 5 years. The
progress of patients from recruitment through the duration of the trial is
shown in figure 1. Exclusion criteria are shown in the box.
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Fig 1. Progress of participants through the trial
Exclusion criteria
Patients were excluded if
They were <18 years or >70 years old
They were pregnant or trying to get pregnant
They had previously taken Ginkgo biloba extract
They had had tinnitus for <12 months
They reported that their tinnitus had varied greatly in the six months
before the screening questionnaire
They had tried any treatment for tinnitus in the six months before
completing the screening questionnaire (for example, acupuncture,
homoeopathy, hypnotherapy, etc.)
They were not generally in good health
They were taking anticoagulant drugs or antidepressants
They had abnormal blood pressure
Methods
This double blind, placebo controlled trial was carried out entirely by mail
and telephone. Patients were contacted by telephone only to resolve problems
or answer inquiries. All procedures were approved by the local ethics
committee (South Birmingham Health Authority). Calculations of sample size
were based on previous unmatched and categorical data because matched and
ordinal data were not available.8 Assuming that there would be a significant
improvement in tinnitus in 30% of participants taking placebo, the
calculations predicted that it would be necessary to have 496 patients in
each group to show a 10% improvement over placebo among those taking active
treatment with a power of 90% at the 0.05 significance level. The sample
size was set to account for withdrawals.
Participants were paired according to the criteria described. Each pair was
then allocated two numbers from a randomly arranged code. One number
corresponded to placebo treatment and one to active treatment.
Tinnitus was assessed subjectively using questionnaires, and no audiological
measurements were taken. Participants were sent four questionnaires. The
first questionnaire was completed before treatment began, the second after 4
weeks of treatment, the third after the end of 12 weeks of treatment, and
the fourth 2 weeks after treatment ended.
Intervention
The treatment was provided as 252 tablets containing 50 mg of either Ginkgo
biloba standardised extract LI 1370 (containing 25% flavonoids, 3%
ginkgolides, and 5% bilobalides) or placebo (both provided by Lichtwer
Pharma). Participants were instructed to take three tablets daily for 12
weeks. The extract and dose of Ginkgo biloba were chosen on the basis of the
results of previous trials in which this dose of this extract had been
reported to be effective in treating cerebral insufficiency.5 Placebo
tablets were identical to the active tablets in shape, size, colour, and
packaging.
The tablets were dispensed in coded bottles, and treatment allocation was
masked. The allocation procedure ensured that all matched participants
received active or placebo tablets without the code being identified. The
blinding for any one pair of participants could be removed without
jeopardising the remainder of the code.
Outcome measures
The scales used in the questionnaires were devised for this study and based
on previously validated self assessment scales.9 The questionnaires
contained 21 questions about the severity of tinnitus. These were divided
into three groups: measures of the perceived loudness of tinnitus, ratings
of the participant's awareness of tinnitus and the ability to ignore it, and
the impact of tinnitus. Summary scores were produced for each of the three
groups of questions. These scores ranged from 0 to 12 for measures of
loudness, from 0 to 22 for measures of awareness and ability to ignore, and
from 0 to 39 for impact. The sum of the scores in these three groups was the
total summary score. A summary score of 0 indicates that a participant has
no tinnitusthat is, it is always silent, can always be ignored, and has no
impact on the participant's life. The maximum summary score of 73 indicates
that a participant has tinnitus that is severely troublesomefor example, it
is always very loud, the participant can never ignore it, and it has a large
impact on the participant's life. The summary scores from all the questions
on severity were calculated and then compared between questionnaires for
each participant to provide a measure of change in severity. The scoring
system is shown in figure 2.
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Fig 2. Scoring system for questionnaire
In the second, third, and fourth questionnaires there were three additional
questions about change in tinnitus: participants were asked to assess
whether they felt that their tinnitus had changed either in loudness or the
amount of trouble that it caused since beginning the treatment (second and
third questionnaires) or since completing it (fourth questionnaire).
Participants were asked to score changes in the loudness of their tinnitus
on a six point scale ranging from 4 (treatment has made tinnitus much
louder) to 6 (treatment has made it disappear). Changes in the amount of
trouble caused were scored on a five point scale ranging from -4 (treatment
has made tinnitus much more troublesome) to 4 (treatment has made it much
less troublesome). The score for "no change" was in the middle or near the
middle of the scale. Mean scores were compared between treatment groups.
Additionally, the total number of participants reporting that their tinnitus
had improved was compared between groups.
The questions on change in tinnitus were the primary outcome measures for
the trial, and the scores of tinnitus severity were used as secondary
outcome measures. Because the condition is perceived as a problem a
clinically relevant improvement requires the participant to perceive an
improvement.
Additional questions about the variability of tinnitus, symptoms of cerebral
insufficiency other than tinnitus, compliance with the treatment regimen,
and side effects were also included (fig 2). Summary scores were again
compared between groups. Scores for the variability of tinnitus ranged from
0 (not at all variable) to 6 (varies hourly). Scores for cerebral
insufficiency ranged from -24 (all symptoms much worse) to 24 (all symptoms
much better). Scores for compliance with treatment ranged from 0
(instructions not followed well) to 8 (instructions followed well).
Data analysis
Data were analysed on an intention to treat basis wherever possible. Data
entry and initial analyses were carried out by a researcher blinded to the
participant's allocation. Statistical analysis was carried out using SPSS
version 9.0 for Windows except for the calculation of confidence intervals
for proportions; these were calculated using the equations given by Gardner
and Altman.10 All reported P values are two tailed. Paired data were
compared between treatment groups using McNemar's test and paired sample t
tests. Unmatched analyses did not provide any additional information and
have therefore been excluded from this paper.
Results
Top
Abstract
Introduction
Participants and methods
Results
Discussion
References
The number of participants who were excluded or who withdrew from the study
is shown in figure 1. Altogether 1121 participants were allocated to
treatment (559 to active treatment and 562 to placebo); of these, 956
participants were paired. Characteristics of the paired participants are
shown in table 1. Analysis of the side effects of treatment was carried out
using data from all 489 matched pairs. However, 26 participants completed no
questionnaires so all other analyses were carried out on the remaining 478
pairs in which both members completed at least one questionnaire. The total
number of participants was considerably smaller for the matched analyses
than for the unmatched analyses. This was because matched analyses required
complete data from each member of the pair and was therefore more affected
by missing or incomplete data.
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Table 1. Characteristics of participants
Outcome measures
The proportion of pairs reporting an improvement in how troublesome they
found their tinnitus at 4 or 12 weeks or a worsening at 14 weeks with either
active or placebo treatment is shown in table 2. There were no significant
differences between the treatments at weeks 4, 12, and 14.
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Table 2. Paired comparison of the No and proportion of pairs in each
group (active treatment or placebo) reporting an improvement in tinnitus.
Treatment was considered to have been successful if participants reported an
improvement at 4 or 12 weeks or a worsening at 14 weeks (2 weeks after
stopping treatment)
Paired sample t tests identified no significant difference between the two
groups with respect to primary outcome measures, secondary outcome measures,
compliance, or cerebral insufficiency (tables 3 and 4 ).
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Table 3. Mean differences (SD; 95% confidence interval) in scores between
matched pairs of participants with tinnitus
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Table 4. Mean difference (SD; 95% confidence interval) between
pre-treatment (baseline) scores and scores at 12 weeks between matched
participants
The number and type of side effects reported during the trial are shown in
table 5. The incidence of adverse events was similar between the treatment
groups but the incidence of beneficial effects was not (beneficial effects
reported by 24/489 (4.9%) in the active treatment group v 11/489 (2.2%) in
the placebo group). This was statistically significant (95% confidence
interval 0.4% to 4.9%). Subgroup analyses failed to find any significant
differences between groups with respect to different types of beneficial
effects.
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Table 5. Adverse and beneficial effects of Ginkgo biloba treatment for
tinnitus among 489 matched pairs of participants
Discussion
Top
Abstract
Introduction
Participants and methods
Results
Discussion
References
Ginkgo biloba extract LI 1370 had no greater therapeutic effect than placebo
in treating tinnitus. In addition, other symptoms of cerebral insufficiency
were not significantly affected by the treatment (table 3). The results from
this trial are similar to some reports and contrast with others.2 This study
differs from other trials in many ways. The main strength of this study was
its large size and controlled design. Previous trials involved fewer than
300 subjects and often lacked adequate controls.2 This study achieved its
large sample size using a simple approach to data collection (postal
questionnaires). A weakness of this approach, however, was that contact with
participants was minimal, and participants were probably provided with less
support than offered in other trials. The lack of contact with participants
may explain the comparatively low response to placebo in this study, but it
should not have affected the overall result because it would have affected
both groups equally. A matched pair method has not previously been used to
study the efficacy of Ginkgo biloba extract, and it was probably an
unnecessary and disadvantageous complication of this trial because analyses
of the matched pairs used considerably smaller numbers than the unmatched
analyses. None the less, unmatched analyses were also carried out (but not
presented here), and the pairing process did ensure that treatment groups
were similar.
Methods of assessing tinnitus have differed between trials, although most
have used a simple, subjective measurement of change in tinnitus, similar to
the primary outcome measure used in this study. Our method of assessing
tinnitus was thorough, enabled small changes to be identified, and
concentrated on the most clinically relevant measurement for this condition
(that is, perceived changes in tinnitus). Another strength of this study was
that this treatment regimen has been shown to be effective in cerebral
insufficiency. Additionally, a measure of the symptoms of cerebral
insufficiency was included in the design to determine whether any
improvements in tinnitus were associated with improvements in symptoms of
cerebral insufficiency.
Most previous trials have used similar treatment doses and been of similar
duration, but the methods of administration and the composition of the
extract have varied.5 Therefore, it is possible that at least some of the
inconsistencies identified by previous studies may be related to the
different types of Ginkgo biloba extract that were used. Measurements of
other symptoms of cerebral insufficiency have not been made in previous
trials. Since neither tinnitus nor other symptoms of cerebral insufficiency
were significantly improved in this study, it would be interesting to learn
whether trials in which Ginkgo biloba was found to be effective in tinnitus
showed that participants had any improvements in other symptoms of cerebral
insufficiency. It is tempting to speculate that positive trials have
involved a greater number of patients who have cerebral insufficiency and
thus improvements in tinnitus were related to an improvement in cerebral
insufficiency rather than being a direct effect of treatment.
What is already known on this topic
Ginkgo biloba extract has been shown to have therapeutic effects on symptoms
of cerebral insufficiency including memory disturbances and other cognitive
deficits, such as tinnitus
Whether it is effective in treating tinnitus alone (without other
accompanying symptoms of cerebral insufficiency) is not clear
Previous studies were small, often poorly controlled, and have had
inconsistent results
What this study adds
This large, double blind, placebo controlled trial found that Ginkgo biloba
extract was no more effective than placebo in treating tinnitus alone
This study has not shown that Ginkgo biloba is effective in treating
tinnitus. The extract used in this study (LI 1370 150 mg/day for 12 weeks)
seems to be ineffective in treating tinnitus alone, but it may be effective
in treating tinnitus in patients who also have other symptoms of cerebral
insufficiency. The composition of other extracts or the use of other
treatment regimens, or both, might be effective in treating tinnitus alone
but there is little evidence of this.
Finally, we would like to raise another issue. Although an effective
pharmacological treatment for tinnitus is unavailable, it may be in
patients' interest to be advised to take a substance that has a reputation
for effectiveness irrespective of the pharmacological value of the
recommendation, particularly if the substance has few side effects, as is
the case with Ginkgo biloba. Should we consider aiming for a placebo
response in treating patients with tinnitus until an effective
pharmacological treatment is available?
Acknowledgments
We thank Mr H Ross for his statistical advice and technical assistance; Dr J
Simpson, Mr P Josling, and Dr R Middleton for their help and advice; and
members of the Birmingham BTA group and Mr P Hopkins for their
administrative help.
Contributors: ED initiated the research. SD and ED designed the study. SD
conducted the research and analysed the data. The paper was co-written by
the authors. SD is guarantor for the paper.
Footnotes
Funding: This work was funded by the British Tinnitus Association in
conjunction with Lichtwer Pharma UK, manufacturer of the extract used in
this study.
Competing interests: The study was financed (two years' salary for SD and
running costs) by a contract between the British Tinnitus Association and
Lichtwer Pharma GmbH, Berlin, who also supplied the Ginkgo biloba extract
and placebo tablets.
References
Top
Abstract
Introduction
Participants and methods
Results
Discussion
References
1. Davis A, Rafaie EA. Epidemiology of tinnitus. In: Tyler RS, ed. .
Tinnitus handbook. San Diego, CA: Singular Press, 2000.
2. Ernst E, Stevinson C. Ginkgo biloba for tinnitus: a review. Clin
Otolaryngol 1999; 24: 164-167[CrossRef][Medline].
3. Winslow LC, Kroll DJ. Herbs as medicines. Arch Intern Med 1998; 158:
2192-2199[Abstract/Free Full Text].
4. Soholm B. Clinical improvement of memory and other cognitive functions
by Ginkgo biloba: review of relevant literature. Adv Ther 1998; 15:
54-65[Medline].
5. Kleijnen J, Knipschild P. Ginkgo biloba for cerebral insufficiency. Br J
Clin Pharmacol 1992; 34: 352-358[Medline].
6. Curtis-Prior P, Vere D, Fray P. Therapeutic value of Ginkgo biloba in
reducing symptoms of decline in mental function. J Pharm Pharmacol 1999; 51:
535-541[Medline].
7. Blumenthal M, Busse WR, Goldberg A, Gruenwald J, Hall T, Riggins CW, et
al, eds. The complete German commission E monographs: therapeutic guide to
herbal medicines. Austin, TX: American Botanical Council, 1998.
8. Duckert LG, Rees TS. Placebo effect in tinnitus management. Otolaryngol
Head Neck Surg 1984; 92: 697-699[Medline].
9. Axelsson A, Coles R, Erlandsson S, Vernon MM, Vernon J. Evaluation of
tinnitus treatment: methodological aspects. J Audiological Med 1993; 2:
141-150.
10. Gardner MJ, Altman DG. Calculating confidence intervals for proportions
and their differences. In: Gardner MJ, Altman DG, eds. Statistics with
confidence: confidence intervals and statistical guidelines. London: BMJ
Publishing, 1989.
(Accepted 11 October 2000)
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© BMJ 2001
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