2. Introduction
• Available treatments for the management of tinnitus are
diverse.
• These include counseling and cognitive behavioral
therapies; different forms of sound therapies; methods that
attempt to increase input to the auditory system, such as
hearing aids and cochlear implants, neurobiofeedback and
various forms of electrical stimulation of brain structures,
either through implanted electrodes or by inducing
electrical current in the brain with transcranial magnetic
stimulation and drug treatments.
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3. • The Royal National Institute for Deaf People (RNID) in
the UK estimates that a novel tinnitus drug could have a
product value of US $689 million in its first year of launch.
• However, we are still left without a single FDAapproved
drug on the market targeting tinnitus relief.
• For the majority of tinnitus sufferers who seek medical
advice, the treatment goals are aimed at symptomatic relief
of their phantom sound and/or the management of the
associated distress.
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4. • Over four million prescriptions are written each year for
tinnitus relief in Europe and the US, but these are all off-
label prescriptions from a wide variety of therapeutic drugs
(Table 1).
• Thus, there is a tremendous need both from patients and
medical doctors to develop a drug targeting tinnitus relief.
• Since in some individuals, tinnitus causes irritability,
agitation, stress, depression, insomnia, and interferes with
normal life – leading to suicidal attempts in severe cases –
even a drug that produces a small but significant effect
would have an enormous therapeutic impact.
• However, ideally a disappearance of tinnitus should be the
ultimate goal of any research and development platform
toward designing a tinnitus drug.
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7. • Lidocaine the voltage-gated sodium channel blocker
lidocaine that is used as a local anesthetic and an
antiarrythmic, given intravenously, leads to the temporary
disappearance of tinnitus or a major change in the nature of
the tinnitus in 70% of patients.
• Several other oral antiarrhythmic drugs like tocainide,
flecainide, and mexiletine have been studied for tinnitus.
None of these compounds have been demonstrated to be
particularly useful. Almost all of them exhibit severe side
effects and are now in disuse.
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8. • Tonicaine is a quaternary ammonium and most likely does
not efficiently pass the blood–brain barrier.Thus, its use in
tinnitus is probably limited.
• Sameridine has additional m-opioid antagonist properties,
a biological system that has not been targeted so far as a
treatment for tinnitus, and a possible avenue to explore.
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9. “Acute State”
• Proposed treatments have included systemic or
intratympanic steroids, vasodilators, antiviral agents, and
hyperbaric oxygen.
• Otoprotectants at clinical development to prevent noise-
induced hearing loss and associated tinnitus are various.
• Daily with 4 g of oral Mg granulate (6.7 mmol Mg
aspartate) showed significantly less permanent threshold
shift 1 week post noise than those in the placebo control
group (11.2% vs. 21.5%).
• 900 mg of the glutathione prodrug N-acetylcysteine 30
min before entering a nightclub where they were exposed
to 2 h of loud music. An average of 14 dB temporary
threshold shift at 4 kHz was reported in subjects
immediately after exposure (within 15 min).
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10. • This observation might be related to the requirement of a
high dose of N-acetylcysteine to effectively prevent
noiseinduced hearing loss in animal models, or possibly to
the limited ability of the compound to prevent temporary
threshold shifts.
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12. Antidepressants
• Tricyclic antidepressants like: (amitriptyline,
trimipramine and nortriptyline).
• They are significantly reduced depression scores, tinnitus
disability scores, and tinnitus loudness (6.4 dB reduction)
relative to placebo.
• Selective serotonin reuptake inhibitors (SSRI) such as
paroxetine or sertraline have been tested.
• In patients without severe hearing loss, but with
depression, anxiety, and a high risk for developing severe
tinnitus, sertraline was significantly more effective than
placebo in reducing tinnitus loudness and tinnitus severity.
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13. • In a double-blind, placebo-controlled study involving
chronic tinnitus patients, few of whom suffered from
depression, the paroxetine group showed little difference
from placebo on tinnitus loudness matching, tinnitus
handicap questionnaire (THQ) scores, and other measures;
however, the paroxetine group showed a significant
improvement on tinnitus aggravation compared to the
control group.
• The combination of paroxetine with vestipitant and
vestipitant alone is currently undergoing a phase II
clinical trial for the treatment of tinnitus by GlaxoSmith
Kline.
• Vestipitant is a novel neurokinin-1 substance P receptor
antagonist.
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14. • Very little information has been reported for serotonin
norepinephrine reuptake inhibitors (SNRI), such as
duloxetine and venlafaxine, or for the dual acting drug
mirtazapine.
• Since activity on norepinephrine reuptake is considered
necessary for an antidepressant to be effective on
neuropathic pain, it might be worthwhile to investigate this
group of drugs for its use in tinnitus treatment.
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15. Benzodiazepines
• 12 weeks of alprazolam administration at an individually
adjusted dosage reduced tinnitus loudness in 76% of
subjects – measured with a tinnitus synthesizer and a
visual analog scale – whereas only 5% showed a reduction
in tinnitus loudness in the control group.
• diazepam, evaluated in a double-blind triple cross-over
trial involving 21 tinnitus patients, had no effect on tinnitus
loudness.
• In a retrospective study of medical records from over 3,000
patients taking clonazepam (0.5–1 mg/day, 60–180 days)
for vestibular or cochleovestibular disorders, 32% reported
an improvement in their tinnitus.
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16. • Due to their immediate effects, short-acting
benzodiazepines such as lorazepam or alprazolam are
widely used for acute treatment of anxiety, agitation, and
insomnia – symptoms that frequently occur with tinnitus.
• The longer acting clonazepam provides some relief in a
considerable subgroup of patients.
• The use of benzodiazepines should be restricted to short
periods of time due to the risk of drug dependency.
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17. Non-Benzodiazepine
Anticonvulsants
• Diverse pharmacological mechanisms of action are
responsible for the therapeutic effects of antiepileptics;
among them effects on voltage-gated sodium and calcium
channels, and on synaptic transmission – mainly mediated
by gamma amino butyric acid type A (GABAA)
receptors.
• Since antiepileptics reduce neuronal excitability, in
principle, they should be beneficial for the treatment of
tinnitus.
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18. • The anticonvulsant carbamazepine, which binds to
voltage-gated sodium channels and stabilizes the sodium
inactivation state, thereby reducing neural firing, has been
investigated for tinnitus with mixed results.
• The anticonvulsant gabapentin acts on voltage-gated
calcium channels and is also used for the treatment of
seizures, neuropathic pain, and migraine.
• Pregabalin, is indicated not only for the treatment of
partial seizures but also for neuropathic pain, fibromyalgia,
and anxiety.
• Beneficial effects on sleep have also been reported.
• There are no data available for its use in tinnitus, but based
on available data and clinical experience, pregabalin seems
to be a promising option for the treatment of tinnitus-
related anxiety and insomnia
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19. • Lamotrigine, which stabilizes neuronal membranes by
inhibiting voltage-sensitive sodium channels, has been
investigated in a double-blind placebo-controlled cross-
over clinical trial on 33 patients where it failed to
demonstrate a beneficial effect.
• Valproic acid, which is one of the most frequently
prescribed antiepileptic drugs and which acts by multiple
mechanisms has not been systematically investigated and
only been reported in case reports as useful in tinnitus.
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20. Antiglutamatergic Compounds
• Glutamate receptor antagonists have been tried in tinnitus
sufferers.
• The rationale behind it is that imbalance between
inhibitory vs. excitatory neurotransmission is observed in
several regions of the auditory pathway in tinnitus.
• Moreover, blocking glutamatergic neurotransmission
could also exert neuroprotectant effects, as it is known that
noise overexposure is followed by an excitotoxic injury of
the hair cells.
• The putative non-selective NMDA receptor antagonist
acomprosate has been tried in a doubleblind study.
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21. • Patients received placebo or acamprosate (333 mg, three
times per day) and rated the loudness and annoyance of
their tinnitus before and at monthly intervals of treatment.
• Acamprosate had no beneficial effects after 30 days of
treatment, a modest benefit at 60 days, and a significant
effect at 90 days.
• Treatment with caroverine, memantine and neramexane
which are antagonist of non-NMDA and NMDA(N-
methyl-D-aspartate) receptors, has been analyzed with
contradictory results was no more effective than placebo.
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22. Dopaminergic–Antidopaminergic
Drugs
• Both dopaminergic and antidopaminergic drugs have been
proposed for treating tinnitus.
• Sulpiride significantly reduced subjective ratings of
tinnitus and tinnitus visual analogue scores.
• Effects were more pronounced when sulpiride was
combined with either hydroxyzine (an antihistamine and
anxiolytic) or melatonin.
• The dopamine agonist piribedil was investigated recently
in a double-blind placebo-controlled cross-over study.
• A clinical trial is under way to assess the efficacy of
flupenthixol (a type of thioxanthene drug that acts by
antagonism of D1 and D2 dopamine, and serotonin type
2A receptors) plus clonazepam, compared to clonazepam
alone.
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23. Other
• Some other miscellaneous drugs have been tested with
limited efficacy or that require further controlled trials.
• These include the HMG-CoA (3-Hydroxy-3-Methyl-
Glutaryl-CoA) reductase atorvastatin,
• the vasodilator cyclandelate,
• the loop diuretic furosemide, some herbal products like
Ginkgo biloba, melatonin,
• the prostagaldin E1 analogue misoprostol,
• the L-type calcium blocker nimodipine,
• the phosphodiesterase type 5 inhibitor vardenafil, and
• minerals including zinc.
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24. • Atorvastatin reduces the synthesis of cholesterol by
inhibiting HMG-CoA reductase.
• In a randomized double-blind placebo-controlled study
over 13 months involving elderly patients with elevated
cholesterol, atorvastatin failed to slow the progression of
age-related hearing loss and significantly reduce tinnitus.
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25. • Cyclandelate, a vasodilator used in the treatment of
cerebrovascular and peripheral vascular disorders, that is
believed to act by blocking calcium influx , has been
investigated for the treatment of tinnitus based on the
assumption that some forms of tinnitus may arise from
cerebrovascular insufficiency.
• In an open multicentric clinical trial of patients with
tinnitus, vertigo, and visual disturbances, 90-day treatment
with cyclandelate reduced the severity and frequency of
these symptoms with minimal side effects.
• However, in a subsequent placebo-controlled double-blind
study, cyclandelate did not significantly change
audiometric measures of tinnitus loudness and pitch and
caused side effects in many patients.
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26. • Furosemide is a loop inhibiting diuretic used to treat
congestive heart failure and edema .
• Furosemide has been proposed as a treatment for tinnitus
of “cochlear” origin because it strongly suppresses the
endolymphatic potential and other cochlear responses.
• One initial study has shown that approximately 50% of
patients exhibited a reduction of tinnitus symptoms
following intravenous furosemide treatment.
• Moreover, furosemide has also been found to suppress
tinnitus in approximately 40% of patients with Ménière’s
disease.
• However, high doses of furosemide can also induce
temporary hearing loss and tinnitus.
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27. • Ginkgo biloba has been proposed for the treatment of a
wide range of disorders including tinnitus.
• In western countries, Ginkgo biloba is commonly available
in form of leaf extracts, which in Europe and in the United
States are among the most widely used and appreciated
herbal medications.
• Ginkgo extract contains two main pharmacologically
active substances such as flavonoid glycosides and terpene
lactones, responsible for many biological effects.
• Even if some studies have suggested beneficial effects of
Gingko on tinnitus, particularly in patients with short
duration symptoms, there is a growing body of evidence
from large, well-controlled double-blind placebo-
controlled clinical studies clearly indicating that Gingko is
no more effective in alleviating tinnitus symptoms than
placebo.
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28. • EGb-761 is a concentrated extract of Ginkgo biloba
(enriched in flavonoids and terpenes) which has a broad
spectrum of pharmacologic actions, including a free-
radical scavenger effect, and which has shown efficacy for
tinnitus in a phase I trial.
• Several other herbs have been proposed for tinnitus
therapy, such as Cimicifuga racemosa, Cornus
officinalis, Verbascum densiflorum, and Yoku-kan-san,
but none of them have been tested in well-controlled trials.
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29. • Melatonin is a neurohormone that is primarily produced
by the pineal gland.
• Since it can influence sleep and circadian rhythms,
melatonin is nowadays widely used for treating sleep
disturbances.
• This effect of melatonin may have been the rationale for
using this drug in the treatment of tinnitus.
• An open label study found statistically significant
improvements on ratings of tinnitus severity and sleep
quality scores, whereas a double-blind placebo-controlled
cross-over study did not demonstrate superiority of
melatonin over placebo.
• A more recent randomized double-blind placebo-controlled
study found that melatonin in combination with sulpiride
reduced subjective rating of tinnitus and tinnitus loudness
more than placebo.
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30. • Misoprostol is a synthetic prostaglandin E1 analogue
which is primarily used to prevent gastric ulcers induced
by non-steroidal anti-inflammatory drugs.
• In a small, placebo-controlled cross-over study, tinnitus
severity improved in 33% of subjects during misoprostol
treatment (escalating to 800 mg/day), while none improved
with placebo.
• A subsequent double-blind placebo-controlled study has
shown a significant reduction of tinnitus loudness with
misoprostol treatment, but no differences in subjective
measures of tinnitus severity.
• A further study has shown efficacy of misoprostol in the
treatment for chronic tinnitus in hypertensive and/or
diabetic patients.
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31. • Nimodipine is a calcium antagonist, which crosses the
blood–brain barrier and blocks L-type calcium channels.
• Although a first open clinical trial suggested positive
effects of nimodipine on tinnitus in some patients , these
could not be confirmed in a second open clinical trial.
• Vardenafil represents a potent and highly selective
phosphodiesterase type 5 (PDE5) inhibitor that induces an
increase of nitric oxide-mediated vasodilatation and which
is marketed for treatment of erectile dysfunction and
pulmonary hypertension.
• A prospective randomized double-blind placebo-controlled
trial did not show any benefit of vardenafil over placebo.
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32. • Zinc is an essential catalytic or structural element of many
proteins and a signaling messenger that is released by
neural activity at many central excitatory synapses.
• Growing evidence suggests that zinc may also be a key
mediator and modulator of the neuronal death associated
with transient global ischemia and sustained seizures, as
well as perhaps other neurological disease states .
• While positive results have been reported in some tinnitus
patients with hypozincemia, zinc therapy did not result in
tinnitus improvement in patients with normal zinc levels in
several double-blind placebo-controlled studies.
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