Tinnitus is derived from the Latin word tinnire and refers to a condition where patient experiences a ringing, buzzing, or hissing auditory sensation in the absence of an external sound. Although many advances have been made in the medical sciences, tinnitus is still thought of as a scientific and clinical enigma for a clinician. Tinnitus is broadly classified into subjective or objective. The objective type of tinnitus is rare and refers to a condition where a real sound is generated by internal biological activity, such as vascular turbulence or pulsations or spasm of the muscle in the middle ear, Eustachian tube, or soft palate. Subjective tinnitus is the most common type and it refers to a phantom auditory sensation for which no objective sound can be identified. The treatment goals for tinnitus patients are aimed at symptomatic relief and its associated distress. There are no standard protocols for treatment of the tinnitus. Drug therapy is one of the treatment approaches for tinnitus. The literature related to pharmacotherapy for tinnitus is vast. Here, this review article will only focus on some of the recent pharmacotherapeutic treatments employed for tinnitus. Despite considerable developments in the understanding of tinnitus, its pharmacological treatment has little progress. The objective of this review article is to discuss the current pharmacological treatment of tinnitus.
METHODS OF LITERATURE SEARCH
Multiple systematic methods were used to find current research publications on the current pharmacological treatment of tinnitus. We started by searching the Scopus, PubMed, MEDLINE, and Google Scholar databases online. A search strategy using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines was developed. This search strategy recognized the abstracts of published articles, whereas other research articles were discovered manually from the citations. Randomized controlled studies, observational studies, comparative studies, case series, and case reports were evaluated for eligibility. There were a total number of articles 68 (21 case reports, 24 cases series, and 23 original articles) [Figure 1]. This article focuses only on the current pharmacological treatment of tinnitus. This review article describes the epidemiology and different pharmacological treatment options for patients with tinnitus. This review article provides a better understanding of the pharmacological treatment of disabling tinnitus. It will also serve as a catalyst for additional study into a newer pharmacological agent for the treatment of tinnitus.
Tinnitus is one of the most common hearing disturbances, affecting approximately 17% of the population and approximately 33% of the elderly. The prevalence of tinnitus increases with the degree of age-related hearing impairment. Chronic tinnitus is more prevalent among elderly persons (12% after the age of 60 years) than in young adults (5% of the 20–30 years of age) but can occur in any age group. However, many patients with hearing loss do not present tinnitus, and some individuals with normal hearing present tinnitus. More than 4 million prescriptions are written every year for tinnitus relief in Europe and USA, but these are all off-label prescriptions of a wide variety of drugs.
There is no effective treatment available for management of the tinnitus, although much research work is underway into the pathophysiology and treatment of tinnitus. There is no specific pharmacological agent which has been established for the treatment of tinnitus. There are a large variety of drugs [Table 1] approved for the treatment of tinnitus in clinical practice. There is a fully satisfactory drug still remains elusive. There are different pharmacotherapies available for patients with tinnitus such as lidocaine, vasodilators, benzodiazepines, spasmodic drugs, tricyclic antidepressants, and Ginkgobiloba.
Lidocaine is often used as a local anesthetic agent or to treat cardiac arrhythmias. It is thought to bind to fast voltage-gated sodium channels, reducing the magnitude of sodium current at the time of depolarization. However, the mechanism of action of lidocaine is more complex, as it is known to affect calcium-, potassium-, and glycine-induced chloride currents at micromolar concentrations. Although intravenous lidocaine is thought to be effective in tinnitus, the effect is transient and the route of administration is not practical in a clinical setting of a chronic condition. The location of action of intravenous lidocaine is not properly understood, but there is evidence that it affects both the cochlea and the central nervous system (CNS). In one study with human brain imaging where lidocaine either increased or decreased the loudness of tinnitus, the changes in loudness were associated with altered neural activity in the right auditory cortex. Tocainide is an analog of lidocaine that can be taken orally and was assessed as a potential long-term therapy for tinnitus. Tocainide has little benefit for tinnitus. Intravenous lidocaine has been used to ameliorate tinnitus, but in general, its effect has been limited. The longer-acting local anesthetic agent such as ropivacaine may be more effective to relieve tinnitus.
Glutamate receptor antagonist
Glutamate receptor antagonists have been tried the patients with tinnitus. The rationale behind their use is that imbalance between the inhibitory and excitatory neurotransmission is found in several parts of the auditory pathway. Blockage of the glutamatergic neurotransmission could exert neuroprotectant effects as it is known that noise exposure is followed by an excitotoxic injury of the hair cells. Hence, the administration of glutamate antagonists might prevent labyrinthine damage and, possibly, tinnitus development in the acute phase.
Antidepressants are usually used for the treatment of tinnitus. The cause for the use of such antidepressants can be found in well-documented comorbidity between depressive disorders and tinnitus. Tricyclic groups of drugs are mainly used for tinnitus due to their analgesic effects. This nature of tricyclic antidepressants could be interesting in view of proposed etiological similarities between neuropathic pain and tinnitus. Among the tricyclic antidepressants (trimipramine, amitriptyline, and nortriptyline), nortriptyline is worth mentioning. One study showed that in subjects with severe tinnitus and severe depression or depressive symptoms, nortriptyline significantly decreased the depression scores, tinnitus disability scores, and tinnitus loudness in comparison to placebo. Antidepressants such as serotonin uptake inhibitors such as paroxetine and sertraline are tested for tinnitus. In one randomized double-blind placebo-control study in patients without severe hearing loss but at high risk for developing severe tinnitus, sertraline was more effective than placebo in decreasing tinnitus loudness and severity of tinnitus.
Severe tinnitus is often a stressful situation and heavily affects every aspect of a patient's life. Anxiolytics like benzodiazepines have been used to help patients cope with their tinnitus. In one study, alprazolam decreased tinnitus loudness in 76% of patients, measured with a tinnitus synthesizer and a visual analog scale, whereas only 5% showed a reduction in tinnitus loudness in the control group. In a prospective, randomized, single-blind clinical trial taking 10 patients per group, clonazepam significantly reduced tinnitus loudness and annoyance (visual analog scale) relative to the control group.
Zinc is a trace element, which is seen in minute quantities in living cells but plays a vital role in the metabolism of the body. Zinc is helpful for the proper functioning of the immune system. Zinc is also protective against reactive oxygen species. 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 CNS. It acts as a synaptic modulator and plays a role in neuronal death in certain pathogenic conditions. Zinc is also found in the synapse of the auditory system. A study showed that patients with tinnitus may have low blood zinc levels and clinical improvement can be achieved by oral zinc medication.
Acamprosate blocks excitatory glutamatergic N-methyl-d-aspartate (NMDA) receptors, whereas enhancing gamma-aminobutyric acid (GABA)-mediated nerve inhibition. The rationale behind the treatment of tinnitus arises from excess glutamatergic activity through NMDA receptors and/or hyperactivity resulting from the loss of GABA-medicated inhibition.
Caroverine is used as a spasmolytic drug and acts as an antagonist of calcium and non-NMDA and NMDA glutamate receptors. Due to limited uptake with oral administration, caroverine is given intravenously or locally. It has been thought that cochlear synaptic tinnitus is from a synaptic disturbance of NMDA or non-NMDA on the afferent dendrites of the spiral ganglion neurons.
Melatonin is a naturally occurring circulating hormone secreted in the pineal gland and other tissues, binds to the melatonin receptors, and plays a vital role in regulating circadian rhythms. It is also a potent antioxidant that protects mitochondrial and nuclear DNA and has been found to protect against noise- and drug-induced hearing impairment. As sleep disturbances are an important complaint and complicating factor in tinnitus, melatonin was evaluated for the treatment of tinnitus. A recent study showed that melatonin reduced the subjective ratings of tinnitus and tinnitus loudness more than placebo; these improvements were larger if melatonin was combined with the antipsychotic sulpiride, a selective dopamine D2 antagonist.
Memantine is presently used for the treatment of Alzheimer's disease and has shown positive effects in managing depression. It also acts as a voltage-dependent antagonist of NMDA receptors and decreases excitotoxicity by preventing the prolonged influx of calcium. Excitotoxicity mediated by NMDA receptors has been proposed as a mechanism for cochlear tinnitus. High doses of salicylate, the active ingredient in aspirin, reliably enhance tinnitus and augment current through NMDA receptors on cochlear spiral ganglion neurons. NMDA antagonists applied locally to the inner ear blocked behavioral evidence of salicylate-induced tinnitus.
This drug is similar to memantine and is being used for Alzheimer's disease, drug dependence, depression, and pain. Like memantine, neramexane acts as a noncompetitive, voltage-dependent NMDA antagonist. It also blocks α9 and α10 nicotinic cholinergic receptors which are expressed on inner hair cells and α10 nicotinic receptors which are expressed on the inner hair cells in the labyrinth. It is helpful for the treatment of tinnitus.
There are several vasoactive drugs investigated that increase the blood flow which causes increased oxygenation of peripheral and central auditory structures that reduce tinnitus as a consequence. The L-type Ca2+ channel antagonist nimodipine is effective for relieving tinnitus, especially in quinine-induced tinnitus in rates. Vasodilatory properties of histamine were studied for the treatment of tinnitus. Betahistine is one of the commonly prescribed treatments for tinnitus, but its effectiveness is mostly limited to the tinnitus associated with Meniere's disease. Prostaglandins have also properties of vasodilation and are found in both the cochlea and CNS. It has been documented that reduction in prostaglandin metabolism is associated with a response to noise exposure, nonsteroidal anti-inflammatory drugs, aminoglycosides, and loop diuretics; all of which have been reported to be tinnitogenic.
The extracts derived from the Chinese tree G. biloba yield extract of Ginkgo biloba 761(EGb-761), the active component, which contains flavonoids, terpenes, and vasoactive compounds. G. biloba extract has been used to treat a wide range of disorders including tinnitus due to its vasodilating and antioxidant properties. Studies showed that Ginkgo alleviates tinnitus symptoms, specifically in patients with short-duration symptom. One behavioral study reported with rats taking EGb-761 reduced the behavioral manifestations of salicylate-induced tinnitus. However, the study showed that Ginkgo is no more effective in alleviating tinnitus symptoms than a placebo. Preparations of G. biloba are not standardized and so it is difficult to compare and evaluate the results from different studies, but placebo-controlled trials have so far failed to reveal any particular efficacy, even when combined with various therapies used for tinnitus.
Several conditions are associated with tinnitus as a result of an imbalance in ion distribution and fluid compartmentalization in the cochlea and vestibular apparatus as in Meniere's syndrome. These ion imbalances can cause an increase in the pressure perilymph (perilymphatic hypertension) and result in dysfunction in the cochlea. There are several diuretics have been studied in an attempt to rectify these imbalances and restore normal fluid pressure. The loop diuretic furosemide was documented to be effective in cases of tinnitus that were deemed to be cochlear in origin.
The use of botulinum toxin Type A (BTXA) is used to treat tinnitus due to stapedius myoclonus. Local application of botulinum toxin is helpful in relive tinnitus due to stapedius myoclonus. A piece of gel foam containing BTXA (25 U/ml) is usually placed through a perforation I tympanic membrane, into the middle-ear cavity of a patient presenting with tinnitus due to stapedius myoclonus.
Hyperbaric oxygen therapy
Hyperbaric oxygen therapy involves breathing pure oxygen in a specially designed chamber. It permits a controlled increase of partial oxygen pressure in the blood. This technique can be utilized in patients with tinnitus and sudden deafness when the development in the inner ear and the brain lead to a lack of oxygen and so to a limited energy provision. Hyperbaric oxygen therapy is thought to be beneficial in patients with tinnitus by enhancing oxygen supply to the inner ear and improving tinnitus.
PHARMACOLOGICAL AGENTS IN THE PIPELINE FOR TINNITUS
Neurokinin receptors are found in the labyrinth, which has a potential treatment target for relieving tinnitus. Vestipitant is a blocker of the neurokinin-1 receptor, which often binds the substance P. Vestipitant and the combination of paroxetine and vestipitant are currently under clinical trials for the treatment of tinnitus. Transdermal lidocaine acts as a vector for delivering low-dose lidocaine to treat tinnitus. This has been developed for the delivery of lidocaine (LidoPAIN TV, EpiCept) applied over the preauricular skin. Its clinical efficacy is also under clinical trial.
Tinnitus is an extremely prevalent clinical condition that impinges on the lives of sufferers to varying degrees. Tinnitus is a distressing symptom that is characterized by a perceived sensation of sound without a corresponding external stimulus. Although a diverse array of pharmacological agents have been tried, only a few are routinely prescribed by clinicians. There is a pressing need for a drug or a combination of drugs to relieve tinnitus. Antidepressants and anxiolytics are commonly used in pharmacological protocols for the treatment of tinnitus. Most patients and clinicians are waiting for drugs that can relieve tinnitus significantly.
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