The nature of tinnitus

Tinnitus is a chronic, auditory disorder characterised by a ‘ringing’ or ‘buzzing’ in the ears. The two main subtypes of tinnitus are ‘objective’ and ‘subjective’ tinnitus: whereas ‘objective’ tinnitus can be heard by someone else and is usually associated with a vascular problem in the ear, ‘subjective’ tinnitus is an auditory illusion. While objective tinnitus can be treated by surgery, there is no known cure for subjective tinnitus. Subjective tinnitus can be caused by damage to the inner ear as a result of physical trauma, excessive noise, vascular insufficiency, a viral or bacterial infection, Meniere’s disease or exposure to ototoxic chemicals (e.g. aspirin or cancer chemotherapeutic agents such as cisplatin). Tinnitus can occur on its own or in combination with vestibular symptoms (e.g. as in Meniere’s disease). Either way, it is a debilitating condition that can affect all aspects of life and sometimes even leads to suicide. Parnes (1997) estimated that approximately 1 % of the population has chronic tinnitus that causes distress and that 90% of patients with hearing loss experience some tinnitus. Almost 40% of people aged 60 or over have tinnitus and as many as 50% of all tinnitus sufferers also have depression.

The mechanisms that underlie the development of subjective tinnitus are unclear. However, animal studies suggest that exposure to intense sound, resulting in cochlear hair cell damage, causes hyper-activity in the brainstem cochlear nucleus, which receives auditory information directly from the inner ear. Similar changes in cochlear nucleus neurones have been reported following outer hair cell loss as a result of treatment with cisplatin. Other studies have confirmed that this type of hyper-activity can be found in higher auditory centres in the brain, including the superior olive, the inferior colliculus and even the auditory cortex, following noise- or chemically induced trauma to the cochlea.

Such neuronal hyperactivity is similar to the epileptiform discharge that occurs in the trigeminal nucleus during trigeminal neuralgia and in the dorsal horn of the spinal cord during phantom limb pain, and it has therefore been suggested that subjective tinnitus is a form of sensory epilepsy. Consistent with this hypothesis, antiepileptic drugs are sometimes used to treat tinnitus. However, they are not always effective and can have serious adverse side-effects. For this reason, many other drugs have been tested and the search for more effective treatments continues. Because of the shortcomings of the conventional medications used to treat tinnitus, herbal remedies have been investigated, particularly Ginkgo biloba extracts. This chapter evaluates their efficacy and safety in comparison with other drug treatments.

Conventional medications for tinnitus

A diverse range of drugs has been used to treat tinnitus, but no single therapy is accepted by all clinicians. Only some of these drug treatment options are based on an understanding of the mechanisms of tinnitus; many others have been discovered serendipitously. Unfortunately, there are many spurious claims for clinical effects.

Intratympanic gentamicin therapy has been used to treat tinnitus associated with Meniere’s disease. Diamond et al. (2003) concluded that a subjective improvement in tinnitus occurred in approximately 57% of patients. Similarly, Lange et al. (2004) reported a significant reduction in tinnitus in 50% of patients treated with intratympanic gentamicin 2-4 years earlier. By contrast, a 5-year follow-up study of patients who had received intratympanic gentamicin therapy showed no significant effect on any hearing measure, even though 74% still reported complete relief from vertigo.

Other kinds of intratympanic drug therapy have been investigated. Sakata et al. (2001) used intratympanic injection of 4% lidocaine in an attempt to depress cochlear hair cell function and relieve tinnitus. Lidocaine relieved tinnitus in 81% of patients; however, vertigo developed as a result of the infusion. Intratympanic administration of steroids has also been used. Cesarani et al. (2002) studied 50 patients who received transtympanic infusion of dexamethasone, 3 times per day for 3 months. Two weeks after the last administration, tinnitus had disappeared in 34% of patients, 40% experienced a significant decrease in its intensity, and 26% reported no effect. Shulman and Goldstein (2000) also reported relief from tinnitus in 7 of 10 patients after intratympanic steroid therapy. Intratympanic administration of acetylcholinesterase inhibitors and acetylcholine receptor agonists has also been investigated, with varying success.

Because benzodiazepines activate the benzodiazepine-binding site on the GABA_A receptor, increasing hyperpolarisation, benzodiazepine treatment is an obvious strategy to reduce neuronal hyperactivity associated with tinnitus. Benzodiazepines such as alprazolam have proven useful, but it is often difficult to determine how much of the therapeutic effect is attributable specifically to the relief of tinnitus and how much is due to a general anxiolytic effect.

The benzodiazepine antiepileptic drug, clonazepam, as well as the antiepileptic drugs gabapentin and phenytoin, have also been used to treat tinnitus. A retrospective survey of 25 years of clinical use suggested that tinnitus was improved in approximately 32% of patients treated with clonazepam. However, adverse side-effects, such as drowsiness, depression, nightmares and reduced libido, were reported in 16.9% of patients although they decreased with continued therapy.

Shulman et al. (2002) have argued that for patients with tinnitus of central origin, benzodiazepines can provide long-term relief in 90% of cases. In an imaging study using single photon emission computed tomography, Shulman et al. (2000) found that patients with severe tinnitus exhibited a reduction in benzodiazepine-binding sites in the medial temporal cortex, suggesting a possible neural basis for the therapeutic effects of benzodiazepines. By contrast, drugs that act as agonists at the GABA_B receptor, such as baclofen, have not proven effective and have been associated with severe adverse side-effects.

Antidepressants have also been used to treat tinnitus. If tinnitus causes depression in a particular patient, then the relief of the depression will usually result in some relief from the tinnitus as well. This finding demonstrates that tinnitus is not just a sensory problem but a phenomenon that involves the entire CNS, including emotional areas of the brain such as the limbic system. Folmer and Shi (2004) studied 30 patients who developed depression after the onset of their tinnitus and received selective serotonin reuptake inhibitor therapy as treatment. At 20.6 months, the patients showed a statistically significant reduction in their tinnitus severity scores, which correlated with a decrease in their depressive symptoms.

One of the more unusual treatments for tinnitus is the intravenous administration of local anaesthetics, which was discovered in 1937. Although lidocaine was shown to reduce tinnitus, its in-vivo instability and adverse side-effects (e.g. nausea, dizziness, potentially fatal cardiovascular effects) have limited its use. There has been some controversy about whether lidocaine actually achieved its effects as a result of blocking sodium channels or as a result of some other non-specific effect of the drug, since other agents with similar actions have not produced the same effect.

Recently, there have been a number of reports of the use of systemically administered lidocaine for the treatment of tinnitus. Marzo et al. (2004) reported that intravenous lidocaine successfully treated incapacitating tinnitus caused by inner-ear tertiary syphillis. Savastano (2004) reported that intradermal injection of lidocaine relieved tinnitus with no adverse side-effects. Otsuka et al. (2003) reported that intravenous lidocaine relieved tinnitus either partially or completely in 70.9% of cases studied over a 24-year period. However, it is not clear how or where lidocaine is acting to achieve these effects, although recent studies using intratympanic injection suggest that it may be working either as a vasodilator or sodium-channel blocker in the inner ear.

Various other vasodilators have been investigated for the treatment of tinnitus but recent studies have failed to confirm their efficacy. Because prostaglandins stimulate vasodilation, the synthetic prostaglandin El (PGE1) analogue, misoprostol, has been investigated and found to be effective in relieving tinnitus in about 33% of patients. Yilmaz et al. (2004) studied 28 patients receiving misoprostol and 12 patients receiving placebo: 64% of the patients receiving misoprostol reported a reduction in tinnitus loudness (33% for placebo), with 33% showing an improvement according to their subjective tinnitus score (17% for placebo).

Finally, diuretics have been used to treat tinnitus associated with Meniere’s disease, which is believed to be caused by hypertension of the endolymphatic fluid. The loop diuretic, frusemide, has been effective in treating Meniere’s-associated tinnitus. However, other attempts to regulate osmotic pressure, using mannitol and glycerol, have had little success.

Herbal remedies

The published peer-reviewed literature on herbal medicines to treat tinnitus is dominated by the use of Ginkgo biloba extracts. From extensive PubMed and other database searches, we could find virtually no other published papers in peer-reviewed journals on the effects of herbal medicines in tinnitus.

Ginkgo biloba extracts

Ginkgo biloba (Ginkgoaceae) is an ancient Chinese tree that has been cultivated for thousands of years. Purified extracts, marketed under the trade names Rokan, Tanakan, Tebonin and Ginkgold, are used throughout the world, although they are especially popular in Europe and in the USA. Ginkgo biloba extracts have been licensed in Germany for the treatment of cerebral vascular insufficiency. They are available as over-the-counter medications in western Europe and as herbal preparations in the USA, Australia and New Zealand.

EGb-761 is a standardised extract containing 24% flavonoids, 7% proanthocyanid ins and 6% terpenoids. The flavonoids are mainly flavonol-glycosides with antioxidant properties, while the terpenoid fraction contains ginkgolides, sesquiter-pene and bilobalide. Ginkgolide B in particular has potent platelet-activating factor receptor antagonist properties. Many of the CNS effects of EGb-761 have been attributed to the combination of its antiox-idant and platelet-activating factor receptor antagonist actions. However, it is also a vasodilator, which might be the only rationale for speculating that it would be useful in the management of tinnitus.

Hilton and Stuart (2004) critically evaluated the clinical evidence for the efficacy of Ginkgo biloba in treating tinnitus and concluded that there were insufficient reliable data on which to base a conclusion, as a result of the methodological flaws of the available studies. Very few studies have used double-blind, placebo-controlled designs. Interestingly, when these sorts of controls have been employed, the results have usually been negative. In an effort to focus on the best-designed clinical trials, Ernst and Stevinson (1999) performed a meta-analysis of only those clinical trials that employed standardised Ginkgo extracts that were compared with either placebo or another active medication, and where the primary complaint was tinnitus. Only five trials fulfilled these criteria.

Meyer (1986) studied 103 patients with tinnitus using a randomised, double-blind, placebo-controlled design. Patients received EGb 761 (Tanakan) daily for 1-3 months and their tinnitus severity was assessed using a three-point scale. The EGb 761 group experienced a decrease in tinnitus severity but Ernst and Stevinson (1999) point out that the paper, available in French only, lacked a clear description of the methods used.

In another study, Meyer (1986) studied 259 patients with tinnitus over 1 year. Patients receiving EGb 761 (Tanakan) daily for at least 1 month were compared with those receiving nicergoline or almitrine-raubasine. According to a specialist analysis, tinnitus appeared to show greater improvement in the EGb 761 group compared with the other two treatments. However, Ernst and Stevinson (1999) criticised this study for lack of random allocation of patients to the different treatment groups and lack of methodological detail in the published report; for example, it was not clear whether the patients and experimenters were blind to the treatment groups.

Holgers et al. (1994) recruited 80 patients into an open trial in which all of them received a Ginkgo biloba extract daily (Seredrin). This was followed by a double-blind, placebo-controlled phase of the trial using only the 20 patients who appeared to respond to the extract. However, according to patients’ subjective reports, there were no significant effects of the Ginkgo biloba extract at the end of the trial.

Morgenstern and Bierman (1997) performed a randomised, double-blind study of 99 patients with chronic tinnitus, who received a Ginkgo biloba extract (Tebonin) or placebo daily for 12 weeks. The loud-ness of the tinnitus was evaluated using audiometry. They reported a significant reduction in loudness (from 42 to 39 dB) in the ginkgo-treated group. Juretzek (1998) treated 60 patients with chronic tinnitus with daily injections of EGb 761 for 10 days, and then randomly allocated them to oral EGb 761 or placebo for 3 months. The second phase of the design was double blind and tinnitus was assessed using audiometry. Juretzek also reported a significant reduction in tinnitus in the EGb 761 group compared with placebo.

The first large, double-blind, placebo-controlled study of the effect of Ginkgo biloba extracts on tinnitus was reported by Drew and Davies (2001). They recruited 1121 people between 18 and 70 years and matched 978 according to sex, age and the duration of their tinnitus. For 12 weeks, participants received either the ginkgo extract LI 1370 (Lichtwer Pharma, Berlin, Germany) or placebo. Subjects assessed their tinnitus in terms of loudness and how much it disrupted their daily life, using rating scales. However, there was no significant difference in either measure compared with placebo. In the most recent randomised, placebo-controlled, double-blind clinical trial, Rejai et al. (2004) also found no therapeutic effect of Ginkgo biloba compared with placebo in 66 patients with tinnitus. The primary outcome measures were the tinnitus handicap inventory, the Glasgow health status inventory and the average hearing threshold at 0.5, 1, 2 and 4 kHz. In a meta-analysis of clinical trials by the same authors, they found that only 21.6% of patients with tinnitus reported benefit from Ginkgo biloba versus 18.4% of patients who reported benefit from a placebo.

Because Ginkgo biloba extracts have vasodilatory effects, when they are combined with drugs such as aspirin, they can increase bleeding. Nonetheless, most of the evidence for haemorrhagic responses following the use of Ginkgo biloba extracts is based on anecdotal and case reports. Kohler et al. (2004) compared bleeding time, coagulation parameters and platelet activity in response to 2 X 120 mg/day EGb 761, or placebo, for 7 days and found no significant difference in any of these measures.

To date, only one study has investigated the effects of EGb 761 on salicylate-induced tinnitus using a conditioned-behaviour paradigm in rats. Daily oral administration of 25, 50 and 100 mg/kg EGb 761 was found to reduce tinnitus behaviour compared with vehicle. It should be noted, however, that these are very high doses and it is unlikely that they could be used in humans without adverse side-effects (even 25 mg/kg/day for a 70 kg adult corresponds to 1750 mg/day, which is more than five times the average daily dose used in humans).

Clearly, the investigation of the effects of Ginkgo biloba extracts on tinnitus has suffered from a lack of systematic clinical trials employing double-blind and placebo-controlled designs. While some clinical trials have yielded positive results, these studies are few and have been limited either by design flaws, the small size of the significant effects, or else the results have not been published in peer-reviewed journals. By contrast, the two most systematic clinical trials, which are double-blind and placebo-controlled, and are published in peer-reviewed journals, have yielded negative results.

Other herbal medicines

Very little has been published on the use of other herbal medicines to treat tinnitus. Yang (1989) has reported a blind trial in which patients with tinnitus were given either ‘Western medicines’ (i.e. diazepam, nicotinic acid, bromides, vitamin B, ATP, carbamazepine or lidocaine) and traditional Chinese medicine (TCM) or the Western medicines alone. TCM consisted of Rhizoma Gastrodiae, Ramulus Uncariae cum Uncis, Poria cocos, Flos Chrysanthemi, Akebia Quinata, Radix Polygoni Multflori, Fructus Liquidambris, Radix Rehmanniae, Rhizoma Alismatis, Radix Scrophulariae, Fructus Lycii, Radix Glycyrrhizae, Semen Plantaginis and Semen Vaccariae. Relief from tinnitus was observed in 84.4% of those receiving Western medicine and traditional Chinese medicine and 55% of those receiving Western medicine only. Unfortunately, given the mixture of drug and herbal remedies the patients received, it is difficult to attribute an improvement in tinnitus to any particular agent, and in any case, there was no placebo control group.

It is important to recognise that in traditional Chinese medicine, tinnitus is believed to be caused by changes in the relationship between the ear and the internal organs, such as the kidney, the liver, the gall bladder, the spleen and the stomach. TCM aims to treat tinnitus by achieving a balance of the yin and yang, external and internal, hot and cold, weak and strong. From the viewpoint of traditional Chinese medicine, tinnitus is only one of the symptoms the patient presents with and the doctor needs to observe a series of symptoms using inspection, by listening and smelling, inquiring and palpation, to make the right diagnosis. For example, it is believed that normal kidney function will be reflected by normal hearing and a kidney dysfunction (Shen kui) will result in hearing loss or tinnitus. If the tinnitus is caused by kidney dysfunction, the patient tends also to experience vertigo and dizziness, a sore back, the tongue has a red look with no ‘fur’ or little fur and there is a weak pulse. There are many different types of tinnitus in traditional Chinese medicine and most recently, tinnitus has been divided into five types at the Third Chinese Zhong Xi Yi Je He Otolaryngology Society Annual Meeting in 2002: Wai Gan Fen Re Xing (related to respiratory infection), Gan Hou Sbang Rao Xing (related to abnormal liver function), Tan Re Yujie Xing (related to the ‘hot’ state in TCM), Shen jing Kui Xu Xing (related to kidney dysfunction) and Pi Qi Xu Ruo Xing (related to abnormal spleen function).

Japanese herbal medicines have also been used to treat tinnitus. Okamoto et al. (2005) used Yoku-kan-san (TJ-54) to successfully treat tinnitus associated with undifferentiated somatoform disorder, presenting with headache and insomnia. Unfortunately, this was only a case report and therefore no controls were employed.

Importance of animal models for testing herbal remedies

A major problem for the development of new drug treatments for tinnitus is the paucity of animal models of the disorder. It is difficult to determine whether an animal such as a rat or a mouse is actually experiencing tinnitus, and many studies of the neurophysiological and neurochemical mechanisms of tinnitus simply assume that an animal has tinnitus following cochlear lesions produced by intense sound, surgery or chemical toxicity. This is not a valid assumption given that similar conditions in humans do not necessarily produce tinnitus.

To overcome this problem, a number of researchers have developed animal models of tinnitus in which rats are trained to respond differentially in a conditioned avoidance task depending upon whether they hear certain frequencies of background noise. For example, rats trained to make a particular response in the presence of a 10-kHz background noise, will continue to make the trained response, in the absence of the background noise, if tinnitus has been induced by the administration of a drug such as salicylate. In humans, salicylates produce tinnitus of approximately 10 kHz, and rats treated with salicylates respond in behavioural tasks as if they hear a continuous background noise at around 10 kHz. Using this type of conditioned-behavioural model, it is possible to screen new drugs for their potential application to the treatment of tinnitus.

Unfortunately, at present, such animal models have not been used extensively for the investigation of the neural mechanisms of tinnitus or for potential drug treatments. In addition to more well-controlled clinical trials, it is vital that herbal medicines be tested in realistic animal models of tinnitus.

Conclusions

It is clear from the studies reviewed here that the published literature on herbal medicines and tinnitus is small and in most cases focused on Ginkgo biloba extracts, where some evidence for efficacy has been found. Nevertheless, even the research on Ginkgo biloba and tinnitus lacks a substantial number of systematic, well-controlled clinical trials, in which double-blind protocols have been used. Unfortunately, most of the trials that have been well designed have failed to demonstrate efficacy for Ginkgo biloba in the treatment of tinnitus.

The only reasonable conclusion that can be reached at present is that the available data indicate that conventional medications offer more therapeutic benefit for patients with tinnitus than herbal alternatives. Given that clinical trials are expensive to run and are usually not undertaken unless there is substantial preclinical evidence to suggest that they may establish the efficacy of a new drug, it is probably very important that researchers and clinicians, who are interested in potential herbal treatments for tinnitus, use conditioned-behavioural models of tinnitus in animals to screen herbal agents. This would provide a clear path for the development of herbal remedies to treat tinnitus before initiating clinical trials.

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