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Drugs2.pdf

THE DRUGS
The only consistently tinnitus reducing or alleviating drug has been Lidocaine. Thiswas first observed by Barany (1935). This is a drug with local anaesthetic, anti-arrhythmic and anticonvulsive properties. The effect of this on tinnitus has beenstudied by many especially Shea et al. (1981), Emmett and Shea (1984).
Unfortunately this can only be administered intravenously for tinnitus suppression.
Its effect lasts between some minutes and some hours and can have unacceptable sideeffects.
Although the intravenous injection of lidocaine is seldom used in treatment atpresent, it provides fertile grounds for research into its mechanism of action.
Research using lidocaine so far indicates that it has effects upon central auditorypathways as well as on the cochlea.
Iontophoresis of lidocaine through the skin of the external auditory canal was used inthe past with no apparent benefit.
Although intratympanic lidocaine injection was advocated by Sakata and Umeda(1976), Coles et al (1992) in their study did not find support for this and thecomplication of vertigo was very common. It is still used in some centres.
Lidocaine is one of the group of cardiac arrythmic or membrane stabiliser drugs. Inthe same class there are drugs that can be taken orally: Tocainide hydrochloride (Tonacard) 400mg tablets.
Flecainide Acetate (Tambocor) 100mg tablets.
Mexiletine (Mexilin) 100mg tablets.
Although these drugs were found to be quite effective in tinnitus alleviation theycannot be used in patients with a variety of health problems including heart disease.
When used, co-operation with the cardiologist is required. Emmett and Sheaconcluded that due to lack of tolerance of the drug's adverse effects, which includecardiovascular problems and blood dyscrasias, there usefulness is not supported.
Clinical use of these drugs has been virtually abandoned.
ANTIEPILEPTIC (anticonvulsant) DRUGS WITH MEMBRANE
STABILISING PROPERTIES

It is likely these drugs were trialled because the anticonvulsant property of lidocaineinspired investigation into the effect of anticonvulsant drugs on tinnitus. Thefollowing were tried: Amylobarbitone sodiumPhenitoine sodiumSodium valporatePrimidone Although some patients benefited from these drugs, they had undesirable side effectsand therefore are seldom used.
BENZODIAZEPINES WITH ANTICONVULSANT PROPERTIES
Carbamazepine (Tegretol) 100-200mg tablets.
The studies of Goodhill (1981) gave promising results, however later studies(Goodey 1981, Lechtenberg and Schulman 1984) did not support these levels ofeffectiveness and the unpleasant side effects of gastrointestinal distress, drowsinessand unsteadiness limit its usefulness.
Clonazepam (Rivotril) 500micrograms tablets.
Lechtenberg and Schulman found clonazepam to have promising effect incomparison with other benzodiazepines such as diazepam, flurazepam andoxazepam. Recently Bumby and Stephens (1997) in a double-blind placebocontrolled crossover pilot study found significant reduction in the annoyance causedby tinnitus in comparison with cinnarizine and placebo. It was concluded that itwould be helpful to use it in brief and intermittent courses when patients' tinnitus isvery troublesome and unresponsive to other management. The effect was explainedin terms of the GABAergic effect of the drug on the excitability of auditory neuralactivity of the cochlea.
Some patients experienced relief of their tinnitus while on alprazolam. This led to acontrolled study by Johnson et al (1993). Of the 17 patients who completed the trial,13 had a reduction of their tinnitus (76%). The authors also explained the actionthrough its GABAergic effect. Although this result sounds promising, alprazolam isknown to lead to dependence/addiction, therefore, as with diazepam, utmost care isneeded in the consideration of the use of this drug.
Other antiepileptic drugs suggested for tinnitus treatment: This drug is a GABA agonist. A trial by Perucca et al (1991) suggested benefit butColes failed to replicate this (personal communication).
Lamotrigine (Lamictal) 25mg tablets.
This candidate, like vigabatrin, is under research.
Research studies show that benzodiazepines work through their effect on gammaaminobituric acid A (GABA A) receptors. GABA A has an inhibitory effect onascending auditory pathways as well as at cochlea level. It has been shown thatbenzodiazepines enhance the GABA A effect and through this the effects are(i) sedative (ii) anxiolytic (iii) anticonvulsant (iv) attenuation of autonomic andendocrine responses. Hence in theory one expects benefit not only directly ontinnitus but also on emotional and autonomic consequences. However in the use ofbenzodiazepines there are problems of dependency/addiction, tolerance and rebound.
TRICYCLIC ANTIDEPRESSANTS
Earlier amitriptyline and trimipramine were thought to have a direct effect on tinnitusalong with the antidepressant effect. However the direct effect is doubtful. Lateranother drug in this group (nortriptyline) was suggested to have tinnitolytic effect.
Nortriptyline (Allegron, Motipress, Motival) 25mg tablets.
Of studies comparing tinnitus patients and tinnitus patients with depressive disorder,(Dobie et al. 1993) this drug was found to have beneficial effect upon depression butno significant effect upon tinnitus.
ANTIHYSTAMINIC DRUGS
Cinnarizine (stugeron) 15mg tabletsFlunarizine (not available in the UK) These are used in the management of vertigo. They have also some cerebralvasodilator effect. They have been prescribed in the hope that they may help otherinner ears related symptoms along with vertigo.
VASODILATOR DRUGS
Nictoinic acid (Hexopal; 500mg tablets, Ronicol; 500mg tablets)Naftidrofuril oxalate (Praxilene) 100mg capsulesBetahistine Hydrocholoride (Serc) 8 and 16mg tablets.
These drugs are used to improve cerebral circulation as vasodilators. Betahistine hasbeen promoted as a specific treatment for Meniere's disease claiming to improve thelabyrinthine circulation. In some patients the severity and frequency of vertiginousattacks are reduced, however its effect on tinnitus is not certain.
CALCIUM CHANNEL BLOCKERS
Based on the knowledge that i) extra and intracellular calcium concentration is ofcritical importance for sound transduction, ii) drug induced tinnitus can be attenuatedby providing the subject with an extragenous calcium supplement and iii) L-typecalcium channel blockers are effective in alleviating drug induced tinnitus(Jastreboff, 1995) an L-type calcium channel blocker, Nipodipine has been a goodcandidate for drug trial.
Davies et al. (1994) found in an 8 week trial that 5 of 31 patients reported greatimprovement, 2 found worsening of tinnitus. Four of those with improvement intheir tinnitus continued a further 4 weeks of the drug, minimum masking levelmeasures showed reduction in their tinnitus. Further research is required beforeconclusions may be drawn concerning these data.
THE LOOP DIURETICS
Based on the knowledge that frusemide reduces the endocochlear potential, it wasthought that it may be suitable for the suppression of tinnitus. Although earlier trialsgave promising results, the study by Jayarajan and Coles (1993) showed that, when itis administered intravenously, tinnitus was reduced in half of the subjects. Howeverit did not appear to reduce tinnitus to a helpful degree when taken orally.
GINKGO BILOBA EXTRACTS
Ginkgo biloba is an extract from the leaves of the maidenhair tree, and is a herbalmedicine with a very long history. It has been promoted for the treatment of chroniccerebral vascular insufficiency and peripheral vascular disease. It is thought toimprove blood flow. It has also been used in the treatment of retinal disease andvertigo. Earlier reports on its effect on tinnitus were optimistic, however the studyby Holgers et al. in 1994 did not find grounds for this optimism. The interest in itspossible value for tinnitus treatment remains and a study is currently being conductedby Ewart Davies.
RECENTLY TRIED DRUGS WHICH TAKE THE
PATHOPHYSIOLOGICAL MECHANISMS OF TINNITUS INTO
CONSIDERATION

GAMMA AMINOBUTYRIC ACID (GABA) AGONISTS
Baclofen (Baclofen, Lioresal) 10mg tablets.
This is a selective GABA receptor drug. It is used for the treatment of trigeminalneuralgia and increased muscle tone and spasticity. L-Baclofen has been shown inanimals to have suppressing effects within the cochlear nucleus (Caspary et al. 1984,Szczepaniak and Moller, 1995). Baclofen appeared to hold promise for the treatmentof tinnitus. Recently Westerberg et al. (1996) made a double blind placebocontrolled study on the effect of baclofen on tinnitus and found that of the 32 patientsin the placebo group, 1 (3.4%) reported improvement and of the 31 subjects onbaclofen 3 (9.7%) reported improvement, no significance was found. Side effectssuch as confusion, drowsiness, dizziness and gastrointestinal upset were related to the drug. Despite this disappointing finding, the drug may have effects on themechanisms involved in tinnitus and further research is indicated.
PROSTAGLANDINS
Based on the knowledge that aspirin, some non-steroid anti-inflammatory drugs and
aminoglycoside antibiotics have toxic effects on the cochlea with resultant hearing
loss and tinnitus could partly be related to an alteration in the prostaglandin
mechanism in the cochlea, Briner et al. (1993) thought it would be worth trying a
synthetic prostaglandin E1 (Misoprostol) in the treatment of tinnitus. 8 of their 24
patients reported improvement during the active drug phase, together with
improvement in sleep and concentration. The researchers felt that this promising
result was worthy of further investigation.
DRUGS ACTING ON GLUTAMATE RECEPTORS
This is a drug used as a spasmolytic in some countries. It has also agonist effect onglutamate receptors in the cochlea. There is growing evidence that glutamate andglutamate receptor dysfunction is implicated in a wide range of inner ear diseasesincluding presbycusis, noise induced hearing loss, Meniere's disease and suddenhearing loss. Denk et al. (1997) based on their earlier clinical experience, carried outa single blind study on its effect on tinnitus. Caroverine is administered only byintravenous infusion. The authors investigated the immediate effects. They foundreduction in the tinnitus in 50% of the subjects. They concluded that the positiverespondents had tinnitus of cochlea origin and that caroverine is probably beneficialin these cases. It is impractical to use this drug for tinnitus treatment at the moment.
However it implies that in the future some drugs which can be taken orally and act onthe glutamate function would be efficacious. This knowledge stimulates furtherresearch.
CONCLUSION
Although one would not discount the possibility that a drug or drugs may be found torelieve tinnitus, as yet no safe, reliable drug to cure or consistently alleviate tinnitushas been found.
DRUG TREATMENT OF INNER EAR DISEASE ASSOCIATED WITH
TINNITUS

Meniere's disease
The pathology of Meniere's disease is endolymphatic hydrops. It is characterised bya)episodic attacks of vertigo, lasting from several minutes to hours, b)autonomicimbalance manifested by nausea/vomiting, c)fluctuating hearing loss, d)usually low-pitched tinnitus, e)sense of pressure/fullness in the ear. In many patients tinnitus ispresent between the attacks but it increases and may change in quality in associationwith the attacks.
There is no known specific drug treatment for Meniere's disease. Individual attacksare treated by drugs to alleviate vertigo, nausea and vomiting.
Diuretics, betahistine hydrochloride and a variety of other drugs have been used forthe purpose of reducing the frequency and severity of the attacks. The effectivenessof drug treatment is uncertain. Patient-management with counselling and eliminationof precipitating factors such as stress, possible dietary factors and high salt intakeappear the best way of helping the patient at present.
If there is constant tinnitus, the ideal approach is habituation with cognitive therapyor retraining therapy (consult audiologist).
Sudden deafness
This may or may not be associated with tinnitus or vertigo. Depending on the cause,vasodilators, corticosteroids, dextran perfusion or hyperbaric oxygen therapy, or acombination of any of these are used.
Autoimmune inner ear disease.
In the case of an inner ear malfunction associated or not associated with tinnitusthrough to be due to an autoimmune abnormality revealed by immunological studies,corticosteroid or immunosuppressant drug therapy is worth trying.
Syphilitic inner ear disease.
If diagnosis is certain it requires specific drug treatment.
TREATMENT OF CONDITIONS WHICH MAY BE CONTRIBUTING OR
AGGRAVATING FACTORS FOR TINNITUS

In some patients there may be extra-auditory factors contributing to the degree oremergence of tinnitus, e.g. hypothyroidism, anaemia, vitamin B12 and zincdeficiency, diabetes, hypoglycaemia, hypertension, hyperlipidaemia, food and drinkallergies, migraine etc. Their treatment may result in diminution of the tinnitus or atleast preventing it from becoming worse.
If the patient is on any known ototoxic medicine it should be discontinued unless themedicine is vitally important. Some patients may have individual susceptibility tocertain drugs, foods or drinks which aggravate their tinnitus and sensible counsellingwhich does not result in the patient becoming obsessive about food and drinks helps.
Reinstatement of sedative drugs or tranquilisers.
When suddenly discontinued, many patients may have a wide range of symptomsincluding emergence or aggravation of tinnitus. In Coles' experience, thereinstatement of the drug followed by very gradual withdrawal results in muchreduction or abolition of tinnitus (Coles, 1997).
MEDICAL TREATMENT OF SOMATOSOUNDS OR OBJECTIVE
TINNITUS

Spontaneous otoacoustic emissions (SOAEs) Tinnitus caused by SOAEs can be treated by aspirin or quinine. (Details inAppendix 6).
Clicking tinnitus caused by palatal or middle ear myoclonus This is a rare neurological condition in which the small muscles contractinvoluntarily in a quiet rhythmic fashion causing clicking noises. It has been shownthat injection of botulinum toxin to the palatal muscle is effective (Saaed and Brooke,1993). Additionally, training in deep relaxation techniques and counselling re stressrelated issues is highly beneficial and strongly recommended.
If this is caused by anaemia or hypertension drug treatment of these may be effective.
If it is caused by intracranial vascular malformation or occlusive cranial vasculardisease the treatment approach would be surgical.
It is reported that tinnitus caused by somatosounds are amenable to habituation andthis may be assisted by retraining therapy (Jastreboff and Hazell, 1993).
MEDICAL MANAGEMENT OF ASSOCIATED OR CONSEQUENTIAL
PROBLEMS WITH TINNITUS

In a considerable proportion of patients the actual perception of the tinnitus sound isprobably less troublesome than the accompanying emotional and autonomicconsequences and the functional effects on day to day life such as sleeplessness,fatigue, difficulties with concentration and memory lapses. These can be moredeleterious to the individual than the noxious experience of tinnitus. These effectsmay occur whether or not the individual makes negative attributes to tinnitus, butnegative attributions impede habituation to tinnitus. Drug treatments for tinnitusneed, in order to be effective, to take into consideration these problems which peopleexperience with tinnitus.
Before being seen in the tinnitus clinic many patients are put on sedative/hypnoticdrugs for their insomnia. It is important to be circumspect in prescribing these drugs,and they should only be given for reasonably short periods. It is advisable to providereasonable counselling for methods of combating insomnia without drugs.
Association of anxiety and/or depression with tinnitus may be a two-wayrelationship, the causal direction is usually difficult to discern. If the condition is sosevere as to be unable to benefit from counselling or professional psychologicalsupport, tranquilisers or antidepressants may be given careful consideration. It isbest to cooperate/consult with psychologist and psychiatrist.
STIMULATORY OR PHYSICAL METHODS IN THE TREATMENT OF
TINNITUS

These are treatment methods which aim to influence or affect the auditory system inways which can rectify or modify its dysfunctional state in order to abolish oralleviate tinnitus. The following is a list of these methods of treatment: Magnetic stimulationUltrasonic stimulationLow intensity laser applicationTranscutaneous electrical nerve stimulation (TENS)AcupunctureHyperbaric oxygen therapyTreatment of temporo-mandibular joint and myo-facial disorders The above methods are beneficial in some patients but they are all open to furtherresearch and development.
Thank you to the Institute of Hearing Research, Nottingham England for permissionto use the above on the properties and uses of various medications.

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