Additional Information and References for Physicians (Page 1)

Based upon the hypothesized etiology of tinnitus some of the possible targets for direct therapy are: (1) voltage-gated Na+ channels, which are responsible for both neuronal firing and neurotransmitter release, (2) voltage-gated Ca++ channels responsible for neurotransmitter release, (3) GABAA receptor-linked chloride channels, which inhibit neuronal firing (4) ionotropic glutamate receptors, including N-methyl-D-aspartate (NMDA) and the non-NMDA receptors, α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) and kainate receptors.  Those drugs that have provided tinnitus relief in well controlled trials generally act at one or more of these receptors and ion channels.  More specifically: (1) Na+ channels: lidocaine,24-27 and tocainide24 target voltage-gated Na+ channels.  The effect of lidocaine is short-lived and directly correlated to blood levels.26 Tocainide is also effective when administered by injection, but far less so after oral administration.24,25,27  Anticonvulsants, such as phenytoin and carbamazepine also modulate Na+ channels28 and have been used with limited success to treat tinnitus29,30.  (2) Ca++ channels: gabapentin31  and the related drug pregabalin are also anticonvulsants, but they interact with the  a2d subunit of Ca++ receptors and have been shown to reduce glutamate release.32-35  Both of these drugs are also effective at treating neuropathic pain, supporting the hypothesis that there is a similar pathophysiology underlying tinnitus and neuropathic pain.  (3) GABA receptors:  Alprazolam and other benzodiazepines enhance inhibitory GABAergic signals acting as positive allosteric modulators to increase the affinity of GABAA receptors for GABA.36,37 (4) Glutamate receptors:  Caroverine38,39 blocks both AMPA and NMDA receptors, but has higher affinity for AMPA receptors. Memantine is intended to treat Alzheimer’s disease, but is a selective NMDA receptor antagonist.9,40 which has some efficacy in treatment of tinnitus.44  Although memantine provides benefit from tinnitus when administered by infusion, it is far less effective orally (unpublished results).
 

References

24.  Lenarz T (1986) Treatment of tinnitus with lidocaine and tocainide, Scan Audiol Suppl 26:49-51.

25.  Lenarz T, Gulzow J (1985) Tinnitus therapy with lidocaine and tocainide, Laryngol Rhinol Otol (Stuttg) 64:604-608.

26.  Perucca E, Jackson P (1985) A controlled study of the suppression of tinnitus by lidocaine infusion: (relationship of therapeutic effect with serum lidocaine levels), J Laryngol Otol 99:657-661.

27.  Hulshof JH, Vermeij P (1985) The value of tocainide in the treatment of tinnitus.  A double-blind controlled study, Arch Otorhinolaryngol 241:279-283.

28.  Rogawski MA, Löscher W (2004) The neurobiology of antiepileptic drugs, Nat Rev Neurosci 5:553-564.

30. Hulshof JH, Vermeij P (1985) The value of carbamazepine in the treatment of tinnitus, ORL J Otorhinolaryngol Relat Spec 47:262-266.

29. Tatemoto K (1990) Clinical and electrophysiological investigations of the influence of phenytoin natrium on tinnitus, Nippon Jibiinkoka Gakkai Kaiho 93:256-67.

31.  Goldstein BA, Shulman A (2003) Tinnitus outcome profile and tinnitus control, Int TinnituJ 9:26-31.

32.  Stahl SM (2004) Anticonvulsants and relief of chronic pain: pregabalin and gabapentin as alpha(2)delta ligands at voltage-gated calcium channels, J Clin Psychiatry 65:596-597.

33.  Schwarz JB, Gibbons SE, Graham SR, Colbry NL, Guzzo PR, Le VD, Vartanian MG, Kinsora JJ, Letarski SM, Li Z, Dikerson MR, Su TZ, Weber ML, El-Kattan A, Thorpe AJ, Donevan SD, Taylor CP, Wustrow DJ (2005) Novel cyclopropyl beta-amino acid analogues of pregabalin and gabapentin that target the alpha2-delta protein, J Med Chem 48:3026-3035.

34.  Czuczwar SJ, Patsalos PN (2001) The new generation of GABA enhancers. Potential in the treatment of epilepsy, CNS Drugs 15:339-350.

35.  Taylor CP (1997) Mechanisms of action of gabapentin, Rev Neurol (Paris) 153 Suppl 1:S39-S45.

36.  Galici R, Pinna G, Stephens DN, Schneider HH, Turski L (1998) Tolerance to and dependence on Alprazolam are due to changes in GABAA receptor function and are independent of exposure to experimental set-up, Restor Neurol Neurosci 12:233-237.

37.  Costa E (1998) From GABAA receptor diversity emerges a unified vision of GABAergic inhibition, Annu Rev Pharmacol Toxicol 38:321-350.

38.  Denk DM, Heinzl H, Franz P, Ehrenberger K (1997) Caroverine in tinnitus treatment.  A placebo-controlled blind study, Acta Otolaryngol 117:825-830.

39.  Ehrenberger K, Felix D (1996) Use of 1-(aminoalkyl)-3-(benzyl)-quinoxaline-2-one derivatives for the preparation of neuroprotective compositions, US Patent No. 5,563,140.

40.  Oestreicher E, Arnold W, Ehrenberger K, Felix D (1999) New approaches for inner-ear therapy with glutamate antagonists, Acta Oto-Laryngologica 119:174-178.

44.  Zenner HP, Ruppersberg JP, Busch A (2000) Method for treating diseases of the inner ear using adamantane derivatives, US Patent No. 6,066,652.