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Annual Review of Pharmacology and Toxicology

Volume 59, 2019

Therapeutic Approaches to the Treatment of Tinnitus

Abstract

Tinnitus is a highly prevalent condition that is associated with hearing loss in most cases. In the absence of external stimuli, phantom perceptions of sounds emerge from alterations in neuronal activity within central auditory and nonauditory structures. Pioneering studies using lidocaine revealed that tinnitus is susceptible to pharmacological interventions. However, lidocaine is not effective in all patients, and no other drug has been identified with clear efficacy for the long-term treatment of tinnitus. In this review, we present recent advances in tinnitus research, including more detailed knowledge of its pathophysiology and involved neurotransmitter systems. Moreover, we summarize results from animal and clinical treatment studies as well as from studies that identified tinnitus as a side effect of pharmacological treatments. Finally, we focus on challenges in the development of pharmacological compounds for the treatment of tinnitus, namely the limitations of available animal models and of standardized clinical research methodologies.

Keyword(s): hearing loss, neural networks, phantom sound, plasticity, tinnitus
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2019-01-06
2024-04-23
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Literature Cited

  1. 1.  Moller AR 2007. Tinnitus: presence and future. Prog. Brain Res. 166:3–16
     [Google Scholar]
  2. 2.  Jastreboff PJ 1990. Phantom auditory perception (tinnitus): mechanisms of generation and perception. Neurosci. Res. 8:221–54
     [Google Scholar]
  3. 3.  De Ridder D, Elgoyhen AB, Romo R, Langguth B 2011. Phantom percepts: tinnitus and pain as persisting aversive memory networks. PNAS 108:8075–80
     [Google Scholar]
  4. 4.  Elgoyhen AB, Langguth B, De Ridder D, Vanneste S 2015. Tinnitus: perspectives from human neuroimaging. Nat. Rev. Neurosci. 16:632–42
     [Google Scholar]
  5. 5.  Norena A, Micheyl C, Chéry-Croze S, Collet L 2002. Psychoacoustic characterization of the tinnitus spectrum: implications for the underlying mechanisms of tinnitus. Audiol. Neurootol. 7:358–69
     [Google Scholar]
  6. 6.  Tang J, Ji B, Liu L 2011. [Study of hearing loss in 200 patients with subjective tinnitus]. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 25:726–29
     [Google Scholar]
  7. 7.  Schaette R, McAlpine D 2011. Tinnitus with a normal audiogram: physiological evidence for hidden hearing loss and computational model. J. Neurosci. 31:13452–57
     [Google Scholar]
  8. 8.  Schecklmann M, Landgrebe M, Langguth B 2014. Phenotypic characteristics of hyperacusis in tinnitus. PLOS ONE 9:e86944
     [Google Scholar]
  9. 9.  Muller K, Edvall NK, Idrizbegovic E, Huhn R, Cima R et al. 2016. Validation of online versions of tinnitus questionnaires translated into Swedish. Front. Aging Neurosci. 8:272
     [Google Scholar]
  10. 10.  Zeng FG 2013. An active loudness model suggesting tinnitus as increased central noise and hyperacusis as increased nonlinear gain. Hear. Res. 295:172–79
     [Google Scholar]
  11. 11.  Langguth B, Kreuzer PM, Kleinjung T, De Ridder D 2013. Tinnitus: causes and clinical management. Lancet Neurol 12:920–30
     [Google Scholar]
  12. 12.  Gallus S, Lugo A, Garavello W, Bosetti C, Santoro E et al. 2015. Prevalence and determinants of tinnitus in the Italian adult population. Neuroepidemiology 45:12–19
     [Google Scholar]
  13. 13.  McCormack A, Edmondson-Jones M, Somerset S, Hall D 2016. A systematic review of the reporting of tinnitus prevalence and severity. Hear. Res. 337:70–79
     [Google Scholar]
  14. 14.  Nondahl DM, Cruickshanks KJ, Huang GH, Klein BE, Klein R et al. 2012. Generational differences in the reporting of tinnitus. Ear Hear 33:640–44
     [Google Scholar]
  15. 15.  Axelsson A, Ringdahl A 1989. Tinnitus—a study of its prevalence and characteristics. Br. J. Audiol. 23:53–62
     [Google Scholar]
  16. 16.  Langguth B 2011. A review of tinnitus symptoms beyond ‘ringing in the ears’: a call to action. Curr. Med. Res. Opin. 27:1635–43
     [Google Scholar]
  17. 17.  Hebert S, Canlon B, Hasson D 2012. Emotional exhaustion as a predictor of tinnitus. Psychother. Psychosom. 81:324–26
     [Google Scholar]
  18. 18.  Kim HJ, Lee HJ, An SY, Sim S, Park B et al. 2015. Analysis of the prevalence and associated risk factors of tinnitus in adults. PLOS ONE 10:e0127578
     [Google Scholar]
  19. 19.  Hoare DJ, Edmondson-Jones M, Sereda M, Akeroyd MA, Hall D 2014. Amplification with hearing aids for patients with tinnitus and co-existing hearing loss. Cochrane Database Syst. Rev. 1:CD010151
     [Google Scholar]
  20. 20.  Hobson J, Chisholm E, El Refaie A 2012. Sound therapy (masking) in the management of tinnitus in adults. Cochrane Database Syst. Rev. 11:CD006371
     [Google Scholar]
  21. 21.  Baldo P, Doree C, Molin P, McFerran D, Cecco S 2012. Antidepressants for patients with tinnitus. Cochrane Database Syst. Rev. 9:CD003853
     [Google Scholar]
  22. 22.  Hilton MP, Zimmermann EF, Hunt WT 2013. Ginkgo biloba for tinnitus. Cochrane Database Syst. Rev. 3:CD003852
     [Google Scholar]
  23. 23.  Hoekstra CE, Rynja SP, van Zanten GA, Rovers MM 2011. Anticonvulsants for tinnitus. Cochrane Database Syst. Rev. 7:CD007960
     [Google Scholar]
  24. 24.  Bennett MH, Kertesz T, Perleth M, Yeung P, Lehm JP 2012. Hyperbaric oxygen for idiopathic sudden sensorineural hearing loss and tinnitus. Cochrane Database Syst. Rev. 10:CD004739
     [Google Scholar]
  25. 25.  Park J, White AR, Ernst E 2000. Efficacy of acupuncture as a treatment for tinnitus: a systematic review. Arch. Otolaryngol. Head Neck Surg. 126:489–92
     [Google Scholar]
  26. 26.  Meng Z, Liu S, Zheng Y, Phillips JS 2011. Repetitive transcranial magnetic stimulation for tinnitus. Cochrane Database Syst. Rev. 10:CD007946
     [Google Scholar]
  27. 27.  Hesser H, Weise C, Westin VZ, Andersson G 2011. A systematic review and meta-analysis of randomized controlled trials of cognitive-behavioral therapy for tinnitus distress. Clin. Psychol. Rev. 31:545–53
     [Google Scholar]
  28. 28.  Vio MM, Holme RH 2005. Hearing loss and tinnitus: 250 million people and a US$10 billion potential market. Drug Discov. Today 10:1263–65
     [Google Scholar]
  29. 29.  Cima RF, Maes IH, Joore MA, Scheyen DJ, El Refaie A et al. 2012. Specialised treatment based on cognitive behaviour therapy versus usual care for tinnitus: a randomised controlled trial. Lancet 379:1951–59
     [Google Scholar]
  30. 30.  Kreuzer PM, Vielsmeier V, Langguth B 2013. Chronic tinnitus: an interdisciplinary challenge. Dtsch. Arztebl. Int. 110:278–84
     [Google Scholar]
  31. 31.  Wilson BS, Tucci DL, Merson MH, O'Donoghue GM 2017. Global hearing health care: new findings and perspectives. Lancet 390:2503–15
     [Google Scholar]
  32. 32.  Cederroth CR, Canlon B, Langguth B 2013. Hearing loss and tinnitus—Are funders and industry listening?. Nat. Biotechnol. 31:972–74
     [Google Scholar]
  33. 33.  Kaltenbach JA, Zacharek MA, Zhang J, Frederick S 2004. Activity in the dorsal cochlear nucleus of hamsters previously tested for tinnitus following intense tone exposure. Neurosci. Lett. 355:121–25
     [Google Scholar]
  34. 34.  Engineer ND, Riley JR, Seale JD, Vrana WA, Shetake JA et al. 2011. Reversing pathological neural activity using targeted plasticity. Nature 470:101–4
     [Google Scholar]
  35. 35.  Basura GJ, Koehler SD, Shore SE 2015. Bimodal stimulus timing-dependent plasticity in primary auditory cortex is altered after noise exposure with and without tinnitus. J. Neurophysiol. 114:63064–75
     [Google Scholar]
  36. 36.  Wu C, Martel DT, Shore SE 2016. Increased synchrony and bursting of dorsal cochlear nucleus fusiform cells correlate with tinnitus. J. Neurosci. 36:2068–73
     [Google Scholar]
  37. 37.  Bauer CA, Turner JG, Caspary DM, Myers KS, Brozoski TJ 2008. Tinnitus and inferior colliculus activity in chinchillas related to three distinct patterns of cochlear trauma. J. Neurosci. Res. 86:2564–78
     [Google Scholar]
  38. 38.  Kalappa BI, Brozoski TJ, Turner JG, Caspary DM 2014. Single unit hyperactivity and bursting in the auditory thalamus of awake rats directly correlates with behavioural evidence of tinnitus. J. Physiol. 592:5065–78
     [Google Scholar]
  39. 39.  Norena AJ, Eggermont JJ 2006. Enriched acoustic environment after noise trauma abolishes neural signs of tinnitus. Neuroreport 17:559–63
     [Google Scholar]
  40. 40.  Norena AJ, Eggermont JJ 2003. Changes in spontaneous neural activity immediately after an acoustic trauma: implications for neural correlates of tinnitus. Hear. Res. 183:137–53
     [Google Scholar]
  41. 41.  Wang H, Brozoski TJ, Turner JG, Ling L, Parrish JL et al. 2009. Plasticity at glycinergic synapses in dorsal cochlear nucleus of rats with behavioral evidence of tinnitus. Neuroscience 164:747–59
     [Google Scholar]
  42. 42.  Zeng C, Nannapaneni N, Zhou J, Hughes LF, Shore S 2009. Cochlear damage changes the distribution of vesicular glutamate transporters associated with auditory and nonauditory inputs to the cochlear nucleus. J. Neurosci. 29:4210–17
     [Google Scholar]
  43. 43.  Zeng C, Yang Z, Shreve L, Bledsoe S, Shore S 2012. Somatosensory projections to cochlear nucleus are upregulated after unilateral deafness. J. Neurosci. 32:15791–801
     [Google Scholar]
  44. 44.  Yang S, Weiner BD, Zhang LS, Cho SJ, Bao S 2011. Homeostatic plasticity drives tinnitus perception in an animal model. PNAS 108:14974–79
     [Google Scholar]
  45. 45.  Shore SE, Roberts LE, Langguth B 2016. Maladaptive plasticity in tinnitus—triggers, mechanisms and treatment. Nat. Rev. Neurol. 12:150–60
     [Google Scholar]
  46. 46.  Tzounopoulos T, Rubio ME, Keen JE, Trussell LO 2007. Coactivation of pre- and postsynaptic signaling mechanisms determines cell-specific spike-timing-dependent plasticity. Neuron 54:291–301
     [Google Scholar]
  47. 47.  De Ridder D, Vanneste S, Langguth B, Llinas R 2015. Thalamocortical dysrhythmia: a theoretical update in tinnitus. Front. Neurol. 6:124
     [Google Scholar]
  48. 48.  Levine RA 1999. Somatic (craniocervical) tinnitus and the dorsal cochlear nucleus hypothesis. Am. J. Otolaryngol. 20:351–62
     [Google Scholar]
  49. 49.  Levine RA, Abel M, Cheng H 2003. CNS somatosensory-auditory interactions elicit or modulate tinnitus. Exp. Brain Res. 153:643–48
     [Google Scholar]
  50. 50.  Marks KL, Martel DT, Wu C, Basura GJ, Roberts LE et al. 2018. Auditory-somatosensory bimodal stimulation desynchronizes brain circuitry to reduce tinnitus in guinea pigs and humans. Sci. Transl. Med. 10:eaal3175
     [Google Scholar]
  51. 51.  D'Arcy S, Hamilton C, Hughes S, Hall DA, Vanneste S et al. 2017. Bi-modal stimulation in the treatment of tinnitus: a study protocol for an exploratory trial to optimise stimulation parameters and patient subtyping. BMJ Open 7:e018465
     [Google Scholar]
  52. 52.  Adjamian P, Hall DA, Palmer AR, Allan TW, Langers DR 2014. Neuroanatomical abnormalities in chronic tinnitus in the human brain. Neurosci. Biobehav. Rev. 45:119–33
     [Google Scholar]
  53. 53.  Vanneste S, De Ridder D 2012. The auditory and non-auditory brain areas involved in tinnitus. An emergent property of multiple parallel overlapping subnetworks. Front. Syst. Neurosci. 6:31
     [Google Scholar]
  54. 54.  De Ridder D, Vanneste S, Weisz N, Londero A, Schlee W et al. 2014. An integrative model of auditory phantom perception: tinnitus as a unified percept of interacting separable subnetworks. Neurosci. Biobehav. Rev. 44:16–32
     [Google Scholar]
  55. 55.  Vanneste S, van Dongen M, De Vree B, Hiseni S, van der Velden E et al. 2013. Does enriched acoustic environment in humans abolish chronic tinnitus clinically and electrophysiologically? A double blind placebo controlled study. Hear. Res. 296:141–48
     [Google Scholar]
  56. 56.  Maudoux A, Lefebvre P, Cabay JE, Demertzi A, Vanhaudenhuyse A et al. 2012. Auditory resting-state network connectivity in tinnitus: a functional MRI study. PLOS ONE 7:e36222
     [Google Scholar]
  57. 57.  Schlee W, Hartmann T, Langguth B, Weisz N 2009. Abnormal resting-state cortical coupling in chronic tinnitus. BMC. Neurosci. 10:11
     [Google Scholar]
  58. 58.  Boly M, Faymonville ME, Peigneux P, Lambermont B, Damas P et al. 2004. Auditory processing in severely brain injured patients: differences between the minimally conscious state and the persistent vegetative state. Arch. Neurol. 61:233–38
     [Google Scholar]
  59. 59.  Vanneste S, Plazier M, der Loo E, Van de Heyning P, Congedo M, De Ridder D 2010. The neural correlates of tinnitus-related distress. Neuroimage 52:470–80
     [Google Scholar]
  60. 60.  Trellakis S, Lautermann J, Lehnerdt G 2007. Lidocaine: neurobiological targets and effects on the auditory system. Prog. Brain Res. 166:303–22
     [Google Scholar]
  61. 61.  Israel JM, Connelly JS, McTigue ST, Brummett RE, Brown J 1982. Lidocaine in the treatment of tinnitus aurium. A double-blind study. Arch. Otolaryngol. 108:471–73
     [Google Scholar]
  62. 62.  Gil-Gouveia R, Goadsby PJ 2009. Neuropsychiatric side-effects of lidocaine: examples from the treatment of headache and a review. Cephalalgia 29:496–508
     [Google Scholar]
  63. 63.  Puel JL, Ruel J, Guitton M, Pujol R 2002. The inner hair cell afferent/efferent synapses revisited: a basis for new therapeutic strategies. Adv. Otorhinolaryngol. 59:124–30
     [Google Scholar]
  64. 64.  Kujawa SG, Liberman MC 2015. Synaptopathy in the noise-exposed and aging cochlea: primary neural degeneration in acquired sensorineural hearing loss. Hear. Res. 330:191–99
     [Google Scholar]
  65. 65.  Lynch ED, Kil J 2005. Compounds for the prevention and treatment of noise-induced hearing loss. Drug Discov. Today 10:1291–98
     [Google Scholar]
  66. 66.  Attias J, Weisz G, Almog S, Shahar A, Wiener M et al. 1994. Oral magnesium intake reduces permanent hearing loss induced by noise exposure. Am. J. Otolaryngol. 15:26–32
     [Google Scholar]
  67. 67.  Lin CY, Wu JL, Shih TS, Tsai PJ, Sun YM et al. 2010. N-Acetyl-cysteine against noise-induced temporary threshold shift in male workers. Hear. Res. 269:42–47
     [Google Scholar]
  68. 68.  Kramer S, Dreisbach L, Lockwood J, Baldwin K, Kopke R et al. 2006. Efficacy of the antioxidant N-acetylcysteine (NAC) in protecting ears exposed to loud music. J. Am. Acad. Audiol. 17:265–78
     [Google Scholar]
  69. 69.  Dolgin E 2012. Sound medicine. Nat. Med. 18:642–45
     [Google Scholar]
  70. 70.  Shim HJ, Song SJ, Choi AY, Hyung LR, Yoon SW 2011. Comparison of various treatment modalities for acute tinnitus. Laryngoscope 121:2619–25
     [Google Scholar]
  71. 71.  Lavigne P, Lavigne F, Saliba I 2016. Intratympanic corticosteroids injections: a systematic review of literature. Eur. Arch. Otorhinolaryngol. 273:2271–78
     [Google Scholar]
  72. 72.  Lee HJ, Kim MB, Yoo SY, Park SN, Nam EC et al. 2018. Clinical effect of intratympanic dexamethasone injection in acute unilateral tinnitus: a prospective, placebo-controlled, multicenter study. Laryngoscope 128:184–88
     [Google Scholar]
  73. 73.  Guitton MJ, Wang J, Puel JL 2004. New pharmacological strategies to restore hearing and treat tinnitus. Acta Otolaryngol 124:411–15
     [Google Scholar]
  74. 74.  Muehlmeier G, Biesinger E, Maier H 2011. Safety of intratympanic injection of AM-101 in patients with acute inner ear tinnitus. Audiol. Neurootol. 16:388–97
     [Google Scholar]
  75. 75.  Staecker H, Morelock M, Kramer T, Chrbolka P, Ahn JH, Meyer T 2017. Safety of repeated-dose intratympanic injections with AM-101 in acute inner ear tinnitus. Otolaryngol. Head Neck Surg. 157:478–87
     [Google Scholar]
  76. 76.  Langguth B, Landgrebe M, Kleinjung T, Sand GP, Hajak G 2011. Tinnitus and depression. World J. Biol. Psychiatry 12:489–500
     [Google Scholar]
  77. 77.  Sullivan MD, Dobie RA, Sakai CS, Katon WJ 1989. Treatment of depressed tinnitus patients with nortriptyline. Ann. Otol. Rhinol. Laryngol. 98:867–72
     [Google Scholar]
  78. 78.  Sullivan M, Katon W, Russo J, Dobie R, Sakai C 1993. A randomized trial of nortriptyline for severe chronic tinnitus. Effects on depression, disability, and tinnitus symptoms. Arch. Intern. Med. 153:2251–59
     [Google Scholar]
  79. 79.  Katon W, Sullivan M, Russo J, Dobie R, Sakai C 1993. Depressive symptoms and measures of disability: a prospective study. J. Affect. Disord. 27:245–54
     [Google Scholar]
  80. 80.  Bayar N, Boke B, Turan E, Belgin E 2001. Efficacy of amitriptyline in the treatment of subjective tinnitus. J. Otolaryngol. 30:300–3
     [Google Scholar]
  81. 81.  Mihail RC, Crowley JM, Walden BE, Fishburne J, Reinwall JE, Zajtchuk JT 1988. The tricyclic trimipramine in the treatment of subjective tinnitus. Ann. Otol. Rhinol. Laryngol. 97:120–23
     [Google Scholar]
  82. 82.  Zoger S, Svedlund J, Holgers KM 2006. The effects of sertraline on severe tinnitus suffering—a randomized, double-blind, placebo-controlled study. J. Clin. Psychopharmacol. 26:32–39
     [Google Scholar]
  83. 83.  Robinson SK, Viirre ES, Bailey KA, Gerke MA, Harris JP, Stein MB 2005. Randomized placebo-controlled trial of a selective serotonin reuptake inhibitor in the treatment of nondepressed tinnitus subjects. Psychosom. Med. 67:981–88
     [Google Scholar]
  84. 84.  Roberts C, Inamdar A, Koch A, Kitchiner P, Dewit O et al. 2011. A randomized, controlled study comparing the effects of vestipitant or vestipitant and paroxetine combination in subjects with tinnitus. Otol. Neurotol. 32:721–27
     [Google Scholar]
  85. 85.  Hwang SM, Lim SH, Oh DJ, Kim SK, Jung HH, Im GJ 2016. Effect of tianeptine on depressed tinnitus patients. J. Audiol. Otol. 20:90–96
     [Google Scholar]
  86. 86.  Elgoyhen AB, Langguth B, Nowak W, Schecklmann M, De Ridder D Vanneste S 2014. Identifying tinnitus-related genes based on a side-effect network analysis. CPT Pharmacometr. Syst. Pharmacol. 3:e97
     [Google Scholar]
  87. 87.  Johnson RM, Brummett R, Schleuning A 1993. Use of alprazolam for relief of tinnitus. A double-blind study. Arch. Otolaryngol. Head Neck Surg. 119:842–45
     [Google Scholar]
  88. 88.  Jalali MM, Kousha A, Naghavi SE, Soleimani R, Banan R 2009. The effects of alprazolam on tinnitus: a cross-over randomized clinical trial. Med. Sci. Monit. 15:PI55–60
     [Google Scholar]
  89. 89.  Kay NJ 1981. Oral chemotherapy in tinnitus. Br. J. Audiol. 15:123–24
     [Google Scholar]
  90. 90.  Bahmad FM Jr., Venosa AR, Oliveira CA 2006. Benzodiazepines and GABAergics in treating severe disabling tinnitus of predominantly cochlear origin. Int. Tinnitus J. 12:140–44
     [Google Scholar]
  91. 91.  Han SS, Nam EC, Won JY, Lee KU, Chun W et al. 2012. Clonazepam quiets tinnitus: a randomised crossover study with Ginkgo biloba. J. Neurol. Neurosurg. . Psychiatry 83:821–27
     [Google Scholar]
  92. 92.  Jufas NE, Wood R 2015. The use of benzodiazepines for tinnitus: systematic review. J. Laryngol. Otol. 129:Suppl. 3S14–22
     [Google Scholar]
  93. 93.  Busto U, Fornazzari L, Naranjo CA 1988. Protracted tinnitus after discontinuation of long-term therapeutic use of benzodiazepines. J. Clin. Psychopharmacol. 8:359–62
     [Google Scholar]
  94. 94.  Sanchez TG, Balbani AP, Bittar RS, Bento RF, Camara J 1999. Lidocaine test in patients with tinnitus: rationale of accomplishment and relation to the treatment with carbamazepine. Auris Nasus Larynx 26:411–17
     [Google Scholar]
  95. 95.  Hulshof JH, Vermeij P 1985. The value of carbamazepine in the treatment of tinnitus. ORL J. Otorhinolaryngol. Relat. Spec. 47:262–66
     [Google Scholar]
  96. 96.  Mardini MK 1987. Ear-clicking “tinnitus” responding to carbamazepine. N. Engl. J. Med. 317:1542
     [Google Scholar]
  97. 97.  Bauer CA, Brozoski TJ 2001. Assessing tinnitus and prospective tinnitus therapeutics using a psychophysical animal model. J. Assoc. Res. Otolaryngol. 2:54–64
     [Google Scholar]
  98. 98.  Bauer CA, Brozoski TJ 2006. Effect of gabapentin on the sensation and impact of tinnitus. Laryngoscope 116:675–81
     [Google Scholar]
  99. 99.  Dehkordi MA, Abolbashari S, Taheri R, Einolghozati S 2011. Efficacy of gabapentin on subjective idiopathic tinnitus: a randomized, double-blind, placebo-controlled trial. Ear Nose Throat J 90:150–58
     [Google Scholar]
  100. 100.  Piccirillo JF, Finnell J, Vlahiotis A, Chole RA, Spitznagel E Jr 2007. Relief of idiopathic subjective tinnitus: Is gabapentin effective?. Arch. Otolaryngol. Head Neck Surg. 133:390–97
     [Google Scholar]
  101. 101.  Simpson JJ, Gilbert AM, Weiner GM, Davies WE 1999. The assessment of lamotrigine, an antiepileptic drug, in the treatment of tinnitus. Am. J. Otol. 20:627–31
     [Google Scholar]
  102. 102.  Kalappa BI, Soh H, Duignan KM, Furuya T, Edwards S et al. 2015. Potent KCNQ2/3-specific channel activator suppresses in vivo epileptic activity and prevents the development of tinnitus. J. Neurosci. 35:8829–42
     [Google Scholar]
  103. 103.  Kumar M, Reed N, Liu R, Aizenman E, Wipf P, Tzounopoulos T 2016. Synthesis and evaluation of potent KCNQ2/3-specific channel activators. Mol. Pharmacol. 89:667–77
     [Google Scholar]
  104. 104.  Langguth B, Elgoyhen AB, Schlee W 2016. Potassium channels as promising new targets for pharmacologic treatment of tinnitus: Can Internet-based ‘crowd sensing’ initiated by patients speed up the transition from bench to bedside?. Expert Opin. Ther. Targets 20:251–54
     [Google Scholar]
  105. 105.  Domeisen H, Hotz MA, Hausler R 1998. Caroverine in tinnitus treatment. Acta Otolaryngol 118:606–8
     [Google Scholar]
  106. 106.  Denk DM, Heinzl H, Franz P, Ehrenberger K 1997. Caroverine in tinnitus treatment. A placebo-controlled blind study. Acta Otolaryngol 117:825–30
     [Google Scholar]
  107. 107.  de Azevedo AA, Figueiredo RR 2007. Treatment of tinnitus with acamprosate. Prog. Brain Res. 166:273–77
     [Google Scholar]
  108. 108.  Sharma DK, Kaur S, Singh J, Kaur I 2012. Role of acamprosate in sensorineural tinnitus. Indian J. Pharmacol. 44:93–96
     [Google Scholar]
  109. 109.  Figueiredo RR, Langguth B, de Oliveira PM, de Azevedo AA 2008. Tinnitus treatment with memantine. Otolaryngol. Head Neck Surg. 138:492–96
     [Google Scholar]
  110. 110.  Suckfüll M, Althaus M, Ellers-Lenz B, Gebauer A, Goertelmeyer R et al. 2011. A randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of neramexane in patients with moderate to severe subjective tinnitus. BMC Ear Nose Throat Disord 11:1
     [Google Scholar]
  111. 111.  Yu H, Vikhe Patil K, Han C, Fabella B, Canlon B et al. 2016. GLAST deficiency in mice exacerbates gap detection deficits in a model of salicylate-induced tinnitus. Front. Behav. Neurosci. 10:158
     [Google Scholar]
  112. 112.  Lopez-Gonzalez MA, Moliner-Peiro F, Alfaro-Garcia J, Esteban-Ortega F 2007. Sulpiride plus hydroxy-zine decrease tinnitus perception. Auris Nasus Larynx 34:23–27
     [Google Scholar]
  113. 113.  Lopez-Gonzalez MA, Santiago AM, Esteban-Ortega F 2007. Sulpiride and melatonin decrease tinnitus perception modulating the auditolimbic dopaminergic pathway. J. Otolaryngol. 36:213–19
     [Google Scholar]
  114. 114.  de Azevedo AA, Langguth B, de Oliveira PM, Figueiredo RR 2009. Tinnitus treatment with piribedil guided by electrocochleography and acoustic otoemisions. Otol. Neurotol. 30:676–80
     [Google Scholar]
  115. 115.  Sziklai I, Szilvassy J, Szilvassy Z 2011. Tinnitus control by dopamine agonist pramipexole in presbycusis patients: a randomized, placebo-controlled, double-blind study. Laryngoscope 121:888–93
     [Google Scholar]
  116. 116.  Szczepaniak WS, Moller AR 1996. Effects of (−)-baclofen, clonazepam, and diazepam on tone exposure-induced hyperexcitability of the inferior colliculus in the rat: possible therapeutic implications for pharmacological management of tinnitus and hyperacusis. Hear. Res. 97:46–53
     [Google Scholar]
  117. 117.  Westerberg BD, Roberson JB Jr., Stach BA 1996. A double-blind placebo-controlled trial of baclofen in the treatment of tinnitus. Am. J. Otol. 17:896–903
     [Google Scholar]
  118. 118.  Coelho C, Figueiredo R, Frank E, Burger J, Schecklmann M et al. 2012. Reduction of tinnitus severity by the centrally acting muscle relaxant cyclobenzaprine: an open-label pilot study. Audiol. Neurootol. 17:179–88
     [Google Scholar]
  119. 119.  Vanneste S, Figueiredo R, De Ridder D 2012. Treatment of tinnitus with cyclobenzaprine: an open-label study. Int. J. Clin. Pharmacol. Ther. 50:338–44
     [Google Scholar]
  120. 120.  Lobarinas E, Blair C, Spankovich C, Le Prell C 2015. Partial to complete suppression of unilateral noise-induced tinnitus in rats after cyclobenzaprine treatment. J. Assoc. Res. Otolaryngol. 16:263–72
     [Google Scholar]
  121. 121.  Darlington CL, Smith PF 2007. Drug treatments for tinnitus. Prog. Brain Res. 166:249–62
     [Google Scholar]
  122. 122.  Olzowy B, Canis M, Hempel JM, Mazurek B, Suckfüll M 2007. Effect of atorvastatin on progression of sensorineural hearing loss and tinnitus in the elderly: results of a prospective, randomized, double-blind clinical trial. Otol. Neurotol. 28:455–58
     [Google Scholar]
  123. 123.  Hameed MK, Sheikh ZA, Ahmed A, Najam A 2014. Atorvastatin in the management of tinnitus with hyperlipidemias. J. Coll. Phys. Surg. Pak. 24:927–30
     [Google Scholar]
  124. 124.  Sonmez O, Kulahli I, Vural A, Sahin MI, Aydin M 2013. The evaluation of ozone and betahistine in the treatment of tinnitus. Eur. Arch. Otorhinolaryngol. 270:1999–2006
     [Google Scholar]
  125. 125.  Hester TO, Theilman G, Green W, Jones RO 1998. Cyclandelate in the management of tinnitus: a randomized, placebo-controlled study. Otolaryngol. Head Neck Surg. 118:329–32
     [Google Scholar]
  126. 126.  Meeus O, De Ridder D, Van de Heyning P 2011. Administration of the combination clonazepam-Deanxit as treatment for tinnitus. Otol. Neurotol. 32:701–9
     [Google Scholar]
  127. 127.  Deleted in proof
  128. 128.  Miroddi M, Bruno R, Galletti F, Calapai F, Navarra M et al. 2015. Clinical pharmacology of melatonin in the treatment of tinnitus: a review. Eur. J. Clin. Pharmacol. 71:263–70
     [Google Scholar]
  129. 129.  Hurtuk A, Dome C, Holloman CH, Wolfe K, Welling DB et al. 2011. Melatonin: Can it stop the ringing?. Ann. Otol. Rhinol. Laryngol. 120:433–40
     [Google Scholar]
  130. 130.  Azevedo AA, Figueiredo RR, Elgoyhen AB, Langguth B, Penido NO, Schlee W 2017. Tinnitus treatment with oxytocin: a pilot study. Front. Neurol. 8:494
     [Google Scholar]
  131. 131.  Vanneste S, Azevedo A, De Ridder D 2013. The effect of naltrexone on the perception and distress in tinnitus: an open-label pilot study. Int. J. Clin. Pharmacol. Ther. 51:5–11
     [Google Scholar]
  132. 132.  Taslimi S, Vahidi H, Pourvaziri A, Modabbernia A, Fallah AY et al. 2013. Ondansetron in patients with tinnitus: randomized double-blind placebo-controlled study. Eur. Arch. Otorhinolaryngol. 270:1635–41
     [Google Scholar]
  133. 133.  Yilmaz I, Akkuzu B, Cakmak O, Ozluoglu LN 2004. Misoprostol in the treatment of tinnitus: a double-blind study. Otolaryngol. Head Neck Surg. 130:604–10
     [Google Scholar]
  134. 134.  Davies E, Knox E, Donaldson I 1994. The usefulness of nimodipine, an L-calcium channel antagonist, in the treatment of tinnitus. Br. J. Audiol. 28:125–29
     [Google Scholar]
  135. 135.  Lim HW, Kim TS, Kang WS, Song CI, Baek S, Chung JW 2016. Effect of a 4-week treatment with cilostazol in patients with chronic tinnitus: a randomized, prospective, placebo-controlled, double-blind, pilot study. J. Int. Adv. Otol. 12:170–76
     [Google Scholar]
  136. 136.  Mazurek B, Haupt H, Szczepek AJ, Sandmann J, Gross J et al. 2009. Evaluation of vardenafil for the treatment of subjective tinnitus: a controlled pilot study. J. Negat. Results Biomed. 8:3
     [Google Scholar]
  137. 137.  Smith PF, Zheng Y 2016. Cannabinoids, cannabinoid receptors and tinnitus. Hear. Res. 332:210–16
     [Google Scholar]
  138. 138.  Singh C, Kawatra R, Gupta J, Awasthi V, Dungana H 2016. Therapeutic role of vitamin B12 in patients of chronic tinnitus: a pilot study. Noise Health 18:93–97
     [Google Scholar]
  139. 139.  Berkiten G, Yildirim G, Topaloglu I, Ugras H 2013. Vitamin B12 levels in patients with tinnitus and effectiveness of vitamin B12 treatment on hearing threshold and tinnitus. B-ENT 9:111–16
     [Google Scholar]
  140. 140.  Person OC, Puga ME, da Silva EM, Torloni MR 2016. Zinc supplementation for tinnitus. Cochrane Database Syst. Rev. 11:CD009832
     [Google Scholar]
  141. 141.  Elgoyhen AB, Langguth B, Vanneste S, De Ridder D 2012. Tinnitus: network pathophysiology-network pharmacology. Front. Syst. Neurosci. 6:1
     [Google Scholar]
  142. 142.  Eggermont JJ 2016. Can animal models contribute to understanding tinnitus heterogeneity in humans?. Front. Aging Neurosci. 8:265
     [Google Scholar]
  143. 143.  Nicolas-Puel C, Akbaraly T, Lloyd R, Berr C, Uziel A et al. 2006. Characteristics of tinnitus in a population of 555 patients: specificities of tinnitus induced by noise trauma. Int. Tinnitus J. 12:64–70
     [Google Scholar]
  144. 144.  Jastreboff PJ, Brennan JF, Coleman JK, Sasaki CT 1988. Phantom auditory sensation in rats: an animal model for tinnitus. Behav. Neurosci. 102:811–22
     [Google Scholar]
  145. 145.  Turner JG 2007. Behavioral measures of tinnitus in laboratory animals. Prog. Brain Res. 166:147–56
     [Google Scholar]
  146. 146.  Moreno-Paublete R, Canlon B, Cederroth CR 2017. Differential neural responses underlying the inhibition of the startle response by pre-pulses or gaps in mice. Front. Cell. Neurosci. 11:19
     [Google Scholar]
  147. 147.  Weible AP, Moore AK, Liu C, DeBlander L, Wu H et al. 2014. Perceptual gap detection is mediated by gap termination responses in auditory cortex. Curr. Biol. 24:1447–55
     [Google Scholar]
  148. 148.  Zheng Y, Hamilton E, McNamara E, Smith PF, Darlington CL 2011. The effects of chronic tinnitus caused by acoustic trauma on social behaviour and anxiety in rats. Neuroscience 193:143–53
     [Google Scholar]
  149. 149.  Hayes SH, Radziwon KE, Stolzberg DJ, Salvi RJ 2014. Behavioral models of tinnitus and hyperacusis in animals. Front. Neurol. 5:179
     [Google Scholar]
  150. 150.  Zheng Y, Hooton K, Smith PF, Darlington CL 2008. Carbamazepine reduces the behavioural manifestations of tinnitus following salicylate treatment in rats. Acta Otolaryngol 128:48–52
     [Google Scholar]
  151. 151.  Fournier P, Hebert S 2013. Gap detection deficits in humans with tinnitus as assessed with the acoustic startle paradigm: Does tinnitus fill in the gap?. Hear. Res. 295:16–23
     [Google Scholar]
  152. 152.  Adamchic I, Langguth B, Hauptmann C, Tass PA 2012. Psychometric evaluation of Visual Analog Scale for the assessment of chronic tinnitus. Am. J. Audiol. 21:215–25
     [Google Scholar]
  153. 153.  Hall DA, Haider H, Szczepek AJ, Lau P, Rabau S et al. 2016. Systematic review of outcome domains and instruments used in clinical trials of tinnitus treatments in adults. Trials 17:270
     [Google Scholar]
  154. 154.  Langguth B, Goodey R, Azevedo A, Bjorne A, Cacace A et al. 2007. Consensus for tinnitus patient assessment and treatment outcome measurement: Tinnitus Research Initiative meeting, Regensburg, July 2006. Prog. Brain Res. 166:525–36
     [Google Scholar]
  155. 155.  Milerova J, Anders M, Dvorak T, Sand PG, Koniger S, Langguth B 2013. The influence of psychological factors on tinnitus severity. Gen. Hosp. Psychiatry 35:412–16
     [Google Scholar]
  156. 156.  Schlee W, Hall DA, Edvall NK, Langguth B, Canlon B, Cederroth CR 2017. Visualization of global disease burden for the optimization of patient management and treatment. Front. Med. 4:86
     [Google Scholar]
  157. 157.  Landgrebe M, Azevedo A, Baguley D, Bauer C, Cacace A et al. 2012. Methodological aspects of clinical trials in tinnitus: a proposal for an international standard. J. Psychosom. Res. 73:112–21
     [Google Scholar]
  158. 158.  Londero A, Hall DA 2017. Call for an evidence-based consensus on outcome reporting in tinnitus intervention studies. Front. Med. 4:42
     [Google Scholar]
  159. 159.  Van de Heyning P, Vermeire K, Diebl M, Nopp P, Anderson I, De Ridder D 2008. Incapacitating unilateral tinnitus in single-sided deafness treated by cochlear implantation. Ann. Otol. Rhinol. Laryngol. 117:645–52
     [Google Scholar]
  160. 160.  Morgan P, Brown DG, Lennard S, Anderton MJ, Barrett JC et al. 2018. Impact of a five-dimensional framework on R&D productivity at AstraZeneca. Nat. Rev. Drug Discov. 17:167–81
     [Google Scholar]
  161. 161.  Maas IL, Bruggemann P, Requena T, Bulla J, Edvall NK et al. 2017. Genetic susceptibility to bilateral tinnitus in a Swedish twin cohort. Genet. Med. 19:1007–12
     [Google Scholar]
  162. 162.  Lopez-Escamez JA, Bibas T, Cima RF, Van de Heyning P, Knipper M et al. 2016. Genetics of tinnitus: an emerging area for molecular diagnosis and drug development. Front. Neurosci. 10:377
     [Google Scholar]
  163. 163.  Donaldson I 1981. Tegretol: a double blind trial in tinnitus. J. Laryngol. Otol. 95:9947–51
     [Google Scholar]
  164. 164.  Witsell DL, Hannley MT, Stinnet S, Tucci DL 2007. Treatment of tinnitus with gabapentin: a pilot study. Otol. Neurotol. 28:111–15
     [Google Scholar]
  165. 165.  Rosenberg SI, Silverstein H, Rowan PT, Olds MJ 1998. Effect of melatonin on tinnitus. Laryngoscope 108:3305–10
     [Google Scholar]
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Therapeutic Approaches to the Treatment of Tinnitus
Annual Review of Pharmacology and Toxicology 59, 291 (2019); https://doi.org/10.1146/annurev-pharmtox-010818-021556
/content/journals/10.1146/annurev-pharmtox-010818-021556
/content/journals/10.1146/annurev-pharmtox-010818-021556
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