Research Research archive Research reviews 2017 2017 ATRR: The pharmacology of tinnitus: ototoxicity and treatment The potential for there to be drug treatment for troublesome tinnitus has been a topic of substantial and long-standing interest, and questions about this arise very often in the clinic. Many compounds of interest have been trialled, and of 219 recruiting or completed tinnitus studies described on clinical trials. gov, 68 (31%) involve drug treatments or dietary supplements. One of the reasons for the sparse progress to date has been the lack of effort: this has not been an area where financial nor time resources have been deployed until relatively recently. In this section, we review what was reported regarding tinnitus and pharmacology in 2016, including tinnitus caused by drug treatments, how that might be prevented, and tinnitus treatment by drugs. The literature search that underpinned this section was conducted on PubMed, used the key words tinnitus and drug, considered human studies only, and papers published in English between 1.1.16 and 31.12.16. Ototoxicity and its prevention Platinum-based chemotherapy is highly effective in treating cancer, and has contributed to modern survival rates which approximate 66% five years after diagnosis . These treatments are ototoxic, however, leading to permanent hearing loss and tinnitus in many cancer survivors, which can potentially lead to reduced quality of life in survivorhood. The extent of ototoxicity appears to depend on several factors, including genetic susceptibility and cumulative dose among others . Van As et al published a Cochrane Review in 2016  of different infusion durations of cisplatin in children, and how this might potentially prevent ototoxicity: only one randomised controlled trial was identified. This had only immediate post-treatment follow-up and no consideration of tinnitus. In a context where post-treatment development or progression of hearing loss can occur with cisplatin treatment in adults, and where tinnitus can develop in 40% of patients, this is inadequate, as van As and colleagues discuss. Some cancer patients receive both platinum-based chemotherapy and radiotherapy, and ototoxicity is a major concern when the tumour is in the head and neck, such that the cochlea is doubly vulnerable. Niemensivu et al  noted that patients undergoing high dose cisplatin and radiotherapy treatment “will suffer from hearing deficits” but sought to investigate the ototoxicity effects of low dose cisplatin, and radiotherapy. Whilst the report of reduced hearing loss and tinnitus compared with higher doses of cisplatin are encouraging, this study did not involve high-frequency audiometry (10-16kHz), and the patient numbers (n=9) were too low for any definitive conclusions. Other drugs that can cause ototoxic tinnitus include quinine and salicylate and their modes of action were studied by Alvan et al . Whilst there is a consensus that both drugs affect the cochlear Outer Hair Cells (OHC), which are involved in the fine-tuning of the mammal cochlea, rather than the Inner Hair Cells (IHC), which convert the vibrational energy of sound into neural impulses, Alvan and colleagues propose that the OHC impact of quinine and salicylate is accomplished by quite different molecular mechanisms, and this may have important implications for prevention, and deeper understandings of cochlear dysfunction. Treatment: reviews Literature reviews can be of major value, allowing assessment of the quality of published evidence, and the synthesis of data across studies to increase the strength of a particular finding. Several reviews in the area of drug treatments for tinnitus were published in 2016 from quite different perspectives. Nguyen et al undertook a fascinating and innovative review  of patents taken out between 2011 and 2015 regarding drug delivery for inner ear disorders. The 34 patents they identified ranged from new therapeutic agents, to systems of sustained release, to new technologies for drug delivery. Whilst tinnitus was not the only topic of this paper, clearly, this is an area of great interest regarding treating tinnitus, and this paper makes a significant contribution to the literature. One particular option for drug treatment of inner ear disorders is the intra-tympanic administration of steroids, and Lavigne et al reviewed the evidence . Their conclusion was that they identified some but not unequivocal evidence that intra-tympanic steroid injection may be beneficial for some inner ear disorders that include tinnitus in their symptom profile, such as Ménière’s disease and idiopathic sudden sensorineural hearing loss, and that there might be some improvement in the associated tinnitus for some patients. There was no evidence of benefit for tinnitus alone however. An exploratory review of an interesting idea was undertaken by Smith and Zheng . They proposed that tinnitus may be considered as a form of ‘sensory epilepsy’, based in part on the finding that some anti-epileptic drugs may improve tinnitus in some cases. They then explore the possibility that cannabis and related compounds may have an anti-epileptic effect and thus may improve tinnitus. Whilst this is essentially speculative, the fact that some in the tinnitus community are prepared to envisage innovative hypotheses and proposals is encouraging. Treatment: clinical trials Two papers each reporting the results of a clinical trial were published in 2016. Singh et al investigated the potential benefits of vitamin B12 in a pilot study. This was a placebo controlled double-blind trial and whilst the results of the pilot indicated some benefits for tinnitus severity, there are some caveats. The outcome measures used were not validated and robust instruments, and the treatment and placebo groups both contained a mixture of vitamin B12 deficient and sufficient individuals, who might be expected to have quite different reactions to the six weekly intramuscular B12 injections that comprised the treatment under investigation. Polanski et al investigated the potential benefits of antioxidant therapy  for tinnitus in older patients, the treatments under study comprising Gingko Biloba, vitamins C and E, and papaverine hydrochloride versus an inert placebo. No benefits for tinnitus with these therapies were found using the Tinnitus Handicap Inventory  as an outcome measure. Whilst not a trial, some other data regarding dietary supplements for tinnitus was published in 2016. Coelho and colleagues  undertook a large survey (n=1788) across 53 countries, and 23.1% of the respondents self-reported taking dietary supplements for tinnitus. There were reported benefits for sleep, emotional state, concentration, and for hearing, with some adverse effects including headaches. The authors reflected on the potential biases in a survey of this kind, and concluded that whilst supplements are not generally beneficial for tinnitus, in some patients there might be an effect. Discussion Although there were some publications of interest regarding potential drug treatments for tinnitus in 2016, they were not replete, and this is an area that might benefit from sustained and comprehensive efforts. References  Frisina RD, Wheeler HE, Fossa SD, Kerns SL, Fung C, Sesso HD, Monahan PO, Feldman DR, Hamilton R, Vaughn DJ, Beard CJ, Budnick A, Johnson EM, Ardeshir-Rouhani-Fard S, Einhorn LH, Lipshultz SE, Dolan ME and Travis LB. Comprehensive Audiometric Analysis of Hearing Impairment and Tinnitus After Cisplatin-Based Chemotherapy in Survivors of Adult-Onset Cancer. Journal of Clinical Oncology, 2016. 34(23): 2712-20. doi: 10.1200/JCO.2016.66.8822  Van As JW, van den Berg H and van Dalen EC. Different infusion durations for preventing platinum-induced hearing loss in children with cancer. Cochrane Database Systematic Review, 2016. (8): CD010885. doi: 10.1002/14651858. CD010885.pub3.  Niemensivu R, Saarilahti K, Ylikoski J, Aarnisalo A and Mäkitie AA. Hearing and tinnitus in head and neck cancer patients after chemoradiotherapy. European Archives of Oto-Rhino-Laryngology, 2016. 273(9): 2509-14. doi: 10.1007/s00405-015-3857-5.  Alvan G, Berninger E, Gustafsson LL, Karlsson KK, Paintaud G and Wakelkamp M. Concentration-Response Relationship of Hearing Impairment Caused by Quinine and Salicylate: Pharmacological Similarities but Different Molecular Mechanisms. Basic Clinical Pharmacology Toxicology, 2017. 120(1): 5-13. doi: 10.1111/bcpt.12640. Epub 2016 Sep 29.  Nguyen K, Kempfle JS, Jung DH and McKenna CE. Recent advances in therapeutics and drug delivery for the treatment of inner ear diseases: a patent review (2011-2015). Expert Opinion on Therapeutic Patents, 2017. 27(2): 191-202. doi: 10.1080/13543776.2017.1252751. Epub 2016 Nov 18.  Lavigne P, Lavigne F and Saliba I. Intratympanic corticosteroids injections: a systematic review of literature. European Archives of Oto-Rhino-Laryngology, 2016. 273(9): 2271-8. doi: 10.1007/s00405-015-3689-3.  Smith PF and Zheng Y. Cannabinoids, cannabinoid receptors and tinnitus. Hearing Research, 2016. 332:210-6. doi: 10.1016/j.heares.2015.09.014.  Singh C, Kawatra R, Gupta J, Awasthi V and Dungana H. Therapeutic role of Vitamin B12 in patients of chronic tinnitus: A pilot study. Noise Health, 2016. 18(81): 93-7. doi: 10.4103/1463-1741.178485.  Polanski JF, Soares AD and de Mendonça Cruz OL. Antioxidant therapy in the elderly with tinnitus. Brazilian Journal of Otorhinolaryngology, 2016. 82(3): 269-74. doi: 10.1016/j.bjorl.2015.04.016.  Newman C, Jacobson G and Spitzer J. Development of the Tinnitus Handicap Inventory. Archives of Otolaryngology – Head and Neck Surgery, 1996. 122(2): 143-8.  Coelho C, Tyler R, Ji H, Rojas-Roncancio E, Witt S, Tao P, Jun HJ, Wang TC, Hansen MR and Gantz BJ Survey on the Effectiveness of Dietary Supplements to Treat Tinnitus. American Journal of Audiology, 2016. 25(3): 184-205. doi: 10.1044/2016_AJA-16-0021. Read your copy here: Download your copy here: The_pharmacology_of_tinnitus.pdf Disclaimer: The views expressed in this publication are those of the author(s) and not necessarily those of the National Institutes of Health, the National Institute for Health Research, or the Department of Health. About the author: David Baguley is a Professor of Hearing Sciences at the University of Nottingham, working in the of Clinical Neurosciences (Faculty of Medicine), and the Otology and Hearing Group. He heads up the Clinical Hearing Sciences group within the NIHR Biomedical Research Centre. David's particular research interests lie in the area of iatrogenic tinnitus and hearing loss associated with the use of platinum-based chemotherapy in adult survivors of cancer. For over 30 years David was the Head of Audiology at Cambridge University Hospitals NHS Foundation Trust, an in the last 5 years the Head of Auditory Implants and of Newborn Hearing Screening also. David has co-authored over 150 research papers, many book chapters, and has co-authored and edited several books. He has twice been awarded the Shapiro Research Prize of the British Tinnitus Association, and in 2006 received an International Award in Hearing from the American Academy of Audiology.