Nitrous Oxide Treatment for Tinnitus

Summary

Tinnitus is perception of sound without the presence of an external acoustic stimulus. Approximately 50 million Americans experience chronic tinnitus and of these, 10 million have bothersome tinnitus. The tinnitus research literature suggests that NMDA receptor antagonists may prove to be useful in reducing tinnitus. Nitrous oxide, a member of the NMDA receptor antagonist class, is a widely-used general anesthetic and sedative with a proven safety profile. The investigators hypothesized that the administration of nitrous oxide, an NMDA receptor antagonist, may be effective in treatment of tinnitus. The study design was a randomized placebo-controlled crossover trial.

Timeline

Start

2016-10

Primary completion

2017-06

Completion

2017-07

Publications

• Background Shargorodsky J, Curhan GC, Farwell WR. Prevalence and characteristics of tinnitus among US adults. Am J Med. 2010 Aug;123(8):711-8. doi: 10.1016/j.amjmed.2010.02.015.
• Background Pierce KJ, Kallogjeri D, Piccirillo JF, Garcia KS, Nicklaus JE, Burton H. Effects of severe bothersome tinnitus on cognitive function measured with standardized tests. J Clin Exp Neuropsychol. 2012;34(2):126-34. doi: 10.1080/13803395.2011.623120. Epub 2011 Dec 14.
• Background Tunkel DE, Bauer CA, Sun GH, Rosenfeld RM, Chandrasekhar SS, Cunningham ER Jr, Archer SM, Blakley BW, Carter JM, Granieri EC, Henry JA, Hollingsworth D, Khan FA, Mitchell S, Monfared A, Newman CW, Omole FS, Phillips CD, Robinson SK, Taw MB, Tyler RS, Waguespack R, Whamond EJ. Clinical practice guideline: tinnitus. Otolaryngol Head Neck Surg. 2014 Oct;151(2 Suppl):S1-S40. doi: 10.1177/0194599814545325.
• Background Langguth B, Elgoyhen AB. Current pharmacological treatments for tinnitus. Expert Opin Pharmacother. 2012 Dec;13(17):2495-509. doi: 10.1517/14656566.2012.739608. Epub 2012 Nov 4.
• Background Beebe Palumbo D, Joos K, De Ridder D, Vanneste S. The Management and Outcomes of Pharmacological Treatments for Tinnitus. Curr Neuropharmacol. 2015;13(5):692-700. doi: 10.2174/1570159x13666150415002743.
• Background Jevtovic-Todorovic V, Todorovic SM, Mennerick S, Powell S, Dikranian K, Benshoff N, Zorumski CF, Olney JW. Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nat Med. 1998 Apr;4(4):460-3. doi: 10.1038/nm0498-460.
• Background Nagele P, Duma A, Kopec M, Gebara MA, Parsoei A, Walker M, Janski A, Panagopoulos VN, Cristancho P, Miller JP, Zorumski CF, Conway CR. Nitrous Oxide for Treatment-Resistant Major Depression: A Proof-of-Concept Trial. Biol Psychiatry. 2015 Jul 1;78(1):10-18. doi: 10.1016/j.biopsych.2014.11.016. Epub 2014 Dec 9.
• Background Sanchez JT, Ghelani S, Otto-Meyer S. From development to disease: diverse functions of NMDA-type glutamate receptors in the lower auditory pathway. Neuroscience. 2015 Jan 29;285:248-59. doi: 10.1016/j.neuroscience.2014.11.027. Epub 2014 Nov 25.
• Background Kaltenbach JA, Zhang J, Finlayson P. Tinnitus as a plastic phenomenon and its possible neural underpinnings in the dorsal cochlear nucleus. Hear Res. 2005 Aug;206(1-2):200-26. doi: 10.1016/j.heares.2005.02.013.
• Background Sahley TL, Nodar RH, Musiek FE. Endogenous dynorphins: possible role in peripheral tinnitus. Int Tinnitus J. 1999;5(2):76-91.
• Background Nicolas-Puel C, Faulconbridge RL, Guitton M, Puel JL, Mondain M, Uziel A. Characteristics of tinnitus and etiology of associated hearing loss: a study of 123 patients. Int Tinnitus J. 2002;8(1):37-44.
• Background Guitton MJ, Dudai Y. Blockade of cochlear NMDA receptors prevents long-term tinnitus during a brief consolidation window after acoustic trauma. Neural Plast. 2007;2007:80904. doi: 10.1155/2007/80904.
• Background Puel JL. Cochlear NMDA receptor blockade prevents salicylate-induced tinnitus. B-ENT. 2007;3 Suppl 7:19-22.
• Background Guitton MJ, Caston J, Ruel J, Johnson RM, Pujol R, Puel JL. Salicylate induces tinnitus through activation of cochlear NMDA receptors. J Neurosci. 2003 May 1;23(9):3944-52. doi: 10.1523/JNEUROSCI.23-09-03944.2003.
• Background Guitton MJ. Tinnitus: pathology of synaptic plasticity at the cellular and system levels. Front Syst Neurosci. 2012 Mar 8;6:12. doi: 10.3389/fnsys.2012.00012. eCollection 2012.
• Background Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001 Sep;16(9):606-13. doi: 10.1046/j.1525-1497.2001.016009606.x.
• Background Standards for Basic Anesthetic Monitoring. Committee of Origin: Standards and Practice Parameters (Approved by the ASA House of Delegates on October 21, 1986, last amended on October 20, 2010, and last affirmed on October 28, 2016) https://www.asahq.org/~/media/Sites/ASAHQ/Files/Public/Resources/standards-guidelines/standards-for-basic-anesthetic-monitoring.pdf
• Background Meikle MB, Henry JA, Griest SE, Stewart BJ, Abrams HB, McArdle R, Myers PJ, Newman CW, Sandridge S, Turk DC, Folmer RL, Frederick EJ, House JW, Jacobson GP, Kinney SE, Martin WH, Nagler SM, Reich GE, Searchfield G, Sweetow R, Vernon JA. The tinnitus functional index: development of a new clinical measure for chronic, intrusive tinnitus. Ear Hear. 2012 Mar-Apr;33(2):153-76. doi: 10.1097/AUD.0b013e31822f67c0.
• Background Andersson G, Westin V. Understanding tinnitus distress: introducing the concepts of moderators and mediators. Int J Audiol. 2008 Nov;47 Suppl 2:S106-11. doi: 10.1080/14992020802301670.
• Background Duckert LG, Rees TS. Placebo effect in tinnitus management. Otolaryngol Head Neck Surg. 1984 Dec;92(6):697-9. doi: 10.1177/019459988409200618.
• Background Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009 Apr;42(2):377-81. doi: 10.1016/j.jbi.2008.08.010. Epub 2008 Sep 30.
• Hong HY, Karadaghy O, Kallogjeri D, Brown FT, Yee B, Piccirillo JF, Nagele P. Effect of Nitrous Oxide as a Treatment for Subjective, Idiopathic, Nonpulsatile Bothersome Tinnitus: A Randomized Clinical Trial. JAMA Otolaryngol Head Neck Surg. 2018 Sep 1;144(9):781-787. doi: 10.1001/jamaoto.2018.1278.

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Indications