Nitrous Oxide Treatment for Tinnitus

NCT03365011 | Completed Phase 4 Results

• 1 other identifier: 201606104
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Tinnitus

Keywords

Nitrous Oxide

Outcome Measures

Primary Outcomes (1)

• Change in Tinnitus Functional Index (TFI) Score

  Change of participant-reported tinnitus symptoms 1 week after each intervention. The Tinnitus Functional Index (TFI) is a 25-question survey assessing tinnitus impact on quality of life. Participants were asked to rate on a scale from 0-10 the degree of unpleasantness, cognitive interference, sleep disturbance, auditory difficulties, interference with relaxation, and emotional distress associated with their tinnitus. Subscores are summed and scaled to a score of 0-100. A score less than 25 indicates mild problems due to tinnitus and little need for intervention, while a score between 25-50 indicates significant problems due to tinnitus with potential need for intervention. A decrease in TFI score indicates decreased bother due to tinnitus over time, a better outcome. An increase in TFI score indicates increased bother due to tinnitus over time, a worse outcome.

  Pre-intervention and 1 week post-intervention

Secondary Outcomes (2)

• Change in Global Bothersome Scale (GBS) Score

  Pre-intervention and 1 week post-intervention

• Patients' Global Impression of Change

  1 week post-intervention

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Placebo was defined as 50% nitrogen and 50% oxygen for 40 minutes. Participants are blinded to the order of interventions administered. Participants have been informed prior to consent that one session will contain the nitrous oxide gas mixture, and the other session will contain the placebo gas mixture.

Drug: Placebo gas for inhalation

Nitrous oxide

EXPERIMENTAL

Nitrous oxide treatment was defined as 50% nitrous oxide and 50% oxygen for 40 minutes. Participants are blinded to the order of interventions administered. Participants have been informed prior to consent that one session will contain the nitrous oxide gas mixture, and the other session will contain the placebo gas mixture.

Drug: Nitrous oxide gas for inhalation

Interventions

Nitrous oxide gas for inhalation DRUG

Nitrous oxide gaseous mixture (50% nitrous oxide and 50% oxygen) for 40 minutes duration under anesthesia supervision with monitoring according to standards set by the American Society of Anesthesiologists.

Nitrous oxide

Placebo gas for inhalation DRUG

Placebo gaseous mixture (50% nitrogen and 50% oxygen) for 40 minutes duration under anesthesia supervision with monitoring according to standards set by the American Society of Anesthesiologists.

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult men and women 18-65 years of age
• Subjective, unilateral or bilateral, non-pulsatile tinnitus scoring "Bothered more than a little but not a lot", "Bothered a lot", or "Extremely bothered" on the Global Bothersome scale
• Able to give informed consent
• Must be able to read, write, and understand English

You may not qualify if:

• Bipolar disorder
• Schizophrenia
• Schizoaffective disorder
• Substance abuse or dependence (except for remote substance abuse or dependence with remission at least 1 year prior to the study and except for nicotine use disorders)
• Acute medical illness that may pose subject at risk during nitrous oxide administration
• Active psychotic symptoms
• Patients with significant pulmonary disease and/or requiring supplemental oxygen
• Contraindication against the use of nitrous oxide:
• Pneumothorax
• Bowel obstruction
• Middle ear occlusion
• Elevated intracranial pressure
• Chronic cobalamin and/or folate deficiency treated with folic acid or vitamin B12
• Pregnant patients
• Breastfeeding women

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (22)

• 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.

  PMID: 20670725 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.

  PMID: 22168528 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.

  PMID: 25273878 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.

  PMID: 23121658 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.

  PMID: 26467416 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.

  PMID: 9546794 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.

  PMID: 25577164 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.

  PMID: 25463512 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.

  PMID: 16081009 BACKGROUND

• Sahley TL, Nodar RH, Musiek FE. Endogenous dynorphins: possible role in peripheral tinnitus. Int Tinnitus J. 1999;5(2):76-91.

  PMID: 10753426 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.

  PMID: 14763234 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.

  PMID: 18301716 BACKGROUND

• Puel JL. Cochlear NMDA receptor blockade prevents salicylate-induced tinnitus. B-ENT. 2007;3 Suppl 7:19-22.

  PMID: 18225604 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.

  PMID: 12736364 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.

  PMID: 22408611 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.

  PMID: 11556941 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.

  PMID: 22156949 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.

  PMID: 19012118 BACKGROUND

• Duckert LG, Rees TS. Placebo effect in tinnitus management. Otolaryngol Head Neck Surg. 1984 Dec;92(6):697-9. doi: 10.1177/019459988409200618.

  PMID: 6440090 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.

  PMID: 18929686 BACKGROUND

• 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.

  PMID: 30073285 DERIVED

MeSH Terms

Conditions

Tinnitus

Interventions

Endothelium-Dependent Relaxing Factors; Inhalation

Condition Hierarchy (Ancestors)

Hearing Disorders; Ear Diseases; Otorhinolaryngologic Diseases; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Vasodilator Agents; Cardiovascular Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses; Respiratory Mechanics; Respiration; Respiratory Physiological Phenomena; Circulatory and Respiratory Physiological Phenomena

Limitations and Caveats

Limitations included ineffective blinding, with significantly greater than 50% of participants correctly guessing the intervention received.

Results Point of Contact

• Title: Jay F. Piccirillo, MD, FACS
• Organization: Washington University School of Medicine in St. Louis

piccirij@wustl.edu

(314) 362-8641

Study Officials

• Jay F Piccirillo, MD

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 15, 2017
• First Posted: December 7, 2017
• Study Start: October 1, 2016
• Primary Completion: June 1, 2017
• Study Completion: July 1, 2017
• Last Updated: December 14, 2018
• Results First Posted: November 6, 2018

Record last verified: 2018-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)