Nitrous Oxide Treatment for Tinnitus

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.

Subjective, idiopathic, non-pulsatile tinnitus ("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. Bothersome tinnitus is associated with poorer working memory, slower processing speeds and reaction times, and deficiencies in selective attention. Currently, effective therapies for tinnitus remain limited. Examples of therapies include external sound therapy to mask the perceived sound, behavioral therapy to habituate the patient to the perceived sound, and counseling such as cognitive behavioral therapy to address the bother and impact that tinnitus has on people's lives. Surgical treatment such as nerve transection remains controversial given its lack of efficacy and adverse event profile. There are no drugs approved by the FDA for the treatment of tinnitus. Antidepressant and antianxiety medications are prescribed to patients with tinnitus with limited benefit. Nitrous oxide is an N-methyl-D-aspartate (NMDA) receptor antagonist, a class of drugs shown to have antidepressant effects. A previous trial examined the use of nitrous oxide as a treatment for major depressive disorder (MDD). Generally, NMDA receptors promote excitation at synapses throughout the auditory pathway and play diverse roles in synaptic development and auditory information processing. In the setting of chronic damage to the auditory system, overactivation of NMDA receptors leads to aberrant spontaneous neuronal firing in the cochlea and auditory brainstem structures, which can further perpetuate damage and disease in a feed-forward mechanism. Studies by Guitton et al. and Puel et al. showed that administration of NMDA receptor antagonists prior to the administration of salicylate was effective in preventing acute excitotoxic tinnitus, establishing that salicylate induces tinnitus through its action on NMDA receptors. Thus, NMDA receptors are thought to be implicated in the generation and perpetuation of several auditory diseases including tinnitus. The investigators hypothesized that the administration of nitrous oxide, an NMDA receptor antagonist, may be a therapeutic strategy in the treatment of tinnitus. The study was a randomized placebo-controlled crossover trial. Each participant attended two intervention sessions, one "treatment" and one "placebo". Participants eligible to participate in the study were randomly assigned to receive either placebo followed by nitrous oxide or nitrous oxide followed by placebo, according to a computer-generated randomization sequence. Only the statistician and the anesthesiology team directly involved in administration of nitrous oxide and placebo had access to the group assignments. All participants and other study team members administering survey assessments remained blinded. The two intervention sessions were held at least two weeks apart and were indistinguishable in setting, setup, and monitoring in order to maintain blinding for the participants and study team members. All intervention sessions were performed at the Washington University Clinical Research Unit, a component of the Center for Applied Research Sciences.

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.

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.

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.

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.

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.

Change in participant-reported tinnitus bother after each intervention. Global Bothersome Scale (GBS) measured participant's self-assessment of tinnitus bother on a 5-point scale ranging from "Not bothered, 0" to "Extremely bothered, 5." A change of 0 indicates no change in tinnitus bother over time. A change of -1 indicates somewhat improved tinnitus bother, and a change of positive 1 indicates somewhat worsened tinnitus bother. A change of positive 2 indicates significantly worsened tinnitus bother.

Participant-reported perception of change in impact of tinnitus on quality of life since receiving each intervention

Inclusion Criteria: 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 Exclusion Criteria: 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 Previous administration of NMDA-receptor antagonists (e.g., ketamine) within the last 3 months Tinnitus related to cochlear implantation, retrocochlear lesion, Meniere's Disease, or other known anatomic lesions of the ear or temporal bone Tinnitus related to a Workman's Compensation claim or litigation-related event that is still pending. Any medical condition, which, in the opinion of the PI, confounds study results or places the subject at greater risk

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