Nitrous Oxide Treatment for Tinnitus

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.

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