Nitrous Oxide Treatment for Tinnitus
Condition: Tinnitus
MeSH terms: Tinnitus
Study type: Interventional
Phase: Phase 4

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.
    

Detailed description: 
      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.
    

Intervention name(s): Nitrous oxide gas for inhalation; Placebo gas for inhalation
Intervention type(s): Drug; Drug
Intervention description(s): 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.
Intervention MeSH terms: Nitrous Oxide
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Nitrous Oxide