Nitrous Oxide as Treatment for Tinnitus: A Randomized Crossover Trial
Phase: PHASE4
Conditions: Tinnitus
Sponsor: Washington University School of Medicine

Nitrous oxide as treatment for tinnitus – a pilot study 
STUDY PROTOCOL 
NITROUS OXIDE AS 
TREATMENT FOR TINNITUS 
– A PILOT STUDY
Principal Investigator:  
Jay F. Piccirillo, MD, FACS, CPI 
Professor of Otolaryngology, Director of Clinical Outcomes Research 
Department of Otolaryngology - Head and Neck Surgery  
Washington University School of Medicine  
Phone: 314-362-8641 (office) 
Piccirilloj@ent.wustl.edu 
Sub-Investigators: 
Peter Nagele, MD, MSc 
Associate Professor of Anesthesiology and Genetics 
Department of Anesthesiology 
Washington University School of Medicine 
Phone: 314-362-5129 
nagelep@anest.wustl.edu 
Charles R. Conway, MD 
Department of Psychiatry, Professor of Psychiatry, Director of Treatment Resistant Depression 
and Neurostimulation Clinic 
Dorina Kallogjeri, MD, MPH, Biostatistician, Department of Otolaryngology - Head and Neck 
Surgery, Washington University School of Medicine 
Helena Hong, Medical Student (MD Candidate), Washington University School of Medicine 
June 23, 2016
NCT03365011

2 Nitrous oxide as treatment for tinnitus – a pilot study 
Study Title 
Nitrous oxide as treatment for tinnitus – a pilot study 
Objective 
This pilot study aims to determine if nitrous oxide (laughing gas) is efficacious as treatment for 
subjective tinnitus. 
Study Period 
Planned enrollment duration: Approximately 6 months. 
Planned study duration: 1 year 
Number of 
Patients 
40 
Study Drug 
Nitrous oxide (laughing gas). This is an FDA-approved general anesthetic and sedative agent used in 
hospitals and dentist offices. The use of nitrous oxide to treat tinnitus is off-label and outside of the 
approved indication. Nitrous oxide will be administered under supervision of an attending-level 
anesthesiologist and using standard anesthesia equipment (mobile anesthesia machine, standard peri-
procedural monitoring, oxygen, rescue equipment). 
Study Design 
Prospective, randomized, double-blinded, placebo-controlled cross-over trial. Subjects will first 
receive either up to 50% nitrous oxide/50% oxygen or “placebo” (50% nitrogen [inert]/50% 
oxygen) in a 40-minute single session. In the subsequent session, subjects will receive the other 
treatment intervention. The two sessions will be held 2 weeks apart and will be indistinguishable 
from each other in setting, setup, and monitoring. 
Inclusion and 
Exclusion Criteria 
Inclusion Criteria 
a) 
Adult men and women 18-65 years of age 
b) Subjective, unilateral or bilateral, non-pulsatile tinnitus for at least 6 months duration 
c) Either “Bothered more than a little but not a lot”, “Bothered a lot”, or “Extremely bothered” on 
the Global Bothersome scale 
d) 
Able to give informed consent 
e) 
Must be able to read, write, and understand English 
 Exclusion Criteria 
History of: 
a) Bipolar disorder 
b) Schizophrenia 
c) Schizoaffective disorder 
d) 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) 
e) Acute medical illness that may pose subject at risk during nitrous oxide administration 
f) 
Active psychotic symptoms 
g)  Patients with significant pulmonary disease and/or requiring supplemental oxygen 
h) Contraindication against the use of nitrous oxide: 
a. 
Pneumothorax 
b. Bowel obstruction 
c. 
Middle ear occlusion 
d. Elevated intracranial pressure 
e. 
Chronic cobalamin and/or folate deficiency treated with folic acid or vitamin B12 
f. 
Pregnant patients 
g. Breastfeeding women 
i) 
Previous administration of NMDA-receptor antagonists (e.g., ketamine) within the last 3 
months 
j) 
Tinnitus related to cochlear implantation, retrocochlear lesion, Meniere’s Disease, or other 
known anatomic lesions of the ear or temporal bone 
k) Tinnitus related to a Workman’s Compensation claim or litigation-related event that is still 
pending. 
l) 
Any medical condition, which, in the opinion of the PI, confounds study results or places the 
subject at greater risk 
Primary Outcome 
and Measurements 
The difference in the difference in patient-reported tinnitus symptoms according to Tinnitus Functional 
Index (TFI) between baseline and 1 week after each intervention.  Secondary outcome measure will be 
the same calculation performed for the Momentary Assessment of Tinnitus (MAT) questionnaire. 

3 Nitrous oxide as treatment for tinnitus – a pilot study 
 
ABSTRACT 
Tinnitus, the perception of sound in the absence of external acoustic stimulation, is a common 
yet poorly understood disease that currently lacks effective front-line treatment. Many therapies 
focus on mitigating the effects of tinnitus on patients’ quality of life, such as through habituation 
or masking with white noise. However, the tinnitus research literature suggests that NMDA 
receptor antagonists may prove to be useful in reducing tinnitus itself.[6, 9, 11, 12] Nitrous oxide 
belongs to the class of NMDA receptor antagonists, and additionally is widely-used, non-
invasive, and has a proven safety profile. As such, nitrous oxide may be the drug of choice for 
testing the efficacy of NMDA receptor antagonists on reducing subjective, bothersome tinnitus. 
 
We propose conducting a pilot randomized placebo-controlled, double-blind crossover study in 
which patients attend two sessions where they receive either 50% nitrous oxide in oxygen or 
50% nitrogen, 50% oxygen for a period of 40 minutes. Tinnitus will be assessed using the 
Tinnitus Functional Index (TFI) upon enrollment, then reassessed 1 week following each 
intervention session. Secondarily, the Momentary Assessment of Tinnitus (MAT) questionnaire 
will be administered at baseline before intervention, 1 hour after intervention, 1 day after 
intervention, and 1 week after intervention. 
 
1. SPECIFIC AIMS 
 
Aim 1. To evaluate the efficacy of nitrous oxide as treatment for tinnitus 
 
 
2. BACKGROUND 
Subjective, idiopathic, non-pulsatile tinnitus (“tinnitus”) is perception of sound without the 
presence of an external acoustic stimulus. Approximately, 60 million Americans experience 
chronic tinnitus and 15 million of these people have bothersome tinnitus. Research at 
Washington University (WU)[1] and elsewhere showed that bothersome tinnitus is associated 
with poorer working memory, slower processing speeds and reaction times, and deficiencies in 
selective attention.  These findings indicate that tinnitus interferes with attention and other 
important non-auditory cortical networks and the effects may be mediated by stress and its 

4 Nitrous oxide as treatment for tinnitus – a pilot study 
effects on the central nervous system. 
 
Currently, no effective front-line therapy exists for tinnitus. Many patients use external sound 
therapy such as white noise generators to mask the perceived sound, or counseling therapy to 
habituate the patient to the perceived sound. While these treatments often help decrease the 
effects tinnitus has on quality of life, they do not alleviate the tinnitus itself. Surgical treatment 
such as nerve transection remains controversial.[2, 3] Currently, there are no FDA-approved 
drugs specifically for tinnitus.[4, 5, 6] However, there are antidepressant and antianxiety 
medications such as desipramine (Norpramin), alprazolam (Xanax), or lorazepam (Ativan) 
prescribed to patients with tinnitus.[6, 7] According to the American Tinnitus Association, these 
psychotropic drugs can reduce the psychological burden of tinnitus for some patients, but again 
do not reduce perception of tinnitus itself. Furthermore, side effects of the drugs include nausea, 
blurred vision, and insomnia, and they can be habit-forming. As such, the side effects often 
interfere with patients’ ability to concentrate and with other cognitive functions.[7] 
 
A previous trial performed by Dr. Peter Nagele at WU examined using nitrous oxide as a 
treatment for major depressive disorder (MDD). Results showed significant and rapid 
improvement of depressive symptoms.[8] Nitrous oxide is an N-methyl-D-aspartate (NMDA) 
receptor antagonist, a class of drugs that have shown to have antidepressant effects.[9] There is 
a general consensus in tinnitus research that subjective neural-generated tinnitus results from 
abnormal spontaneous activity somewhere in the auditory pathway, and the neural events that 
lead to tinnitus are themselves a result of altered activity in the cochlea.[10, 11] Cochlear NMDA 
receptors have been implicated in neural-generated tinnitus.[10, 12, 13] Acute excitotoxic 
tinnitus results from administration of salicylate, but prior administration of NMDA receptor 
blockers prevents salicylate-induced tinnitus.[12] Given this proposed mechanism of action, 
nitrous oxide, an NMDA receptor antagonist, presents a possible therapeutic strategy for 
treating tinnitus. 
 
In this pilot study, we plan to assess the impact of nitrous oxide on tinnitus symptoms and 
degree of bother.  For this pilot study, we will not exclude patients with depression, and thus 
we will not be able to assess whether the mechanism of nitrous oxide on reducing tinnitus is 
independent of the aforementioned mechanism in depression. Regardless, we believe nitrous 
oxide may be an effective treatment for tinnitus and believe a pilot study is indicated. 
 
3. DRUG INFORMATION 
Nitrous oxide (laughing gas) is a colorless, odorless gas. Nitrous oxide is the oldest and most 
widely used FDA-approved anesthetic gas. It is commonly used as a component of general 

5 Nitrous oxide as treatment for tinnitus – a pilot study 
anesthesia and as a sedative/analgesic agent used in hospitals and dentist offices. The onset as 
well as offset of effect is within a few minutes. Nitrous oxide is the least potent of inhalational 
anesthetics. Concentrations above 1atm are theoretically needed to produce complete general 
anesthesia when nitrous oxide is used as a sole agent. Therefore, concentrations typically used 
(50%) in dentistry and pediatrics achieve only mild to moderate sedation (but potent analgesia) 
and are not sufficient to produce general anesthesia. Well-known side effects include euphoria, 
sedation, nausea and vomiting, and inactivation of vitamin B12 (commensurate with the 
duration of exposure and concentration used). In general, exposure to 50% nitrous oxide for 40 
minutes is considered extremely safe. The use of nitrous oxide to treat tinnitus is off-label and 
outside of the approved indication. 
 
4. ELIGIBILITY 
 
Inclusion Criteria 
a) Adult men and women 18-65 years of age 
b) Subjective, unilateral or bilateral, non pulsatile tinnitus for at least 6 months duration 
c) Either “Bothered more than a little but not a lot”, “Bothered a lot”, or “Extremely 
bothered” on the Global Bothersome scale 
d) Able to give informed consent 
e) Must be able to read, write, and understand English 
 
Exclusion Criteria 
a) History of: 
a. Bipolar disorder 
b. Schizophrenia 
c. Schizoaffective disorder 
d. 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) 
b) Acute medical illness that may pose subject at risk during nitrous oxide administration 
c) Active psychotic symptoms 
d) Patients with significant pulmonary disease and/or requiring supplemental oxygen 
e) Contraindication against the use of nitrous oxide, including: 
a. Pneumothorax 
b. Bowel obstruction 
c. Middle ear occlusion 
d. Elevated intracranial pressure 
e. Chronic cobalamin and/or folate deficiency treated with folic acid or vitamin B12 

6 Nitrous oxide as treatment for tinnitus – a pilot study 
f. Pregnancy 
g. Breastfeeding women 
f) Previous NMDA-receptor antagonist treatment (e.g., ketamine) within the last 3 months 
g) Tinnitus related to cochlear implantation, retrocochlear lesion, Meniere’s Disease, or 
other known anatomic lesions of the ear or temporal bone 
h) Tinnitus related to a Workman’s Compensation claim or litigation-related event that is 
still pending. 
i) Any medical condition, which, in the opinion of the PI, confounds study results or places 
the subject at greater risk 
 
 
5. SCREENING AND ENROLLMENT 
 
Participants will be recruited from Washington University School of Medicine Department of 
Otolaryngology-Head and Neck Surgery clinics, including the Division of Audiology. The 
Washington University Volunteers for Health Research Participant Registry and 
Otolaryngology Research Participant Registry will be queried to identify potential participants. 
Potential participants will be screened according to inclusion and exclusion criteria over the 
telephone, and those who meet inclusion criteria will be invited to the 8th floor McMillan 
Building Clinical Research Outcomes Office to discuss study participation. The potential 
participant will have the opportunity to review the consent form and have questions about the 
study answered by the study team. The PI, or designee, will obtain written consent prior to the 
start of study related procedures. 
 
We will enroll a total of 40 participants with bothersome tinnitus to achieve at least 30 
evaluable participants. Participants will be offered $50 in remuneration for their time and effort 
in this study, to be given upon completion of study participation. 
 
6. METHODS 
 
Study Design 
This is a prospective, randomized, double-blinded, placebo-controlled crossover trial where 40 
patients will undergo two treatment sessions in randomized order. In one session, subjects will 
receive up to 50% nitrous oxide/50% oxygen for 40 minutes (“Treatment”). In the other session, 
subjects will receive up to 50% nitrogen [inert]/50% oxygen for 40 minutes (“Placebo”). The two 
sessions will be held 2 weeks apart and will be indistinguishable from each other in setting, 
setup, and monitoring. 

7 Nitrous oxide as treatment for tinnitus – a pilot study 
No pre-enrollment laboratory assessments will be required. However, a health history will be 
taken at screening. 
Randomization 
Each participant will be randomly assigned to either the “Treatment first” or “Placebo first” 
group. The randomization scheme will use permuted blocks of randomly varying sizes 
generated by the study statistician using SAS statistical software and a password-protected 
Microsoft Excel spreadsheet will be used to create and store the study IDs and the 
randomization order. Each block will contain equal numbers of assignments to the treatment 
first and placebo first in randomized order. To account for the anticipated 20% dropout rate (i.e., 
as a result of withdrawal, being lost to follow-up, and so on), the randomization table will be 
generated for 50 subjects. 
Blinding 
Participants will be blinded to the randomization order. Nitrous oxide is a colorless and 
odorless gas, which makes it unlikely for participants to identify the group assignment. 
Likewise, the study setup will be identical for both sessions, which will make an inadvertent 
unblinding of the study unlikely. For the anesthesiology team responsible for the administration 
of the nitrous oxide treatment, the group assignment will be known. This team is completely 
separate from the team assessing the study outcomes, which will be blinded to the treatment 
received. Treatment administration and outcomes assessment will also be physically separated 
in different rooms within the Clinical Research Unit (CRU) to prevent unblinding.  To assess the 
integrity of the blind, subjects will be asked immediately after each administration to guess 
which treatment – active or placebo they just received. 
 
Setting 
 
The study will be performed in the Clinical Research Unit (CRU) at the Center for Applied 
Research Sciences, located on the 4th and 5th floors of Barnard Hospital. The CRU is staffed by 
nurses, technicians, and medical assistants with experience in implementing clinical research 
studies, including specialized protocol-required procedures. The facility consists of 6 rooms and 
12 semi-private beds, and is equipped with state-of-the art anesthesia machines, monitoring and 
anesthesia equipment, and resuscitation equipment and devices. The CRU has anesthesia 
equipment set up to allow for treatment of two participants at once. We will pay the CRU an 
annual fee of $500 for this active protocol. 
 
Administration of Study Treatment 
 

8 Nitrous oxide as treatment for tinnitus – a pilot study 
Except for the choice of gas (nitrous oxide or nitrogen [inert]; both mixed with 50% oxygen), 
treatment sessions will be identical. The gas mix will be administered via a standard anesthesia 
face mask through tubing connected to the inhalation apparatus. Inhaled and exhaled gas 
concentrations of nitrous oxide, oxygen and nitrogen will be monitored and adjusted according 
to protocol. Total gas flow will be 2-4 L/min. 
 
Participants will be NPO (although liquids may be freely consumed) for 2 hours prior to each 
intervention session as a precaution for possible nausea. Participants will be monitored during 
and after the treatment according to American Society of Anesthesiologists (ASA) standard, 
which includes continuous 3-lead ECG, pulsoximetry, non-invasive blood pressure and end 
tidal CO2 under the supervision of an attending-level anesthesiologists.[15] After the 40 minute 
treatment session, participants will be monitored in the CRU for 1 hour. Participants will then 
be asked to complete the Momentary Assessment of Tinnitus (MAT) questionnaire before 
leaving. A study team physician will determine when the participant meets criteria for 
discharge as described by the ASA standard.  
 
7. DATA COLLECTION 
 
Assessment of Treatment Efficacy 
 
Baseline and Treatment Efficacy Assessment Forms: 
1. Demographics 
2. Tinnitus Description and History Form 
3. Global Bothersome Scale (GBS) 
4. Tinnitus Functional Index (TFI) 
5. Momentary Assessment of Tinnitus Questionnaire (MAT) 
6. Patient Health Questionnaire (PHQ-9) 
7. Patients’ Global Impression of Change (PGIC) 
 
The effects of the treatment will be assessed using repeat administration of GBS, TFI, MAT, 
PHQ-9, and PGIC. 
 
Participants will be asked to complete forms 1-6 (detailed above) immediately before each of 
two sessions as baseline assessment, with Demographics and Tinnitus Description and History 
Form only required before the first session. One hour and then one day following each 
intervention, participants will complete EMA. One week following each session, participants 
will complete GBS, TFI, MAT, PHQ-9, and PGIC. These constitute the treatment efficacy 
assessment. In total, each participant will complete the baseline assessment at two timepoints 
and treatment efficacy assessment at 6 timepoints. The two sessions will be 14 days (2 weeks) 

9 Nitrous oxide as treatment for tinnitus – a pilot study 
apart. These questionnaires can be completed online via a link provided through REDCap in an 
email to the participant. At 14 days after administration of nitrous oxide, we expect the effects of 
nitrous oxide to wear off fully and patients’ tinnitus should have returned to baseline. The 
baseline assessment for the second session will take place no sooner than 14 days after the first 
session, and therefore will assess whether this washout period of 14 days is accurate. The 
patient will not be allowed to participate in the second arm of the study until their Global 
Bother Scale score is within one category of their baseline score. 
 
Assessment of Treatment Safety 
 
Treatment safety will be assessed at several levels: adverse events (AE) related to (i) 
cardiovascular status; (ii) respiratory function; (iii) central nervous system; (iv) psychiatric 
symptoms,. 
(i) Cardiovascular AEs, such as hyper- and hypotension, tachy-/bradycardia, will be 
identified by continuous hemodynamic monitoring during and after the treatment 
(ii) Respiratory AEs, such as respiratory depression and desaturation, will be identified 
by continuous pulsoximetry during and after treatment 
(iii) Central nervous system AEs will be assessed clinically. 
(iv) Psychiatric AEs, will be assessed clinically. 
 
8. DATA AND SAFETY MONITORING 
 
 
The specific monitoring plan for this study is commensurate with the risks and the size and 
complexity of the investigations planned. The potential risks are attributable to the use of 
nitrous oxide. Based on these considerations the monitoring plan involves a DSMC including 
Dr. Peter Nagele, an attending anesthesiologist knowledgeable in nitrous oxide pharmacology, 
Dr. Jay Piccirillo, an attending otolaryngologist with experience with tinnitus patients, and Dr. 
Dorina Kallogjeri, a biostatistician with experience in conducting clinical trials. All reports of 
Serious Adverse Events or Unexpected Adverse Events will be investigated by the DSMC and 
reported to the WU HRPO/IRB per reporting guidelines. 
 
Furthermore, the study principal investigator and study coordinator will monitor for breaches 
of confidentiality and other adverse events on an ongoing basis.  Once the PI or study 
coordinator becomes aware of a reportable adverse event, the event will be reported to HRPO 
according to institutional guidelines.   
 
9. DATA ANALYSIS 

10 Nitrous oxide as treatment for tinnitus – a pilot study 
Standard descriptive statistics will describe the study population, responses to assessments, and 
severity of tinnitus.  Data will be analyzed using SAS version 9.4 statistical software (SAS 
Institute, Inc. Cary, NC). 
 
Aim 1. To evaluate the effect of nitrous oxide as treatment of tinnitus. 
The primary efficacy parameter will be the in the change in TFI. Secondary outcome measure 
will be the change in MAT. Baseline TFI and MAT will be defined as those determined 
immediately before a session. Post-treatment TFI and MAT will be compared to baseline TFI 
and MAT at each time point.  A mixed model analysis using SAS Proc Mixed procedure will be 
used to explore the change in TFI score after treatment as compared to after placebo through 
exploration of the interaction effect of time*treatment. The mixed procedure allows for 
exploring information from measures nested within subjects nested within treatment groups. In 
addition, this analytical approach allows for investigation of the carry-over effect due to cross-
over design. 
And finally, the number of subjects with 13 or more points difference in TFI (clinically 
important difference)[16] after each treatment arm will be identified and compared between 
active and placebo treatments using McNemars test. 
 
10. RISK ASSESSMENT 
 
Nitrous oxide. The side effects of nitrous oxide are well known to anesthesiologists. The dose 
(50%) and duration (40 minutes) used in this protocol are considered extremely safe and of low 
risk. Similar doses and durations are used in everyday dental practice without vital sign 
monitoring or supervision by a resuscitation-trained physician. With this dose of nitrous oxide, 
sedation may occur but not general anesthesia or respiratory depression. Previous evidence 
shows that the inactivating effect of nitrous oxide on vitamin B12 is dose and duration-
dependent and are minor when used as described in this protocol. An increase in plasma 
homocysteine by +25% and return to baseline within the next 24 hours is expected. Minor side 
effects after nitrous oxide exposure such as nausea and vomiting may occur which are typically 
self-limited and short. As a precaution against nausea, patients will be NPO for 2 hours prior to 
each intervention session, although liquids may be freely consumed. If a patient develops 
moderate to severe nausea and vomiting, we will administer 4mg of ondansetron. 
 
Questionnaires. Participants may experience frustration and/or boredom completing the 
questionnaires. The participants may refuse to answer any questions for any reason. 

11 Nitrous oxide as treatment for tinnitus – a pilot study 
 

12 Nitrous oxide as treatment for tinnitus – a pilot study 
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