Treatment of Tinnitus With Migraine Medications: A Randomized Clinical Trial
Phase: PHASE4
Conditions: Tinnitus, Subjective, Tinnitus
Sponsor: University of California, Irvine

Treatment of Tinnitus with Migraine Medications: A Randomized Clinical Trial 
IRB #20184458 
NCT04404439 
Version 23 
IRB Approval to Date: December 12, 2023 
Initial Approval Date: July 9, 2021 
Background and Rationale 
Tinnitus can be categorized into objective and subjective types. In objective tinnitus, there is a 
physical explanation for the sound, such as abnormal blood flow or muscular contractions (e.g., 
palatal myoclonus). In contrast, subjective tinnitus is only perceived by the individual and is far 
more common. Emerging research has identified a significant relationship between subjective 
tinnitus and migraine, with studies reporting that 26–47% of patients with tinnitus experience 
concomitant headache, particularly unilateral migraines. 
Several observational and questionnaire-based studies have demonstrated that patients with both 
tinnitus and migraine report lower quality of life, greater symptom burden, and a higher 
prevalence of comorbid conditions such as hyperacusis, vertigo, pain syndromes, and depressive 
symptoms. Migraine laterality (left-sided or bilateral) and type (migraine with aura, cluster 
headache) have also been shown to influence symptom severity. Other case series suggest that 
the intensity of tinnitus may increase during migraine episodes, potentially due to shared 
mechanisms such as central sensitization or cortical hyperexcitability. 
Additional large-scale studies in young adults have found statistically significant associations 
between tinnitus and migraine, especially in those with migraine with aura. This supports the 
hypothesis that migraine and tinnitus may share underlying pathophysiological pathways. 
Currently, there is no FDA-approved pharmacologic treatment for tinnitus. Existing management 
strategies are limited to lifestyle modifications, cognitive behavioral therapy (CBT), and sound 
therapy. Psychoactive medications are sometimes used off-label to alleviate the psychological 
distress associated with tinnitus, though they are not curative. Among them, tricyclic 
antidepressants like nortriptyline have shown promise in reducing tinnitus severity, even in 
patients without comorbid depression. The neural circuits implicated in tinnitus overlap with 
those affected in mood, anxiety, and pain disorders — particularly in limbic and fronto-
subcortical regions — suggesting a shared neurological basis involving maladaptive cortical 
plasticity. 

We hypothesize that patients may benefit from medications targeting migraine-related neural 
dysregulation, even in the absence of formal headache diagnosis. This includes agents like 
nortriptyline, topiramate (a sodium-calcium channel blocker), verapamil (a calcium channel 
blocker), and paroxetine (a selective serotonin reuptake inhibitor). These medications may help 
modulate cortical excitability and reduce the perception and intensity of tinnitus. 
This randomized, placebo-controlled trial aims to evaluate the efficacy of nortriptyline plus 
topiramate and verapamil plus paroxetine in reducing tinnitus symptoms. We will assess changes 
in tinnitus severity using a visual analog scale (VAS) and the Tinnitus Functional Index (TFI), as 
well as the frequency and duration of tinnitus episodes. Secondary outcome measures include the 
impact on comorbid symptoms such as motion sensitivity, photophobia, phonophobia, facial 
pain, neck stiffness, and headache-related features. 
Our goal is to generate high-quality clinical evidence for migraine-prophylactic pharmacotherapy 
as a novel treatment strategy for subjective tinnitus. 
Objectives 
Aim 1: To determine if tinnitus symptoms improve with specific migraine regimens compared to 
those taking no medication based on number of tinnitus episodes per week, duration of tinnitus 
episodes, and tinnitus severity.  
Aim 2: The doses at which these medications should be given for tinnitus not yet been 
determined; thus, one aim would be to further elucidate this.  
Aim 3: To study the effect of the medications on presence and duration of other concomitant 
symptoms, presence of migraine related symptoms and clinical features such as sensitivity to 
motion, light, sound, pain in face or scalp, neck stiffness, and headaches as secondary outcomes. 
Study Design 
This study is a randomized controlled study. There will be three arms in the experiment. The first 
will be the placebo group, the second will be the nortriptyline (7.5 mg) plus topiramate (10 mg) 
group, and the third will be the verapamil (30 mg) plus paroxetine (4 mg) group. Both 
medication combinations may include dosage increases, as will be explained in the following 
paragraph. The placebo pill’s ingredient is microcrystalline cellulose. 
The symptomatic survey scores from each arm will be compared before and after treatment. This 
will be a double-blinded trial to avoid bias. One unblinded research staff member will be in 
charge of randomization, treatment assignment tracking, and coordinating with the pharmacy to 
ensure proper labeling and blinding. Simple randomization, using a computer-generated number 
sequence, will be performed in a 1:1:1 ratio for the two treatment groups and the placebo group. 

During the 2-month study course, each patient assigned to the treatment groups will receive 
nortriptyline plus topiramate or verapamil plus paroxetine. Failure to improve with one 
combination will not result in crossover to another group. Files containing treatment group 
assignments and follow-up survey results will be stored securely on REDCap servers. 
An unblinded clinical team member will serve as the data safety monitor. This individual will 
oversee symptom progression and provide safety oversight, including recommendations for dose 
adjustments or withdrawal if adverse effects occur. 
Patients receiving nortriptyline plus topiramate will begin treatment at 7.5 mg nortriptyline and 
10 mg topiramate taken at bedtime. A baseline tinnitus visual analog scale (VAS) score and 
tinnitus functional index (TFI) score will be obtained. A designated, unblinded study physician 
will contact participants weekly by phone to assess VAS improvement and potential side effects. 
If symptoms do not improve by at least 20% compared to baseline VAS, patients will be 
instructed to increase their dosage by 7.5 mg nortriptyline and 10 mg topiramate, respectively, 
for one week. If improvement is ≥20%, dosage will be maintained until the next check-in. 
This dose adjustment protocol will continue until the maximum dosage is reached (60 mg for 
nortriptyline and 80 mg for topiramate). Participants will attend in-person visits at the beginning 
of the trial (Week 0), Week 4, and Week 8. During these appointments, a blinded physician will 
administer a VAS and oversee completion of TFI and secondary outcome questionnaires using a 
tablet device. All responses will be securely stored in REDCap. 
Blood pressure and ECG readings will be obtained at each in-person visit. TFI and secondary 
outcome measures will be analyzed at the end of the trial by the principal investigator, who 
remains blinded to treatment assignment. Weekly symptom reports and monthly safety data 
(blood pressure, ECG results) will be reviewed by the unblinded safety monitor to assess for any 
adverse effects. Based on clinical judgment, the safety monitor may recommend dosage changes 
or participant withdrawal from the trial. 
The same experimental design will apply to the verapamil plus paroxetine group, with different 
starting doses. Verapamil will begin at 30 mg and increase by 30 mg weekly until symptom 
improvement, up to a maximum dose of 240 mg. Paroxetine will start at 4 mg and increase by 4 
mg weekly up to a maximum dose of 32 mg. With both treatment combinations, gradual titration 
is required to reach therapeutic levels. Dosage reductions must also be tapered to avoid 
withdrawal effects. 
The placebo group will receive capsules identical in size and shape to the treatment groups. 
Participants in this group will follow the same weekly dose escalation protocol unless they report 
≥20% symptom improvement. 

All participants will be asked to report potential side effects. These reports will be reviewed by 
the clinical team and communicated to the unblinded safety monitor, who will oversee patient 
safety and determine the need for dose modifications or early withdrawal. At the end of the 2-
month study period, participants who are symptom-free will undergo a tapering schedule to 
discontinue medication. Participants who continue to experience symptoms may be offered 
additional treatment outside the context of the trial based on the clinical discretion of the lead 
investigator. Because there is currently no standard of care for this condition, individualized 
follow-up care will be based on best available treatment options. 
Primary and Secondary Endpoints 
Efficacy will be evaluated using validated survey instruments that assess tinnitus severity and its 
impact on daily life. 
• 
The primary endpoint is the change in Tinnitus Functional Index (TFI) score from 
baseline to the end of treatment. 
• 
Secondary endpoints include: 
o Midpoint TFI (Week 4) 
o Perceived Stress Scale (PSS) 
o Sleep Quality Index (PSQI) 
o Patient Health Questionnaire (PHQ-9) 
o Self-reported symptoms related to tinnitus and vestibular migraine, including: 
▪ 
Sensitivity to motion 
▪ 
Sensitivity to light 
▪ 
Sensitivity to sound 
▪ 
Pain in the face or scalp 
▪ 
Neck stiffness 
▪ 
Headaches 
Side effects will be assessed and recorded during follow-up appointments and weekly phone 
calls. 

At the end of the trial: 
• 
Treatment success is defined as a >20% improvement in TFI score compared to 
baseline. 
• 
Treatment failure is defined as an improvement of <20% in TFI score compared to 
baseline. 
Statistical Analysis Plan (SAP) 
To determine the statistical significance the three arms of the experimental groups will be 
compared using ANOVA. 
The primary statistical method used to compare the three groups is ANOVA. Multiple 
instruments will be used to determine the difference between treatment and control (placebo) 
groups. The primary outcomes measure is the tinnitus functional index (TFI) score before and 
after treatment. ANOVA will be used to compare secondary outcome variables including 
perceived stress scale, sleep quality index, and patient health questionnaire scores, number and 
duration of tinnitus episodes, and presence and duration of migraine related symptoms and 
clinical features such as sensitivity to motion, light, sound, pain in face or scalp, neck stiffness, 
and headaches. 
Bonferroni correction will be necessary because both experimental groups (nortriptyline plus 
topiramate and verapamil plus paroxetine) will be compared to control outcomes and also to each 
other. Thus, comparisons will be made between all three groups using two groups at a time. 
Based on our pilot data, we hypothesized that the mean change in tinnitus functional index (TFI) 
after 2 months of treatment would be 70% (± 10%) among patients receiving 
nortriptyline+topiramate, 50% (± 10%) among patients receiving verapamil+paroxetine, and 
20% (± 10%) among patients receiving placebo. A sample size of 10 patients per group would 
yield at least 80% power to test this hypothesis using two-sided t tests at 1.7% significance level, 
adjusted for an attrition rate of 20% (Bonferroni correction was applied to adjust the significance 
level for multiple treatment comparisons). Thus, the proposed sample size of 21 patient per 
group would provide more than adequate power to test the hypothesis. 
Eligibility: Patients with tinnitus 
Inclusion Criteria: 
1) Patients with moderate to severe tinnitus.  
2) Male or female between the ages of 25 to 85 years.  

3) Subject must be compliant with the medication and attend study visits.  
4) Must be able to read and write in the English language to provide consenting. 
Exclusion Criteria: 
1) Pregnancy will result in automatic exclusion from the study. Rule out of pregnancy will 
be done by a urine pregnancy test to confirm the situation for all women who are of 
childbearing potential.  
2) Subject with history of an adverse reaction to medication being prescribed.  
3) Subject suffers from a medical condition or has history that may be concerning to the 
investigator’s clinical opinion.  
4) All contraindications for the medications which prevent subjects from randomization will 
be considered as exclusion criteria. 
Outcome Measures 
The criteria for evaluation of efficacy in treatment will be the administration of surveys that 
measure severity of tinnitus and impact on daily life of the subject. The primary endpoint is the 
comparison of tinnitus functional index (TFI) scores before and after treatment. Secondary 
endpoints include additional questionnaires including the perceived stress scale, sleep quality 
index, patient health questionnaire, mid-point TFI, and questions that address the presence and 
duration of other signs and symptoms related to tinnitus, vestibular migraine, presence of 
migraine related symptoms and clinical features such as sensitivity to motion, light, sound, pain 
in face or scalp, neck stiffness, and headaches. Side effects will be assessed and recorded during 
follow-up appointments and regular phone calls to patients. 
At the end of the trial, treatment success will be defined as an improvement in TFI score of 
>20% as compared to baseline TFI score. Treatment failure will be defined as an improvement in 
TFI score of <20%.