Optimal Dosing of Nortriptyline-Topiramate and Verapamil-Paroxetine Combinations in Tinnitus Treatment

Abstract

Objective:

To determine effective dose strategies for nortriptyline-topiramate (NT) and verapamil-paroxetine (VP) combinations for tinnitus treatment.

Methods:

This secondary analysis examined data from an 8-week, randomized, double-blind, placebo-controlled trial (RCT) evaluating treatment outcomes in 41 patients. Tinnitus Functional Index (TFI) scores were used as the primary outcome measure, administered at baseline, week 4, and week 8 to assess achievement of minimal clinically important differences (MCID) of 13-point reduction. Descriptive statistics were employed to characterize treatment responses and assess dose-response relationships.

Results:

In the NT group (n=19), 42% of the participants achieved a reduction in TFI scores meeting MCID with a mean dose of 44±12 mg nortriptyline plus 59±16 mg topiramate, all showing greater than 15% improvement. In the VP group (n=22), 41% reached MCID with a mean of 207±36 mg verapamil plus 28±5 mg paroxetine. Of these, 88.9% showed at least a 15% improvement in TFI. Early responders who achieved MCID by the midpoint of the trial required continued dose escalations due to limited improvement in weekly VAS scores afterward. However, subsequent TFI changes were not statistically significant.

Conclusions:

Both NT and VP regimens effectively reduce tinnitus severity in approximately half of the patients at moderate doses within 8 weeks. However, long-term effects may not have been fully captured, particularly among late improvers.

Introduction

Tinnitus is a prevalent and often debilitating condition that can significantly impact patients’ quality of life.^1,2 Despite its widespread prevalence, there is currently no pharmacotherapy approved by the U.S. Food and Drug Administration (FDA) for its treatment. As a result, management strategies based on existing research and clinical experience vary widely.^3–5 There has been considerable interest among researchers in exploring a range of nonpharmacological approaches and drug classes as potential treatments for the condition.^5,6 Pharmacological approaches for tinnitus typically target multiple pathways involved in tinnitus.⁴ Recent interest has turned to combination therapies which may offer additive or synergistic effects by simultaneously targeting these pathways.

In our previous study, we conducted a randomized placebo-controlled trial (RCT) to investigate the efficacy of nortriptyline plus topiramate (NT) and verapamil plus paroxetine (VP) in managing tinnitus.⁶ These medication combinations, commonly used in migraine treatment, were selected due to increasing evidence of an epidemiological and pathophysiological association between migraine and tinnitus.^7–12 The results demonstrated that both drug combinations significantly reduced tinnitus severity, as measured by the Tinnitus Functional Index (TFI) scores, compared to placebo. While our initial trial highlighted the potential benefits of these treatments, the optimal dosing strategies and the long-term effects were not fully explored. Determining an effective dosing strategy is critical for maximizing therapeutic benefits and minimizing adverse effects, particularly in conditions like tinnitus, where treatment responses show considerable variability among individuals. To address this gap, we conducted a secondary analysis of the data from our initial trial to evaluate the dose-based treatment outcomes of NT and VP combinations. By identifying optimal dosing strategies, this work aims to contribute to the development of more standardized and effective treatment protocols for tinnitus.

Methods

We conducted a secondary analysis of data obtained from an 8-week parallel-arm, double-blind, placebo-controlled RCT investigating the efficacy of NT and VP combinations in managing tinnitus.⁶ The study was approved by the UC Irvine Institutional Review Board, and registered on ClinicalTrials.gov (NCT04404439). The initial trial enrolled English-speaking adults aged 18 to 85 years with chronic (>6 months) moderate to severe tinnitus (TFI> 25). Participants underwent a comprehensive otolaryngologic assessment, which included an audiogram and otoacoustic emissions. Additionally, patients with unilateral tinnitus or asymmetric hearing loss who had not previously undergone imaging also received magnetic resonance imaging (MRI) of the internal auditory canals. Those with other medical conditions, such as neurological neoplasms, active ear diseases impacting hearing, psychosis, contraindications to the study medications, or those who were pregnant, were excluded from the study.

Participants were randomly assigned to one of three treatment arms: Group NT, Group VP, and placebo, with capsules of identical appearance to maintain blinding. Treatment began with an initial dosage of 1 capsule, containing 7.5 mg nortriptyline and 10 mg topiramate for Group NT, or 30 mg verapamil and 4 mg paroxetine for Group VP. Dosage escalation was guided based on a weekly assessment of tinnitus severity, measured using the Visual Analogue Scale (VAS). If a patient reported less than 20% improvement compared to the baseline tinnitus VAS, their dosage was increased by one additional capsule for the following week. If improvement was at least 20%, the dosage remained unchanged until the next weekly check-in. This stepwise regimen was adopted to minimize the potential side effects of the study medications. The maximum dose by the end of the 8-week trial was eight capsules (Figure 1).

Figure 1.

Flowchart illustrating the randomization, recruitment, and follow-up process of patients over the 8-week trial period.

During clinical visits at baseline, week 4, and week 8, participants completed a tablet-based TFI. A reduction of 13 points or more from baseline was designated as the Minimal Clinically Important Difference (MCID).¹³ In this follow-up analysis, a total of 41 patients from Group NT and Group VP who completed the original trial were included. The optimal dose was defined as the final dose among participants who achieved MCID reduction in TFI scores by the end of the trial. Additionally, the effective maintenance dose was determined by examining the dose required to sustain improvement among early responders. Paired t-tests were used to compare the change in TFI from baseline to weeks 4 and 8 for this subset, with a significance set at p<0.05. Descriptive statistics were used to characterize the optimal dose range for all responders. Baseline Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) scores were used to assess depression and anxiety levels, respectively. These variables, along with migraine history, were included in a multivariate linear regression to evaluate their potential as confounders in the treatment response.

Results

A total of 41 patients who completed the original 8-week RCT were included in this follow-up analysis: 19 in the NT group and 22 in the VP group. Baseline demographic and clinical characteristics of the participants across treatment arms are summarized in Table 1. In the NT group, 42% (n=8) of participants showed a clinically meaningful improvement with a mean dose of 44±12 mg nortriptyline and 59±16 mg topiramate, and a median dose of 49 mg nortriptyline and 65 mg topiramate. All responders achieved a minimum of 15% reduction in TFI scores (Table 2). Of these responders, two patients experienced side effects: one reported experiencing a metallic taste with a dose of 22.5 mg nortriptyline plus 30 mg topiramate, which resolved with temporary dose de-escalation. Another patient developed a bothersome dry mouth while taking a dose of 37.5 mg nortriptyline plus 50 mg topiramate.

Table 1.

Baseline Demographic and Clinical Characteristics of Participants

	Group NT	Group VP	Placebo
Number of Patients	19	22	26
Age (Mean ± SD)	58.1 ± 14.1	59.7 ± 14.2	58.3 ± 12.2
Sex
Male	15 (79%)	12 (55%)	17 (65.4%)
Female	4 (21%)	10 (45%)	9 (34.6%)
Ethnicity
White	13 (68%)	16 (73%)	18 (69%)
Black/African American	1 (5%)	1 (5%)	0 (0%)
Asian	1 (5%)	1 (5%)	3 (12%)
Other Race/ Mixed Race	1 (5%)	0 (0%)	2 (8%)
Unknown	3 (16%)	4 (18%)	3 (12%)
Tinnitus History (months)	33.7	69.6	107.2
Tinnitus Cause
Idiopathic	15 (79%)	19 (86%)	21 (81%)
Noise-Induced	0 (0%)	2 (9%)	1 (4%)
Stress-Related	3 (16%)	0 (0%)	1 (4%)
Trauma	0 (0%)	0 (0%)	1 (4%)
Post-Infectious/Immune-Related	2 (11%)	1 (5%)	0 (0%)
Medication-Related	0 (0%)	0 (0%)	2 (8%)
Laterality
Both ears equally or in the head	9 (47%)	9 (41%)	13 (50%)
Both ears but louder in right ear	3 (16%)	4 (41%)	4 (15%)
Both ears but louder in left ear	2 (11%)	5 (23%)	6 (23%)
Right ear only	1 (5%)	2 (9%)	0 (0%)
Left ear only	4 (21%)	2 (9%)	3 (12%)
Tinnitus Pattern
Constant	14 (74%)	16 (73%)	14 (54%)
Fluctuating	5 (26%)	6 (27%)	12 (46%)
Relevant Medical History
Migraine History	2 (11%)	7 (32%)	10 (38%)
Previous Migraine Treatment	2 (11%)	4 (18%)	4 (15%)
History of Anxiety and/or Depression	5 (26%)	1 (5%)	5 (19%)
Hearing Aids	2 (11%)	1 (5%)	2 (8%)

Table 2.

Average Doses of Nortriptyline and Topiramate by TFI Reduction Categories

ΔTFI (points)	Nortriptyline (mg)	Topiramate (mg)
>0	44±13	58±17
≥13 (MCID)	44±12	59±16
≥15	44±12	59±16

In the VP group, 41 % (n=9) of participants reached the MCID with a mean dose of 207±36 mg verapamil and 28±5 mg paroxetine, and a median dose of 210 mg verapamil and 28 mg paroxetine. Among responders, 89% (n=8) also demonstrated ≥15% improvement in TFI scores at an average dose of 206±38 mg verapamil and 28±5 mg paroxetine (Table 3) (Figure 2). Within the VP group, one patient reported a side effect of erectile dysfunction at a dose of 180 mg verapamil plus 24 mg paroxetine; one experienced a migraine headache while taking 210 mg verapamil plus 28 mg paroxetine, and another experienced fatigue and insomnia at the maximum dose of 240 mg verapamil plus 32 mg paroxetine, all three without achieving significant improvement (Table 4).

Table 3.

Average Doses of Verapamil and Paroxetine by TFI Reduction Categories

ΔTFI (points)	Verapamil (mg)	Paroxetine (mg)
>0	212±33	28±4
≥13 (MCID)	207±36	28±5
≥15	206±38	28±5

Figure 2.

Average Doses of NT and VP Combinations.

Table 4.

Reports of Adverse Effect

Adverse Effect	Group NT n (% of group)	Group VP n (% of group)
Change in taste	1 (5.3%)	0
Dry mouth	1 (5.3%)	0
Erectile dysfunction	0	1 (4.5%)
Migraine headache	0	1 (4.5%)
Insomnia	0	1 (4.5%)
Fatigue	0	1 (4.5%)

Responders in both treatment groups included a subset of participants who achieved a reduction in TFI scores meeting MCID by week 4, with mean initial doses of 21±8 mg nortriptyline and 28±11 mg topiramate in the NT group, and 114±12 mg verapamil and 15±2 mg paroxetine in the VP group. In the patients who had at least a 15% improvement in the TFI scores by week 4, further escalation to week 8 did not achieve a significant additional benefit. These early responders reported less than a 20% improvement compared to baseline in their weekly VAS assessments at various points between weeks 4 and 8. At the conclusion of the study, the final mean doses for these participants increased to 47±10 mg nortriptyline plus 63±13 mg topiramate, and 192±33 mg verapamil plus 26±4 mg paroxetine in NT and VP groups, respectively. No statistically significant differences were observed between baseline-to-week 4 and baseline-to-week 8 changes in TFI for either group (p>0.05). Multivariate analysis revealed that baseline PHQ-9 scores (p=0.42), GAD-7 scores (p=0.53), and migraine history (p=0.91) were not significant predictors of tinnitus improvement.

Discussion

This study aimed to determine the optimal dosing strategies for NT and VP combinations in managing tinnitus. Our findings show that moderate doses of both combinations—44±12 mg nortriptyline with 59±16 mg topiramate in the NT group and 207±36 mg verapamil with 28±5 mg paroxetine in the VP group—led to clinically meaningful improvement in tinnitus severity for approximately 40% of patients, as measured by the TFI score. Importantly, this was achieved using lower average doses of each medication compared to typical monotherapy dosing in the literature.

In our previous works, we proposed that the pathogenesis of loud or fluctuating tinnitus may be linked to spreading cortical depression—a phenomenon observed in migraine—that can trigger neurogenic inflammation and increase central sensitivity.^11,12 In contrast to migraine, where treatment protocols are well-established, the pharmacological management of tinnitus remains variable and lacks standardization.^3–5 Therefore, many drugs used to treat tinnitus are adapted from those used for migraine management, including antidepressants, anticonvulsants, and calcium channel blockers.⁴ Prior studies have demonstrated the efficacy of some of these drugs as monotherapies for tinnitus, allowing for some comparison with the dosing regimens used in our study.^14,15 For instance, in studies by Sullivan et al. and Dobie et al., nortriptyline was initiated at 25 mg and titrated up to 75–100 mg daily, with both studies showing nortriptyline to be superior to placebo for certain tinnitus measures, including loudness, tinnitus-related disability, and perceived improvement.^14,15

In our study, nortriptyline was initiated at just 7.5 mg, with the maximum dose reaching 60 mg, and a MCID reduction in TFI was observed with a mean dose of 44 mg. Topiramate is not specifically studied for tinnitus but is widely used for migraine prophylaxis, with typical doses being at least 100–200 mg/day.¹⁶ Its utility in migraine prevention is attributed to its ability to reduce cortical hyperexcitability, inhibit trigeminovascular neurons, and modulate central pain pathways.¹⁷ These mechanisms are also thought to be implicated in tinnitus, particularly through their interaction with auditory pathways.¹⁸ Our study utilized a maximum dose of 80 mg, with the optimal dose identified being 59 mg. Despite the lower doses used for these medications, we observed significant improvements in tinnitus severity. We believe these outcomes result from the synergistic effects of the combined medications, which target different pathways involved in migraine. In fact, a combination of nortriptyline-topiramate has been effective in treating migraine patients who are resistant to either drug alone.¹⁹ Taken together, this suggests that each agent may actively modulate tinnitus symptoms rather than merely serving as a passive adjunct.

Similarly, paroxetine has been investigated as a monotherapy for tinnitus in several studies, where higher doses were typically used compared to our study.^20,21 In an earlier RCT involving 120 patients with chronic tinnitus, paroxetine was initiated at 10 mg/day and titrated in 10 mg increments every two weeks to a maximum of 50 mg daily.²⁰ The authors reported only the highest dose of 50 mg/day demonstrated potential benefits in some tinnitus measures, such as hearing ability and reductions in tinnitus severity and bothersome.²⁰ Another trial involving 75 patients with moderate tinnitus also adopted a similar protocol, with an initial dose of 10 mg/day and a maximum dose of 40 mg/day.²¹ However, nearly 30% of participants in the first study and 20% in the second study receiving paroxetine treatment reported adverse effects, including sexual dysfunction, gastrointestinal disorders, and drowsiness.^20,21 In contrast, our VP group started with 4 mg/day of paroxetine and titrated up to a maximum of 32 mg/day. This was combined with verapamil, typically used at 240 to 320 mg/day for migraine prophylaxis,^22,23 due to its effects on cerebrovascular tone and its interaction with the serotonergic system, which may help alleviate central sensitization.²⁴ In our study, the dose was capped at 240 mg/day. The mean doses required for responders were even lower, at 28 mg paroxetine and 207 mg verapamil.

Notably, less than 15% of the participants experienced adverse effects, suggesting a more favorable tolerance profile at these lower doses. It is important to note that direct comparison between our findings and prior studies is challenging due to differences in methodology (combination vs. single drug) and outcome measures. However, a key insight from these findings is that combination therapy enables the use of lower doses than those typically required for monotherapy, while still eliciting considerable improvements in tinnitus severity. To further illustrate the clinical relevance of these responses, it is helpful to consider the concept of MCID. Studies suggest that a reduction of around 13 points in TFI scores is generally perceived as a meaningful change by patients, with some estimates ranging between 8 and 17 points depending on the methodology used.¹³ On the other hand, a score reduction below zero may indicate a potentially harmful effect. In our randomized clinical trial, we observed an absolute change in TFI scores of 12±13, 12±18, and 6.0±14 for the NT group, VP group, and placebo group, respectively (Figure 3).⁶ Despite the substantial variability, as indicated by the standard deviations, the results show that both the NT and VP combinations led to more clinically meaningful responses overall compared to placebo, even at lower doses (Figure 4).

Figure 3.

Mean change in TFI scores across treatment groups. The dashed line represents the MCID threshold of 13.

Figure 4.

Scattergram of changes in TFI scores for (a) Group NT, (b) Group VP, and (c) placebo between week 4 and baseline, and between week 8 and baseline. The dashed line represents the MCID threshold of 13.

The stepwise escalation strategy proved beneficial as a subset of patients achieved a clinically meaningful improvement in symptoms at a relatively lower dose by the midpoint of the trial. These early responders, comprising approximately half of the overall responder group, demonstrated that lower doses within the escalation protocol were sufficient to elicit notable reductions in tinnitus severity measured by TFI. However, in both groups, the escalation from weeks 4 to 8 did not yield additional statistically significant reductions in TFI scores, suggesting that dose increases during this period were effective primarily in sustaining initial improvements rather than driving further TFI reductions. The remaining responders experienced improvements later in the trial. One possible explanation for the plateau in early responders is that medication alone may not be sufficient for some patients. Studies suggest that avoiding dietary triggers and incorporating physical activity can alleviate tinnitus symptoms, indicating that integrating lifestyle modifications may help achieve further reductions in severity.^25–27

A small portion of the participants in each group experienced transient adverse effects (Table 4). These included dry mouth, changes in taste, and erectile dysfunction, which are known side effects associated with the study medications.^28–30 Rarer side effects, such as migraine headache and insomnia, were also noted. In some cases, these side effects required a temporary dose reduction. However, they were generally tolerable, with most patients either continuing dose escalation or maintaining the same dose.

This study has limitations. The 8-week trial duration may not have been sufficient to capture the full therapeutic potential or assess the long-term safety of the proposed regimens. Notably, most patients reached a plateau at week 7, possibly representing the typical timeframe for the medication to take full effect. Further investigation is needed to determine whether this finding is consistent across a larger population or coincidental. Additionally, we recognize that longer follow-up is necessary to evaluate potential delayed side effects, especially given the use of multiple medications in combination. Moreover, the study relied on self-reported measures, such as VAS, which may introduce bias or variability in assessing treatment effects. Despite these limitations, our study provides valuable insight into the optimal dosing of combination therapies for tinnitus, addressing a critical gap in the literature, where most existing research focuses on single-drug treatment. Based on our findings, lower-dose combination therapy may offer a synergistic effect and a viable approach to tinnitus management, particularly for patients who have not responded to previous monotherapy or are constrained by side effects at higher doses. Clinicians are encouraged to monitor for the need for dose escalation to sustain symptom relief and consider integrating non-pharmacological strategies if patients do not achieve the desired improvement with medication alone. In our practice, we always combine medical therapy with lifestyle changes to achieve the greatest effectiveness.

Conclusion

Both nortriptyline-topiramate and verapamil-paroxetine combination at moderate doses effectively reduce tinnitus severity in approximately 40% of patients, with fewer adverse effects compared to higher monotherapy doses typically used. These lower-dose combination therapies can expand treatment options for tinnitus management, especially for patients who have not responded to monotherapy or are unable to tolerate higher doses. While short-term results are promising, future studies should evaluate and confirm the long-term efficacy of these regimens.