Comparative analysis of efficacy, safety, and cost-effectiveness of betahistine alone, caroverine alone, and caroverine plus ginkgo biloba in moderate tinnitus

Abstract

BACKGROUND:

Tinnitus or “phantom sound” continues to be a significant health problem without a uniformly accepted treatment. Numerous pharmaceutical options have been investigated, but satisfactory results are yet to be obtained.

OBJECTIVES:

The objectives of this study were to study and compare the efficacy, safety, and cost-effectiveness of caroverine alone, caroverine combined with ginkgo biloba and betahistine alone in patients of moderate tinnitus.

MATERIALS AND METHODS:

In this prospective, observational, hospital-based study, wherein 72 patients were distributed equally across three groups – Group A received caroverine 20 mg twice daily, Group B received caroverine 20 mg combined with ginkgo biloba 120 mg twice daily, and Group C received betahistine 8 mg thrice daily for 12 weeks. Efficacy was zanalyzed assessing the changes in tinnitus handicap inventory (THI), tinnitus functional index (TFI), Visual Analog Scale (VAS) score, and pure tone audiometry values from baseline at 4, 8 and 12 weeks. The cost-effectiveness analysis was done at the end of 12 weeks zutilizing the incremental costeffectiveness ratio. The Chi-square test and one-way ANOVA were used to evaluate the statistical significance of the results.

RESULTS:

The reduction in the THI, TFI and VAS scores was maximum in Group B followed by Group A and Group C. All the drugs were well-tolerated, and the adverse effects encountered were mild and nonserious. Combination therapy of caroverine with gingkgo biloba was the most expensive.

CONCLUSION:

Caroverine and ginkgo biloba combination therapy was the most effective in reducing the handicap of moderate tinnitus.

Introduction

Tinnitus is defined as perception of an auditory sensation perceived in the ears or head that is not related to an external acoustic stimulus.[1] It can be zcategorized into subjective or objective tinnitus. While subjective tinnitus is the perception of sound in the absence of an acoustic stimulus and is limited to those who are affected, objective tinnitus is the generation of sound close to the ear that can be heard by the examiner using a stethoscope.[1,2] Tinnitus is prevalent among 6%–7% of the Indian population, of which <1% suffer from tinnitus of sufficient severity to seriously impair their quality of life, affecting sleep, concentration, emotional balance and social activity, and disabling the pursuit of normal activities.[3,4]

In our setup, caroverine, ginkgo biloba, and betahistine are frequently used to treat moderate tinnitus. Caroverine is a glutamate receptor antagonist that inhibits both AMPA- and NMDA-induced neuronal firing, hence reducing the excitability of nerve cell activity. Ginkgo biloba is a plant extract having antioxidant, vascular smooth muscle relaxant properties, and antagonistic action to platelet-activating factor that alleviates tinnitus symptoms by improving microcirculation to the affected cochlear hair cells.[5,6] Betahistine (an H3 antagonist and H1 agonist) enhances microcirculation in the inner ear, consequently promoting and enabling central vestibular compensation. Caroverine, being an expensive alternative, is crucial to correlate its effectiveness and cost as a monotherapy and combination therapy to the less expensive alternatives. Apparently, there are relatively few studies that compare the efficacy and cost-effectiveness of these three drugs. With this background, the current study was designed to compare the efficacy, safety, and cost-effectiveness of the aforementioned treatment alternatives for moderate tinnitus.

Materials and Methods

This 2-year prospective, observational, hospital-based study was conducted in the Department of Pharmacology in collaboration with the Department of ENT at S.C.B. Medical College and Hospital, Cuttack with the aim to compare the effectiveness of caroverine monotherapy, caroverine with ginkgo biloba, and betahistine monotherapy in the treatment of moderate tinnitus. The primary objective was to determine the efficacy and safety of the aforementioned drugs, and the secondary objective of the study was to evaluate their cost-effectiveness. Ethical approval was obtained from the institutional ethics committee before the start of the study (ECR/84/Inst/OR/2013/RR-20). Written informed consent was taken from all the participants before enrolling them and strict confidentiality was maintained throughout the study. The study was executed in accordance with the principles of the International Conference on Harmonization Good Clinical Practices and the Declaration of Helsinki.

Patients clinically diagnosed with moderate tinnitus attending the Department of ENT, SCBMCH were screened. A case of moderate tinnitus was defined as one having tinnitus handicap inventory (THI) score between 38 and 56.[7] These patients experience tinnitus even in the presence of background noise, yet they are able to perform their routine activities without any difficulties. Individuals between 18 and 60 years, having tinnitus for at least 6 months’ duration, with normal hearing or mild-to-moderate sensorineural hearing loss, and ability to comprehend and follow the instructions were included in the study. Those with severe tinnitus, other otological conditions (Meniere’s disease and otosclerosis), history of blast injury to the ear, history of substance abuse, serious medical conditions (cardiovascular disease, uncontrolled diabetes, uncontrolled hypertension, and hepatic or renal disease), psychiatric illness, history of ototoxic medications within the last 3 months, expectant or lactating mothers were excluded from the study. X-ray radiograph of the mastoid and high-resolution computer tomography of the temporal bone was done to rule out any organic anomalies. The sample size was calculated using the formula N = 2 (Z_α/2 + Z_β)²× (SD)²/δ², where SD = standard deviation and δ = effect size. Assuming 95% confidence interval (α =0.05), 80% power (β =0.02), 5% effect size, and expecting a 20% loss to follow-up, the sample size in each group was calculated to be 24. Hence, the total sample size was 24 × 3 = 72.

Patients in Group A (n = 24) received tabletcaroverine 20 mg twice daily, Group B (n = 24) were given caroverine 20 mg and ginkgo biloba 120 mg twice daily, and Group C (n = 24) received tablet betahistine 8 mg thrice daily [Figure 1]. The course of treatment lasted for 12 weeks for each patient. The patients were followed-up at 4 weeks, 8 weeks, and at the end of 12 weeks of initiation of treatment. They are strictly instructed to report any kind of adverse effects in the course of the study.

Figure 1.

STROBE flow diagram

Efficacy, safety, and cost-effectiveness analysis

Subjective assessment was done by comparing THI score, Visual Analog Scale (VAS) score, tinnitus functional index (TFI) score and tuning fork tests (TFT) findings. Objective assessment was done by pure tone audiometry (PTA). Safety was evaluated in terms of the adverse drug reaction(s) (ADRs) encountered during the study period. The ADRs were recorded in the suspected ADR reporting form issued by the Pharmacovigilance Programme of India.[8] The causality and severity of the reported ADRs were evaluated using the WHO-UMC causality assessment scale and modified Hartwig–Siegel severity assessment scale, respectively.[9,10] Cost-effectiveness of the three treatment modalities was determined at the end of 12 weeks by employing the incremental cost- effectiveness ratio (ICER) and cost-effective plane analysis.[11]

The patient details collected on the case record form were entered into a Microsoft Excel sheet and statistically zanalyzed using SPSS v20.0 IBM SPSS Inc., Chicago, IL, USA. Numerical data were expressed in terms of mean ± SD, and categorical data were expressed in terms of frequency and percentage. Categorical data were evaluated using Chi-square test and numerical unpaired data were evaluated using analysis of variance (ANOVA). Results were deemed statistically significant at P < 0.05.

Results

A total of 110 patients with moderate tinnitus were screened of which 72 (46 males and 26 females) were enrolled into the study. The average age of the participants was 46.7 ± 4.5 years and 44% aged between 41 and 50 years. The baseline THI, TFI, and VAS scores of the three groups were comparable (P > 0.05); the difference in the baseline PTA values was statistically significant [Table 1].

Table 1.

Baseline parameters

	Group A (n=24), n (%)	Group B (n=24), n (%)	Group C (n=24), (%)	P
Gender distribution
Male	17 (70.8)	15 (62.5)	14 (58.3)	0.66*
Female	7 (29.2)	9 (37.5)	10 (41.7)
Other	-	-	-
Age distribution (years)
Average age	43.8±3.4	44.4±2.8	42.3±3.6	0.08#
18–30	4 (16.7)	9 (37.5)	6 (25)	0.67*
31–40	7 (29.2)	5 (20.8)	4 (16.7)
41–50	8 (33.3)	6 (25)	7 (29.2)
51–60	5 (20.8)	4 (16.7)	7 (29.2)
THI score	48.66±3.93	49.66±5.34	47.16±4.70	0.186#
TFI score	49.66±3.93	50.66±5.34	48.16±4.70	0.186#
VAS score	5.33±0.49	5.33±0.49	5.11±0.51	0.216#
PTA value
Left ear	36.46±4.53	38.89±5.69	33.76±3.02	0.038#
Right ear	37.26±4.53	35.54±4.44	32.78±2.82	0.019#

*Chi-square test, ^#One-way ANOVA, results are significant at P<0.05. THI=Tinnitus handicap inventory, TFI=Tinnitus functional index, VAS=Visual Analog Scale, PTA=Pure tone audiometry

The reduction in the THI, TFI, and VAS scores was maximum in Group B followed by Group A and Group C [Table 2]. The difference in the THI and TFI scores across the three groups was statistically significant at 8 weeks (P = 0.000) and at 12 weeks (P = 0.000), whereas the difference in the VAS score across the three groups was statistically significant at 12 weeks (P = 0.000).

Table 2.

Intergroup comparison in the tinnitus handicap inventory score, tinnitus functional index score, and Visual Analog Scale score

	Group A (n=24)	Group B (n=24)	Group C (n=24)	P #
THI score
At 4 weeks	28.75±3.33	28.20±3.82	28.76±4.16	0.842
At 8 weeks	14.16±2.85	12.59±2.87	20.33±3.5	0.000
At 12 weeks	8.25±1.71	6.76±1.97	13.5±2.25	0.000
TFI score
At 4 weeks	30.75±3.33	30.29±3.82	30.82±4.16	0.871
At 8 weeks	15.16±2.85	13.71±2.87	19.2±3.5	0.000
At 12 weeks	8.16±1.84	6.38±1.97	14.36±2.25	0.000
VAS score
At 4 weeks	3.5±0.52	3.5±0.52	3.41±0.53	0.790
At 8 weeks	2.25±0.45	2.08±0.28	2.29±0.38	0.130
At 12 weeks	1.0±0.1	0.79±0.28	1.5±0.15	0.000

^#One-way ANOVA results are significant at P<0.05. THI=Tinnitus handicap inventory, TFI=Tinnitus functional index, VAS=Visual Analog Scale

Table 1 shows the average PTA values (in decibels) of the affected ears (unilateral or bilateral) at baseline. At 12 weeks, the PTA values significantly decreased in all the three groups [Figure 2] – in Group A (left: 68% reduction, right: 66.6% reduction [P < 0.05]), Group B (left: 71.7% reduction, right: 68.4% reduction [P < 0.05]), and Group C (left: 60.5% reduction, right: 65.7% reduction [P < 0.05]). However, the difference in the reduction in the PTA values across the three groups at 12 weeks was not statistically significant (left ear [P = 0.253], right ear [P = 0.43]).

Figure 2.

Trend in the pure tone audiometry values of the affected ears in the three treatment groups. PTA = Pure tone audiometry

Ten out of 72 participants reported ADR. The most common ADR was dryness of the mouth (n = 3) and nausea (n = 3), followed by headache (n = 2), dizziness (n = 1), and vomiting (n = 1 each). Although ADRs were more common with Groups A and B, the frequency of ADRs across the three groups was comparable (Group A: 4, Group B: 4, Group C: 2; Chi-square test, P = 0.63). Out of 10, 8 ADRs were mild and 2 were moderate; none were severe or serious in nature. Causality assessment of the ADRs revealed that five were probable/likely, three were possible, and two were unlikely due to the suspected drug.

At the end of 12 weeks, the cost-effectiveness of caroverine monotherapy (Group A) and caroverine combined with ginkgo biloba (Group B) was compared against betahistine monotherapy (Group C). When comparing Group A and Group C, it was shown that for every unit increase in efficacy (expressed as a percentage change in the mean THI scores), the cost of treating moderate tinnitus was increased by 75 INR with caroverine. Similarly, comparing Group B and Group C revealed that the cost of treating moderate tinnitus with caroverine and ginkgo biloba dual therapy was 327 INR more than with betahistine for each unit improvement in the mean THI score. Precisely, the cost-effectiveness analyses lie in the second quadrant of the cost-analysis plane, i.e. more effective and more costly [Figure 3].

Figure 3.

Cost-effective analysis of the three treatment modalities

Discussion

With a baseline prevalence of 8.2% and 5-year incidence of 5.7%, idiopathic subjective tinnitus is the most prevalent type of tinnitus.[2] Being a subjective phenomenon, assessment of the outcome of tinnitus is the most challenging aspect of conducting clinical research. Several drugs have been tried from time to time for subjective tinnitus, but none have demonstrated promising results.[12,13,14] Due to the advances in our knowledge of molecular pharmacology of tinnitus that ensure a more rational approach towards pharmacotherapy of tinnitus, the last decade has given patients hope that their distress may be alleviated. This comparative prospective study was conducted to assess the efficacy, safety, and cost-effectiveness of caroverine monotherapy, betahistine monotherapy, and caroverine with ginkgo biloba combination therapy in patients with moderate tinnitus in a tertiary health care center.

The average ages of the study subjects in Groups A, Group B, and Group C were 43.8 ± 3.4, 44.4 ± 2.8, and 42.3 ± 3.6 years, respectively (P = 0.08). The age group of 41–50 years accounted for the majority of cases. These findings were consistent with the findings of Nishad et al. and Laskar et al.[15,16] However, our findings differed from the findings of Turunen-Taheri et al. where most of the patients belonged to the age range of 51–60 years, and Reddy.[17,18] It has been observed that tinnitus can occur at earlier ages, despite its substantial correlation with advancing age. Approximately 5% of teenagers and 8% of young people between the ages of 18–30 experience concerning tinnitus.[19] Risk factors for younger people include chronic exposure to loud noise, poor attitude toward hearing protection, substance abuse, ear infections and exposure to ototoxic drugs. 63.8% of the participants in our study were men and 36.2% were women. Similar male preponderance was found in other comparable studies.[15,18,20] In some cases, although there was a female preponderance in others.[17] The higher male preponderance is not biological but could be due to environmental and lifestyle factors such as higher occupational exposure towards loud noise, greater prevalence of tobacco, and alcohol abuse and their higher probabilities of visiting the hospital than women.[21]

An intragroup analysis revealed that following treatment, the reduction in mean THI score, and mean TFI score from baseline was extremely significant in each group at 4 weeks, 8 weeks, and 12 weeks (P < 0.0001). Our study’s results were consistent with findings of other studies.[15,22] Our findings differed from studies by Jain et al. and Mahendru et al.[20,23] The notable effect of caroverine could be explained by glutamate receptor blockade, which halts the impulses between the inner hair cells and cochlear nerve fibers. While betahistine is a useful treatment option in other vestibular disorders like Meniere’s disease, some studies advocate it is equivalent to placebo.[24] The antitinnitus benefits of ginkgo biloba could be attributed to the vasodilation-mediated improved cochlear blood supply along with its antioxidant and neuroprotective actions. Studies in support of ginkgo biloba have reported that its effectiveness persists even after cessation of its treatment. A comparative study by Nishad et al. suggested that contrary to caroverine ginkgo is capable of completely abolishing tinnitus. This study further concluded that combination therapy of caroverin and ginkgo biloba, appropriately zcustomized to the patient’s needs will provide improved outcomes in greater majority of patients.[15]

In our study, the TFTs revealed that air conduction was better than bone conduction in all cases, indicating sensorineural hearing loss to some degree. As compared to the baseline values, there was a significant reduction in the PTA threshold values and improvement in hearing in both the affected ears in Groups A, B, and C at the end of 12 weeks (P < 0.05). However, an intergroup comparison showed that the three groups did not differ significantly in terms of the improvement of PTA values (one-way ANOVA, P > 0.05). These findings were consistent with the findings of previous studies.[15,18,20]

All the drugs were well tolerated. The most frequently encountered ADRs were dryness of mouth, nausea (n = 3 each), headache (n = 2), and dizziness and vomiting (n = 1 each) – a total of 10 ADRs. Most of the ADRs were mild (n = 8) and moderate (n = 2). No serious ADRs were observed. These findings were consistent with findings of Mahendru et al.[23]

To zanalyze the relative costs and effects (outcomes) of the various treatment plans, pairwise cost-effectiveness analysis was performed in our study [Table 3]. A pair-wise comparison was conducted between the following combinations–betahistine monotherapy and caroverine monotherapy (pair 1), betahistine monotherapy and caroverine plus ginkgo biloba combination therapy (pair 2), and caroverine alone and caroverine plus ginkgo biloba (pair 3).

Table 3.

Relative costs and outcomes of the three treatment modalities in our study

	Caroverine alone	Caroverine plus ginkgo biloba	Betahistine alone
Cost per tablet (INR)	20.46	20.46+25=45.46	9.73
Number of patients	24	24	24
Dosage	Twice daily	Twice daily	Thrice daily
Total duration (days)	90	90	90
Total cost (INR)	20.46×24×2×90=88,387	45.46×24×2×90=196,387	9.73×24×3×90=63,050
Cost per patient	3683	8183	2627
Percentage change in THI at 12 weeks	83	86.4	69.4

ICER=Difference in costs/difference in outcomes. INR=Indian National Rupees, THI=Tinnitus handicap inventory, ICER=incremental costeffectiveness ratio

The per-patient cost of caroverine and betahistine was Rs 3683 and Rs 2627, respectively. The incremental cost-effective ratio (ICER) between Groups A and C was 75. The data indicated that for a unit increase in the efficacy of caroverine, there was a rise in the cost by Rs 75. The following cost-effectiveness quadrant analysis, caroverine appeared to be more expensive and less effective as compared to betahistine [quadrant 1, Figure 3]. The per-patient cost of caroverine plus ginkgo biloba was Rs. 196,387. The ICER between Group B and C was found out to be 327. That meant that for every unit increase in the efficacy of the combination of ginkgo biloba and caroverine, the cost increased by Rs. 327. Like caroverine, caroverine plus ginkgo biloba combination also seemed to be more expensive and less effective as compared to betahistine [quadrant 1, Figure 3]. When caroverine monotherapy and combination therapy were compared, the combination therapy emerged to be costlier than the monotherapy, with every unit increase in efficacy of the combination therapy costing an additional Rs. 1323.

Given the unique challenges and constraints following the outbreak of the COVID-19 pandemic, notably limited time, resources and access to patients, it was not feasible to implement a randomized study design. Although the study was an observational one, adhering to a uniform protocol and incorporating objective, quantifiable tools to complement subjective observations aided in minimizing bias, ensuring integrity of the results. This study can be viewed as a proof of concept investigation underlining the importance of undertaking a robust randomized blinded trial with a larger sample size to draw important conclusions and help develop a treatment plan for tinnitus.

Conclusion

Caroverine monotherapy and combination therapy with ginkgo biloba was more effective in reducing the severity of moderate tinnitus when compared to betahistine. Caroverine combination therapy with ginkgo biloba was the most expensive, followed by caroverine monotherapy and betahistine monotherapy. To conclude, all the three drugs were safe and effective; yet the combination of caroverine and ginkgo biloba proved to be to be most successful in terms of efficacy, safety and cost-effectiveness.

Future research must focus on the long-term outcomes of these treatment modalities and the integration of pharmacological and nonpharmacological interventions to optimize patient outcomes while keeping costs in mind.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.