Claudia Coelho

Methodological aspects of clinical trials in tinnitus: A proposal for an international standard

Chronic tinnitus is a common condition with a high burden of disease. While many different treatments are used in clinical practice, the evidence for the efficacy of these treatments is low and the variance of treatment response between individuals is high. This is most likely due to the great heterogeneity of tinnitus with respect to clinical features as well as underlying pathophysiological mechanisms. There is a clear need to find effective treatment options in tinnitus, however, clinical trials differ substantially with respect to methodological quality and design. Consequently, the conclusions that can be derived from these studies are limited and jeopardize comparison between studies. Here, we discuss our view of the most important aspects of trial design in clinical studies in tinnitus and make suggestions for an international methodological standard in tinnitus trials. We hope that the proposed methodological standard will stimulate scientific discussion and will help to improve the quality of trials in tinnitus.

Tinnitus Handicap Inventory for Evaluating Treatment Effects Which Changes Are Clinically Relevant

Objective. To determine the minimum change of the Tinnitus Handicap Inventory (THI) score that could be considered clinically relevant, the authors compared the absolute change of the THI with the Clinical Global Impression–Improvement (CGI-I) score. Study Design. International studies register with standardized data collection. Setting. Tinnitus Research Initiative (TRI). Subjects and Methods. Two hundred ten patients of the TRI database were eligible for this study. In the first analysis, the THI score change and CGI-I ratings were compared with equipercentile linking. In a second analysis, the authors categorized the CGI-I into the 4 groups much better or better, minimally better, no change, and worse and calculated the corresponding differences of the THI score and the effect sizes. An effect size separating the minimally better and the no-change groups was chosen, and the referring THI mean score difference was calculated. Results. According to the linking method, a CGI-I value of 3 (minimally better) corresponded to a THI score reduction of 6 to 16, whereas the CGI-I value of 4 (no change) corresponded to the range between improvement by 5 points and worsening by 4 points. For separating the no-change and minimally better groups, an effect size d = 0.5 was determined, resulting in a minimal clinically relevant difference of ΔTHI = 7. Conclusion. Two different methods yielded comparable results in identifying a reduction in the THI score of 6 and 7 points, respectively, as the minimal clinically relevant change. This study provides a first orientation for sample size calculations and for planning the design of future studies.

Clinical trials for tinnitus: study populations, designs, measurement variables, and data analysis.

We review a few issues related to clinical trials for treating patients with tinnitus, including the study population, design, choice of measurement variables, and some new approaches to data analysis. We emphasize the importance of being aware of different subgroups of tinnitus patients, and that patients who have had tinnitus for less than 6 months could be more amenable to treatment than patients who have had their tinnitus for a longer period. We distinguish the tinnitus itself, from the reactions to the tinnitus. When the treatment is intended to reduce the tinnitus, we recommend measuring the magnitude of the tinnitus. We provide arguments and data to support the use of the Tinnitus Handicap Questionnaire as a measure of the reaction to the tinnitus. We suggest that the current quality of life measures are not valid for measuring lifestyle effects of alleviating tinnitus. Because tinnitus likely has different subgroups, and because tinnitus affects people differently, we believe data analysis should emphasize individuals, not groups. A clinically meaningful effect should represent a valid and reliable statistical change for an individual.

A Review of Hyperacusis and Future Directions: Part I. Definitions and Manifestations

PURPOSE Hyperacusis can be extremely debilitating, and at present, there is no cure. We provide an overview of the field, and possible related areas, in the hope of facilitating future research. METHOD We review and reference literature on hyperacusis and related areas. We have divided the review into 2 articles. In Part I, we discuss definitions, epidemiology, different etiologies and subgroups, and how hyperacusis affects people. In Part II, we review measurements, models, mechanisms, and treatments, and we finish with some suggestions for further research. RESULTS Hyperacusis encompasses a wide range of reactions to sound, which can be grouped into the categories of excessive loudness, annoyance, fear, and pain. Many different causes have been proposed, and it will be important to appreciate and quantify different subgroups. Reasonable approaches to assessing the different forms of hyperacusis are emerging, including psychoacoustical measures, questionnaires, and brain imaging. CONCLUSIONS Hyperacusis can make life difficult for many, forcing sufferers to dramatically alter their work and social habits. We believe this is an opportune time to explore approaches to better understand and treat hyperacusis.

The relationship between tinnitus pitch and the audiogram.

We studied the relationship between tinnitus pitch and the audiogram in 195 patients. Patients with tone-like tinnitus reported a higher pitch (mean = 5385 Hz) compared to those with a noise-like quality (mean = 3266 Hz). Those with a flat audiogram were more likely to report: a noise-like tinnitus, a unilateral tinnitus, and have a pitch < 2000 Hz. The average duration of bilateral tinnitus (12 years) was longer than that of unilateral tinnitus (5 years). Older subjects reported a less severe tinnitus handicap questionnaire score. Patients with a notched audiogram often reported a pitch ≤8000 Hz. Subjects with normal hearing up to 8000 Hz tended to have a pitch ≥8000 Hz. We failed to find a relationship between the pitch and the edge of a high frequency hearing loss. Some individuals did exhibit a pitch at the low frequency edge of a hearing loss, but we could find no similar characteristics among these subjects. It is possible that a relationship between pitch and audiogram is present only in certain subgroups.

Tinnitus: Standard of Care, Personality Differences, Genetic Factors

We comment on three areas related to tinnitus. The standard of care should include counseling that is collaborative and that addresses the overall emotional well-being of the patient. Utilizing management and coping strategies is desirable. Our new tinnitus activities treatment is an example of such a protocol. We believe that the notions of fearfulness and acceptance have the potential to be integrated into tinnitus treatment. Some patients reject, control or accept their tinnitus. We believe in some instances there may be a common genetic cause of tinnitus and depression. A potential candidate is the serotonin transporter gene SLC6A4.

Tinnitus retraining therapy: mixing point and total masking are equally effective.

Objectives: Habituation to tinnitus cannot occur with total masking, an argument made by proponents of “tinnitus retraining therapy.” We also compared the effectiveness of retraining therapy with mixing-point masking, total masking, and with counseling alone. Design: Forty-eight tinnitus patients were randomly assigned to one of three groups: counseling, counseling plus bilateral noise generators set to completely mask the tinnitus, or counseling plus bilateral noise generators with a focus on the mixing point (partial masking just below total masking). A picture-based counseling protocol was used to assist in providing similar counseling among all three groups. The Tinnitus Handicap Questionnaire was administered before and after about 12 months of treatment. Results: After 12 months, in the counseling group, three of 18 patients benefited significantly, in the mixing-point group, six of 19 patients benefited, and in the total masking group, four of 11 patients benefited from the treatment. The average decrease in the questionnaire was 16.7% for the counseling group, 31.6% for the retraining group, and 36.4% for the total masking group. No significant average differences among groups were observed. Conclusions: One premise of retraining therapy is incorrect; a focus on mixing-point masking is not required for habituation.

A Review of Hyperacusis and Future Directions: Part II. Measurement, Mechanisms, and Treatment

PURPOSE Hyperacusis can be extremely debilitating, and at present, there is no cure. In this detailed review of the field, we consolidate present knowledge in the hope of facilitating future research. METHOD We review and reference the literature on hyperacusis and related areas. This is the 2nd of a 2-part review. RESULTS Hyperacusis encompasses a wide range of reactions to sounds, which can be grouped into the categories of excessive loudness, annoyance, fear, and pain. Reasonable approaches to assessing the different forms of hyperacusis are emerging, including brain-imaging studies. Researchers are only beginning to understand the many mechanisms at play, and valid animal models are still evolving. There are many counseling and sound-therapy approaches that some patients find helpful, but well-controlled studies are needed to measure their long-term efficacy and to test new approaches. CONCLUSIONS Hyperacusis can make life difficult in this increasingly noisy world, forcing sufferers to dramatically alter their work and social habits. We believe this is an opportune time to explore approaches to better understand and treat hyperacusis.

Development and validation of the tinnitus primary function questionnaire.

PURPOSE To create a questionnaire focused on the primary activities impaired by tinnitus and therefore more sensitive to treatments. METHOD Questions were developed on (a) emotions, (b) hearing, (c) sleep, and (d) concentration. A 20-item questionnaire was administered to 158 patients. First, confirmatory factor analysis was used to select 3 questions per domain. Second, factor analysis was used to evaluate the appropriateness of the 12-item questionnaire. RESULTS The analysis indicated that the selected questions successfully represented 4 independent domains. Scores were correlated with the Tinnitus Handicap Questionnaire ( r = .77, p < .01) and loudness ( r = .40, p < .01). The Sleep subscale correlated with the Pittsburgh Sleep Index ( r = .68, p < .01); the Emotion subscale correlated with the Beck Inventory ( r = .66, p < .01) and the Trait Anxiety questionnaire ( r = .67, p < .01). The average scores went from 51% to 38% following treatment. CONCLUSION The Tinnitus Primary Function Questionnaire is valid, reliable, and sensitive and can be used to determine the efficacy of clinical trials.

Zinc to treat tinnitus in the elderly: a randomized placebo controlled crossover trial.

Objective Several reports suggest that zinc, which is involved in several neural transmissions systems throughout the auditory pathway, might help some tinnitus patients. However, previous studies used inadequate experimental designs. Therefore, we tested the effectiveness of zinc to reduce tinnitus. Study Design Randomized, prospective double-blind placebo-controlled design. Setting Tertiary referral center. Patients Tinnitus subjects older than 60 years, who are more likely to have a zinc deficiency. Intervention(s) In Phase 1, 58 subjects were randomized to receive 50 mg of zinc per day for 4 months, and 58 subjects received a placebo. After a 1-month washout period, the 2 groups were crossed over to receive the alternative regime (Phase 2). Main Outcome Measure Difference scores between before and after measures of the Tinnitus Handicap Questionnaire. Changes on the difference scores 20 or greater were considered as a statistically significant and, therefore, clinically meaningful improvement for THQ. Results Five percent (5 of 93 patients) had an improvement of 20 points or greater in THQ scores after zinc treatment, whereas 2% (2 of 94 patients) had an improvement of 20 or greater in THQ scores after placebo. The difference between 2 proportions is 5/93 - 2/94 = 0.03, the estimate of relative improvement is (5/93) / (2/94) = 2.53, with 95% confidence interval from 0.5 to 12.7. From chi-square independent test, there was no significant evidence that patients treated by zinc improved better than those treated by placebo (X2 (1) = 1.4, p > 0.05). The observed power in THQ for zinc is 0.16, and that for placebo is 0.06. Conclusion Zinc is not an effective treatment for tinnitus in this subgroup of patients.