Tinnitus involves the perception of sound or sounds in the ear or head without an external source. Most individuals experiencing tinnitus have a neutral reaction to the perception [1]. Although tinnitus may be induced by a peripheral insult such as cochlear pathology, the structures responsible for generating tinnitus are mainly found centrally, in and around the primary auditory cortex and in many nonauditory higher-order processing centers [2]. Reduced input to the auditory nerve shifts the balance of central excitation and inhibition, which may lead to hyperactivity, increased burst activity, and a more predominant pattern of synchrony [2].

The 2014 American Academy of Otolaryngology-Head and Neck Surgery Foundation Clinical Practice Guidelines for Tinnitus only recommend cognitive behavioral therapy as an evidence-based therapy for persistent, inconvenient tinnitus [3]. These guidelines also recommend against (1) antidepressants, anticonvulsants, anxiolytics, or intratympanic medications; (2) Ginkgo biloba, melatonin, zinc, or other dietary supplements; and (3) transcranial magnetic stimulation as routine treatment [4]. To date, however, a standard treatment for tinnitus has not been well established, and treatment is often insufficient.

Intratympanic steroid injection (ITSI) is an effective treatment modality for various inner ear diseases such as sudden sensorineural hearing loss and Menière disease. Intratympanic dexamethasone injection (ITDI) has been introduced as a treatment option for subjective tinnitus. In 1982, Sakata et al. [5] first reported the effectiveness of ITDI in patients suffering from cochlear tinnitus. They reported overall good results in 77% of patients 1 month after ITDI. Additionally, Shulman and Goldstein [6] showed that five of 10 patients experienced tinnitus control for at least 1 year after ITDI. However, in 2005, Araujo et al. [7] published a randomized single-blind study showing that ITDI had no advantage over saline in the treatment of severe, disabling tinnitus. In light of the inconsistent findings described above, the benefits of ITDI in patients with tinnitus remain unclear. In the present meta-analysis, we evaluated the efficacy of ITDI for tinnitus treatment.

This systematic review and meta-analysis for prospective and retrospective studies that investigated the efficacy of ITDI in the treatment of tinnitus followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A PRISMA flow diagram was used to outline the various phases of the systematic review. This study used quantitative methods to examine the reasons for differences in posttreatment outcomes.

Among the various attempts to treat tinnitus, ITDI is clinically burdensome in that it is slightly invasive. Complications such as hearing loss, eardrum perforation, and middle ear inflammation are known to be rare after ITDI [22], but clinicians feel these complications to be more difficult than those after ITDI used to treat other diseases (such as sudden sensorineural hearing loss or Menière disease). In this study, we evaluated the effectiveness of ITDI for tinnitus treatment. Four papers were included in the quantitative meta-analysis, according to which ITDI did not show evidence of tinnitus improvement compared with placebo (Fig. 2). This result demonstrates that ITDI alone may have no therapeutic effect on tinnitus. However, most studies included in the qualitative synthesis suggested that ITDI may contribute to the improvement of tinnitus. Shim et al. [19] reported that combination treatment of ITDI and oral alprazolam was appropriate for unilateral acute idiopathic tinnitus within 3 months after onset. Some researchers have suggested that the combination of a benzodiazepine and an endogenous neuroactive steroid can produce both supra-additive anxiolytic effects and infra-additive reinforcing effects [23]. Further RCTs are needed on the synergistic effects of combination steroid and benzodiazepine therapy. In the future, ITDI may have therapeutic applications for tinnitus in limited situations considering various confounding factors, but more objective comparative research is required.

Several noncontrolled studies have demonstrated positive effects of ITDI on the management of tinnitus. Sakata et al. [24] reported that tinnitus improved in 75% of 3,978 ears immediately after ITDI and in 68% after 6 months. Cesarani et al. [15], who treated 54 patients with tinnitus using ITDI, demonstrated that complete resolution of tinnitus was observed in five of 50 patients (10.0%), and 17 of 50 (34.0%) reported a significant decrease of tinnitus 6 weeks after treatment. However, no controlled study has shown significantly better outcomes than those obtained using placebo. Araujo et al. [7] showed no difference between intratympanic injections using dexamethasone and normal saline in the treatment of severe disabling tinnitus; the duration of tinnitus was greater than 1 year in 96% of the enrolled subjects, and the early improvement rate was 29% in the control group (n=14 ears) and 33% in the study group (n=21 ears). In another controlled study with 79 patients (84 ears), at 6 months of follow-up after treatment, the effectiveness in the ITDI group was not superior to that in the control group, which received carbamazepine alone [21]. Those authors reported that the improvement rates after intratympanic prednisolone and dexamethasone injections were 45.7% and 29.2%, respectively, while that for oral carbamazepine was 36.0% [21].

The mechanism of action of ITSI in the management of tinnitus is still unclear [24]. Steroids are known to exert their effects by penetrating into the inner ear by diffusion through the round window membrane (RWM) and binding with the steroid receptors found in the inner ears of both animals and humans [25]. The putative mechanisms of steroids in treating tinnitus may include suppression of irritability or hypersensitivity of the sensory cells in the inner ear due to damage of cochlear hair cells [26], reduction of the inflammation caused by immune-mediated or autoimmune dysfunction in the inner ear, increase of inner ear vascularity, and/or direct effects on the inner ear neuroepithelium [26].

In the quantitative meta-analysis and qualitative synthesis, most studies (8/15) selected the THI as the main measurement tool for evaluation of tinnitus improvement. Four studies used the VAS alone as a tool for the initial assessment of tinnitus. In five studies, the severity of tinnitus was assessed using the THI alone. Three studies used both the VAS and THI. The THI was developed by Newman et al. [27] in 1996. Since 2000, the THI has been the main evaluation tool for tinnitus, and it was used in nine out of 15 studies. It has been demonstrated that the THI is a brief, easily administered, and reliable measure to evaluate the impact of tinnitus on daily living and the outcomes of medical, surgical, and/or rehabilitative interventions [28]. Moreover, this inventory has shown excellent clinical usefulness for detecting changes in self-perceived tinnitus handicap following interventions such as ITDI [28]. The definition of tinnitus improvement differed from study to study. In terms of the VAS score, tinnitus improvement was defined as a reduction by at least two gradations on the VAS [7,18]. Because we tried to investigate the effectiveness of ITDI for tinnitus control in the meta-analysis, the definition of tinnitus improvement using THI scores or tinnitograms could not be standardized. Furthermore, changes in THI scores or the loudness of tinnitus on tinnitograms were not monitored and analyzed for a long period in most studies. Usually, tinnitus improvement was defined as a reduction in the THI score of 5 or more points [9,10]. However, a study used a definition of a reduction of more than 7 points or more than 20% in the THI score [11] and other studies defined tinnitus improvement as a >20-point reduction in THI [12,17,19,20]. Tinnitus loudness matching was defined as a decrease in loudness by at least 5 dB SL [21]. Since the parameters for evaluating tinnitus and the definitions of tinnitus improvement were different from paper to paper, it was difficult to integrate the parameters and consistently define tinnitus improvement.

This study has a few limitations. First, only four published articles that reported the effectiveness of ITDI compared with placebo for treating tinnitus were included in the quantitative meta-analysis. To ensure the quality of the present research, only double-blind RCTs were selected, and only studies comparing ITDI and placebo were included to unify the characteristics of the experimental and control groups. The sample size was relatively small, and thus, our results regarding the efficacy of ITDI compared with placebo are inconclusive because of the wide CIs. Further studies with larger sample sizes are needed in the future. Second, each study had a different tinnitus duration. Three of the four RCTs in the quantitative meta-analysis enrolled patients who had tinnitus for more than 3 months. In reports by Cesarani et al. [15] and Shea and Ge [29], better ITSI results were obtained in patients with a shorter duration of tinnitus, especially when the treatment was started within 3 months of tinnitus onset. An et al. [17] sought to identify prognostic factors for the outcomes of ITDI in patients with acute subjective tinnitus and demonstrated that the duration of tinnitus was the only variable significantly associated with the cure rate. Therefore, the duration of tinnitus should be considered in tinnitus treatment. An early intervention may be an important factor in the therapeutic efficacy of tinnitus treatment. Among the articles included in the qualitative synthesis, Shim et al. [19] and Albu and Chirtes [20] demonstrated that ITDI combined with other medications (alprazolam and melatonin, respectively) showed effectiveness in improving the development of acute idiopathic unilateral tinnitus within 3 months. However, the article of Lee et al. [11], which was included in the quantitative meta-analysis, reported that ITDI might not be more effective than placebo in the treatment of acute unilateral tinnitus. Although the mechanism of tinnitus in the central auditory system remains unclear, some authors agree that tinnitus is initially triggered by cochlear damage in almost all patients [4,30,31]. Moreover, there might be a short therapeutic window to reverse cochlear damage, and if the initiation of ITDI is rapid enough to reverse cochlear damage and subsequent changes in the central auditory system, elimination or management of tinnitus may be possible. Therefore, the timing of treatment initiation has also been reported to be an important factor related to the cure of tinnitus [17,19]. In addition, we compared the effect of injection time intervals of ITDI in patients with tinnitus. Patients who received ITDI every day showed significantly better improvement of tinnitus than those who received ITDI once or twice a week. Considering the drug dynamics of steroids, which have rapid clearance rates, repetitive injections with short intervals can maintain a higher steroid concentration in the cochlea [32]. Therefore, an ITDI protocol with daily interventions may be considered as an option for better improvement of tinnitus.

The effect of hearing loss could not be ruled out in the current study. Depending on its cause, tinnitus may be related to hearing loss. Of the 15 papers included in the meta-analysis and systemic review, only nine papers described hearing thresholds. Four articles studied tinnitus patients with normal hearing, while four papers described patients with mild hearing loss and one article analyzed patients with moderate to severe hearing loss. Although the current study mostly included cases of subjective idiopathic tinnitus showing normal hearing, further research is needed to rule out confounding factors such as the degree of hearing loss.

Additionally, fibrosis or ossification around the RWM, which may cause poor permeability of the RWM, may affect the efficacy of ITDI. Silverstein et al. [33] reported the results of round window niche examinations in 41 patients with middle ear endoscopy before intratympanic infusion. Of the 41 patients, seven had partial obstruction of the RWM, and five had complete obstruction. Furthermore, Nordang and colleagues also revealed that hydrocortisone could cause functional obstruction during the course of intratympanic injection treatment by thickening the RWM [34]. Further studies will be needed to address this factor related to fibrosis or ossification around the RWM.

ITDI alone did not show a significant effect for treating tinnitus compared with placebo. However, the potential of combination treatment of ITDI with other drugs for tinnitus control should be further studied through more systematic research to identify therapeutic evidence for tinnitus.