In a phase III randomized controlled trial involving 213 patients with idiopathic sudden sensorineural hearing loss and concurrent tinnitus, researchers found that acoustic therapy didn't improve acute tinnitus during 10-day hospitalization, but significantly increased tinnitus remission rates in patients with severe hearing impairment who continued treatment at home for 6 months.

The researchers conducted the study across 19 hospitals in Sichuan, China, from May 2019 to April 2024, and  compared four treatment approaches: systemic steroids alone (international standard care), systemic steroids plus intravenous batroxobin (Chinese standard care), systemic steroids combined with daily acoustic therapy (AT) and systemic steroids plus intravenous batroxobin combined with daily AT. Among patients with severe idiopathic sudden sensorineural hearing loss (ISSHL)—the only subgroup that showed benefit—those receiving long-term home-based AT achieved remission rates of 45.5% vs 20% without AT. No serious adverse events occurred, according to senior study author Yu Zhao, MD, PhD, of the Department of Oto-Rhino-Laryngology and the National Clinical Research Center for Geriatrics at West China Hospital at Sichuan University, and colleagues.

Key Finding: Benefit Limited to Severe Hearing Loss

Overall tinnitus remission rates at 180 days showed no statistically significant difference between patients using home AT (49%) vs those who didn't (35%). However, stratification by hearing loss severity revealed a clinically meaningful finding in the severe ISSHL subgroup (46% of enrolled patients).

The 25–percentage point difference remained robust in sensitivity analysis excluding patients who received alternative therapies (50.0% vs 21.0%). No statistically significant benefits were observed in patients with mild or moderate hearing loss nor when stratified by audiogram curve type or baseline tinnitus severity.

Short-Term Hospitalization: No Benefit Detected

After 10 days of inpatient treatment, tinnitus remission rates didn't differ significantly among groups: 63% (steroids alone), 67% (steroids plus batroxobin), 55% (steroids combined with AT), and 59% (steroids plus batroxobin combined with AT). Secondary outcomes—including the Tinnitus Handicap Inventory, Tinnitus Questionnaire, Beck Anxiety/Depression Inventories, 36-Item Health Survey Short Forms, and Pittsburgh Sleep Quality Index—showed no intergroup differences.

However, the study was substantially underpowered. Planned enrollment was 302 patients per arm to detect 15% absolute differences with 80% to 95% power; actual enrollment was about 50 per arm. Post-hoc analysis revealed that the observed effect size (0.1) was too small for the achieved statistical power (64% for 0.2 effect size), raising the possibility of false-negative findings.

Treatment Protocol

AT consisted of two frequency-matched components tailored to each patient's tinnitus:

• Tinnitus masking (TM): Narrowband noise or multi-frequency amplitude-modulated pure tones delivered at tinnitus frequency, 5 dB above perceived loudness, modulating between 0% to 100% over 160-millisecond cycles.
  
  
• Tinnitus retraining therapy (TRT): Environmental sounds (wind and electrical current) matched within 1 to 3 dB of tinnitus loudness, not exceeding perceived levels.

During hospitalization (days 1 to 10), patients received TM and TRT three times daily (30 minutes each). Postdischarge, the protocol shifted primarily to TRT (three to five times daily, minimum 1.5 hours total), with TM reserved for tinnitus exacerbations.

Why Patients With Severe ISSHL May Respond Differently

The researchers proposed that severe hearing loss could trigger more pronounced alterations in auditory system processing, potentially making these patients more responsive to sustained acoustic stimulation. Severe hearing loss also correlates with greater psychological distress (anxiety, depression), which exacerbates tinnitus intensity. Long-term sound therapy may provide dual benefits: auditory stimulation supporting neural adaptation plus extended time to address the emotional burden.

Tinnitus pathophysiology involves central mechanisms beyond peripheral cochlear damage, including reduced cortical inhibition, tonotopic map reorganization, and widespread network activation in nonauditory regions processing emotion, memory, attention, and salience. AT's theoretical framework integrates peripheral modulation (frequency-matched masking) with central habituation (structured sound enrichment) to disrupt both initiation and maintenance of tinnitus percepts.

Safety Profile

The treatment combinations proved safe and well-tolerated. Among 24 all-cause adverse events, only dysfibrinogenemia (fibrinogen <1 g/L) and dermal ecchymosis (7 cases) were considered possibly related to batroxobin. No serious adverse events or deaths occurred. The study's fibrinogen monitoring protocol (testing on days 0, 1, 3, 5, 7, and 9; pausing batroxobin if fibrinogen < 1 g/L) successfully prevented hemorrhagic complications. Insomnia was the only adverse event reported by multiple patients across treatment arms.

Study Limitations

COVID-19 infections disrupted operations at participating hospitals, limiting enrollment and preventing many patients from completing required examinations. The substantial shortfall in sample size (50 vs 302 per arm) meant the study achieved only 64% to 85% power to detect small-to-moderate effect sizes, potentially explaining the negative short-term findings.

Additional limitations included absence of true placebo control for AT (patients knew whether they received sound therapy), lack of objective hearing data at long-term follow-up, reliance on telephone questionnaires for 180-day assessments, and voluntary selection of postdischarge treatments. The researchers employed partial blinding during hospitalization (masked intravenous drug labels, sham "silent headphones" for non-AT groups), but blinding couldn't be maintained postdischarge when treatment effects emerged.

Interpretation was also complicated by substantial spontaneous improvement across all groups. By day 10, tinnitus-related distress scores improved markedly regardless of treatment, and long-term visual analog scale scores declined 21+ points in both AT and non-AT groups. This natural history—likely driven by neuroplastic adaptation, resolution of inflammation, and psychological habituation—made it difficult to isolate treatment effects without adequately powered comparisons.

Given the exploratory nature of the severe ISSHL subgroup finding, these results require validation in prospective trials specifically powered for this patient population.

Clinical Implications

For clinicians managing ISSHL-related tinnitus, the findings suggested:

• Short-term AT during acute hospitalization doesn't provide immediate relief and shouldn't be prioritized over established ISSHL treatments (systemic steroids with or without batroxobin per regional guidelines).

• Patients with severe hearing loss may benefit from extended home-based AT (6 months, 1.5 to 3 hours daily). The observed 25–percentage point difference in remission rates is clinically substantial if confirmed in larger trials.

• Treatment requires specialized tinnitus matching to tailor frequency and amplitude parameters, plus sustained patient commitment.

• Batroxobin adds no benefit for tinnitus compared with steroids alone, though it may improve hearing recovery per prior literature (not assessed here).

Future research should focus on adequately powered trials in populations with severe ISSHL, optimal treatment duration/intensity, and potential synergies with cognitive behavioral therapy or pharmacologic interventions.

Source: BMC Medicine