Tinnitus Treatments
Number: 0406
(Replaces CPB 478)
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses treatments for tinnitus.
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Medical Necessity
Aetna considers the following interventions medically necessary:
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Transcutaneous electrical nerve stimulation (TENS) as durable medical equipment (DME) for members with severe tinnitus when all of the following criteria are met:
- Medically correctable causes of tinnitus have been ruled out; and
- Member has experienced severe tinnitus for more than 6 months, and
- Member has tried and failed conservative tinnitus treatments, including counseling and reassurance, dietary modifications, and drug therapy;
Note: More than 10 TENS sessions per year are not considered medically necessary for the treatment of tinnitus because of a lack of evidence that more frequent TENS treatments provides additional clinically significant benefits for this condition.
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Cortical mastoidectomy and restoration of separation between the sigmoid sinus and middle ear for tinnitus resulting from bony defect in the mastoid/temporal bone (described as sigmoid sinus dehiscence or sigmoid sinus wall dehiscence, and sometimes caused by sigmoid diverticulum), when a bony defect with dehiscence of the sigmoid sinus is documented on imaging of the temporal bone.
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Experimental, Investigational, or Unproven
Aetna considers the following interventions experimental, investigational, or unproven because the effectiveness of these approaches has not been established:
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Tinnitus instruments (e.g., maskers, hearing aids, or combination of maskers and hearing aids) for the management of members with tinnitus because the effectiveness of these instruments has not been demonstrated in randomized controlled studies with large sample size and long-term follow-up evaluation;
Note: Tinnitus instruments such as maskers and hearing aids are approved by the Food and Drug Administration (FDA) and are classified as Class III devices; however, tinnitus masking is not approved for coverage by the Centers for Medicare & Medicaid Services (CMS).
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The following interventions for the management of members with tinnitus (not an all-inclusive list):
- Acoustic coordinated reset neuromodulation
- Acupuncture
- Antioxidant therapy (e.g., alpha-lipoic acid, Ginkgo biloba, papaverine, vitamin C and vitamin E)
- Audiotherapy (e.g., acoustic stimulation and auditory perceptual training)
- BeyondTinnitus system
- Botulinum toxin
- Cochlear implants
- Competitive kinesthetic interaction therapy (KKIT)
- Cortical stimulation
- Deep brain stimulation
- DNA (daytime-nighttime appliance) oral appliance therapy
- Ear canal magnets
- Electromagnetic stimulation (including transcranial magnetic stimulation)
- Eye movement desensitization and reprocessing (EMDR)
- Hyperbaric oxygen therapy
- Intra-cranial venous sinus stenting
- Intra-tympanic administration of corticosteroids
- Intravenous lidocaine
- Intravenous mexiletine
- Lenire device (bi-modal neuromodulation)
- Lidocaine iontophoresis
- Low-level laser therapy (also known as photobiomodulation)
- Lysis of middle ear tendons
- Melatonin (alone or in combination with sulodexide)
- Microvascular decompression of the cochlea-vestibular nerve
- Music therapy
- Neurofeedback
- Neuromonics Tinnitus Treatment/Neuromonics Oasis device
- Noise/sound generators
- Oxytocin
- Ozone therapy
- Peripheral muscle magnetic stimulation
- Radiofrequency lesion of the superior cervical sympathetic ganglion (including pulsed radiofrequency of C2 dorsal root ganglion)
- Repetitive transcranial magnetic stimulation (including continuous theta burst stimulation)
- Sequential phase shift sound cancellation treatment
- Sound therapy (including the Otoharmonics Levo System sound therapy)
- Tinnitus retraining therapy
- Topographical filter dermal patch
- Transcranial electrical neuromodulation (e.g., alternating current stimulation, direct current stimulation, and random noise stimulation)
- Transmeatal laser irradiation (low-level laser)
- Vagus nerve stimulation
- Vitamin B12 injections.
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Related Policies
- CPB 0113 - Botulinum Toxin
- CPB 0132 - Biofeedback
- CPB 0135 - Acupuncture
- CPB 0172 - Hyperbaric Oxygen Therapy (HBOT)
- CPB 0238 - Chronic Vertigo
- CPB 0469 - Transcranial Magnetic Stimulation and Cranial Electrical Stimulation
- CPB 0514 - Meniere's Disease and Related Disorders: Surgery
- CPB 0583 - Eye Movement Desensitization and Reprocessing (EMDR) Therapy
Background
- subjective tinnitus, and
- objective tinnitus.
Subjective tinnitus, which is more common, is audible only to the patient. It may arise from some types of electrophysiological disturbance anywhere in the auditory system – the external ear canal, tympanic membrane, ossicles, cochlea, auditory nerve, brainstem or cerebral cortex. The underlying causes of subjective tinnitus include otological (presbycusis, noise-induced hearing loss, Meniere's disease, or chronic otitis media), metabolic (diabetes, thyroid diseases, hyperlipidemia, or zinc deficiency/vitamin deficiency), pharmacological (aspirin compounds, non-steroidal anti-inflammatory drugs, caffeine, nicotine, aminoglycosides, or antidepressants), neurological (whiplash, skull fracture/closed head trauma, multiple sclerosis, or following meningitis), psychological (depression or anxiety), as well as infectious and neoplastic (syphilis, acoustic neuroma, autoimmune diseases, or acquired immune deficiency syndrome) disorders.
Objective tinnitus, the less common type of tinnitus, usually refers to noises that can be heard by an examiner. The physician must put his/her ear against the patient's ear or use a stethoscope against the patient's external auditory canal. Objective tinnitus usually has a vascular (arteriovenous malformations/shunts, arterial bruits, hypertension, arteriosclerosis, venous hums, or aneurysms) or mechanical (Eutaschian tube dysfunction, temporomandibular joint disease, palatal myoclonus, or idiopathic stapedal muscle spasm) origin (Schuler and Schleuring, 1994; Seidman and Jacobson, 1996).
Although there is no cure for tinnitus, treatments are designed to provide relief of symptoms. The management of patients with tinnitus often depends on the severity of the condition. If the patient's activities of daily living are not affected by tinnitus, treatment options include counseling, reassurance, and/or behavioral and dietary modifications (avoidance of excessive noise, nicotine, salt, and caffeine). All medications should also be evaluated to eliminate ototoxic drugs. Currently, the medications for patients with severe tinnitus include amitriptyline (Elavil), alprazolam (Xanax), diazepam (Valium), and clonazepam (Klonopin); however, none of these drugs has been approved by the U.S. Food and Drug Administration for the specific treatment of tinnitus. The American Academy of Otolaryngology - Head and Neck Surgery Foundation’s clinical practice guideline on "Tinnitus" (2014) stated that clinicians should not routinely recommend anti-depressants, anti-convulsants, and anxiolytics for a primary indication of treating persistent, bothersome tinnitus.
Biofeedback is a technique in which a person learns to gain control over unconscious bodily functions, such as the triggers that cause tinnitus. May include stress reduction and relaxation exercises to help the person change their reaction to the condition.
Cognitive behavioral therapy (CBT) attempts to teach coping strategies or distraction skills and relaxation techniques so that the psychological response to the condition may be altered.
Botulinum toxin injections (BTX) controls muscle spasms by temporarily weakening or paralyzing nerves.
Electrical Stimulation
Another therapeutic modality is electrical stimulation (ES). Electrical stimulation may include placing electrodes directly on the bony cochlea or the round window niche (one of two openings that connect the inner ear to the middle ear), or anywhere in the vicinity of the ear. The exact mechanism by which electrical stimulation is proposed to reduce tinnitus is unclear.
In a review on tinnitus, Siedman and Jacobson (1996) indicated that ES is a possible treatment modality for patients with severe tinnitus. Hatton et al (1960) reported that only anodal (positive electrode) stimulation produced the suppressive effect. In general, ES is provided through electrodes in the vicinity of the ear. The exact mechanism(s) by which ES suppresses/reduces tinnitus is unclear. However, it has been postulated that positive electrical currents produce a hyperpolarization of nerve fibers, which inhibit and reduce spontaneous discharge rates (Portmann et al, 1983).
Hatton et al (1960) observed that the intensity of tinnitus was reduced in 15 (45.5 %) of 33 patients with ES. Chouard et al (1981) reported that 30 (47 %) of 64 patients achieved success (as determined by reduced intensity that lasted for a few days to more than 1 week) following electrotherapy. None of the 12 patients who received placebo stimulation attained relief. The authors stated that if a patient failed to achieve improvement after 2 to 3 sessions, it is unlikely that this form of therapy will be successful.
Engelberg and Bauer (1985) performed two experiments to examine the effects of transcutaneous electrical stimulation (TENS) on tinnitus. Experiment 1 had 10 subjects (18 ears) and improvement (defined as either a complete remission or a decrease in the frequency of tinnitus) was seen in 6 of them with tinnitus being eliminated in 3 ears. Experiment 2 employed a single-blind study design with 20 patients (experimental group, n = 10, 17 ears; control group, n = 10, 15 ears). It was found that 9 of 10 patients with 15 (88.2 %) of 17 ears reported improvement following stimulation. These changes lasted from 20 minutes to at least 6 months. On the other hand, only 1 patient (1 ear) in the control group improved (a 13 % decrease in frequency of tinnitus).
Steenerson and Cronin (1996) reported their findings of 246 patients with severe tinnitus of various etiologies treated with ES (a total of 6 to 10 sessions). One hundred and thirty patients (53 %) reported significant benefit (an improvement of at least 2 points in a 1 to 10 subjective rating scale) with 32 patients (13 %) having complete suppression of their tinnitus. At 3-month follow-up, 72 % had continuous benefit.
In a subsequent report, Steenereson and Cronin (1999) reported their findings in 500 patients with tinnitus who were treated with probe electrical stimulation. The authors reported that 53 % of patients showed decreases in their tinnitus as measured by a subjective rating scale. At 3-month follow-up, 72 % had no loss of benefit.
Rahko and Kotti (1997) treated 26 patients with transcutaneous nervous stimulation (TNS) for tinnitus. Except for 3 normal hearing patients, all had cochlear hearing losses. The authors found that tinnitus disappeared in none of the patients, but diminished in 7 patients, versus diminution of tinnitus in 3 in 24 nontreated controls.
In a study that evaluated the effects of psychological factors on the outcome of TENS for patients with chronic tinnitus (n = 27), Collet and associates (1987) found that the 15 patients (55.6 %) who did not improve showed higher pre-treatment scores of depression, psychasthenia, and schizophrenia. These findings indicated that patients having psychiatric problems such as those mentioned above are unlikely to benefit from treatment.
According to available literature, transcutaneous electrical stimulation for tinnitus is contraindicated in persons with the following conditions:
- Persons taking medications for other diseases/conditions known to have a side effect of tinnitus, such as aspirin, Vasotec (enalapril maleate), etc.; or
- Persons with active ear disease; or
- Persons with cardiac pacemakers, implanted stapes prostheses or other implanted devices, which may be affected by electrical signals; or
- Persons with psychiatric problems such as schizophrenia, depression, hysteria, or hypochondria; or
- Women who are pregnant.
Masking Instruments
Tinnitus masking instruments such as maskers, hearing aids, and tinnitus devices (combination of hearing aid and tinnitus masker) have been used for alleviating symptoms associated with tinnitus. However, the effectiveness of these instruments for treating tinnitus has not been established. These devices are all worn behind, or in either the same or opposite ear affected by tinnitus. Tinnitus maskers generate a grossly broad-band high-energy noise, which most patients find an excessive noise intrusion that is unacceptable and intolerable.
The goal of hearing aids is to bring in more sounds from the person’s surroundings, thus naturally covering the tinnitus and making it less noticeable. Some hearing aids may exist as a combination hearing aid and a broadband noise generator or masking device for tinnitus relief. An example of a combination hearing aid includes, but may not be limited to, the Phonak hearing aid combined with the Phonak tinnitus balance.
Masking devices are similar in appearance to hearing aids; however, they do not amplify sounds, but instead produce constant low-level white noise, intended to provide a distraction from the internal tinnitus. Masking may also be accomplished by using or enhancing background noise with tabletop sound machines, etc. Examples of masking devices include, but may not be limited to, the following: Levo tinnitus symptoms masking systems; Neuromonics tinnitus treatment; Phonak tinnitus balance; Refuge tinnitus masker; Serenade tinnitus treatment; The Inhibitor; The Jump C TRT; and Unitron tinnitus masker.
A review of 69 randomized clinical trials of therapies for tinnitus (Dobie, 1999) concluded that no treatment (pharmacotherapy, psychotherapy, and various non-drug treatments including masking) could yet be considered established in terms of providing reproducible long-term benefits, in excess of placebo effects.
A systematic review of the evidence for tinnitus treatments by BMJ Clinical Evidence concluded that tinnitus masking devices and hearing aids are of "unknown effectiveness" (Savage et al, 2011).
The Centers for Medicare and Medicaid Services (CMS, 2006) has concluded: "Tinnitus masking is considered an experimental therapy at this time because of a lack of controlled clinical trials demonstrating effectiveness and the unstudied possibility of serious toxicity in the form of noise induced hearing loss."
In a Cochrane review, Hobson et al (2010) examined the effects of sound therapy (masking) in the management of tinnitus in adults. Prospective, randomized controlled trials recruiting adults with persistent, distressing, subjective tinnitus of any etiology in which the management strategy included maskers, noise-generating device and/or hearing aids, used either as the sole management tool or in combination with other strategies, including counselling were included in this review. A total of 6 trials (553 subjects) were included in this review. Studies were varied in design, with significant heterogeneity in the evaluation of subjective tinnitus perception, with different scores, scales, tests and questionnaires as well as variance in the outcome measures used to assess the improvement in tinnitus sensation/quality of life. This precluded meta-analysis of the data. There was no long-term follow-up. These researchers assessed the risk of bias as medium in 3 and high in 3 studies. No side effects or significant morbidity were reported from the use of sound-creating devices. The authors concluded that the limited data from the included studies failed to show strong evidence of the efficacy of sound therapy in tinnitus management. The absence of conclusive evidence should not be interpreted as evidence of lack of effectiveness. The lack of quality research in this area, in addition to the common use of combined approaches (hearing therapy plus counselling) in the management of tinnitus are, in part, responsible for the lack of conclusive evidence.
Ear Canal Magnets and Electromagnetic Stimulation
A systematic evidence review published in BMJ Clinical Evidence (Savage, et al., 2009; Savage, et al., 2011) concluded that the effectiveness of ear canal magnets and electromagnetic stimulation for tinnitus are unknown.
The systematic evidence review identified two small randomized, controlled clinical trials comparing electromagnetic stimulation to placebo. The first trial (n = 58) found that 15 minutes per day of electromagnetic stimulation significantly increased the proportion of people who had subjective improvements in tinnitus compared to placebo after one week (citing Roland et al, 1993). Based upon subjective responses assessed by a 4-point questionnaire, 14 of 31 subjects assigned to electromagnetic stimulation improved compared to 2 of 23 subjects assigned to placebo (p = 0.0013). The systematic review noted that 4 subjects withdrew from the trial, and that the analysis was not by intention to treat. A second randomized controlled clinical trial (n = 20) used a crossover design and did not report results before the crossover (citing Dobie et al, 1986). The crossover trial found similar effects between electromagnetic stimulation and a placebo device in reducing tinnitus severity. Severity, measured on a scale of 0-7, was reported as less severe in 2 of 20 subjects with the active device versus three of 20 subjects with a placebo device.
The systematic evidence review found one randomized controlled clinical trial (n = 49) that found similar effects between a simple ear-canal magnet and placebo (similar unmagnetized material) in tinnitus symptoms after 4 weeks' treatment (citing Coles et al, 1991). Symptom improvement was reported in 7 of 26 persons with the magnet compared to 4 of 23 persons with placebo.
Tinnitus Retraining Therapy
Tinnitus retraining therapy (TRT) is a neurophysiological approach centering on behavioral retraining of the associations induced by perception of tinnitus. TRT uses a combination of low-level broad-band noise along with counseling to achieve the habituation of tinnitus. The goal is to become unaware of the tinnitus unless it is consciously focused on and to remain unbothered by it, even when aware of it.
- the actual spectrum of the emitted noise,
- the ear canal resonance of the patient, and
- the hearing sensitivity of the patient.
Furthermore, a study stated that methodological limitations of the research published to date preclude any claims about the efficacy of TRT at the present time (Wilson et al, 1998). A technology assessment prepared for the Wessex Institute for Health Research and Development (Leal and Milne, 1998) concluded that the available case series are inadequate, owing to problems of methodology, and that there is no evidence to suggest that TRT is effective in the treatment of debilitating tinnitus in adult patients.
Kroener-Herwig et al (2000) stated that there is no published study evaluating TRT using a randomized group design even though this is the only design able to give valid information on the empirical status of a therapy. They concluded that the praise of TRT as the most promising therapy for chronic tinnitus can only be regarded as premature, and the claim of its effectiveness by its advocates await scientific corroboration. Randomized, controlled clinical studies that include no-treatment and placebo groups are needed to ascertain the effectiveness of TRT in the management of patients with tinnitus.
An assessment by the Washington Department of Labor and Industries Office of the Medical Director (Wang, 2004) concluded that "[d]ue to the lack of prospective trials with comparison groups, the efficacy of TRT for subjective tinnitus has not been established. Therefore, TRT is considered investigational and controversial."
A systematic review of the evidence for tinnitus treatments by BMJ Clinical Evidence concluded that tinnitus training therapy is of "unknown effectiveness" (Savage et al, 2011).
Hiller and Haerkotter (2005) reported that noise generators had benefit in persons with tinnitus. However, post-hoc analysis revealed benefits in a subgroup of tinnitus patients with hyperacusis. They stated that this finding would need to be replicated in a prospective well-controlled study to evaluate sound generators in hyperacusis.
Transcranial Magnetic Stimulation
Repetitive transcranial magnetic stimulation (rTMS) treatment consists of low-level electrical stimulation emitted from an electrostimulator device placed on the earlobes or behind the ears.
Clinical, neurophysiological and neuroimaging data suggest that chronic tinnitus resembles neuropsychiatric syndromes characterized by focal brain activation. Low-frequency repetitive transcranial magnetic stimulation (rTMS) has been proposed as a method in treating brain hyperexcitability disorders by reducing cortical excitability. Kleinjung et al (2005) examined the effects of rTMS on patients with chronic tinnitus (n = 14). Increased metabolic activation in the auditory cortex was verified in all patients. After 5 days of rTMS, a highly significant improvement of the tinnitus score was found whereas the sham treatment did not show any significant changes. The treatment outcome after 6 months still demonstrated significant reduction of tinnitus score. The authors concluded that these preliminary results showed that neuro-navigated rTMS offers new possibilities in the understanding and treatment of chronic tinnitus. The findings of this study need to be verified by further investigation with larger sample size and long follow-up.
Pridmore et al (2006) examined the literature and considered the potential for TMS as a treatment for patients with tinnitus. These researchers noted that a small number of studies have suggested that TMS may be effective in the treatment of tinnitus. There is a good theoretical basis and early research evidence suggesting that TMS may have treatment potential in tinnitus. Moreover, they stated that further, larger studies are necessary to ascertain the effectiveness of this approach.
In a randomized, placebo-controlled (sham stimulation) cross-over pilot study, Smith et al (2007) evaluated the effectiveness of neuro-navigated rTMS and its effects on attentional deficits and cortical asymmetry in 4 patients with chronic tinnitus using objective and subjective measures and employing an optimization technique refined in their laboratory. Patients received 5 consecutive days of active, low-frequency rTMS or sham treatment (using a 45-degree coil-tilt method) before crossing over. Subjective tinnitus was assessed at baseline, after each treatment, and 4 weeks later. Positron emission tomography/computed tomography (PET/CT) scans were obtained at baseline and immediately after active treatment to examine change in cortical asymmetry. Attentional vigilance was assessed at baseline and after each treatment using a simple reaction time test. All patients had a response to active (but not sham) rTMS, as indicated by their best tinnitus ratings; however, tinnitus returned in all patients by 4 weeks after active treatment. All patients had reduced cortical activity visualized on PET immediately after active rTMS. Mean reaction time improved (p < 0.05) after active but not sham rTMS. The authors concluded that rTMS is a promising treatment modality that can transiently diminish tinnitus in some individuals, but more studies are needed to determine the optimal techniques needed to achieve a lasting response. It is unclear if the improved reaction times were caused by tinnitus reduction or a general effect of rTMS. PET/CT scans immediately after treatment suggest that improvement may be related to reduction of cortical asymmetry associated with tinnitus.
Khedr et al (2008) compared the effect of different frequencies of rTMS (1 Hz, 10 Hz, 25 Hz and sham (occipital, 1 Hz)), given daily over the left temporo-parietal cortex for 2 weeks, on 66 patients with chronic tinnitus randomly divided into four treatment groups. Patients were assessed using the Tinnitus Handicap Inventory (THI), self-ratings of symptoms and audiometric measures of residual inhibition before, immediately after 2 weeks' treatment and monthly thereafter for 4 consecutive months. There were no significant differences in basal measures between the four groups of patients. A 2-factor ANOVA revealed a significant "rTMS" x "time" interaction for all measures. This was because real rTMS produced greater improvement than sham. However, there was no significant difference between the responses to different frequencies of rTMS. The response to rTMS depended on the duration of tinnitus: patients who had tinnitus for the longest period of time were the least likely to respond to treatment. The authors concluded that daily sessions of rTMS over the temporo-parietal cortex may be a useful potential treatment for tinnitus.
In a pilot study, Lee and colleagues (2008) examined the effectiveness of rTMS in veterans with debilitating tinnitus. A total of 8 patients received 5 consecutive days of rTMS (0.5 Hz, 20 minutes) to the left temporo-parietal area. Outcome was measured by means of THI before sessions 1 and 3 and after session 5. Patient 1's THI decreased from 40 to 34 to 26, patient 4 reported a subjective improvement, patient 8 withdrew, and the remaining 5 patients reported no improvement. Side effects included temporary soreness, restlessness, and photophobia. The authors concluded that with these current parameters, rTMS did not improve tinnitus in veterans.
Kleinjung et al (2008) stated that a growing number of studies demonstrate reduction of tinnitus after repeated sessions of low-frequency rTMS and indicate that rTMS might represent a new promising approach for the treatment of tinnitus. Single sessions of high-frequency rTMS over the temporal cortex have been successful in reducing the intensity of tinnitus during the time of stimulation and could be predictive for treatment outcome of chronic epidural stimulation using implanted electrodes. Because most available studies have been performed with small sample sizes and show only moderate effect sizes and high inter-individual variability of treatment effects, further development of the technique is needed before it can be recommended for use in clinical routine. Both patient-related (e.g., hearing loss, tinnitus duration, age) and stimulation-related (e.g., stimulation site, stimulation protocols) factors seem to influence treatment outcome; however, their exact impact still remains to be clarified.
In a Cochrane review, Meng et al (2011) evaluated the safety and effectiveness of rTMS versus placebo in patients with tinnitus. These investigators searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was May 24, 2011. Randomized controlled trials of rTMS versus sham rTMS were selected for this analysis. Two review authors reviewed the titles, abstracts and keywords of all records retrieved; 3 review authors independently collected and extracted data, and assessed the risk of bias of the trials. A total of 5 trials comprising of 233 participants met inclusion criteria. Each study described the use of a different rTMS device that delivered different waveforms at different frequencies. All 5 trials were relatively small studies but generally they demonstrated a low-risk of bias. When considering the impact of tinnitus on patients' quality of life, the results of only 1 study demonstrated a statistically significant improvement in THI scores at 4 months follow-up (defined as a "partial improvement" by the study authors (THI reduction of 21 % to 80 %)) when low-frequency rTMS was compared with a sham control treatment. However, no statistically significant improvement was demonstrated by another 2 studies that considered rTMS at the same frequency. Furthermore, this single positive finding should be taken in the context of the many different variables which were recorded at many different points in time by the study authors. In accordance with the authors' pre-specified subgroup analysis, they extracted the data from 1 study to consider the differential effectiveness between "lower" low-frequency rTMS (1 Hz) and "higher" low-frequency rTMS (10 Hz, 25 Hz). In doing this they were able to demonstrate a statistically significant difference between rTMS employing a frequency of 1 Hz and the sham group when considering tinnitus severity and disability after 4 months follow-up ("partial" improvement). However, no statistically significant difference was demonstrated between 10 Hz and 25 Hz rTMS, and the sham control group, when considering the severity and disability of tinnitus at 4 months follow-up. When considering tinnitus loudness in patients undergoing rTMS these investigators were able to demonstrate a statistically significant reduction in tinnitus loudness when the results of 2 studies were pooled (risk ratio 4.17, 95 % confidence interval [CI]: 1.30 to 13.40). However, this finding was based on 2 small trials and consequently the confidence interval was particularly wide. No serious adverse effects were reported in any of the trials. The authors concluded that there is very limited support for the use of low-frequency rTMS for the treatment of patients with tinnitus. When considering the impact of tinnitus on patients' quality of life, support is from a single study with a low-risk of bias based on a single outcome measure at a single point in time. When considering the impact on tinnitus loudness, this is based on the analysis of pooled data with a large confidence interval. Studies suggested that rTMS is a safe treatment for tinnitus in the short-term, however there were insufficient data to provide any support for the safety of this treatment in the long-term. The authors stated that more prospective, randomized, placebo-controlled, double-blind studies with large sample sizes are needed to confirm the effectiveness of rTMS for tinnitus patients. Furthermore, uniform, validated, tinnitus-specific questionnaires as well as measurement scales should be used in future studies.
Plewnia et al (2012) examined if 4 weeks of bilateral rTMS to the temporal or temporo-parietal cortex is effective and safe in the treatment of chronic tinnitus. In this controlled 3-armed trial, a total 48 patients with chronic tinnitus were treated with 4 weeks (20 sessions) of bilateral continuous theta burst stimulation (cTBS). They were randomized to stimulation above the temporal cortex, the temporo-parietal cortex, or as sham condition behind the mastoid. Patients were masked for the stimulation condition. Tinnitus severity was assessed after 2 and primarily 4 weeks of treatment and at 3 months follow-up with the tinnitus questionnaire and by a tinnitus change score. Audiologic safety was monitored by pure-tone and speech audiometry after 2 and 4 weeks of cTBS. Tinnitus severity was slightly reduced from baseline by a mean (standard deviation [SD]) 2.6 (8.2) after sham, 2.4 (8.0) after temporo-parietal, 2.2 (8.3) after temporal treatment of 16 patients each, but there was no significant difference between sham treatments and temporal (CI: -5.4 to +6.7) or temporo-parietal cTBS (CI: -5.9 to +6.3) or real cTBS (CI: -7 to +5.1). Patients' global evaluation of tinnitus change after treatment did not indicate any effects. Audiologic measures were unaffected by treatment. The authors concluded that treating chronic tinnitus for 4 weeks by applying cTBS to the temporal or temporo-parietal cortex of both hemispheres appears to be safe but not more effective than sham stimulation.
In a review on "Repetitive transcranial magnetic stimulation as a treatment for chronic tinnitus", Theodoroff and Folmer (2013) concluded that "Although optimism for the clinical use of rTMS as an effective treatment for tinnitus remains high among many researchers, clinicians, and patients, several key questions and procedural issues remain unresolved. Suggestions for improving rTMS research protocols are described and discussed".
The American Academy of Otolaryngology - Head and Neck Surgery Foundation’s clinical practice guideline on "Tinnitus" (2014) stated that clinicians should not recommend transcranial magnetic stimulation (TMS) for the treatment of patients with persistent, bothersome tinnitus.
Sahlsten and colleagues (2019) stated that rTMS has shown variable effect on tinnitus. In a prospective, randomized, 6-month follow-up study on parallel groups, these researchers compared the effects of neuro-navigated rTMS to non-navigated rTMS in chronic tinnitus. A total of 40 patients (20 men, 20 women), mean age of 52.9 years (SD = 11.7), with a mean tinnitus duration of 5.8 years (SD = 3.2) and a mean tinnitus intensity of 62.2/100 (SD = 12.8) on VAS (0 to 100) participated. Subjects received 10 sessions of 1-Hz rTMS to the left temporal area overlying auditory cortex with or without neuro-navigation. The main outcome measures were VAS scores for tinnitus intensity, annoyance, and distress, and THI immediately and at 1, 3, and 6 months following treatment. The mean tinnitus intensity (hierarchical linear mixed model: F3 = 7.34, p = 0.0006), annoyance (F3 = 4.45, p = 0.0093), distress (F3 = 5.04, p = 0.0051), and THI scores (F4 = 17.30, p < 0.0001) decreased in both groups with non-significant differences between the groups, except for tinnitus intensity (F3 = 2.96, p =0 .0451) favoring the non-navigated rTMS. Reduction in THI scores persisted for up to 6 months in both groups. Cohen's d for tinnitus intensity ranged between 0.33 and 0.47 in navigated rTMS and between 0.55 and 1.07 in non-navigated rTMS. The responder rates for VAS or THI ranged between 35 % and 85 % with no differences between groups (p = 0.054 to 1.0). The authors concluded that rTMS was effective for chronic tinnitus, but the method of coil localization was not a critical factor for the treatment outcome. These researchers stated that more research on neuro-navigated rTMS for tinnitus is still needed to finally define the most optimal target site(s) and the coil orientation for the most successful tinnitus treatment.
This study had several drawbacks. This was a relatively small study (n = 40) with relatively short-term follow-up (6 months). Furthermore, there was no placebo group, so the outcomes may partly be due to a placebo effect. However, the authors noted that they had previously conducted a placebo-controlled randomized study on the topic with borderline results.
In a systematic review and meta-analysis, Liang and colleagues (2020) examined the safety and effectiveness of rTMS in the treatment of chronic tinnitus. Studies of rTMS for chronic tinnitus were retrieved from PubMed, Embase, and Cochrane Library through April 2020. Review Manager 5.3 software was employed for data synthesis, and Stata 13.0 software was used for analyses of publication bias and sensitivity. A total of 29 randomized studies involving 1,228 chronic tinnitus patients were included. Compared with sham-rTMS, rTMS exhibited significant improvements in the THI scores at 1 week (mean difference [MD]: - 7.92, 95 % CI: - 14.18 to - 1.66), 1 month (MD: -8.52, 95 % CI: - 12.49 to - 4.55), and 6 months (MD: -6.53, 95 % CI: - 11.406 to - 1.66) post-intervention; there were significant mean changes in THI scores at 1 month (MD: -14.86, 95 % CI: - 21.42 to - 8.29) and 6 months (MD: -16.37, 95 % CI: - 20.64 to - 12.11) post-intervention, and the TQ score at 1 week post-intervention (MD: -8.54, 95 % CI: - 15.56 to - 1.52). Non-significant efficacy of rTMS was found regarding the THI score 2 weeks post-intervention (MD: -1.51, 95 % CI: - 13.42 to - 10.40); the mean change in TQ scores 1 month post-intervention (MD: -3.67, 95 % CI: - 8.56 to 1.22); TQ scores 1 (MD: -8.97, 95 % CI: - 20.41 to 2.48) and 6 months (MD: -7.02, 95 % CI: - 18.18 to 4.13) post-intervention; and adverse events (AEs) (odds ratios [OR]: 1.11, 95 % CI: 0.51 to 2.42). Egger's and Begg's tests indicated no publication bias (p = 0.925). The authors concluded that the findings of this meta-analysis demonstrated that rTMS was effective for chronic tinnitus; however, its safety needs more validation. These researchers stated that this analysis was restrained by the insufficient number of included studies and the small sample size; hence, large, randomized, double-blind, multi-center trials are needed for further verification.
Marder et al (2022) noted that treatment approaches targeting both attentional/limbic and auditory systems may better alleviate tinnitus distress than approaches targeting the auditory system alone. In a case-series study, these investigators examined sequential prefrontal and temporo-parietal rTMS for the treatment of tinnitus with and without co-morbid depression A total of 10 subjects with chronic tinnitus received sequential rTMS treatment involving excitatory stimulation administered to the left dorsolateral prefrontal cortex (DLPFC) or inhibitory stimulation administered to the right DLPFC, followed by inhibitory stimulation administered to primary auditory cortex (Heschel's gyrus or HG). These investigators also carried out a systematic literature review to examine the existing literature on sequential rTMS treatment approaches for tinnitus. Results of the case series were interpreted in the context of tinnitus neurobiology and the extant literature. Subjects experienced a significant decrease (average of 21.7 %) in symptoms on the TFI. Those with tinnitus alone experienced a greater mean symptom reduction than those with co-morbid major depressive disorder (MDD) (27.7 % versus 17.0 %, respectively). Adverse effects were transient and minor. Literature review confirmed that sequential approaches had some advantages compared to single site rTMS; in general, the addition of 1-Hz treatment at DLPFC was superior to single site rTMS in the short-term (1 to 12 weeks), while the addition of 20-Hz treatment at DLPFC appeared superior in the long-term (90 to 180 days). The authors concluded that sequential rTMS approaches for the treatment of tinnitus, especially those administering low-frequency treatment at left DLPFC, merit further investigation.
Transcranial Electrical Neuromodulation
- alternating current stimulation (tACS) and
- random noise stimulation (tRNS), both applied on the auditory cortex.
A database with 228 patients with chronic tinnitus who underwent non-invasive neuromodulation was retrospectively analyzed. The results of this study showed that a single session of tRNS induced a significant suppressive effect on tinnitus loudness and distress, in contrast to tACS. Multiple sessions of tRNS augmented the suppressive effect on tinnitus loudness but have no effect on tinnitus distress. The authors concluded that the findings of this preliminary study showed a possibly beneficial effect of tRNS on tinnitus and can be a motivation for future randomized placebo-controlled clinical studies with auditory tRNS for tinnitus. They stated that auditory alpha-modulated tACS does not seem to be contributing to the treatment of tinnitus.
Joos et al (2015) noted that recently tRNS applied over the auditory cortex induced a more pronounced effect on tinnitus loudness than transcranial direct current and alternating current stimulation. These investigators performed tRNS over the temporo-parietal cortex in 154 patients with non-pulsatile tinnitus. A total of 119 patients received low-frequency tRNS (lf-tRNS), 19 high-frequency tRNS (hf-tRNS) and 16 whole frequency spectrum tRNS (wf-tRNS). The effect was evaluated by using the numeric rating scale loudness and distress pre- and post-stimulation. This study revealed a significant reduction in tinnitus loudness when lf-tRNS and hf-tRNS were applied as well as a reduction in tinnitus-related distress with lf-tRNS. Moreover, these researchers observed a significantly more pronounced reduction in loudness and distress in pure tone (PT) tinnitus compared to narrow band noise (NBN) tinnitus when hf-tRNS was applied, a difference that could not be obtained with lf-tRNS. The authors concluded that based on these results, tRNS might be a promising treatment option for non-pulsatile tinnitus; however, they cannot yet provide a clear mechanistic explanation for the different results obtained with different types of stimulation, i.e., lf-tRNS, hf-tRNS and wf-tRNS, or with different types of tinnitus, i.e., PT and NBN tinnitus.
In a systematic review and meta-analysis, Martins and colleagues (2022) examined the effectiveness of transcranial direct current stimulation (tDCS) on tinnitus distress, loudness and psychiatric symptoms. These researchers carried out a systematic literature search of PubMed, Web of Science, Cochrane Library, VHL, Embase, PsycINFO, OVID, and CINAHL databases on articles published until July 2021. Inclusion criteria were published controlled trials using tDCS intervention with tinnitus patients, using a sham/control group, and measuring tinnitus loudness, distress and/or psychiatric symptoms. A meta-analysis was carried out for the overall effect as well as to compare subgroups according to tDCS target (left temporoparietal area (LTA) and dorsolateral prefrontal cortex (DLPFC)). A total of 14 articles with 1,031 patients were included; 6 studies used tDCS over the DLPFC, 6 over the LTA and 2 over both areas. Although the overall meta-analysis showed that tDCS significantly decreased tinnitus loudness (SMD = -0.35; 95 % CI: -0.62 to -0.08, p = 0.01) and distress (SMD = -0.50, 95 % CI: -0.91 to -0.10, p = 0.02), the subgroup analysis showed a significant effect only for tDCS over LTA for loudness (SMD = -0.46, 95 % CI: -0.80 to -0.12, p = 0.009), and no other area resulted in significant change. There was no significant effect of treatment on psychiatric symptoms. The authors concluded that tDCS may improve tinnitus loudness and distress with a small-to-moderate effect size. Moreover, these investigators stated that despite the overall positive effect, only LTA tDCS yielded a significant effect. They stated that further well-controlled studies with larger sample sizes and broader examination of tDCS montages and doses are needed.
Transmeatal Laser Irradiation
With transmeatal laser irradiation, a low-level laser irradiation applied through the external acoustic meatus of the affected ear. The treatment takes place once a week for six minutes over a four week period or more.
In a prospective, randomized, double-blinded, controlled study, Nakashima et al (2002) assessed the effectiveness of 60-mW laser irradiation in the treatment of tinnitus. A total of 68 ears in 45 patients with disabling unilateral or bilateral tinnitus were included in this trial. The active or placebo laser treatment was administered transmeatally once a week for 6 minutes. Laser irradiation was performed four times during a 4-week period. A questionnaire was administered to evaluate the loudness, duration, quality, and annoyance of tinnitus before and after irradiation. The loudness and pitch match for tinnitus were obtained, and distortion product otoacoustic emissions were also examined. No significant difference was observed between the active and placebo laser groups with regard to outcome of loudness, duration, quality, and annoyance of tinnitus. In 1 patient who received active laser treatment, acute hearing deterioration occurred after the third irradiation. These investigators concluded that transmeatal low-power laser irradiation with 60 mW is ineffective for the treatment of tinnitus.
Tauber et al (2003) presented their findings of a feasibility study on the use of a laser application system in patients with chronic cochlear tinnitus and sensorineural hearing loss (n = 35). The laser TCL-system, consisting of 4 diode lasers (lambda = 635 to 830 nm) was developed on the basis of dosimetric data from a former light-dosimetric study. The chronic symptoms persisted after standard therapeutic procedures for at least 6 months, while retrocochlear or middle-ear pathologies have been ruled out. The patients were randomised and received 5 single-diode laser treatments (lambda = 635 nm, 7.8 mW cw, n = 17 and lambda = 830 nm, 20 mW cw, n = 18) with a space irradiation of 4 J/cm2 site of maximal cochlear injury. For evaluation of laser-induced effects complete otolaryngological examinations with audiometry, tinnitus masking and matching, and a tinnitus-self-assessment were performed before, during, and after the laser-irradiation. The first clinical use of the TCL-system has been well-tolerated without side-effects and produced no observable damage to the external, middle or inner ear. Changes of tinnitus loudness and tinnitus matching have been described. After a follow-up period of 6 months, tinnitus loudness was attenuated in 13 of 35 irradiated patients, while 2 of 35 patients reported their tinnitus as totally absent. Hearing threshold levels and middle ear function remained unchanged. These researchers stated that further investigations by large double-blind placebo-controlled studies are mandatory for clinical evaluation of the presented TCL-system and its therapeutic effectiveness in acute and chronic cochlear dysfunction.
A systematic review of randomized controlled clinical trials of low-powered laser treatments for tinnitus found no statistically significant difference between laser and placebo (Meehan et al, 2004).
Gungor et al (2008) assessed the effectiveness of laser irradiation in the treatment of chronic tinnitus. This study included 66 ears in 45 patients with chronic unilateral or bilateral tinnitus. A 5 mW laser with a wavelength of 650 nm, or placebo laser, was applied transmeatally for 15 minutes, once-daily for a week. A questionnaire was administered which asked patients to score their symptoms on a 5-point scale, before and 2 weeks after laser irradiation. A decrease of 1 scale point, regarding the loudness, duration and degree of annoyance of tinnitus, was deemed as improvement. The loudness, duration and degree of annoyance of tinnitus were improved, respectively, in up to 48.8, 57.7 and 55.5 % of the patients in the active laser group. No significant improvement was observed in the placebo laser group. The authors concluded that transmeatal, low power (5 mW) laser irradiation was found to be useful for the treatment of chronic tinnitus. The findings of this study need to be validated by larger studies with longer follow-up.
Noble (2008) stated that the various forms of treatment for tinnitus that have been tested in properly controlled trials can be classified as pharmacological, acoustic-physical, and psychological. In clinical trials, no pharmacological agent has been shown to have lasting effect on the presence or severity of tinnitus, although there are promising signs in an animal model. Acoustic devices do not seem to influence tinnitus, although appropriately fitted hearing aids may slightly reduce its prominence. Of physical treatments, cortical implantation may hold some promise of being effective for tinnitus suppression in selected cases. There was no mention on the use of laser.
- one group received active laser therapy 20 mins a day for 3 months with a 650-nm, 5-mW soft laser (group L), and
- the second group received a dummy device which duplicated all aspects of active laser therapy except for the activation of the laser beam (group C).
One subject in both groups dropped out due to an increase in tinnitus loudness. Two more patients in each group ceased to comply with the protocol due to familiar problems. The THI was considered the main outcome measure; no statistical difference was detected between the two groups in the THI total score (p = 0.97), and its functional (p = 0.89), emotional (p = 0.89) and catastrophic (p = 0.89) sub-scales. Moreover, a visual analog scale for self-perceived loudness of the tinnitus showed no difference between the groups (p = 0.69). Regarding psycho-acoustic parameters, the minimum masking level showed no difference (p = 0.42), while loudness expressed in sensation level exhibited lower values in group L (p = 0.0127). Group L subjects also presented a decreased rate of hyper-acusis (p = 0.02). No changes were detected in the audiometric threshold in both groups. The authors concluded that soft laser therapy demonstrated no efficacy as a therapeutic measure for tinnitus.
In a prospective, double-blinded, randomized, placebo-controlled trial, Ngao et al (2014) examined the effectiveness of transmeatal low-power laser stimulation (TLLS) in treating tinnitus. Patients with persistent subjective tinnitus as their main symptom were recruited into the study from the out-patient clinics.
- the THI and
- visual analogue scale (VAS) symptoms rating scales, before starting the treatment and at the end of the 10-week treatment period.
The total score of the THI questionnaire was further graded into 5 grades, grade 1 being mild and grade 5 being catastrophic. Wilcoxon-signed ranks test and Mann-Whitney test were used to compare and analyze the THI and VAS scores before and after treatment for each group. Changes with p value of < 0.05 were considered as statistically significant. Chi-square test was used to analyze the change of parameters in categorical forms (to compare between TLLS+ and TLLS-). Changes with p value of < 0.05 were considered as statistically significant. A total of 43 patients successfully and diligently completed their treatment. It was noted that using any condition of the device, TLLS+ or TLLS-, patient's tinnitus symptoms improved in terms of THI scores (TLLS+, p value = 0.038; TLLS-, p value = 0.001) or VAS scores with a change of at least one grade (TLLS+, p value = 0.007; TLLS-, p value = 0.002) at p value <0.05 significant level. In contrast when TLLS+ group was compared with TLLS- group, no statistically significant result was obtained. In term of VAS scores, there seemed to be no statistically significant improvement in patients' annoyance, sleep disruption, depression, concentration and tinnitus loudness and pitch heard between the two groups. They stated that transmeatal low-power laser stimulation did not demonstrate significant efficacy as a therapeutic measure in treating tinnitus.
In a prospective, double-blind, placebo-controlled study, Dehkordi et al (2015) examined the effect of low-dose laser therapy on chronic cochlear tinnitus. The study population was made up of 66 patients – 33 who received active laser treatment (case group) and 33 who received inactive dummy treatment (control group).
- the TSI,
- a subjective 10-point self-assessment scale for tinnitus loudness, and
- the Tinnitus Evaluation Test (TET).
At study's end, these researchers found no statistically significant differences between the case and control groups in the number of patients who experienced a reduction in TSI values (p = 0.589) or a reduction in subjective self-assessment scores (p = 0.475). In addition, these investigators did not find any significant reductions in the loudness (p = 0.665) and frequency (p = 0.396) of tinnitus as determined by the TET. The authors concluded that 5-mV laser therapy with a wavelength of 650 nm is no better than placebo for improving hearing thresholds overall or for treating tinnitus with regard to age, sex, environmental noise level, and the duration of tinnitus.
Hyperbaric Oxygen Therapy
Hyperbaric oxygen therapy has been proposed as a treatment for tinnitus that often accompanies sensorineural hearing loss. A patient is placed in a specially designed chamber as the pressure in the chamber is increased and 100% oxygen is breathed.
In a Cochrane review on the use of hyperbaric oxygen therapy (HBOT) for the treatment of idiopathic sudden sensorineural hearing loss (ISSHL) and tinnitus, Bennett et al (2005) stated that HBOT improved hearing, but the clinical significance of the level of improvement is unclear. Routine application of HBOT to patients with ISSHL is not justified by this review. These investigators noted that more research is needed.
A systematic evidence review of tinnitus treatments by BMJ Clinical Evidence concluded that hyperbaric oxygen is of "unknown effectiveness" (Savage et al 2009).
Competitive Kinesthetic Interaction therapy (KKIT)
Competitive kinesthetic interaction therapy (KKIT) is adapted physiotherapy using expressive movements of body language. Different groups of muscles in the hand, arm, leg, foot and body, from the feet up to the face, are activated, which purportedly guides the patient into a situation of peaceful resting, reduction of tension and finally into relaxation. This scheme was adapted from a rehabilitation program for treating pain. There is a lack of reliable evidence for KKIT for treatment of tinnitus.
Sequential Phase Shift Sound Cancellation Treatment
Sequential phase shift sound cancellation is a novel treatment for predominant-tone tinnitus. It entails the use of a phase-shift sound cancellation protocol in which a patient’s tinnitus is first identified as to frequency and amplitude. Then, a signal, 6 degrees out-of-phase with the identified tinnitus signal, is fed sequentially (6 degrees, 12 degrees, etc.) into the patient’s headphones for 30 seconds each for 30 minutes, or until 360 degrees is achieved. Available evidence on the effectiveness of this approach has mainly been in abstract forms (Noik, 2005; Choy and Kaminow, 2005; Lipman et al, 2006). The only published full-length paper on this subject is by Lipman and Lipman (2007) who assessed phase shift treatment for predominant tone tinnitus in a prospective, single-blinded, cross-over study. A total of 61 patients participated in 2 weeks of control and 2 weeks of phase shift treatment. Outcome measures included frequency and intensity matching, pre- and post-treatment tinnitus handicap inventory (THI) scores, and patient diaries. Initial volume comparisons showed a strong relationship between treatment and decrease in tinnitus intensity, with 57 % of patients achieving successful treatment. Thirty-seven percent decreased by one THI grade, 5 % by two. Utilizing patient diaries, 42 % of patients reported periods of complete residual inhibition (CRI) ranging from 1 hour to 7 days (average of 2 days). No periods of CRI were reported in control weeks. The authors concluded that phase shift treatment significantly benefited the majority of patients. These findings suggested that this device may be a valuable tool. They noted that further long-term studies with home therapy are needed.
In a double-blind, cross-over, randomized-controlled trial, Heijneman et al (2012) compared the effectiveness of the treatment of tinnitus with a phase-shifting pure tone to that of the same tone treatment without phase shifting. A total of 22 patients with predominantly tonal tinnitus underwent both intervention and control treatments. Each treatment consisted of three 30-minute sessions in 1 week. The control treatment was identical to the intervention treatment, except that the stimulus was a pure tone without phase shifting. Questionnaires, tinnitus loudness match, and annoyance and loudness ratings were used to measure treatment effects. Pure-tone treatment and phase-shift treatment had no significant effect on tinnitus according to questionnaires (Tinnitus Handicap Index, Tinnitus Reaction Questionnaire, Hospital Anxiety and Depression Scale, and Maastricht Questionnaire), audiological matching procedures, and loudness and annoyance ratings of tinnitus. Furthermore, phase-shift treatment showed no additional significant improvement in comparison with pure-tone treatment. Changes in questionnaire scores due to pure-tone and the phase-shift treatment were correlated. The authors concluded that on average across the group, both treatments failed to demonstrate a significant effect. Both treatments were beneficial for some patients. However, a positive effect was not demonstrated that could be attributed to the periodic shifting of the phase of the stimulus tone.
Thus, there is currently insufficient evidence to support the use of sequential phase shift sound cancellation treatment for tinnitus.
Neuromonics Tinnitus Treatment
The Neuromonics Tinnitus Treatment (NTT) combines the use acoustic stimulation with a structured program of counseling and support by a clinician specifically trained in tinnitus rehabilitation. The acoustic component has been designed to provide stimulation to auditory pathways deprived by hearing loss, engage with the limbic system, and allow intermittent, momentary tinnitus perception within a pleasant and relaxing stimulus, thereby facilitating desensitization to the tinnitus signal. Davis and colleagues (2007) examined the effectiveness of NTT, when enhanced with various modifications since previously reported trials and tested the relative clinical effectiveness of two variations of the approach. In the first, intermittent tinnitus perception was facilitated throughout treatment via the use of a stimulus in which intensity peaks allowed the subjects' tinnitus perception to be completely covered up, whereas in the intensity troughs their tinnitus was briefly discernible. In the second, subjects experienced little tinnitus perception while listening to the treatment for the first 2 months, then experienced intermittent perception. A total of 35 subjects with a predominantly moderate-to-severe level of tinnitus-related distress before treatment were randomly allocated into one of two treatment groups, corresponding to the 2 stage-based variations of the NTT. Subjects were provided with a high-fidelity personal sound player with earphones and an acoustic stimulus that had been spectrally modified according to their individual audiometric profile. They were instructed to use the acoustic stimulus for at least 2 hours per day, particularly at those times when their tinnitus was usually disturbing. Each group had equal amounts of clinician time for education, monitoring, and support. At 2, 4, 6, and 12 months after commencing treatment, both groups displayed clinically and statistically significant improvements in tinnitus distress, awareness, and minimum masking levels as well as loudness discomfort levels. Improvements increased with time over the first 6 months of therapy, at which time 91 % of all subjects across the 2 groups reported an improvement in tinnitus disturbance (as measured by the Tinnitus Reaction Questionnaire) of at least 40 %, with a mean improvement of 65 %. Furthermore, 80 % of subjects at 6 months reported a level of tinnitus disturbance that was no longer clinically significant. There was some indication of a more consistent benefit over 12 months for the group that was provided initially with a high level of tinnitus interaction; however, inter-group differences were not statistically significant. A relation between reported treatment usage (hours per day) and clinical outcomes was observed, suggesting that a "dosage effect" may apply with the stimulus provided. The authors concluded that this study found that the NNT provides rapid and profound improvements to the severity of tinnitus symptoms and their effect on the subject's quality of life. This was a consistent effect, provided by a treatment that subjects reported as being pleasant to use. Both of the stage-based variations of the treatment that were tested in this study were shown to be successful in achieving these outcomes.
Davis and associates (2008) conducted another clinical study on the effectiveness of NTT. This treatment approach is provided as part of a structured rehabilitation program. In this study, patients who received the customized stimulus (NTT group) reported significantly greater and more consistent alleviation of tinnitus symptoms than did patients who participated in a counseling and support program with and without delivery of a broad-band noise stimulus (Noise + Counseling group and Counseling-Only group, respectively). After 6 months of treatment, 86 % of the NTT patients met the minimum criterion for clinical success, defined as an alleviation of tinnitus disturbance of at least 40 % (as judged by the Tinnitus Reaction Questionnaire score). By contrast, only 47 % and 23 % of the Noise + Counseling and Counseling-Only groups, respectively, reported a successful result according to this criterion. Mean improvements in tinnitus disturbance scores in the NNT, Noise+Counseling, and Counseling-Only groups were 66 %, 22 %, and 15 %, respectively. The differences between the NTT group and the control groups were statistically significant. Significant differences were observed in other clinical outcomes. Patient reports of user acceptability were more consistently positive in the NTT group. It is unclear whether they wren overlapping of patients in these two studies.
- small numbers of subjects, and
- short-term follow-up (not exceeding 12 months).
Moreover, it is unclear whether they were overlapping of patients in these two studies. These findings need to be validated by further investigation.
Auditory Perceptual Training
Hoare et al (2010) stated that auditory perceptual training affects neural plasticity and so represents a potential strategy for tinnitus management. These investigators assessed the effects of auditory perceptual training on tinnitus perception and/or its intrusiveness via a systematic review of published literature. An electronic database search using the keywords 'tinnitus and learning' or "tinnitus and training" was conducted, updated by a hand search. The 10 studies identified were reviewed independently by 2 reviewers, data were extracted, study quality was assessed according to a number of specific criteria and the information was synthesised using a narrative approach. Nine out of the 10 studies reported some significant change in either self-reported or psychoacoustic outcome measures after auditory training. However, all studies were quality rated as providing low or moderate levels of evidence for an effect. The authors identified a need for appropriately randomized and controlled studies that will generate high-quality unbiased and generalisable evidence to ascertain if auditory perceptual training has a clinically relevant effect on tinnitus.
Intra-Tympanic Administration of Corticosteroids
- lidocaine, although effective in decreasing tinnitus, has been largely abandoned because of its severe side-effect profile and need for inpatient administration,
- corticosteroids have been associated with few if any side effects,
- the good results reported in the literature with intra-tympanic steroids for treating tinnitus of various causes should be viewed with caution, because most are retrospective and uncontrolled studies,
- some Meniere's disease patients with tinnitus may experience tinnitus improvement following intra-tympanic steroids. This treatment may be considered in such patients, especially for those with good hearing,
- gentamicin is effective in eliminating or reducing tinnitus in a significant number of patients with Meniere's disease and may be considered especially for those with non-serviceable hearing,
- further prospective, randomized, controlled studies to evaluate the effect of intra-tympanic perfusion for the treatment of tinnitus are warranted.
In a randomized, prospective, single-blind study, Araújo and colleagues (2005) tested the effectiveness of intra-tympanic dexamethasone injections as a treatment for severe disabling cochlear tinnitus. A total of 36 patients with severe disabling tinnitus predominantly of cochlear origin were randomly assigned to receive intra-tympanic injections of a dexamethasone solution or isotonic saline solution. Under topical anesthesia and after randomization, 36 patients received 0.5 ml intra-tympanic injections once per week for 4 weeks of either a 4 mg/ml dexamethasone solution or saline solution. Five patients were excluded from analysis because they did not complete the treatment or did not return for follow-up. Main outcome measure was improvement of tinnitus measured with a VAS. The 2 groups were similar in age, sex, tinnitus laterality, measurement of tinnitus intensity on the VAS, and main otologic diagnosis. These researchers considered a 2-point improvement on the VAS to be significant. Twenty-nine percent of the ears in the saline group and 33 % of the ears in the dexamethasone group showed significant improvement immediately after completion of treatment. These measurements were not significantly different from each other. Follow-up varied from 13 to 31 months, and the patients with improved tinnitus returned to the initial measurements over time. The authors concluded that there was no advantage in intra-tympanic injections of dexamethasone over saline solution in the treatment of severe, disabling tinnitus. Both solutions produced a placebo-like improvement.
In a prospective, randomized, placebo-controlled, single-blinded study, Topak et al (2009) examined if intra-tympanically injected methylprednisolone is effective in treating subjective tinnitus refractory to medical treatment. A total of 70 adult patients with subjective tinnitus of cochlear origin were randomly assigned to receive intra-tympanic injection of either methylprednisolone or saline solution. The treatment protocol comprised 3 intra-tympanic injections, 1 per week for 3 weeks. Improvement in tinnitus severity was measured by a self-rated tinnitus loudness scale and by the tinnitus severity index, at baseline and 2 weeks after the last injection. Data for 59 patients were available for analysis. There was no significant difference between the 2 treatment groups regarding age, sex, pure tone average, pre-treatment tinnitus intensity, tinnitus laterality or tinnitus duration. There was a significant post-treatment improvement in self-rated tinnitus loudness scale results in both groups. No significant post-treatment changes in the tinnitus severity index individual and total scores were observed in either group. The most frequently encountered side effects were pain during injection, vertigo, a burning sensation around the ear and in the throat, and a bitter taste. A burning sensation and bitter taste were observed more often in the methylprednisolone group compared with the placebo group. The authors concluded that these findings indicated that intra-tympanic methylprednisolone has no benefit, compared with placebo, for the treatment of subjective tinnitus of cochlear origin refractory to medical treatment.
In a Cochrane review, Phillips and Westerberg (2011) assessed the effectiveness of intra-tympanic steroids on the frequency and severity of attacks of vertigo, on chronic symptoms such as tinnitus, imbalance and hearing loss, and on the progression of these symptoms in patients with definite Meniere's disease or syndrome, as defined by the AAO-HNS Committee. These investigators searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was January 13, 2011. Randomized controlled trials of intra-tympanic dexamethasone versus placebo in patients with Meniere's disease were selected fo this analysis. Two authors independently assessed trial risk of bias and extracted data. They contacted study authors for further information where possible. A single trial containing 22 patients, with a low-risk of bias was included. This trial found that after 24 months, compared with placebo, the use of intra-tympanic dexamethasone demonstrated a statistically significant improvement in vertigo as defined by a respective improvement in functional level (90 % versus 42 %), class (82 % versus 57 %), change in Dizziness Handicap Inventory scores (60.4 versus 41.3) and mean vertigo subjective improvement (90 % versus 57 %). The treatment regime described by the authors involved daily injections of dexamethasone solution 4 mg/ml for 5 consecutive days. These results were clinically significant. No complications were reported. The authors concluded that these findings of a single trial provide limited evidence to support the effectiveness of intra-tympanic steroids in patients with Meniere's disease. This trial demonstrated a statistically and clinically significant improvement of the frequency and severity of vertigo measured 24 months after the treatment was administered. It is important to note that there were a few aspects of the study that the authors were unable to clarify with the study authors.
The American Academy of Otolaryngology - Head and Neck Surgery Foundation’s clinical practice guideline on "Tinnitus" (2014) stated that clinicians should not routinely recommend intra-tympanic medications for a primary indication of treating persistent, bothersome tinnitus.
In a prospective, randomized, placebo-controlled, double-blinded, multi-center study, Lee and colleagues (2018) examined the effectiveness of intra-tympanic dexamethasone injection (ITDI) in acute tinnitus of presumed cochlear origin. Between August 2013 and December 2015, a total of 54 patients with unilateral tinnitus were enrolled at 4 different centers. Patients were assigned either to an ITDI (n = 27) or an intra-tympanic normal saline injection (ITNI; n = 27) group through block randomization. Intra-tympanic injections were administered 4 times over 2 weeks. At 4 weeks after initial injection, these researchers analyzed the improvement rates of tinnitus using the THI and VAS for loudness, awareness, and annoyance. They defined improvement as the reduction of more than 7 points or of more than 20 % in the final THI score compared to the initial THI score. The initial mean hearing thresholds and VAS and THI scores of the 2 groups did not differ significantly. At 4 weeks after initial injection, the mean VAS and THI scores of both groups had significantly reduced. However, the improvement rate did not differ significantly between the groups (ITDI, 51.9 %; ITNI, 59.3 %). The authors concluded that these findings indicated that ITDI might not be more effective than ITNI for the treatment of acute unilateral tinnitus; thus, ITDI should not be considered as the main treatment for patients presenting with acute tinnitus as the primary symptom.
Sayoo and Kumar (2019) noted that different methods had been developed for managing tinnitus but none has offered a permanent cure. In this trial, these researchers employed a simple procedure of intra-tympanic injection of dexamethasone in managing tinnitus patients. A total of 40 subjects (26 females and 14 males aged spanned 15 to 65 years) were included in this study; 22 of them complained of tinnitus only; and the remaining 18 complained of tinnitus with impaired hearing that was confirmed further by pure-tone audiometry. Dexamethasone injection was administered under otologic microscopic guidance via the postero-inferior quadrant of tympanic membrane in weekly interval. After receiving several number of injections, 24 patients (60 %) reported complete disappearance of tinnitus, 10 (25 %) still had residual tinnitus but comparatively less severe, and 6 (15 %) reported no improvement. This was a small, uncontrolled study; its findings need to be validated by well-designed studies.
Chung and colleagues (2022) stated that ITDI has been introduced as a therapeutic option for subjective tinnitus; however, the effects of ITDI on patients with tinnitus remain unclear. In a systematic review and meta-analysis, these researchers examined the effectiveness of ITDI for tinnitus treatment. They searched Medline, the Cochrane Central Register of Controlled Trials, and Embase. A total of 4 double-blind RCTs that examined the effectiveness of ITDI compared with a placebo were deemed eligible for a quantitative meta-analysis, while 4 prospective studies and 7 retrospective studies reporting the effectiveness of ITDI on tinnitus treatment were included in a qualitative synthesis. In the 4 studies included in the quantitative meta-analysis, ITDI did not show evidence of tinnitus improvement compared with placebo (odds ratio [OR], 1.38; 95 % CI: 0.53 to 3.61). In the 11 studies included in the qualitative synthesis, 7 retrospective studies without controls reported rates of tinnitus improvement after ITDI ranging from 35.9 % to 91.3 %. In the 4 prospective studies with controls, ITDI appeared to be effective when combined with other drugs for tinnitus treatment. The authors concluded that 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 therapy should be further studied in more systematic research.
Deep Brain Stimulation
In a case series with chart review, Shi et al (2009) reported deep brain stimulation (DBS) effects in patients with tinnitus. A total of 7 patients implanted with deep brain stimulation (DBS) systems for movement disorders who also reported having tinnitus were interviewed about their tinnitus conditions. Four were available for testing in a specialized tinnitus clinic with their DBS systems turned off or on. Testing included matching of self-rated and psychoacoustically measured tinnitus loudness to measure the impact of DBS on tinnitus; 3 of the 7 patients reported reduced tinnitus loudness when DBS was turned on. Of the 4 patients tested in the clinic, results indicated that DBS of the ventralis intermedius nucleus of the thalamus caused decreases in tinnitus loudness in 2 patients with relatively prolonged residual inhibition. The authors concluded that these results suggested that DBS of non-auditory thalamus structures may provide tinnitus relief for some patients. This preliminary findings needs to be validated by well-designed studies.
Cheung and Larson (2010) reported that that application of DBS therapy to a locus of caudate neurons (area LC) can decrease or increase tinnitus loudness perception. The DBS lead traversed through or was adjacent to area LC in 6 Parkinson's disease and essential tremor subjects with concomitant tinnitus who underwent implantation of the subthalamic or ventral intermediate nucleus. In 5 subjects where the DBS lead tip traversed area LC, tinnitus loudness in both ears was suppressed to a nadir of level 2 or lower on a 0 to 10 rating scale. In 1 subject where the DBS lead was outside area LC, tinnitus was not modulated. In 3 subjects with pre-operative and post-operative audiograms, hearing thresholds were unchanged by area LC stimulation. Neuromodulation of area LC may be interrupting perceptual integration of phantom sensations generated in the central auditory system. The authors stated that this new, basal ganglia-based approach to tinnitus modulation warrants further investigation and may be ultimately refined to treat patients with refractory symptoms.
Vagal Nerve Stimulation
Schnupp (2011) stated that recent observations linking the vagus nerve to plasticity in the central nervous system could pave the way to new treatments for tinnitus, one of the most common and intractable disorders of the auditory system. Furthermore, an UpToDate review on "Treatments for tinnitus" (Dinces, 2012) does not mention the use of vagal nerve stimulation as a therapeutic option.
In a systematic review, Stegeman and colleagues (2021) examined the effect of vagus nerve stimulation (VNS) on distress and symptom severity in patients with chronic tinnitus. These investigators searched PubMed, Embase and the Cochrane Library systematically for RCTs, observational studies and case studies on the effect of VNS for the treatment of tinnitus on October 29, 2019. Studies including adult patients with subjective tinnitus, comparing transcutaneous or implantable VNS to placebo or no treatment or before and after application of VNS on tinnitus distress and tinnitus symptom severity measured with a validated questionnaire were eligible. The risk of bias was assessed with the appropriate tool for each type of study. The search identified 9 primary studies of which 2 were RCTs, 5 were cohort studies and 2 were case series or reports; 5 studies used transcutaneous VNS treatment and 4 used implanted VNS treatment; 6 studies combined VNS treatment with sound therapy. There was a serious risk of bias in all studies, especially on confounding. Most studies reported a small decrease in tinnitus distress or tinnitus symptom severity. The authors concluded that due to methodological limitations and low reporting quality of the included studies, the effect of VNS on tinnitus remains unclear. These researchers stated that to draw conclusions for which patient population and to what extent (t)VNS is beneficial in the treatment of tinnitus, a RCT should be considered.
Cochlear Implant
A cochlear implant is a surgically implanted electronic device that can provide improved speech and hearing communication abilities for people who have severe to profound hearing loss in both ears. Purportedly, the device may help tinnitus by masking with ambient sound or by suppression when electrical stimulation is sent through the auditory nerve.
Tao and Chen (2012) evaluated the effects of cochlear implantation (CI) on ipsilateral tinnitus. With standard assessment table and standard testing program, 48 post-lingual hearing-impaired adults aged 18 to 62 years (mean age at implantation: 35.0) were operated at 5 clinical centers from June 2009 to March 2010. There were 23 males (47.9 %) and 25 females (52.1 %). These researchers evaluated the pre- and post-implantation degrees of tinnitus, performed free sound field audiometry and scored speech perception during different periods. Secondary analyses were conducted to examine the correlation between the effects of implantation on tinnitus and hearing or speech perception rehabilitation. Before implantation, there were 16 cases with ipsilateral tinnitus and 32 cases without tinnitus. After implantation, among 16 cases, the outcomes were recovery (n = 6), tinnitus suppression (n = 1) and no change in symptoms (n = 9). The total effective rate was 43.8 %. Among another 32 cases without pre-operative tinnitus, 2 cases developed tinnitus after implantation. The effects of CI on tinnitus were negatively correlated with the course of tinnitus. There was no more correlation with other factors. The authors concluded that CIs have significant therapeutic effects on tinnitus in 43.8 % of implant users. Better efficacies are correlated with a shorter course of tinnitus. However, they stated that tinnitus suppression using electrical stimulation via CI for deafness needs to be further evaluated.
Tavora-Vieira et al (2013) examined the effectiveness of CI in patients with unilateral deafness with and without tinnitus. A total of 9 post-lingually deafened subjects with unilateral hearing loss, with and without tinnitus ipsilaterally, and functional hearing in the contralateral ear were implanted with a standard electrode. Speech perception in noise was tested using the Bamford-Kowal-Bench presented at 65 dB SPL. The Speech, Spatial, and Qualities (SSQ) of Hearing Scale was used to evaluate the subjective perception of hearing outcomes, and the Tinnitus Reaction Questionnaire assessed the effect on tinnitus. All patients were implanted with the Med-El Flex soft electrode, Innsbruck, Austria. They were regularly wearing the speech processor and found it beneficial in improving their ability to hear, particularly in noise. Decrease of tinnitus perception and an improvement of sound localization sounds were also reported by these patients. The authors concluded that in this case series, CI was successful for all 9 patients, with improvement of speech recognition in noise, self-perceived improvement of hearing, and for tinnitus control. Moreover, they stated that several factors such as deafness duration, age of deafness onset, the presence of residual hearing, patient motivation, and the rehabilitation intensity need to be further investigated in order to understand their impact on performance after implantation. (It is unclear how many of the 9 patients had tinnitus).
In a review on "Cochlear implantation for single-sided deafness: The outcomes. An evidence-based approach", Vlastarakos et al (2014) reviewed the current evidence on the effectiveness of CI as a treatment modality for SSD, and/or unilateral tinnitus. Systematic literature review in Medline and other database sources was conducted along with critical analysis of pooled data. The study selection includes prospective and retrospective comparative studies, case series and case reports. The total number of analyzed studies was 17. A total of 108 patients with SSD have been implanted; 66 patients due to problems associated with SSD, and 42 primarily because of debilitating tinnitus. Cochlear implantation in SSD leads to improved sound localization performance and speech perception in noise from the ipsilateral side with an angle of coverage up to (but not including) 90° to the front, when noise is present in the contralateral quartile (Strength of recommendation B). Speech and spatial hearing also subjectively improve following the insertion of a CI (Strength of recommendation B); this was not the case regarding the quality of hearing. Tinnitus improvement was also reported following implant placement (Strength of recommendation B); however, patients need to be advised that the suppression is mainly successful when the implant is activated. The overall quality of the available evidence supports a wider use of CI in SSD following appropriate selection and counseling (overall strength of recommendation B). It remains to be seen if the long-term follow-up of large number of patients in well conducted high quality studies will confirm the above mentioned results.
Blasco and Redleaf (2014) noted that in recent years, otologists have begun to place cochlear implants into non-functioning ears after sudden unilateral hearing loss. Patients in these trials demonstrated differing degrees of hearing loss in the un-implanted ear. Few studies have examined the role of implantation in patients with normal hearing in the un-implanted ear. These researchers reviewed the available literature to understand if this practice benefits these patients in terms of tinnitus, sound localization, and speech understanding. Medline, Embase, and Cochrane databases were searched for publications from database inception to June 1, 2013, without restriction of language. A search of multiple medical databases was performed to identify articles reporting cases series of CI for unilateral hearing loss. Subjects were included for analysis only if the course of hearing loss was acute and rapidly progressive, if the loss was severe to profound, and if the contralateral ear had normal hearing. A total of 9 appropriate articles were identified, in which 36 patients met the inclusion criteria. Three meta-analyses were performed: of tinnitus (22 patients); of the lowest signal-to-noise ratio, which still allowed 50 % sentence understanding (16 patients); and of sentence understanding at a fixed signal-to-noise ratio (12 patients). They found that measures of tinnitus reduction and decreased signal-to-noise ratios to still allow 50 % speech discrimination were statistically significantly reduced. Systematic review of subjective changes of tinnitus in 27 patients, speech understanding in 16 patients, and sound localization in 16 patients found 96 %, 100 %, and 87 % improvements, respectively. The authors concluded that CI in unilateral sudden hearing loss with a normal functioning contralateral ear might prove to be an effective therapy. Tinnitus is reduced as is the signal-to-noise ratio, which still allows 50 % speech discrimination. All patients felt that they localized sound better, and most felt that they understood speech better. They stated that further studies should be conducted to compare the success of hearing rehabilitation of CI and traditional modalities such as contralateral routing of signal and bone-anchored hearing aids.
Furthermore, an August 2013 Agency for Healthcare Research and Quality’s comparative effectiveness review on "Evaluation and treatment of tinnitus" (Pichora-Fuller et al, 2013) indicated that the use of cochlear implants for tinnitus and single-sided deafness is a very recent off-label indication, and indicated insufficient evidence for the use of this and other sound therapies for tinnitus.
Acupuncture
Acupuncture is the technique of inserting and manipulating very fine needles into the skin to stimulate specific anatomic points in the body for therapeutic purposes.
Liu and colleagues (2016) performed a systematic review and meta-analysis of all available randomized controlled trials (RCTs) using acupuncture to treat tinnitus. A total of 5 electronic databases, in both English and Chinese, were searched. All studies in this review and meta-analysis included parallel RCTs of tinnitus patients, which compared subjects receiving acupuncture (or its other forms, such as electro-acupuncture) to subjects receiving no treatment, sham treatment, drugs or basic medical therapy. Data from the articles were validated and extracted using a predefined data extraction form. Nearly all of Chinese studies reported positive results, while most of English studies reported negative results. Analysis of the combined data found that the acupuncture treatments appeared to provide some advantages over conventional therapies for tinnitus. It had difference in acupuncture points and sessions between Chinese studies and English studies. Methodological flaws were also found in many of the RCTs, especially in Chinese studies. The authors concluded that the findings of this review suggested that acupuncture therapy may offer subjective benefit to some tinnitus patients. They noted that acupuncture points and sessions used in Chinese studies may be more appropriate, however, these studies have many methodological flaws and risk bias, which prevented them making a definitive conclusion.
He et al (2016) examined the effect of electro-acupuncture for alleviating the symptoms of subjective tinnitus. These researchers performed literature searches in 3 English and 4 Chinese databases (PubMed, EMBASE, Cochrane Library, CNKI, Wanfang Chinese Digital Periodical and Conference Database, VIP, and ChiCTR). The date of the most recent search was June 1, 2014. Randomized controlled trials or quasi-RCTs were included. The titles, abstracts, and keywords of all records were reviewed by 2 authors independently; the data were collected and extracted by 3 authors. The risk of bias in the trials was assessed in accordance with the Cochrane Handbook, version 5.1.0. A total of 89 studies were retrieved; after discarding 84 articles, 5 studies with 322 subjects were identified. Assessment of the methodological quality of the studies identified weaknesses in all 5 studies. All studies were judged as having a high risk of selection and performance bias. The attrition bias was high in 4 studies. Incompleteness bias was low in all studies. Reporting bias was unclear in all studies. Because of the limited number of trials included and the various types of interventions and outcomes, these researchers were unable to conduct pooled analyses. The authors concluded that due to the poor methodological quality of the primary studies and the small sample sizes, no convincing evidence that electro-acupuncture is beneficial for treating tinnitus could be found. There is an urgent need for more high-quality trials with large sample sizes for the investigation of electro-acupuncture treatment for tinnitus.
In a RCT, Laureano and associates (2016) examined the effect of acupuncture on brain perfusion using ethyl cysteinate dimer single-photon emission computed tomography (99mTc-ECD SPECT) in patients with tinnitus. This randomized, single-blind, sham-control study examined patients (18 to 60 years old) with normal hearing and CIT. A total of 57 subjects were randomly assigned to true (n = 30) or sham (n = 27) acupuncture (ACP); 99mTc-ECD SPECT examinations were performed before and after 12 twice-weekly ACP sessions. Secondary outcomes included changes in the THI, VAS, Hamilton Anxiety Scale (HAS) and Beck Depression Inventory (BDI). Imaging data were analyzed using Statistical Parametric Mapping (SPM8) software. Regression models were used to examine secondary outcomes via 2 paradigms: intention-to-treat (ITT; where multiple imputations were conducted because of study attrition) and complete cases. No between-group brain perfusion differences were observed. However, a significant improvement in THI scores was observed at the end of true ACP treatment for all domains (all p values < 0.01) except the catastrophic scale. The authors concluded that ACP might reduce the effects of tinnitus on daily life; however, additional studies should be conducted to verify the effects of ACP on the neural architecture and brain function of tinnitus patients.
The American Academy of Otolaryngology - Head and Neck Surgery Foundation’s clinical practice guideline on "Tinnitus" (2014) stated that no recommendation can be made regarding the effect of acupuncture in patients with persistent bothersome tinnitus.
Lidocaine
Kallio et al (2008) stated that intravenous (IV) lidocaine has been used to ameliorate tinnitus, but in general its effect has been limited. The longer acting local anesthetic ropivacaine may be more effective. These investigators compared ropivacaine with lidocaine for the treatment of tinnitus. A total of 19 randomized, double-blind, cross-over study patients suffering from chronic tinnitus were given a 30-min IV infusion of ropivacaine or lidocaine 1.5 mg/kg at an interval of 2 to 3 months. The intensity of tinnitus was evaluated on THI scale and on the VAS. Plasma ropivacaine and lidocaine concentrations were determined. In both treatments, the infusion decreased the VAS score significantly. At the end of infusion, a greater than or equal to 50 % reduction in VAS score was observed in 5 patients by ropivacaine and in 1 patient by lidocaine, but this effect was sustained for 1 hour only in 3 patients. However, the THI scores did not differ significantly within or between treatments. On the post-infusion day, 3 patients after ropivacaine and 5 after lidocaine treatment had greater than or equal to 30 % improvement in the THI score. Four weeks later, 1 patient after ropivacaine and 2 after lidocaine had a greater than or equal to 30 % reduction in the THI score. One patient developed seizures soon after ropivacaine infusion from which he recovered uneventfully. His plasma concentration of ropivacaine was 1,817 ng/ml. The highest individual ropivacaine and lidocaine concentrations were 3,483 and 1,680 ng/ml, respectively. The authors concluded that temporary clinically significant alleviation of tinnitus was observed only in a few individuals after both IV ropivacaine and lidocaine.
Hahn et al (2008) performed a retrospective study of patients suffering from chronic unilateral or bilateral tinnitus that was previously ineffectively treated by oral drugs [betahistine (Betaserc), extract of Ginkgo biloba (EGb 761), tanakan (Tebokan), and cinnarizine-dimenhydrinate (Arlevert), singly or in combination]. These researchers divided 150 tinnitus patients (80 men, 70 women) into 7 treatment groups. Treatments consisted of application of intravenous pentoxifylline, lidocaine, or vinpocetine (Cavinton) and combination of these agents with physiotherapy and soft laser. Mean duration (+/- standard deviation) of tinnitus in these patients was 7.4 +/- 6.0 years; their mean age was 55.6 +/- 12.5 years. The aim of the study was to compare treatment modalities and define their effectiveness for tinnitus relief. The most effective treatment was defined as a combination of Cavinton and physiotherapy. The authors found that pure lidocaine infusion therapy was ineffective. None of the treatment modalities had an objective correlate of improvement, though improvement was reported by a VAS.
Also, an UpToDate review on "Treatment of tinnitus" (Dinces, 2014) states that "Historically, lidocaine, either intratympanic or intravenous, has been found in observational studies to be modestly efficacious in reducing symptoms of tinnitus. However, given the adverse effects of intravenous lidocaine that clearly outweigh any small benefits, lidocaine should not be used in the treatment of tinnitus".
The American Academy of Otolaryngology - Head and Neck Surgery Foundation’s clinical practice guideline on "Tinnitus" (2014) stated that clinicians should not routinely recommend intra-tympanic medications for a primary indication of treating persistent, bothersome tinnitus.
Mexiletine
In a pilot study, Berninger et al (2006) examined the effect of intravenously administered mexiletine on subjective tinnitus and hearing in 6 patients, who initially responded positively to lidocaine. Distinct mexiletine-induced decreases in tinnitus loudness were demonstrated in 3 subjects, as reflected by maximum VAS level reduction of 34 %, 95 %, and 100 %, respectively. One subject reported change in tinnitus pitch, another one showed a slight (18 % on VAS) tinnitus reduction, and 1 subject disclosed no effect. Side effects were seen only during 1 of 7 infusions. Mexiletine induced shifts in pure-tone threshold, transient evoked oto-acoustic emission, and acoustic reflex threshold, probably reflecting a reversible interference in the function of organ of Corti. The concentration effect relationship remained unclear and no general "therapeutic" level could be identified. The authors concluded that this study confirmed the effect of mexiletine on the auditory function and its potential as a possible therapeutic agent or a model for further development in tinnitus pharmacotherapy.
An UpToDate review on "Treatment of tinnitus" (Dinces, 2014) does not mention the use of mexiletine as a therapeutic option.
Melatonin
Miroddi et al (2015) performed a review to summarize, analyze and discuss the evidence provided by clinical studies evaluating effectiveness of melatonin in the cure of tinnitus. Due to the fact that there is no satisfactory treatment for tinnitus, clinical research has explored new therapeutic approaches. A search of PubMed, Medline, Embase, Central and Google Scholar was conducted to find trials published prior March 2014 on melatonin in the treatment of tinnitus. Design of the studies, randomization, allocation concealment procedures and diagnostic instruments (scales for tinnitus evaluation) were critical evaluated. A total of 5 clinical studies were included; 3 of them tested effectiveness of melatonin alone, the remaining 2 along with sulpiride and sulodexide, respectively. Considered clinical trials adopted various experimental designs: single-arm, randomized placebo-controlled and randomized placebo-controlled followed by cross-over. These studies were characterized by several methodological weaknesses. The authors concluded that confirmation of melatonin clinical effectiveness in the treatment of tinnitus cannot be given in the light of the biases observed in the considered evidence. Melatonin seems to improve sleep disturbance linked to tinnitus.
In a retrospective study, Ferrari and colleagues (2015) determined the effectiveness of combined treatment with sulodexide (a natural glycosaminoglycan with anti-thrombotic, pro-fibrinolytic and vascular anti-inflammatory properties) and melatonin for the treatment of tinnitus. A total of 30 patients with tinnitus were treated with sulodexide (250 LSU BID, in the morning and in the evening) and melatonin (3 mg in the evening before going to sleep) for 80 days. Evaluations were performed comparing different parameters at basal (T0) and after 40 days (T1) and 80 days (T2) of treatment. The results of THI and acufenometry showed a significant improvement of tinnitus after treatment with sulodexide and melatonin. In particular, THI total score was reduced from 37 ± 20 to 27 ± 18 (p < 0.001) and 21 ± 19 (p < 0.001) at T1 and T2, respectively. The percentage of patients with improved symptoms (i.e., reduced score at THI) was 76.7 % at T1 and 90.0 % at T2. Finally a significant improvement was also detected in the tone audiometry test. No side effects were observed during the treatment period. The authors concluded that the combined use of sulodexide and melatonin confirmed to an important and promising therapeutically option in the tinnitus management.
Larsen and Ovesen (2014) performed a literature search on tinnitus guidelines and treatment. The authors stated that anti-depressants, melatonin and cognitive behavioral therapy have no effect on tinnitus, whereas sound generators, hearing aids and tinnitus retraining therapy show some but limited improvement. They stated that national recommendations are needed to ensure a homogenous and optimum offer for all patients.
Miscellaneous Interventions
Zenner and associates (2015) stated that chronic idiopathic tinnitus (CIT) is the most frequent type of tinnitus. A considerable number of treatment strategies are used to treat CIT; however, there is no evidence of effectiveness for many of these interventions. In order to enable scientific evidence-based treatment of CIT, German inter-disciplinary S3 guidelines have recently been constructed for the first time. These investigators presented a short form of these S3 guidelines. The guidelines were constructed based on a meta-analysis of the treatment of chronic tinnitus performed by the authors. Additionally, a systematic literature search was performed in the PubMed and Cochrane Library databases. Furthermore, a systematic search for international guidelines was performed in Google, as well as in the Guidelines International Network and National Guideline Clearinghouse (USA) database. Evidence was classified according to the Oxford Centre for Evidence-Based Medicine system. According to the guidelines, alongside counselling, manualized structured tinnitus-specific cognitive behavioral therapy (tCBT) with a validated treatment manual is available as evidence-based therapy. In addition, the guidelines recommended concurrent treatment of co-morbidities, including drug-based treatment, where appropriate. Particularly important is treatment of anxiety and depression. Where a psychic or psychiatric co-morbidity is suspected, further diagnosis and treatment should be performed by an appropriately qualified specialist (psychiatrist, neurologist, psychosomatic medicine consultant) or psychological psychotherapist. In cases accompanied by deafness or hearing loss bordering on deafness, cochlear implants may be indicated. The authors concluded that no recommendations can be made for drug-based treatment of CIT, audiotherapy, transcranial magnetic or electrical stimulation, specific forms of acoustic stimulation or music therapy; or such recommendations must remain open due to the lack of available evidence. Moreover, they stated that poly-pragmatic tinnitus treatment with therapeutic strategies for which there is no evidence of effectiveness from controlled studies is to be refused.
Zenner and colleagues (2017) stated that for auditory therapeutic measures, transcranial magnetic or direct current stimulation and specific forms of acoustic stimulation (e.g., noiser/masker, retraining therapy, music, and coordinated reset) for the treatment of chronic tinnitus the currently available evidence is not yet sufficient for supporting their recommendation.
Antioxidant Therapy
In a prospective, randomized, double-blinded, placebo-controlled, clinical trial, Polanski et al (2015) evaluated the effects of antioxidant therapy for tinnitus in a group of elderly patients. The sample consisted of 58 subjects aged 60 years or older, with a complaint of tinnitus associated with sensorineural hearing loss. These individuals completed the THI questionnaire before and after 6 months of therapy. The treatment regimens were: Ginkgo biloba dry extract (120 mg/day), alpha-lipoic acid (60 mg/day) + vitamin C (600 mg/day), papaverine hydrochloride (100 mg/day) + vitamin E (400 mg/day), and placebo. There was no statistically significant difference between THI by degree (p = 0.441) and by score (p = 0.848) before and after treatment. The authors concluded that there was no benefit from the use of antioxidant agents for tinnitus in this sample.
Radiofrequency Lesion of the Superior Cervical Sympathetic Ganglion
Koning et al (2016) examined the effectiveness of radiofrequency lesioning of the superior cervical sympathetic ganglion for patients with tinnitus. This was a retrospective long-term clinical review of patients with tinnitus treated with a blockade of the superior cervical sympathetic ganglion. Subjects were 366 consecutive patients who came to the DC Klinieken in Almere and Amsterdam from January 2010 to January 2014 for consultations on their tinnitus that persisted for 1 month or longer. Data were recorded from patients whose charts were reviewed retrospectively to identify the patients who were treated with a blockade of the superior cervical sympathetic ganglion for tinnitus. An independent observer conducted a long-term follow-up assessment of the therapy by telephone interview. Relief of tinnitus at 7-week follow-up was achieved in 64 % of the patients treated with a radiofrequency lesion of the superior cervical sympathetic ganglion after a positive test blockade of this structure. Two years after the treatment, the maintenance of a tinnitus relief occurred in almost 40 % of the patients with a follow-up period of 2 years or longer. The authors concluded that radiofrequency lesion of the superior cervical sympathetic ganglion may be a useful alternative for patients with tinnitus not responding to conventional therapy. These preliminary findings need to be validated by well-designed studies.
Koning and Meulen (2019) examined the effectiveness of pulsed radiofrequency (PRF) of C2 dorsal root ganglion (DRG) in the treatment of patients with tinnitus, and surveyed the parameters related with a long-term advantage. Participants were 61 consecutive patients who attended the authors’ facility from October 2016 to October 2018 for discussions of their tinnitus that endured for 1 month or more and were treated with PRF of C2 DRG. Clinical information of these patients were recorded; an independent spectator evaluated the long-term impact of the treatment by phone. In patients with tinnitus that persevered for 1 month or more, 15 (25 %) of them reacted with a reduction of their tinnitus after PRF of C2 DRG. At 13.5 months following treatment, 50 % of at first effective treated patients still encountered an advantage. Unfavorable occasions of the PRF of C2 dorsal root ganglion at 7 weeks of follow-up were an expansion of the force of the tinnitus in 7 % of the patients. In patients under the age of 43 years at the time tinnitus commencement, 45 % of them had a reduction of their tinnitus at 7 weeks following treatment with PRF of C2 DRG. The authors concluded that PRF of C2 DRG could reduce the power of tinnitus extensively and for the long-term in 25 % of the patients with tinnitus without genuine antagonistic impacts. Moreover, these researchers stated that a prospective, a follow-up study with a larger cohort is needed to confirm these findings. The authors stated that the main drawbacks of this were its retrospective design and its small sample size; and only 25 % of participants experience positive effects of the treatment.
Vitamin B12 Injections
In a randomized, double-blind, pilot study, Singh et al (2016) examined the role of vitamin B12 in treatment of chronic tinnitus. A total 40 patients were enrolled, of which 20 in Group A (cases) received intramuscular therapy of 1 ml vitamin B12 (2,500 ug) weekly for a period of 6 weeks and Group B (20) patients received placebo isotonic saline intramuscular injection. Subjects were subjected to vitamin B12 assay and audiometry pre- and post-therapy. Of the total patients of tinnitus, 17 were vitamin B12 deficient (i.e., 42.5 % showed deficiency when the normal levels were considered to be 250 pg/ml). A paired t-test showed that in Group A, patients with vitamin B12 deficiency showed significant improvement in mean tinnitus severity index score and VAS after vitamin B12 therapy. The authors concluded that the findings of this pilot study highlighted the significant prevalence of vitamin B12 deficiency in North Indian population; and improvement in tinnitus severity scores and VAS in cobalamin-deficient patients receiving intramuscular vitamin B12 weekly for 6 weeks further provided a link between cobalamin deficiency and tinnitus thereby is suggestive of a therapeutic role of vitamin B12 in cobalamin-deficient patients of tinnitus. These preliminary findings need to be validated by well-designed studies.
Acoustic Coordinated Reset Neuromodulation
Wegger and colleagues (2017) noted that there are growing technological advances in the development of sound-based methods for the treatment of tinnitus. Most of these methods intend to affect the speculated underlying neurological causes of tinnitus. Acoustic coordinated reset (CR) neuromodulation is a novel method that as of yet seems inadequately reviewed. These investigators evaluated the current evidence on acoustic CR neuromodulation as a method for the treatment of tinnitus and examined if the method can be implemented in daily clinical practice. They performed a systematic literature search in 13 databases in the period from February 1, 2015 to May 1, 2016. Studies regarding acoustic CR neuromodulation as a treatment method for tinnitus were included in the present review. A total of 8 studies were eligible for being reviewed comprising a total of 329 patients. Overall, the evidence level of the published literature was low. The main findings in the included studies were that acoustic CR neuromodulation was safe and well-tolerated and most patients reported reduction of tinnitus symptoms. The neurophysiological basis of the method was claimed to be desynchronization, anti-kindling, and change of abnormal frequency couplings in a widespread tinnitus network comprising both auditory and non/auditory brain areas based on electroencephalographic (EEG) analyses. The authors concluded that the available evidence is insufficient for clinical implementation of acoustic CR neuromodulation. They stated that the limited level of evidence suggested that acoustic CR neuromodulation may have positive effects on tinnitus symptoms. The authors stated the these preliminary EEG data are compatible with the claim that tinnitus reduction after CR treatment is mediated by a desynchronizing effect; however, a proof for this claim is still lacking.
Haller and Hall (2017) noted that the therapeutic effects of coordinated reset (CR) neuromodulation were originally discovered by researchers at the Forschungzentrum Juelich GmbH (FZJ) in Germany. Acoustic CR Neuromodulation is designed as a patient specific targeted sound therapy. The treatment has been provided to over 3,000 patients worldwide to date. Several peer-reviewed papers have reported reduction of tinnitus symptoms (from baseline) in populations of tinnitus sufferers by using a portable acoustic neurostimulator providing Acoustic CR Neuromodulation; including tinnitus loudness measured using a VAS neuronal synchrony and pathological synaptic connectivity) results in a substantial and long-lasting reduction of disease symptoms. In October 2011, Nottingham University Hospitals NHS Trust agreed to conduct an investigator-led evaluation of acoustic CR neuromodulation versus placebo effects, recruiting 100 participants with a 1:1 allocation ratio (the RESET 2 Trial). Participants were adults aged greater than or equal to 18 years of age, chronic subjective tinnitus for more than 3 months with a minimum score of 18 points measured using the THI and a dominant tinnitus pitch corresponding to a frequency between 0.2 and 10 kHz, and with an average hearing loss no greater than 60 dB (0.5, 1, 2, and 4 kHz). The formal results of the RESET2 trial were non-conclusive, which was unexpected, considering the past and current volumes of observational data showing substantial benefit. The authors concluded that controlled trials to test clinical effectiveness of acoustic CR neuromodulation for tinnitus are worthwhile. With the knowledge gained from the RESET2 trial, it is suggested that future trials should include a placebo or "usual standard of care" control group that is well characterized, should follow a well-defined and trained pitch matching protocol, should assess the status of tinnitus for longer than 12 weeks (these researchers suggested at least 6 months), should better control the baseline characteristics to avoid floor and ceiling effects and should use an outcome instrument with known measurement properties for the target population.
Microvascular Decompression of the Cochlea-Vestibular Nerve
- tinnitus,
- vertigo, and
- tinnitus combined with vertigo.
For the meta-analysis, IPD were collected from the papers and/or from the authors; IPD were analyzed with logistic regression analysis while accounting for study clustering. A total of 35 studies (572 patients) were included. The level of evidence provided by these studies was low. In 28 % of patients with tinnitus and 32 % of patients with vertigo, complete relief following MVD was reported. Patients with both tinnitus and vertigo had complete relief in 62 % of cases. In 11 % of patients, greater than or equal to 1 complications were reported. Meta-analysis of IPD (165 patients) demonstrated that patients with both tinnitus and vertigo had a higher chance of success (odd ratio [OR] 3.8, 95 % CI: 1.45 to 10.10) than patients with tinnitus alone. No other variables were significantly related to success. The authors concluded that due to low success rates, MVD cannot be considered as a standard treatment method for tinnitus or vertigo. Moreover, a substantial complication rate was found. However, patients with combined symptoms had a higher chance of success. When combined symptoms occur, it is more likely that an NVC is the underlying pathology and MVD might be appropriate. Due to the low level of evidence in the included studies, this conclusion must be taken with caution. They stated that further validation is needed to examine if patients with combined symptoms are indeed better candidates for MVD.
Nash and colleagues (2017) examined the outcomes in cases of MVD of cranial nerve (CN) VIII for tinnitus through a critical review of the literature. A total of 43 English-language articles were gathered from PubMed and analyzed. In this review, 2 different case types were distinguished. First, tinnitus-only symptomatology, which was defined as a patient with tinnitus with or without sensorineural hearing loss. Second, mixed symptomatology, which was defined as tinnitus with symptoms of other CN dysfunction. This review reported outcomes of those with tinnitus-only symptoms. A total of 43 tinnitus-only cases were found in the literature with a 60 % positive outcome rate following MVD. Analysis revealed a 5-year cut-off of pre-operative symptom duration before which a good outcome can be predicted with 78.6 % sensitivity, and after which a poor outcome can be predicted with 80 % specificity. The authors concluded that as the 60 % success rate is more promising than several other therapeutic options open to the chronic tinnitus sufferer, future research into this field is needed.
Low-Level Laser Therapy / Photobiomodulation
Montazeri and colleagues (2017) determined alterations in auditory physiological and electrophysiological responses associated with temporary suppression of tinnitus induced by low-level laser therapy (LLLT). A total of 20 subjects with subjective tinnitus were included in this trial; VAS for loudness, loudness matching of tinnitus (LMT), pitch matching of tinnitus (PMT), Persian-tinnitus questionnaire (P-TQ) and Persian-tinnitus handicap inventory (P-THI) were conducted pre- and post-LLLT for all the subjects. Electrocochleography (ECochG) and distortion product oto-acoustic emissions (DPOAEs) were recorded in 11 subjects. Continuous wave diode lasers, including red (630 nm) and infra-red (808 nm) were applied, and were both designed by the Canadian Optic and Laser (COL) Center. A total of 12 sessions of LLLT were performed, 2 sessions per week for each subject. Total dose was 120 Joule/ ear/session. LLLT caused a significant decrease in subjective tests scores consisting of VAS for loudness, PMT, P-TQ, P-THI, but did not result in a significant improvement of objective evaluating parameters except for compound action potential (CAP) amplitude. The authors concluded that therapeutic effects of LLLT on tinnitus are still under investigation. Based on these findings, it appeared that their laser protocol might not be objectively qualified and defining a new protocol for optimizing LLLT parameters may be an option. It was suggested that the study be repeated with including tinnitus subjects with cochlear damage showed by oto-acoustic emissions. Also using input-output function of DPOAE may be a better choice than DPOAE thresholds to investigate the effects of LLLT on cochlea. Conducting a randomized clinical trial using animal models with larger groups of subjects in a longer time period may better reveal the effects.
In a systematic review, Ferreira and associates (2021) examined the effects of LLLT on the severity of tinnitus when compared to no therapy or other modalities of therapies. These researchers registered a systematic review protocol at the International Prospective Register of Systematic Reviews (PROSPERO) under the Registration Number CRD42019119376. They carried out a search in each of the following databases: Embase, LILACS, PubMed, Science Direct, Scopus, Web of Science, Google Scholar, and ProQuest. The inclusion criteria consisted of studies in adults over 16 years of age, randomized clinical trials in which subjects presented chronic (greater than or equal to 6 months) and subjective tinnitus (unilateral or bilateral) as well as with or without bilateral sensorineural hearing loss (SNHL), and studies that used only LLLT for treatment of tinnitus compared to no-therapy group or other modalities of therapy. No language or time restrictions were stipulated. The references were managed by Endnote Web and Rayyan QCRI. After the screening process, a total of 7 studies remained that attained the eligibility criteria. Regarding the risk of bias, only 1 study was categorized as low-risk of bias; the 6 remaining studies were classified as moderate-risk of bias. The 7 included studies mainly examined the LLLT effects on tinnitus by VAS, THI, pitch and loudness matching, minimum masking level, and pure-tone audiometry. All the 7 selected studies found different degrees of significant results regarding tinnitus severity; however, there was no consensus among the results. The authors concluded that although LLLT showed positive effects in the tinnitus severity in some studies, it was not possible yet to make any recommendation over its uses for the treatment of tinnitus severity.
Talluri and colleagues (2022) stated that there is a controversy regarding the effectiveness of photobiomodulation (PBM; also known as low-level laser therapy) in the management of tinnitus. These researchers systematically reviewed RCTs that examined the effectiveness of PBM in the management of tinnitus. The focused question was "Is PBM effective in the management of tinnitus?". Indexed databases were searched up to and including June 2020 using different combinations of the following key words: laser; diode; low-level laser therapy; photobiomodulation; tinnitus; medium-level laser; photo-biomodulation; and low-power laser; and RCTs performed on humans were included. Letters to the editor; case reports/series; commentaries; experimental studies and historic reviews were excluded. The risk of bias was assessed using the modified Cochrane collaboration tool. The format of the current systematic review was personalized to summarize the appropriate information. A total of10 RCTs (2 single-blinded and 8 double-blinded) were included; 1 study reported 30 % and 100 % resolution of tinnitus using diode and neodymium-doped yttrium aluminum Garnet lasers; respectively. One study reported that PBM was effective in relieving tinnitus for up to 3 months; 8 studies reported that PBM was ineffective in the management of chronic tinnitus. The risk of bias was high; medium, and low in 4; 5 and 1 studies; respectively. The authors concluded that the effectiveness of PBM in the management of tinnitus remains debatable; these researchers stated that further power-adjusted and well-designed RCTs with long-term follow-up are needed.
Sound Therapy / The Otoharmonics Levo System Sound Therapy
In a RCT, Theodoroff and colleagues (2017) examined if a customized stimulus from the Otoharmonics Levo System reduces tinnitus perceptions and reactions for people with bothersome tinnitus. A total of 60 subjects were randomized to 1 of 3 groups that used sound therapy devices during sleep that differed in their acoustic stimulus: tinnitus-matched (TM), noise stimulus (NS), and bedside sound generator (BSG). Outcome measures were the Tinnitus Functional Index (TFI), numeric rating scale of tinnitus loudness, and tinnitus loudness match. A Bayesian hierarchical model was fit to estimate the differences in treatment efficacy among groups. Average tinnitus reactions and perceptions improved across treatment groups. These investigators were at least 87 % certain that treatment with TM or NS reduced mean TFI compared to treatment with BSG, with an estimated relative efficacy of 4.5 to 5 points greater reduction. They were at least 95 % certain that treatment with TM resulted in greater reduction in mean numeric rating scale (NRS) of tinnitus loudness compared to the other groups, with an estimated relative efficacy of about 0.75 points greater reduction. The authors concluded that the findings of this study offered some support for greater average improvement in reactions to tinnitus with TM or NS devices compared to the BSG device. The TM group, compared to the BSG and NS groups, showed a greater reduction in ratings of tinnitus loudness on the NRS on average. Moreover, they stated that the magnitude of these relative effects and the extent to which they generalize to other clinical environments and patient populations require additional study; future controlled trials are needed to determine if these results are replicable and to evaluate additional variables and patient factors that would inform clinical practice.
The authors stated that this study had several drawbacks. Because of the nature of the sound therapy devices used in this study, blinding was not possible nor was it feasible to create a true placebo device. All participants knew up front that 2 groups would be receiving custom earbuds for devices to be used at ear level, whereas the third group was to use a sound therapy device that played sounds through a BSG. It was possible that participants who received custom earbuds to be used with the in-ear devices (TM and NS groups) were influenced by receiving something "special," and the degree that might have contributed to the outcomes of this study is unknown. The BSG and NS groups served as control groups, but not in the same manner as a placebo-controlled group; therefore, it was not possible to quantify how much of a placebo effect might also have contributed to these outcomes. When interpreting these findings, it is important to recognize that this study used self-reported outcomes. Just the act of participating in a clinical trial can have a positive effect on outcomes, regardless of the treatment received. It was not uncommon for individuals with tinnitus to report fluctuations in their tinnitus perceptions, and no established standard exists to assess the reliability of subjective ratings of tinnitus loudness. Finally, this study was not designed to look at sustainability of improvement. No measurements were performed at any time point after the "end of treatment" to determine how long any reported benefit continued. Future prospective studies involving the TM device should include assessments after 3 months to investigate how long possible benefit is sustained. Another limitation was the unknown generalizability of these results to tinnitus patients seen in the clinic. All participants in the current study were given their respective devices free of charge within the context of a research study. In a clinical setting, tinnitus patients may have different expectations than in a research study and would likely take into account the cost of different sound therapy device options and consider the cost-to-benefit ratio of each. The economic value compared to expected benefit of a therapy device is something that would commonly be discussed and factored into the decision-making process and is not something this study can address.
Lv and colleagues (2020) stated that to determine the neural mechanism underlying the effects of sound therapy on tinnitus, they hypothesized that sound therapy may be effective by modulating both local neural activity and functional connectivity (FC) that is associated with auditory perception, auditory information storage or emotional processing. In a prospective, observational study, 30 tinnitus patients underwent resting-state functional MRI scans at baseline and after 12 weeks of sound therapy; and 32 age- and gender-matched healthy controls also underwent 2 scans over a 12-week interval; 30 of these healthy controls were enrolled for data analysis. The amplitude of low-frequency fluctuation (ALFF) was analyzed, and seed-based FC measures were shown to significantly alter spontaneous local brain activity and its connections to other brain regions. Interaction effects between the 2 groups and the 2 scans in local neural activity as assessed by the ALFF were observed in the left para-hippocampal gyrus and the right Heschl's gyrus. More importantly, local functional activity in the left para-hippocampal gyrus in the patient group was significantly higher than that in the healthy controls at baseline and was reduced to relatively normal levels after treatment. Conversely, activity in the right Heschl's gyrus was significantly increased and extended beyond a relatively normal range after sound therapy. These changes were found to be positively correlated with tinnitus relief. The FC between the left para-hippocampal gyrus and the cingulate cortex was higher in tinnitus patients after treatment. The alterations of local activity and FC in the left para-hippocampal gyrus and right Heschl's gyrus were associated with tinnitus relief. Resting-state functional MRI could provide functional information to explain and “visualize” the mechanism underlying the effect of sound therapy on the brain. The authors concluded that they proved their hypothesis that sound therapy is effective by modulating both local neural activity and FC, which is associated with auditory perception, auditory information storage or emotional processing. The alterations of local activity and FC in the left para-hippocampal gyrus and right Heschl's gyrus were associated with tinnitus relief. Increased levels of FC between the left para-hippocampal gyrus and cingulate cortex may serve as neural feedback routes within the limbic system.
The authors stated that several issues need to be further addressed. First, ALFF is a widely used analytic method; however, the concept that ALFF reflects local brain activity may not be universally accepted. Furthermore, FC measurements were based on the selection of regions of interest (ROIs). In this study, only 2 brain regions were selected as seeds according to the results of voxel-wise ALFF calculation, potentially explaining the limited number of significantly altered FCs observed. Second, altered FC values observed within and between neural networks should be further discussed. More studies using different analytical methods may examine the effect of sound therapy on different factors. Third, the tinnitus patients enrolled in this study did not suffer from hearing loss, which was not representative of most patients with tinnitus. Additional auditory brainstem response (ABR) tests may better characterize hearing impairment. It may be more helpful to analyze non-responders to better characterize the mechanism of sound therapy. It may also be helpful to analyze patients with a wider range of THI scores or patients whose disease severity was evaluated by other methods (e.g., the VAS, tinnitus loudness, the tinnitus functional index). Furthermore, patients with sham treatment may be needed to account for the placebo effect of sound therapy.
In a network meta-analysis (NMA), Liu and colleagues examined the acceptability and effectiveness of different sound therapies for the management of patients with tinnitus. These investigators carried out a literature search to identify articles in Embase, PubMed/Medline, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Chinese Biomedical Literature, and Wanfang and Weipu from inception to April 1, 2021. The THI, TQ, and effective rate were used to evaluate perceived tinnitus suppression following treatment. These researchers used Review Manager 5.4 for the standard meta-analysis; R 4.0.4 and Stata 15.1 were used for the NMA and the publication bias and sensitivity analyses. The effect estimates of the direct comparisons (when available) were very similar to those of the NMA. Overall, sound stimulation alone performed better than medication alone, educational consultation alone, and no treatment. Combination therapy, such as sound stimulation plus educational consultation and sound stimulation plus drug therapy, yielded significantly better outcomes with regard to the alleviation of tinnitus than individual treatments. The authors concluded that this was the 1st NMA to evaluate and compare the effectiveness of different sound therapies for the management of tinnitus. It may help inform the selection of sound therapy and the development of guidelines in clinical practice. Moreover, these researchers stated that future studies of sound therapy with larger sample sizes and longer follow-up periods involving multiple medical centers are needed to improve the current evidence.
Oxytocin
In a pilot study, Azevedo and colleagues (2017) evaluated the potential of oxytocin as a tinnitus treatment. Two studies were performed. Study 1 was a long-term open pilot study, while study 2 investigated short-term effects with a double-blinded placebo-controlled cross-over study. In study 1, a total of 15 patients were investigated over a 10-week period in an open pilot study. In study 2, 16 patients were included in a placebo-controlled cross-over trial to investigate short-term effects following a single dose. For the long-term study (study 1), analysis of variance revealed a significant decrease in tinnitus sensation, both for the THI and Clinical Global Impression (CGI). Also, the short-term effects in study 2 revealed a significant reduction of tinnitus because of the oxytocin nasal spray as measured with the VAS and the CGI Scale. The authors conclude that these preliminary studies demonstrated that oxytocin may represent a helpful tool for treating tinnitus; and further larger controlled studies are needed.
Peripheral Muscle Magnetic Stimulation
Vielsmeier and colleagues (2018) stated that while brain stimulation techniques have been examined as therapeutic options for chronic tinnitus for many years, they have recently been extended to multi-modal treatment approaches. As chronic tinnitus is often accompanied by co-morbid muscular tension in the neck and back, these researchers performed a 1-arm pilot study to examine the feasibility of a new multi-modal therapeutic approach. Repetitive peripheral magnetic stimulation (rPMS) of the back was performed before and after each session of rTMS of the brain. Data of 41 patients were analyzed, all of which were treated with 10 sessions of rTMS of the left prefrontal and left temporo-parietal cortex followed by rPMS of the neck and back muscles. Tinnitus severity was measured using the tinnitus questionnaire (TQ). Neck pain was assessed using the neck pain and disability scale (NPAD). The new treatment approach was feasible and well accepted by the majority of patients. However, the overall patient group did not improve significantly in either of the questionnaires. If patients were divided in different subgroups depending on whether they were suffering from neck pain or somatosensory tinnitus, explorative post-hoc tests suggested differential effects: patients with both neck pain and somatosensory tinnitus had better outcomes than patients without those conditions or with neck pain only. This was true for both the TQ and the NPAD. This effect was of transient nature though: the TQ score went back to its baseline level after a follow-up period of 12 weeks. Based on these findings, the authors recommended that in studies that examine interventions of tinnitus targeting somatosensory afferents patients should be stratified according to somatic co-morbidities as well as somatosensory influence on the tinnitus percept. Moreover, they stated that the combination of 2 techniques – such as rPMS plus rTMS – is challenging to explore, as the complexity is increased by additional aspects such as the temporal relationship between peripheral and central stimulation. Consequently, future studies should try to concentrate on subgroup-specific effects of different treatment strategies or, more generally, on individualized treatment programs considering the very specific combination of possible causes and/or tinnitus-related alterations of a particular patient.
The authors stated that this was the first study to report combined rTMS and rPMS for the treatment of patients suffering from chronic subjective tinnitus. As it was designed as a pilot study, there were some limitations that should be kept in mind when interpreting the results. First, in order to examine the feasibility of the combined treatment, a 1-arm trial with no control group was chosen. Second, these investigators chose a well-studied standard rTMS protocol in order to combine it with rPMS treatment. This standard rTMS protocol consisted of left-hemispherical treatment and did not account for tinnitus laterality. The question if and how tinnitus laterality should be considered for the choice of the "right" rTMS treatment protocol has partly been examined for unilateral tinnitus but is still an open question for bilateral tinnitus or tinnitus which is perceived inside the head. A recent study indicated that tinnitus laterality has no association with rTMS response. Although important, it was not part of the current study's hypothesis to add to this question. Third, the exploratory analyses were done post-hoc, which meant that also the subdivision of patients to the different subgroups was done post-hoc. Thus, the subgroups were not matched with respect to demographical and clinical characteristics.
Topographical Filter Dermal Patch
Ahnblad (2017) stated that a new topographical filter in a dermal administration patch that organizes water molecules has been suggested as an alternative treatment for manifested tinnitus. In a pilot study, these researchers evaluated the safety and effectiveness of this dermal patch in patients with tinnitus. A total of 12 patients were included (10 completed) in an open study all receiving treatment with daily changed patches. The objectives were to evaluate safety and performance of the patch during and after treatment. The primary objective was to evaluate the tinnitus severity (by Tinnitus Severity Questionnaire, TSQ) and tinnitus annoyance (by VAS). The secondary objective was to evaluate if the patch could improve the patient's quality of life (by SF-36 QOL questionnaire) and sleep initiation time (self-rated). At visit 4, after 21 days of treatment, an improvement (decrease in TSQ score) was seen in 5 responder patients, which was sustained at the post-treatment visit. A marginal increase in TSQ score was seen also initially in 5 non-responder patients, 4 of which were responders post-treatment. The rated tinnitus annoyance, quality of life (QOL) and sleep initiation time did not show significant changes. The safety evaluation did not present any safety concerns. The authors concluded that the findings of this small pilot study indicated that it can be reasonable to recommend on a risk-benefit and safety perspective treatment with the dermal patch to patients with tinnitus as a consumer product based on the lack of other effective alternative treatment. Moreover, they stated that further and larger studies, and also proven experience, are needed for stronger evidence.
Sigmoid Sinus Resurfacing for the Treatment of Pulsatile Tinnitus
Santa Maria (2013) reported a case of sigmoid sinus dehiscence presenting with pulsatile tinnitus and treated successfully with resurfacing. This patient presented with pulsatile tinnitus due to sigmoid sinus dehiscence. This was successfully treated using only soft tissue resurfacing. The author concluded that sigmoid sinus dehiscence is a rare but treatable cause of pulsatile tinnitus. It can occur in the absence of a diverticulum, and is not necessarily limited to the transverse sigmoid junction. When resurfacing, care must be taken not to significantly alter the extra-luminal diameter of the sigmoid in a dominant sinus, as this raises the risk of post-operative hydrocephalus.
Song and colleagues (2015) noted that pulsatile tinnitus (PT) caused by venous sinus diverticulum is a relatively common, potentially incapacitating condition. Although treatment via an external approach or endovascular coiling has been reported, much remains unknown about the possible pathophysiological mechanisms and appropriate management of PT. These investigators reviewed their case series of PT resulting from either sigmoid sinus diverticulum (SSD) or middle cranial fossa venous sinus diverticulum (MFD-VS) and discussed the possible pathophysiological mechanisms and desirable therapeutic options. A total of 4 PT patients with either SSD or MFD-VS were treated with trans-mastoid resurfacing. In 1 case, a revision operation was performed as a result of recurrence of PT 4.5 years after the initial operation. The medical records and temporal bone imaging findings were retrospectively reviewed. PT was resolved in all cases immediately after trans-mastoid resurfacing, but 1 patient in whom bone wax was used for initial resurfacing experienced PT 4.5 years later. The PT was successfully managed with revision resurfacing with autologous bone chips/bone cement. In the other cases, the resolution of PT lasted throughout a median follow-up of 5.75 years. Notably, 2 of 4 cases had pre-operative low-frequency hearing loss (LFHL) and experienced immediate post-operative improvement in LFHL. The authors concluded that PT resulting from either SSD or MFD-VS can be treated successfully with trans-mastoid resurfacing of the venous wall. Pre-operative ipsilesional LFHL and the improvement of hearing threshold after surgical intervention may be pre-operative and post-operative surrogate objective signatures of PT. To ensure the resolution of symptoms, secure reconstruction with firm materials and long-term follow-up are mandatory.
Zeng and associates (2016) evaluated clinical characteristics and presented surgical outcomes of PT caused by sigmoid sinus wall dehiscence (SSWD). This study retrospectively reviewed 34 patients with PT who were diagnosed with SSWD in the authors’ institution between December 2008 and July 2013. Among them, 27 patients underwent SS wall reconstruction (SSWR; surgery group) and 7 patients refused surgery (non-surgery group). Pre-operative data were obtained from the patients’ medical records. All patients were followed-up regularly for at least 25 months. Pre-operative and post-operative CT angiography (CTA) images were compared. Student’s t-tests were used to compare age, body mass index (BMI), and pre-operative THI scores between the surgery and the non-surgery groups and to compare pre- and follow-up THI scores. There was no significant difference in age, BMI, or pre-operative THI scores between groups. Following surgery, 14 patients had complete resolution, 5 had partial resolution, 7 experienced no change and PT was aggravated in 1 patient. The difference between pre-operative and post-operative THI scores was significant. No severe complications were found post-operatively. Comparison of the pre-operative and post-operative CTA images revealed that remnant unrepaired dehiscences were the cause of unsatisfactory outcomes following surgery. In the non-surgery group, PT remained largely unchanged. The authors concluded that SSWR was a safe and effective treatment for PT caused by SSWD. They stated that it was imperative that all regions of the dehiscence were sufficiently exposed and re-surfaced during surgery.
Raghavan and co-workers (2016) stated that trans-mastoid SSWDR is a surgical technique increasingly used for the treatment of PT arising from SS wall anomalies. The imaging appearance of the temporal bone following this procedure has not been well-characterized. These researchers evaluated the post-operative imaging appearance in a group of patients who underwent this procedure. The medical records of 40 consecutive patients who underwent trans-mastoid SSWD were reviewed; 13 of 40 patients underwent post-operative imaging; 19 CT and 7 magnetic resonance imaging (MRI) examinations were assessed for the characteristics of the materials used for reconstruction, the impact of these on the adjacent SS, and complications. Tinnitus resolved in 38 of 40 patients; 9 patients were imaged post-operatively for suspected complications, including dural sinus thrombosis, facial swelling, and wound drainage; 2 patients underwent imaging for persistent tinnitus, and 2, for development of tinnitus on the side contralateral to the side of surgery. The materials used for reconstruction (NeuroAlloderm, HydroSet, bone pate) demonstrated characteristic imaging appearances and could be consistently identified. In 5 of 13 patients, there was extrinsic compression of the SS by graft material. Dural sinus thrombosis occurred in 2 patients. The authors concluded that the imaging findings following SSWR were characteristic. Graft materials may result in extrinsic compression of the SS, and this finding may be confused with dural venous thrombosis. Awareness of the imaging characteristics of the graft materials used enables this differentiation.
Tian and associates (2017) noted that sigmoid sinus cortical plate dehiscence (SSCPD) is common in PT patients, and is treated through SSCPD resurfacing surgery in clinic, but the bio-mechanism is unclear. These researchers clarified the bio-mechanism of PT sensation induced by SSCPD, and quantify the relationship of cortical plate (CP) thickness and PT sensation intensity. It was hypothesized that SSCPD would induce PT through significantly amplifying sigmoid sinus (SS) venous sound in this study. Finite element (FE) analysis based on radiology data of typical patient was used to verify this hypothesis, and was validated with clinical reports. In cases with different CP thickness, FE simulations of SS venous sound generation and propagation procedure were performed, involving SS venous flow field, vibration response of tissue overlying dehiscence area (including SS vessel wall and CP) and sound propagation in temporal bone air cells. It was shown that SS venous sound at tympanic membrane was 56.9 dB in SSCPD case and -45.2 dB in intact CP case, and was inaudible in all thin CP cases. The authors concluded that SSCPD would directly induce PT through significantly amplifying SS venous sound, and thin CP would not be the only pathophysiology of PT. This conclusion would provide a theoretical basis for the design of SSCPD resurfacing surgery for PT patients with SSCPD or thin CP.
Wang and co-workers (2017) stated that although studies demonstrated 4 to 20 % of patients with PT have associated SS anomalies, no consensus exists regarding optimal management. These investigators performed a systematic review exploring surgical and endovascular intervention of PT caused by SS anomalies. A systematic review was performed using the PRISMA guidelines for reporting of results, with a target population encompassing patients with PT and either SSD or sigmoid wall dehiscence. From an initial search yielding 74 articles, 21 manuscripts met inclusion criteria. Of 139 patients, 90.4 % were women; mean age was 39.0 years. Diagnosis was SSD/aneurysm in 47.5 % of patients, sigmoid sinus dehiscence in 35.3 % of patients, and both in 17.3 %. Sigmoid sinus wall reconstruction/resurfacing (SSW R/R) was used in 91.4 % and endovascular procedures in 7.9 % of patients. Post-operative recurrence was 3.5 % (mean follow-up of 21.1 months). Although there was no association between resolution rate and age or sex, right-sided PT resolved at a higher rate. For every increase in body mass index (BMI) by 1 kg/m, the odds of PT resolution increased 9.2 %. The authors concluded that PT as a result of SSD, aneurysms, and dehiscence is a rare, but largely treatable condition. Available interventions include SSW R/R, endovascular intervention, and cardiac U-clip techniques. In SSW R/R, bone pate, unspecified soft-tissue graft, and bone cement had the highest rates of PT resolution. While temporalis fascia and autologous bone chips were the materials most commonly used, they had significantly lower rates of PT resolution compared with the other materials, with the exception of auricular cartilage and bone cement. Most episodes of recurrence were resolved with medical management or a revision procedure.
Yeo and colleagues (2018) noted that jugular bulb and SS anomalies are well-known causes of vascular PT. Common anomalies reported in the literature include high-riding and/or dehiscent jugular bulb, and sigmoid sinus dehiscence. However, cases of PT due to diverticulosis of the jugular bulb or SS were less commonly encountered, with the best management option yet to be established. In particular, reports on surgical management of PT caused by jugular bulb diverticulum have been lacking in the literature. These investigators reported 2 cases of PT with jugular bulb and/or SSD, and their management strategies and outcomes. In this series, these researchers described the first reported successful case of PT due to jugular bulb diverticulum that was surgically-treated. Two patients diagnosed with either jugular bulb and/or SSD, who had presented to the Otolaryngology clinic with PT between 2016 and 2017, were studied. Demographic and clinical data were obtained, including their management details and clinical outcomes. Two cases (1 with jugular bulb diverticulum and 1 with both SS and jugular bulb diverticula) underwent surgical intervention, and both had immediate resolution of PT post-operatively. This was sustained at subsequent follow-up visits at the out-patient clinic, and there were no major complications encountered for both cases intra- and post-operatively. The authors concluded that trans-mastoid reconstruction/resurfacing of jugular bulb and SSD with/without obliteration of the diverticulum was a safe and effective approach in the management of PT arising from these causes.
In a retrospective, case-series study, Lee and associates (2019) discussed the possible pathophysiologic mechanism of PT perception due to high jugular bulb with bony dehiscence (HJBD) and its improvement after the dehiscent jugular bulb (JB) resurfacing using bone cement, and described the efficacy of an objective measure of PT using trans-canal sound recording and spectro-temporal analysis (TSR/STA). A total of 3 patients underwent trans-tympanic resurfacing after the source of PT was confirmed by temporal bone imaging and TSR/STA. Improvement of symptom and the changes in the TSR/STA were analyzed. In the first case, a revision operation was performed due to slightly improved but persistent PT after initial resurfacing with bone pate and a piece of conchal cartilage. Revision trans-tympanic JB resurfacing was performed in this case using bone cement, and PT resolved immediately after the surgery. In the second and third cases, PT resolved completely, or was much abated, immediately after trans-tympanic resurfacing with bone cement. The TSR/STA also revealed improvement of PT. The median follow-up duration was 28 months, and all 3 patients remained asymptomatic or much improved compared with their pre-operative status. The authors concluded that trans-tympanic resurfacing with bone cement, reinforcing the dehiscent JB to reduce focal turbulent flow, was a simple and effective surgical therapeutic option in patients with PT due to HJBD. In patients with HJBD, the objective measurement of PT by TSR/STA may be of help in selecting appropriate surgical candidates and objective evaluation of the treatment outcome.
Eye Movement Desensitization and Reprocessing
In a prospective, interventional, single-center study, Phillips and colleagues (2019) examined the effectiveness of eye movement desensitization and reprocessing (EMDR) for the treatment of tinnitus. Subjects were provided with tEMDR, which bespoke EMDR protocol that was developed specifically to treat individuals with tinnitus. Subjects received a maximum of 10 sessions of tEMDR. Outcome measures including tinnitus questionnaires and mood questionnaires were recorded at baseline, discharge, and at 6 months post-discharge; THI and BDI scores demonstrated a statistically significant improvement at discharge after EMDR intervention (p = 0.0005 and p = 0.0098, respectively); this improvement was maintained at 6 months post-discharge. There was also a moderate but not significant (p = .0625) improvement in Beck Anxiety Inventory (BAI) scores. The authors concluded that the findings of this study has demonstrated that the provision of tEMDR has resulted in a clinically and statistically significant improvement in tinnitus symptoms in the majority of those who took part. Furthermore, the treatment effect was maintained at 6 months after treatment ceased. This study is of particular interest, as the study protocol was designed to be purposefully inclusive of a diverse range of tinnitus patients. However, as a small uncontrolled study, these results do not consider the significant effects of placebo and therapist interaction. These researchers stated that larger high-quality studies are needed for the verification of these preliminary results. Level of evidence = 4.
Luyten and associates (2019) noted that in scientific research, tinnitus is compared to phantom limb pain. Starting from tinnitus as a phantom percept , these researchers aim to show that the operating mechanisms of EMDR may also be an effective treatment method for patients with subjective tinnitus. The aim of this randomized controlled study with blind evaluator is to examine the effect of EMDR compared to CBT in chronic tinnitus patients. To the authors’ knowledge, there are no other studies that evaluate both methods simultaneously. A total of 166 patients with subjective, chronic, non-pulsatile tinnitus will be randomized in 2 treatment groups: TRT + CBT versus TRT + EMDR. The experimental group will receive the bi-modal therapy TRT/EMDR and the active control group will receive the bi-modal therapy TRT/CBT. Evaluations will take place at baseline before therapy, at the end of the treatment and 3 months after therapy. The score on the TFI will be used as the primary outcome measurement; secondary outcome measurements are the VAS of loudness, TQ, hospital anxiety and depression scale (HADS), hyperacusis questionnaire (HQ), psycho-acoustic measurements and event-related potentials (ERP). The objective is to examine if the bi-modal therapy TRT and EMDR could provide faster and/or more relief from the annoyance experienced in chronic tinnitus patients' daily lives compared to the bi-modal therapy TRT and CBT. So far there has been no prospective, randomized controlled, clinical trial with blind evaluator that compares CBT and EMDR as a treatment for tinnitus.
Cortical Stimulation
Deklerck and colleagues (2020) noted that although the prevalence and burden of tinnitus is high, none of the available tinnitus treatments has been proven to be effective for the majority of tinnitus patients so far. Neuromodulation is currently gaining more interest to explore as tinnitus treatment. Because non-invasive neuromodulation has been shown to be effective in some tinnitus patients in the short-term, more invasive techniques have been applied with variable success and without clear clinical applicability. As new insights into the neuro-pathophysiology of tinnitus arise, it appeared essential to recapitulate the current evidence of invasive neuromodulation for tinnitus, to evaluate the quality of the available studies and identify gaps in this research domain. Data sources included Medline, Embase, Web of Science and Clinical Trial Register. These researchers carried out a systematic review following the PRISMA statement. Studies since 2005 that reported on adult human subjects with chronic subjective tinnitus, who underwent some form of invasive neuromodulation, were included. Quality evaluation was conducted using the modified Downs and Black checklist. A total of 21 studies were included. Studies were often of low-quality due to small sample sizes, lack of controlled designs, or examining tinnitus as a secondary indication of neuromodulation. The authors concluded that current research results provided insufficient evidence to generally recommend invasive neuromodulation as an alternative treatment for intractable tinnitus, although some promising effects were mentioned. These researchers stated that further research is needed to gain more insight in this treatment including optimization of the technique, and standardization of tinnitus evaluation in subgroups. Key words in the review included cortical stimulation, and deep brain stimulation.
Ozone Therapy
De Faria and colleagues (2022) noted that tinnitus is a frequent complaint in otorhinolaryngology. Numerous therapeutic interventions and studies claimed success in the treatment of tinnitus, but the cure remains undefined. However, ozone therapy has been suggested as potential treatment for tinnitus. In a systematic review, these investigators examined the effectiveness of ozone therapy in the treatment of tinnitus. They carried out a systematic search in Medline, Web of Science, Cochrane Library, Science Direct, Scopus, Google Scholar, Embase and LILACS. Data were processed by 2 independent reviewers. Only systematic reviews, RCTs, observational studies and case series published in English or Spanish with no date limit that evaluated the use of ozone therapy for the treatment of tinnitus were included. From 264 references retrieved after duplicates removal, 260 articles were excluded according to the pre-established selection criteria. The assessed articles were then subjected to risk of bias analysis, and 1 of them was excluded. The authors concluded that high-level evidence, such as well-conducted randomized clinical trials, are still needed to confirm the safety and effectiveness of this therapy.
Lidocaine Iontophoresis
Bulow et al (2023) noted that tinnitus is a common symptom with multiple causes and therapeutic options; previous studies have examined the effect of lidocaine iontophoresis. In a systematic review, these investigators examined the effects of lidocaine iontophoresis on tinnitus. They carried out the search and analysis according to the PRISMA statement. An abstract in German or English and a performed intervention with lidocaine iontophoresis for the treatment of tinnitus, independent of the study design, were considered as inclusion criteria. Due to the heterogeneity of the studies, only a narrative synthesis was carried out. The search yielded 179 studies of which 170 were excluded. A total of 6 full-texts and 3 abstracts were included; 957 patients were treated with lidocaine iontophoresis. The % improvement in symptoms following lidocaine iontophoresis ranged from 4 % to 62 %. The qualitative assessment of the studies resulted in an overall "weak" rating for all of them. The authors concluded that due to the heterogeneity and the limited quality of the studies found, no clear statement could be made regarding the effectiveness of lidocaine iontophoresis for the treatment of tinnitus. The number of patients who benefited from therapy varied widely. Furthermore, it could not be ruled out that the effect was merely due to electrical stimulation of the cochlea. These researchers stated that further high-quality studies are needed to clarify the evidence and confirm the clinical relevance. In this context, double-blinding and placebo control should be considered in the study design. Collaboration with other professions such as pharmacologists and biochemists could aid in improving the basic understanding of this form of therapy.
The authors noted that the lack of some full texts significantly limited the synthesis and conclusion, as inadequate information was available on the interventions implemented. Due to the heterogeneity in the study design of the included studies, it was not possible to conduct a meta-analysis. In addition, the existing weak quality of the intervention studies limited the informative value of this systematic review.
Neurofeedback
Guillard et al (2021) noted that several clinical studies have shown that neurofeedback (NFB) has the potential to significantly improve the QOL of patients complaining of chronic subjective tinnitus. Yet the clinical applicability of such a therapeutic approach in the everyday practice has not been tested so far. In a single-arm, pilot study, these researchers examined the feasibility and effectiveness of a semi-automated NFB intervention by means of a portable device that eventually could be used by the patients at home on an everyday basis. The duration of setup procedures was minimized via the use of a dry electrodes electroencephalography (EEG) headset and an automated user-interface. According to a pre-determined power calculation, a homogeneous population of 33 subjects with strict inclusion criteria was enrolled. After inclusion, all patients underwent 10 NFB sessions lasting 50 mins each, over a period of 5 weeks and a 3-month follow-up period. According to previous studies, the NFB training aimed at increasing the alpha-band power (8 to 12 Hz) in the EEG power spectrum on the averaged signal of leads FC1, FC2, F3 and F4. THI was used as a primary outcome measure; secondary outcome measures were the VAS and the change of the alpha-band power within sessions and across training. Time-points of assessment were before intervention (T1), after intervention (T2) and at the 3-month follow-up (T3). Patient exhibited a clinically significant decrease of the THI score, with a 23 % decrease (n = 28) on average between T1 and T2 and a 31 % decrease (n = 25) between T1 and T3. A significant increase of the alpha-band power within sessions was observed. No significant increase of the alpha-band power across sessions was observed. For the 19 subjects where sufficient data were exploitable, a significant correlation was found between the evolution of the alpha-band training across sessions and the evolution of the THI between T1 and T2. The sessions were well-tolerated; and no AE was reported. The authors concluded that the findings of this study suggested that NFB has potential to suit everyday clinical practice with the objective to significantly reduce tinnitus intrusiveness. Moreover, these investigators stated that this study was a single-arm trial without control, and did not evaluate placebo effect; thus, the analyses and conclusion of the training performance should be taken in account with caution as only 72.5 % of the EEG recordings were exploitable, due to the choice of the use of dry EEG electrodes. These researchers stated that further investigation (placebo-controlled study) is needed to confirm or infirm these preliminary conclusions.
In a systematic review, Barrenechea et al (2023) examined the effectiveness of NFB treatment parameters in reducing the perception of tinnitus and in reducing the behavioral consequences triggered by the symptom. The data search was performed in Spanish and English on PubMed/MedLine, EBSCO Host, Embase, Scopus, CENTRAL, SpringerLink and OpenGrey databases. The systematic review was conducted according to the stages established by PRISMA and 5 studies were identified to be included in the qualitative analysis. All studies showed that NFB training for tinnitus decreased symptom perception and related consequences. At the neural level, there was an increase in the activity of the alpha wave and a decrease in the activity of delta, gamma and beta. The authors concluded that NFB has a modulating effect on brain activity patterns; however, although all the studies reported a decrease in the consequences related to the symptom at the behavioral level after treatment, due to the lack of development of this technique for the symptom and the characteristics of the studies reviewed, it could not be certainty of efficacy on behavioral and neurophysiological consequences.
Telerehabilitation Interventions
In a systematic review, Demoen et al (2023) provided an overview of the research concerning the effectiveness of telerehabilitation interventions for self-management of tinnitus. This systematic review followed the PRISMA guidelines. Studies were eligible for inclusion if subjects were adult patients with complaints of primary subjective tinnitus and the study intervention comprised any possible telerehabilitation form for the self-management of tinnitus complaints. A search for eligible studies was conducted on PubMed, ScienceDirect, Scopus, Web of Science, and Cochrane Library. The Cochrane Risk of Bias 2 tool was used to the evaluate risk of bias. A total of 29 studies were found eligible, and of these, 5 (17 %) studied multiple telerehabilitation forms. Internet-based CBT with guidance by a psychologist or audiologist was examined in 17 studies (n = 1,767), internet-based CBT without guidance was examined in 4 studies (n = 940), self-help manuals were examined in 1 study (n = 72), technological self-help devices were examined in 2 studies (n = 82), smartphone apps were examined in 8 studies (n = 284), and other internet-based interventions were examined in 2 studies (n = 130). These rehabilitation categories were proven to be effective in decreasing tinnitus severity and relieving tinnitus distress as measured by tinnitus questionnaires such as TFI, THI, or Tinnitus Reactions Questionnaire (TRQ). However, drop-out rates were often high (range of 4 % to 71.4 %). All studies reported between some concerns and high concerns of risk of bias, resulting in low-to-moderate certainty levels. The authors concluded that there is low-to-moderate quality evidence that telerehabilitation interventions effectively reduce tinnitus severity and distress. These interventions form a possible tool to improve the self-management capacities of the patient and the accessibility of tinnitus care as a replacement or an addition to in-person care. Nevertheless, barriers such as lack of time, engagement, motivation, and openness of the patient causing high drop-out should be considered. Moreover, these researchers stated that factors such as lack of time, engagement, motivation, and openness of the patient resulted in participant drop-out and should be considered. Furthermore, it was noted that all included studies showed some-to-high concerns of the risk of bias (RoB) resulting in low-to-moderate certainty of the statements concerning the effectiveness of the telerehabilitation treatment forms. These researchers stated that future research should consider limiting the RoB and should further examine which factors are most likely to cause the lack of compliance and how clinicians can counteract these factors.
The authors stated that this systematic review had several drawbacks. First, all included studies scored some-to-high concerns of RoB. As a result, the included studies were of low-to-moderate certainty. Second, a comparison of effectiveness among studies was not feasible owing to the variety of questionnaires used to measure the level of tinnitus complaints, severity, or distress. Third, some crucial confounding parameters were not considered by all studies. Only a minority of studies concerning internet-based CBT (iCBT) in this review observed the proportion of participants with hearing loss or how many patients used hearing aids. However, how these studies define the presence of hearing loss was often not clarified. The studies concerning other telerehabilitation forms such as self-help manuals, self-help devices, and smartphone apps did seldom define the percentage of participants with hearing loss. Hearing loss is an important risk factor for developing tinnitus. Fourth, there were patients with audiometrically normal hearing who experienced tinnitus; however, tinnitus severity and distress are known to be significantly worse in patients with tinnitus with hearing loss in comparison with patients with tinnitus without hearing loss. Thus, hearing loss might be an important confounding variable to consider. An audiometric examination of patients with tinnitus is therefore of value when researching patients with tinnitus.
BeyondTinnitus System
BeyondTinnitus is a customized tinnitus rehabilitation strategy. Unlike using a generic white noise or sound from hearing aids, the sound therapy provided by BeyondTinnitus supposedly aids in directing the sound to the area of the brain most responsible for one’s tinnitus. Based on protocols developed at the University of California, BeyondTinnitus is designed to provide users with harmonic sound therapy to provide relief.
Mahboubi et al (2012a) examined the accuracy of a web-based protocol for tinnitus frequency matching compared to that of tinnitus pitch matching conducted by an audiologist using an audiometer in an anechoic chamber. A total of 20 subjects underwent tinnitus frequency-matching in a random order using an audiometer in an anechoic chamber and using web-based software with a multiple-choice protocol in octave or half-octave steps from 250 Hz to 12,000 Hz, and a slider in 25-Hz steps from 20 to 20,000 Hz. Octave challenge testing was performed. Participants were asked to indicate which protocol resulted in the closest match to their tinnitus frequency. The median tinnitus frequency was 6,000 Hz (range of 2,000 to 12,000 Hz) with use of the audiometer and self-directed multiple-choice protocol. With the slider, the median frequency was 5,925 Hz (range of 1,850 to 16,000 Hz). Subjects with a tinnitus frequency higher than 12,000 Hz experienced a greater level of satisfaction when using the computer-based slider system; 5 subjects experienced octave confusion with self-directed multiple-choice tinnitus matching that was corrected accurately after the octave challenge step. The authors concluded that a web-based protocol for tinnitus frequency matching was as accurate as a standard audiometric protocol. An octave challenge test might be necessary for patient-directed tinnitus frequency matching. The authors stated that the findings of this trail should be interpreted with consideration of its drawbacks. The validity of the matches could not be evaluated since there is no way to directly measure a phantom sensation. This study was also limited by a small sample size (n = 20). These researchers stated that future studies with larger sample sizes and repeated measures are needed to further evaluate web-based protocols for tinnitus pitch matching.
Mahboubi et al (2012b) stated that traditional masking efforts have presented broad-band noises, most typically white noise. Targeted (customized) sound therapies have been introduced to overcome the limitations of traditional maskers. These researchers examined the effectiveness of a web-based delivery of customized sound therapy in reducing tinnitus loudness and increasing the residual inhibition. A total of 32 subjects matched their tinnitus frequency using a web-based protocol. A customized Harmonic Sound Therapy file was produced by the web-based software and down-loaded by the patient onto an MP3 player. The subjects listened to the sound file for 1 hour. Tinnitus loudness mean was 6.0 ± 2.3 standard deviation (SD), which decreased to 3.3 ± 1.9 SD after 1 hour of sound therapy. Some reduction in loudness was reported in 81 %, while 72 % experienced a reduction of 25 % or more. Tinnitus annoyance decreased from an average of 6.1 ± 2.6 SD to 3.1 ± 2.0 SD. Median duration of residual inhibition was 32.5 mins, with an average of 75 mins ± 132 SD. The authors conclude that customized sound therapy could be delivered via the internet. Harmonic Sound Therapy was effective in reducing the loudness and annoyance of tinnitus.
Mahboub et al (2017) examined the effectiveness of a customized sound therapy and compared its effectiveness to that of masking with broad-band noise. Subjects were randomized to receive either customized sound therapy or broad-band noise for 2 hours per day for 3 months, and then switched to the other treatment after a washout period. The outcome variables were tinnitus loudness (scored 0 to 10), THI, BAI, minimum masking levels (MML), and residual inhibition (RI). A total of 18 subjects completed the study. Mean age was 53 ± 11 years, and mean tinnitus duration was 118 ± 99 months. With customized sound therapy, mean loudness decreased from 6.4 ± 2.0 to 4.9 ± 1.9 (p = 0.001), mean THI decreased from 42.8 ± 21.6 to 31.5 ± 20.3 (p < 0.001), mean BAI decreased from 10.6 ± 10.9 to 8.3 ± 9.9 (p = 0.01), and MML decreased from 22.3 ± 11.6 dB SL to 17.2 ± 10.6 dB SL (p = 0.005). After 3 months of broad-band noise therapy, only BAI and, to a lesser degree, MML decreased (p = 0.003 and 0.04, respectively). The authors concluded that customized sound therapy could decrease the loudness and THI scores of tinnitus patients, and the results may be superior to broad-band noise.
The authors stated that this study had several drawbacks. First, the lack of improvement in the subjects’ tinnitus, worsening of the tinnitus, and the inability to maintain the benefit achieved in the sound therapy. These might have partially contributed to the follow-up losses and drop-outs. The stimulation may not reduce the tinnitus, which may result in psychological distress such as anxiety or depression. Given significant reduction in the QOL in tinnitus sufferers, administration of acoustic stimulus via head-phones was a very small risk that was far out-weighed by the possibility of suppressing the tinnitus. The 3-scale nature of the THI questionnaire may limit its sensitivity to perform a question-by-question analysis compared to 100-scale questionnaires. However, it is a validated questionnaire that has been used in various tinnitus studies. Second, the long-term nature of the study and the number of tests conducted on each subject, which required a significant amount of time dedicated by the subjects and made it difficult to achieve high numbers for enrollment. The time commitment for the follow-up visits precluded 2 of the subjects to finish the study as their employment status changed during the study. Third, contralateral presentation of sound stimuli for audiometric pitch matching was used as a part of the psycho-acoustic assessments of the subject. This technique may occasionally yield different pitch matches between the ear due to binaural diplacusis. However, the soft-ware used binaural presentation for pitch matching to create the sound files. The randomization of the starting arm and the washout period were considered to account for any possible carrying effect from one treatment to the other. Overall, the randomized and cross-over design of this clinical trial provided a unique opportunity to examine the long-term outcomes of customized sound therapy and compare them to those of non-customized therapy.
Abouzari et al (2021) developed a smartphone application providing sound therapy and CBT for treating tinnitus and carried out a proof-of-concept (POC) pilot study examining its potential effectiveness. These researchers developed an interactive smartphone application available on iOS and Android platforms, which provided an 8-week tinnitus-specific CBT and personalized and frequency-matched sound therapy. Included patients presented to the authors’ tertiary clinic between 2017 and 2018, while those on the waiting list were regarded as controls. A total of 3 surveys were administrated: THI, Generalized Anxiety Disorder 7-item (GAD-7), and Perceived Stress Scale (PSS). A total of 30 patients enrolled in this study consisting of 20 treatment and 10 control patients; mean age was 55.4 ± 11.6 years. Treatment and control patients had similar age, sex, and pre-enrolment GAD and PSS (all p > 0.05). Baseline THI scores were also similar between treatment and control cohorts (50.1 ± 21.9 versus 62.0 ± 20.7; p = 0.15). After 8 weeks, though changes in GAD and PSS scores were similar (p > 0.05), the treatment group reported a significantly greater improvement in THI scores (17.7 ± 15.8 versus 5.3 ± 10.5, p = 0.04). The authors concluded that the findings of this pilot study showed potentially promising effectiveness of a smartphone-based CBT and sound therapy platform for treating tinnitus; future RCTs with larger sample sizes are needed to examine the psycho-social effectiveness of such application-delivered management for patients with tinnitus..
The authors stated that this study had several drawbacks including selection bias, small patient cohorts, and lack of extensive evaluation of quantitative or qualitative outcomes. These researchers stated that the change in THI warrants further investigation of this platform’s potential efficacy. Besides the low sample size, this pilot study was limited based on patient selection and the lack of randomization of the participants into the 2 groups. The trial was also limited by the level of scaling and analysis to determine/compare tinnitus severity. Another drawback was a lack of patients’ clinical history of auditory masking, which could be important when examining which group of patients were more susceptible to improvement from sound therapy. This was significant because patients’ auditory masking may be the most significant predictor of the level of therapeutic effectiveness that could be received from customized sound therapy. To address this, these researchers would continue investigating this program, and implement Feldmann H masking evaluation to associate it with the sound therapy’s relative masking effect. Tinnitus and its effect on people can be uniquely individualized in other ways as well, making the proposed program more suitable for certain patients compared to the others. Due to these drawbacks, the findings may not be generalized to the general population until further investigations of such mobile applications with appropriate methodologies are applied. Future studies should also collect and analyze THI questionnaire’s subscale scores beyond this manuscript’s reported total score. With the positive feedback from participants and the promising results of the pilot study, this report will be followed by a proper randomized controlled clinical trial. By investigating detailed tinnitus-related and behavioral questionnaires before and after the program, these investigators could assess specific factors associated with program responsiveness, and which patients would be most likely to improve.
Furthermore, an UpToDate review on “Treatment of tinnitus” (Dinces, 2024) does not mention BeyondTinnitus / customized sound therapy as a management option.
DNA (Daytime-Nighttime Appliance) Oral Appliance Therapy
The DNA appliance is a removable oral appliance that stretches the upper arches of one’s teeth. This allows for room for the tongue to occupy without blocking your airway; it is designed for the treatment of obstructive sleep apnea. There is a lack of evidence regarding the effectiveness of DNA oral appliance for the treatment of tinnitus.
An UpToDate review on “Treatment of tinnitus” (Dinces, 2024) does not mention the use of oral appliance as a management option.
Lenire Device (Bi-Modal Neuromodulation)
In an open-label, pilot study, Hamilton et al (2016) examined the safety and feasibility of a device that delivers simultaneous auditory and somatosensory stimulation (bi-modal stimulation ) for the treatment of the symptoms of chronic tinnitus. A cohort of 54 patients used the stimulation device for 10 weeks. Auditory stimulation was delivered via headphones and somatosensory stimulation was delivered via electrical stimulation of the tongue. Patient usage, logged by the device, was used to classify patients as compliant or non-compliant. Safety was assessed by reported adverse events (AEs) and changes in tinnitus outcome measures. Response to treatment was evaluated using tinnitus outcome measures: minimum masking level (MML), tinnitus loudness matching (TLM), and THI. The device was well-tolerated by patients and no AEs or serious difficulties using the device were reported. Overall, 68 % of patients met the defined compliance threshold. Compliant patients (n = 30) showed statistically significant improvements in mean outcome measures after 10 weeks of treatment: THI (-11.7 points, p < 0.001), TLM (-7.5 dB, p < 0.001), and MML (-9.7 dB, p < 0.001). The non-compliant group (n = 14) showed no statistical improvements. The authors concluded that the findings of this study showed the safety and feasibility of a new bi-modal stimulation device and supported the potential effectiveness of this new treatment for tinnitus. These researchers stated that the results of this study supported the continued evaluation of this intervention as a treatment for tinnitus. The next step is a series of clinical trials to disassociate the specific and unspecific effects of this therapeutic intervention. Parameter optimization studies will examine the association of the bi‐modal stimuli to determine the optimal stimulation settings. These studies will be followed by a Randomised Control Trial to compare this intervention to a sham treatment. Finally, follow‐up assessments will be included in all subsequent studies to examine the permanency of the effect observed in treatment groups.
D'Arcy et al (2017) presented the study protocol for an exploratory trial to optimize stimulation parameters and patient subtyping on bi-modal stimulation in the treatment of tinnitus. This is a 2-site, randomised, triple-blind, exploratory study of a proprietary neuromodulation device with a pre-post and 12-month follow-up design. A total of 3 different bi-modal stimulation parameter sets will be examined. The study will enroll 342 patients, split 80:20 between 2 sites (Dublin, Ireland and Regensburg, Germany), to complete 12 weeks of treatment with the device. Patients will be allocated to 1 of 3 arms using a step-wise stratification according to 4 binary categories: tinnitus tonality, sound level tolerance (using loudness discomfort level of less than 60 dB SL as an indicator for hyperacusis), hearing thresholds and presence of a noise-induced audiometric profile. The main indicators of relative clinical efficacy for the 3 different parameter sets are 2 patient-reported outcomes measures (PROMs), the THI and the TFI, after 12 weeks of intervention. Clinical effectiveness will be further examined in a series of patient subtypes, split by the stratification variables and by presence of a somatic tinnitus. Evidence for sustained effects on the psychological and functional impact of tinnitus will be followed up for 12 months. Safety data will be collected and reported. A number of feasibility measures to inform future trial design include the following: reasons for exclusion, completeness of data collection, attrition rates, patient's adherence to the device usage as per manufacturer's instructions and evaluation of alternative methods for estimating tinnitus impact and tinnitus loudness. (It should be noted that this work was supported by Neuromod Devices Ltd).
Conlon et al (2019) noted that there is increasing evidence from animal and human studies that bi-modal neuromodulation combining sound and electrical somatosensory stimulation of the tongue could induce extensive brain changes and treat tinnitus. These researchers stated that the principal goals of the proposed clinical study are to confirm the safety, tolerability, and effectiveness of treatment showed in a previous large-scale study of bi-modal auditory and trigeminal nerve (tongue) stimulation (Treatment Evaluation of Neuromodulation for Tinnitus - Stage A1); examine the therapeutic effects of adjusting stimulation parameters over time; and determine the contribution of different features of bi-modal stimulation in improving tinnitus outcomes. This study will be a prospective, randomized, double-blind, parallel-arm, comparative clinical trial of a 12-week treatment for tinnitus using a Conformité Européenne (CE)-marked device with a pre-post and 12-month follow-up design. A total of 4 treatment arms will be examined, in which each arm consists of 2 different stimulation settings, with the 1st setting presented during the first 6 weeks and the 2nd setting presented during the next 6 weeks of treatment. The study will enroll 192 participants, split in a ratio of 80:80:16:16 across the 4 arms. Subjects will be randomized to 1 of 4 arms and stratified to minimize baseline variability in 4 categories: 2 separate strata for sound level tolerance (using loudness discomfort level as indicators for hyperacusis severity), high tinnitus symptom severity based on the THI, and tinnitus laterality. The primary effectiveness endpoints are within-arm changes in THI and TFI as well as between-arm changes in THI after 6 weeks of treatment for the full cohort and 2 subgroups of tinnitus participants (i.e., 1 hyperacusis subgroup and a high tinnitus symptom severity subgroup). Additional effectiveness endpoints include within-arm or between-arm changes in THI after 6 or 12 weeks of treatment and in different subgroups of tinnitus subjects as well as at post-treatment assessments at 6 weeks, 6 months, and 12 months. Treatment safety, attrition rates, and compliance rates will also be assessed and reported. This study protocol was approved by the Tallaght University Hospital/St. James's Hospital Joint Research Ethics Committee in Dublin, Ireland. The 1st participant was enrolled on March 20, 2018. The data collection and database lock are expected to be completed by February 2020, and the data analysis and manuscript submission are expected to be conducted in the fall of 2020. The authors stated that the findings of this study will be disseminated to relevant research, clinical, and health services and patient communities via publications in peer-reviewed journals, and presentations at scientific and clinical conferences.
These investigators stated that a limitation of the study design is that the effectiveness due to stimulation settings used during the second 6 weeks of treatment may not be directly comparable with effectiveness due to the stimulation settings in the first 6 weeks of treatment because of possible carry-over effects. The cumulative effects from both stimulation settings used in each treatment arm can still be compared between arms to achieve one of the main objectives of the study. (It should be noted that several authors (BC, CH, SH, EM, and HHL) have financial interest and/or are employed by Neuromod Devices Limited. Also, several authors (DAH, SV, and BL) serve on the Scientific Advisory Board of Neuromod Devices Limited and receive financial compensation for their services to the company).
Conlon et al (2020) stated that tinnitus is a phantom auditory perception coded in the brain that can be bothersome or debilitating, affecting 10 % to 15 % of the population. Currently, there is no clinically recommended drug or device treatment for this major health condition. Animal research has revealed that sound paired with electrical somatosensory stimulation could drive extensive plasticity within the brain for tinnitus treatment. To examine this bi-modal neuromodulation approach in humans, these investigators evaluated a non-invasive device that delivers sound to the ears and electrical stimulation to the tongue in a randomized, double-blinded, exploratory study that enrolled 326 adults with chronic subjective tinnitus. Subjects were randomized into 3 parallel arms with different stimulation settings. Clinical outcomes were evaluated over a 12-week treatment period and a 12-month post-treatment phase. For the primary endpoints, subjects achieved a statistically significant reduction in tinnitus symptom severity at the end of treatment based on 2 commonly used outcome measures, THI (Cohen's d effect size: -0.87 to -0.92 across arms; p < 0.001) and TFI (-0.77 to -0.87; p < 0.001). Therapeutic improvements continued for 12 months after treatment for specific bi-modal stimulation settings, which had not previously been observed in a large cohort for a tinnitus intervention. The treatment also achieved high compliance and satisfaction rates with no treatment-related serious AEs. The authors concluded that these positive therapeutic and long-term results motivated further clinical trials toward establishing bi-modal neuromodulation as a clinically recommended device for the treatment of tinnitus.
The authors stated that one drawback of this trial was that all 3 arms consisted of bi-modal neuromodulation with supra-threshold intensities of sound and tongue stimulation that were required to maintain blinding, and they showed similar improvements in THI and TFI scores at the end of treatment. On the basis of the concept of paired plasticity, a significant difference would have been expected between the synchronized arm 1 and less synchronized arm 3. Although this between-arm endpoint was not achieved at the end of treatment, differences in THI and TFI scores emerged between arms during the post-treatment phase, suggesting that different stimulation settings could lead to different long-term therapeutic outcomes. Prolonged residual effects lasting 12 months would also not be expected for placebo effects. The bi-modal stimulation paradigm used by Marks et al (2018) resulted in a significant improvement in tinnitus symptoms that returned back to baseline within 3 weeks. This intervention was believed to be a legitimate treatment by the tinnitus participants, showing that simply informing subjects that they are receiving an effective bi-modal treatment did not result in a 12-month residual effect. As described above, there appeared to be a minimum duration of bi-modal neuromodulation (greater than 14 to 36 hours) needed to achieve long-term effects, which could be further sustained by using shorter delays between sound and tongue stimulation (less than 50 to 550 ms); thus, future clinical studies can be designed to show differences in long-term outcomes between treatment arms that diverge toward opposite extremes of those 2 parameter dimensions. (Several authors [B.C., C.H., S.H., E.M., C.O.C., S.L.L., S.D., and H.H.L] are/were employees, consultants, and/or shareholders of Neuromod Devices; and several authors [B.L., S.V., and D.A.H.] serve on the clinical advisory board of Neuromod Devices and receive monetary compensation for their contribution).
De Ridder et al (2021) stated that the pathophysiological mechanisms that underlie the generation and maintenance of tinnitus are being unraveled progressively. Based on this knowledge, a large variety of different neuro-modulatory interventions have been developed and are still being designed, adapting to the progressive mechanistic insights in the pathophysiology of tinnitus. rTMS targeting the temporal, temporo-parietal, and the frontal cortex has been the mainstay of non-invasive neuromodulation. Yet, the evidence is still unclear; thus, systematic meta-analyses are needed for drawing conclusions on the effectiveness of rTMS in chronic tinnitus. Different forms of transcranial electrical stimulation (tDCS, tACS, tRNS), applied over the frontal and temporal cortex, have been examined in tinnitus patients, also without robust evidence for universal efficacy. Cortex stimulation and DBS with implanted electrodes have shown benefit, yet there is insufficient evidence to support their routine clinical use. Recently, bi-modal stimulation approaches have revealed promising results and it appeared that targeting different sensory modalities in temporally combined manners may be more promising than single target approaches. The authors concluded that while most neuro-modulatory approaches appeared promising, further research is needed to aid in translating the scientific outcomes into routine clinical practice.
Conlon et al (2022) noted that more than 10 % of the population suffers from tinnitus. A new neuromodulation approach for the treatment of tinnitus has emerged that combines sound with electrical stimulation of somatosensory pathways, supported by multiple animal studies showing that bi-modal stimulation could elicit extensive neural plasticity within the auditory brain. More recently, in a large-scale clinical trial, bi-modal neuromodulation combining sound and tongue stimulation produced significant reductions in tinnitus symptom severity during the first 6 weeks of treatment, followed by diminishing improvements during the second 6 weeks of treatment. The primary objective of the large-scale randomized and double-blinded study presented in this paper was to determine if background wide-band noise as used in the previous clinical trial was necessary for bi-modal treatment effectiveness. An additional objective was to determine if adjusting the parameter settings after 6 weeks of treatment could overcome treatment habituation effects observed in the previous study. The primary endpoint at 6-weeks entailed within-arm, as well as between-arm comparisons for 2 treatment arms with different bi-modal neuromodulation settings based on two widely used and validated outcome instruments, THI and TFI. Both treatment arms exhibited a statistically significant reduction in tinnitus symptoms during the first 6-weeks, which was further reduced significantly during the second 6-weeks by changing the parameter settings (Cohen's d effect size for full treatment period per arm and outcome measure ranged from - 0.7 to - 1.4). There were no significant differences between arms, in which tongue stimulation combined with only pure tones and without background wide-band noise was sufficient to reduce tinnitus symptoms. These therapeutic effects were sustained up to 12 months after the treatment ended. The study included 2 additional exploratory arms, including 1 arm that presented only sound stimuli during the first 6 weeks of treatment and bi-modal stimulation in the second 6 weeks of treatment. This arm showed the criticality of combining tongue stimulation with sound for treatment effectiveness. Overall, there were no treatment-related serious AEs and a high compliance rate (83.8 %) with 70.3 % of subjects indicating benefit. The authors concluded that the discovery that adjusting stimulation parameters overcame previously observed treatment habituation could be used to attain greater therapeutic effects and opens up new opportunities for optimizing stimuli and enhancing clinical outcomes for tinnitus patients with bi-modal neuromodulation. (The study was sponsored by Neuromod Devices Limited).
Furthermore, an UpToDate review on “Treatment of tinnitus” (Dinces, 2024) does not mention the Lenire device/bi-modal neuromodulation as a management option.
Lysis of Middle Ear Tendons
Dang and Liu (2019) described a case of bilateral middle ear myoclonus (MEM) that was treated with trans-palatal Botox injection after failing surgery to section the tensor tympani and stapedial tendons. MEM is a rare disorder resulting from rhythmic contraction of middle ear muscles. An 8-year old girl presented with audible clicking tinnitus, and resultant inability to focus on school. Her parents declined medical therapy, and she underwent surgeries for tendon lysis, with only temporary relief. She had successful response to trans-palatal Botox injection to the tensor veli palatini aponeurosis. The authors concluded that trans-palatal Botox injection was a safe and reasonable alternative for treatment of MEM.
Furthermore, an UpToDate review on “Treatment of tinnitus” (Dinces, 2024) does not mention lysis of middle ear tendons as a management option.
Intra-Cranial Venous Sinus Stenting
Boddu et al (2016) examined the role of venous sinus stenting (VSS) in the treatment of pulsatile tinnitus among patients with Idiopathic Intracranial Hypertension (IIH) and significant venous sinus stenosis. A total of 37 consecutive patients with IIH and venous sinus stenosis who were treated with VSS between January 2012 and January 2016 were prospectively evaluated. Patients without pulsatile tinnitus were excluded. Tinnitus severity was categorized based on THI at pre-stent, day-0, 1-month, 3-month, 6-month, 12-month, 18-month, and 2-year follow-up. Demographics, BMI, pre- and post-VSS trans-stenotic pressure gradient were documented. Statistical analysis was carried out using Pearson's correlation, Chi-square analysis and Fischer's exact test. A total of 29 patients with a mean age of 29.5 ± 8.5 years (male:female = 1:28) were included in this trial. Median (mean) THI pre- and post-stenting were: 4 (3.7) and 1 (1), respectively. Median time of tinnitus resolution post-VSS was 0-days. There was significant improvement of THI (Δ mean: 2.7 THI [95 % CI: 2.3 to 3.1 THI], p < 0.001) and transverse-distal sigmoid sinus gradient (Δ mean: -15.3 mm Hg [95 % CI: 12.7 to 18.0 mm Hg], p < 0.001) post-stenting. Mean follow-up duration of 26.4 ± 9.8 months (3 to 44 months); VSS was feasible in 100 % patients with no procedural complications; and 3 patients (10 %) had recurrent sinus stenosis and tinnitus at mean follow-up of 12 months (6 to 30 months). The authors concluded that VSS was a feasible, safe and effective technique for successful treatment of pulsatile tinnitus in patients with IIH and significant venous sinus stenosis. Complete resolution of the tinnitus was reported immediately after VSS in this patient cohort. Moreover, these researchers stated that larger, prospective studies with specific focus on audiometric evaluation and long-term follow-up are needed to confirm these findings. This group of investigators has initiated a prospective trial examining the safety and effectiveness of VSS in patients with pulsatile tinnitus and venous sinus stenosis.
The authors stated that this study had several drawbacks. First, there was a subjective component and possible bias when using a self-rating scale for tinnitus, although frequently reported and widely used previously, have been validated for discriminative purposes only in clinical practice. Second, otologic evaluation based on pure tone audiometry was not included in this study, which precluded the objective evaluation of hearing impairment, which is an important aspect in tinnitus patients in general. However, as the patients reported complete resolution of tinnitus post-stenting as opposed to mere improvement or partial resolution, it was reasonable to consider this change an actual effect rather than variability of the self-reported scale. Third, this study cohort included only patients with proven IIH; these findings must be applied with caution when extrapolated to non-IIH patients with pulsatile tinnitus.
In a prospective study, Patsalides et al (2021) examined the safety and effectiveness of VSS for patients with isolated pulsatile tinnitus and lateral sinus stenosis. Patients with isolated pulsatile tinnitus and lateral sinus stenosis with a minimum trans stenotic gradient of 4 mm Hg were treated with stenting. Pulsatile tinnitus before and after treatment was assessed with the THI. Peri-procedural AEs, neurological complications, as well as clinical and radiographic follow-up were also recorded. A total of 42 patients (41 females and 1 male) were included in the study (median age of 37.5 years); 30 patients had post-stenotic fusiform, and 12 had post-stenotic saccular venous sinus aneurysm. In addition to stenting, coils were used to treat the patients with saccular venous aneurysms. The median follow-up was 5 months (range of 1 to 34 months). Most patients had complete (39/42) or near-complete (2/42) resolution of their pulsatile tinnitus post-procedure. There were no serious AEs. The authors concluded that the findings of this study demonstrated that in carefully selected patients, VSS offered durable resolution of pulsatile tinnitus caused by lateral sinus stenosis. These investigators noted that proper clinical and imaging work-up was needed, as the effectiveness of this approach depended on the correct diagnosis.
The authors stated that the drawbacks of this trial included the lack of control or comparison group and the relative short-term follow-up (median of 5 months). In the 2 patients who were treated for the lateral sinus stenosis and the jugular bulb diverticulum at the same time, it was impossible to know how much each condition was contributing to the pulsatile tinnitus. Similarly, these researchers acknowledged the fact that saccular aneurysms of the venous sinuses or the jugular bulb could independently cause pulsatile tinnitus. By treating the stenosis and aneurysms at the same time, it was impossible to know how much each lesion contributed to pulsatile tinnitus, and whether treating the saccular aneurysms was in fact absolutely necessary. Lastly, as lumbar puncture was not carried out in every patient, it was possible that some patients had increased intracranial pressure.
Fiani et al (2021) noted that pulsatile tinnitus presents as a unique variation of tinnitus in which a conscious perception of the heart beat is localized to the ears in either unilateral or bilateral fashion. The sensation is typically caused by an increase in turbulent blood flow in the affected ear, in most cases, due to a structural abnormality of the venous sinuses -- the most common of which being stenosis. These investigators discussed the etiology of pulsatile tinnitus followed by indications for treatment of various pathologies that have been successfully treated with VSS and have resulted in resolution of auditory symptoms. They queried PubMed database using combinations of the keywords "venous sinus stenting", "endovascular treatment", and "pulsatile tinnitus" to identify relevant studies published in English after 2001 and before December 1, 2020 and verified selected. The findings corroborated with those published in previous reviews reporting a high rate of pulsatile tinnitus resolution with VSS. The authors concluded that the success of VSS was clinically relevant as an effective treatment option for patients suffering from pulsatile tinnitus. Moreover, these researchers stated that future applications and studies with larger cohorts of patients are needed; and are currently being developed to further demonstrate the effectiveness of VSS in the treatment of pulsatile tinnitus.
These investigators stated that although the data regarding resolution of pulsatile tinnitus via stenting is promising, there are limitations in the interpretation of available data due to smaller study cohorts. This was especially true in studies describing AVM which are typically single case studies presenting with various complications making it difficult to ascertain the effectiveness of stenting when a patient was high-risk for rupture and re-stenosis. Although the Dandy criteria are currently used for diagnosis of IIH, criteria for determining whether venous stenting is needed are not entirely clear and a consensus on such criteria has yet to be established. These researchers noted that additional studies are also needed to determine long-term resolution of pulsatile tinnitus in patients with venous sinus thrombosis as the current literature available did not present with sufficient data specifically investigating the connection between stenting in venous sinus thrombosis and pulsatile tinnitus severity (and ultimately resolution). These researchers stated that although there is currently no randomized data supporting VSS for the treatment of pulsatile tinnitus, a prospective and randomized trial is ongoing at the Weill Medical College of Cornell University (NCT02734576).
Pandey et al (2024) stated that although many case series and meta-analyses have shown the effectiveness of VSS in the treatment of IIH and IIH-associated pulsatile tinnitus, there remain numerous challenges to be resolved. There is no widespread agreement on candidacy; pressure gradient, and failed medical treatment are common indications; however, not all clinicians require medical refractoriness as a criterion. Venous manometry, venography, and cerebral angiography are essential tools for patient assessment, but again disagreements exist regarding the best, or most appropriate, diagnostic imaging choice. Challenges with the VSS technique also exist, such as stent choice and deployment. There are considerations regarding post-procedural balloon angioplasty and pharmacotherapy, but there is insufficient evidence to formalize post-operative decision-making. Although complications of VSS are relatively rare, they include in-stent stenosis, hemorrhage, and subdural hematoma, and the learning curve for VSS presents specific challenges in navigating venous anatomy, emphasizing the need for wider availability of high-quality training. Recurrence of symptoms, especially stent-adjacent stenosis, poses challenges, and although re-stenting and cerebrospinal fluid (CSF)-diverting procedures are options, there is a need for clearer criteria for re-treatment strategies. The authors concluded that despite these challenges, when comparing VSS with traditional CSF-diverting procedures, VSS emerges as a favorable option, with strong clinical outcomes, lower complication rates, and cost-effectiveness. Moreover, these researchers stated that further research is needed to refine techniques and indications and address specific aspects of VSS to overcome these challenges.
Wang et al (2024) provided an updated approach to the evaluation and management of pulsatile tinnitus, an uncommon but often treatable subtype of tinnitus. These researchers noted that secondary pulsatile tinnitus can be due to either vascular or non-vascular etiologies, including, but not limited to: neoplasm, arterio-venous malformation or fistula (AVM or AVF), IIH, dural venous sinus stenosis, oto-acoustic etiologies (e.g., oto-sclerosis, patulous eustachian tube) and bony defects (e.g., superior semicircular canal dehiscence). Computed tomography (CT) and MRI have comparable diagnostic yield, although each may be more sensitive to specific etiologies. If initial vascular imaging is negative and a vascular etiology is strongly suspected, digital subtraction angiography (DSA) may further aid in the diagnosis. Many vascular etiologies of pulsatile tinnitus can be managed endovascularly, often resulting in improvement or resolution of pulsatile tinnitus. Notably, VSS is an emerging approach for the treatment of pulsatile tinnitus secondary to IIH with venous sinus stenosis. Careful history and physical examination could aid in establishing the differential diagnosis for pulsatile tinnitus and guide subsequent evaluation and management. These investigators stated that additional studies on the effectiveness and long-term outcome of VSS for venous stenosis are needed.
Furthermore, an UpToDate review on “Treatment of tinnitus” (Dinces, 2024) does not mention venous sinus stenting as a management/therapeutic option.
References
The above policy is based on the following references:
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Ear Canal Magnets and Electromagnetic Stimulation
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Transmeatal Laser Irradiation
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Hyperbaric Oxygen Therapy
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Sequential Phase Shift Sound Cancellation Treatment
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Neuromonics Tinnitus Treatment
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Auditory Perceptual Training
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Intra-Tympanic Administration of Corticosteroids
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Deep Brain Stimulation
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Vagal Nerve Stimulation
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Intra-Cranial Venous Sinus Stenting
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Miscellaneous Treatments
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