INTRODUCTION
In this review, the current evidence for the management of tinnitus will be summarized and discussed with specific emphasis for practical clinical application. The review is based on a systematic literature research, as well as on earlier reviews and meta-analyses [1,2,3▪,4–13].
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Box 1: no caption available
DEFINITION
Tinnitus refers to the sensation of sound in the absence of a corresponding external acoustic stimulus and can, therefore, be classified as a phantom phenomenon. Tinnitus sensations are usually of an unformed acoustic nature such as buzzing, hissing or ringing. Tinnitus can be localized unilaterally or bilaterally but it can also be described to emerge within the head. The matched loudness of the phantom sound may vary from a subtle noise just above hearing threshold to high intensity sounds. ‘Objective tinnitus’ or ‘somatosound’ describes sounds that are generated in the body such as myoclonic contractions of the tensor tympani muscle or altered blood flow in vessels near the ear, whereas ‘subjective tinnitus’, which is by far more common lacks a specific innerbody sound source [10].
EPIDEMIOLOGY AND SOCIOECONOMIC RELEVANCE
In a large survey from Norway, 21.3% of men and 16.2% of women reported to perceive tinnitus, with 4.4% and 2.1%, respectively, reporting high tinnitus intensity [14]. Even if prevalence rates in other countries are in a similar range, there is a remarkable tendency toward lower prevalence rates in more southern countries of the northern hemisphere [15]. Hearing impairment, increasing age and male sex have been identified as the most relevant risk factors for tinnitus [16]. Prevalence rates of tinnitus have increased during the last decades [17] also because tinnitus is among the most frequent sequelae of modern warfare [18]. The socioeconomic burden of tinnitus is enormous as illustrated by a dramatically increased risk for disability pension among tinnitus patients [19].
PATHOPHYSIOLOGY OF TINNITUS
It is assumed that in most cases abnormal auditory input (e.g. because of cochlear damage) triggers neuroplastic changes in central auditory pathways [20,21]. In addition, abnormal somatosensory afferent input from the neck and face region can interact with activity in central auditory pathways and may also contribute to tinnitus generation [22].
These neuroplastic processes can be explained by mechanisms of homeostatic plasticity that aim to compensate for the reduced input along the auditory pathways [23–26] and are mediated by plasticity of potassium channels, as well as by GABAergic, glycinergic and glutamatergic neurotransmission [25,27–29].
After auditory deafferentiation specific changes have been described at the cortical level, which include reduced inhibition in the deafferentiated area [25] and the extension of the cortical edge region (that still receives input) into the deafferentiated cortical regions. Whether these distortions of the tonotopic map play also a causal role for the generation of tinnitus is still a matter of debate [25,30,31]. Magnetoencephalographic and electroencephalographic (EEG) studies suggest that inhibitory dysfunction in the auditory cortex (reflected by decreased alpha activity [32,33]) leads to increased gamma band activity in the auditory cortex of tinnitus patients [34,35]. In addition, alterations of nonauditory structures and altered connectivity between auditory and nonauditory structures have been observed in tinnitus [36–38]. Involved nonauditory structures include consciousness supporting, salience and emotion-processing networks, which all can be more or less pronounced depending on the individual form of tinnitus [36,39▪]. As an example, in people who can easily suppress the conscious perception of tinnitus, the connections between the auditory system and the ‘consciousness’ and ‘salience‘ networks are presumably weaker than in those patients who continuously perceive tinnitus. In patients who are more severely emotionally affected by their tinnitus, an increased coactivation of ‘stress’ networks has been demonstrated [40].
Importantly, the tinnitus related spontaneous activity and functional connectivity changes over time with increasing tinnitus duration [37,41] indicating the principal usefulness of therapeutic interventions that aim at the modification of neuroplastic changes.
DIFFERENT FORMS OF TINNITUS
Tinnitus presents as clinically heterogeneous with respect to its cause, its perceptual characteristics, its modulating factors and its accompanying symptoms. With so much clinical heterogeneity it is assumed that there exist different forms of tinnitus, which also differ in their underlying pathophysiology. Examples of proposed tinnitus subtypes include tinnitus with temporomandibular disorder [42], posttraumatic tinnitus [43,44] or tinnitus with hyperacusis [45]. On the contrary, clearcut clinical criteria for differentiating the different forms of tinnitus are still missing and imaging criteria might be better suited for delineation of subtypes [46].
As the different subtypes of tinnitus presumably differ in their pathophysiology and the response to specific therapeutic intervention, the heterogeneity of tinnitus provides a potential explanation why many treatments failed in clinical trials [47]. Thus, for the design of future trials it is of utmost importance to identify valid subtypes. For this purpose, large patient databases have been developed [48,49], which should enable data-driven identification of clinically meaningful subtypes.
DIAGNOSTIC ASSESSMENT OF TINNITUS PATIENTS
The management of tinnitus should be individualized and multidisciplinary, as tinnitus can be a symptom of a variety of underlying disorders and can be accompanied by different comorbidities and as various factors (hearing impairment, musculoskeletal and somatosensoric factors [22,50] and emotional aspects [51]) may be relevant in the individual case. Fundamentally different is the cause of objective tinnitus (somatosounds), in which an internal sound source can be identified (e.g. vascular pathologies or increased blood flow in pulsatile tinnitus, spontaneous otoacoustic emissions or middle ear myoclonus). Differential diagnosis of tinnitus should also focus on rare subgroups of tinnitus with defined causes, which can benefit from specific treatments, such as cochlear implants in unilateral deafness [52], microvascular decompression in tinnitus resulting from a microvascular conflict [53] and carbamazepine in typewriter tinnitus [54].
In clinical practice a stepwise approach is proposed that starts with basic diagnostic steps that are recommended in all patients (detailed case history, assessment of tinnitus severity for example by standardized questionnaires, clinical ear examination, audiological measurement of tinnitus and hearing function) (Fig. 1) [10].
FIGURE 1: Flowchart for patient management. Algorithm for diagnostic and therapeutic management of
tinnitus patients (modified from:
www.tinnitusresearch.org/en/projects/flowchart_en.php and previously published in
[10]). Basic diagnostic assessment should be performed in all
tinnitus patients, further diagnostic and therapeutic steps only under the mentioned specific conditions.
Further diagnostic steps are only indicated in cases of [1] acute tinnitus, [2] a potentially dangerous underlying condition, [3â–ª] a possible causal treatment option or [4] relevant subjective impairment. Immediate action is required in tinnitus with sudden, acute hearing loss, in acute posttraumatic tinnitus and in case of concomitant suicidal tendencies.
Heart-beat-synchronous pulsatile tinnitus requires a neurovascular examination.
Nonpulsatile tinnitus should be further differentiated according to duration, concomitant symptoms and etiologic factors. Acute tinnitus in combination with sudden hearing loss requires diagnosis and treatment of the acute hearing loss. For differential diagnosis of paroxysmal tinnitus, which can be a symptom of auditory nerve compression, superior canal dehiscence syndrome, Ménière's disease, palatal myoclonus, migraine or epilepsy MRI, auditory evoked potentials, vestibular tests and EEG may be indicated. In case of conductive or sensorineural hearing loss further diagnostic procedures are indicated for identifying the exact cause, including MRI and otoacoustic emissions for assessment of outer hair cell function. Tinnitus with vertigo can be caused by Ménière's disease, vestibular migraine, superior canal dehiscence or damage to the vestibulocochlear system and requires detailed assessment of vestibular function. Tinnitus accompanied by headache can be indicative of vestibular migraine, trigeminoautonomal headache, space occupying lesions, benign intracranial hypertension, disorders of cerebrospinal fluid circulation or craniocervical anomalies. Cooccurring mental disorders such as depression, anxiety, cognitive impairment or insomnia should be explored and specifically treated if present. Hyperacusis and phonophobia occur frequently together with tinnitus and can be a symptom of an anxiety disorder. Neck or temporomandibular dysfunction or pain should be examined in detail by experienced dentists and physiotherapists. Specific diagnostic tests are indicated if tinnitus begins or worsens within 3 months after a traumatic event [43].
If a specific underlying disorder of tinnitus is identified it should be specifically treated. Moreover, tinnitus management should always include comprehensive, insightful and empathic counseling. Further available treatment options for tinnitus include cognitive-behavioral therapy (CBT) [2,6], sound therapy [4], hearing aids [3▪,55], cochlear implants [52], pharmacotherapy [56] and brain stimulation [7,57,58]. Evidence levels for most treatment strategies are low [11,59–61], which is at least partly due to the heterogeneity of tinnitus, the difficulties in the assessment of tinnitus, substantial placebo effects and low methodological quality of many treatment trials [62].
This situation has resulted in a low standardization of tinnitus treatment [11,59–61]. However, recently national guidelines of high methodological quality have been developed in the United States [63▪▪] and in Germany [64▪▪].
COUNSELING
There is general consensus that provision of information and advice, which is typically called ‘counseling’ in the context of tinnitus treatment, should always be offered to tinnitus patients in order to help them to facilitate habituation to the perception of the phantom sound and to better cope with consequences such as emotional distress, sleep difficulties, loss of concentration, disruption to personal, occupational and social lives. By providing information, counseling aims to help individuals understand their tinnitus, to demystify the condition and to correct false beliefs. Finally, counseling is important to ensure compliance with treatment strategies by providing the necessary information about realistic goals of the different treatment interventions. Controlled studies for estimating the efficacy of counseling are not available and also difficult to perform.
COGNITIVE-BEHAVIORAL THERAPY
CBT is a form of psychotherapy that aims to reduce the tinnitus related handicap by altering maladaptive cognitive, emotional and behavioral responses to tinnitus via cognitive restructuring and behavioral modification. CBT typically includes different modules. Among the techniques for the modification of maladaptive behavior are psychoeducation, relaxation training, mindfulness-based training, attention control techniques, imagery training and exposure to difficult situations. A meta-analysis revealed clear evidence for an improvement in quality of life and reduction of depression scores after CBT compared with no treatment or another intervention, but no effect on tinnitus loudness [6]. Also long-term follow-up data from controlled trials are still missing [6]. In a recent large randomized clinical trial, a multidisciplinary stepped care approach involving counseling and elements of CBT and tinnitus retraining therapy (TRT) has demonstrated significant benefit in tinnitus severity, tinnitus impairment and health-related quality of life as compared with treatment as usual [65].
On the basis of its evidence in meta-analytic reviews all guidelines recommend CBT for the treatment of tinnitus. However, it has to be stated that not every tinnitus patient is willing or able to undergo CBT and that CBT is probably only of limited use in those patients who already apply efficient coping strategies, but still suffer from the loudness of their tinnitus.
TINNITUS RETRAINING THERAPY
TRT is a specific combination of counseling and sound therapy [66]. The aim of TRT is to achieve habituation by using teaching/counseling for reclassification of the tinnitus signal as a neutral stimulus and by using sound therapy for reducing the strength of the tinnitus signal. Whereas some studies suggest beneficial effects [67,68] a recent Cochrane meta-analysis stated that due to the lack of high-quality randomized clinical trials no final conclusions concerning the efficacy of TRT can be drawn [69].
HEARING AIDS
As hearing loss is the most important trigger for tinnitus, the use of hearing aids, to compensate for the lack of auditory input in the impaired frequency range, seems to be an obvious treatment strategy. However, most tinnitus patients suffer from hearing loss in the high frequency range (and a tinnitus sound with high pitch), in which amplification of sound by hearing aids is limited because of technical reasons. Accordingly, recent observational studies found a benefit of hearing aids only in those patients with tinnitus below 6 kHz and, thus, in the amplification range of the hearing aids [55,70]. Also evidence for the efficacy of hearing aids on tinnitus from controlled trials is still lacking [11]. It should be mentioned that hearing aids are conventionally fitted in order to optimize speech understanding and that this might not be optimal for suppressing tinnitus. In a recent study, hearing aids with linear octave frequency transposition had pronounced beneficial effects on tinnitus [71], suggesting that alternative forms of amplification may be more efficient for tinnitus suppression than conventional fitting for optimizing speech understanding.
COCHLEAR IMPLANTS
In patients with bilateral profound sensorineural hearing loss and tinnitus, a significant suppression of tinnitus has been reported after hearing was restored by cochlear implantation [72]. Recently, cochlear implants have also been shown beneficial in tinnitus patients with unilateral profound deafness with concomitant ipsilateral incapacitating tinnitus [52]. Thus, there is convincing evidence that cochlear implants offer significant long-term tinnitus suppression in patients with severe sensorineural hearing loss by restoring input to the central auditory system.
SOUND THERAPY
Sound therapy can be applied as unspecific background sound or as individualized specific sound therapy. Background sounds can either be provided by custom sound generators that look like regular hearing aids and are worn behind the ear or by environmental sound generators that play sounds such as sea waves, creeks, waterfalls, rain or white noise or by tabletop fountains or similar devices. Also hearing aids with integrated sound generators are available [73]. The principle of this form of sound generation is that the additionally generated sound is perceived as less disturbing than the tinnitus sound and either partially or completely masks the tinnitus. Even if sound stimulation is widely established, evidence for its efficacy based on controlled studies is still insufficient [4,11].
For individualized sound stimulation three main strategies have been proposed. One approach is based on the concept that an enriched acoustic environment compensating for the hearing loss can abolish the neural correlates of tinnitus in animals [74]. However, initial positive results for auditory stimulation consisting of music with an individually adapted frequency spectrum to compensate for the individual hearing loss [75] could not be independently replicated [76].
For patients with tonal tinnitus two individualized auditory stimulation strategies have been developed. One approach uses music stimulation in which the frequency range around the tinnitus pitch is removed from the frequency spectrum. The resulting edges are supposed to reduce tinnitus-related activity in the auditory cortex by enhancing lateral inhibition [77]. A first pilot study has shown a small but significant reduction of tinnitus loudness and auditory evoked cortical activity after 1 year of daily stimulation with tailor-made notched music, as compared with a control condition [77].
Another approach for tonal tinnitus consists in auditory stimuli presented as short tones above and below the tinnitus frequency with the goal to renormalize tinnitus-related neuronal synchrony. A pilot study has demonstrated significant reductions of tinnitus loudness and annoyance, as well as normalization of abnormal oscillatory activity by this so called ‘coordinated reset stimulation’ as compared with a control group [78]. Results were confirmed in a large uncontrolled trial [79].
All presented individualized sound stimulation procedures have in common that they still have to be considered as experimental until results will be confirmed in large randomized controlled trials.
AUDITORY PERCEPTUAL TRAINING
Several auditory training procedures have been developed with the aim to renormalize tinnitus-related neuroplastic changes. Training procedures include frequency discrimination training, intensity discrimination training and auditory object identification and localization [80]. These training procedures have been performed both within the tinnitus frequency region and outside of it, and both as active training procedures requiring behavioral responses as well as passive ones with background sounds. However, because of the relatively low methodological quality of most studies no conclusions can be drawn about the efficacy of auditory training for tinnitus treatment [81].
PHARMACOLOGICAL TREATMENT
From the many pharmacological agents that have been investigated for the treatment of tinnitus none has provided replicable long-term reduction of tinnitus impact in excess of placebo effects [82].
Transient tinnitus suppression can be achieved by intravenous application of the local anesthetic, voltage-gated sodium channel blocker lidocaine [83] indicating that tinnitus can be pharmacologically targeted. However, intravenous lidocaine cannot be used as long-term treatment because of its side-effect risk and the only short-lasting tinnitus suppression.
Antidepressants have been investigated for the treatment of tinnitus [1,82] and have not shown a direct effect on the tinnitus [1], but an improvement of comorbid depressive or anxiety disorders [82]. The anticonvulsants carbamazepine, gabapentine and lamotrigine have not demonstrated additional benefits compared with placebo in controlled studies [5]. Carbamazepine may have a beneficial effect in a rare subgroup of tinnitus patients, in which tinnitus sounds like a ‘type-writer’ [84]. Benzodiazepines have shown some beneficial effect on tinnitus distress [85], but in light of the adverse effects of regular benzodiazepine intake their routine use cannot be recommended for the treatment of tinnitus.
BRAIN STIMULATION
Therapeutic brain stimulation enables focal modulation of neuronal activity and has been investigated for the normalization of tinnitus-related abnormal neuronal activity.
Repetitive transcranial magnetic stimulation (rTMS) uses the rhythmic application of brief magnetic pulses delivered by a coil placed on the scalp to modulate cortical activity. rTMS has been investigated in an increasing number of studies with mixed results [7,58]. Beneficial effects have been demonstrated [7,86], but the effect sizes are small, the interindividual variability high and the duration of treatment effects remains often limited [7,58]. Vagus nerve stimulation paired with auditory stimulation has been highly effective in animal models [87] and has shown promising first results in human studies [88], whereas vagus nerve stimulation alone had no relevant effects [89].
CONCLUSION
With little evidence for successful therapies from randomized clinical trials the treatment of chronic tinnitus remains difficult, but there is no justification for therapeutic nihilism. The systematic application of the currently available treatments is definitively much better than leaving tinnitus patients untreated.
Within the last years animal research and neuroimaging techniques have generated a more and more detailed understanding of the pathophysiological mechanisms of the different forms of tinnitus. This knowledge has resulted in the identification of potential therapeutic targets and the development of innovative treatment approaches. Among them are pharmacological studies [90–92], paired auditory and neural stimulation for targeted induction of neuroplastic effects [93–95], and electrical stimulation of the brain [96,97] and the cochlea [98]. For most of these new approaches further development is mandatory before they can be considered established treatments.
Moreover, new methods have been developed to overcome currently existing barriers in the development of better treatments for tinnitus. As an example, a systems pharmacology side-effect analysis approach has been recently applied to search for targets that are involved in tinnitus generation. The analysis of a network of 1313 drug-target pairs, based on 275 compounds that elicit tinnitus as side-effect, identified emergent significant tinnitus-related targets [99]. Among the significant targets were known structures like cyclooxygenase, sodium channels or serotonin transporter and receptors, but also previously unknown targets such as angiotensin converting enzyme.
Another example is the systematic collection of clinical data in large samples undergoing specific interventions. This approach may complement established forms of knowledge acquisition by clinical trials [62]. Such information collection can be easily done by specific smart phone apps (e.g. www.trackyourtinnitus.org). Whereas clinical trials aim to reduce the complexity by high standardization in order to increase the signal to noise ratio, the collection of large datasets with well designed methodology and their analysis by sophisticated mathematical methods may provide knowledge which takes into account the individuality of patients, the heterogeneity of tinnitus and the complex interaction of different therapeutic interventions [48]. Similar to nowadays wherein Amazon provides individualized offers (‘Customers Who Viewed This Item Also Viewed…. ’), one may envisage that a large tinnitus database may provide one day individual treatment recommendations based on the individual's characteristics: ‘Patients with similar demographic and clinical characteristics to patient A had the best treatment effect under treatment with drug B’.
Thus, the increasingly better understanding of pathophysiological mechanisms of the different forms of tinnitus and the development of new treatments give rise to the hope that soon better treatment options will become available for the many tinnitus sufferers worldwide.
Acknowledgements
No funding source had any influence on this review article.
Financial support and sponsorship
Grants and support for research from the Tinnitus Research Initiative, the German Research Foundation, the German Bundesministerium fĂ¼r Bildung und Forschung, the American Tinnitus Association, Astra Zeneca, Cerbomed, Deymed, Magventure, Siemens and Otonomy, and travel and accommodation payments from the European Union (COST), Lilly, Servier and Pfizer.
Conflicts of interest
B.L. received honoraria for speaking and consultancy from ANM, Astra Zeneca, Autifony, Gerson Lehrman Group, Lundbeck, McKinsey, Merz, Magventure, Novartis, Neuromod Devices, Pfizer and Servier.
B.L. holds patents for the use of neuronavigation for transcranial magnetic stimulation for tinnitus treatment and for the use of cyclobenzaprine for tinnitus treatment.
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Papers of particular interest, published within the annual period of review, have been highlighted as:
- â–ª of special interest
- ▪▪ of outstanding interest
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