Tinnitus: Comparison
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Tinnitus is traditionally described as the perception of a sound in the absence of corresponding external stimuli. In a very recent consensus article, a more precise definition of tinnitus has been proposed: Tinnitus was defined as “the conscious awareness of a tonal and/or noise sound for which there is no identifiable corresponding external acoustic source” and tinnitus disorder was defined as “tinnitus plus tinnitus-associated emotional distress and functional disability”.

  • tinnitus
  • tinnitus treatment
  • randomized controlled trial

1. Introduction

Tinnitus is considered an enigmatic situation and universally accepted answers to fundamental questions about its pathophysiology, course, and optimal treatment are still pending [1][2][3]. Its prevalence is estimated more than 10% in the general population; however, it is considered bothersome only in approximately 1% [2][3]. These numbers are of paramount importance, since, according to the recently released European Tinnitus Guidelines, clinical approach and decision ma-king should take into account not only tinnitus existence but also patient’s reaction to tinnitus [1]. Tinnitus is considered as a symptom well tolerated by the majority of individuals; however, it might cause levels of annoyance which can be adequate to make tinnitus the determining factor for significant impairment of the perceived health status and the overall quality of life.

One of the few things considered common ground among tinnitus community is that no optimal and universal tinnitus treatment has been reached yet [1][4]. Despite the fact that a wide range of interventions including, but not limited to, drugs and medicinal products, sound amplification, sound therapy, psychological interventions, and transcranial magnetic stimulation have been applied, none of them is universally accepted as an adequate and globally effective solution for the whole spectrum of tinnitus sufferers [1].

Hence, there is a pattern across the tinnitus literature according to which, a varying subgroup of responders is found in most of the studies [4]. This could be attributed to statistical variance, but it could also be claimed that some therapeutic interventions could potentially be beneficial in a specific subgroup of patients with identifiable characteristics. Very few studies, however, attempt to create and identify a certain profile correlating with treatment response and the main research question is limited to whether an intervention is effective or not in a group of patients, rather than which factors influence treatment response [5][6].

Moreover, tinnitus related literature has some specific barriers, on top of the issues identified as problematic in medical literature in general, such as sample size calculation, study settings, statistical analysis, and selection bias [7]. These drawbacks include the heterogeneity of tinnitus patients, the fluctuation in tinnitus perception, the subjective nature of tinnitus and therefore the lack of objective outcome measures, the common existence of comorbidities, as well as their interaction with tinnitus perception and the different perception of tinnitus in different cultures, as well as in different times by the same individual [8][9][10].

Consequently, it could be stated that the reasons for the lack of an established and effective treatment are both native and intrinsic, as well as subjective. Aim of this paper is to summarize factors, objective restraints, methodological flaws, and research insufficiencies, in order to provide some explanation for the fact that no universal tinnitus treatment has been established yet.

2. Discussion on Tinnitus

2.1. Tinnitus Duration and Intermittent Character

Tinnitus is a subjective symptom and in many cases it fluctuates over time [1]. Typically, patients report either fluctuations that might or might not be influenced by external factors or by their emotional status, for example levels of environmental noise or stress [1]. In the vast majority of studies, the outcome measures consist of questionnaires that are handed out at specific time points and supposed to evaluate a certain period of time [5]. This method has a fundamental flaw by default: even if patients are asked to provide information about the tinnitus severity over a defined time period (e.g., one week), the tinnitus severity at the moment when the questionnaire is filled out dominates. Tinnitus fluctuations over time or even periods without tinnitus are typically not sufficiently reflected due to memory and reporting bias. When patients are asked to fill in the questionnaire, the results will depend on their emotional status in general and particularly at the time information was provided, their overall attitude and tinnitus perception, and also on their tendency to focus on negative aspects. These confounding factors influence both the presence as well as the level of annoyance and consequently the tinnitus reporting. Therefore, they can be considered as an intrinsic difficulty that is present as a systematic bias across tinnitus related studies.

A potential solution to this could be the use of ecological momentary assessment, which is commonly integrated through mobile applications and allows ongoing recording of fluctuations in tinnitus severity as well as the correlation with certain incidents and behaviors which are captured at the same time (e.g., environmental noise, road traffic, etc.) [11]. This approach, if not well designed or capable of adjustments, may contradict efforts of habituation, since it requires that patients be frequently occupied with their tinnitus and its characteristics.

Only one of the studies took into account the duration of tinnitus within specific time intervals [12]. This finding is remarkable, as an expert consensus initiative from 2007 for tinnitus assessment and outcome measurement proposed that tinnitus patients should be asked about which percentage of their time they perceive their tinnitus?” [13].

Of course, even if asked, this information would be difficult to collect, due to recall bias and inability of patients to provide reliable information in regards to tinnitus duration due to different factors commonly mentioned, including fluctuation of tinnitus occurrence and perceived loudness if present, masking in noisy environments and lack of focus. Intrinsic issues already mentioned have not allowed a universally accepted answer to fundamental question in regards to tinnitus fluctuations, like whether patients with intermittent tinnitus tend to experience less annoyance or whether their treatment response is expected to be better [14]. Consequently, tinnitus duration and fluctuation and whether it was intermittent or not and under which conditions, was not taken into account as a factor in data analysis and interpretation neither, which is a possibly interesting point that should be considered by future studies.

2.2. Level of Perceived Annoyance

One of the few things that are considered common ground in tinnitus literature is the fact that the majority of people with tinnitus do not consider their tinnitus bothersome [3]. Overall prevalence, often replicated in the introductory parts of tinnitus studies considered as exceeding 10% in the general population is based on surveys in large samples [3]. On one hand, in the generation of these epidemiological data, some methodological considerations might arise about the criterion used to define tinnitus. On the other hand, the phrasing of the probably largest survey (“In the past 12 months, have you been bothered by ringing, roaring, or buzzing in your ears or head that lasts for 5 min or more?) seems clear enough in terms of adequate duration (excluding brief spikes), type of sound (noise rather than hallucinations), and time frame (one year and not whole life time). In any case, reproducibility of similar numbers in different countries confirms that these estimations should be close to reality [15].

As expected, the number of tinnitus sufferers seeking help by health professionals are much lower than the estimated prevalence [1]. This is of course easily explained by the fact that tinnitus is considered either as not a problem, or a small problem, often reported as non-bothersome. This also reflects to common clinical experience, according to which, a considerable group of patients with other chief complaints might mention tinnitus only when specifically asked. At the same time there is a subgroup of people with catastrophic tinnitus, who describe their tinnitus and the consequences as dramatical.

The discrepancy between the number of people with tinnitus and the number of those who seek medical help might also partly be due to the limited therapeutic options. A person suffering from tinnitus, who is told by the physician that there are no established possibilities to reduce the loudness of the tinnitus, might try to accept the situation without seeking further medical help.

As a result, it would be expected that tinnitus treatment studies, aiming to offer a solution to tinnitus sufferers, should select their participants accordingly and only include patients with a satisfactory level of annoyance, in order to fulfill a fundamental principle of medical research: ability to replicate their results to the target population.

According to the findings of our review, only 22 out of 73 RCTs clearly mention a minimum level of tinnitus annoyance in their inclusion criteria (Table 1). All popular questionnaires (THI, TFI, and TQ) are used, as well as Visual Analog Scales. THI is used in 12 of the studies, thresholds for inclusion however vary from 18 to 38 with four additional intermittent values: 20, 25, and 30. Only one study has set both lower and upper limits, using TFI, in order to define a certain range [12].

Of course, it is reasonable to assume that individuals with non-bothersome tinnitus will not easily reach a tinnitus clinic and on top of this, be motivated for a usually demanding participation in an RCT. In addition, baseline values give an estimation of the overall annoyance.

Including a reasonable level of annoyance, using the outcome measures chosen for the specific RCT ideally not only setting lower but also upper limits, should be considered good practice in future RCTs.

2.3. Tinnitus Audiological Characteristics

Tinnitus frequency can vary from constant to less than weekly. There is also a considerable proportion of patients who state that their tinnitus is only detectable in the absence of any acoustic stimulation, typically before they fall asleep. On top of this, there is a wide range of sounds considered similar to the type of tinnitus sound. Typically, tinnitus pitch is better matched with high frequencies, although there is a considerable proportion of patients who either cannot easily identify a matching sound or better attribute to low frequencies [15]. Determination of tinnitus pitch, loudness, and minimum masking level can be useful in clinical practice, in spite of their questionable role and their fluctuating nature.

However, a robust relationship between tinnitus pitch, loudness and masking level and tinnitus prognosis and severity in terms of annoyance, functionality and handicap has not been established [16]. This means that in the studies investigating the effect of various treatments these characteristics are not useful as outcome parameter. This has been confirmed in our review, in which none of the studies used this type of data neither for outcome measurement, nor as a predictor for treatment outcome.

2.4. Tinnitus and Hearing Loss

It is widely reproduced in the literature that hearing loss is present in approximately 90% of tinnitus patients [3]. However, it is also common ground that existence as well as degree of hearing loss are not able to predict tinnitus occurrence and severity [1]. Since pathophysiology of tinnitus is complex and involves both auditory and brain function, it is impressive that hearing loss, although present in the vast majority of tinnitus patients, has not been thoroughly studied as a prognostic factor of tinnitus course, prognosis, and treatment response [1].

This gap is clearly reflected in the extracted literature. Only seven out of 73 studies clearly state in their inclusion criteria that tinnitus was considered as primary complaint by the participants (Table 1). It could be assumed that patients with hearing loss as their primary complaint would not be motivated to participate in tinnitus oriented RCTs. This means that an unknown proportion of study participants could have tinnitus, but not as primary complaint. The primary complaint could be hearing loss and tinnitus only the secondary complaint. Moreover, it is commonly seen in clinical practice that patients present with their primary complaint of tinnitus, but when they are clinically evaluated it is discovered that their main complaint and everyday handicap is their hearing loss. Consequently, and in accordance with common clinical experience, it could be hypothesized that these groups of patients are not homogenous in principle and combine patients in a wide spectrum between hearing loss and tinnitus as primary complaints—and all the shades in between. It is assumed that this could influence results and treatment response, especially in treatments like hearing aids. On top of this, even if identifying tinnitus as primary (but not only) complaint could potentially improve sample homogeneity, it could still exclude a significant group of patients who would consider hearing loss as their cardinal problem and also have adequately bothersome or even catastrophic tinnitus at the same time.

Table 1. Characteristics of included studies: Inclusion criteria.
Author, YearPrimary ObjectiveNAge (Years)Tinnitus as Primary ComplaintTinnitus Onset (Months)Tinnitus Laterality

Uni/Bilateral		Minimum Tinnitus ThresholdHearing LossUse of Hearing Aids

Considered
Anders, 2010 [17]Evaluation of the efficacy of 1 Hz repetitive transcranial magnetic stimulation (rTMS) in the treatment of tinnitus.4218–70No>6 monthsBothNoAge-adjusted normal sensorineural hearingNo
Biesinger, 2010 [18]Effect of a Qigong intervention on patients with tinnitus with somatosensoric components80 Yes>3 monthsNot determinedNoNormal audiogramNo
Dehkordi, 2011 [19]Effect of gabapentin therapy on idiopathic tinnitus8018–85No>2 monthsUnilateralNoNot determinedNo
Sziklai, 2011 [20]Effect of pramipexole, a dopamine receptor agonist, influenced tinnitus associated with presbycusis40>50No>1 yearNot determinedNoBilateral SNHLNo
Westin, 2011 [21]Comparison of acceptance and commitment therapy (ACT) with tinnitus retraining therapy (TRT) on tinnitus64≥18Yes≥6 monthsNot determinedTHI ≥ 30Hearing thresholds which would allow for the use of wearable sound generatorsNo
Cima, 2012 [22]Effect of cognitive behavioral therapy (CBT) versus usual care492>18No Not determinedNoNot determinedNo
Han, 2012 [23]Comparison between Clonazepam and gingko biloba38 No2 monthsNot determinedNoNot determinedNo
Hesser, 2012 [24]Effects on global tinnitus severity of 2 Internet-delivered psychological treatments, acceptance, and commitment therapy (ACT) and CBT, in guided self-help format99>18No>6 monthsNot determinedTHI ≥ 38Not determinedNo
Hoare, 2012 [25]Comparison between different methods of frequency discrimination training on tinnitus percept70 No6 monthsNot determinedNo<40 dB in at least one frequencyNo
Jeon, 2012 [26]Effect of acupuncture versus sham3318–60No6 monthsUnilateralNoMean of 0.5, 1, and 2 kHz

Audiogram > 50 dB		No
Kreuzer, 2012 [27]Efficacy of a specific mindfulness- and body-psychotherapy based program in patients suffering from chronic tinnitus3618–80No>6 monthsNot determinedNoNot determinedNo
Ngao, 2012 [28]Effect of transmeatal low-power laser stimulation (TLLS)43 Yes Not determinedNoNot determinedNo
Plewnia, 2012 [29]Safety and efficacy of bilateral CTBS to the temporal and temporoparietal cortex in the treatment of chronic tinnitus.48 No<5 yearsNot determinedNoNot determinedNo
Rocha, 2012 [30]Efficacy of myofascial trigger point (MTP) deactivation for tinnitus relief in patients with myofascial pain syndrome71 No>3 monthsNot determinedNoNot determinedNo
Tass, 2012 [31]Comparison between CR (4 different groups) vs. placebo63>18No6 monthsNot determinedNo<50 dB in all frequenciesNo
Choi, 2013 [32]Comparison between intratympanic steroids and placebo30 No Not determinedNoNot determinedNo
Coelho, 2013 [33]Effect of zinc versus placebo115>60No6 monthsNot determinedNoNot determinedNo
Hoekstra, 2013 [34]Effect of repetitive transcranial magnetic stimulation(rTMS) on tinnitus50 No>2 monthsNot determinedNoNot determinedNo
Mollasadeghi, 2013 [35]Effect of low laser beam in tinnitus89≤50No Not determinedNo>15 dB at least at one of 3, 4, and 6 kHzNo
Nyenhuis, 2013 [36]The efficacy of CBT-oriented interventions for acute tinnitus on a broader data basis.18518–75No2–26 weeksNot determinedNoNot determinedNo
Sönmez, 2013 [37]Comparison between ozone and betahistine6818–75No6 monthsNot determinedNoNoNo
Taslimi, 2013 [38]Effect of ondansedron5318–70No3 monthsNot determinedNoNot determinedNo
Dos Santos, 2014 [39]Evaluation of combined use of amplification and sound generator and their combination49 NoAt least 6 monthsNot determinedTHI > 20Mild to moderate symmetrical sensorineural hlNo
Hoare, 2014 [40]Frequency discrimination training (FDT) delivered in a gaming format have significant therapeutic benefit in tinnitus60 No Not determinedNo≥20 dB in at least one frequency, ≤40 dB averageNo
Jasper, 2014 [41]Effects of conventional face-to-face group cognitive behavioral therapy (GCBT) and an Internet-delivered guided self-help treatment iCBT on tinnitus distress128≥18Yes≥6 monthsNot determinedTHI ≥ 18 or mini-TQ ≥ 8Not determinedNo
Shekhawat, 2014 [42]Comparison of multisession anodal transcranial direct current stimulation (TDCS) of the left temporoparietal area would enhance sound therapy from hearing aids.40 No>2 yearsNot determinedTFI > 25Aidable HLNo
Teismann, 2014 [43]Combine (TMNMT) with transcranial direct current stimulation (TDCS) in an effort to modulate TMNMT efficacy in the treatment of tinnitus34 No≥3 monthsBothNoNot determinedNo
Dehkordi, 2015 [44]Effect of low-dose laser therapy on chronic cochlear tinnitus66 No Not determinedNoNot mentionedNo
Bilici, 2015 [45]5 groups: 3 types of rTMS, paroxetine, placebo75 No1 yearNot determinedNoNormal hearingNo
Folmer, 2015 [46]Effect of repeated transcranial magnetic stimulation61 No Not determinedNoNot determinedNo
Kreuzer, 2015 [47]Comparison of medial frontal stimulation with double cone coil and conventional prefrontal left dorsolateral prefrontal cortex (DLPFC)-stimulation (study arm 2/control group) both followed by stimulation of the left temporo-parietal junction area40 No>6 monthsNot determinedNoNot determinedNo
Malinvaud, 2015 [48]Comparison between CBT and virtual reality interactive intervention14818–70No12 monthsUnilateralNoNormal to mildNo
Pal, 2015 [49]Investigation of the efficacy and safety of repeated sessions of a novel transcranial direct current stimulation (TDCS) protocol by combining bilateral cathodal TDCS to the auditory cortex (AC) with anodal stimulation of the prefrontal cortex (PFC).42 No≥1 yearNot determinedNoAge-adjusted normal hearing according to the presbycusis scaleNo
Thabit, 2015 [50]Effect of different types of rTMS and their combination30>18No6 monthsBothNoNot determinedNo
Albu, 2016 [51]Effectiveness of intratympanic (IT) steroids and melatonine versus melatonine only in acute tinnitus60 NoAcute (within 3 months)UnilateralNoNot mentionedNo
Doi, 2016 [52]Effectiveness of acupuncture therapy for tinnitus50 NoNot determinedNot determinedTHI: moderate to severeNot determinedNo
Henry, 2016 [53]Effect on tinnitus severity by using tm-TRT-ted148 No Not determinedNoNot determinedNo
Laureano, 2016 [54]Effect of acupuncture on brain perfusion using (99m) ethyl cysteinate dimer single-photon emission computed tomography ((99m) Tc-ECD SPECT) in patients with tinnitus5718–60No>3 monthsBothNoUp to 25 dBNo
Lehner, 2016 [55]Comparison between two types of rTMS4918–70No6 monthsNot determinedTHI > 38Not determinedNo
Li, 2016 [56]Compare the effects of personalized, altered music to unaltered music on subjective tinnitus34≥18No≥12 monthsBothTHI > 26Hearing loss ≤70 dBNo
Lim, 2016 [57]Efficacy of cilostazol, a selective phosphodiesterase 3 inhibitor, in patients with chronic tinnitus50>19No3–12 monthsBothVas ≥ 4Not determinedNo
Rojas-roncancio, 2016 [58]Effect of manganese and lipoflavonoid plus on tinnitus40 No>6 monthsNot determinedTinnitus loudness and annoyance > 50%Not determinedNo
Roland, 2016 [59]Evaluation of the neural network changes in patients with bothersome chronic tinnitus who underwent rTMS treatment targeting the left temporoparietal junction (TPJ), as compared to those who received sham therapy.3018–60No≥6 monthsNot determinedTHI > 30Not determinedNo
Singh, 2016 [60]Effect of B12 versus placebo4018–60No6 monthsNot determinedNoNot determinedNo
Stein, 2016 [61]The effect of a sound therapy (tailor-made notched music training, TMNMT) against tinnitus10018–70No≥3 monthsBothNoHl ≤70 dB hl in the frequency ranges of one-half octave above and below the tinnitus frequencyNo
Weise, 2016 [62]Effect of iCBT61>18Yes>6 monthsNot determinedTHI > 38 or mini-TQ > 13Not determinedNo
Wise, 2016 [63]Effects of an auditory attention training game with those of a control game across tinnitus, attention, and electrophysiological measures3118–70No>6 monthsNot determinedTinnitus problem rating scale > mild<80 Db HL nonconductive HLNo
Zarenoe, 2016 [64]Effects of motivational interview (MI) as an adjunct to regular HA fitting for patients with tinnitus and hearing loss.46 No Not determinedNoNot determinedNo
Elzayat, 2016 [65]To evaluate the effectiveness of adding lidocaine to intratympanic steroid in the patients with idiopathic subjective tinnitus (IST).44 No Not determinedNoNot determinedNo
Kallogjeri, 2017 [66]To evaluate the effect of the brain fitting program-tinnitus on tinnitus.6020–65No>6 monthsNot determinedAccording to bothersome scaleNot determinedNo
Kim, 2017 [67]Effect of different approaches of acupuncture3920–75No2 weeksNot determinedNoNot determinedNo
Landgrebe, 2017 [68]Evaluation of the efficacy of a two-week 1-Hz-RTMS in patients with chronic tinnitus.14618–70No>6 monthsNot determinedTHI > 38Normal, age-adjusted hearing levels. Conductive hearing loss ≤ 15 db.No
Mckenna, 2017 [69]Effect of mindfulness based cognitive therapy (MBCT) in tinnitus severity, psychological distress, functional disability, avoidance, and negative cognitions and a greater increase in tinnitus acceptance.75≥18No>6 monthsNot determinedNoHearing levels allowing participation in group discussionsNo
Arif, 2017 [70]Relaxation therapy and mindfulness61>18Yes Not determinedNoNot determinedNo
Beukes, 2017 [71]Efficacy of guided internet based cognitive behavioral treatment (iCBT)146>18No>3 monthsBothTFI > 25Not determinedNo
Sahlsten, 2017 [72]E-field navigation should versus non-navigated rTMS3918–65No6 months–10 yearsBothNoNot determinedNo
Theodoroff, 2017 [73]To determine if an acoustic stimulus mimicking the tinnitus perception delivered during sleep from the Otoharmonics corporation’s LEVO system reduces tinnitus-related distress and/or perceived loudness of tinnitus during awake hours for people who experience bothersome tinnitus5830–72No>6 monthsNot determinedTFI > 25<70 dB hl, in all frequencies between 0.25 and 8 kHzNo
Tyler, 2017 [74]Effect of vagus nerve stimulation (VNS) paired with sounds in chronic tinnitus patients3022–65No>1 yearBothNoNot determinedNo
Lee, 2018 [75]Effect of intratympanic steroids on acute tinnitus54 NoAcute (one month)UnilateralNoNot determinedNo
Beukes, 2018 [76]Evaluation of an Internet-based cognitive behavioral therapy intervention versus face to face92>18NoNot determinedNot determinedNoNot determinedYes
Abtahi, 2018 [77]Effectiveness of anodal and cathodal methods in reducing the intensity of tinnitus5118–80No>1 yearNot determinedNoNot determinedNo
El Beaino, 2018 [78]Effect of sulodexide (heparin and dermatan) vs. placebo124>18No12 monthsNot determinedNoNot determinedNo
Hong, 2018 [79]Effect of nitrous oxide on tinnitus 18–65No>6 monthsNot determinedAccording to bothersome scaleNot determinedNo
Godbehere, 2019 [80]Theta burst TMS are an effective treatment for chronic tinnitus40>18NoNot determinedBothNoNo HL, mild and moderate HLNo
Hall, 2019 [12]Effect of AUTt00063, a novel centrally acting drug) potent and selective modulator of kv3.1 and kv3.2 voltage-gated potassium channels) vs. placebo76>18Yes>6, <18 monthsBothTFI > 24 and <68<60 db in 0.5,1,2,4 kHzNo
Li, 2019 [81]Clinical efficacy of cognitive behavioral therapy (CBT) for treatment of chronic subjective tinnitus100 No>3 monthsNot determinedNoNot determinedNo
Noh, 2019 [82]To investigate the effects of active dual-site rTMS treatment on reducing tinnitus using a double-blind randomized controlled trial.30 No Not determinedNoNot determinedNo
Prozchazkova, 2019 [83]Comparison between gingko biloba and pentoxifylline197>30No3 monthsNot determinedMini TQ > 5Not determinedNo
Radunz, 2019 [84]Comparison between ginkgo biloba, HA, and their combination35>18No3 monthsBothNoAll types of hearing lossNo
Sahlsten, 2019 [85]Comparison of neuronavigated versus non-navigated repetitive transcranial magnetic stimulation4018–65No6 months–10 yearsBothNumeric scale > 4Not determinedNo
Scherer, 2019 [86]To compare the efficacy of tinnitus retraining therapy (TRT) and its components, ST, and TC, with the standard of care (SOC) in reducing the negative effect of tinnitus on quality of life.98 No>1 yearNot determinedTQ > 40Functionally adequate hearing sensitivity without requirement of amplificationNo
Yakunina, 2019 [87]Evaluation of the effects on tinnitus of hearing aids (HA) alone without accompanying counseling or any other therapy additionally, whether FL techniques (LFT and FT) performed compared with conventional WDRC in the same open-fit HA in terms of tinnitus suppression for patients with high frequency hearing loss (HFHL).94>18No≥3 monthsNot determinedTHI > 18

Vas ≥ 50%		SNHLNo
Tutar, 2020 [88]Efficacy of transcutaneous electric stimulation applied to the auricula6018–65No>3 monthsNot determinedNoNot determinedNo

If just dealing with the existence of hearing loss is complex, taking the degree of hearing loss into account is even more challenging. More than one third of RCTs (25 out of 73) include a range of hearing loss in their inclusion criteria, whereas none of them analyzed the audiogram as a predictor for treatment response. Even those studies in which hearing levels were mentioned as inclusion criterion, they have typically vague descriptions of hearing functions, such as “normal hearing levels”, hearing levels allowing conversation or mild, moderate, or severe hearing loss without an explicit definition or the respective thresholds.

In accordance, among the studies that evaluated other interventions than hearing aids, there was no study that took into consideration the use of hearing aids neither as an inclusion/exclusion criterion nor as a predictor nor as a confounder. The latter is potentially a hidden but significant risk of bias, since tinnitus improvement is considered as high as 55% in several case series analyzing hearing aids [4]. This could influence results in two ways; first, a selection bias, since only patients were included in the trial, in which hearing aid use was not effective to sufficiently decrease tinnitus annoyance; second, an unclear effect of a prolonged or recent use of hearing aids, which might influence the performance of an unknown proportion of hearing aids users both in the interventional and control arms. A clear exclusion of patients with a relatively recent hearing aid fitting should be considered as good practice in future RCTs.

The currently starting UNITI trial is strategically planned as an attempt to overcome the mentioned issues. Only patients with tinnitus as primary complaint will participate, and degree of hearing loss will be analyzed with sophisticated techniques as a potential confounder for treatment response. In addition, the efficacy of hearing aids as a sole measure to improve tinnitus will be tested for the first time in the context of a RCT against interventions based on other disciplines, like CBT [11].

2.5. Remarks on Study Methodology

Tinnitus interventions, in accordance with tinnitus pathophysiology, are heterogenous. In the RCTs collected, a wide spectrum of therapeutic strategies is performed ranging from transcranial magnetic and vagus nerve stimulation to internet-based CBT and altered/notched music (Table 2). A pattern that causes deviation from an optimal study design and is valid for various interventions is the inability to blind patients with respect to control interventions. For example, a blinded RCT comparing true and sham hearing aids is not feasible, since participants in the sham group will immediately recognize the sham devices, given that they will be unable to provide acoustic amplification.

Table 2. Characteristics of included studies: study procedures and outcome measures.
Author,

Year		TreatmentControl Group InterventionRandomizationOutcome MeasuresMonitoring DurationPower AnalysisResultsIs Treatment Effective?
Abtahi,

2018 [77]		Anodal Stimulation, Cathodal StimulationSham StimulationUnclearTinnitus Intensity Variations on A Scale Between −4 and +4. In This Scale, −4 Indicated Worsening Conditions, +4 Meant Full Recovery, And Zero Conveyed No Change in The Tinnitus Intensity.2 MonthsNoAnodal Stimulation Was More Effective Than the Cathodal and Control Stimulation in Reducing the Intensity of Tinnitus in The Short TermYes, Between Two Versions of The Same Treatment
Albu,

2016 [51]		Intratympanic (IT) Steroid and MelatoninMelatoninUnclearTHI, PSQI, BDI3 MonthsNoBetter Response in The Combined Group of Melatonine And IT In Acute Tinnitus PatientsYes
Anders,

2010 [17]		Active or Sham repetitive transcranial magnetic stimulation (rTMS)Sham RtmsUnclearVAS, THI26 WeeksNo1 Hz Rtms Treatment Was Capable of Significantly Reducing the Total Baseline Score of Basic Scales That Measure Tinnitus SeverityNo
Arif,

2017 [70]		Relaxation Therapy or Mindfulness Meditation Treatment Over A Period Of 15 WeeksRelaxation ProcedureClearPrimary: TRQ

Secondary VAS and A Health State Thermometer.		15 WeeksNoChanges in Tinnitus Loudness and THI (but not TRQ) with the Customized Sound Therapy Were Statistically Greater Than Those of The Broadband Noise TherapyNo
Beukes,

2017 [71]		Internet-based cognitive behavioral treatment (iCBT) InterventionICBT After 8 WeeksAlgorithm Implemented by Independent ResearcherPrimary: TFI, Secondary: ISI, GAD-7, PHQ-9, HHIA-S, HQ, CFQ, SWLS2 Months80%Guided ICBT For Tinnitus Using Audiological Support Resulted in Statistically Significant Reductions in Tinnitus Distress and Comorbidities (Insomnia, Depression, Hyperacusis, Cognitive Failures) And Improved Quality of Life.Yes
Beukes,

2018 [76]		Internet-

Based Intervention		Face-To-Face Tinnitus CareUnclearTHI, TFI2 Months90%ICBT And F2F Interventions Are not Effective for Reducing Tinnitus Distress and Most Tinnitus-Related Difficulties.No
Biesinger,

2010 [18]		10 Qigong Training SessionsNo TreatmentUnclearVAS, TBF-123 MonthsNoNo Statistically Significant Changes in Both GroupsNo
Bilici,

2013 [45]		rTMSParoxetine, PlaceboUnclearTHI, TSI, BAS, PSS6 MonthsNoNo Significant Improvement Neither for Rtms Groups nor For ControlsNo
Choi,

2013 [32]		IT SteroidsPlaceboClearTHI. VAS1 MonthNoNo Significant Difference Between IT Steroids and PlaceboNo
Cima,

2012 [22]		CBTUsual CareClearHUI, HADS, TFQ12 MonthsNoSuperiority Of CBTYes
Coelho,

2013 [33]		ZincPlaceboUnclearTHQ4 Months90%No Significant Differences Between Zinc and PlaceboNo
Dehkordi,

2011 [19]		GabapentinPlaceboUnclearTSI26 MonthsNoNo Statistically Significant Difference Between the Two Groups In TSI.No
Dehkordi,

2015 [44]		Active Laser TreatmentInactive Dummy TreatmentUnclearTSI4 WeeksNoNo Statistically Significant Improvement Neither in Laser nor In Control GroupNo
Doi,

2016 [52]		AcupunctureNo TreatmentRandomization Was Carried Out with The Aid of Computerized Table of Random Numbers Created by A Microsoft Excel Spreadsheet.VAS, THI5 WeeksNoTreatment with Acupuncture Improves the Perception of Tinnitus, Decreases the Intensity Level, Hence There Is No Comparison Between Levels of ImprovementYes,

Against Placebo In 5 Weeks, However No Comparison of Decrease
Dos Santos, 2014 [39]Hearing Aids + Sound GeneratorHearing AidsUnclearTHI3 Months80,0%No Superiority of The Combined Use of Amplification and Sound Generator Over Conventional Amplification Alone in Reducing the Discomfort of Tinnitus. Both Groups Presented Similar Responses in Both Reduction of Discomfort Caused by TinnitusNo
El Beaino,

2018 [78]		SulodexidePlaceboUnclearTHI, Mini TQRight After Treatment80%Improvement in THI and Mini TQ Right After the End of Treatment with SulodexideYes
Elzayat,

2018 [65]		Group A Was Injected with Combined Lidocaine 2% And Dexamethasone 8 Mg/2 mL (ITLD). Group B Was Injected Only by Dexamethasone 8 Mg/2 ML. (ITD).ITD As A Controlled GroupClearTHI, VAS, ATQ6 MonthsNoBoth Treatments Were Effective but No Difference Between Groups Was FoundYes
Folmer,

2015 [46]		rTMS Daily For 2 WeeksSham Rtms With A Same Looking CoilUnclearTFI26 MonthsNoSignificant Improvement in Active Compared to Placebo GroupYes
Godbehere, 2019 [80]Theta Burst TMSPlacebo ArmUnclearTFI4 WeeksNoNo Significant Difference in Scores Between the Active Treatment Group and The Sham Control GroupNo
Hall,

2019 [12]		AUT00063PlaceboClearTFI, VAS28 Days90%No Significant Improvement for Both Groups (Channel Blocker and Placebo)No
Han,

2012 [23]		ClonazepamGinkgo BilobaUnclearTHI, VAS, Loudness Scale NoImprovement with Use of Clonazepam and Not Gingko Biloba, but Right After TreatmentYes
Henry,

2016 [53]		TM-TRT-TEDNo TreatmentClearTHI18 Months80%No Statistically Significant Improvement In THI. By 6 Months, The TED Group Showed Significant Improvement from Baseline and Its Improvement Was Not Significantly Different from That Shown in TM Or TRT.No
Hesser,

2012 [24]		CBT Or ACTMonitored Internet Discussion ForumClearPrimary: THI, Secondary: HADS1 Year80%The Effect of ACT Compared with The Control Condition at Posttreatment on The Primary Outcome Was in The Moderate Range and Comparable to The Effect Observed Following CBT (D = 0.68 vs. D = 0.70).No
Hoare,

2012 [25]		Frequency TrainingDifferent Frequency Training THQ4 Weeks80%Statistically and Clinically Meaningful Improvement in All Groups. No Difference Between GroupsYes
Hoare,

2014 [40]		To Play A Tailored Video Game For 30 Minutes, 5 Days A Week For 4 WeeksAnother Type Of FDTClearTHQ4 Weeks80%Statistically but Not Clinically Significant Changes in One of The Games UsedNo
Hoekstra,

2013 [34]		rTMS in 1000HzPlaceboUnclearPrimary: TQ. Secondary THI, VAS6 Months80%No Significant Difference Between GroupsNo
Hong,

2018 [79]		40 Minutes Session of Nitrous Oxide Under General AnesthesiaSame Procedure Without Nitrous OxideClearTFI2 Weeks81%No Significant Differences Between Intervention and Control Group. Neither Groups Had Clinical or Statistically Significant ImprovementNo
Jasper,

2014 [41]		GCBT, iCBTWeb-Based Discussion Forum (DF)UnclearTHI, Mini-TQ, Secondary: HADS, ISI, TAQ6 MonthsNoICBT And Conventional GCBT Do Not Have Significant Differences Effects on Tinnitus Distress and Associated Problems.No
Jeon,

2012 [26]		AcupunctureShamUnclearTHI, VAS NoNo Significant Differences Between Acupuncture and ShamNo
Kallogjeri,

2017 [66]		Brain fitness program tinnitus (BFP-T)No TreatmentUnclearTHI, TFI, Global Bother Score8 Weeks85%No Statistically Significant Changes Between Study Groups.No
Kim,

2017 [67]		Manual AcupunctureElectroacupunctureUnclearTHI, VAS 80%No Significant Improvement for Any Acupuncture Group In Regards To THI and LoudnessNo
Kreuzer,

2012 [27]		Mindfulness and Body Group TherapyWaiting List (Therapy After 24 Weeks)UnclearTQ24 WeeksNoA Significant Reduction in The TQ Score (Baseline vs. Week 9) Compared to The Waiting List Control Group, However Difference Was Not Stable in Long Term F/UNo
Kreuzer,

2015 [47]		Medial Frontal Stimulation with Double Cone Coil + Stimulation of The Left Temporo-Parietal Junction AreaConventional Prefrontal Left DLPFC-Stimulation + Stimulation of The Left Temporo-Parietal Junction AreaUnclearTQ, Secondary: THI, CGI-CHANGE, Whoqol-Bref-Questionnaire12 WeeksNoΤICDC-Stimulation Non-Superior to Standard Rtms Regarding Both Primary and Secondary Outcome Measures.No
Landgrebe, 2017 [68]2 Week Treatment Real 1-Hz-Rtms vs. Sham RtmsSham RtmsClearPrimary: The Change of Tinnitus Severity Assessed by Means of The Change of The TQ Sum Score Between Baseline Score vs. Day 12. Secondary: Changes of The TQ Sum Score, The THI and TSS During the Treatment and The Follow-Up Period. Further: Changes of Overall Illness Severity, Changes in Depressive Symptoms, Changes in Quality of Life and Changes in Psychoacoustic Measures of Tinnitus.26 WeeksNoReal 1-Hz-Rtms Applied to The Left Temporal Cortex Did Not Provide Any Therapeutic Benefit as Compared to Sham Treatment in Patients with Chronic Tinnitus.No
Laureano,

2016 [54]		True

Acupuncture 99mTC-ECD SPECT		Sham AcupunctureUnclearPrimary: SPECT Measurements, Secondary: THI, VAS, HAS, BDI12 Weeks80%No Significant Differences After Treatment Were Observed with Regard to the VAS, HAS or BDI Between the Treatment Groups.No
Lee,

2018 [75]		IT SteroidsPlacebo (Saline)ClearTHI, VAS1 Month80%No Difference Between IT And Placebo GroupsNo
Lehner,

2016 [55]		High Frequency rTMSSingle Site RtmsClearTQ, THI,6 Months80%No Difference Between GroupsNo
Li,

2016 [56]		Music Altered by The Software to Treat TinnitusUnaltered MusicUnclearTHI, TFI, HADS12 Months80%Statistically Significant and Clinically Meaningful Effects of The Therapy as Indicated by The Consistent Treatment-Control Group Difference in THI Score and The Significant Reduction in THI Score Within the Treatment Group During The 12-Month Period.Yes
Li,

2019 [81]		Masking Therapy+ Sound Treatment + CBTMasking Therapy + Sound Treatment (Tinni Test)UnclearTHI, SCL-906 MonthsNoEffective Rate in Intervention Group Was Significantly Higher Than That in Control Group (P < 0.01)Yes
Lim,

2016 [57]		Oral 100 mg CilostazolPlaceboUnclearVAS, THI, SF-364 WeeksNoTHI Failed to Show A Significant Drug Effect of CilostazolNo
Malinvaud, 2015 [48]Virtual reality (VR)CBTClearSTSS, THI, THQ, VAS NoBoth VR And BT Groups ImprovedYes
Mckenna,

2017 [69]		RT Or MBCT Treatment vs. Waiting Period Without TreatmentRT Treatment GroupClearPrimary: TQ, CORE-NR, Secondary: CORE-OM, VAS, TFI, HADS, TCS, T-FAS, TAQ, MAAS, WSAS6 Months80.0%MBCT Is More Effective in Reducing Tinnitus Severity Than Both A Waiting Period and An Active Treatment of Equal Intensity (RT)Yes
Mollasadeh, 2013 [35]Low Laser BeamPlaceboUnclearTHI, VAS, Loudness Scale3 MonthsNoLarger Improvement in Low Beam Laser Compared to Placebo, Hence More Than 50% Of Intervention Group Without ImprovementYes
Ngao,

2012 [28]		TLLSShamUnclearTHI, VASRight After InterventionNoNo Significant Difference Between TLLS And ShamNo
Noh,

2019 [82]		Dual-Site Rtms Or Sham RtmsSham RtmsUnclearPrimary: THI, Secondary: VAS8 WeeksNoA Beneficial Effect of Rtms On Tinnitus Suppression Was Found in The Dual-Site Active Rtms Group, but Not in The Sham Rtms Group.Yes
Nyenhuis,

2013 [36]		Internet Training, Bibliotherapy, Group Treatment or An Information-Only Condition.Information OnlyClearPrimary: TQ, Secondary: BL, PHQ-D9 Months80.0%Improvement Rates Were Higher in The Active Training Conditions Than in The Control Condition, And Deterioration Rates Were Generally Lower in The Training Conditions In TQ.Yes
Pal,

2015 [49]		transcranial direct current stimulation (TDCS) UnclearPrimary: THI, Secondary: STSS, HAD, VAS, CGI3 Months80.0%This TDCS Protocol Did Not Show A Beneficial Effect on Tinnitus.No
Plewnia,

2012 [29]		CTBS Over the Secondary Auditory Cortex (SAC), The Temporoparietal Association Cortex (TAC), Or Sham Stimulation [Placebo (PLC)].PlaceboClearTQ3 Months80%No Difference Between Real and Sham Treatments nor Between Temporal and Temporoparietal Ctbs.No
Prozchazkova,

2019 [83]		Ginkgo BilobaPentoxifyllineUnclearVAS, Mini TQ, HADS3 MonthsNoBoth Gingko Biloba and Pentoxifylline Improve Mini TQ. No Difference Between GroupsYes
Radunz,

2019 [84]		Gingko BilobaHAUnclearTHI, VAS6 MonthsNoBoth Gingko Biloba Improved Compared to Baseline, No Difference Between Groups Though, Apart from Long Lasting TinnitusYes
Rocha,

2012 [30]		10 Sessions of Myofascial Trigger Point Deactivation10 Sessions with Sham DeactivationUnclearTHI3 MonthsNoMTP Deactivation Through Digital Pressure Was Deemed Effective in Each and Every Tinnitus Variable Under Evaluation and In the Medium Run Responsiveness to Treatment Remained Stable In 75.8% Patients.Yes
Rojas-Roncancio, 2016 [58]Manganese and Lipoflavonoid PlusLipoflavonoid PlusUnclearTHQ, TPFQ6 MonthsNoNo Significant Improvement in Both GroupsNo
Roland,

2016 [59]		Sham or Active Treatment rTMS to TPJSham Rtms to TPJClear 2 or 4 WeeksNoNo Changes in Neural Connectivity Following Rtms Therapy. Results Suggest Instead That the TPJ May Not Be an Ideal Target for Tinnitus Treatment.No
Sahlsten,

2017 [72]		rTMSPlacebo RtmsUnclearTHI, VAS6 Months80%Improvement for The VAS Scores (Intensity, Annoyance, Distress) And THI Scores Both in The Active Rtms Group and The Placebo Group.No
Sahlsten, 2019 [85]rTMS With and Without Neuronavigation for 2 Weeks In 2000 HzWith and Without NeurostimulationUnclearTHI, Global Impression of Change3 MonthsNoNo Significant Difference Between Groups, However Significant Improvement in BothNo
Scherer,

2019 [86]		TRT, including tinnitus specific counseling (TC) and sound-therapy (ST) Implemented with Ear- Level sound generators (SGS); Partial TRT, Including TC and Placebo SGS; Or Standard of Care (SoC)Placebo SGS Or Standard of Care (Soc)ClearPrimary: TQ, Secondary: TFI, THI, VAS18 Months80.0%No Meaningful Differences Between TRT And Soc (Our Primary Comparison) Or Between Partial TRT And Soc Or TRT (Our Secondary Comparisons).No
Shekhawat, 2014 [42]Transcranial direct current stimulation (TDCS)Sham StimulationClearTFI, THI, THQ, MML7 MonthsNoNo Significant Differences for Any of The Questionnaires; Decrease in MML For the RTMS GroupNo
Singh,

2016 [60]		B12PlaceboUnclearMatching, TSI1 MonthNoImprovement in Patients with B12 Insufficiency, Hence in A Very Small SampleNo
Sönmez,

2013 [37]		OzoneBetahistineUnclearTHI, Loudness Scale6 MonthsNoNo Differences Between Ozone and Betahistine, Both Showed Improvement Compared to Baseline ThoughYes
Stein,

2016 [61]		Fixed Notch-TMNMTPlacebo (Moving Notch)ClearTHQ, VAS4 Months90.0%Tinnitus Loudness and Other Measures of Tinnitus Distress Do Not Show Relevant Changes.No
Sziklai,

2011 [20]		PramipexolePlaceboClearTHI4 WeeksNoNo Cumulative Analysis. Greater Proportion of Patients Reporting Tinnitus Disappearance in The Interventional Group. Results Not Confirmed by Electrocochleography.Unclear
Taslimi,

2013 [38]		OndansedronPlaceboClearTHI, TSI, VAS, HADS NoNo Significant Differences Between Ondansedron And PlaceboNo
Tass,

2012 [31]		CRPlacebo VAS, TQ12 WeeksNoImprovement Before and After Treatment and Also Compared to PlaceboYes
Teismann,

2014 [43]		Anodal TDCS, Cathodal TDCS + TMNMTSham Stimulation + TMNMTUnclearTHQ, THI, TQ31 DaysNoNo Significant Modulating Effect of TDCS Polarity: Significant Main Effects or Interactions of TDCS Condition Were Neither Found in The Primary Outcome Measure nor In Any of The Secondary Outcome Measures (THI, TQ, Or Loudness VAS;No
Thabit,

2015 [50]		rTMSRTMSUnclearTHI, VAS1 MonthNoCombination Treatment Significantly BetterYes
Theodoroff, 2017 [73]LEVO System with A Tinnitus-Matched Stimulus (TM Group) vs. LEVO System with A Noise Stimulus (NS Group; White Noise And/or Band Noise) vs. Marsona 1288 Sound Conditioner/Tinnitus Masker (Bedside Sound Generator Device; BSG Group).BSG And NS Groups, but Not in The Same Manner as A Placebo-Controlled GroupUnclearTFI, NRS, And LM at 1 kHz3 MonthsNoGreater Average Improvement in Reactions to Tinnitus with TM or NS Devices Compared to The BSG Device.Yes
Tutar,

2020 [88]		10 Sessions Of 30 Minutes in One MonthPlaceboUnclearTHI, DASS4 WeeksNoSignificant Improvement in Uni- And Bilateral Groups Compared to PlaceboYes
Tyler,

2017 [74]		VNS Implant-PairedVNS Implant-Unpaired (Paired After 6 Weeks)ClearTHI, TFI, THQ1 YearNoNo Significant Differences for Any of The Outcome MeasuresNo
Weise,

2016 [62]		10-Week Guided Internet-Based Self-Help ProgramDFUnclearPrimary: THI, Mini-TQ, Secondary: HADS1 YearNoICBT Resulted to Significantly Better THI Scores Compared to Participation in An Online ForumYes
Westin,

2011 [21]		ACT, TRTWait List ControlUnclearPrimary: THI, Secondary: ISI, QOLI, HADS, CGI-I18 Months80%ACT Is More Effective in Reducing Tinnitus Impact Than Tinnitus Retraining Therapy or Being on A Wait List.Yes
Wise,

2016 [63]		Experimental Attention Training Game (“Terrain”)A Control Game (“Tetris”)UnclearTFI, Secondary: THI, Tinnitus Severity Numeric Scales20 Days92%TFI Scores Improved Following The 20-Day Use for the “Terrain” Program Compared with The Nonauditory “Tetris” Group.Yes
Yakunina,

2019 [87]		HAs With WDRC, HAs With FT, Or HAs With LFTFL Techniques (LFT and FT) GroupClearPrimary: THI, Secondary: VAS6 Months80.0%No Significant Differences Were Found Between Conventional Has And FL-Type Has in Terms of Tinnitus Relief Among Patients With HFHL.No
Zarenoe,

2016 [64]		MI Group Received A Brief MI Program, Whereas Patients in The SP Group Underwent Conventional Hearing Aid Fitting.Conventional Hearing Aid Fitting GroupUnclearTHI, IOI-HA3 MonthsNoThe MI Intervention Did Not Appear to Have Any Additional Effect on Hearing Aid Fitting Compared to Conventional Hearing Rehabilitation.No

Apart from intrinsic limitations and barriers, tinnitus literature also suffers from methodological insufficiencies which are common in other fields, as well. Median number of participants per RCT is as low as 54, whereas only 10 exceed 100 participants. Most of the studies (46 out of 73) did not provide power analysis; hence, the rest reported power over 80%. The same proportion of papers did not provide a clear, detailed, and reproducible description of their randomization procedure, a fact that clearly questions their qua-lity. Moreover, randomization procedure was found to be unclear in 46 of the studies (63.01%) under the sense, that relevant information provided was generic and not adequate for the procedure to be replicated.

Although out of the scope of this review, what needs to be underlined is that many of the RCTs concerning tinnitus are supported by pharmaceutical companies or hearing and tinnitus-related devices manufacturers. So, results must always be read with caution and extra consideration for potential biases or conflicts of interests.

2.6. Outcome Measures

Tinnitus is a condition affecting everyday life in many ways, causing a list of issues including, but not limited to annoyance, functional disturbances, tinnitus intrusiveness and acceptance, disability for certain actions and tasks like concentration, ability to ignore negative emotions, sense of control, malaise, and loathsomeness. Hall et al. (2019) have recently suggested proper outcome measures for each type of intervention. These recommendations could not have been applied to the body of the RCTs examined; however, lack of justification for the choice of a certain outcome measure is the rule [1789].

Majority of studies (63 out of 73, 86.30%) use more than one outcome measures, a procedure that has been proposed to enable comparison across trials [13][1890]. However, the use of multiple outcome measurements requirerequires the a priori definition of the primary outcome, which was the case only in 14 studies out of the 64. It is also interesting, that 34 of the RCTs use at least three outcome measures, which shows a relatively wide range of domains targeted and also increases the possibility of results ought to randomness.

2.7. Time Course

Relatively little is known about the course of tinnitus over time [6][1991][2092][2193]. There are a lot of factors contributing to this. Tinnitus installation is often prolonged and there is a considerable proportion of patients that cannot clearly identify an exact date of tinnitus onset. Especially in the cases where tinnitus habituation has occurred, patients may not clearly recall or may underestimate both time of onset or severity of their tinnitus, when they are asked about it or when they are filling retrospectively a relevant questionnaire. A considerable proportion with total relapse might not even contact health services, and therefore never be recorded, which means that estimation of the course of tinnitus over time is in current studies at based assessed retrospectively by questionnaires, which are subject to recall bias as well as to suboptimal phrasing of the relevant questions in the self-filled questionnaires. Consequently, there is lack of reliable information about the actual incidence, the course and the profile of the patients who experience tinnitus for a short period of time and then stop experiencing it. On top of this, patient trajectories differ strongly across countries depending in the health system.

Tinnitus is usually dichotomized into acute and chronic; however, recent European guidelines have also included the sub-acute type (from 3 to 6 months), in order to reflect the transition from acute to chronic tinnitus [1]. However, all these definitions are arbitrary, and little is known about differences in the pathophysiology of acute and chronic tinnitus and the time when this transition occurs. It is remarkable that only two of the RCTs identified focused on acute tinnitus [2251][2375].

The majority of the studies (58 of 73) clearly defines a minimum time interval from tinnitus onset, however variability in time intervals is large. Eleven trials set as minimum duration 3 months and 22 the 6 months interval, whereas a wide range of smaller or larger intervals occur. This variance may be relevant for the tinnitus course, since a recent systematic review has indicated a statistically significant decrease in the impact of tinnitus over time, although clinical significance could not be interpreted due to heterogeneity [2494]. This practically means that in the comparison between RCTs differences in the tinnitus duration might matter.

2.8. Trial Design and Results

As expected, there is a large heterogeneity among the RCTs included. About one third of the included studies examine the efficacy of pharmaceutical agents either as sy-stemic or as topical administration. Second most common topic is various types of TMS, whereas 10 focus on CBT either face to face or online, 5 on non-CBT psychological interventions, 7 on HAs (alone or in combination with motivational interview), and 8 on sound therapy. Finally, acupuncture and laser beam have also been evaluated as monotherapy for chronic tinnitus [2526][2628][2735][2844][2952][3054][3167]. The variance of the interventions with respect to their intended mechanisms, targets and duration should have led to different trial designs in terms of outcome measures as well as follow up schedule. For instance, TMS is usually implemented in strict and well-defined time periods (typically one to two weeks), whereas CBT is an intervention lasting several weeks and should be finished before the effect can be evaluated. At the same time, HAs have a continuous and possibly long-lasting effect. This is not reflected in the design of the studies, since criteria in regards to tinnitus onset, follow up duration and outcome measures are more or less equally distributed in these sub-groups of RCTs.

It is noteworthy that two third of control groups use different types of methods in order to be non-interventional: placebo, sham devices or interventions, participants from the waiting list or usual care. Ideally, the recommendation is to use best available treatment instead of placebo, at least for pharmacological studies. This is probably not applicable in the tinnitus field, since universally acceptable treatment is pending [3295]. Hence, majority of the remaining studies use as control arms active interventions of the same discipline (different TMS protocols, HA fitting parameters, stimuli used for sound therapies). Very few RCTs compare two totally independent interventions. This design should be considered in future studies, because on top of efficacy superiority, it could potentially identify profiles of patients who could be more prompt to one intervention compared to other.

Although evaluation of results was not within the core scopes of this review, it should be mentioned, that roughly one third of the RCTs concluded that the intervention tested was considered effective. RCTs targeting CBT and different types of sound therapy re-presented more than one third of the RCTs with a positive outcome, whereas their proportion in the whole body of RCTs was significantly lower (13.6% and 10.96%, respectively). All other types of interventions had at least one clinical trial with a positive result (superiority against the control intervention).

One important aspect is that with regards to several RCTs in which different active interventions were compared, it remains unclear whether the results differ from placebo. Even if there were significant within arm comparisons for all investigated interventions, one cannot unambiguously differentiate between spontaneous improvement and an effect of the investigated intervention.

Moreover, with very few exceptions, only statistical and not clinical significance was examined, and any minimum benefit considered as significant was set ad hoc.

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