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 (

). 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 (

). 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.

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 (

). 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.

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 ^[17].

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][18]. 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][19][20][21]}. 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 ^[22][23].

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 ^[24]. This practically means that in the comparison between RCTs differences in the tinnitus duration might matter.