Betahistine for tinnitus

Background

This is a new protocol for a new Cochrane Review. The ‘Description of the condition’ and ‘Diagnosis and clinical management of tinnitus’ sections are based on the Cochrane Review ‘Amplification with hearing aids for patients with tinnitus and co‐existing hearing loss’ (Hoare 2014). Other sections are based on the Cochrane protocol ‘Betahistine for Ménière’s disease or syndrome’ (van Esch 2018). They are both reproduced with permission.

Tinnitus is defined as the perception of sound in the absence of an external source (Jastreboff 2004). It is typically described by those who experience it as a ringing, hissing, buzzing or whooshing sound and is thought to result from abnormal neural activity at some point or points in the auditory pathway, which is erroneously interpreted by the brain as sound. Tinnitus can be either objective or subjective. Objective tinnitus refers to the perception of sound that can also be heard by the examiner and is usually due to turbulent blood flow or muscular contraction (Roberts 2010). Most commonly, however, tinnitus is subjective; the sound is only heard by the person experiencing it and no source of the sound is identified (Jastreboff 1988).

Tinnitus affects between 5% and 43% of the general population and prevalence increases with age (McCormack 2016). It can be experienced acutely, recovering spontaneously within minutes to weeks, but is considered chronic and unlikely to resolve spontaneously when experienced for more than three months (Gallus 2015Hall 2011).

For many people, tinnitus is persistent and troublesome, and has disabling effects such as insomnia, difficulty concentrating, difficulties in communication and social interaction, and negative emotional responses such as anxiety and depression (Hall 2018). In approximately 90% of cases chronic subjective tinnitus is co‐morbid with some degree of hearing loss, which may confound these disabling effects (Fowler 1944Sanchez 2002). Nevertheless, the association between hearing loss and tinnitus is not simple or straightforward; not all people with hearing loss experience tinnitus, and conversely some people with clinically normal hearing have tinnitus (Baguley 2013). It has been reported that 40% of patients are unable to identify what health condition is associated with their tinnitus onset, i.e. the tinnitus is idiopathic (Henry 2005).

Description of the condition

Diagnosis and clinical management of tinnitus

There is no standard procedure for the diagnosis or management of tinnitus. Practice guidelines and the approaches described in studies of usual clinical practice typically reflect differences between the clinical specialities of the authors or differences in the clinical specialities charged with meeting tinnitus patients’ needs (medical, audiology/hearing therapy, clinical psychology, psychiatry), or the available resources of a particular country or region (access to clinicians or devices, for example) (Biesinger 2011Cima 2012Department of Health 2009Hall 2011Henry 2008Hoare 2011). Common across current clinical guidelines for the assessment of subjective tinnitus (Fuller 2017), is a recommendation for the use of written questionnaires to assess tinnitus and its impact on patients by measuring tinnitus symptom severity (e.g. impact of tinnitus on quality of life, activities of daily living or sleep), and a judgement about patients who are experiencing a degree of psychological distress (including depression or anxiety).

Clinical management strategies include education and advice, relaxation therapy, tinnitus retraining therapy (TRT), cognitive behavioural therapy (CBT), sound enrichment using ear‐level sound generators or hearing aids, and drug therapies to manage co‐morbid symptoms such as sleep difficulties, anxiety or depression (for example, Department of Health 2009Tunkel 2014). As yet, no drug has been approved for tinnitus by a regulatory body (e.g. the European Medicines Agency or US Food and Drug Administration).

Pathophysiology

Many people with chronic tinnitus have some degree of measurable hearing loss (Ratnayake 2009), and the prevalence of tinnitus increases with greater hearing loss (Han 2009Martines 2010). The varying theories of tinnitus generation involve changes in either function or activity of the peripheral (cochlea and auditory nerve) or central auditory nervous systems (Henry 2005). Theories involving the peripheral systems include the discordant damage theory, which predicts that the loss of outer hair cell function, where inner hair cell function is left intact, leads to a release from inhibition of inner hair cells and aberrant activity (typically hyperactivity) in the auditory nerve (Jastreboff 1990). Such aberrant auditory nerve activity can also have a biochemical basis, resulting from excitotoxicity or stress‐induced enhancement of inner hair cell glutamate release with upregulation of N‐methyl‐D‐aspartate (NMDA) receptors (Guitton 2003Sahley 2001).

In the central auditory system, structures implicated as possible sites of tinnitus generation include the dorsal cochlear nucleus (Middleton 2011Pilati 2012), the inferior colliculus (Dong 2010Mulders 2010), and the auditory and non‐auditory cortex (discussed further below). There is a strong rationale that tinnitus is a direct consequence of maladaptive neuroplastic responses to hearing loss (Moller 2000Mühlnickel 1998). This process is triggered by sensory deafferentation and a release from lateral inhibition in the central auditory system allowing irregular spontaneous hyperactivity within the central neuronal networks involved in sound processing (Eggermont 2004Rauschecker 1999Seki 2003). As a consequence of this hyperactivity, a further physiological change noted in tinnitus patients is increased spontaneous synchronous activity occurring at the subcortical and cortical level, measurable using electroencephalography (EEG) or magnetoencephalography (MEG) (Dietrich 2001Tass 2012Weisz 2005). Another physiological change thought to be involved in tinnitus generation is a process of functional reorganisation, which amounts to a change in the response properties of neurons within the primary auditory cortex to external sounds. This effect is well demonstrated physiologically in animal models of hearing loss (Engineer 2011Noreña 2005). Evidence in humans, however, is limited to behavioural evidence of cortical reorganisation after hearing loss, demonstrating improved frequency discrimination ability at the audiometric edge (Kluk 2006McDermott 1998Moore 2009Thai‐Van 2002Thai‐Van 2003), although Buss 1998 did not find this effect. For comprehensive reviews of these physiological models, see Adjamian 2009 and Noreña 2011.

It is also proposed that spontaneous hyperactivity could cause an increase in sensitivity or ‘gain’ at the level of the cortex, whereby neural sensitivity adapts to the reduced sensory inputs, in effect stabilising mean firing and neural coding efficiency (Noreña 2011Schaette 2006Schaette 2011). Such adaptive changes would be achieved at the cost of amplifying ‘neural noise’ due to the overall increase in sensitivity, ultimately resulting in the generation of tinnitus.

Increasingly, non‐auditory areas of the brain, particularly areas associated with emotional processing, are also implicated in bothersome tinnitus (Rauschecker 2010Vanneste 2012). Vanneste 2012 describes tinnitus as “an emergent property of multiple parallel dynamically changing and partially overlapping sub‐networks”, implicating the involvement of many structures of the brain more associated with memory and emotional processing in tinnitus generation. However, identification of the structural components of individual neural networks responsible for either tinnitus generation or tinnitus intrusiveness, which are independent of those for hearing loss, remains open to future research (Melcher 2013). One further complication in understanding the pathophysiology of tinnitus is that not all people with hearing loss have tinnitus and not all people with tinnitus have a clinically significant and measurable hearing loss. Other variables, such as the profile of a person’s hearing loss, may account for differences in their tinnitus report. For example, König 2006 found that the maximum slope within audiograms was higher in people with tinnitus than in people with hearing loss who do not have tinnitus, despite the ‘non‐tinnitus’ group having the greater mean hearing loss. This suggests that a contrast in sensory inputs between regions of normal and elevated threshold may be more likely to result in tinnitus. However, this finding is not consistent across the literature (Sereda 2011Sereda 2015).

Description of the intervention

First registered in 1968, betahistine is an oral drug that, by 2006, was estimated to have been prescribed to more than 130 million people worldwide (Jeck‐Thole 2006). The indication for taking betahistine is to treat patients with Ménière’s disease (Electronic Medicines Compendium 2015). However, many patients are given betahistine off‐licence to treat idiopathic subjective tinnitus (Hall 2011McFerran 2018) and vertigo (Murdin 2016), even when these symptoms are not associated with Ménière’s disease. The recommended daily dose of betahistine is 24 mg to 48 mg per day divided into two or three single doses containing 8 mg, 16 mg or 24 mg (Jeck‐Thole 2006). Although gastrointestinal side effects are cited in many formularies, the rate of adverse effects in patients taking betahistine is not significantly different from those taking placebo in comparison studies (Murdin 2016).

Betahistine hydrochloride (or dihydrochloride) is a derivative of betahistine. Alternative formulations of betahistine include betahistine mesylate (or mesilate), dimesylate and maleate.

How the intervention might work

Betahistine is a weak histamine H1 receptor agonist and a potent histamine H3 receptor antagonist. One postulated mechanism of action of the drug is reduction of endolymphatic pressure through improved microvascular circulation in the stria vascularis of the cochlea (Martinez 1972). In addition, inhibition of activity in the vestibular nuclei may contribute to rebalancing neural activity and expedite the recovery process (Lacour 2007Timmerman 1994). Studies have shown that betahistine reaches a peak plasma concentration in about one hour and it has a plasma half‐life of approximately 3.5 hours (Electronic Medicines Compendium 2015). The maximal vestibular therapeutic effect will last approximately three to four hours (Electronic Medicines Compendium 2015).

For Ménière’s disease/syndrome these pharmacological characteristics are thought to reduce the intensity and duration of vertigo symptoms in the short term (under three months) and additionally prevent attacks in the longer term (over three months). For tinnitus, betahistine is thought to work by improving blood flow to certain areas within the inner ear. However, it is not fully understand how betahistine actually interacts within the inner ear to reduce tinnitus symptoms. In some countries, prescription behaviour differs according to whether tinnitus is acute (< 3 months) or chronic (≥ 3 months) (Hall 2011). This may reflect a belief that duration of tinnitus is a modifier of treatment success.

Why it is important to do this review

In England alone there are an estimated ¾ million GP consultations every year where the primary complaint is tinnitus (El‐Shunnar 2011), equating to a major burden on healthcare services. A study reported over 100,000 prescriptions for betahistine being filled every month in England (Phillips 2008), and nearly 10% of general practitioners prescribe betahistine for tinnitus. There is a published Cochrane Review of betahistine for Ménière’s disease (idiopathic) or Ménière’s syndrome (secondary to established inner ear disorders) (James 2001), and a new protocol for an update (van Esch 2018). Both examine tinnitus as a secondary outcome. However, there is no existing Cochrane Review of betahistine for tinnitus as a primary outcome, without the comorbidities of vertigo and hearing loss. Assessment of the effect of betahistine in the treatment of subjective idiopathic tinnitus is therefore warranted.

Objectives

To assess the effects of betahistine in patients with subjective idiopathic tinnitus.

Methods

Criteria for considering studies for this review

Types of studies

We will include studies with the following design characteristics:

  • randomised controlled trials, including cluster‐randomised (cross‐over trials will be eligible if data from before the cross‐over are extractable, to avoid the potential for a carry‐over phenomenon).

We will exclude studies with the following design characteristics:

  • quasi‐randomised controlled studies.

We will apply no restrictions on language, year of publication or publication status.

Types of participants

Patients of any age with acute or chronic subjective idiopathic tinnitus. Participants who have received betahistine previously will be eligible for inclusion.

Types of interventions

Betahistine: any dose regimens or formulations and for any duration of treatment.

The comparators are placebo, no intervention or education and information only.

The main comparison will be:

  • betahistine versus placebo.

Other possible comparison pairs include:

  • betahistine versus no intervention; or
  • betahistine versus education and information only.

Concurrent use of other medication or other treatment will be acceptable if used equally in each group. For example, betahistine with an additional intervention versus placebo with an identical additional intervention. Where an additional intervention was used equally in both groups, we will analyse this as a separate comparison.

Types of outcome measures

We will analyse the following outcomes in the review, but we will not use them as a basis for including or excluding studies.

Primary outcomes
  • Tinnitus loudness (a change in subjective perception) measured using either patient‐reported instruments (including visual analogue scales or numerical rating scales) or performance‐based procedures (including Tinnitus Loudness Matching or Minimum Masking Level).
  • Significant adverse effects: upper gastrointestinal discomfort.
Secondary outcomes
  • Tinnitus symptom severity (such as the impact of tinnitus on quality of life, activities of daily living and sleep), as measured by the global score on a multi‐item tinnitus questionnaire ( Table 1). These include:
    Open in table viewer

    Table 1. Examples of questionnaires measuring tinnitus symptom severity
    Measurement instrument (author, year) Number of items and subscales Internal consistency (Cronbach’s alpha for the global score)
    Tinnitus Functional Index (Meikle 2012) 25 items, 8 subscales 0.97
    Tinnitus Handicap Inventory (Newman 1996) 25 items, 3 subscales 0.93
    Tinnitus Handicap Questionnaire (Kuk 1990) 27 items, 3 subscales 0.94
    Tinnitus Reaction Questionnaire (Wilson 1991) 26 items 0.96
    Tinnitus Questionnaire, English version (Hallam 2009) 52 items, 5 subscales 0.94
    Tinnitus Questionnaire, German version (Hiller 2006) 52 items, 6 subscales 0.93
    Tinnitus Severity Scale (Sweetow 1990) 15 items Not reported
  • Depressive symptoms or depression as measured by a validated instrument including the Beck Depression Inventory (Beck 1988Beck 1996), the depression scale of the Hospital Anxiety and Depression Scale (HADS; Zigmond 1983), or the Hamilton Rating Scale for Depression (Hamilton 1960).
  • Anxiety symptoms or generalised anxiety as measured by a validated instrument including the Beck Anxiety Inventory (Beck 1988a), the anxiety scale of the HADS (Zigmond 1983), or the Anxiety Sensitivity Index (Reiss 1986).
  • Health‐related quality of life as measured by any appropriate scale including the Short‐Form health survey (Hays 1993), WHOQOL‐BREF (Skevington 2004), other WHOQOL versions and the Health Utilities Index (Furlong 2001).
  • Other adverse effects; headache, allergic skin reactions (pruritis, rashes) and exacerbation of tinnitus.

In addition, we will report the new core outcome for trials of pharmacological interventions for tinnitus, this being tinnitus intrusiveness (Fackrell 2017). As there is not yet an agreed definition of this concept, intrusiveness will be measured by a single item patient‐reported visual analogue scale or numerical rating scale.

Based on the pharmacological properties of the drug described above, we will assess outcomes as short‐term (less than three months) and long‐term (three to six months). We will also consider whether these outcomes are sustained beyond six months.

Search methods for identification of studies

The Cochrane ENT Information Specialist will conduct systematic searches for randomised controlled trials and controlled clinical trials. There will be no language, publication year or publication status restrictions. We may contact original authors for clarification and further data if trial reports are unclear and we will arrange translations of papers where necessary.

Electronic searches

Published, unpublished and ongoing studies will be identified by searching the following databases from their inception:

  • the Cochrane ENT Register (search to date);
  • the Cochrane Central Register of Controlled Trials (CENTRAL, via the Cochrane Register of Studies (CRS) to date);
  • Ovid MEDLINE(R) Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) (1946 to date);
  • Ovid Embase (1974 to date);
  • LILACS (Latin American and Caribbean Health Science Information database; 1982 to date);
  • Web of Knowledge, Web of Science (1945 to date);
  • ClinicalTrials.gov, www.clinicaltrials.gov (search via the Cochrane Register of Studies to date);
  • World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (search to date).

The subject strategies for databases will be modelled on the search strategy designed for CENTRAL (Appendix 1). Where appropriate, these will be combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomised controlled trials and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.b. (Handbook 2011)).

Searching other resources

We will scan the reference lists of identified publications for additional trials and contact trial authors if necessary. In addition, the Information Specialist will search Ovid MEDLINE to retrieve existing systematic reviews relevant to this systematic review, so that we can scan their reference lists for additional trials. The Information Specialist will also run non‐systematic searches of Google Scholar to retrieve grey literature and other sources of potential trials.

We will not perform a separate search for adverse effects of betahistine for tinnitus. We will consider adverse effects described in the included studies only.

Data collection and analysis

Selection of studies

Three authors (DAH, DM and IS) will independently scan the initial search results to identify studies that appear to meet the inclusion criteria. The authors will then review the full‐text articles of the retrieved studies and apply the inclusion criteria independently. We will resolve any differences in opinion about which studies to include in the review by discussion or, failing that, by consultation with one of the other authors (IW, DS).

Data extraction and management

Three authors (DAH, IW and DS) will independently extract data from the studies using a purposefully designed data form. We will extract data so as to allow an intention‐to‐treat analysis. We will pilot the data extraction form on a subset of articles and revise it as indicated before formal data extraction begins. Where necessary or where insufficient data are provided for the study, we will contact the authors for further information.

Information to be extracted will include: trial design, country of recruitment, setting, funding, conflict of interest (any author), methods or randomisation and blinding, power, number of participants, inclusion and exclusion criteria, type of intervention and control(s), total dose per day (mg), method of administration, concomitant treatment, treatment duration, treatment fidelity, type and duration of follow‐up, definition of outcomes and endpoints, and statistical tests.

Data to be extracted will include: baseline characteristics of participants (age, sex, duration of tinnitus, tinnitus symptom severity, tinnitus loudness estimates, details of co‐morbid hearing loss, anxiety or depression), and details of any attrition or exclusion.

Outcome data to be extracted will include: group mean and standard deviation at pre‐ and post‐intervention and follow‐up, and results of any statistical tests of between‐group comparisons.

With regard to subgroup analysis, we will extract data to allow grading according to duration of tinnitus and treatment protocol (dose and duration of drug treatment). If betahistine doses differ among the intervention groups within a study, we will extract data on the highest dose and compare this to placebo. Extraction of data on co‐morbidity will involve, for example, depressive symptoms, generalised anxiety and reduced sound level tolerance).

We will also contact authors where further information is required that is not contained within the trial publication or in an accessible database. If not reported or provided by the authors we will estimate standard deviations in RevMan 5.3 (RevMan 2014) using the available data, such as standard errors, confidence intervals, P values and t values. Where data are only available in graph form, authors will make and agree numeric estimates.

After independent data extraction, all authors will review the extracted data for disagreements, and revisit and discuss the relevant studies as required to reach a final consensus.

Assessment of risk of bias in included studies

Two authors (IW and IS) will undertake assessment of the risk of bias of the included trials independently, with the following taken into consideration, as guided by theCochrane Handbook for Systematic Reviews of Interventions (Handbook 2011):

  • sequence generation;
  • allocation concealment;
  • blinding;
  • incomplete outcome data;
  • selective outcome reporting; and
  • other sources of bias (e.g. lack of an intervention control as a comparator, improper statistical analysis).

We will use the Cochrane ‘Risk of bias’ tool in RevMan 5.3 (RevMan 2014), which involves describing each of these domains as reported in the trial and then assigning a judgement about the adequacy of each entry: ‘low’, ‘high’ or ‘unclear’ risk of bias. We will resolve differences of opinion by discussion. If no consensus is reached, we will consult the other authors.

Measures of treatment effect

The primary outcome in this review will be the change in tinnitus loudness, which is likely to be a continuous variable. For intervention effect measures using continuous data, we plan to calculate the mean difference (MD) between groups with a 95% confidence interval (CI), provided that the selected studies used the same scale of measurement. If different scales having been used, we plan to calculate the standardised mean difference (SMD) (Cohen’s d effect size (ES)). A positive effect size indicates that the treatment group achieved better outcomes than the control group.

We will analyse dichotomous data as risk ratios (RR) with 95% CIs.

Unit of analysis issues

Cluster‐randomised trials

We will include cluster‐RCTs with the cluster as the unit of analysis. For more recent studies, it is most likely that clusters have been taken into account in the analyses. If not, we will adjust for the clusters using the methods set out in the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011).

Cross‐over trials

For subjective idiopathic tinnitus, it is unlikely that symptom severity returns to its baseline level after the first treatment period. Therefore, we will only use data from cross‐over trials if data from before the cross‐over can be obtained.

Multi‐arm studies

In the event that we find studies with more than two groups (e.g. two or more active treatments being tested against placebo), we will establish which of the comparisons are relevant to the systematic review and relevant to each of the meta‐analyses that we may implement. As we anticipate that participants will have been included in several groups, there is a risk of unit of analysis error. As a result, we will ensure that participants are included only once per meta‐analysis. Where the study design used independent groups, we will treat the study as an independent comparison.

Repeated observations on participants

The unit of analysis will be the participant. If studies evaluate the effect over a longer time period, we may record the results at multiple time points. To avoid unit of analysis error when combining study results in a single meta‐analysis (and therefore counting the same participants in more than one comparison), we will define different outcomes related to the periods of follow‐up and we will perform separate analyses.

Dealing with missing data

Where necessary and where sufficient data from the study are not provided, we will contact the authors of the study requesting further details about missing data and reasons for the incompleteness of the data. If no useful response is obtained, we will impute data if we judge the data to be ‘missing at random’. If we judge data to be ‘missing not at random’, the missing data may affect the overall results; we will therefore not impute data. In the latter case, we will conduct sensitivity analysis with different assumptions.

We will be alert to potential mislabelling or non‐identification of standard errors and standard deviations. Our methods for imputation will be according to chapter 7.7.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011).

If data are missing, we will use available case analysis using all data (as reported) for all randomised patients available at the end of the study/time point of interest, regardless of the actual treatment received. We will consider the quality of outcome assessment as a study limitation (GRADE) and not as a stratifying factor.

Assessment of heterogeneity

We will determine whether the selected studies suffer from clinical, statistical and methodological heterogeneity. We will quantify statistical heterogeneity using the I2 statistic and the Chi2 test. With respect to the I2 statistic, an approximate guide to interpretation is provided in the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011). If the I2 value is 50% or higher, the data can be considered to suffer from substantial or considerable heterogeneity. For the Chi2 test, we will use the indicator that where the Chi2 is greater than the degrees of freedom (where the degrees of freedom are the number of studies K minus 1), then heterogeneity is likely to be present. We will consider heterogeneity to be statistically significant if the P value is less than 0.10. Subsequently, we will perform the meta‐analysis using fixed‐effect (in the absence of heterogeneity) and random‐effects modelling (in the presence of heterogeneity). If the level of heterogeneity remains unclear we will seek statistical advice.

Assessment of reporting biases

We will search for and request study protocols for the included studies and, where available, we will evaluate whether there is evidence of selective reporting. If a meta‐analysis contains at least 10 studies, we will assess publication bias using a funnel plot and Egger’s test.

Data synthesis

If more than one study is identified for a given option, and if combining studies is appropriate, we will use RevMan 5.3 to perform meta‐analyses (RevMan 2014). We will pool data from RCTs using a fixed‐effect model, except when heterogeneity is found. We will pool continuous data using the SMD measure, if more than one instrument is used to measure the same outcome.

We will consider the psychometric properties of the outcome instruments with regard to their suitability for pooling. For meta‐analyses of the primary outcome (tinnitus loudness), whenever studies report outcomes measured by more than one instrument, data will be included only when those instruments are known to measure the same underlying construct of tinnitus loudness (high convergent validity) and show a similar direction of treatment‐related effect. We will take the same approach for secondary outcomes.

Subgroup analysis and investigation of heterogeneity

If sufficient data are available, we will carry out subgroup analyses. This will be restricted to a very small number of subgroups and we will perform a significance test for interaction with the treatment effect. We will clearly specify the boundaries for defining inclusion and exclusion in advance, and for age we will consider whether specifying a cut‐off of 16 or 18 years has an effect on the findings. The planned subgroups are defined by:

  • age (children < 16 or 18 years and adults ≥ 16 or 18 years);
  • duration of tinnitus (acute ≤ 3 months and chronic > 3 months);
  • dose of betahistine administered (minimum daily dose of 8 mg to a maximum of 148 mg);
  • additional interventions (betahistine with and without an additional intervention).

Sensitivity analysis

We will conduct a sensitivity analysis by excluding those studies with a high risk of bias, thereby checking the robustness of the conclusion from the studies included in the meta‐analysis. In addition, we will use sensitivity analyses for studies in which data were imputed.

GRADE and ‘Summary of findings’ table

Two independent authors (IW and IS) will use the GRADE approach to rate the overall quality of evidence using GRADEpro GDT (https://gradepro.org/). The quality of evidence reflects the extent to which we are confident that an estimate of effect is correct and we will apply this in the interpretation of results. There are four possible ratings: high, moderate, low and very low. A rating of high quality of evidence implies that we are confident in our estimate of effect and that further research is very unlikely to change our confidence in the estimate of effect. A rating of very low quality implies that any estimate of effect obtained is very uncertain.

The GRADE approach rates evidence from RCTs that do not have serious limitations as high quality. However, several factors can lead to the downgrading of the evidence to moderate, low or very low. The degree of downgrading is determined by the seriousness of these factors:

  • study limitations (risk of bias);
  • inconsistency;
  • indirectness of evidence;
  • imprecision; and
  • publication bias.

We will include a ‘Summary of findings’ table, constructed according to the recommendations described in Chapter 11 of the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011), for the following comparison(s):

  • betahistine versus placebo;
  • betahistine versus no intervention; and
  • betahistine versus education and information only.

We will include the following outcomes in the ‘Summary of findings’ table:

  • tinnitus loudness;
  • significant adverse events (tinnitus exacerbation);
  • tinnitus symptom severity;
  • other adverse effects (upper gastrointestinal discomfort, headache and allergic skin reactions);
  • depressive symptoms; and
  • symptoms of generalised anxiety.

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