Scoping a suite of priority reviews ... - Cochrane ENT



Scoping a suite of priority reviews: Subjective tinnitusMagdalena Sereda 1,2*, Don McFerran 3, Emma Axon 4, David M Baguley 1,2,5, Deborah A Hall 1,2,5,6, Iskra Potgieter 1,2, Rilana Cima 7,8, Samantha Cox 9, Derek J Hoare 1,21 National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Ropewalk House, 113 The Ropewalk, Nottingham, UK2 Hearing Sciences, Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, UK3 East Suffolk and North Essex NHS Foundation Trust, Colchester General Hospital, Turner Road, Colchester, UK 4 Cochrane Skin, Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK5 Nottingham University Hospitals NHS Trust, Queens Medical Centre, Derby Road, Nottingham, UK6 University of Nottingham Malaysia, Jalan Broga, 43500 Semeniyh, Selangor Darul Ehsan, Malaysia7 Maastricht University, Department of Clinical Psychological Science, Maastricht, Netherlands8 Adelante, Centre for Expertise in Rehabilitation & Audiology, Hoensbroek, Limburg, Netherlands9 Cochrane ENT, Nuffield Department of Surgery, University of Oxford, Oxford, UKExecutive summaryA scoping exercise was conducted to prioritise new or updated evidence syntheses on treatment interventions for subjective tinnitus in children and adults. Specifically, the objective was to scope and catalogue (1) what evidence exists for the effectiveness of tinnitus interventions, and (2) which tinnitus interventions are a priority for inclusion in future systematic (particularly Cochrane) reviews. We conducted searches for Randomised Controlled Trials (RCTs) in the Cochrane ENT Trials Register. For each intervention we recorded whether there were existing RCTs, how many, and whether they were included in existing Cochrane reviews. The interventions were prioritised for systematic review according to a set of pre-defined primary and secondary criteria. In the UK, there are commissioning guidelines for tinnitus services for adults (Department of Health, 2009) but no current evidence-based clinical practice guidelines. However, two national guidelines are in development by the National Institute for Health and care Excellence (NICE), and the British Society of Audiology (BSA), and a multidisciplinary pan-European guideline for diagnostics, assessment and treatment of tinnitus was recently published (Cima et al. 2019). A national guideline for the assessment, diagnosis, and management of subjective tinnitus in children also exists. This practice guidance by the British Society of Audiology (2015) offers a pragmatic approach to the management of tinnitus in children up to the age of 16 years. There is currently no singularly effective treatment for tinnitus, rather, various management strategies are used and trialled. Those include pharmacology-based interventions, sound-based interventions, psychology-based interventions, magnetic stimulation, electrical stimulation, manual physical therapy, relaxation therapy, complementary and alternative therapies, education and information, self-help interventions, and combinations of two or more approaches (complex interventions). At the time of the scoping exercise there were 10 published Cochrane reviews on tinnitus: Tinnitus Retraining Therapy (TRT), Cognitive Behavioural Therapy (CBT), anticonvulsants, repetitive Transcranial Magnetic Stimulation (rTMS), antidepressants, sound therapy (masking), Ginkgo biloba, hyperbaric oxygen (for idiopathic sudden sensorineural hearing loss and tinnitus), and amplification with hearing aids. A further eight protocols for systematic reviews in tinnitus had been published: neuromodulation (desynchronisation), neurophysiological model-based treatments, Cognitive Behaviour Therapy, glutamate receptor antagonists, and melatonin. Eight Cochrane reviews were assessed as having outdated methods. The number of records included in each Cochrane review was between one and eight. Our searches identified 365 new (i.e. not included in published Cochrane reviews) RCTs. Those included 158 trials of pharmacological interventions, 43 trials of sound-based interventions, 39 trials of psychological interventions, 24 trials of complex interventions, 41 trials of magnetic stimulation, 23 trials of electrical stimulation, five trials of manual-physical therapy, 18 trials of relaxation therapy, 56 trials of alternative and complementary therapies, eight trials of education and information, and one trial of self-help intervention. Based on the pre-defined priority criteria, three high priority reviews in tinnitus were identified: 1) Sound therapy using amplification devices and/or sound generators; 2) Betahistine, and 3) Cognitive Behaviour Therapy. Further priorities were: 1) Gingko biloba, 2) Anxiolytics, 3) Hypnotics, 4) Antiepileptics, and 5) Neuromodulation. 1. The remitA review of the evidence for all treatment interventions for children and/or adults with subjective tinnitus. 2. Background 2.1 Description of the conditionTinnitus is described as the perception of the sound in the absence of an external sound source (Jastreboff and Hazell 2004). Commonly reported tinnitus sensations include ringing, hissing, buzzing, or whooshing. Tinnitus can be objective or subjective. Objective tinnitus usually has an underlying physical cause such as blood flow or muscle movement (Roberts et al. 2010) and can be heard by an examiner. The underlying cause of objective tinnitus is often treatable. However, objective tinnitus is rare. Subjective tinnitus can only be heard by the person experiencing it, and it cannot be attributed to a physical sound source or cause. This form of tinnitus is much more common than objective tinnitus. This scoping review focuses on subjective tinnitus only, hereafter simply referred to as ‘tinnitus’. 2.2 Epidemiology and patient burden Tinnitus is a symptom experienced by 5.1-42.7% of adults (McCormack et al. 2016), and across studies 3.0-30.7% of adults experience tinnitus as bothersome and negatively affecting quality of life (McCormack et al. 2016). Problems associated with tinnitus include sleep disturbances, hearing difficulties, difficulties with concentration, social isolation, anxiety, depression, and emotional difficulties such as irritation or stress (Davis and El Refaie 2000). It is estimated that the prevalence of tinnitus in those adults seeking medical help for hearing problems is as high as 85% (Meikle and Taylor-Walsh 1984; Axelsson and Ringdahl 1989; Davis and El Refaie, 2000). In England the incidence of bothersome tinnitus that leads individuals to seek additional resources from within the NHS health care system is 5.4 (CI = 5.3-5.5) new cases of significant tinnitus per 10,000 person-years (Martinez et al. 2015). The incidence rate does not appear to depend on gender but increases with age, peaking at 11.4 (CI = 11.0-11.8) per 10,000 in those aged 60-69 years (Martinez et al., 2015). This equated to approximately 0.75 million GP consultations each year where the primary complaint is tinnitus (El‐Shunnar et al. 2011). The average cost to the NHS of tinnitus treatment per patient per year is GB?717, adding up to an annual NHS expenditure of GB?750M. The annual societal costs were estimated to be ?2.7 billion (Stockdale et al. 2017). Tinnitus therefore represents a major financial burden on the NHS and society.Epidemiological data on tinnitus in children suggests that the incidence is similar to that in adults (Nemholt Rosing et al. 2016). Generally, children do not spontaneously complain about tinnitus. This may be because the child with tinnitus considers the noise to be normal, that it has always been there. They are unlikely to associate their tinnitus with problems they may be experiencing because of it. 2.3 Current practiceIn the UK, there are commissioning guidelines for tinnitus services for adults (Department of Health 2009) but no current evidence-based clinical practice guidelines. However, two national guidelines are in development by the National Institute for Health and care Excellence (NICE), and the British Society of Audiology (BSA), and a multidisciplinary pan-European guideline for diagnostics, assessment and treatment of tinnitus was recently published (Cima et al. 2019). The latter was produced by a working group of the EU COST action TINNET (tinnet.). A systematic review identified all national guidelines which make recommendations on the assessment, diagnosis, and management of subjective tinnitus in adults (i.e., people aged 16 years or older; Fuller et al. 2017a). Only clinical guidelines from Denmark, Germany, Sweden, The Netherlands, and the United States met these inclusion criteria. The review found agreement across the guidelines in recommending audiometric assessment, physical examination, use of a standardised questionnaire(s) to assess tinnitus-related distress, referral to a psychologist when required, cognitive behavioural treatments, and use of hearing aids in instances of hearing loss. There was also consistent recommendation against the use of prescribed medicines. There was less agreement on the use of imaging in assessment procedures, and the use of sound therapy. To our knowledge, only one national guideline for the assessment, diagnosis, and management of subjective tinnitus in children has been published. This practice guidance by the British Society of Audiology (2015) offers a pragmatic approach to the management of tinnitus in children up to the age 16. The guidance promotes a holistic approach to care involving the child, parents, and the child’s school.We note that existing guidelines are restricted to high-income countries. However, the levels of commonality between those guidelines offers the potential for relevance to other countries where clinical guidelines do not yet exist, should the health care system be adequate to support the recommended care pathway. The uptake of country-specific guidance is unknown, but is likely to be variable (Hoare et al. 2012a).2.4 Description of tinnitus interventions includedThere is currently no singularly effective treatment for tinnitus, rather, various interventions are used and trialled. Those include pharmacology-based interventions, sound-based interventions, psychology-based interventions, magnetic stimulation, electrical stimulation, manual physical therapy, relaxation therapy, complementary and alternative therapies, education and information, self-help interventions, and combinations of two or more approaches (complex interventions). Pharmacology-based interventionsCurrently there are no curative pharmacological treatments for tinnitus. For the purpose of this scoping review, trials of the effects of drugs on tinnitus are collated according to the World Health Organization Collaborating Centre for Drug Statistics Methodology Anatomical Therapeutic Chemical (ATC) Classification System (). In the ATC classification system, active substances are grouped according to the organ or system on which they target and their therapeutic, pharmacological and chemical properties:Alimentary tract and metabolismDrugs for functional gastrointestinal disordersAntiemetics and antinauseantsVitamins – Ascorbic acid (vitamin C)Vitamins – other plain vitamin preparationsVitamins – B-complex, including combinationsMineral supplements – Zinc Mineral supplements – MagnesiumBlood and blood forming organsAntithrombotic agentsAntianemic preparations Cardiovascular systemAntiarrhytmicsPeripheral vasodilatorsLipid modifying agentsOther cardiac preparations Genito-urinary system and sex hormonesUterotonicsUrologicalsMusculo-skeletal systemAnti-inflammatory and antirheumatic productsMuscle relaxantsNervous systemAnesthetics - General anestheticsAnesthetics - Local anestheticsAntiepilepticsAnti-parkinson drugsPsycholeptics - AntipsychoticsPsycholeptics - AnxiolyticsHypnotics and sedativesPsychoanaleptics - AntidepressantsPsychostimulants and nootropicsAnti-dementia drugsOther nervous system drugs – Drugs used in addictive disordersAntivertigo preparationsCombinations of medicationsRespiratory systemRespiratory stimulantsSystemic hormonal preparations, excluding sex hormones and insulinsPituitary and hypothalamic hormones and analoguesCorticosteroids for systemic useVariousMedical gases - OxygenNon-classified medications (i.e. experimental)Sound-based interventionsElectronic devices are used to amplify external sounds (e.g. hearing aids) or to produce sounds for therapeutic use. Suggested benefits of sound-based interventions include making tinnitus less audible (masking, reducing contrast between external environment and tinnitus), providing distraction from tinnitus, promoting relaxation, providing ‘sound enrichment’ (stimulation to the central auditory system to compensate for the loss of auditory stimulation due to hearing loss), and reversing pathological changes in the central auditory system caused by hearing loss (Henry et al. 2008; Newman and Sandridge 2012). Examples include:Acoustic Coordinated Reset NeuromodulationAmplification only devices Auditory trainingCombination devices (i.e. combined amplification and sound generators)Phase-tailored sound treatmentSound generators only devices (sometimes referred to as ‘maskers’)Spectrally-tailored sound treatmentPsychology-based interventions‘Talking’ or ‘thinking-based’ treatments are used to help people cope with or overcome how tinnitus makes them feel or behave (Thompson et al. 2017). Examples include:Cognitive/Behavioural approaches Client centered counsellingMagnetic stimulationInterventions using strong magnetic fields aim to suppress activity or reverse maladaptive neuroplastic change in the central auditory system. Examples include:Transcranial Magnetic StimulationElectrical stimulationInterventions using electrical stimuli aim to suppress neural activity or reverse maladaptive neuroplastic change in the central auditory system. Examples include:Cochlear implantsTranscranial Alternating Current Stimulation (tACS)Transcranial Direct Current Stimulation (tDCS)Transcutaneous electrical stimulation Vagus nerve stimulation Manual physical therapyManual physical therapy involves use of hands-on techniques, including but not limited to manipulation or mobilisation of joints (Cherkin et al. 1998). For tinnitus, this may be relevant where there is dysfunctions of the cervical spine or the temporomandibular joint (TMJ). Examples include:Cervical Spine treatmentMyofascial trigger point deactivation Temporomandibular Joint treatment Relaxation therapyRelaxation therapy involves use of technique that helps a person to reduce muscle tension and stress; to attain a state of increased calmness; or otherwise reduce blood pressure, level of pain, anxiety, or anger they are experiencing. It may relaxation therapies use guided imagery (focusing the mind on positive images) or meditation (focusing thoughts) and may involve tensing and relaxing muscles throughout the body (Carmen and Svihovec 1984; Weber et al. 2002). Examples include:Biofeedback/neurofeedbackHypnosis/hypnotherapyRapid or progressive muscle relaxationComplementary and alternative therapiesComplementary and alternative therapies are defined as “treatment…which complements mainstream medicine by contributing to a common whole, by satisfying a demand not met by orthodoxy or by diversifying the conceptual frameworks of medicine.” (Ernst et al. 1995). Put simply, complementary and alternative therapies are used in addition to or instead of traditional healthcare interventions. Examples include:AcupunctureDietary supplements and herbal remediesEar magnetsLaser treatmentOzoneUltrasoundVibratory stimulation Virtual realityEducation and informationInformation and educational interventions typically includes explanation that tinnitus is a symptom not a dangerous disease, explanation of association between tinnitus and hearing loss, education about lifestyle factors that may have positive and negative effects on tinnitus and explanation of available management strategies (Thompson et al. 2017). Self-help interventionsSelf-help interventions involve working through a set of therapeutic materials either unguided’ or with minimal guidance from a therapist. Interventions can be delivered using printed books, the internet, computer packages, DVDs, or smartphone applications (Greenwell et al. 2016). Examples also include: Support groups (Professional or peer support organisations)Complex interventionsMany approaches to tinnitus management includes a combination of two or more interventions delivered as a programme or package of care, e.g. combined use of psychological therapy and sound devices. Examples include: Heidleberg Neuro-Music TherapyPerceptual/Cognitive trainingProgressive Tinnitus ManagementTinnitus Retraining Therapy3. MethodsA scoping review was undertaken to answer two questions:(1) What evidence exists for the effects of tinnitus interventions?(2) Which tinnitus interventions are a priority for updates of existing or production of new Cochrane systematic review?3.1 Databases/Search strategyWe searched for RCTs, using the methods for scoping searches of the Cochrane ENT Trials Register (via the Cochrane Register of studies). Searches were conducted in July 2017. There were no language, publication year or publication status restrictions. Results were narrowed by (a) by screening for ‘randomized’ and (b) screening for records that mentioned ‘tinnitus’ in the title. The strategy was run in the Cochrane ENT Register using:1 MESH DESCRIPTOR Tinnitus EXPLODE ALL AND INREGISTER2 tinnit* AND INREGISTER3 #1 OR #2 AND INREGISTER4 randomized AND INREGISTER5 (tinnit*):TI,TO AND INREGISTER6 #3 AND #4 AND #5 AND INREGISTERFor this scoping search, the decisions were based on the assumptions that (1) modern, well-conducted RCTs will mention randomisation, (2) studies assessing an intervention aimed at treating tinnitus will mention tinnitus in the title, and (3) the aim of the tinnitus scoping project was to identify new RCTs for each of the interventions of interest, in order to assess the potential value of new or updated reviews on these interventions. The aim of the searches was not to comprehensively identify all potential RCTs for inclusion in future new or updated Cochrane reviews, but to estimate the amount of new evidence available to enable prioritisation of these reviews and to aid in the design of a template protocol, and to estimate the volume of work required to conduct the proposed reviews. Any new or updated Cochrane review will require full, up to date searches across the wide range of databases that we search as standard for our systematic reviews.3.2 Selection of studiesThree authors (MS, DHo, DHa) independently screened all abstracts to determine eligibility for inclusion in the review. Records were carried forward for full screening if at least one of the authors requested it. We considered multiple records reporting the same study together as a single record. Disagreements were discussed between authors until a consensus was reached. Records were considered for inclusion according to PICOS:Population: Children and/or adults with subjective tinnitus Intervention: Any interventions for subjective tinnitus (please see 2.4)Comparator: No intervention (e.g. waiting list), other intervention, placeboOutcome: Any outcome Study design: Randomised controlled trials only.3.3 Data extraction Data were extracted using a data extraction form which was designed specifically for the review, piloted on a subset of records, and revised before formal data extraction was undertaken. Data were extracted on population, intervention, comparator, outcomes or outcome measures used, and study design. All extracted data were verified by at least one other author. 3.4 Where is the evidenceFor each intervention, we recorded whether there were existing RCTs, the number of RCTs, comparisons and whether they were included in existing Cochrane reviews. Trials of interventions not yet subject to a Cochrane review were also identified. 3.5 PrioritisationFour main criteria were identified to aid prioritisation decisions. These were: Whether the intervention is available for tinnitus management within the NHS,Whether the intervention is within the scope of the NICE tinnitus guidelines that are currently in development,Whether there was ‘No recommendation’ or disagreement in recommendations in current management guidelines,Whether existing Cochrane systematic reviews concluded there was a lack of evidence, but new RCTs are now available or there is no Cochrane review.The following secondary criteria were considered in addition:Whether the intervention had been prioritised in the James Lind Alliance Priority Setting Partnership for tinnitus as a ‘top 10’ uncertainty,The number of new RCTs identified, Whether interventions are referred to in the TINNET European clinical practice guideline,Whether there is evidence for variability in clinical practice, within or across countries.When judging whether a Cochrane systematic review is ready to be updated, we first considered the date of the literature search and whether ongoing studies were identified in the review. Both these pieces of information indicate that there may be new research which may alter the estimates of effect or the quality of the evidence in the review (via GRADE assessments), and hence the conclusions drawn. Other methodological aspects of the systematic reviews were assessed such as: whether a PRISMA diagram was included; whether the latest risk of bias tool was used; whether a summary of findings table was included; whether GRADE was used to assess the quality of evidence; whether the assessed outcomes included measures of benefits and harms of the intervention; and whether the review included all of the methods sections recommended by Cochrane. All methodological considerations, and the importance of the review to key stakeholders were considered together in prioritising updated and new systematic reviews. 4. ResultsFiltered scoping searches identified 1080 records. Based on title/abstract screening 731 records were selected for full text screening by at least one of the authors. Further 315 records were excluded that were duplicates (n=127), out of scope (n=11), not randomised (n=86), conference abstracts with no results published (n=70), abstracts/full texts requiring translation (Chinese, Japanese, Swedish, Spanish; n=15). Nine abstracts/full texts were not available. An additional 24 records were then identified from lists of references of systematic reviews bringing the overall number of records for data charting to 437. Among those, 365 records were identified that were new (not covered in existing Cochrane reviews) RCTs with published results and data regarding PICOS were extracted from those records. In addition, 51 unpublished registered randomised trials were identified and data regarding PICOS and trial status were extracted.Figure 1. Flow diagram illustrating search strategy and scoping review stages4.1 Pharmacology-based interventionsAlimentary tract and metabolismDrugs for functional gastrointestinal disordersFour RCTs investigated the effects of drugs for functional gastrointestinal disorders; one trial of papaverine (Polanski et al. 2016) and three trials of caroverine (Denk et al. 1997; Mahendru et al. 2013; Schwab et al. 2004; Table 1). Additionally, one registered trial comparing caroverine to placebo was identified; however, that trial was suspended due to recruitment failure (EUCTR2009-018046-38). Table 1. Trials of drugs for functional gastrointestinal disordersInterventionCochrane systematic reviewNumber of trials included in the Cochrane reviewNumber of new potentially eligible trials identifiedComparisons in new studiesDrugs for functional gastrointestinal disordersNoNA4See belowCaroverineNoNA3- caroverine vs placebo;- caroverine vs betahistine;- caroverine vs lidocaine;- caroverine vs L-glutamate diethyl ester (GDEE);- caroverine vs glutamatePapaverineNoNA1- papaverine hydrochloride plus vitamin E vs placebo;- papaverine hydrochloride plus vitamin E vs Ginkgo biloba extract; - papaverine hydrochloride plus vitamin E vs alpha-lipoic acid plus vitamin CAntiemetics and antineuseantsOne RCT was identified which compared the serotonin antagonist ondasteron to placebo (Taslimi et al. 2013).Vitamins – Ascorbic acid (vitamin C)One RCT was identified comparing a combination of vitamin C and alpha-lipoid acid with Ginkgo biloba to papaverine hydrochloride with vitamin E (Polanski et al. 2016).Vitamins – other plain vitamin preparationsOne trial examined the effects of nicotinamide (vitamin B3) compared to placebo (Hulshof & Vermeij 1987). Another trial examined the effects of a combination of pyridoxine (vitamin B6) and flunarizine compared to betahistine mesilate and flunarizine hydrochloride (Ma et al., 2006). Vitamins – Vitamin B-complex, including combinationsTwo trials of vitamin B-complex (Markou et al. 2001; 2004) were identified, One trial compared the effects of vitamin B-complex with trimetazidine or prednisolone, and one compared the effects of a combination of vitamin B-complex with other drugs (trimetazidine, prednisolone) compared to trimetazidine and piracetam plus prednisolone. Mineral supplements – ZincThe current Cochrane review of zinc supplementation for tinnitus included three trials involving 209 participants which yielded moderate to high risk of bias and provided no evidence that the use of oral zinc supplementation improves symptoms in adults with tinnitus (Person et al. 2016). No new published or ongoing trials of zinc for tinnitus were identified. Mineral supplements – MagnesiumOne registered trial with published results compared effects of magnesium to placebo (NCT01273883).Blood and blood forming organsAntithrombotic agentsFour RCTs trialled antithrombotic agents; two examined enoxaparin (Mora et al. 2003; 2006), one examined sulodexide (Neri et al. 2009a,b ; Table 2), and one examined the platelet aggregation inhibitor cilostazol (Lim et al. 2016). One further registered trial of sulodexide comparing to placebo was identified (NCT02737670). Table 2. Trials of antithrombotic agentsInterventionNumber of potentially eligible trials identifiedComparisons in new studiesAntithrombotic agents4See belowEnoxaparin 2- sodium enoxaparin vs corticosteroids, vasoactive agents, multivitamins (A, E, B-complex), and anticoagulants;- hemofiltration and subcutaneous sodium enoxaparin vs cortisone, vasoactive agents, and vitamin complexes administered intravenouslySulodexide 1- sulodexide and melatonin vs no treatmentCilostazol1- cilostazol vs placeboAntianemic preparationsTwo RCTs examining the effects of vitamin B12 (Singh et al. 2016; Wang et al. 2008) were identified. One trial compared vitamin B12 to placebo and one compared vitamin B12 at acupoint injection with intramuscular injection of vitamin B12.Cardiovascular systemAntiarrhytmicsEleven trials of antiarrhythmics were identified (Table 3). Ten investigated the effects of the class Ib antiarrhythmics mexiletine or tocainide (Blayney et al. 1985; Cathcart 1982; Emmett & Shea 1980; Hulshof & Vermeij 1984; Hulshof & Vermeij 1985; Kay 1981; Lenarz 1986; Lenarz & Gülzow 1985a, 1985b; McCormick & Thomas 1981). One trial investigated the effects of the class Ic antiarrhythmic flecainide (Fortnum & Coles 1991). Table 3. Trials of antiarrhythmicsInterventionNumber of new potentially eligible trials identifiedComparisons in new studiesAntiarrhythmics, class Ib10See belowMexiletine2– mexiletine vs placebo (2 records); - mexiletine vs betahistine;- mexiletine vs diazepam Tocainide8– tocainide vs placebo– tocainide vs placebo (6 records); - tocainide vs lidocaine;– tocainide vs microcrystalline cellulose (placebo?);- tocainide vs lidocaine (2 records)Antiarrhythmics, class Ic1See belowFlecainide1- flecainide vs placeboPeripheral vasodilatorsFour RCTs of peripheral vasodilators were identified (Table 4). Two reported on the purine derivative pentoxifylline (Salama et al. 1989; Schwab et al. 1998), and two reported the effects of the peripheral vasodilators cyclandelate (Hester et al. 1998) and naftidrofuryl (Gutmann & Mees 1995). Table 4. Trials of peripheral vasodilatorsInterventionNumber of new potentially eligible trials identifiedComparisons in new studiesPeripheral vasodilators – purine derivatives2See belowPentoxifilline2- pentoxifilline vs placebo; - hydroxyethyl starch and pentoxifylline vs hyperbaric oxygen;Other peripheral vasodilators2See belowCyclandelate1- cyclandelate vs placeboNaftidrofuryl1- naftidrofuryl vs piracetamOne further registration was found for a trial comparing the Ginkgo Biloba extract, EGb 761? plus pentoxifylline placebo to pentoxifylline plus EGb 761? placebo (ISRCTN68772788). Lipid modifying agentsOne RCT of β-Hydroxy β-methylglutaryl-CoA (HMG CoA) reductase inhibitor atorvastatin compared to placebo was identified (Olzowy et al. 2007). Other cardiac preparationsThree RCTs trialling trimetazidine were identified (Kumral et al. 2016; Markou et al., 2004, 2001). Comparisons were: a) trimetazidine and placebo), b) trimetazidine and prednisolone, c) trimetazidine and vitamin B, d) trimetazidine versus trimetazidine plus prednisolone plus vitamin B complex versus prednisolone plus vitamin B complex versus piracetam plus prednisolone.Genito-urinary system and sex hormonesUterotonicsThree RCTs of prostaglandins were identified. All three compared misoprostol to placebo (Briner et al. 1993; Akkuzu et al. 2004; Yilmaz et al. 2004). UrologicalsTwo RCTs of drugs used in erectile dysfunction were identified (Ogawa et al. 2002; Mazurek et al. 2009). One compared prostaglandin E1 and hydrocortisone with placebo and hydrocortisone, and the other compared vardenafil to placebo.Musculo-skeletal systemAnti-inflammatory and antirheumatic productsOne RCT comparing azapropazone (non-steroid anti-inflammatory and antirheumatic agent) to placebo was identified (Stoney et al. 1991). Muscle relaxantsOne RCT of the peripherally acting muscle relaxant botulinum toxin, compared to saline injection (Stidham et al. 2005), and one trial of the centrally acting muscle relaxant baclofen compared to placebo (Westerberg et al. 1996) were identified. Nervous system Anesthetics - General anestheticsThree RCTs examining the effects of the general anaesthetic esketamine (AM-101) were identified. All three trials compared AM-101 to placebo (Muehlmeier et al. 2011; Staecker et al. 2015; Staecker et al. 2017; van de Heyning et al. 2014). In addition, one trial registration was identified comparing AM-101 to placebo (NCT02040194). AM-101 will likely be one of the compounds included in an ongoing Cochrane review of glutamate receptor antagonists for tinnitus (Imsuwansri et al., 2016). Anaesthetics - Local anaestheticsSixteen RCTs of local anaesthetics were identified (Table 5). Amongst those, 15 studies investigated the effect of lidocaine (Baguley et al. 2005; Canlu et al. 2008; den Hartigh et al. 1993; Duckert & Rees 1983; Emmett & Shea 1983; Israel et al. 1982; Hulshof & Vermeij 1984; Kallio et al. 2008; Lenarz 1985, 1986, Lenarz & Gülzow 1985a, 1985b; Martin & Colman 1980; Perucca & Jackson 1985; Reyes et al. 2002; Schwab et al. 2004), and one study examined ropivacaine (Kallio et al. 2008). Two further registered trials were identified, one examining Eutectic Mixture of Local Anesthetics (EMLA) 5% Cream (NCT02266160) and one examining lidocaine (NCT02750969).Table 5. Trials of local anaestheticsInterventionNumber of new potentially eligible trials identifiedComparisons in new studiesLocal anaesthetics16See belowLidocaine15– lidocaine vs placebo (11 records);– lidocaine vs tocainide ( 4 records)– lidocaine vs saline (2 records);– lidocaine vs ropivacaine;– Vitamin B12 and lidocaine injection at the Yifeng point vs Vitamin B12 only;– Lidocaine vs Glutamate; - lidocaine vs L-glutamate diethyl ester (GDEE);- lidocaine vs caroverine Ropivacaine1- Lidocaine vs ropivacaineAntiepileptic drugsEleven trials of antiepileptic drugs were identified (Table 6). Among those, five studies investigated the benzodiazepine, clonazepam (Lechtenberg & Shulman 1983; Bumby & Stephens 1997; Bahmad et al. 2006; Meeus et al. 2011; Han et al. 2012), six studied the carboxamide derivatives carbamazepine (Gerami et al. 2013; Lechtenberg and Shulman 1983; Mashali et al. 2016; She et al. 2008; She et al. 2009) and oxcarbazepine (Gerami et al. 2013), one studied the barbiturate, primidone (Castagno 1989), and two investigated gabapentin, classified as ‘other antiepileptics’ (Bahmad et al. 2006; Dehkordi et al. 2011). Table 6. Trials of antiepileptic drugsInterventionCochrane systematic reviewNumber of trials included in the Cochrane reviewNumber of new potentially eligible trials identifiedComparisons in new studiesAntiepilepticsYes711See belowCarbamazepineYes25- carbamazepine vs active placebo; - carbamazepine vs diazepam; - carbamazepine vs flurazepam; - carbamazepine vs oxazepam; - carbamazepine vs clonazepam;- carbamazepine vs prednisolone (2 records); - carmazepine vs dexamethasone (2 records);- carbamazepine vs placebo (2 records);- carbamazepine vs oxcarbazepine;- carbamazepine vs betahistineClonazepamYes05- clonazepam vs active placebo; - clonazepam vs cinnarizine (active placebo);- clonazepam vs placebo;- clonazepam vs diazepam; - clonazepam vs flurazepam; - clonazepam vs carbamazepine; - clonazepam vs oxazepam;- clonazepam vs placebo; - clonazepam and gabapentin vs placebo; - clonazepam vs clonazepam and gabapentin;- clonazepam vs Ginkgo biloba (2 records);- Deanxit and clonazepam (Rivotril) vs Placebo and clonazepam (Rivotril)GabapentinYes32- clonazepam and gabapentin vs placebo; - clonazepam and gabapentin vs clonazepam;- gabapentin vs placeboOxcarbazepineYes01- oxcarbazepine vs placebo;- oxcarbazepine vs carbamazepinePrimidoneYes01- primidone vs placebo;- primidone vs cinnarizineThe existing Cochrane review of antiepileptics (anticonvulsants) for tinnitus included seven trials with 453 patients (Hoekstra et al. 2009). Different anticonvulsants were assessed in different studies. Three studies investigated the effect of gabapentin, two of carbamazepine, one – of lamotrigine, and one of flunarizine. All studies were placebo-controlled. Authors concluded that the current evidence for effectiveness of anticonvulsants for tinnitus carried significant risk of bias. Authors concluded that there was a small positive effect for treatment of tinnitus. They stated that this small effect was of ‘doubtful clinical significance’. According to the ACT classification, flunarizine, included in the Cochrane review, is actually classified as an anti-vertigo preparation, and not an antiepileptics drug so is reported as such in this scoping review.Anti-Parkinsons drugsTwo RCTs of dopamine agonists were identified: pramipexole compared to placebo (Sziklai et al. 2011) and piribedil compared to placebo (de Azevedo et al. 2009). Psycholeptics – AntipsychoticsTwo RCTs of the benzamide dopamine antagonist, sulpiride were identified (Lopez-Gonzalez et al. 2007a; Lopez-Gonzalez et al. 2007b; Table 7). Table 7. Trials of antipsychoticsInterventionNumber of new potentially eligible trials identifiedComparisons in new studiesSulpride2- sulpiride vs placebo (2 records);- sulpride plus hydroxyzine vs placebo; - sulpiride vs sulpiride plus hydroxyzine;- sulpiride plus melatonin vs placeboPsycholeptics – AnxiolyticsEight RCTs of anxiolytics were identified (Table 8). Three trialled benzodiazepine derivatives including alprazolam (Johnson et al. 1993; Jalali et al. 2009; Shim et al. 2011), two diazepam (Kay 1981; Lechtenberg & Shulman 1983) and two oxazepam (Holgers et al. 2011; Lechtenberg & Shulman, 1983). One trial examined the diphenylmethane derivative hydroxyzine (Lopez-Gonzalez et al., 2007b).Table 8. Trials of anxiolyticsInterventionNumber of new potentially eligible trials identifiedComparisons in new studiesAnxiolytics - Benzodiazepine derivatives8See belowAlprazolam3- alprazolam vs placebo;- alprazolam vs active placebo;- alprazolam orally vs alprazolam orally and intratympanic dexamethasone injections; - alprazolam orally vs intratympanic dexamethasone injections plus intravenous lipo-prostaglandin E1; - alprazolam orally and intratympanic dexamethasone injections vs alprazolam orally vs intratympanic dexamethasone injections plus intravenous lipo-prostaglandin E1Diazepam2- diazepam vs placebo; - diazepam vs active placebo;- diazepam vs mexiletine; - diazepam vs betahistine;- diazepam vs flurazepam;- diazepam vs carbamazepine;- diazepam vs oxazepam; - diazepam vs clonazepamOxazepam2- oxazepam vs active placebo; - oxazepam vs diazepam; - oxazepam vs flurazepam; - oxazepam vs carbamazepine; - oxazepam vs clonazepam; - sertraline plus oxazepam vs placeboAnxiolytics - Diphenylmethane derivativesHydroxyzine1- sulpride plus hydroxyzine vs placebo; - sulpride plus hydroxyzine vs sulprideHypnotics and sedativesEight RCTs of hypnotics and sedatives were identified including the benzodiazepine flurazepam (Lechtenberg & Shulman, 1983; Marks et al. 1981), the melatonin receptor agonist melatonin (Albu & Chirtes 2014; Hurtuk et al. 2011; Lopez-Gonzalez et al. 2007b; Neri et al. 2009a; Rosenberg et al. 1998;) and the barbiturate, amylobarbitone sodium (Marks et al. 1981; Table 9). Table 9. Trials of hypnotics and sedativesInterventionNumber of new potentially eligible trials identifiedComparisons in new studiesHypnotics and sedatives – Barbiturates 1See belowAmobarbital1- amylobarbitrone sodium vs placebo; - amylobarbitrone sodium vs carbamazepineHypnotics and sedatives – benzodiazepine derivatives2See belowFlurazepam2flunazepam vs active placebo; flunazepam vs diazepam; flunazepam vs carbamazepine; flunazepam vs oxazepam; flunazepam vs clonazepamHypnotics and sedatives – melatonin receptor agonists5See belowMelatonin5- melatonin vs placebo (2 records);- melatonin vs no treatment; - melatonin plus sulodexide vs no treatment;- melatonin vs melatonin and sulodexide;- melatonin vs melatonin plus dexamethasonePsychoanaleptics - AntidepressantsThe existing Cochrane review of antidepressants identified six trials with 610 patients (Baldo et al. 2006). Different antidepressants were assessed in different trials, with four trials evaluating the effects of three tricyclic antidepressants on tinnitus (amitriptyline (two trials), nortriptyline and trimipramine), one examining a selective serotonin uptake inhibitor (paroxetine) and one examining a serotonin 5-HT2A receptor antagonist (trodazone). Trial quality was reported as ‘generally low’ with only one trial of SSRI judged as high quality. Authors concluded that there is insufficient evidence to say that antidepressant drug therapy improves tinnitus. In line with the above AAO HNS guidelines (Tunkel et al. 2014) recommend against routine recommendation of antidepressants for a primary indication of treating persistent, bothersome tinnitus. It is worth noting that three trials excluded from the Cochrane review might need revisiting due to exclusion criteria that were used at the time. One trial was excluded as the comparison was not a placebo but another drug (Roberts et al. 2011), two were excluded due to high drop-out rate and because nine of the 76 patients receiving the intervention also received an additional drug, and there was high attrition (Zoger et al. 2006; Holgers et al. 2011).Two trials examining the selective serotonin reuptake inhibitor paroxetine were identified (Bilici et al. 2015; Roberts et al. 2011). The first one compared vestipitant plus paroxetine with vestipitant with placebo. The second compared low frequency rTMS, high frequency rTMS, rTMS and paroxetine, sham rTMS with paroxetine alone. Two further registered trials of the selective serotonin reuptake inhibitors fluoxetine and fluvoxamine were identified (ACTRN12613000213741 and IRCT2012101811157N1). Psychostimulants and nootropicsOne RCT comparing cytidine diphosphate to placebo (Makishima et al. 1971) was identified.Anti-dementia drugsSix new trials of anti-dementia drugs were identified examining memantine and Ginkgo biloba. One trial compared memantine to placebo (Figueiredo et al. 2008). Five new trials of Gingko biloba were identified (Han et al. 2012; Kim et al. 2015; Morgenstern & Biermann 2002; Olivier & Plath 1993; Polanski et al. 2016). The effects of Gingko biloba were compared to: i) placebo (2 records), ii) clonazepam (2 records), iii) papaverine hydrochloride plus vitamin E, iv) alpha-lipoic acid plus vitamin C and Korean Red Ginseng. One trial compared Ginkgo biloba plus laser with Ginkgo biloba plus placebo laser. One study (Morgenstern & Biermann, 2002) was excluded from the Cochrane review, however the reason for exclusion was high attrition, which is not in line with current Cochrane methods. Two ongoing trials involving EGb 761? were identified (ISRCTN38408464 and ISRCTN68772788). The existing Cochrane review on Ginkgo biloba included four trials with 1543 participants showed no evidence for effectiveness for tinnitus as a primary complaint (Hilton et al. 2004).Other nervous system drugs – Drugs used in addictive disordersThree RCTs examined the anti-addiction drug acamprosate (Azevedo & Figueiredo 2005; Sharma et al. 2012; Sharmendra et al. 2014). In addition, one trial registration was identified (NCT00596531) comparing acamprosate to placebo. The ongoing Cochrane review of glutamate receptor antagonists (Imsuwansri et al. 2016) will likely include trials of acamprosate. Table 10. Trials of drugs used in addictive disordersInterventionNumber of new potentially eligible trials identifiedComparisons in new studiesAcamprosate3- acamprosate vs placebo;- TRT plus acamprosate vs TRT.Antivertigo preparationsEleven RCTs examining antivertigo preparations were identified. Six trials examined betahistine (Kay 1981; Ma et al. 2006; Mahendru et al. 2013; Mashali et al. 2016; Ngao et al. 2014; S?nmez et al. 2013), two flunarizine (Hulshof & Vermeij 1986; Ma et al. 2006) and three cinnarizine (Bumby & Stephens 1997; Castagno 1989; Podoshin et al. 1991). Table 11. Trials of antivertigo preparationsInterventionNumber of new potentially eligible trials identifiedComparisons in new studiesAntivertigo preparations11See belowBetahistine6- betahistine vs placebo (2 records);- betahistine vs no treatment- betahistine vs mexiletine;- betahistine vs diazepam;- betahistine mesilate and flunarizine hydrochloride vs vitamin B6 and flunarizine hydrochloride;- betahistine vs caroverine;- betahistine vs carbamazepine; - laser plus betahistine vs placebo laser pplus betahistine.Cinnarizine 3- cinnarizine vs placebo; - cinanrizine vs clonazepam;- cinnarizine vs biofeedback vs acupuncture vs placebo biofeedbackFlunarizine2- flunarizine vs placebo; - flunarizine hydrochloride plus betahistine mesylate vs flunarizine hydrochloride plus Vitamin B6Combinations of medicationsOne RCT examined Deanxit? which is a combination of the antipsychotic flupentixol and the non-selective monoamine reuptake inhibitor melitracen (Meeus et al. 2011), comparing Deanxit? plus clonazepam with placebo plus clonazepam. Respiratory systemRespiratory stimulantsOne RCT examined almitrine-raubasine combination (Dauman et al. 1995) and compared it to placebo.Systemic hormonal preparations, excluding sex hormones and insulinsPituitary and hypothalamic hormones and analoguesOne RCT of the posterior pituitary lobe hormone oxytocin (Azevedo et al. 2017) comparing oxytocin with placebo) was identified. Corticosteroids for systemic useTen RCTs of glucocorticoids were identified of which seven trialled dexamethasone (Albu & Chirtes 2014; Araújo et al. 2005; Lee et al. 2017; Parelkar et al. 2015; She et al. 2008, 2009; Shim et al. 2011), four prednisolone (Markou et al.2004, 2001; She et al. 2008, 2009), one hydrocortisone (Ogawa et al., 2002) and one triamcinolone acetonide (Diao et al. 2013; Table 12).Table 12. Trials of corticosteroids for systemic useInterventionNumber of new potentially eligible trials identifiedComparisons in new studiesGlucocorticoids13See belowDexamethasone7- dexamethasone vs saline injection (placebo?; 2 studies);- dexamethasone vs placebo (2 records);- dexamethasone vs carmazepine; - dexamethasone vs prednisolone;- alprazolam orally vs alprazolam orally plus intratympanic dexamethasone injections;- alprazolam orally vs alprazolam orally plus intratympanic dexamethasone injections plus intravenous lipo-prostaglandin E1;- alprazolam orally plus intratympanic dexamethasone injections vs alprazolam orally plus intratympanic dexamethasone injections plus intravenous lipo-prostaglandin E1;- dexamethasone plus melatonin vs melatonin;- dexamethasone vs carbamazepinePrednisolone4- prednisolone vs trimetazidine; - prednisolone vs vitamin B;- prednisole vs carbamazepine;- prednisole vs dexamethasone;- prednisolone plus vitamin B complex vs piracetam plus prednisolone vs trimetazidine plus prednisolone plus vitamin B complex vs trimetazidineHydrocortisone1- prostaglandin E1 and hydrocortisone vs placebo and hydrocortisoneTriamcinolone 1- Triamcinolone acetonide vs saline (placebo?)VariousMedical gases - OxygenTwo RCTs were identified (Porubsky et al. 2007; Stiegler et al. 2006). Both trials compared two treatment protocols, namely hyperbaric oxygen at 2.2 Bar with hyperbaric oxygen at 2.5 Bar.The existing Cochrane review of Hyperbaric Oxygen Therapy (HBOT) reviewed the treatment of idiopathic sudden sensorineural hearing loss and tinnitus (Bennett et al. 2012). It included seven trials with 392 participants. Most trials concentrated on hearing loss and did not report outcomes for tinnitus. Only two trials reported mean improvement in tinnitus score and one trial reported proportion of participants with improvement in tinnitus. However, the pooled analysis of improvement in tinnitus score was not possible due to lack of sufficient data reporting. Authors concluded that there is no evidence of a beneficial effect of HBOT on tinnitus and they did not recommend the use of HBOT for this purpose. Experimental drugs not included in the ATC ClassificationAmino-oxyacetic acid Two RCTs examined amino-oxyacetic acid (Guth et al. 1990; Reed et al. 1985) and compared it to placebo. This experimental drug prevents the metabolism of GABA.GlutamateOne trial examined glutamate and compared glutamate with lidocaine, glutamate with L-glutamate diethyl ester (GDEE) and glutamate with caroverine (Schwab et al. 2004). Neramexane Neramexane is an experimental drug for dementia and addiction and is an NMDA antagonist similar to memantine. Three RCTs examined neramexane (Suckfull et al. 2011; MRZ 92579/TI/3002; MRZ 92579 – 0508 /1). In addition, three trial registrations were identified, all comparing neramexane with placebo (JapicCTI-111648, NCT00739635 and NCT00772980. Two registrations (NCT00739635 and NCT00772980) may be registrations for the same trial taking place at different study sites. Nerve growth factorTwo trials examining nerve growth factor were identified (Wang et al. 2008; Zhou et al. 2009). Selurampanel One RCT compared selurampanel (a competitive antagonist of AMPA and kainate receptors) with placebo (NCT01302873). Vestipitant One RCT compared vestipitant (a selective antagonist of neurokinin 1 receptors that has been trialled as an antiemetic and anxiolytic) (Roberts et al. 2011) to placebo, vestipitant plus paroxetine to placebo, and vestipitant to vestipitant and paroxetine.4.2 Sound-based interventionsThe existing Cochrane review of sound therapy (masking) in the management of tinnitus included RCTs in which management strategy included maskers, noise-generating devices and/or hearing aids, combination hearing aids, Neuromonics Tinnitus Treatment and Tinnitus Masking Therapy both as the only management tool and in combination with other management strategies (e.g. counselling; Hobson et al. 2010). Six trials with 553 participants were included. Risk of bias was assessed as medium in three and high in three trials. Considerable variability in study design, tinnitus evaluation methods, and outcome measures did not allow for performing meta-analysis. Although the review specifies ‘masking’ as the main purpose of the sound therapy none of the studies were excluded based on this criterion. For example one of the included trial that evaluated the Neuromonics Tinnitus Treatment - a protocol that incorporates the principle of systematic desensitisation through structured rehabilitation programme. The authors concluded the lack of strong evidence for efficacy of sound therapy in tinnitus management. However, they stressed the lack of evidence in this case is not equivalent to lack of effectiveness. Also, sound therapy is the first line of tinnitus management in many countries including the UK and was judged to be safe. One reason for the lack of evidence identified by authors was application of combined approaches in many of the studies (e.g. TRT). Historically, sound was used to mask tinnitus, i.e. reduce perceived loudness of tinnitus or make tinnitus inaudible (Hoare et al. 2014a), which would be in line with the Cochrane systematic review title and scope. However, current views on sound therapy acknowledge that masking is only one of the goals of sound therapy, alongside achieving tinnitus relief (i.e. reduction in tinnitus annoyance), providing distraction from tinnitus, aiding relaxation etc. (Henry et al. 2008). This can be achieved without achieving complete or even partial masking of tinnitus. Different sound therapy options postulate different mechanisms via which tinnitus relief can be achieved, therefore it would be justified to look at different sound therapy options separately. This approach has already been adapted and separate Cochrane review was conducted looking specifically at amplification for tinnitus (Hoare et al. 2014b). Acoustic Coordinated Reset (CR) NeuromodulationTwo RCTs have trialled Acoustic CR Neuromodulation treatment for tinnitus and compared it to placebo stimulation (Hoare et al. 2013; NCT01541969 - result available); Tass et al. 2012). However, as the postulated mechanism of action of this intervention is to change the abnormal synchronous activity in the brain that leads to tinnitus it will be one of the management options included in the ongoing neuromodulation review (Hoare et al. 2015). One further trial comparing Acoustic CR Neuromodulation to CBT is ongoing and recruiting participants (NCT03022084).Amplification only devicesThe existing Cochrane review on amplification with hearing aids included one trial with 91 participants comparing hearing aid use to sound generator use (Hoare et al. 2012). Lack of evidence to support or refute hearing aid use as a more routine intervention for tinnitus was concluded. Eight randomised trials examining hearing aids were identified. It is worth noting however, that all eight trials seem to use comparisons that do not represent controls. Namely, one trial compared tDCS or sham tDCS followed by hearing aids (Shekhawat et al. 2014; both groups received amplification), one trial compared hearing aids with or without frequency compression (Hodgson et al. 2017; both groups received amplification), one trial compared extended wear hearing aids with conventional hearing aids (Henry et al., 2017a), one compared open moulds vs pressure-vented moulds (Munhoes dos Santos Ferrari et al. 2007), one trial examined combination aids and sound generators with betahistine; (Oz et al. 2013) and three trials compared combined amplification and sound generation with amplification only (dos Santos et al. 2014 a,b; Henry et al. 2015; Henry et al. 2017a; both groups received amplification). In addition, one record examined motivational interviewing during hearing aid fitting versus conventional hearing rehabilitation (Zarenoe et al. 2016). One trial (Melin et al. 1987) was identified that was excluded from the Cochrane review of amplification with hearing aids for tinnitus because it lacked a usable outcome measure. This can no longer be used as an exclusion criterion so in an updated version of this Cochrane review this exclusion would need to be bination devices (i.e. combined amplification and sound generators)Five RCTs trialled combined amplification and sound generation for tinnitus, either with both options being available within one device or through wireless streaming (dos Santos et al. 2014 a,b; Henry et al. 2015; Henry et al. 2017a; Oz et al., 2013; Searchfield et al. 2016).Table 13. Trials of combination devicesInterventionCochrane systematic reviewNumber of trials included in the Cochrane reviewNumber of new potentially eligible trials identifiedComparisons in new studiesSound therapyYes6Combination aidsYes25- combination hearing aids or sound generators plus betahistine vs betahistine alone;- amplification with noise vs amplification only (2 records);- hearing aids connected to Apple iPod Shuffles with 3D masking vs hearing aidsconnected to Apple iPod Shuffles with equal masking;- hearing aids connected to iPod Shuffles with 3D masking vs Tinnitus Retraining Therapy;- combination aids vs extended wear hearing aids;- combination aids vs hearing aids.Phase-tailored sound treatmentPhase-shift therapy postulates to provide relief from tinnitus through residual inhibition. One trial examined Phase-shift sound therapy comparing it to pure-tone stimulus (Heijneman et al. 2012). Sound generators only devices (sometimes referred to as ‘maskers’)The searches identified 15 published RCTs trialling various types of sound generators (Attias et al. 1993; Dineen et al. 1997; Dineen et al. 1999; Durai & Searchfield 2017; Goebel et al. 1999; Heijneman et al. 2012; Henry et al. 2016; Hiller & Haerk?tter 2005; Jakes et al. 1992; Oz et al. 2013; Theodoroff et al. 2017; Tian et al. 2017; Tyler et al. 2012; Vanneste et al. 2013a; Zhong et al. 2014). Five further registered trials were identified (NCT01177137, NCT01480193, NCT01487447, NCT00578058, NCT02774122). Table 14. Trials of sound generatorsInterventionCochrane systematic reviewNumber of trials included in the Cochrane reviewNumber of new potentially eligible trials identifiedComparisons in new studiesSound therapyYes6Sound generators (various types)Yes615 (plus 5 ongoing trials)- CBT or Tinnitus Education and white noise generators vs CBT or tinnitus education alone;- pure-tone stimulus vs Phase-shift Sound Therapy;- counseling plus bilateral noise generators set to completely mask the tinnitus vs counselling; - counseling plus bilateral noise generators with a focus on the mixing point vs counselling;- counseling plus bilateral noise generators set to completely mask the tinnitus vs counseling plus bilateral noise generators with a focus on the mixing point;- nature sounds via mp3 player vs broadband noise via mp3 player;- combination hearing aids or sound generators plus betahistine vs betahistine alone;- pure broadband Noise Generator Therapy vs Tinnitus Retraining Therapy (TRT);- pure broadband Noise Generator Therapy vs Tinnitus Coping Therapy;- pure broadband Noise Generator Therapy vs waiting list control;- Masking vs Self-hypnosis;- Masking vs attentiveness to patients' complaints;- tinnitus-matched stimulus (Otoharmonics levo system) vs noise stimulus (Otoharmonics levo system);- CBT vs masking therapy;- group cognitive therapy (GCT) vs GCT plus masker- aural masker vs group GCT;- aural masker vs placebo masker;- GCT plus masker vs aural masker;- GCT plus masker vs placebo masker;- aural masker vs waiting list;-GCT plus masker vs waiting list;- tinnitus-matched stimulus (Otoharmonics levo system) vs bedside sound generator;- noise stimulus (Otoharmonics levo system) vs bedside noise generator;- analogous sound masking vs notched music;- Tinnitus Retraining Therapy vs Tinnitus Masking;- CBT plus white noise vs information vs information vs CBT plus white noise plus information vs information plus relaxation;- Tinnitus Masking vs tinnitus educational counseling (and hearing aids if needed);- Tinnitus Masking vs 6-month-wait-list controlSpectrally-tailored sound treatmentOne RCT compared tailor-made notched music with sound masking (Tian et al. 2017). Vanneste et al. (2013a) trialled music to provide enriched acoustic environment and prevent maladaptive neuroplastic changes that might lead to tinnitus. They provided music spectrally tailored to compensate for hearing loss or music tailored to overcompensate for hearing loss and compared it to unmodified music. Li et al. (2017) examined altered classical music (based on tinnitus characteristics) and compared it with unaltered classical music.Auditory trainingFour RCTs examined auditory training (Herraiz et al. 2010; Hoare et al. 2012b; Hoare et al. 2014c; Tugumia et al. 2016). Herraiz et al. (2010) compared auditory discrimination training in the same frequency of tinnitus pitch or around frequency of tinnitus pitch but not the same frequency with waiting list control and other auditory discrimination training protocols. Hoare et al. (2012) compared frequency discrimination training with a pure-tone standard at a frequency within the region of normal hearing to a pure-tone standard within the region of hearing loss or to a high-pass harmonic complex tone spanning a region of hearing loss. In another study Hoare et al. (2014) compared interactive game-based frequency discrimination training to conventional task-based training. Tugumia et al. (2016) compared auditory training with visual training.4.4 Psychology-based interventionsCognitive-Behavioural Therapy (CBT)The existing Cochrane review of CBT for tinnitus includes eight trials including 486 participants (Martinez‐Devesa et al. 2010). The review found that for subjective tinnitus loudness (their primary outcome) there was no evidence of a difference between CBT and no treatment or another treatment (yoga, education and 'minimal contact - education'). However, quality of life scores (secondary outcome measure) were improved for CBT when compared to no treatment or another intervention (education and 'minimal contact education') and depression scores improved when comparing CBT to no treatment. There was no evidence of improvement in depression scores when comparing CBT to other treatments (yoga, education and 'minimal contact - education'). There is a published protocol for a revised Cochrane review of CBT for tinnitus (Fuller et al. 2017b). This review will examine all interventions for tinnitus that include cognitive, behavioural or combination of those elements. Those would include Acceptance and Commitment Therapy (ACT) and Mindfulness-based therapies, described as different ‘waves’ of CBT. For the purpose of this scoping review we included all studies using cognitive and/or behavioural approaches to treatment. Thirty-three relevant records were identified (Abbott et al., 2009; Andersson et al. 2002; Arif et al. 2017; Beukes et al. 2017; Davies et al. 1995; Henry & Wilson 1996; Henry & Wilson 1998; Hesser et al. 2012; Hesser et al. 2014; Hiller & Haerk?tter 2005; Jakes et al. 1992; Jasper et al. 2014; Kaldo et al. 2008; Kreuzer et al. 2012; Krings et al. 2015; Lindberg et al. 1989; Malinvaud et al. 2016; McKenna et al. 2017; Nyenhuis et al. 2013; Philippot et al. 2012; Rheker et al. 2015; Robinson et al. 2008; Scott et al. 1985; Tucker 2013; Weise et al. 2016; Westin et al. 2011; Wise et al. 1998; Zachriat & Kr?ner-Herwig 2004; Zenner et al., 2013; Zhong et al. 2014; NCT00724152; NCT01229709). Among those were trials of therapy delivered either face-to-face in individual or group settings, internet-delivered therapy, and bibliotherapy. Twenty trials specifically examined the effects of CBT, three ACT, and six Mindfulness-based therapy. Seven trials examined either behavioural or cognitive elements of CBT. Three registered trials with unpublished results have been identified (NCT02293512, NCT02665975, NCT03022084). According to the inclusion criteria of the new CBT protocol (Fuller et al. 2017b), all identified trials are likely to be included. CounsellingTwo RCTs examined counselling (Argstatter et al. 2007; Henry et al., 2016). Henry et al. (2016) compared tinnitus education and counselling (control group) with TRT or Tinnitus Masking or waiting list control. Argstatter et al. (2007) compared tinnitus counselling (control group) to Music Therapy according to Heidelberg Model. One registered trial was identified comparing tinnitus counselling (control) to Mindfulness Based Tinnitus Reduction (NCT01229709).4.5 Complex interventionsHeidleberg Neuro-Music TherapyTwo RCTs examined Neuro-Music Therapy according to Heidelberg model (Argstatter et al. 2007; Argstatter et al. 2015). One trial compared this therapy to tinnitus counselling and one compared this therapy combined with counselling to counselling alone. Perceptual/cognitive trainingFour RCTs examined various types of cognitive/perceptual training (Eysel-Gosepath et al. 2004; Spiegel et al. 2015; Wise et al. 2016; Kallogjeri et al. 2017). Eysel-Gosepath et al. (2004) compared distraction and relaxation training with auditory perception training based on TRT. Kallogjeri et al. (2017) compared the Brain Fitness Programme (auditory processing speed, discriminating sounds, sound precision, sound sequencing, working memory, narrative memory) with no treatment group. Spiegel et al. (2015) examined the effects of multisensory attention training and compared integration (attempting to reduce salience to tinnitus by binding with multisensory stimuli) with attention diversion (multisensory stimuli opposite side to tinnitus) training. Wise et al. (2016) compared effects of an attention training game with a control game. Progressive Tinnitus ManagementFour RCTs of Progressive Tinnitus Management (PTM) were identified (Henry et al. 2017b; NCT01015781; NCT00371436; NCT01129141). Two trials compared PTM with waiting list control, one with usual care, and one trial compared telephone-delivered PTM for patients with tinnitus and traumatic brain injury with waiting list control. Tinnitus Retraining TherapyThe existing Cochrane review of TRT (Phillips & McFerran 2010b) included one trial with 123 participants. The trial showed that TRT was more effective than Tinnitus Masking therapy. Three RCTs were excluded as they followed a modified TRT protocol, however one might argue that the scope of this review can be widened to include modified TRT protocols (Caffier et al. 2006; Goebel et al. 1999; Schmitt et al. 2002). The Cochrane review of TRT also identified two ongoing trials potentially eligible for inclusion (NCT00578058; NCT00124800). However, one of those trials has not been published and the other one was quasi-randomised. Our searches identified seven RCTs examining TRT or modified-TRT in addition to those in the previous Cochrane review (Eysel-Gosepathet al. 2004; Henry et al. 2007; Seydel et al. 2010; Sharmendra et al. 2014; Tyler et al. 2012; Westin et al. 2011; Zachriat & Kroner Herwig 2004). It is beyond the scope of the current review to differentiate records as TRT or modified-TRT. Tyler et al. (2012) compared different elements and approaches included in TRT, namely comparing counselling only element of the TRT with counselling plus bilateral noise generators set to completely mask the tinnitus, or counselling plus bilateral noise generators with a focus on the mixing point (partial masking just below total masking) (Tyler et al. 2012). Another study looking at structured counselling included in TRT approach compared educational counselling with traditional support and no treatment (Henry et al. 2007). Seydel et al. (2010) compared effects of modified TRT and compared it with waiting list control (Seydel et al. 2010). Three studies compared TRT approaches to different cognitive-behavioural approaches namely Zachriat et al. (2004) compared effects of habituation-based treatment based on Jastreboff with cognitive-behavioural tinnitus coping training (Zachriat et al. 2004) and Westin et al. (2011) compared TRT with ACT (Westin et al. 2011). One study compared auditory perception training based on TRT with distraction and relaxation training (Eysel-Gosepath et al. 2004), and one TRT with TRT plus acamprosate (Sharmendra et al. 2014). Two registered trials were identified. One examined TRT and compared to TRT plus EGb 761? (ISRCTN38408464 347). However that trial was stopped due to participant recruitment issues. Another compared different elements of TRT: tinnitus specific educational counselling and placebo sound generators with full TRT and standard care (Scherer et al. 2014).VariousThree RCTs compared combined approaches of psychological and other management strategies. Heinecke et al. (2009) compared manual-based psychological treatment especially developed for tinnitus sufferers (15 sessions of CBT combined with psychophysiological treatment using biofeedback) with a waiting list control. Weise et al. (2007) compared effects of cognitive behavioural strategies with biofeedback with waiting list. Cima et al. (2012) compared specialised care CBT with sound-focused TRT with usual care model. Two further registered trials have been identified, one examining a bimodal treatment involving TRT with EMDR compared to TRT with CBT (NCT03114878, recruiting participants), and the other examining sound based and educational therapies, integrated medicine therapies and a combination of both (NCT01480193).4.6 Magnetic stimulationTranscranial Magnetic Stimulation (TMS)The existing Cochrane review of rTMS (Meng et al. 2011) included five trials with 233 participants describing different devices delivering different waveforms at different frequencies. Authors concluded very limited support for the use of low-frequency rTMS for the treatment of patients with tinnitus. Short term safety was demonstrated in the studies. However no data were available on the long term safety of rTMS. In addition to those in the previous Cochrane review 29 RCTs examining rTMS were identified (Barwood et al. 2013; Bilici et al. 2015; Chung et al. 2012; Folmer et al. 2015; Forogh et al. 2014; Khedr et al. 2010; Kim et al. 2014; Kleinjung et al. 2005, 2006, Kreuzer et al. 2011, 2015; Landgrebe et al. 2017; Langguth et al. 2004, 2008; Lehner et al. 2016; Mennemeier et al. 2011; Noh et al. 2017; Piccirillo 2016; Piccirillo et al. 2011, 2013; Roland et al. 2016; Rossi et al. 2007; Smith et al. 2007; Thabit et al. 2015; Vanneste & De Ridder 2012; Wobrock et al. 2006; Yilmaz et al. 2014; NRT1293). Among those there were three trials that were excluded from the Cochrane review because they used a cross-over design and one excluded because it did not have a sham stimulation comparator (Khedr et al. 2010; Langguth et al. 2004; Rossi et al. 2007; Smith et al. 2007). According to current Cochrane methodology, those would likely be eligible for inclusion in an updated review. Seven further registered trials were identified (NCT01407133; NCT02071732; NCT02617953; NCT01944501; NCT00926237; NCT02269839; NCT02653547). Other non-repetitive TMS protocols were used in two studies. Scheklmann et al. (2016) compared neuro-navigated continuous theta burst TMS (cTBS) with sham stimulation. Plewnia et al. (2012) compared cTBS above the temporal cortex or temporoparietal cortex to sham stimulation. One registered trial examining deep TMS (dTMS) was identified (NCT02053961). However, this trial status shows as ‘withdrawn’. One registered trial examined deep TMS (dTMS) was identified (NCT02053961). However, this trial status shows as ‘withdrawn’. VariousRoland et al. (1996) examined electromagnetic stimulation of the ear using Therapak' device and compared it to placebo device. Coles et al. (1991) examined the effects of rare-earth magnets placed close to the tympanic membrane and compared this to placebo magnets.4.7 Electrical stimulationCochlear implantThree RCTs examined cochlear implantation (Arts et al. 2016; Liu et al. 2015; van Zon et al. 2016). The first study compared cochlear Implant looped (repeated) electrical stimulation (without environmental sound perception) with cochlear Implant standard stimulation pattern (with environmental sound perception). The second compared cochlear implants with regular programming, to cochlear implants without regular programming. The third trial compared the effects of simultaneous bilateral cochlear implants with unilateral cochlear implants. Cochlear implants are likely to be included in the ongoing Cochrane review of neuromodulation for tinnitus (Hoare et al. 2015).Transcranial Alternating Current Stimulation (tACS)One RCT examined tACS and compared it with tDCS (Vanneste et al. 2013b). As stated in the review protocol tACS is included in the ongoing Cochrane review of neuromodulation for tinnitus (Hoare et al. 2015).Transcranial Direct Current Stimulation (tDCS)Nine RCTs examined tDCS (Cavalcanti et al. 2015; Faber et al. 2012; Forogh et al. 2016; Henin et al. 2016; Pal et al. 2015; Rabau & Van de Heyning 2015; Shekhawat et al. 2014, 2016; Vanneste et al. 2013b). Three trials compared tDCS to sham stimulation, two compared tDCS applied at different areas of the head, one compared tDCS to tDCS combined with usual care or usual care alone, one compared tDCS with transcranial alternating current stimulation (tACS), one compared tDCS with sham tDCS both used in conjunction with hearing aids and one compared tDCS with sham tDCS both used in conjunction with compensatory and non-compensatory auditory stimulation. tDCS is included in the ongoing Cochrane review of neuromodulation for tinnitus (Hoare et al. 2015).Two registered trials were identified (NCT03036137, NCT01575496) both comparing tDCS with sham stimulation, however recruitment status of both studies was unclear.Transcutaneous electrical nerve stimulationTwo RCTs examined transcutaneous electrical nerve stimulation (TENS; Bonaconsa et al. 2010; Lee et al. 2014). One trial compared TENS to sham stimulation and one to osteopathic manipulations. Transcutaneous electrical stimulation is included in the ongoing Cochrane review of neuromodulation for tinnitus (Hoare et al. 2015).Vagus nerve stimulationMei et al. (2014) examined electrical stimulation on acupoint in the distribution area of ear vagus nerve combined with sound masking and compared with flunarizine hydrochloride capsules. Tyler et al. (Tyler et al. 2017) compared vagus nerve stimulation paired with tones (implantable device) with inactive device (no stimulation but device implanted). Vagus nerve stimulation is included in the ongoing Cochrane review of neuromodulation for tinnitus (Hoare et al. 2015).VariousMahmoudian et al. (2013) examined auditory electrical stimulation and compared it to placebo stimulation (device turned off). Stimulation was delivered by inserting active surface tympanic membrane electrode through external auditory canal and electrode on the forehead and filling ear canal with saline solution. Pilgramm et al. (1986) trialled external electrical stimulation via mastoid bones and compared it with waiting list. Engelhard et al. (2014) compared electrical epidural stimulation of the auditory cortex with ‘non-significant stimulation’. According to the published Cochrane protocol of neuromodulation (desynchronisation) for tinnitus (Hoare et al. 2015), all RCTs of electrical stimulation for tinnitus will be included.4.8 Manual physical therapyCervical Spine Treatment One RCT compared manual osteopathic therapy with transcutaneous dynamic electrical stimulation (Bonaconsa et al. 2010) and one compared physical therapy (manual mobilisations, exercise therapy and home exercises) with waiting list control (Michiels et al. 2014). One ongoing trial comparing specific manual therapy with conventional physiotherapy has been identified (NCT02850055). Myofascial trigger point deactivationOne trial examined myofascial trigger point deactivation and compared this to placebo/sham deactivation (Rocha & Sanchez 2012). Temporomandibular Joint Treatment One RCT examined stomatognatic treatment (stabilisation splints, occlusal adjustments, exercise therapy) and compared it to combination of biofeedback and relaxation therapy (Erlandsson et al. 1991). 4.9 Relaxation therapyBiofeedback/NeurofeedbackSeven RCTs examined biofeedback/neurofeedback (Erlandsson et al. 1991; Heinecke et al. 2009; Podoshin et al. 1991; Podoshin et al. 1995; Rief et al. 2005; Weise et al. 2007; White et al. 1986). In some trials biofeedback was combined with psychological therapy (Heinecke et al. 2009; Rief et al. 2005), relaxation training (White et al. 1986; Erlandsson et al. 1991) and/or counselling (Erlandsson et al. 1991; White et al. 1986) making it a complex intervention and therefore potentially difficult to interpret the results in the context of biofeedback alone. Two trials used biofeedback alone (i.e. feedback on muscle tension) (Podoshin et al. 1991, 1995). One registered trial currently recruiting participants is examining Tomographic Neurofeedback (specific localized neurofeedback training) and comparing it to non-Tomographic Neurofeedback (global relaxing neurofeedback training) (NCT02383147).Hypnosis/hypnotherapyThree published RCTs trialling hypnosis/hypnotherapy were identified (Attias et al. 1993; Marks et al. 1985; Mason et al. 1996). One trial compared trance with non-specific hypnosis and with specific hypnosis, one compared hypnotherapy with counselling and one compared self –hypnosis with masking and with attentiveness to patients’ complaints, and one compared combination of hypnosis and self-hypnosis with stress management. RelaxationSeven RCTs examining relaxation or relaxation training were identified (Arif et al. 2017; Dineen et al. 1997; Freidenberg 2004; Ireland et al. 1985; Jakes et al. 1986; McKenna et al. 2017; Philippot et al. 2012). Three trials compared relaxation training with mindfulness, two were trials of Progressive Muscle Relaxation, and one compared information and relaxation training with information only or combination of white noise, information and relaxation. One compared relaxation training with counter-demand instructions or relaxation training with neutral demand instructions with no treatment. One trial examined computer-aided and machine-assisted distraction and relaxation training (DRT). 4.10 Complementary and alternative therapiesAcupunctureThe Cochrane review on acupuncture (Li et al. 2016) was withdrawn in 2016. Twenty-two RCTs examined acupuncture, including manual and electric acupuncture (Axelsson et al. 1994; de Azevedo et al. 2007; Hansen et al. 1981, 1982; Jeon et al. 2012; Kim et al. 2017; Laureano et al. 2016; Li et al. 2013; Marks et al. 1984; Nielsen et al. 1999; Okada et al. 2006; Podoshin et al. 1991; Rogha et al. 2011; Stener-Victorin 2012; Tan et al. 2007; Yugi Doi et al. 2016; Vilholm et al. 1998; Wang et al. 2010; Yang et al. 2012; Yin et al. 2015; Zhou et al. 2015). Four registered trials have been identified (ISRCTN58013563; ISRCTN29230777; Li et al. 2015; Xie et al. 2014). Table 15. Trials of acupunctureInterventionCochrane systematic reviewNumber of trials included in the Cochrane reviewNumber of potentially eligible trials identifiedComparisons in studiesAcupunctureNoNA23- acupuncture vs placebo (12 records);- electrical acupuncture vs placebo (3 records)- verum acupuncture (creating deqi) vs shallow acupuncture(not creating deqi);- manual acupuncture vs electric acupuncture (2 records); - acupuncture vs no treatment- acupuncture vs Chinese herbs;- acupuncture vs Western medicine;- acupuncture at different acupoints;- combined therapy of Zhuang medicine at Qineihuan point combined with the conventional acupuncture vs simple conventional acupuncture; - deep needlingvs shallow needling;- acupuncture vs biofeedback;- acupuncture vs cinnarizine;- conventional acupuncture vs acupuncture aimed at spinal balancing Dietary supplements and herbal remedies One RCT compared alpha-lipoic plus vitamin C with Ginkgo biloba (Polanski et al. 2016). One RCT examined Bu-Zhong-Yi-Qi – Chinese herbal medicine and compared it to acupuncture and western medicine (bandazol, Dextran 40, Danshen tablet, and vitamin B12) (Tan et al. 2007). One RCT examined caffeine with placebo (St.Claire et al. 2010). One RCT compared Gushen Pian - Chinese medicinal herb with placebo (Zhai et al. 2013). One RCT compared Hangekobokuto Japanese herbal medicine with placebo (Ino et al. 2013). Two RCTs examined enzymolyzed, lyophilized powder of honeybee larvae (Aoki et al., 2012; Aoki et al. 2015). One RCT compared effects of Korean Red Ginseng to Ginkgo biloba extract (Kim et al. 2015). One RCT examined manganese and compared manganese and Lipoflavonoid Plus((R)) with Lipoflavonoid Plus((R)) only (Rojas-Roncancio et al. 2016). One trial examined homeopathy (Simpson et al. 1998). Tablets containing sodium salicylate, ascaridole, conine and quinine at homeopathic dilution were compared to placebo tablets.Laser treatmentThe published protocol for a Cochrane review of laser treatment has been withdrawn (Peng et al. 2012).Fourteen RCTs of laser treatment for tinnitus were identified (Cuda & De Caria 2008; Dehkordi et al. 2015; Demirkol et al. 2017; Gungor et al. 2008; Mirvakili et al. 2014; Mirz et al. 1999, 2000; Mollasadeghi et al. 2013; Nakashima et al. 2002; Ngao et al. 2014; Olivier & Plath 1993; Tauber et al. 2003; Teggi et al. 2008; NCT00845975 – results available). Ten of those trials compared laser treatment with placebo/sham (inactive laser), one compared Ginkgo biloba with laser to Ginkgo biloba with placebo laser, one compared counselling with laser to counselling alone, one compared different laser wave lengths, one compared laser with betahistine to placebo laser with betahistine, and one compared treatment with two different laser types. Ozone One RCT comparing ozone treatment with betahistine to no treatment was identified (Sonmez et al. 2013). UltrasoundTwo trials examining ultrasound for tinnitus were identified (Carrick et al. 1986; Rendell et al. 1987). Both studies compared ultrasound device with placebo device.Vibratory stimulation Two RCTs examining combined auditory and somatosensory stimulation for tinnitus were identified (Thomas et al. 1989; NCT02974543- result available). One trial examined vibratory stimulation compared to (1) combined vibratory and sound stimulation (associated with the vibration) to (2) sound stimulation only. The second trial looked at the effects of bimodal auditory-somatosensory stimulation and compared it to unimodal auditory stimulation.Virtual reality One RCT compared Virtual Reality (VR) immersion in auditory and visual 3D environments and compared it to CBT (Malinvaud et al. 2016). 4.11 Education and informationEight RCTs examined information or education (Henry et al. 1996; Dineen et al. 1997; Zachriat et al. 2004; Hiller & Haerkotter 2005; Abbott et al. 2009; Nyenhuis et al. 2013; Tucker 2013; NCT00724152-results available). Dineen et al.(1997) trialled different approaches to tinnitus management and compared information about tinnitus with information and white noise or Information and relaxation training or information and white noise and relaxation training. Abbott et al. (2009) compared information only programme (serving as a control) to CBT. Nyenhuis et al. (2013) compared information-only control condition with cognitive-behavioural intervention (delivered as Internet self-management, bibliotherapy or group training). Henry et al. (1996) compared education only with cognitive coping skills training or waiting list control. Hiller and Haerkotter (2005) looked at effects of sessions focussing on education either with or without noise generators. Tucker (2013) compared effects of tinnitus workshops (tinnitus education, relaxation exercise techniques, a distraction exercise and educational sleep hygiene) with CBT in patients with cochlear implants and tinnitus. Zachriat and Kroner-Herwig (2004) compared educational intervention with habituation-based treatment or tinnitus coping training. One trial (NCT00724152, results posted) compared Tinnitus Education (Tinnitus education and skills related to attention control, sleep hygiene and relaxation training such as imagery techniques) with CBT or with standard care (audiological measurement and brief education during the standard care appointment). 4.12 Self-help interventionsSupport Groups (Professional or peer support organisations)One trial compared effects of web-based discussion forum (control condition) with iCBT or group CBT (Jasper et al. 2014). 4.13 Summary of existing Cochrane reviewsAt the time of this scoping exercise there were 10 published Cochrane reviews (Baldo et al. 2012; Bennett et al. 2012; Hilton et al. 2013; Hoare et al. 2014a; Hobson et al. 2012; Hoekstra et al. 2011; Martinez‐Devesa et al. 2010; Meng et al. 2011; Person et al. 2016; Phillips & McFerran 2010a; Table 17) published in The Cochrane Library. The interventions reviewed were Tinnitus Retraining Therapy (TRT), Cognitive Behavioural Therapy (CBT), anticonvulsants, repetitive Transcranial Magnetic Stimulation (rTMS), antidepressants, sound therapy (masking), Ginkgo biloba, hyperbaric oxygen (for idiopathic sudden sensorineural hearing loss and tinnitus), and amplification with hearing aids. A further eight protocols for systematic reviews have been published (Table 16). Five were protocols for reviews in progress, the protocols plan to review neuromodulation (desynchronisation), neurophysiological model-based treatments, CBT, glutamate receptor antagonists, and melatonin (Ajayi et al. 2014; Fuller et al. 2017b; Hoare et al. 2015; Imsuwansri et al., 2016; Phillips & McFerran, 2010b). The other three published protocols (reviews of acupuncture, low-level laser therapy, and an overview of systematic reviews of interventions) were withdrawn before the reviews were conducted or completed (Li et al. 2016; Maldonado Fernández et al. 2015; Peng et al. 2014). Eight Cochrane reviews were assessed as having outdated methods. The protocol for neurophysiological-based treatments for tinnitus (Phillips and McFerran, 2010a) planned to include unmodified and modified TRT, meaning it would constitute an update to the TRT review. However, the status of the new review is not clear. Methods in this protocol were judged as needing updating. The review of zinc supplementation was judged as up-to-date and the methods robust (Person et al. 2016). The review of amplification with hearing aids was judged to have up-to-date methods such that the decision to update would depend on whether additional RCTs were identified. The number of records included in each Cochrane review was between one and eight. Table 16. List of published Cochrane systematic reviews in tinnitus with decision to updateRecordSearch dateNumber of records/ Ongoing studiesDecision to updatePerson et al. Zinc supplementation for tinnitus. 2016.July 20163/0NO - methods are robust and search date is recent. No ongoing studies identified.Phillips et al. Tinnitus Retraining Therapy (TRT) for tinnitus. 2010August 20091/2YES - (if the topic is clinically important). Search and methods are dated. Two ongoing studies foundHobson et al. Sound therapy (masking) in the management of tinnitus in adults. 2012February 20126/0YES - (if the topic is clinically important). Search and methods are dated. No ongoing studies identifiedHoare et al. Amplification with hearing aids for patients with tinnitus and co-existing hearing loss. 2014August 20131/1UNCLEAR - could be updated if clinically important as one ongoing study was identified Meng et al. Repetitive transcranial magnetic stimulation for tinnitus. 2011May 20115/6YES - (if the topic is clinically important). Search and methods are dated. Six ongoing studies found. Martinez-Devesa et al. Cognitive behavioural therapy for tinnitus. 2010May 20108/2YES - (if the topic is clinically important). Search and methods are dated. Two ongoing studies found so may be worth updating. Hilton et al. Ginkgo biloba for tinnitus. 2013March 20124/0YES - (if the topic is clinically important). Search and methods are dated. No ongoing studies were found so may not be a fast-moving field. Hoekstra et al. Anticonvulsants for tinnitus. 2011May 20107/0YES - (if the topic is clinically important). Search and methods are dated. No ongoing studies found so may not be a fast-moving field. Baldo et al. Antidepressants for patients with tinnitus. 2012January 20126/0YES - (if the topic is clinically important). Search and methods are dated. No ongoing studies were found so may not be a fast-moving field. Bennett et al. Hyperbaric oxygen for idiopathic sudden sensorineural hearing loss and tinnitus. 2012May 20127/2YES - (if the topic is clinically important). Search and methods are dated. Two ongoing studies identified.Table 17. List of published protocols for Cochrane systematic reviews RecordStatusHoare et al. Neuromodulation (desynchronisation) for tinnitus in adults. 2015OngoingPhillips et al. Neurophysiological model-based treatments for tinnitus. 2010Ongoing (?) – protocol published in 2010 but no review published. The methods do need updating – so potentially needs a new protocol if this topic is still clinically relevant.Fuller et al. Cognitive behavioural therapy for tinnitus. 2017bOngoingImsuwansri et al. Glutamate receptor antagonists for tinnitus. 2016OngoingAlayi et al. Melatonin for tinnitus. 2014Ongoing (?) – protocol published in 2014. Some methods need updating (e.g. GRADE). Maldonado et al. Interventions for tinnitus in adults: an overview of systematic reviews. 2017The overview was withdrawn in 2017. The full reason for withdrawal is not clear. Li et al. Acupuncture for tinnitus. 2016The review was withdrawn in 2016 for not meeting the deadline. If the review is still clinically important then the methods will need updating. Peng et al. Low-level laser therapy for tinnitus. 2014The review was withdrawn in 2014 because the review authors were unable to complete. If the review is still clinically important then the methods will need updating. 4.14 Summary of priority criteriaSummary of interventions with ratings according to the primary and secondary criteria for prioritisation. To aid prioritisation decisions, four primary criteria were considered, in the order 1. Whether the intervention is available for tinnitus management within the NHS; 2. Whether the intervention is within the scope of the NICE tinnitus guidelines that are currently in development; 3. Whether there was ‘no recommendation’ or disagreement in recommendations across current management guidelines; and 4. Whether existing Cochrane systematic reviews concluded there was a lack of evidence, but new RCTs are now available or there is no Cochrane review.In addition, four secondary criteria consider 5. Whether the intervention has been prioritised in the James Lind Alliance Priority Setting Partnership for tinnitus as a ‘top 10’ uncertainty; 6. The number of new RCTS identified; 7. Whether interventions are referred to in the TINNET European clinical practice guideline; and 8. Whether there is evidence for variability in clinical practice, within or across countries. Primary criteriaSecondary criteriaIntervention1. NHS2.NICE3. Recommendations4. Cochrane5. JLA6. RCTs7. TINNET8. VariabilityPharmacological approaches - Alimentary tract and metabolismDrugs for functional gastrointestinal disordersXXVNAV4XVAntiemetics and antinauseantsVXVNAV1XVVitamins – Ascorbic acid (vitamin C)XXVNAV1VVVitamins – other plain vitamin preparationsXXVNAV2VVVitamins – Vitamin B-complex, including combinationsXXVNAV2VVMineral supplements – ZincXXVXV0VVMineral supplements – MagnesiumXXVNAV1VVPharmacological approaches - Blood and blood forming organsAntithrombotic agentsVXVNAV5XVAntianemic preparationsXXVNAV2Vvitamin B12VPharmacological approaches - Cardiovascular systemAntiarrhytmicsVXVNAV11XVPeripheral vasodilatorsVXVNAV5XVLipid modifying agentsXXVNAV1XVOther cardiac preparationsVXVNAV3XVPharmacological approaches - Genito-urinary system and sex hormonesUterotonicsXXVNAV3XVUrologicalsXXVNAV2XVPharmoacological approaches - Musculo-skeletal systemAnti-inflammatory and antirheumatic productsVXVNAV1XVMuscle relaxantsXXVNAV1XVPharmacological approaches – Nervous systemAnesthetics - General anestheticsXXVongoingV4XVAnesthetics - Local anestheticsVXVNAV18XVAntiepilepticsVXVVV11VbenzodiazepinesVAnti-parkinson drugsVXVNAV2XVPsycholeptics - AntipsychoticsVXVNAV2XVPsycholeptics - AnxiolyticsVXVNAV8XVHypnotics and sedativesVXVVmelatoninV8VmelatoninVPsychoanaleptics - AntidepressantsVXVXV4VVPsychostimulants and nootropicsVXVNAV1XVAnti-dementia drugsVXGinkgo bilobaVVV6VVOther nervous system drugs – Drugs used in addictive disordersXXVongoingV3XVAntivertigo preparationsVVbetahistineVNAV11XVCombinations of medicationsXXVNAV1XVPharmacological approaches – respiratory system Respiratory stimulantsVXVNAV1XVPharmacological approaches - Systemic hormonal preparations, excluding sex hormones and insulinsPituitary and hypothalamic hormones and analoguesXXVNAV1XVCorticosteroids for systemic useVXVNAV10XVPharmacological approaches – VariousMedical gases - OxygenVXVVV2XVPharmacological approaches - Non-classified medications (i.e. experimental)Amino-oxyacetic acidXXVNAV2XVGlutamateXXVNAV1XVNermaexaneXXVNAV6XVNerve growth factorXXVNAV2XVDextran 40XXVNAV1XVSelurampanelXXVNAV1XVVestipitantXXVNAV1XVSound-based interventionsAcoustic CR NeuromodulationXVtinnitus reprogrammingVongoing3VVAmplification only devicesVVVVV8VVCombination devices (i.e. combined amplification and sound generation)VVVVV5VVPhase-tailored sound treatmentXXVNAX1XVSound generators only devices (sometimes referred to as ‘maskers’)VVVVX20VVSpectrally-tailored sound treatmentXXVVX3VVAuditory trainingXVtinnitus reprogrammingVNAX4XVPsychology-based interventionsCognitive/Behavioural approachesVVXongoingV36VVCounsellingVVXNAX3VVComplex interventionsHeidleberg Neuro-Music TherapyXXVNAX2XVPerceptual/Cognitive trainingXXVNAX4XVProgressive Tinnitus ManagementXVcombined sound therapy & counsellingVNAX4XVTinnitus Retraining TherapyXVVongoingX9VVVarious – CBT plus biofeedback XXVNAX2XVVarious - CBT plus TRT (Cima)XXVNAX1XVMagnetic stimulationTranscranial Magnetic StimulationXXVVX39VVVarious - electromagnetic stimulation of the earXXVNAX1XVVarious – ear magnetsXXVNAX1XVElectrical stimulationCochlear implantsXXVongoingX3VVTranscranial Alternating Current Stimulation (tACS)XXVongoingX1VVTranscranial Direct Current StimulationXXVongoingX11VVTranscutaneous electrical stimulationXXVongoingX2XVVagus nerve stimulationXXVongoingX2VVVarious – electrical stimulation of the ear (tympanic membrane) XXVongoingX1XVVarious – electrical stimulation via mastoid bonesXXVongoingX1XVVarious – electrical epidural stimulation of the cortexXXVongoingX1XVManual physical therapyCervical Spine TreatmentVXVNAX2XVMyofascial trigger point deactivationXXVNAX1XVTemporomandibular joint treatmentVXVNAX1XVRelaxation or stress managementBiofeedback/ NeurofeedbackXXVNAX8XVHypnosis/ hypnotherapyXXVNAX3XVRelaxationVXVNAX7XVComplementary and alternative therapiesAcupunctureXXVNA V26VVDietary supplements and herbal remedies – Alpha lipoic acidXXVNAV1VVDietary supplements and herbal remedies – Bu-Zhong-Yi-QiXXVNAV1VVDietary supplements and herbal remedies –CaffeineXXVNAV1VVDietary supplements and herbal remedies – Gushen PianXXVNAV1VVDietary supplements and herbal remedies – HangekobokutoXXVNAV1VVDietary supplements and herbal remedies – Honeybee larvaeXXVNAV2VVDietary supplements and herbal remedies – Korean Red GinsengXXVNAV1VVDietary supplements and herbal remedies – ManganeseXXVNAV1VVDietary supplements and herbal remedies – HomeopathyXXVNAV1VVLaser treatmentXXVNAV14XVOzoneXXVNAV1XVUltrasoundXXVNAV2XVVibratory stimulationXXVNAV2XVVirtual realityXXVNAV1XVEducation and informationEducation and informationVVXNAX8XVSelf-help interventionsSupport groupsVVVNAX1XVX : not meeting the criterion, V: meeting the criterion5. Prioritisation based on scoping evidence 5.1. High priority reviewsSound therapy using amplification devices and/or sound generators for tinnitusSound therapy meets the first three primary priority criteria, the existing Cochrane reviews concluded a lack of evidence of clinical effectiveness (Hoare et al. 2014a, Hobson et al. 2012) and new trials were identified. The priority Cochrane review should include amplification only devices, combination devices (combined amplification and sound generation), and sound generators. Suggested comparisons are:Amplification only vs waiting-list control, placebo, education/information only with no bination devices vs waiting-list control, placebo, education/information only with no device, amplification only, sound generator only.Sound generator only vs waiting-list control, placebo, education/information only with no device.Trials that have conditions that explicitly include counselling (such as TRT, PTM, Neuromonics) should be excluded from the review.Betahistine for tinnitusBetahistine also met the first three primary priority criteria and there is no existing Cochrane review. We identified six trials for consideration. Comparisons should include placebo, no intervention, education and information only. However, it should be noted that only three trials include the above comparisons (n=3) and the others would not be suitable for synthesis. Subgroup analyses with and without Ménière’s disease should also be considered, but we note that there is an ongoing Cochrane review on Betahistine for Ménière’s disease or syndrome (van Esch et al. 2018).Cognitive Behaviour Therapy for tinnitusCBT met the first three primary priority criteria. A Cochrane review examining all cognitive and behavioural approaches for tinnitus is currently ongoing (Fuller et al. 2017b).5.2. Other priority reviewsGingko biloba for tinnitusGingko biloba met the first two primary priority criteria (it is not in the scope of the NICE guidelines). The existing Cochrane review concluded a lack of evidence for effectiveness (Hilton et al. 2013) and new trials were identified. Suggested comparisons include placebo, no intervention, education and information only.Anxiolytics for tinnitusAnxiolytics met the first two primary criteria (it was not in the scope of the NICE guidelines) and there is no existing Cochrane review. Nine trials have been identified which may be eligible. Suggested comparisons are placebo, no intervention, education and information only.Hypnotics for tinnitusHypnotics meets the first two primary criteria (they were not in the scope of NICE guidelines) and there is no existing Cochrane review. Eight trials have been identified which may be eligible for inclusion. Suggested comparisons are placebo, no intervention, education and information only.Antiepileptics for tinnitusAntiepileptics met the first two primary criteria (they were not in the scope of NICE guidelines) and there is no existing Cochrane review. Eleven trials have been identified. Suggested comparisons include placebo, no intervention, education and information only.Neuromodulation for tinnitusNeuromodulation met two primary criteria including being in scope of the NICE guidelines (they are not available for tinnitus on the NHS). However, a Cochrane review of neuromodulation for tinnitus is currently ongoing (Hoare et al. 2015). 5.3. Methodological challenges for suite of priority Cochrane systematic reviews5.3.1. Outcomes Tinnitus is a symptom rather than a unique disease and so it has a complex presentation which includes the auditory perception of the tinnitus sound, and the emotional, cognitive and behavioural reactions to it. As a consequence, there are many different ways in which benefits from a tinnitus intervention can be conceptualised, and many different measurements for quantifying that benefit. A systematic review of 228 clinical trials for tinnitus published between 2006 and 2015 demonstrated a lack of consensus about what should be measured and how it should be measured (Hall et al. 2016). For example, the review authors identified more than 130 different measurements of tinnitus-related change (i.e. endpoints) in those included clinical trials. This means that few clinical trials have assessed clinical efficacy or effectiveness using the same instrument. One of the challenges is therefore to identify different measurement instruments for tinnitus that have sufficient convergent validity to input into a meta-analysis for evidence synthesis.We would not recommend inclusion of any objective physiological measures (EEG, MRI, blood parameters etc.) since there are no validated biomarkers for tinnitus.Investigators have commonly identified the construct ‘tinnitus severity’ as an outcome of interest with respect to assessing patient benefit. However, tinnitus severity merely expresses the magnitude of complaining. It does not explain the dimension of complaint on which severity should be assessed and it does not inform the choice of most suitable outcome instrument. This means that there are limitations with this construct as an outcome, in the way it is currently phrased. In most instances, when researchers have used ‘tinnitus severity’ they are actually referring to ‘the impact of tinnitus’ as reported by the patient. The impact of tinnitus is synonymous with the reactions to the tinnitus; one of the two major dimensions mentioned earlier. There are many questionnaire instruments for assessing the impact of tinnitus. Examples that have been most frequently used in clinical trials over the past decade or so include the Tinnitus Handicap Inventory and Tinnitus Questionnaire (German version) (Hall et al. 2016). Questionnaire developers make a claim about the ‘validity’ of these measurement instruments, but this has been challenged by several independent groups who have carefully scrutinised the evidence for their measurement properties, especially with respect to responsiveness (Meikle et al. 2008, Kamalski et al. 2010, Fackrell et al. 2014). One challenge is therefore to define whether ‘validity’ in the context of their face and content validity (what they are measuring), as well as their sensitivity to treatment-related change. Of course, when conducting an evidence synthesis, it is necessary to decide on the most important outcome measures for the target population and the intervention of interest. Otherwise, those outcomes may not be sensitive to measuring relevant therapeutic changes in the relevant patient group. Broadly speaking, there are three classes of intervention approach for chronic subjective tinnitus in the UK; self-management (strategies provided by healthcare professionals in collaboration with patients), sound therapies (including hearing aids, sound generators and combination devices), and psychological therapies (including cognitive behaviour therapy, counselling and mindfulness-based techniques). Each of these different intervention approaches is often offered to patients based on a different targeted rationale, and is probably therefore focussed on alleviating different tinnitus-related outcomes. For example, sound therapies such as hearing aids and sound generators, intend to enhance the ability to ignore the tinnitus, whilst psychologically informed interventions are intended to reduce negative thoughts and feelings about tinnitus. Therefore, outcome measures that are most appropriate for one intervention strategy might not be for another. The COMiT’ID study () has identified and made recommendations that the following minimal reporting set should be assessed and reported in all clinical trials (Figure 1). Descriptions of all outcomes have been published (Fackrell et al. 2017). One challenge is that it is uncertain whether valid instruments currently exist for measuring each of these recommended minimal reporting standards. Figure 1. Minimal reporting outcome set that should be assessed and reported in all clinical trials5.3.2. Synthesising education and informationEducation and information is usually included in the studies as a control group. Available comparisons are mostly with higher level interventions such as for example psychological therapy. There is a wide variability in what is included as education and information and often limited information what constitutes education and information in particular studies. 5.3.3. Defining ‘Counselling’A precise definition of counselling is needed to clearly distinguish it from education and information in tinnitus trials. Culley and Bond (2011) describe counselling as a process that aims to empower patients to reach decisions and take actions for themselves. Establishing a therapeutic relationship, clarifying and defining problems, planning actions, and managing expectations are all key features of the approach. Education and information giving can be entirely one way processes, whereas counselling is about empowerment and enabling patients to arrive at their own solutions using their own internal resources. Counselling may well include education and information giving but not necessarily, and the opposite is not necessarily or maybe even often true. NHS Choices defines counselling as a talking therapy involving a trained therapist, and distinguishes it from other talking therapies such as CBT, psychotherapy, etc. Counsellor is also a protected term with the expectation that they are registered with a professional organisation that's been accredited by the Professional Standards Authority. So, unless there is explicit efforts and description of process towards empowerment in trial reports, and it is delivered by a trained therapist, then it may not constitute counselling. ReferencesAbbott J, Kaldo V, Klein B, Austin D, Hamilton C, Piterman L, Williams B, Andersson G. 2009. 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