www.bjorl.org
Brazilian
Journal
of
OTORHINOLARYNGOLOGY
ORIGINAL
ARTICLE
Clinical
randomized
trial
study
of
hearing
aids
effectiveness
in
association
with
Ginkgo
biloba
extract
(EGb
761)
on
tinnitus
improvement
夽
Camila
L.
Radunz
a,
Cristina
E.
Okuyama
a,
Fátima
C.A.
Branco-Barreiro
b,
Regina
M.S.
Pereira
c,
Susana
N.
Diniz
c,∗aUniversidadeAnhangueradeSãoPaulo(UNIAN),ProgramadeMestradoProfissionalemFarmácia,SãoPaulo,SP,Brazil bUniversidadeFederaldeSãoPaulo(UNIFESP),DepartamentodeFonoaudiologia,SãoPaulo,SP,Brazil
cUniversidadeAnhangueradeSãoPaulo(UNIAN),ProgramadeMestradoProfissionalemFarmáciaeMestradoeDoutoradoem BiotecnologiaeInovac¸ãoemSaúde,SãoPaulo,SP,Brazil
Received16March2019;accepted15May2019 Availableonline18June2019
KEYWORDS Ginkgobiloba; Hearingaids; Hearingloss; Tinnitus Abstract
Introduction:Tinnitusisdefinedastheperceptionofsoundwithoutitsactualpresenceinthe
environment.Ithasbeenthesubjectofagreatnumberofstudies,especiallyconsideringits consequencesonpatient’squalityoflife.
Objective:This study aimedto investigate theeffectofhearing aidsand/or Ginkgobiloba
extractEGb761ontinnitusinpatientswithhearingloss.
Methods:Thisisatrialrandomized-controlledtreatment,parallel,double-blind,with
three-arm.Thirty-threeadultssubjectsweredividedintothreegroups:group1----subjectsundergoing drug therapywith Ginkgobiloba extractEGb 761; group2---- individualsfitted with digital hearingaids;group3----individualssubmittedtodrugtherapywithGinkgobilobaextractEGb 761andusinghearingaids.Thetinnitushandicapinventoryandvisualanaloguescalewereused toevaluateself-perceptionoftinnitusloudnessandseveritybeforetreatmentand90daysafter treatment.
Results:Thisstudydemonstratedasignificantcorrelationbetweentinnitushandicapinventory
andvisualanaloguescale,beforeandaftertreatment.Weobservedasignificantimprovement inself-perceptionoftinnitus loudnessandseverity after 90days oftreatmentwith Ginkgo
bilobaextractEGb761and/orhearingaids.Nocorrelationwasfoundbetweentinnitusonset
timeandself-perceptionoftinnitusloudnessandseverity.Hearingaidsweremoreeffectivein patientswithashortertinnitusonsettimeandGinkgobilobaextractwaseffectiveregardless oftinnitusduration.
夽 Pleasecitethisarticleas:RadunzCL,OkuyamaCE,Branco-BarreiroFC,PereiraRM,DinizSN.Clinicalrandomizedtrialstudyofhearing aidseffectivenessinassociationwithGinkgobilobaextract(EGb761)ontinnitusimprovement.BrazJOtorhinolaryngol.2020;86:734---42.
∗Correspondingauthor.
E-mails:dinizsusana@gmail.com,susana.diniz@anhanguera.com(S.N.Diniz).
PeerReviewundertheresponsibilityofAssociac¸ãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial.
https://doi.org/10.1016/j.bjorl.2019.05.003
1808-8694/©2019Associac¸˜aoBrasileiradeOtorrinolaringologiaeCirurgiaC´ervico-Facial.PublishedbyElsevierEditoraLtda.Thisisanopen
Conclusions: Itwaspossibletoprovetheeffectivenessofthehearingaidsand/orGinkgobiloba
extractEGb761treatment,whichshowssuccessinthecontroloftinnituscontributingtothe improvementofthissymptom.
© 2019 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Published by Elsevier Editora Ltda. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). PALAVRAS-CHAVE Ginkgobiloba; Próteseauditiva; Perdaauditiva; Zumbido
Estudoclínicorandomizadodaeficáciadapróteseauditivaassociadaaoextratode
Ginkgobiloba(EGb761)namelhoriadozumbido
Resumo
Introduc¸ão: Ozumbidoédefinidocomo apercepc¸ãodeumsomsemasuapresenc¸arealno
ambienteetemsidoobjetodeumgrandenúmerodeestudos,especialmentedevidoàssuas consequênciasnaqualidadedevidadopaciente.
Objetivo: Investigaroefeitodeprótesesauditivase/ouextratodeGinkgobilobaEGb761
sobreozumbidoempacientescomperdaauditiva.
Método: Ensaioclínicorandomizadocontrolado,paralelo,duplo-cego,comtrêsbrac¸os.Trinta
e trêsindivíduos adultos foramdivididos em trêsgrupos: Grupo 1-indivíduos submetidos à terapiamedicamentosacomextratodeGinkgobilobaEGb761;Grupo2-indivíduosequipados comprótesesauditivasdigitais;Grupo3-indivíduossubmetidosàterapiamedicamentosacom extratodeGinkgobilobaEGb761eprótesesauditivas.OTinnitushandicapinventoryeaescala visualanalógicaforamusadosparaavaliaraautopercepc¸ãodeintensidadeedagravidadedo zumbidoantesdotratamentoe90diasapósotratamento.
Resultados: Este estudo demonstrou uma correlac¸ão significante entreo Tinnitus handicap
inventoryeaescalavisualanalógica,anteseapósotratamento.Observou-semelhoria
signi-ficativanaautopercepc¸ãodeloudnessedaintensidadedozumbidoapós90diasdetratamento comextratodeGinkgobilobaEGb761e/oupróteseauditiva.Nãofoiencontradacorrelac¸ão entreotempodeiníciodozumbidoeaautopercepc¸ãodaintensidadeegravidadedozumbido. Asprótesesauditivasforammaiseficazesempacientescommenortempodeiníciodezumbido eoextratodeGinkgobilobafoieficaz,independentementedadurac¸ãodozumbido.
Conclusões: Foi possível comprovar a eficácia do tratamento com a prótese auditiva e/ou
extratodeGinkgobilobaEGb761,oquedemonstrasucessonocontroledozumbidoecontribui paraamelhoriadessesintoma.
© 2019 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Publicado por Elsevier Editora Ltda. Este ´e um artigo Open Access sob uma licenc¸a CC BY (http:// creativecommons.org/licenses/by/4.0/).
Introduction
Tinnitushas been the subjectof a greatnumber of stud-ies,especiallyduetoitsconsequencesonpatient’squality of life. It is defined as the perception of sound without itsactual presencein theenvironment1 and isconsidered a symptom, not an ailment in itself, of anomalies from cochlearfunctionandsignalprocessinginthecentral ner-voussystem.2 Commonly,tinnitusis associatedwithother diseases,anditisdifficulttoisolatethecauses:otological ailments; cardiovascular alterations; metabolic, neurolog-ical and psychiatric diseases; odontological factors and possiblyconsequenceofdrugs,caffeine,nicotineand alco-holingestion.2Healthprofessionalsareincreasinglyinvolved in obtaining a more precise and accurate evaluation of patients,lookinginadditionforefficientandlasting thera-peuticalternatives.3
Mostpatientswithtinnitus(85---96%)havesomedegreeof hearingloss,4whichshowsthatregardlessofthehearingloss degreetinnitushasagreaterimpactonpeople’squalityof life.5,6Thepositivecorrelationbetweenhearinglossand
tin-nituscanbejustifiedifoneconsidersthattheformermaybe thetriggeringfactorofthelatter,sincedamageor degenera-tionoftheinnerearandofthevestibulocochlearnervemay causethissymptom.5AconventionalamplificationHearing Aid(HA)isoneofthemostfrequentdevicesusedto reha-bilitatehearingloss.6TheHAhasalsobeenemployedinthe treatmentoftinnitus,becauseitisanefficientalternative tominimizeitsperception by thepatients andtoinitiate andfacilitatetheprocessofgettingusedtotinnitus.7
Drug therapy is used to treat tinnitus and several drugs/activeprinciplesarecommonlyusedtominimizethis symptom; amongthem we found lidocainehydrochloride, carbamazepine, gabapentine, fluoxetine hydrochloride, sertralinehydrochloride,clonazepam,alprazolam, betahis-tine,cinnarizine,flunarizineandtheGinkgobilobaextract.3 Moreover,associationsofdifferentdrugsusedinthe treat-mentoftinnituswithG.bilobaextract8,9arealsodescribed intheliterature,althoughthesestudiesarecontroversial.
The extract from G. biloba leaves is rich in flavones andglycosylated flavonoids, terpenes, lactones and other constituents, which are responsible for the
pharmaco-logical properties of the extract.10 The extract is used in medicine and is prescribed for cognitive dysfunctions, including dementia11 and cerebrovascular insufficiency,12 recentmemoryloss,headache,vertigo13,14 andtinnitusin additiontoemotionalinstabilityaccompaniedbyanxiety.15 ThepreparationscontainingG.bilobaincreasebloodflow, with the resulting improvement of oxygen supply to the cells,protecttissuesfromthedamageresultingfromlack ofoxygen.Furthermore,aninhibitionof platelet aggrega-tionhasbeen found,thusbeingrecommendedinthecase ofdeficitinthecerebralbloodflow,whichmaygiveriseto memoryloss,dizziness,headachesandtinnitus.13,14Studies haveshownthatterpenelactonessuchasginkgolideBand bilobalidearetheconstituentsoftheextractresponsiblefor theseproperties.10
Thus,inviewofthetherapeuticpropertiesofGingkoand employmentofHAinauditoryrehabilitation,wedetermined toinvestigatetheeffectoftheuseofG.bilobaextractEGb 761 and/or hearing aids (HA)on tinnitus in patients with hearingloss.
Methods
Studydesign
This is a trial utilizing randomized-controlled treatment, parallel, double-blind, with three-arm, (TRIAL: RBR-2SN8XV)registry atRegistroBrasileiro deEnsaiosClínicos (ReBEC)(http://www.ensaiosclinicos.gov.br/).Therandom allocation process has consisted in generating a random sequenceusinganExcelfileforrandomizationandusedthe randomallocationrule,whichchoosesatrandomoneof pos-siblebalancedassignmentsofthegivennumberofsubjects pertreatment.
The examiners responsible for applying the question-nairesduringthestudywereblindedtotheintervention.In addition,an employeeoutsidetheresearchteaminserted dataintothecomputerinseparatedatasheetssothatthe researcherscananalyzedatawithouthavingaccessto infor-mationabouttheallocation.
Participants
The participants’ selection process was performed after consultationwith theotolaryngologist, who identifiedthe individualsappropriately,generatedtherandomallocation sequence,andenrolledanddesignatedtheparticipantsfor theinterventions.Thesamplesize(n=35)wasdetermined bythenumberofindividualssubmittedtomedical consulta-tionbetweenJulyandAugust2015atanaudiologicalcenter inRondonópolis(MT),Brazil.
Inclusionandexclusioncriteria
Patientswereinformedaboutthestudyandinvitedto par-ticipate.Allwerecompletelyfreetorefusetoparticipate withoutanylosstothetreatmentintheclinic. The inclu-sioncriteriaofthepatientswere:individualsover18years ofage;complaintoftinnitus(uni-orbilateral)foratleast3 months;(singleorbilateral)sensorineuralormixedhearing lossindependentofdegreeandconfiguration.Bothmaleand femalewererecruited.Theexclusioncriteriaofthepatients were:havingusedaspirinoracetylsalicylicacid(ASA)inthe lastmonth; havingusedofG.bilobainthelast3months;
onantidepressantuse;diagnosedwithcompromisedmiddle ear(otitisortubaldysfunction)atthetimeofevaluation. Interventions
The groups weredivided into:group 1----patients (n=11) whoreceiveddrugtherapywithG.bilobaextractEGb761, doseof240mg/day/patient;group2----patients(n=11)who wereequippedwithBeltone®individualHAdigital;group3 ---- wascomposedofindividuals(n=11)whounderwentboth drugtherapywithG.biloba,identicaltoGroup1,andtothe HA.Afterstartingthestudy,thetreatmentwasperformed for90days.
EGb761Equitam® leafextract (patented/trademarked by Eurofarma Laboratórios S.A.), is a well-characterized complexmixtureofbiologicallyactiveconstituentsobtained fromG.bilobaleavesaccordingtoastandardizedmethod.16 EGb 761contains the activecompounds: 24% of flavonoid glycosides, 6% of terpenoid trilactones, 5---10% of organic acids.17---19Theflavonoidsandterpenoidsareproposedasthe biologicalactivecompoundsofEGb761with pharmacolog-icalactivityanddifferentproperties.20 Thedoseof240mg ofEGb761,suppliedbyMomenta,wasadministereddailyby theoralroute.DigitalBeltone®HAcomposedofthreebasic components:amicrophone,anamplifierandaspeakerand obtainedataprivateHearingAidscenter(MT,Brazil).The route ofadministrationofG.bilobashouldbementioned, alongwiththeoraldoses.
Clinicalprocedures
Participants wereseen 5 times overa 6month periodfor thislongitudinalstudy.Thestudywasperformedina clini-caloutpatientclinicoftheaudiologicalcenter.Theservices wereprovidedbyotorhinolaryngologists,speechtherapists andresearchersinvolvedwiththepresentstudy.Thevisits oftheparticipantsweredividedintothefollowingstages:
Visit 1: All the patients underwent an evaluation with otolaryngologists who guided and gave all the clarifica-tionregardingtheresearchinquestion. Subsequently,the otolaryngologistsreferredthesepatientsforadaptation of individualhearingaid,treatmentwithG.bilobaor associa-tionofboth.
Visit 2: During the hearing aids fitting, tinnitus coun-seling and education was provided by an audiologist and speech therapist. Information about G. biloba treatment andthe questionnaireswere presentedtothesubjects by researchers.
Visits3and4:Thequestionnaireswereappliedtocollect thedescriptionandevaluationoftinnitusfrompatientsat aprivateaudiologicalcenter.Allparticipantsansweredthe TinnitusHandicapInventory(THI),adaptedbyBrazilian Por-tuguesebyFerreiraetal.,21theonlyinstrumenttranslated andadaptedforthislanguagetoinvestigatetheseverityof tinnitusandthevisual analoguescale (VAS).BothTHI and VASwereappliedattheearly(pre-treatment,Visit3)stage andfollowing90daysoftreatments(Visit4).
Visit5: After completing the research,all participants were individually called for clarification of the results obtainedinthestudy bytheresearchers,accompanied by speechtherapists.
Outcomemeasures
Thisstudycomparedtheeffectoftheuseoftheindividual hearingaid,theuseofG.bilobapreparationandthe
asso-Assessed for eligibility (n = 35)
Excluded (n = 02) Not meeting inclusion criteria (n = 01) Other reason (n = 01) Evaluation pre
intervention (THI / VAS)
Evaluation pos intervention (THI / VAS) Group 1 Received allocated intervention (n = 11) Received allocated intervention (n = 11) Received allocated intervention (n = 11) Group 2 Group 3 Randomized (n = 33)
Figure1 Flowdiagramillustratingtheparticipantsnumber whowererandomlyassignedforeachgroup.
ciationbetweenthehearingaidandtheG.bilobaextract, throughtheapplicationoftwoquestionnaires,THIandVAS, seekinganeffectivealternative tothetreatment of tinni-tus.Asasecondaryoutcomemeanpercentageofvariation oftheTHI scorebeforeandaftertreatment inrelationto thetinnitusonsettimewasalsoanalyzed.
THI
The THI is comprised of 25 questions, and the possible answersare:Yes,SometimesorNo.Thescoresgiventothe answers are,respectively: four,twoand zero points.The totalscorevariesfrom0to100,andthehigherthescorethe greatertheeffectoftinnitusonthepatient’squalityoflife. Thisquestionnairewastranslatedandculturallyadaptedto beappliedtothepopulation,andhasproventobeareliable tooltoevaluatethedamagecausedbytinnitustopeople’s qualityoflife.21
VAS
TheapplicationoftheVAStopatientswithtinnitusconsists inattributingascorefrom0to10fordiscomfortandanother scorefortheintensityofthesymptom,withthehelpofan
appropriaterule,22 the first attribution beingused in the questionnaireposedtothepatientinthissurvey.
Ethicalapproval
A favorable ethical opinion was granted from the Ethics Committee, under decision no
1,062,277 (http://plataformabrasil.saude.gov.br/login.jsf), as it conformstoResolution466/2012,whereallsubjectsofthis studyreceiveatreatment.
Statisticalanalysis
Thequantitativedataandsignificantdifferences(*p<0.05) were evaluatedthrough ANOVA in the pre-treatment and post-treatmentperiodfor comparisonbetween thegroups (G1,G2andG3).Therelationbetweenthetoolsused(THI andVAS)intheperiodsbothbeforeandaftertreatmentwas alsoanalyzedinaccordancewithPearson’scorrelation coef-ficient(r). Lastly,the relation betweenthe tinnitusscore measured by the different scales and the time of tinni-tus (measured in months) wasevaluated. The mean time (59months)of tinnituswascalculated amongallpatients includedinthestudy.TheGraphPadPrism® 5softwarewas usedforthebiostatisticalanalyses.
Results
From the population sample of 35 individuals recruited fromJulytoAugust,2015,twowereexcludedand33were allocatedin3differentgroupsasillustratedinFig.1.In addi-tion,oneindividualwithhearinglossandtinnituswithnull scoreofVASandTHIwasexcludedfromthestudyforthis reason.Anotherpatientwasexcluded becausehedidnot presenthearinglossbutpresentedaseveretinnitus. Demo-graphicinformationofparticipantsofthestudyisshownin
Table1.
This study evaluated the correlation between the THI andVAS scales inthe periods beforeand after treatment (Fig.2).InaccordancewithPearson’scorrelationcoefficient (r),wecanobservetheexistenceofasignificantcorrelation (r=0.6785;p<0.0001)beforethetreatment(Fig.2A).Inthe post-treatment period(Fig. 2B), a statistical dependency wasalsofound,withasignificantcorrelationbetweenboth tools (r=0.7519; p<0.0001). This means that the greater thevalueofVASfound,thegreateristheexpectedvalueof THI(positivecorrelation),asshowninFig.2.
15
A
B
10 5 0 0 25 50 THI VA S VA S THI 75 100 0 20 40 60 80 0 2 4 6 8 10Figure2 Pearson’scorrelationofthescoresobtainedbytheTHIandVASmethodologicalinstrumentsinthepre-treatment(A)of alltheresearchvolunteers(r=0.6785;p<0.0001)andintheposttreatment(B)ofallvolunteers;(r=0.7519,p<0.0001).
Table1 Demographicsummarydataofparticipantsbynumberofindividuals,gender,ageandtimeoftinnitusinmonths.
Variable Participants(useabledata) Fullpopulation
Numberofindividuals(male/female) 33(45.5%/54.5%) 35(45.7%/54.3%)
Meanageinyears(SD) 56.3(16.8) 56.3(16.8)
Meantimeoftinnitusinmonthsbeforetreatment(SD) 58.9(17.7) 55.9(21.1)
SD,standarddeviation. 100 80 60 40 20 0 G1 G2 THI scale
*
*
*
G3Pre Post Pre Post Pre Post
Figure3 Analysisoftheimprovementoftinnitusannoyance aftertheinterventions.AveragesofTHIscoresinG1,G2 and G3groupsbeforeandaftertreatment.Statisticalsignificance (ANOVArepeatedmeasures);*p<0.05.
Inthecomparisonof G.bilobaextractEGb761and/or HAeffectsontinnitus,thevalueswerepresentedasmean andstandard deviation ofTHI and VASscales. The groups (G1,G2 andG3) werehomogeneous inthe pre-treatment period,whenTHIscores(points)werecomparedwithinthe confidenceintervalsusingtheANOVAtestwiththe applica-tionoftheTukeyAverageComparisonPostTest(p=0.4708) (Fig.3).Themultiplecomparisonstestalsofoundthatthere was no significant difference between the groups in the pre-treatment period, when VAS responses regarding the averageandstandarddeviationwereconsidered(p=0.7514) (Fig.4).Thus,theresultsoftinnitusevaluationdidnot dif-ferbetween the randomizedgroups in the pre-treatment period(Figs.3and4).
Theresultsdemonstratedanimprovementobtainedafter treatmentsproposed,takingintoconsideration THIasthe toolapplied.Itcanbeobservedthatinalltreatment situa-tions,beitthroughmedication,throughtheuseofhearing aidsorbothatthesametime,therewassignificant improve-mentafter90daysoftreatment(Fig.3).Thispointssharply atthedecreaseoftinnitusthroughTHIforthethreetypesof treatmentproposed(p<0.0001).Theresultsalsoshowthat G2(patientsfittedwithHA)wasalsooutstandingregarding theimprovementoftinnituswhentheresponsesofpatients totheTHIquestionnairewereanalyzed(Fig.3).
IntheresultsobtainedafterVASanalysis,itwasobserved thatallgroupsshowedadecreaseintinnitusperceptionand discomfortscore.However,thisdifferencewasstatistically significantonlyinGroup2(p= 0.0002),whentheVASwas applied(Fig.4).
Thecorrelationbetweentinnitusonsettimeandtinnitus perceptionanddiscomfortscorewasevaluatedatthe dif-ferentstagesofthesurveyandtreatment,withthetinnitus scorecoming fromthe THI andVAS. Regardingthe
evalu-G1
V
AS scale
G2 G3
Pre Post Pre Post Pre Post
2 4 6 8
0
Figure4 Analysisofimprovementoftinnitusdiscomfortafter interventions.AveragesofVASscoresinG1,G2andG3groups before and after treatment. Statistical significance (ANOVA repeatedmeasures);*p<0.05.
Table2 MeanpercentageTHIscorevariationbeforeand aftertreatmentinrelationtotinnitustimeinmonths.The groups were subdivided into two groups: above (Ga) and below(Gb)themeantinnitustimeofpatientsineachgroup.
Ga Gb
G1 54.3% 74.5%
G2 34.7% 71.2%
G3 53.0% 68.1%
ationof the correlation betweenthe timeof tinnitusand thetinnitusscoremeasuredbytheTHIinthepre-treatment (r=0.0035;p= 0.9849)andpost-treatment(r=0.2936;p= 0.1089)periods,itwasfoundthatitwasimpossibleto estab-lishsuchanassociation(Fig.5AandC).InthecaseofVAS, alsointhepre-treatment(r=0.1828;p= 0.3250)and post-treatment(r=0.2482;p=0.1782)periods,itwasfoundthat therewasnosignificantcorrelationbetweentinnitusonset timeandthetinnitusTHIandVASscores(Fig.5BandD).
ThemeanpercentageofvariationoftheTHIscorebefore andafter treatmentin relation tothetinnitusonsettime was also analyzed. The results demonstrated that in the evaluationoftinnitusscore,whendividingthegroupsinto subgroupsaccordingtotinnitustime,above(Ga)andbelow (Gb)themeantimeoftinnitusfromallpatients,adiscrete correlation between tinnitusonset timeand tinnitus per-ception and discomfort score measured before and after treatmentwasobserved(Table2).Thecorrelationwas bet-terobservedintheG2group(patientsfittedwithHA),where thevariationoftheTHIscoreshowedimprovementof34.7% inpatientswithlongertinnitustime(G2asubgroup),whilein
150
A
C
D
B
15 10 5 0 100 50 0 0 50 100Time in months Time in months
Time in months Time in months
Tinnitus score (THI)
Tinnitus score (THI) Tinnitus score (V
AS) Tinnitus score (V AS) 150 0 50 100 150 0 50 100 150 0 50 100 150 0 20 40 60 80 10 8 6 4 2 0
Figure5 Analysisofthecorrelationbetween timeandtinnitus score.RepresentationofTHIscoresversus timeoftinnitus in months,pre-treatment(A)andpost-treatment(C).RepresentationofVASscoresversustimeoftinnitusinmonths,pre-treatment (B)andpost-treatment(D).
thesubgroupwithshortertinnitustime(G2b)the improve-mentwas71.2%,muchhigherthanG2asubgroup(Table2). Theseresultsshowthattheuseofthehearingdevicewas moreeffectivetheshorterthepatients’tinnitusduration. Ontheotherhand,ingroupstreatedwithG.bilobaextract, G1andG3,thetinnitusonsettimedoesnotseemtoaffect thetreatmenteffect.ThevariationoftheTHIscoreinthe subgroupsG1aandG1bwas54.3%and74.5%,respectively. WhileinthesubgroupsG3aandG3bthevariationoftheTHI score was 53.0% and 68.1%, respectively (Table 2). Thus, according to these data, it can bedemonstrated that G. bilobaextractEGb761treatmentwaseffectiveregardless ofthepatients’tinnitusduration.IntheVASscale,the dif-ferencebetweenthepercentageofvariationofthescoring scorebeforeandafterthetreatmentinrelationtothe tin-nitustimeofthepatientswasnotsoevident.
Discussion
Theheterogeneity oftinnitusisachallengeinclinical tin-nitus research as it can differ in many aspects such as localization, sound characteristics, underlying cause, and others.Sincetherearedifferentformsoftinnitus,onemay presumethattheydifferinpathophysiologyand,therefore, inresponsetospecifictreatments.Thismayjustifythegreat variabilityoftheresultsfromclinicalstudies.Thusan accu-ratedescriptionofthepatientsunderstudyinaspecifictrial ismandatory.23Duetothedifficultyofmeasuringand treat-ingthetinnitussymptom,someevaluationsrequiredtoset upparameters,suchastheuseofVASandofquestionnaires ontheimpactonthequalityoflifeofpatientsandTHI.24The presentstudyhasusedtheTHI,whichiscurrentlytheonly instrument translated and culturally adapted to Brazilian
Portuguese.AlthoughtheTinnitusFunctionalIndexhasbeen developed withthe purpose to detect treatment-induced changes and has been recommended as the ideal instru-mentforoutcomemeasurespurposeitwasnotavailablein Portugueseat thetimeofdatacollection.25 Discrepancies arefoundintheliteratureregardingtheexistenceofa cor-relationbetweenthepsychoacousticevaluationoftinnitus andthesubjectivequestionnaires(suchastheTHI).These questionnairesexamineseveralaspectsrelatedwith tinni-tus(emotional,functionalandcatastrophic).AsfortheVAS, itevaluatestinnitusperceptionanddiscomfort,which gen-eratesa scorewithoutspecifying whichaspect causesthe greaterdiscomfort.26 Regardingtheirsimplicity,the meth-odsofevaluatingtheperception,discomfortandseverityof tinnitusmostusedin the publishedliteraturearethe THI questionnaireandtheVASscale.21,22 Thisstudy hasshown theexistenceof asignificant correlationbetween theTHI andVAS scales (Fig.2). The substantial correlation found inthisstudybetweentheTHIandVAStoolsappliedbefore andaftertreatmentcorroboratesthedataobtainedbyother authors,27 which demonstrates that the use of these two methodswouldincreasethecredibilityofthesurveys.
G.bilobaisdescribedasanherbalmedicinewhoseactive pharmacologicalgroupsareflavonoidswithantioxidantand vasodilator action, and terpene lactones, which act as antiplateletagents.28ThestandardizedextractofG.biloba leafEGb761resultsamongthemainpharmacological activ-itiesan increaseincognition, improvementinmetabolism andblood flow.29 Inthe present study,treatment withG.
biloba (Equitam®/EGb 761) has shown to be effective in thereduction and improvement of the tinnitus handicap. Thepositiveresultagreeswiththebeneficialeffectfound inotherclinicalstudies,13,30andinothersdiseasessuchas
indementia.31 Themost importantclinicalapplicationsof
G. biloba extractEGb 761 arein the treatment of tinni-tus,acutecochlear deafness,vertigo, anddisturbancesin equilibrium.13,14Studieswithanimalmodelshaveshownthat thetreatmentwithEGb761resultedinadecreaseoftinnitus whenbehavioralmanifestationswereevaluatedinmice.32 Kraussetal.33demonstratedthattheprophylactic applica-tionofG.bilobaextractEGb761significantlyreducesnoise inducedhearinglossandtinnitusdevelopmentinMongolian gerbil(Merionesunguiculatus). G.bilobaextractalso sig-nificantlyminimizes cochlear damage againstLPS-induced otitismediawithlabyrinthitisin aguineapigmodel34 and exerts an anti-neuroinflammatoryeffects in LPS-activated primarymicroglial cells suggesting a role on neurodegen-erativeconditions.35 EGb 761is a standardized extractof a well-defined complex mixture of active compounds of heterogeneouschemicalcompositionthatgivetothis phy-tomedicinetheadvantageofmodulatingseveralfactorswith mechanism of action such as antioxidanteffect, modula-tion of neurotransmission, neuroendocrine regulation and upregulationofneurotrophicfactors.29,31Thosearepossible mechanismsof action that underline the potential thera-peutic effectof EGb 761 on tinnitus, probablyregulating theneuromodulationinthecentralauditorypathway.36
Ontheotherhand,theliteraturealsorecords inconclu-sive studies regarding the association between G. biloba and tinnitus,30 and other studies have not found dif-ferences after treatment with G. biloba in comparison withplacebo.37---39 TheconflictingtherapeuticresultsofG.
biloba as a treatment for tinnitus can be attributed to thelack of standardization of theextracts used,no stan-dard rigorous methodologies regarding the evaluation of therapeuticeffectiveness,nooptimaldosagesand pharma-ceuticalforms.15
Inthepresentstudysignificantimprovementwasfound intheself-perception oftinnitusloudnessandseverity90 daysafterHAfitting.Severalformsofinterventionareused tominimizetinnitusseverity, withHAbeingmentioned as atherapeuticalsuggestion.7Inpatientswithtinnitus,sound therapydonewiththeuseofHAaimsatauditorystimulation throughsoundenrichment.4Otherstudieshavealso demon-stratedtheefficiencyoftheuseofHAinthereductionor elimination of tinnitus in patients with hearing loss asso-ciatedwithtinnitus,statingthatitis possibletodecrease tinnitusperceptionandseveritybyenrichingthesound envi-ronmental (for example, using the HA).40,41 This fact can bepartiallyexplained bythe peripheral auditory masking causedbytheamplificationofenvironmentsounds,butfor manypatientsthiseffectisnotinstantaneousandmaytake time,whichshowstheneedoftakingintoaccountthe plas-ticchanges in the centralnervoussystem. Data fromthe existingliteratureregardingtheadaptation periodneeded toperceiveimprovementoftinnitusdemonstratedthatthe timeofuseofHAneededforthisimprovementvariesfrom threetoeightmonthsforthemajorityofthesubjects stud-ied.
We observe that the associations of G. biloba extract EGb 761 with HA showed significant improvement in the pre-treatmentandpost-treatmentcomparison,butwasnot outstandingregardingtheimprovementoftinnitusin com-parison with the group that used either HA or G. biloba extractEGb761alone.As for thebenefits thatthe medi-cation mentioned offers in clinical practice,aswell asin accordancewithsomeofthepublishedstudiesabouttheuse ofhearingaid,itwasinitiallythoughtthatthisassociation hada greater effectivenessthan theisolatedtreatments, but,unexpectedly,weobservedthesameeffectofall
treat-ments.Theseresultsdemonstratedthatwasnotpossibleto determineasynergismbetweenthetreatments.
No correlation was found between the tinnitus onset time andthe tinnitus THI and VASscores. However, com-paringpatient’ssubgroupsclassified inrelation oftinnitus onsettime,itwasobservedthattheuseofthedevicewas more effective in patients withshorter tinnitus duration. Thismaybeassociatedwiththefactthatthepatientwith a shorter time of tinnitus may not have undergone plas-tic changes in the central nervous system, so it is often easier to obtain a better clinical response. As time goes by, the lossof compensation mechanism occursand, con-sequently,the treatment becomes complex,due tothese centralnervoussystemalterations.42,43Also,improved audi-tory performance and consequently improved tinnitus as wellasenhancedcommunicationmayreducethesymptoms often associated with tinnitus such as stress or anxiety.7 On theother hand,theresultsdemonstratedthat theuse ofG.bilobaextractEGb761aloneorincombinationwith HA,waseffectiveregardlessofpatient’stimetinnitus.This resultsuggeststhatimprovementof symptoms,regardless oftinnitusonsettime,maybeassociatedwithG.biloba’s free radical scavenger activity, anti-inflammatory activity andenhancedneuronalplasticitythatcanreducetissueand neurologicaldamage.29
Itis importanttoconsiderthedifficulties inthe treat-ment of tinnitus and the lack of treatment options with proven effectiveness. However, the efficacy of cognitive behavioral therapy is well established, and studies have shownabeneficialeffectontinnitusdistress.Othermethods include medical treatmentsand psychological approaches in combination with therapeutic sound, such as tinnitus retrainingtherapy.3,44,45Altogethertheresultsindicatethat the treatment options, asused in thisstudy, can achieve satisfactory results and possibly have significant conse-quences for the care and quality of life in patients with tinnitus.However,thereis aneed forstudies donewitha largernumberof patientsand alongerclinical evaluation time.
The absence of follow-up may be a limitation of this study.Therefore,itwasnotpossibletoassesswhether treat-mentwithhearingaidsand/orG.bilobaextractEGb761had a long-termeffectontheperception, intensity,and qual-ityoflifeintinnitusindividuals.Anotherlimitationwasthe possibility of the placebo effecton tinnitus intervention, sincethecontrol groupwasnotsubjected tointervention toruleoutthispossibilityandthereforewecannotknowif theeffectofplacebotreatmentwouldberelatedtotinnitus improvement.Boththenumbersofparticipants per treat-mentandthesample sizeofpatientswithtinnituscanbe seenasalimitationoftheresearch,duetothe heterogene-ityoftriggersandtinnitusmechanisms.So,alargernumber ofpatientsandasamplesizewouldberecommended.
Conclusion
Inconclusion,ourstudydemonstratedtheeffectivenessof treatmentwiththeindividualhearingaidsand/orG.biloba extractEGb761associated,throughthesignificant improve-ment in self-perception of tinnitusloudness and severity, byanalysisoftheTHIscore.Inaddition,hearingaidswere moreeffectiveinpatientswithshortertimetoonsetof tin-nitus. G. bilobaextract aloneor in combination withthe hearingaids waseffectiveregardless of tinnitusduration. Further studies with high methodological quality and low riskofbiasarenecessarytoevaluatetheeffectofhearing aidsand/orG.bilobaextractEGb761inthetreatment of
tinnitus.Consortrulesshouldbefollowedanddescribedin detail,aswellasparticipants’tinnitusvariability.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgements
S.N.D is grateful to Anhanguera University of São Paulo (UNIAN) for providing financial supportand Momenta Far-macêutica Ltdafor provide theEGb761 Equitam® Ginkgo bilobaextract.
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