Effects of the reduction of caffeine consumption on tinnitus perception

Brazilian

Journal

of

OTORHINOLARYNGOLOGY

www.bjorl.org

ORIGINAL

ARTICLE

Effects

of

the

reduction

of

caffeine

consumption

on

tinnitus

perception

夽

Ricardo

Rodrigues

Figueiredo

,

Marcelo

José

Abras

Rates

,

Andréia

Aparecida

de

Azevedo

,

Ronaldo

Kennedy

de

Paula

Moreira

,

Norma

de

Oliveira

Penido

a_{Post-GraduatePrograminOtorhynolaryngology,UniversidadeFederaldeSãoPaulo(UNIFESP),SãoPaulo,SP,Brazil} b_{FaculdadedeMedicinadeValenc¸a,RiodeJaneiro,RJ,Brazil}

c_{TinnitusResearchInitiative,Regensburg,Germany}

d_{UniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,Brazil} e_{CentrodeTratamentoePesquisaemZumbido,BeloHorizonte,MG,Brazil} f_{OtorrinolaringologiaSul-Fluminense(OTOSUL),VoltaRedonda,RJ,Brazil} g_{SantaCasadeMisericórdiadeBeloHorizonte,BeloHorizonte,MG,Brazil}

Received3September2013;accepted17November2013 Availableonline12June2014

KEYWORDS Tinnitus; Caffeine; Coffee

Abstract

Introduction:Formany years,excessivecaffeineconsumptionhasbeentoutedasan aggra-vatingfactor fortinnitus.The pathophysiologybehindthiseffectisprobablyrelatedtothe blockageofadenosinereceptorsbytheactionofcaffeineonthecentralnervoussystem.

Objective:Toevaluatetheeffectsofreductionofcoffeeconsumption ontinnitus sensation andtoidentifysubgroupsmorepronetobenefitfromthistherapeuticstrategy.

Studydesign:Prospective.

Methods:Twenty-sixtinnituspatientswhoconsumedatleast150mLofcoffeeperdaywere selected.Allwereaskedtoreducetheircoffeeconsumption.TheTinnitusHandicapInventory (THI)questionnairewascompletedby thepatientsbeforeandafterthereductionofcoffee consumption,aswellasavisual-analogscale(VAS)graduatedfrom1to10.

Results:THIandVASscoresweresignificantlyreduced(p<0.05).Inthesubgroupslessthan60 yearsold,bilateraltinnitusanddailycoffeeconsumptionbetween150and300mLshoweda significantlygreaterreductionofTHIandVASscores.

夽

Pleasecitethis articleas:Figueiredo RR, Rates MJ,deAzevedo AA, Moreira RK,PenidoNO. Effects ofthe reductionof caffeine consumptionontinnitusperception.BrazJOtorhinolaryngol.2014;80:416---21.

∗_{Correspondingauthor.}

E-mail:[email protected](R.R.Figueiredo).

http://dx.doi.org/10.1016/j.bjorl.2014.05.033

1808-8694/©2014Associac¸ãoBrasileiradeOtorrinolaringologia eCirurgiaCérvico-Facial. PublishedbyElsevierEditoraLtda.All rights

Conclusion: Patientsunder60yearsofagewithbilateraltinnitusanddailycoffeeconsumption between 150and300mLaremorepronetobenefitfromconsumptionreduction. Thirty-day observationperiodsmaybehelpfulforabettertherapeuticaldecision.

© 2014Associac¸ãoBrasileira de Otorrinolaringologiae CirurgiaCérvico-Facial. Publishedby ElsevierEditoraLtda.Allrightsreserved.

PALAVRAS-CHAVE Zumbido;

Cafeína; Café

Efeitosdareduc¸ãonoconsumodecafeínasobreapercepc¸ãodozumbido

Resumo

Introduc¸ão: Oconsumoabusivo decafeínavemsendodescritocomo fatordepiora ecausa dozumbidohámuitosanos.Afisiopatologiadesteefeitoestáprovavelmenterelacionadaao bloqueiodosreceptoresinibitóriosadenosínicospelacafeínanosistemanervosocentral.

Objetivo: Avaliarosefeitosdareduc¸ãodo consumode cafeínanapercepc¸ãodozumbidoe identificarsubgruposdepacientesmaispropensosabenefícioscomestaproposta.

Tipodeestudo:Prospectivo.

Métodos: Selecionados26pacientescomzumbidoneurossensorialeconsumodiáriosuperiora 150mLdecafé.Osefeitosdareduc¸ãodoconsumoforamavaliadosatravésdoTinnitusHandicap Inventory(THI)edaescalavisual-análoga(EVA).

Resultados: Houvereduc¸ãoestatisticamentesignificativa(p<0.05)nosescoresdoTHIeEVA. Nossubgruposcomidadeinferiora60anos,zumbidobilateraleconsumodiáriodecaféentre 150e300mLapresentarammaiorreduc¸ãodosescoresTHIeEVA.

Conclusão:Empacientescomidadeinferiora60anos,zumbidobilateraleconsumodiáriode caféentre150e300mLapresentarambenefícioscomareduc¸ãonoconsumodiáriodecafeína. Períodosobservacionaisde30diaspodemserúteisparaadecisãoterapêutica.

©2014Associac¸ãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial.Publicado por ElsevierEditoraLtda.Todososdireitosreservados.

Introduction

Caffeine,also knownasmethyltheobromin, is part of the groupofmethylxanthines,andisconsideredthemostwidely usedpsychoactivesubstanceintheworld.Themajorityof itsconsumptionisderivedfromdietarysourcessuchas cof-fee,tea,colasoftdrinks,andchocolate;themoststriking behavioral effects are increasesin alertness, energy, and concentration skills. These effects are more pronounced afteringestionofsmalltomoderateamounts(50---300mg).1 The caffeinecontent by coffee cup varies depends on theformofpreparation(Table1).1_{InBrazil,thepercapita} consumption, according to the Associac¸ão Brasileira de IndústriasdoCafé(ABIC),is currentlyabout73Lperyear, andthefiltrationmethod ofpreparationisthemost com-monly used.2 _{A worldwide trend toward increased coffee} consumptionhasbeennoted.Thecaffeinecontentofother beverages varies, on average, from 32 to 42mg/150mL (tea), 32 to70mg/330mL (cola beverages), and approxi-mately4mg/150mL(chocolateflavoredmilk).1

The absorptionof caffeineinthe gastrointestinaltract israpid,reaching99%after45min.Peakplasmalevelsare achievedbetween15and120minafteroralingestion,and thehalf-lifeisabout 2.5---4.5h.Caffeineismetabolizedby theliver.1

Currently, most authors believe that the main mecha-nismofaction ofcaffeineistheantagonismofadenosinic

receptors.1,3---5_{Adenosinereducesthefiringrateofneurons,} exertingan inhibitoryeffect onsynaptictransmissionand inthe releaseof various neurotransmitters. In1993, Daly observed increased brain levels of norepinephrine, gluta-mate,andadrenalineaftercaffeineintake.3_{Theadenosinic} receptorsinvolvedwiththeeffectsofcaffeineareA1and A2.Neurostimulanteffects of caffeinehave been demon-stratedinfunctionalimagingstudies.6

A2 adenosinic receptors interact with dopaminergic receptors in the nucleus striatum and nucleus accum-bens by modulating them. Therefore, the blockage of thesereceptors,exertedbycaffeine,couldpotentiatethe dopaminergicneurotransmission.1

Table 1 Amount of caffeine in various forms of coffee preparation.

Coffeepreparation Volumeof cup(mL)

Caffeine content (mg/cup)

Coction(boiling) 150---190 111---177 Filtering 50---190 28---161 Espresso 50---150 74---99 Percolation 150---190 55---88 Instant(soluble) 50---190 19---34

Otherdemonstratedactionsofcaffeineincludeincreased releaseof intracellularcalciumandinhibitionof phospho-diesterases;seemingly,thesemechanismsareunrelatedto thecentraleffectsofcaffeine.1

In addition to the neuroexcitatory effects, caffeine also has a vasoconstrictor effect, and this is the pre-dominant effect at higher doses.6 _{Studies with blood} oxygenation level-dependant (BOLD) functional magnetic resonance imaging demonstrated a reduction in cerebral perfusionaftercaffeineintake.Some authorsbelievethat the neurostimulant effects of caffeine are due primarily toitsactiononA1receptors,whereasthevasoconstrictor effectsarerelatedtoitseffectsonA2receptors.6

Basedontheseneurostimulanteffectsofcaffeine, sev-eralstudiesaddressedtheeffectsofthissubstanceonthe centralauditory pathways.4---8 _{Loristetal. found} improve-ment of the central auditory processing after caffeine intake5_{andKawamuraetal.}6_{foundincreaseinthe} ampli-tudeandareaofP300approximately30minaftercaffeine ingestion.

Dixit et al.4_{, also studying the effects of caffeine on} P300,observed an increase in P3amplitude and reduced reactiontime,indicatingfacilitationofauditoryprocessing andaccelerationofmotorresponses.Inanotherstudy,the sameauthors found asignificant reductionin latencies of wavesIVandVinauditorybrainstempotentials(ABR),and asignificantdecreaseintheI---Vinterval.9

In the cochlea, it was demonstrated that caffeine inducedshorteningofouterhaircells (OHC).10---12 _Thisfact wouldhavesomebearingontherapidcontractionofOHC, increasingtheexcitabilityoftheperipheralauditory path-waysThereisdisagreementabouttheeventsinvolvedinthis shortening. Slepecky et al.10_{, in a 1988 study, suggested} thattheshorteningofOHCoccursbymechanismsassociated withrianodinicreceptors.Conversely,Yamamotoetal.11_,in 1995,suggested thatOHC depolarizationoccursby potas-siumchannelblockage.Finally,Skellett etal.12_,inastudy from1995,suggestedanosmoticmechanism.

Mostclinicalstudiesontheeffectsofcaffeinein otoneu-rologyrefertochangesinthevestibularsystem.13---15_Several authors suggest a daily intake of up to three small cups (50mL) of filtered coffee asa beneficial practice for the treatment,andmayevenpotentiatethetherapeuticeffects ofsomemedications.15_{Abovethisdose,thevasoconstrictor} effectswouldpredominate.

Withregardtotinnitus,severalauthorssuggestreducing theintake of caffeine asa supplementary treatment,16,17 butintheonlycontrolledstudyeverconducted,18_beneficial effectsofcaffeinereductionontinnituswerenotobserved. Themainobjectiveofthisstudywastoassesswhether sen-sorineuraltinnituspatientscanobtainsomebenefitfromthe reductionofcaffeineintake.The secondaryobjectivewas totrytoidentifythe subgroupsof patientsmost likelyto benefitwiththisstrategy.

Methods

Thiswasacontemporarylongitudinalcohortstudy.The sam-plesizewasinitiallydeterminedconsideringassignificanta differenceof20pointsinTHI scoreandof2 pointsinVAS score(Fig.1)intheintervalfromthebeginningtotheendof

Visual analogue scale (VAS)

0

1

2

3

4

5

6

7

8

9

10

Figure1 VisualAnalogScale(VAS).

thestudy.Consideringastatisticalpowerof0.80,the min-imumsamplesizewassetat16patients(fordifferencesin THIscoresandVSAinferiorto20and2points,respectively, therequiredsamplesizewouldbeevensmaller).

Thisstudyincluded26patientswithsensorineural hear-ingloss,aged24---76yearsold,15males,treatedincenters participatinginthestudybetweenJanuary2008and Decem-ber2009.

Thefollowingcriteriawereused: Inclusioncriteria

• Patientswithtinnitusformorethansixmonths • Non-useofcentrallyactingdrugsinthelastsixmonths

• TympanogramtypeA-n

• Dailycoffeeintakeexceedingthreesmallcups/day (cor-respondingto150mL/day)

• Ageover18yearsold.

Exclusioncriteria:

• THI<16points

• Tinnitusofmuscularandvascularorigin

• Audiogramswithconductiveandmixedhearingloss

• Association with disorders of the temporomandibular joint.

At first visit, patients underwent a complete otorhi-nolaryngological exam. In the same consultation, tonal andvocalaudiometryandimitanciometrywereperformed. PatientsincludedinthestudycompletedtheTinnitus Hand-icap Inventory (THI), in itsversion validated for Brazilian Portuguese,19 _{andalsoquantifiedthetinnituswithrespect} tothediscomfortandintensity,accordingtoaVisualAnalog Scale(VAS)gradedfrom1(minimalannoyance/intensity)to 10(maximumannoyance/intensity).

Table2 Generalcharacterizationofsample.

Characteristics Frequency

n %

Coffeeintake(mL)

≤300 9 40.9

>300 13 59.1

Age(years)

<60 12 54.5

≥60 10 45.5

Laterality

Bilateral 14 63.6

Unilateral 8 36.4

Aweeklycontactbyphonecallwasestablishedtoconfirm thereductionofconsumption.AnewreassessmentwithTHI andVASwasperformedafter30days,andallpatientswho did not achieve the aforementioned reduction goal were excluded.

The absolute change of the situation before/after the treatmentwasgivenbythefollowingformula:

THI/VSA=(finalTHI/VSA−initialTHI/VSA

AsthemaincriterionforreductionofTHI,thelevelofseven pointswasused,i.e.areductionofsevenpointsinthescore wasconsideredasanimprovement,accordingtothestudy byZemanetal.20_{Symptomsrelatedtocaffeinewithdrawal} wereregistered.

Thestatisticalanalysisconsistedofthefollowingtests: Comparisons betweenthe characteristics and improve-ment of THI wereperformed usingFisher’sexact test (at leastoneexpectedfrequency<5).

Then. the adjustment of the logistic model containing thecharacteristicswithp-value<0.25wasperformed.Only those characteristics with p-value <0.05 remained in the finalmodel.Allinteractionsweretested.

Finally,theSpearmancorrelationcoefficientwasapplied toassessthedegreeofassociationbetweennumerical varia-blesandTHI/VAS.

Thecriterionfordeterminingthesignificancewassetat 5%. The statistical analysis wasperformed by SAS version 6.11(SASInstitute,Inc.---Cary,NorthCarolina),Rversion 2.7.1,and EpiInfoversion 6.04.The latter twoarepublic domainprograms.

The study was approved by the Ethics Committee for MedicalResearchunderCAAEnumber---0002.0.334.000-08.

Table3 Descriptionofcoffeeintakelevels,age,and lat-eralityofthesample.

Characteristic Improvement p-Value

Yes No

n % n %

Coffeeintake(mL)

≤300 7 77.8 2 22.2 0.027a

>300 3 23.1 10 76.9

Age(years)

<60 8 66.7 4 33.3 0.043a

≥60 2 20.0 8 80.0

Laterality 9 64.3 5 35.7 0.03a

Bilateral 287.5

Unilateral 1 12.5 7 87.5

a _{Fisher’sexacttest.}

Results

Ofthe26patientsinitiallyincluded,fourdidnotreturnfor thesecond evaluation. Table2 shows general dataof the sample,andTable 3liststhesubcategories distributionof the22patientswhocompletedthestudy.

Ofthe22patientswhocompletedthestudy,therewas improvement in the THI scores (reduction of at least 7 points)intenofthem(45.5%).Theobservedmeandecrease was10.2pointsforTHIand0.86pointsforVSA;bothwere statisticallysignificant (p=0.030and 0.017,respectively). Table4presentsthedescriptionofinitialandfinalTHIand thevariation(final−initial).

Table 5 shows the comparison of coffee intake, age, andlateralitywithimprovementof THI.Allfeatureswere selectedforinclusionintheinitialmultivariatemodel.

Interpretingoneoftheintersections,forinstance,among the nine patients who consumed up to 300mL of coffee perday,seven(77.8%)showedimprovementinTHI.Among the13patientswhoconsumedmorethan300mL/day,three (23.1%)showedimprovementinTHI.Withap-valueof0.027, thisfeaturewasselectedtobeincludedintheinitial multi-variatemodel.

Table6showstheadjustmentsoftheregressionmodels. Threelogisticregressionmodelswereelaborated.

Thus, itwas observed thatthose whoconsumed up to 300mLofcoffeehadapproximately12timesthechanceof improvementinTHIversuspatientswhoconsumemorethan 300mLofcoffee(95%CI:1.5---89.1).

In addition, patients younger than 60 years had eight timesthechanceofimprovementinTHIversusthoseaged

Table4 DescriptionofinitialandfinalTHI,andvariation(THI=finalTHI−initialTHI).

Characteristics n Mean SD Minimum 1stQ Median 3rdQ Maximum

THI,initial 22 46.6 19.9 16.0 27.0 51.0 63.0 78.0

THI,final 22 36.4 18.4 14.0 16.0 34.0 52.5 66.0

THIvariation 22 −10.2 19.4 −56.0 −19.0 −6.0 4.0 12.0

Table5 Comparisonbetweencoffeeintake,ageandlateralityandimprovementofTHIscores.

Variable n Mean SD Median Minimum Maximum

Age(years) 26 56.9 14.1 58.5 24 76

Tinnitustime(years) 26 6.44 6.30 5 0.5 20

Totalcoffeeintake/day(mL) 26 509.6 292.6 400 150 1200

THI,initial 26 48.8 21.9 53 16 100

VAS,initial 26 6.88 1.84 6.5 5 10

SD,standarddeviation.

Table6 Logisticregressionmodel.

Models Coefficient Standarderror p-Value OR 95%CI

Inferior Superior

ModelI

Constant −1.2 0.7 0.067

Coffeeintake(mL)

≤300 2.5 1.0 0.018 11.7 1.5 89.1

>300 1.0

ModelII

Constant −1.4 0.8 0.008

Age(years)

<60 2.1 1.0 0.038 8.0 1.1 56.8

≥60 1.0

ModelII

Constant −1.9 1.1 0.069

Laterality

Bilateral 2.5 1.2 0.036 12.6 1.2 133.9

Unilateral 1.0

OR,oddsratio.

over 60 years (95% CI 1.1---56.8). Patients with bilateral tinnitushadapproximately13timesthechanceof improve-mentin THI versus thosewithunilateral tinnitus (95% CI, 1.2---133.9).

Analyzingthequantitativevariable‘‘coffeeintake’’(in mL)bythe Spearmancoefficient relativetoTHI,Fig.2 wasobtained,confirmingpreviousdata(thehigherthe cof-feeintake,thelowertheobserveddecreaseinTHIandVAS). Ofthe22patientswhocompletedthestudy,onlyone(4.54%) showedasideeffect(anxiety),possiblyassociatedwiththe

80

60

40

20

–20

–40

–60

–80

–100

r₁ = 0.581: p=0.005

Total daily coffee intake (mL)

Δ

TH

I

queda

aumento

0 100 200 300 400 500 600 700 800 900 10001100 12001300 0

Figure2 AnalysisofTHI,accordingtodailycoffeeintake (Spearmancoefficient).

caffeine reduction. This patient consumed an average of 1200mLofcoffeedaily.

Discussion

Severalarticlesontinnitushave recommendedthe reduc-tionofcaffeineconsumpion,16_{butuntilrecently,therewere} nospecificstudiesonthissubject.Theoretically,the stimu-latingactionofcaffeineonthecentralnervoussystemcan playaroleintheexcitabilityoftheauditorypathwaysand, therefore,canmodifysomeclinicalaspectsoftinnitus.9

Inarecentstudy(2010)18_{,theeffectsoftheremovalof} caffeineontinnitusin patientswhoconsumed >150mg of caffeinedailywereevaluated.Inthispseudo-randomized, crossed-over, placebo controlled study of 66 patients, no evidencetojustifyareductionincaffeineintakewasfound. Conversely, some side effects caused by withdrawal from caffeinewerenoted.Accordingtotheauthors,theseeffects couldalsoleadtoaworseningoftinnitus.

difficult, sincechroniccaffeineuserscan easily recognize the removalof this substance, regardless of theflavor of thebeverage.1

Despitethestatisticalsignificanceofdatafound inthis study(areductionof10.2pointsinTHIand0.86pointsin VAS),itwasobservedthattheeffectsofreducingcaffeine intakeonatinnituspopulationasawholewouldbesmall, accordingtothecriteriausedbyNewman,whichrequireas significantvariations≥20pointsforTHI.21Onlyfour(18.4%) of22patientsshowedsuchreduction.Conversely,thestudy byZemanetal.demonstratedthatdifferencesof6---7points in THI scores are clinically relevant.20 _{In this case, ten} patients (45.5% of the total sample) of this study fit into thisprofile. Inthesubgroup analysis,itwasfound thatin subgroupswith<60years,bilateraltinnitus,andinitialdaily intake up to300mL, the reduction in THI scores reaches closeto20points.As apossibleexplanationfor these dif-ferences,itmaybesurmisedthatelderlypatientsprobably presentagreaternumberoffactorsinvolvedinthe percep-tionoftinnitus,suchaspresbycusisanduseofmultipledrugs totreatvariousmedicalconditions.

Patientswithhighercoffeeintakemaybemore suscepti-bletosymptomsafterwithdrawalfromcaffeine,asreported bySt.Claireetal.18_{Althoughonlyoneofthepresentstudy’s} patientshaveshownsignscompatiblewithwithdrawal,the possibilitythattheworseningofthetinnitusisasymptom relatedtoabstinencecannotberuledout,whichcould out-weighanypotentialbenefitofareductionincaffeineintake. Furthermore, the present study did not examine the percentage of caffeine reduction in each patient. Thus, consideringthemethodologyused,thegreatertheamount ofcaffeineconsumed,thegreatertheimpactcausedbythe reductionofintake,whichcouldberesponsiblefora possi-bleworseningoftinnitus,relatedtocaffeinewithdrawal.

Consideringthedata,theauthorsbelievethatthis repre-sentsanappropriatemanagementstrategyforeachpatient. Whiletherearenodatasupportingthebeneficialeffectsof reducingcaffeineforalltinnituspatients,somesubgroups, suchasyoungpatientswithbilateraltinnitusandthosewith moderatecaffeineintakearemorelikelytoimprove.

Muchliketheproceduresforvestibulardisturbances,and considering thepossible effectsof an abruptreductionof caffeineintake,perhapsthebestoptionisagradual reduc-tion,ratherthanthecompletesuppressionofthissubstance. Periodsof30daysofobservationappeartobesufficientto evaluateapossiblebeneficialeffectandshouldberoutinely usedintherapeutictests.

Conclusion

Theresultsobtainedinthisstudysuggestthatthereisno jus-tificationfortheuniversalrestrictionofcaffeineintakeasa treatmentforallpatientswithtinnitus.However,patients youngerthan60years,withbilateraltinnitus,andwithdaily coffeeintakebetween150and300mLpresentgreater ben-efits.Theobservationperiodof30daysmaybeusefulfor thetherapeuticdecision.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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