Alberto Rodríguez-Archilla , Tarik Raissouni for recurrent aphthous stomatitis Randomized clinical trial of the effectiveness of complementarytherapies

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w w w . e l s e v i e r . e s / m e d i c i n a c l i n i c a

Original article

Randomized clinical trial of the effectiveness of complementary therapies for recurrent aphthous stomatitis

^夽

Alberto Rodríguez-Archilla

^a,∗

, Tarik Raissouni

^b

aMedicinaOral,FacultaddeOdontología,UniversidaddeGranada,Granada,Spain

bCentroOdontológicoM’fedalAfailalBabOkla,Tetuán,Morocco

a r t i c l e i n f o

Articlehistory:

Received22September2016 Accepted22December2016 Availableonline3July2017

Keywords:

Complementarytherapies Juglans

Propolis Rheum Silvernitrate Stomatitis,aphthous

a b s t r a c t

Backgroundandobjective:Despitethehighprevalenceofrecurrentaphthousstomatitis(RAS),itsaeti- ologyisnotyetcompletelyclearandthereisnocompletelyremedialtreatmentavailableatpresent.

Theobjectiveofthisstudywastoevaluatetheclinicalefﬁcacyandsafetyof4treatments(silvernitrate, propolis,rhubarbandwalnut)forRAS.

Patientsandmethod:Arandomizedclinicaltrialwasconductedwith125patientswithminoraphthae, including25patientspergroup:cauterizationwithsilvernitrate,propolis,rhubarbextract,walnutextract andplacebo.

Resultsandconclusions:Nopatientreportedadverseeffectsrelatedtothetreatmentreceived.Therewere signiﬁcant(p<0.001)differencesinthetimeelapseduntilsymptomresolution.Thefastesttreatmentwas silvernitrate(1.16days),followedbythe3alternativetreatments(1.60dayswithpropolis,1.84with rhubarband2.00withwalnut;withnodifferencesbetweenthem),andﬁnallytheplacebo(4.64days).

Themeanhealingtimeofthelesionswasstatisticallyhigher(8.96days)fortheplacebothanforthe4 treatments:silvernitrate(7.32days),propolis(6.80),rhubarb(7.72)andwalnut(8.00).

Ensayoclínicoaleatorizadosobrelaefectividaddetratamientosalternativos enlaestomatitisaftosarecurrente

Palabrasclave:

Estomatitisaftosarecurrente Extractodenogal

Extractoderuibarbo Nitratodeplata Própolis

Tratamientosalternativos

re s um e n

Fundamentoyobjetivo: Apesardelaelevadaprevalenciadelaestomatitisaftosarecurrente(EAR),su etiologíanoestádeltodoaclaradaynoexisteuntratamientototalmentecurativo.Elobjetivodeeste trabajofueevaluarlaeﬁcaciaclínicaylaseguridadde4tratamientos(nitratodeplata,própolis,ruibarbo ynogal)delaEAR.

Pacientesymétodo:Serealizóunensayoclínicoaleatorizadocon125pacientesconaftasmenores,con 25pacientesporgrupo:cauterizaciónconnitratodeplata,própolis,extractoderuibarbo,extractode cortezadenogalyplacebo.

Resultadosyconclusiones:Ningúnpacientereﬁrióefectosadversosrelacionadosconeltratamiento.Hay diferenciassigniﬁcativas(p<0,001)globaleseneltiempohastaladesaparicióndelossíntomas.Elmás rápidofueelnitratodeplata(1,16días),despuéslos3tratamientosalternativos(1,60díasconprópolis, 1,84conruibarboy2,00connogal,sindiferenciasentreellos),yporúltimoelplacebo(4,64días).En cuantoaltiempomediodecuracióndelaslesiones,fueestadísticamentemayor(8,96días)paraelplacebo queparalos4tratamientos:nitratodeplata(7,32días),própolis(6,80),ruibarbo(7,72)ynogal(8,00).

夽 Pleasecitethisarticleas:Rodríguez-ArchillaA,RaissouniT.Ensayoclínicoaleatorizadosobrelaefectividaddetratamientosalternativosenlaestomatitisaftosarecurrente.

MedClin(Barc).2017;149:55–60.

∗ Correspondingauthor.

E-mailaddress:[email protected](A.Rodríguez-Archilla).

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Introduction

Recurrentaphthousstomatitis(RAS)isthemostcommonulcer- ativediseaseoftheoralmucosa,affectingapproximately20%ofthe generalpopulation.¹RASischaracterizedbythedevelopmentof oneormorepainfululcers(aphthousulcers),coveredbyawhite orgreyish pseudomembraneand surroundedbya well-deﬁned erythematoushalo.The lesionsare usually locatedin the non- keratinizedoralmucosa,maypersistfordaysorweeksandpresent recurrencesafterveryvariableremissionperiods.²Accordingtothe sizeofthelesions,threeclinicalformsofRAShavebeendescribed:

minoraphthousulcers, major aphthousulcers and herpetiform aphthousulcers.³

RASisadiseaseofunknownorigin,sothereisnospeciﬁctreat- mentforit.ThetreatmentofRASisbasicallyaimedatminimizing symptoms and preventing recurrences. The choice of a topical and/orsystemictreatmentwilldependontheseverityofthesymp- toms,thesizeandnumberoflesions,aswellasthefrequencyof recurrentepisodes.¹

A wide variety of therapeutic agents are currently used for the treatment of RAS. The topical treatment includes:

analgesic-anti-inﬂammatory drugs (aminosalicylic acid, benzy- damine,amlexanox,hyaluronicacid,lacticacid);localanaesthetics (lidocaine, xylocaine); topical antibiotics (tetracyclines); anti- septic agents (chlorhexidine, hexetidine, hydrogen peroxide, povidoneiodine);cytoprotectors(sucralfate,carbenoxolone,car- boxymethylcellulose);chemicalcauterizers(silvernitrate,sulfuric acid derivatives); antihistamines (diphenhydramine, dexchlor- pheniramine);localphysicaltreatments(laser,ultrasound);orthe mostfrequentlyused,topicalcorticosteroids(hydrocortisone,triamcinolone, dexamethasone,clobetasol). Systemic treatment is indicated inpatientswithout response totopicaltherapy, with majoraphthousulcersandwithveryfrequentrecurrences.Oral corticosteroids(prednisone),immunosuppressants(cyclosporine, cyclophosphamide,azathioprine,chloroquine)orimmunodulators (colchicine,levamisole,pentoxifylline,thalidomide)^1,4–6areused.

TheWorldHealthOrganizationestimatesthatone-thirdofthe world’spopulationdoesnothaveregularaccesstomodernbasic medicines.InpartsofAfrica,AsiaandLatinAmerica,almosthalfof thepopulationfacesapersistentshortageofthesedrugs.However, asanalternative,theyhavetraditional medicine,easilyaccessi- bleandrelativelyinexpensive.Similarly,theuseofbothmedicinal plantsandalternativeandcomplementarymedicineisincreasing indevelopedcountries.⁷

Alternativetherapies havealso beenproposedforthetreat- ment of RAS, mainly based on the use of different medicinal plants.^5,8,9Althoughmanyoftheseremediesareconsideredtobe fairlysafeandmaybevalidforthetreatmentofRAS,consideration shouldbegiventothepossibilityofinteractionwithconventional medications.^10,11

InMorocco,traditionalmedicinewithremediesbasedonthe useofmedicinalplantsisacheapandaffordablesourceforalarge partofthepopulation,especiallytheruralpopulation.Thus,inthis study,severalnaturaltherapeuticagentsthatareeasilyaccessible forpatientsinthisgeographicenvironmentinNorthAfricaareana- lyzedasanalternativetoconventionalpharmacologicaltreatments forRAS.¹²

Theobjectiveofthisstudywastoevaluatetheclinicalefﬁcacy andsafetyof4therapeuticoptions(silvernitrate,propolis,rhubarb extractandwalnutextract)againstaplaceboforthetreatmentof RAS.

Patientsandmethods

Arandomizedclinicaltrialwasconducted,followingtheCON- SORTguidelines,¹³with125patientswhocametoreceivedental

careforcankersorestoadentalofﬁceinTetuan(Morocco)inthe periodbetweenJanuary2013andJune2016.Apriori,patientswho cameduetoapainfullesionintheoralmucosaand,onthesameday, afterexaminationbythedentist,provedtobeacankersore;thatis, traumainjuriessuchasburns,self-cuts,etc.wereexcluded.Inclu- sioncriteriaincludednotbeingaregulardrinker/smoker,patients withknownalterationsin thebloodcountand thosewithsys- temicdiseasesrelatedtothedevelopmentoforalulcers.Thestudy protocolwasapprovedbytheHumanResearch EthicsCommit- teeoftheFacultyofDentistryoftheUniversityofGranada(Ref.

FOD-UGR-012/2013).Patientswereprovidedwiththenecessary informationaboutthepurposesofthisstudyinordertoobtaintheir consent.

Thecalculationofthesamplesizewasperformedtocomparethe quantitativeeffectvariables(daysofsymptom/lesionremission) withapowerof80%,analphaerrorof5%andtodetectastandard- izeddifferenceof0.8,substantialaccordingtotheCohenscale.¹⁴ Twenty-ﬁvepatientswouldbeneededineachgroup,accordingto SamplePower2.0(SPSSInc.,Chicago,IL,USA).

Ofthe173patientswithaphthousulcerstreatedsequentially in the clinicduring the 3 years of the study, the125 patients included (who met the inclusion criteria and who agreed to participate in the study) (Fig. 1) were enumerated from 1 to 125dependingontheirorderofentryintothestudy.Withthe helpofacomputerprogram,patientswererandomlydistributed in 5 groups of 25, one for each therapeutic option, including placebo.Thetreatmentswereadministeredbya dentalhygien- ist, except silver nitrate, which was applied by thedoctor. All patientswerediagnosedandtreatedontheﬁrstdayoftheirlesion development.

Theagentsusedwerethefollowing:

a)Silvernitrate(Argenpal^®,B.BraunMedical,SA,Barcelona,Spain).

Itisadministeredintheformof50mgbarsfordirectapplication onlesions.Theadministrationofthisdrugwasperformedby thedoctorinthedentalofﬁce,inasinglesession.Fiveminutes beforeapplyingthecausticagentthelesionswereanesthetized withaspraycontaining10%lidocaine(Xilonibsa^®,Aerosol10%, Barcelona,Spain).Immediatelypriortotheuseofsilvernitrate, topreventburnsinthehealthytissuesurroundingthelesion, theperilesionalareawasprotectedwithpetroleumjelly.After application,thepatientwasinstructedtorinsethoroughlywith water.

b)18%propolisadministeredinaerosolform(OropropolisSpray Buccal^®,LaboratoirePharmasoft,Fez,Morocco).

c)5%rhubarbextract(Rheumpalmatum)administeredasasolu- tionwithanapplicatorbrush(SouakineSoluté^®,Cosmetique Medicale,Rabat,Morocco).

d)5%extractofwalnutbark(Juglansregia),whichisadministered asasolution(PyralvexSoluté^®,LaboratoiresNorginePharma, Casablanca,Morocco).

e)Finally, theplacebo iscomposedof ﬂavoured distilled water administered as an aerosol. In the treatments of propolis, rhubarb, walnut, or placebo, the patient was instructed to apply/spray3timesa day,and wasaskedtoavoideatingor drinkingaftertheadministrationforaslongaspossibletoopti- mizeitspermanenceandactiononthelesion.

Inadditiontothetreatmentapplied,datawerecollectedon eachpatient’sage,sex,numberoflesionsperepisode,morphology andlocation,recurrencerate(numberofepisodes/year),possible treatmentadverseeffects(badtaste,burningintheapplicationsite, allergytosomecomponent,interactionwithotherdrugs,etc.)and thetimetoremission(indays)ofbothsymptomatologyandlesions afterstartingtreatment.

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Evaluated for selection (n = 173)

Excluded (n = 48)

Randomized (n = 125)

No group experienced loss of follow-up or intervention interruption

Silver nitrate Propolis Rhubarb

Analysed (n = 25)

AnalysisFollow-upAssignmentRecruitment

Analysed (n = 25)

Walnut Placebo

Assigned and administered (n = 25)

Did not meet the selection criteria (n = 36)

Refused to participate (n = 8) Other reasons (n = 4)

Assigned and administered (n = 25)

Fig.1.Flowchartshowingphase-progressoftherandomizedclinicaltrial.

Thetreatmentshavedifferentadministrationvehicles(theyare marketedproducts)and,therefore,thestudyisnotblindtothe patient,exceptfortheplacebogroup,asitwasindicatedthatit wasanadditionaltreatment.Thetimetosymptomremissionwas assessedbythephysicianthroughdailytelephonefollow-up,advis- ingthepatienttogototheclinicwhenthesymptomshadceased, allowingthecliniciantoverifytheresolutionofthelesions.The clinicianwasblindtothetreatmentreceived,exceptinthecaseof theresolutionoflesionsthroughsilvernitrate.Nopatientdiscon- tinuedtreatment.

Data wereprocessedusingthestatistical softwareIBM SPSS Statistics22.0 (IBMCorp.,Armonk, NY,USA), withthemethods speciﬁedatthebottomofeachtableofresults.Avalueofp<0.05 wasconsideredaminimumlevelofsigniﬁcance.Theexpertwho performedtheanalysiswasblindtothegroupassignedtoeach patient.

Results

Table1showsthedescriptionofthepatientsatbaseline.The mean age±standard deviationof the125 patientswas33±12 years, 46 menand 79 women.The majority(75.2%) had a sin- gle lesion, predominating a rounded morphology (54.4%). The mostfrequentsiteswerethetongue(28.8%)andthelowerlabial mucosa(25.6%).Onaverage,therewere3.11episodes/year.Noneof thesevariablesshowedstatisticallysigniﬁcantdifferencesaccord- ing togroup. Otherbaseline data not shown in Table1 are as follows: whencomparingagewithsomeclinicalparameters of the study, a higher mean age was observed in patients with

irregular morphology lesions (43±7 years) compared to those withrounded(33±13years)orovalmorphology(31±12years) (p<0.001,withANOVA).Comparisonofagewiththerestofthe parameters(numberoflesions,lesionsite,annualrecurrencerate, disappearanceofsymptomsand/orlesions)wasnotstatistically signiﬁcant.

Table2showstimetoremission(indays)regardingsymptoma- tologyandlesions.Signiﬁcantdifferenceswereobserved(p<0.001) overtimeuntilthedisappearanceofsymptoms.Thefastestwas silvernitrate(1.16days,95%CI1.01–1.31)(1.60dayswithpropo- lis,1.84withrhubarband2.00withwalnut,withnodifferences betweenthem),andﬁnally,placebo(4.64days).Asforthemean time tolesionhealing,it wasstatisticallyhigher(8.96days)for placebothanforthe4treatments:silvernitrate(7.32days),propolis(6.80),rhubarb(7.72)andwalnut(8.00).Inmostpatientstreated withsilvernitrate,thesymptomsdisappearedafteroneday;most patientstreatedwithpropolis,rhubarbextractorwalnutextract, after2days;andinmostofthosetreatedwithplacebo,thesymp- tomsdisappearedafter5days.Finally,althoughnotshowninthe tables,noadverseeffectsrelatedtothedifferenttreatmentsapplied wereobservedduringfollow-up.

Discussion Validityofthestudy

Thisstudypresentssomelimitationsderivedfromitsdesign, butwebelievethattheydonotcompromiseitsvalidity.Inrelation tointernalvalidity,theacceptancerate(only8patientsdeclined

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Table1

Baselinedescriptionofpatientswithrecurrentaphthousstomatitis(n=125).

Variable All(n=125) Group Overallp-value

Silvernitrate(n=25) Propolis(n=25) Rhubarb(n=25) Walnut(n=25) Placebo(n=25) Age(years)

Range 8–56 8–51 11–56 12–56 13–56 12–54

x¯±SD 33±12 33±11 31±14 34±13 36±13 30±11 0.559^a

Sex,n(%)

Male 46(36.8) 8(32.0) 8(32.0) 10(40.0) 9(36.0) 11(44.0)

Female 79(63.2) 17(68.0) 17(68.0) 15(60.0) 16(64.0) 14(56.0) 0.883^b

No.oflesions,n(%)

1 94(75.2) 19(76.0) 17(68.0) 22(88.0) 17(68.0) 19(76.0)

2 26(20.8) 6(24.0) 6(24.0) 1(4.0) 7(28.0) 6(24.0)

3 5(4.0) – 2(8.0) 2(8.0) 1(4.0) –

x ±¯ SD 1.29±0.54 1.24±0.44 1.40±0.65 1.20±0.58 1.36±0.57 1.24±0.44 0.630^a

Morphologyoflesions,n(%)

Rounded 68(54.4) 13(52.0) 14(56.0) 15(60.0) 13(52.0) 13(52.0)

Oval 45(36.0) 9(36.0) 9(36.0) 6(24.0) 11(44.0) 10(40.0)

Irregular 12(9.6) 3(12.0) 2(8.0) 4(16.0) 1(4.0) 2(8.0) 0.861^b

Locationoflesions,n(%)

Tongue 36(28.8) 8(32.0) 4(16.0) 9(36.0) 8(32.0) 7(28.0)

Lowerlipmucosa 32(25.6) 6(24.0) 7(28.0) 6(24.0) 4(16.0) 9(36.0)

Upperlipmucosa 13(10.4) 2(8.0) 3(12.0) 2(8.0) 2(8.0) 4(16.0)

Buccalmucosa 9(7.2) 1(4.0) 2(8.0) 4(16.0) 1(4.0) 1(4.0)

Softpalate 8(6.4) 2(8.0) 1(4.0) 1(4.0) 3(12.0) 1(4.0)

Several 27(21.6) 6(24.0) 8(32.0) 3(12.0) 7(28.0) 3(12.0) 0.435^c

Annualrecurrencerate,n(%)

Onceayear 3(2.4) 1 1(4.0) 1(4.0) – 1(4.0)

2times/year 37(29.6) 7(28.0) 6(24.0) 8(32.0) 7(28.0) 9(36.0)

3times/year 49(39.2) 10(40.0) 8(32.0) 10(40.0) 11(44.0) 10(40.0)

4times/year 19(15.2) 4(16.0) 4(16.0) 4(16.0) 4(16.0) 3(12.0)

5times/year 13(10.4) 4(16.0) 5(20.0) – 2(8.0) 2(8.0)

6times/year 4(3.2) – 1(4.0) 2(8.0) 1(4.0) –

x¯±SD 3.11±1.12 3.20±1.04 3.36±1.29 3.00±1.19 3.16±1.07 2.84±0.99 0.535^a

¯x ±SD:media±standarddeviation.

aANOVA.

b Chisquared.

c Chisquareaftercollapsinginto3categories:tongue,labialmucosaandtherest.

Table2

Time(days)untildisappearanceofrecurrentaphthousstomatitissymptomsandlesions(n=125).

Untilthedisappearanceof: Group Comparison

Silvernitrate[A]

(n=25)

Propolis[B]

(n=25)

Rhubarb[C]

(n=25)

Walnut[D]

(n=25)

Placebo[E]

(n=25)

Overallp-value^a Inpairs^b

Symptoms,n(%)

Oneday 21(84.0) 10(40.0) 8(32.0) 4(16.0) –

2days 4(16.0) 15(60.0) 13(52.0) 17(68.0) –

3days – – 4(16.0) 4(16.0) –

4days – – – – 10(40.0)

5days – – – – 14(56.0)

6days – – – – 1(4.0)

x ±¯ SD 1.16±0.37 1.60±0.50 1.84±0.69 2.00±0.58 4.64±0.57 <0.001 A/=BCD /=E

95%CI 1.01–1.31 1.39–1.81 1.56–2.12 1.76–2.24 4.41–4.87

Lesions,n(%)

6days 6(24.0) 9(36.0) 2(8.0) 1(4.0) –

7days 7(28.0) 12(48.0) 9(36.0) 4(16.0) –

8days 11(44.0) 4(16.0) 11(44.0) 17(68.0) 9(36.0)

9days – – – – 9(36.0)

10days 1(4.0) – 3(12.0) 3(12.0) 6(24.0)

11days – – – – 1(4.0)

x¯±SD 7.32±0.99 6.80±0.71 7.72±1.06 8.00±0.91 8.96±0.89 <0.001 ABCD/=E,

B/=CD

95%CI 6.91–7.73 6.51–7.09 7.28–8.16 7.62–8.38 8.59–9.33

95%CI:95%conﬁdenceinterval; ¯x ±SD:mean±standarddeviation.

The“/=”symbolreferstoastatisticallysigniﬁcantcomparison(p<0.05).

aANOVA.

b WithBonferronimethodafterperforming10comparisonsinpairs.

toparticipate)ishigh. On theotherhand,although blindingof thepatientwasnotpossible,sincetreatmentswerealreadybeing marketedand were alldifferent,thestudy wasdesigned tobe observer-blind regarding the variable “disappearance of symptoms”,and partially(not possiblewithsilver nitrate) regarding the variable “disappearance of lesions”. Regarding external

validity,notethatthesearepatientswhorequirecarebythedentist onthesameday.Itcouldreasonablybearguedthatthesepatients aremorelikelytorequiredentalcareormorepainful aphthous ulcers.Somedataleadustobelievethat ourpatientsrequiring dentalcarewouldbesimilartothosethatdonotrequiredental care.Forexample,inthis study,patientsolderthan40 yearsof

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agehadirregularmorphologyandlocalizedlesions,especiallyin thesoftpalate.Thesedatacoincidewiththosepublishedinother studies,^1,15whichindicateadirectrelationshipbetweenageand RASlesionswithirregularmorphologyofthelesionsandtheirpref- erenceforthesoftpalateandtonsillarpillars.Finally,aconservative attitudewouldleadustoconsiderthattheconclusionsofthisstudy, inrelationtopatientsnotrequiringdentalcarefortheiraphthous ulcers,shouldbetakenwithcaution.

Therapeuticoptions

Manytherapeuticoptionshavebeenproposedforthetreatment ofRAS,although,sofar,nonehaveshowntoresultincomplete remission.¹ Manyofthesetreatmentsareusedwithoutresearch thatdemonstratetheirspeciﬁctherapeuticusefulnessinthetreat- mentofRASandcanhaveimportantsideeffects.⁵Forthisreason, alternativetherapiesbasedonnaturalproductsaresought,espe- ciallyamongmedicinalherbs,whichhavefeweradverseeffectsand aremoreaccessibletothepopulationduetotheirlowercost.¹⁶

Below,ourﬁndingsarecomparedwiththoseofotherauthors.

The differences between the results published in the different studiesregardingthedisappearanceofsymptomsand/orlesions mightbedeterminedbythedifferentsamplesizes,theirsociode- mographiccharacteristics,differentformsofdrugadministration, differentconcentrationsandexcipients,diseasestreatedandsym- ptomatology evaluation subjectivity. Therefore, caution is also requiredintheinterpretationoftheﬁndings.

Disappearanceofsymptoms

Inthepresentstudy,thesymptomshaddisappearedin84%of thepatientstreatedwithsilvernitrateonedayafterthecauteri- zationofthelesions,beingthemosteffectivetreatmentregarding thedisappearanceofsymptoms.Cauterizationdestroysnerveter- minals,reducingpain.OurresultscoincidewiththoseofAlidaee etal.,¹⁷whoobservedareliefofsymptomsonedayaftercauteri- zationin70%oftheirpatientstreatedwithsilvernitrate.Similarly, SoyluÖzler,¹⁸inacomparativestudybetweensilvernitrateand placebo,foundasignificantreductionofpainonthefirstdayafter treatmentwithsilvernitrate.Othercausticagentsbasedonsul- fonatedphenolics(Debacterol^®,HybenX^®)havebeenusedforthe treatmentofRAS. Porteretal.¹⁹observeda significantdecrease insymptomatology2daysaftertreatment.RhodusandBereuter²⁰ foundthatmostofthepatients(over70%)experiencedsymptom reliefslightlylater,3daysaftertreatment.

Propolisisaresinouscompoundrichinﬂavonoidsobtainedby beesandwidelyusedsinceancienttimesforitsanti-inﬂammatory, antisepticandfungicidalproperties.Inthepresentstudy,thesymp- tomswererelievedafter2daysinallpatientstreatedwithpropolis (100%).Thisdataagreeswithsomepublishedworks,^21,22 which coincidein indicatingthat symptomatologydisappeared2 days afterthestartof treatment.Bellón Leyvaand CalzadillaMesa²³ observedsymptomatology reliefwithin3 daysin mostof their patientstreatedwith5%propolis.Inthissense,Vynogradetal.²⁴ conductedacomparativestudyofthetreatmentofulcerativegeni- talherpeslesionswithpropolis,acyclovirandaplacebo,observing thatpainhaddisappeared3dayslaterin90%ofthepatientstreated withpropolis, beingthis treatmentthe mosteffective of the3 administered.

Rhubarbextractisoneoftheoldestandbestknownmedicinal herbsoftraditionalChinesemedicine.Itisusedforthetreatment ofconstipation,gastrointestinalbleedingandulcers thatappear onmucousmembranes,includingtheoralmucosa.²⁵Inthisstudy, symptomshadceasedin84%ofthepatientstreatedwithrhubarb extract2dayslater.However,theresultsfoundbyotherstudies differfromours.Khademietal.²⁶ observedanaverageduration

of symptomatologyof 6.10±0.29 daysin patientstreated with rhubarbextract.Salleretal.²⁷conductedastudyin145patients withrecurrentherpeslabialiswhoweretreatedwithaplacebo, rhubarbextractandacyclovir,ﬁndingthattherhubarbextractwas theonethathadthebestbehaviourintheremissionofpain,2days aftertreatment.

Walnutbarkextracthastraditionallybeenusedforthetreat- ment of ulcers, burnsand warts.²⁸ In ourstudy, in 84% of the patientstreatedwithwalnutextractthesymptomshadreturned within2days.PauloFilhoetal.²⁹comparedthetreatmentwith Eupatoriumlaevigatum,whichsharesmanyitscomponentswithJ.

regiaextract,suchasjuglonesorﬂavonoids,tothetreatmentwith 0.1%triamcinoloneacetonideinOrabaseinpatientswithRAS.2 daysafterthestartoftreatment,theyfoundremissionofthesym- ptomatologyin70%ofpatientstreatedwiththepasteandin33.3%

ofthosetreatedwithtriamcinoloneacetonide.

Disappearanceoflesions

Inthepresentstudy,in52%ofthepatientstreatedwithsilver nitrate,thelesionshadbeenresolvedafter7daysandpractically allofthem(96%)after8days.Theresultsobservedbyotherauthors whoalsousedchemicalcauterizationforthetreatmentofRASdiffer somewhatfromours.Alidaeeetal.¹⁷observedthatin83%oftheir patientstreatedwithsilvernitratethelesionshealedafter7days.

SoyluÖzler¹⁸foundthat60%ofpatientstreatedwithsilvernitrate hadtheirlesionsresolvedafter7days.Porteretal.¹⁹foundthatthe lesionshaddisappearedafter8daysin50%ofpatientstreatedwith HybenX^®causticagent.ThebestresultisthatoftheRhodusand Bereuterstudy,²⁰with80%ofpatientsinwhomthelesionshealed after6days.

Inthepresentstudy,amongpatientstreatedwithpropolis,the lesionshealedafter6daysin36%ofthecasesandafter7daysin84%.

Comparedtoourresults,QuintanaDíaz²²found56%ofpatientsin whomthelesionshealed7daysaftertheapplicationofpropolis.

Also,Lotufoetal.,¹⁶inastudyof40patientswithminoraphthous ulcerstreatedwithahydroalcoholicsolutionof10%propolisand othertreatments,showedadecreaseinthedurationoftheepisodes to7orfewerdaysin38%oftheircasestreatedwithpropolis,aﬁg- urelowerthan48%ofthepresentstudy.Thesepatientsalsohad betterresultsintermsofthedurationoftheepisodes,thenum- beroflesionsandtheannualrecurrencerate.Otherstudieshave demonstratedtheefﬁcacyofpropolisinreducing recurrences.³⁰ Vynogradetal.,²⁴inacomparativestudyof3treatments,observed that,at7days,lesionshealedin33.3%ofthesubjectstreatedwith propolis,withthistherapybeingtheonewithwhichthelesions healedquicker.

Inthisstudy,thepercentageofpatientstreatedwithrhubarb extractwhoselesionshaddisappearedafter7dayswas44%.The meanhealingtimeofthelesionsofpatientstreatedwithrhubarb extract was 7.72±1.06 days. Khademi et al.²⁶ found a lower meanhealingtime forRASlesionstreatedwithrhubarbextract (6.80±0.27days).

Inourstudy,thelesionshadhealedafter7daysonlyin20%of thepatientstreatedwithwalnutextract,andin12%ofthecasesthe lesionsdisappearedwithin10days.InBrazil,PauloFilhoetal.²⁹ treatedtheirRASpatientswithE.laevigatum,aplantthatshares manyofitscomponentswithJ.regia,ﬁndingthatdisappearance oflesionsafter5daysoftreatmentoccurredin40%ofpatients,a ﬁguremuchhigherthantheoneobservedbyus.

Adverseeffects

Noneofthepatientsincludedinthisstudyhadadverseeffects relatedtoanyofthe5treatmentsapplied,afactthatcoincideswith thatpublishedinthemedicalliterature.^5,8–12,16

(6)

Inconclusion,therapiesforRAS,conventionalorsilvernitrate, andalternativesorpropolis,rhubarbandwalnut,wereeffective (comparedtoplacebo)forthetreatmentofaphthousulcers.Asfor thedisappearanceofsymptoms,silvernitratewassuperior,buthas asimilarefﬁcacyintermsofdisappearanceoflesions.Finally,no patientreportedadverseeffectsrelatedtothedifferenttreatments.

Conﬂictofinterests

Theauthorsdeclarenoconﬂictofinterest.

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