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UNIVERSIDADE FEDERAL FLUMINENSE

FACULDADE DE ODONTOLOGIA

USO PRÉ-OPERATÓRIO DA DEXAMETASONA NO CONTROLE DA

SENSIBILIDADE DENTAL CAUSADA PELO CLAREAMENTO DENTÁRIO NA

TÉCNICA EM CONSULTÓRIO. ESTUDO CLÍNICO RANDOMIZADO, TRIPLO

CEGO.

Niterói

2017

UNIVERSIDADE FEDERAL FLUMINENSE

FACULDADE DE ODONTOLOGIA

USO PRÉ-OPERATÓTIO DA DEXAMETASONA NO CONTROLE DA

SENSIBILIDADE DENTAL CAUSADA PELO CLAREAMENTO DENTÁRIO NA

TÉCNICA EM CONSULTÓRIO. ESTUDO CLÍNICO RANDOMIZADO, TRIPLO

CEGO.

LUIZ AUGUSTO DA COSTA POUBEL

Tese apresentada à Faculdade de Odontologia da Universidade Federal Fluminense, como parte dos requisitos para obtenção do título de Doutor, pelo Programa de Pós-Graduação em Odontologia. Área de Concentração: Odontologia Orientador: Prof. Dr. Cresus Vinícius Depes de Gouvea Orientador: Prof. Dr. Marcos de Oliveira Barceleiro

Niterói

2017

BANCA EXAMINADORA

Prof(a). Dr(a). Cresus Vinícius Depes de Gouvea

Instituição: Universidade Federal Fluminense - UFF

Decisão: _________________________Assinatura: ________________________

Prof(a). Dr(a). Marcos de Oliveira Barceleiro



Prof(a). Dr(a). Ricardo Carvalhaes Fraga



Prof(a). Dr(a). Larissa Maria Assad Cavalcante

Instituição: Universidade Veiga de Almeida - UVA


Prof(a). Dr(a). Kátia Regina Hostilho Cervantes Dias

Instituição: Universidade Federal do Rio de Janeiro - UFRJ


DEDICATÓRIA

Dedico esse trabalho ao meu amigo, irmão e orientador, Professor

Doutor Marcos de Oliveira Barceleiro, que esteve ao meu lado desde o início do

nascimento do tema deste trabalho, até a sua completa conclusão, sempre me

incentivando, transmitindo conhecimentos e transformando dificuldades em simples

desafios, a serem ultrapassados com naturalidade.

Durante todo esse tempo de convívio, passando por ansiedades,

estresse e também muitas alegrias, tive a chance de aumentar ainda mais a minha

admiração pela pessoa que você é, e por tudo que me ensinou a acreditar na

profissão, assim como para toda vida.

Agradeço por fazer parte da sua vida como amigo, e além disso, por

participar dessa equipe, ou melhor dizendo, dessa família, formando futuros

docentes e pesquisadores que você gerencia com tanta dedicação e carinho.

Afirmo com toda certeza que a sua parceria foi o alicerce que sustentou

todo esse trabalho, transformando todos os grandes obstáculos, em pequenos,

ultrapassando-os com facilidade.

Participar de qualquer tipo de trabalho, tendo você como integrante da

equipe, será sempre um aprendizado constante, prazeroso e principalmente

divertido.

Muito obrigado meu amigo!

Luiz Augusto da Costa Poubel

AGRADECIMENTOS

Ao Professor Doutor Cresus Vinícius Depes de Gouvea, agradeço

por me aceitar como seu orientado, e por acreditar em minha capacidade e

responsabilidade na condução desse trabalho.

Ao Professor Doutor Ricardo Carvalhaes Fraga, por ter sido

responsável por toda a minha formação profissional, desde a graduação, até à

docência. Obrigado por ter acreditado no meu potencial e por fazer parte da minha

vida como conselheiro e grande amigo.

Ao Professor Doutor Vittório Moraschini, pela sua amizade, por ter

ajudado na minha produção científica, um dos pré-requisitos para ingressar nesse

doutorado.

Ao Professor Wesley Weltri Alves, pela sua amizade e grande

dedicação na condução clínica desse trabalho.

À Professora Doutora Fernanda Signorelli Calazans, pela sua

amizade e pela contribuição com seus conhecimentos e sugestões, na realização de

todas as etapas desse trabalho.

À Professora Doutora Etyene Dip, pela sua contribuição, com o seu

conhecimento e sua orientação no delineamento da parte farmacológica desse

trabalho.

À Professora Doutora Roberta Barcellos, pela sua contribuição, com

o seu conhecimento na realização da estatística desse trabalho.

À Aluna de iniciação científica Stella Soares Marins, pela sua

dedicação e carinho na contribuição de toda fase clínica desse trabalho,

principalmente na organização dos materiais, como também no controle do

agendamento dos voluntários da pesquisa.

Ao ISNF- Instituto de Saúde de Nova Friburgo, representado pelo

diretor Professor Doutor Amauri Favieri, e por todos os funcionários de clínicas e

do setor de esterilização, pelo carinho e presteza para a realização dessa pesquisa

clínica.

Aos voluntários, os meus sinceros agradecimentos, pois vocês foram

fundamentais para que esse trabalho pudesse ter sido realizado.

À Empresa SDI Dental Ltda, meus sinceros agradecimentos pela

doação de todos os materiais clareadores utilizados nessa pesquisa.

À Farmácia de Manipulação Bem Viver Ltda, localizada na Rua

Santa Rosa, 180 – Icaraí – Niterói – RJ, representada por Vinícius Cantarino

Nicolau, meus sinceros agradecimentos pela doação de todos os medicamentos

utilizados nessa pesquisa.

.

RESUMO

Poubel LAC. Uso pré-operatório da dexametasona no controle da sensibilidade dental causada pelo clareamento dentário na técnica em consultório. Estudo clínico randomizado, triplo cego. [tese]. Niterói: Universidade Federal Fluminense, Faculdade de Odontologia; 2017.

Objetivos: Este estudo avaliou o efeito da administração da dexametasona pré-

operatória na sensibilidade dentária decorrente da técnica de clareamento em

consultório. Métodos: Um ensaio clínico randomizado, triplo cego, foi realizado em

70 voluntários que receberam cápsulas de dexametasona ou placebo. Os

medicamentos foram administrados em um protocolo de 3 doses diárias de 8 mg do

medicamento, começando 48 horas antes do tratamento de clareamento em

consultório. Duas sessões de clareamento com gel de peróxido de hidrogênio a

37,5% foram realizadas com um intervalo de 1 semana. A sensibilidade dental (SD)

foi registrada em escalas analógicas visuais (VAS) e escalas com classificação

numérica (NRS) em diferentes períodos, até 48 horas após o clareamento. As

avaliações de cores também foram realizadas. O risco absoluto de SD e sua

intensidade foram avaliados pelo teste exato de Fischer. As comparações da

intensidade de SD (dados NRS e VAS) foram realizadas usando o teste U de Mann-

Whitney e um teste ANOVA de medidas repetidas de 2 vias, além do teste de Tukey,

respectivamente. Resultados: Em ambos os grupos, os autores detectaram um alto

risco de SD (Dexametasona: 80% x Placebo: 94%). Não houve diferença

significativa em termos de intensidade SD. Um clareamento de aproximadamente 3

unidades de cor da escala VITA Classical foi detectado em ambos os grupos, os

quiais foram considerados estatisticamente similares. Conclusões: Os autores

concluíram que a administração pré-operatória da dexametasona, no protocolo

proposto, não reduz a incidência ou a intensidade da sensibilidade dentária induzida

pelo clareamento. Significado clínico: O uso da dexametasona antes do tratamento

de clareamento na técnica em consultório não reduz a incidência ou a intensidade

da sensibilidade ao dente. Número de registro de ensaio clínico: NCT02956070

Palavras-chave: sensibilidade dentinária; clareamento dental; dexametasona

ABSTRACT

Poubel LAC. Pre-operative use of dexamethasone to control in-office bleaching-induced tooth hypersensitivity. A randomized triple blind clinical trial. [thesis]. Niterói: Universidade Federal Fluminense, Faculdade de Odontologia; 2017. Objectives: This study evaluated the effect of the administration of preoperative

dexamethasone on tooth sensitivity stemming from in-office bleaching. Methods: A

triple-blind, parallel-design, randomized clinical trial was conducted on 70 volunteers

who received dexamethasone or placebo capsules. The drugs were administered in

a protocol of 3 daily 8-mg doses of the drug, starting 48 hours before the in-office

bleaching treatment. Two bleaching sessions with 37.5% hydrogen peroxide gel were

performed with a 1-week interval. Tooth sensitivity (TS) was recorded on visual

analog scales (VAS) and numeric rating scales (NRS) in different periods up to 48

hours after bleaching. The color evaluations were also performed. The absolute risk

of TS and its intensity were evaluated by using Fischer’s exact test. Comparisons of

the TS intensity (NRS and VAS data) were performed by using the Mann-Whitney U

test and a Two-way repeated measures ANOVA and Tukey’s test, respectively.

Results: In both groups, the authors detected a high risk of TS (Dexamethasone:

80% x Placebo: 94%). No significant difference was observed in terms of TS

intensity. A whitening of approximately 3 shade guide units of the VITA Classical was

detected in both groups, which were considered statistically similar. Conclusions: The

authors concluded that the administration preoperatively of dexamethasone, in the

proposed protocol, does not reduce the incidence or intensity of bleaching-induced

tooth sensitivity. Clinical Significance: The use of dexamethasone drug before in-

office bleaching treatment does not reduce incidence or intensity of tooth sensitivity.

Clinical Trial Registration Number: NCT02956070

Keywords: dentin sensitivity; dental bleaching; dexamethasone

8

1 - INTRODUÇÃO

Atualmente, o clareamento dentário em dentes vitais é um dos

procedimentos odontológicos mais solicitados pelos pacientes que desejam sorrisos

mais agradáveis, exigidos pela mídia como modelo de saúde e beleza [1,2]. O

clareamento dental tem sido o tratamento de eleição para dentes com alterações

cromáticas, por ser uma técnica segura, eficaz e conservadora [3-8]. Este

procedimento é realizado com a aplicação de géis de peróxido de hidrogênio ou

carbamida na superfície dos dentes e pode ser feito em casa, com ou sem a

supervisão do dentista ou durante a própria sessão clínica no consultório [9,10].

Embora a técnica de clareamento caseiro seja mais adequada para dentes vitais

[11], alguns pacientes não se adaptam ao uso de moldeiras ou não querem aguardar

por algumas semanas para terem os resultados visíveis desejados [7, 8, 11, 12].

Para estes pacientes, o clareamento em consultório é uma excelente alternativa,

pois além de dispensar a moldeira de clareamento, os resultados podem ser

observados após 1 ou 2 sessões clínicas de clareamento, executada e controlada

pelo profissional [11-15]. Além disso, esta técnica possibilita um rigoroso controle

pelo profissional, evitando ingestão de gel e exposição a tecidos moles, reduzindo o

percentual de pacientes com irritação gengival e reduzindo o tempo total de

clareamento [6, 8, 14, 16-18].

Apesar da eficácia das técnicas na obtenção do clareamento dentário

desejado, os efeitos adversos são evidenciados [6,11], destacando-se a

sensibilidade dentária (SD) como sendo o efeito mais amplamente citado pela

literatura, tendo sido relatada em aproximadamente 67% a 100% dos pacientes após

a realização do clareamento em consultório [19-23]. A SD gerada pelo clareamento

ainda não é bem compreendida. Parece resultar de um processo inflamatório na

polpa dentária em diferentes magnitudes, provocado pela ação do peróxido de

hidrogênio (H202) aplicado durante o tratamento clareador [24, 25]. O peróxido de

hidrogênio aumenta a permeabilidade do esmalte, difunde-se através da dentina [10]

e penetra na câmara pulpar [11,12]. A sensibilidade associada a uma técnica de

clareamento dental pode resultar da ação de produtos químicos, resultantes da

degradação do peróxido de hidrogênio, que penetram na câmara pulpar e conduzem

à ativação de sensores nociceptivos [13] e reações inflamatórias transitórias [14]. A

9

SD normalmente é leve e pode perdurar por até 48 horas após o clareamento

[22,26,27]; no entanto, pode ser uma experiência desagradável para o paciente, e

que pode impulsionar a interrupção do tratamento clareador [28].

Foram propostos vários materiais e técnicas para reduzir a sensibilidade

dentária induzida pelo clareamento, dentre eles o uso de agentes clareadores com

menor concentração de peróxido de hidrogênio e a utilização dos mesmos por

menores períodos de tempo [13,27] e também o uso de agentes dessensibilizantes

tópicos (fluoretos, nitrato de potássio, glutaraldeído) [29-32] antes ou após o

clareamento dental [11,22,33,34]. No entanto, embora os agentes tópicos de

dessensibilização reduzam o risco de SD, um grande número de pacientes relata SD

em algum momento do clareamento, mesmo após a utilização desses produtos

[11,23,30].

Alguns autores avaliaram a ação de drogas antiinflamatórias na redução

desse efeito adverso [20,21,35]. O uso pré-operatório do ibuprofeno, um fármaco

anti-inflamatório não esteróide (AINE), reduziu a SD imediata decorrente do

clareamento dental [20,35], mas não foi efetivo na redução da SD nas 48 horas

subseqüentes. Além disso, o uso de um medicamento anti-inflamatório seletivo

(Etoricoxib - 60 mg) não conseguiu reduzir o risco absoluto e a intensidade da SD

decorrente do clareamento dental [21].

Os corticosteróides previnem ou reprimem a resposta da inflamação através

de mecanismos múltiplos quando comparados com anti-inflamatórios não esteróides

[36]. Na medida em que a dexametasona, um corticosteróide sintético, reprime a

síntese induzível de cicloxigenase 2 (COX-2) e bloqueia toda a via do ácido

araquidônico. Como conseqüência, a produção de eicosanóides (prostaglandinas e

leucotrienos) em macrófagos/monócitos é limitada [37]. Além disso, a dexametasona

reduz a liberação de citocinas, incluindo IL-1, IL-6, IL-2, IL-3 e TNF-alfa em linfócitos.

O edema pós-operatório menor é relacionado à secreção diminuída de proteínas

vasoativas (molécula de adesão intercelular, ICAM-1) em células endoteliais ou à

diminuição do extravasamento de leucócitos na área lesada [38].

Como o tempo é necessário para modular a expressão gênica e a síntese

protéica, a maioria dos efeitos anti-inflamatórios dos corticosteróides não são

imediatos, mas tornam-se evidentes após várias horas ou até dias. De fato, a

dexametasona após ligação a um receptor de glicocorticóide intracelular fornece

especificidade para a indução ou repressão da transcrição de genes que participa da

10

resposta inflamatória. Este fato é de grande significado clínico, já que um atraso

geralmente é observado, antes que os efeitos benéficos anti-inflamatórios da

dexametasona se manifestem [39]. Por esse motivo, realizou-se um protocolo pré-

operatório de curto prazo usando dexametasona via oral para inibir a SD induzida

pela técnica de clareamento em consultório. Portanto, este ensaio clínico

randomizado, paralelo, triplo-cego, teve como objetivo avaliar o efeito da

administração pré-operatória do anti-inflamatório corticosteróide (dexametasona),

começando 48 horas antes de cada sessão clínica de clareamento para a redução

da SD decorrente da técnica de clareamento dental em consultório com peróxido de

hidrogênio a 37,5%.

11

2 – METODOLOGIA

Este estudo clínico foi aprovado por meio do parecer nº 1.376.881 pelo

Comitê de Ética em Pesquisa do Instituto de Saúde de Nova Friburgo da

Universidade Federal Fluminense. O delineamento do estudo seguiu as normas do

CONSORT (Consolidated Standards of Reporting Trials). Com registro de ensaios

clínicos nº NCT02956070. Esta pesquisa clínica foi realizada no Instituto de Saúde

de Nova Friburgo da Universidade Federal Fluminense, na cidade de Nova

Friburgo/Rio de Janeiro/Brasil. Com base em critérios pré-estabelecidos, foram

selecionados 70 voluntários para este estudo. O estudo foi realizado de 15 de

fevereiro de 2016 à 12 de julho de 2016. Após a assinatura do termo de

consentimento livre e esclarecido (TCLE), os voluntários foram alocados em grupos

de forma aleatorizada, e foram tratados conforme os diferentes grupos de alocação.

Desenho do estudo: é um ensaio clínico randomizado, paralelo, triplo

cego, em que o voluntário, o operador e o avaliador foram cegos à distribuição do

grupo. Um outro pesquisador, não envolvido no processo de avaliação, foi

responsável pela entrega dos medicamentos. O estudo foi realizado nas clínicas da

Faculdade de Odontologia da Universidade Federal Fluminense (Nova Friburgo, RJ,

Brasil). Os pacientes foram recrutados à medida que procuravam tratamento nas

clínicas de Odontologia. Nenhum anúncio foi feito para o recrutamento de

participantes. Os pacientes foram recrutados na ordem em que chegavam para a

sessão de triagem, formando assim uma amostra de conveniência.

Critérios de inclusão e exclusão: os voluntários incluídos neste ensaio

clínico eram obrigados a ter um bom estado de saúde geral, terem no mínimo 18

anos de idade, sem distinção de gênero, cor/raça e etnia. Eram obrigados a ter uma

higiene bucal aceitável, apresentando as arcadas superior e inferior sem ausência

de elementos dentários de primeiro pré-molar direito ao primeiro pré-molar esquerdo.

Esses elementos também tinham que ser hígidos. Os voluntários eram obrigados a

assinar o termo de consentimento livre e esclarecido (TCLE), terem o compromisso

de retornarem para os exames periódicos. Além disso, os incisivos centrais tinham

que ser classificados como A1 ou mais escuros, por comparação com a escala

Vitapan Classical (VITA Classical, VITA Zahnfabrik). Apesar da cor A1 ser uma das

12

mais claras na escala Vitapan Classical (VITA Classical, VITA Zahnfabrik), muitos

pacientes procuraram clareamento dental por estarem insatisfeitos com a cor de

seus dentes.

Dois pesquisadores cegos e calibrados realizaram de forma independente

as avaliações de cores utilizando a escala Vitapan Classical (VITA Classical, VITA

Zahnfabrik). Os 2 examinadores deveriam apresentar concordância de pelo menos

85% (teste estatístico Kappa) antes de iniciar a avaliação do estudo.

Os voluntários que já haviam realizado clareamento dental, com

restaurações anteriores ou próteses dentárias, com aparelhos ortodônticos

anteriores ou com pigmentação severa (manchas de tetraciclina, fluorose ou

endodontia) não foram incluídos no estudo. Além disso, mulheres grávidas e

lactantes, participantes com qualquer outra característica que possa causar

sensibilidade (como recessão gengival, sensibilidade dental, fissuras visíveis nos

dentes), foram excluídos. Aqueles que relataram problemas de saúde passados ou

presentes no estômago, coração, rins ou fígado, assim como o uso contínuo de

drogas anti-inflamatórias ou analgésicas, com diabetes, hipertensão ou uso de

drogas anti-hipertensivas, alergias a dexametasona e lactose também foram

excluídos do estudo.

Cálculo do tamanho da amostra: o desfecho primário deste estudo foi

avaliar o risco absoluto de SD (ou seja, o número de pacientes [por cento] que

relataram dor em algum momento durante o clareamento dental em consultório).

Este percentual foi relatado como sendo de aproximadamente 90% para um produto

clareador similar com peróxido de hidrogênio 35% [20,21,36]. Assim, foi necessário

um tamanho mínimo de amostra de 70 voluntários, para que com um poder de 90%,

fosse possível se detectar, com nível de significância de 5%, uma diminuição na

medida de resultado primário de 90% no grupo controle para 60% no grupo

experimental.

Randomização e cegamento. Os autores utilizaram blocos para

randomização com tamanho de 2 e 4 blocos, com igualdade de chances em relação

à alocação dos grupos. Os voluntários foram randomizados em dois grupos, em um

13

mesmo momento, através de um programa de computador disponível gratuitamente

online no site http://www.sealedenvelope.com. O processo de aleatorização foi

realizado por um pesquisador que não estava envolvido na pesquisa. O operador

abria o envelope selado que definia o grupo ao qual o voluntário estava alocado

somente no momento da primeira sessão clínica de clareamento. Desta forma, o

estudo foi triplo cego, no qual o operador (cirurgião dentista que realizou o

clareamento dental), o voluntário (paciente) e o avaliador estavam cegos em relação

aos grupos que os voluntários foram designados.

Intervenção do estudo. Os voluntários foram distribuídos aleatoriamente

em dois grupos: Grupo experimental (GE) (dexametasona) e grupo controle (GC)

(placebo). No grupo da dexametasona (GE), os voluntários receberam o anti-

inflamatório (dexametasona, cápsula - 8 mg) e a aplicação de um gel placebo, e no

grupo controle (GC), os voluntários receberam cápsulas placebo e a aplicação de

gel dessensibilizante contendo nitrato de potássio a 6% e 0,10% de fluoreto de sódio

(Soothe, SDI, Victoria, Austrália). Todos os voluntários receberam o mesmo

tratamento de clareamento. Uma semana antes da sessão de clareamento em

consultório, os voluntários receberam potes individuais contendo 6 cápsulas no total,

com a dexametasona (Manipulada por Bem Viver laboratório Ltda), ou placebo, em

cápsulas idênticas, dependendo do seu grupo de alocação, que continha os mesmos

componentes da cápsula com o medicamento de dexametasona, exceto o

ingrediente ativo (Tabela 1).

http://www.sealedenvelope.com/

14

TABELA 1

PRODUTO COMPOSIÇÃO

Pola Office + SDI* peróxido de hidrogênio 37,5%

nitrato de potássio

Soothe SDI* nitrato de potássio 6,0%

fluoreto de sódio 0,10%

água 89,60%

espessante 4,20%

benzoato de sódio 0,10%

Cápsulas de dexametasona** dexametasona 8mg

amido 50%

lactose monohidratada 35%

fosfato de cálcio dibasico14%

estearato de magnésio 1%

Cápsulas placebo** amido 50%

lactose monohidratada 35%

fosfato de cálcio dibasico14%

estearato de magnésio 1%

Gel placebo** carbopol * SDI, Victoria, Australia ** Manipulada pelo laboratório Bem Viver Ltda, número de registro 09047030 / 0001-28, localizado na rua Santa Rosa, Icaraí-Niterói, RJ, Brasil. Lote do produto: 189155.

Os voluntários foram tratados em 2 sessões clínicas com um intervalo de 7

dias (uma semana) entre eles. O protocolo para uso do produto foi o seguinte: os

voluntários do GE receberam 6 cápsulas de dexametasona de 8 mg cada, para

serem administradas por via oral, da seguinte forma: iniciavam 2 dias antes da 1ª

consulta de clareamento (8 mg, 9h, 2 dias antes da sessão clínica de clareamento;

8mg, 9h, 1 dia antes da sessão clínica de clareamento, e 8mg, 9h, no dia da sessão

clínica de clareamento) [40]. Este mesmo esquema foi realizado para a 2ª sessão de

clareamento, que foi realizada 7 dias após a primeira. Um pesquisador ficou

responsável por organizar a agenda e também manter contato com os voluntários

através de mensagem por aplicativos de telefone, lembrando dos horários do

medicamento e também via e-mail, com o objetivo de aumentar a adesão ao

protocolo de uso dos medicamentos, e também em relação a necessidade de

intervenção, caso houvesse um alto grau de sensibilidade durante o tratamento

clareador.

Para o clareamento dental, foi utilizado um afastador de lábios (OptraGate -

Ivoclar Vivadent). Em seguida, foi realizada uma barreira de proteção gengival com

resina fotopolimerizável (Gengival Barrier, SDI) que a cada dente foi

15

fotopolimerizada por 10 segundos (Radii-cal, SDI). Após os tecidos gengivais

estarem protegidos, o operador usou o gel de peróxido de hidrogênio a 37,5%

(polaoffice +, SDI) em três aplicações de 8 minutos para ambos os grupos de acordo

com as instruções do fabricante. O agente clareador foi reaplicado a cada 8 minutos,

totalizando 24 minutos após a terceira e última aplicação do gel. No final de cada

sessão, um único pesquisador responsável pelo cegamento entregava uma única

seringa ao operador, que conteria gel dessensibilizante se o paciente estivesse no

GC ou um gel placebo contendo apenas carbopol (sem ingrediente ativo- nitrato de

potássio e fluoretro se sódio) se o paciente estivesse no grupo de GE. O gel foi

aplicado com um pincel descartável (KG Brush, KG Sorensen) na superfície

vestibular dos dentes clareados durante 2 a 3 minutos, conforme orientações do

fabricante (Soothe, SDI). Duas sessões de clareamento foram realizadas com uma

semana de intervalo entre elas.

Avaliação da SD. A SD foi avaliada durante o clareamento e até 1 hora, 24

horas e 48 horas pós-clareamento. O voluntário foi solicitado a indicar o valor

numérico do grau de sensibilidade para cada um dos períodos acima, usando uma

escala de classificação numérica de 5 pontos (NRS), com escores de 0-4, em que 0

= nenhum, 1 = leve, 2 = moderado, 3 = considerável e 4 = grave [2,4,5,7,23].

Além disso, os voluntários também foram instruídos para registrar a

intensidade da dor usando a escala analógica visual (VAS) [3, 6-9]. Esta escala é

uma linha horizontal de 100 milímetros com pontuações de 0 e 100 nas

extremidades, em que 0 = ausência de sensibilidade e 100 = sensibilidade severa. O

voluntário teve que marcar com uma linha vertical através da linha horizontal da

escala a intensidade da SD. Então, a distância em milímetros das extremidades zero

foi medida com a ajuda de uma régua milimetrada.

Os dados de cada sessão de clareamento foram avaliados separadamente

e foram mesclados. Para este fim, a pior pontuação ou valor numérico obtido em

ambas as sessões de branqueamento foi considerado para fins estatísticos e a

determinação do risco absoluto e intensidade de SD.

16

Se o voluntário marcou 0 (sem sensibilidade) em todas as avaliações de

tempo de ambas as sessões de clareamento, este voluntário foi considerado

insensível ao protocolo de clareamento. Em todas as outras circunstâncias,

considerou-se que os voluntários tinham sensibilidade decorrente do procedimento

de clareamento. Esta dicotomização nos permitiu calcular o risco absoluto de SD, o

que representou a porcentagem de voluntários que relataram SD pelo menos uma

vez durante o tratamento. Também calculamos a intensidade média da SD.

Avaliação de cor. A avaliação da cor foi realizada 1 semana antes da

primeira consulta de clareamento, após a 1ª sessão de clareamento, mas antes da

2ª sessão e 1 semana após a 2ª sessão de clareamento. A avaliação da cor não foi

realizada imediatamente após cada sessão de clareamento, por causa do possível

efeito da desidratação e desmineralização, dificultando o registro real da cor final do

dente. A avaliação das cores foi feita usando as escalas VITA Classical e a VITA

Bleachedguide 3D-MASTER. (VITA Zahnfabrik).

Para a avaliação de cores, as 16 guias de cor da Vitapan Classical (VITA

Zahnfabrik), foram organizadas do valor maior (B1) para o menor valor (C4). Embora

esta escala não seja linear, ela foi organizada por valor, representando um ranking

contínuo e linear com o objetivo de análise, como já foi realizado em vários estudos

publicados [2,3,5,8,9,15,23, 25]. A escala VITA Bleachedguide 3D-MASTER contém

guias de cores mais claras e já está organizada a partir do valor mais alto (0M1)

para o mais baixo (5M3) [24]. A área de medição de interesse para a combinação de

tons foi o 1/3 médio da superfície vestibular do incisivo central, de acordo com as

diretrizes da American Dental Association [4,12,15].

Os 2 examinadores, cegos em relação à distribuição, agendaram os

voluntários para o clareamento e avaliaram a coloração dos dentes com o auxílio

das escalas de cor. As alterações de cor foram calculadas desde o início da fase

ativa até e incluindo os tempos de rechamada, calculando a mudança no número de

unidades de guia de cor (ΔSGU), que ocorreu em direção à extremidade mais clara

da escala de cor tendo como referência o valor. No caso de desentendimentos entre

os examinadores durante a avaliação da cor, um consenso foi alcançado através da

discussão.

17

Análise estatística. Realizou-se a análise estatística utilizando um

protocolo de intenção de tratar, envolvendo todos os participantes que foram

distribuídos aleatoriamente [21]. Nos casos em que faltaram dados, a última

observação foi utilizada como padrão para aquele paciente. O estatístico foi cegado

para os grupos de estudo. O risco absoluto de SD e sua intensidade foram avaliados

pelo teste exato de Fischer (α = 0,05). Os autores calcularam o risco relativo como o

intervalo de confiança para o tamanho do efeito.

A comparação da intensidade de SD (dados NRS) dos 2 grupos nos 2

momentos de avaliação diferentes foi realizada usando o teste U de Mann-Whitney e

as comparações entre os tempos dentro de cada grupo foram realizadas com o teste

de Friedman. As comparações da intensidade da SD obtidas com a escala VAS

foram avaliadas usando ANOVA de medidas repetidas de 2 vias e teste de Tukey.

As mudanças de cor entre grupos (ΔSGU entre a cor inicial versus 1

semana após a 2ª sessão de clareamento) foram comparadas usando um teste t, e

as mudanças de cores foram avaliadas usando o teste t de Student. Em todos os

testes estatísticos, o nível de significância foi de 0,05. Realizou-se todas as análises

usando o software SPSS para Windows versão 20.0 (IBM).

18

3 - ARTIGO PRODUZIDO (Segundo as normas da revista Clínical Oral

Investigations)

TITLE PAGE

Title: Pre-operative use of dexamethasone does not reduce incidence or intensity of bleaching-induced

tooth sensitivity. A triple-blind, parallel-design, randomized clinical trial.

Short title: Pre-bleaching dexamethasone

Authors:

A. Luiz Augusto da Costa Poubela ; Assistant Professor

B. Cresus Vinicius Deppes de Gouveab; Head Professor

C. Fernanda Signorelli Calazansa; Post-Doctoral Stage

D. Etyene Castro Dipa; Associate Professor

E. Wesley Veltri Alvesa ; Researcher

F. Stella Soares Marinsa; Undergraduate Student

G. Roberta Barcelosa; Associate Professor

H. Marcos Oliveira Barceleiroa; Associate Professor

Afiliation:

a. Fluminense Federal University / School of Dentistry, Nova Friburgo, RJ, Brazil

R. Dr. Silvio Henrique Braune, 22 – Centro – ZIP: 28625-650 - Nova Friburgo - RJ - Brazil

[email protected]

[email protected]

[email protected]

[email protected]

[email protected]

[email protected]

[email protected]

b. Fluminense Federal University / School of Dentistry, Niterói, RJ, Brazil

R. Mario Santos Braga, 28 – Centro – ZIP: 24020-140 - Niterói - RJ - Brazil

[email protected]

Corresponding author:

Marcos de Oliveira Barceleiro

Rua Dr. Silvio Henrique Braune, 22, Centro

Nova Friburgo – RJ

CEP: 28625-650

Fone: +55 21 99991-5236

[email protected]

Keywords: dentin sensitivity; hydrogen peroxide; dexamethasone

ACKNOWLEDGEMENTS

The authors thanks SDI Dental Limited for the donation of the bleaching gel used, and Bem Viver

laboratory Ltda for the donation of dexamethasone capsules and the gel placebo in this investigation.

19

Pre-operative use of dexamethasone does not reduce incidence or intensity of bleaching-

induced tooth sensitivity. A triple-blind, parallel-design, randomized clinical trial

Abstract

Objectives: This study evaluated the effect of the administration of preoperative dexamethasone on

tooth sensitivity stemming from in-office bleaching. Materials and Methods: A triple-blind, parallel-

design, randomized clinical trial was conducted on 70 volunteers who received dexamethasone or

placebo capsules. The drugs were administered in a protocol of 3 daily 8-mg doses of the drug,

starting 48 hours before the in-office bleaching treatment. Two bleaching sessions with 37.5%

hydrogen peroxide gel were performed with a 1-week interval. Tooth sensitivity (TS) was recorded on

visual analog scales (VAS) and numeric rating scales (NRS) in different periods up to 48 hours after

bleaching. The color evaluations were also performed. The absolute risk of TS and its intensity were

evaluated by using Fischer’s exact test. Comparisons of the TS intensity (NRS and VAS data) were

performed by using the Mann-Whitney U test and a 2-way repeated measures ANOVA and Tukey’s

test, respectively. Results: In both groups, the authors detected a high risk of TS (Dexa: 80% x

Placebo: 94%). No significant difference was observed in terms of TS intensity. A whitening of

approximately 3 shade guide units of the VITA Classical was detected in both groups, which were

statistically similar. Conclusions: The authors concluded that the administration preoperatively of

dexamethasone, in the proposed protocol, does not reduce the incidence or intensity of bleaching-

induced tooth sensitivity. Clinical Relevance: The use of dexamethasone drug before in-office

bleaching treatment does not reduce incidence or intensity of Tooth Sensitivity. Clinical Trial

Registration Number: NCT02956070

Keywords: dentin sensitivity; dental bleaching; hydrogen peroxide; dexamethasone

20

1. Introduction

Currently, dental bleaching is one of the most requested dental procedures by patients

who want more pleasant smiles, which the media demands as a model of health and beauty [1,2].

Dental bleaching has been the treatment of choice for teeth with shade alterations, as it is a safe,

effective and conservative technique [3-8]. This procedure is performed with the application of

hydrogen or carbamide peroxide gels on the surface of the teeth and can be done at home, with or

without the supervision of the dentist, or in office [9,10]. Although the home bleaching technique is

most suitable for vital teeth [11], some patients do not get used to the use of trays or do not want to

wait for some weeks to have the desired visible results [7,8,11,12]. For these patients, in-office

bleaching is an excellent alternative, as the results can be observed after 1 or 2 bleaching sessions, and

the professional executes and controls the process [11-15]. Furthermore, this technique allows for

strict control by the professional, avoiding gel ingestion and exposure to soft tissues, reducing the

percentage of patients with gingival irritation and reducing total bleaching time [6,8,14,16-18].

Despite the effectiveness of the techniques in achieving desired tooth whitening,

adverse effects are evidenced [6,11], with tooth sensitivity (TS) highlighted as the most widely

reported effect in the literature, reported in approximately 67% to 100% of patients after in-office

bleaching [19-23]. The TS generated due to dental bleaching is still not well understood. It appears to

result from an inflammatory process in the dental pulp in different magnitudes, stemming from the

action of hydrogen peroxide (H202) applied during the bleaching treatment [24,25]. Hydrogen peroxide

increases the permeability of the enamel, diffuses through the dentin [10] and penetrates the pulp

chambre [11,12]. Tooth sensitivity (TS) associated with a dental bleaching technique may result from

the action of chemicals resulting from the degradation of hydrogen peroxide, which penetrate the pulp

chamber and lead to the activation of nociceptive sensors [13] and transient inflammatory reactions

[14]. TS is usually mild and can last for up to 48 hours after bleaching [22,26,27]; however, it can be

an unpleasant experience for the patient, and this can spur discontinuation of the bleaching treatment

[28].

Several materials and techniques for reducing bleaching-induced tooth sensitivity have

been proposed, among them the use of bleaching agents with lower concentration of hydrogen

peroxide and the use of them for shorter periods of time [13,27] and also the use of topical

desensitizing agents (fluorides, potassium nitrate, glutaraldehyde) [29-32] before or after dental

bleaching [11,22,33,34]. However, although topical desensitizing agents reduce the TS risk, a large

number of patients report TS at some moment of a bleaching treatment, even after the use of these

products [11,23,30].

Some authors have evaluated the action of anti-inflammatory drugs in reducing this adverse

effect [20,21,35]. The preoperative use of ibuprofen, a non-steroidal anti-inflammatory drug (NSAID),

reduced the immediate TS stemming from dental bleaching [20,35] but was not effective in reducing

21

TS in the subsequent 48 hours. In addition, the use of a selective anti-inflammatory drug (Etoricoxib -

60 mg) was not able to reduce the absolute risk and the TS intensity stemming from dental bleaching

[21].

Corticosteroids prevent or suppress inflammation response via multiple mechanisms when

compared with non-steroid anti-inflammatory drugs [36]. Inasmuch, dexamethasone, a synthetic

corticosteroid, represses inducible cyclooxygenase 2 (COX-2) synthesis and blocks the entire

arachidonic acid pathway. As a consequence, eicosanoid production (prostaglandins and leukotrienes)

on macrophages/monocytes is limited [37]. In addition, dexamethasone reduces the release of

cytokines, including IL-1, IL-6, IL-2, IL-3 and TNF-alfa on lynfocytes. Less postoperative edema is

either related to the diminished secretion of vasoactive proteins (intercellular adhesion molecule,

ICAM-1) on endothelial cells or the decrease of leukocytes extravasation in the injured area [38].

Because time is required to modulate gene expression and protein synthesis, most of the anti-

inflammatory effects of corticosteroids are not immediate but become apparent after several hours or

even days. Indeed, dexamethasone after binding to an intracellular glucocorticoid receptor provides

specificity to the induction or the repression of gene transcription that participates in the inflammatory

response. This fact is of clinical significance, as a delay generally is seen, before the beneficial anti-

inflammatory effects of dexamethasone become manifest [39]. Taken this, we hypothesized that a

short-term pretreatment protocol using oral dexamethasone would prevent bleaching-induced TS. To

test this hypothesis, we designed a randomized, triple-blinded, parallel-group clinical trial quantifying

TS in patients who received single doses of dexamethasone beginning 48 hours prior to each bleaching

procedure.

2. Materials and Methods

The scientific review committee and the committee for the protection of human participants of

the local university (protocol number 1.376.881) approved this clinical investigation. It was registered

in the clinical trials.gov registry under the identification number NCT02956070. We performed this

study using the protocol that the Consolidated Standards of Reporting Trials (CONSORT) statement

established. Based on pre-established criteria, we selected 70 volunteers for this study. The study was

performed from February 15, 2016, to July 12, 2016.

Two weeks before the bleaching procedures, each volunteer received a dental prophylaxis with

pumice and water in a rubber cup and signed an informed consent form.

Study design: This was a randomized, triple-blinded, parallel-group clinical trial in which the

volunteer, operator, and evaluator were blinded to the group assignment. A third researcher, not

involved in the evaluation process, was responsible for the administration of the drugs. The study was

carried out in the clinics of the School of Dentistry of Fluminense Federal University (Nova Friburgo,

RJ, Brazil). Patients were recruited as they seek for treatment in the clinics of Dentistry of both

22

Universities. No advertisement was made for participant recruitment. Patients were recruited in the

order in which they reported for the screening session, thus forming a sample of convenience.

Inclusion and exclusion criteria: Volunteers included in this clinical trial were at least 18

years old, had good general and oral health, and did not report any type of TS. The volunteers were

required to have 8 caries-free maxillary anterior teeth without restorations, be free of periodontal

disease and review and sign the informed consent form. The central incisors had to be shade A1 or

darker as judged by comparison with a value-oriented shade guide (VITA Classical, VITA

Zahnfabrik). Despite the fact that the color shade A1 is one of the lightest colors measurable using

VITA Classical, many volunteers with A1 shade teeth seek dental bleaching, as they are dissatisfied

with the color of their teeth.

Two calibrated investigators (SM and CG) independently performed the color evaluations

with the shade guide. The 2 examiners, blinded to the allocation assignment, schedule the volunteers

for bleaching and evaluated their teeth against the shade guide at baseline and 1 week after the

procedure. The 2 examiners were required to have an agreement of at least 85% (Kappa statistic test)

before beginning the study evaluation.

Volunteers with anterior restorations or dental prostheses, with anterior orthodontic

apparatuses or with severe internal tooth discoloration (tetracycline stains, fluorosis, pulpless teeth)

were not included in the study. In addition, pregnant and lactating women, participants with any other

pathology that could cause sensitivity (such as gingival recession, dentinal exposure, visible cracks in

teeth), those taking anti-inflammatory or analgesic drugs, those who smoked or volunteers who had

undergone tooth-whitening procedures were excluded. Those who reported past or present health

problems in the stomach, heart, kidneys or liver; those who reported the continuous use of anti-

inflammatory or analgesic drugs; those patients with diabetes, hypertension or the use of

antihypertensive drugs; or patients who reported allergies to dexamethasone and lactose were also

excluded from the study.

Sample size calculation: The primary outcome of this study was the absolute risk of TS. The

absolute risk of TS (that is, the number of patients [percent] who reported pain at some point during

dental bleaching) was reported to be approximately 90% for a similar 35% hydrogen peroxide

bleaching product [20,21,36]. Thus, a minimum sample size of 70 participants was required to have a

90% chance of detecting, as significant at the 2-sided 5% level, a decrease in the primary outcome

measure from 90% in the control group to 60% in the experimental group.

Random sequence generation and allocation concealment: The authors used blocked

randomization (block sizes of 2 and 4) with an equal allocation ration, using a 3rd-party service

(Sealed Envelope), which did not intervene in the study. Opaque and sealed envelopes containing the

identification of the groups were prepared.

Study intervention: We divided volunteers into the dexamethasone group, who received the

anti-inflammatory (dexamethasone, capsule – 8 mg) and application of a placebo gel, and the control

23

group, who received placebo capsules and the application of desensitizing gel containing 6%

potassium nitrate and 0.10% fluoride sodium (Soothe, SDI, Victoria, Australia). All volunteers

received the same bleaching treatment, which 4 experienced operators (LP, FC, WA, ED) performed.

One week before the in-office bleaching session, volunteers received individual pots containing 6

capsules in total, with the dexamethasone (Handled by Bem Viver laboratory Ltda), or placebo, in

identical capsules depending on their allocation group, which contained the same components of the

dexamethasone drug except for the active ingredient (Table 1).

The control group received placebo capsules and the application of desensitizing gel

containing 6% potassium nitrate and 0.10% fluoride sodium, and the dexamethasone group received

the anti-inflammatory (dexamethasone, capsule - 8mg) and application of a placebo gel. Volunteers

were treated in 2 clinical sessions with an interval of 7 days (one week) between them. The protocol

for use of the product was as follows: The volunteers in the experimental group received 6 capsules of

dexamethasone 8 mg each, which was administered orally, initially 2 days before the 1st bleaching

query (8mg, 9 AM, 2 days before the bleaching session; 8mg, 9 AM, 1 day before the bleaching

session; 8mg, 9 AM, on the day of the bleaching session) [40]. This same scheme was performed for

the 2nd bleaching session, which was 7 days after the 1st. The operators instructed the volunteers to

increase adherence to the protocol, and the researches made telephone calls and sent cell phone text

messages to remind the volunteers of every capsule to be taken.

Before the dental bleaching, gingival tissue was isolated from teeth using a light-cured resin

(Gingival Barrier, SDI), and each tooth was light-cured for 10 seconds using a light curing unit with

1200 mW/cm2 light intensity (Radii-cal, SDI). After the placement of a lip retractor (OptraGate –

Ivoclar Vivadent), the operator used the 37.5% hydrogen peroxide gel (polaoffice+, SDI) in three 8-

minute applications for both groups in accordance with the manufacturer’s directions. The bleaching

agent was refreshed every 8 minutes during the 24-minute application period. At the end of each

session, a single researcher responsible for the blinding (MB) delivered a single syringe to the

operator, which would contain desensitizing gel if the patient was in the control group, or placebo gel

containing only carbopol (no active ingredient) if the patient was in the dexamethasone group. The gel

was applied with a brush on the labial surface of the whitened teeth for 2 to 3 minutes as the

manufacturer (Soothe SDI Dental Limited) directed. Two bleaching sessions were performed 1 week

apart.

TS evaluation: TS was evaluated during bleaching and up to 1 hour, 24 hours and 48 hours

postbleaching. The volunteer was asked to indicate the numeric value of the degree of sensitivity for

each of the periods above, using a 5-point numeric rating scale (NRS) in which 0= none, 1= mild, 2=

moderate, 3= considerable and 4= severe [2,4,5,7,23].

In addition, the volunteers were also instructed to record the pain intensity using the visual

analogic scale (VAS) [3,6-9]. This scale is a 100-milimeter horizontal line with scores of 0 and 100 at

their ends, in which 0 = no sensitivity and 100 = severe sensitivity. The volunteer had to mark with a

24

vertical line across the horizontal line of the scale the intensity of the TS. Then, the distance in

millimeters from the zero ends was measured with the aid of a millimeter ruler.

The data from each bleaching session were evaluated separately and were merged. For this

purpose, the worst score or numeric value obtained in both bleaching sessions was considered for

statistical purposes and the determination of the overall risk and intensity of TS.

If the volunteer scored 0 (no sensitivity) in all time assessments from both bleaching sessions,

this volunteer was considered to be insensitive to the bleaching protocol. In all other circumstances,

the volunteers were considered to have sensitivity stemming from the bleaching procedure. This

dichotomization allowed us to calculate the absolute risk of TS, which represented the percentage of

volunteers who reported TS at least once during treatment. We also calculated the overall TS intensity.

Color evaluation: Shade evaluation was performed before 1 week after the 1st bleaching

session, but before the 2nd session, and 1 week after the 2nd bleaching session. Color evaluation was

not performed immediately after each bleaching session so that the effect of dehydration and

demineralization on color measures could be avoided. We performed the color evaluation using the

shade guides of VITA Classical and the VITA Bleachedguide 3D-MASTER. (VITA Zahnfabrik).

For the color evaluation, the VITA Classical shade guide’s 16 tabs were arranged from highest

(B1) to lowest (C4) value. Although this scale is not linear in the truest sense, we treated the changes

as representing a continuous and approximately linear ranking for the purpose of analysis, as already

performed in several published studies [2,3,5,8,9,15,23,25]. The VITA Bleachedguide 3D-MASTER

contains lighter shade tabs and is already organized from the highest (0M1) to lowest (5M3) value

[24]. The measurement area of interest for shade matching was the middle 1/3 of the facial surface of

the central incisor, according to the American Dental Association guidelines [4,12,15].

The 2 examiners, masked to the allocation assignment, scheduled the volunteers for bleaching

and evaluated their teeth against the shade guide at the different time assessments. Color changes were

calculated from the beginning of the active phase up to and including recall times by calculating the

change in the number of shade guide units (∆SGU), which occurred toward the lighter end of the

value-oriented list of shade tabs. In the event of disagreements between the examiners during shade

evaluation, a consensus was reached through discussion.

Statistical analysis: We performed the analysis after the intention-to-treat protocol, and we

involved all participants who were randomly assigned [21]. In cases of missing data, the last

observation was carried forward. The statistician was masked to the study groups. The absolute risk of

TS and its intensity were evaluated by using Fischer’s exact test. (α = 0.05). The authors calculated the

relative risk as the confidence interval for the effect size.

Comparison of the TS intensity (NRS data) of the 2 groups at the 2 different assessment points

were performed by using the Mann-Whitney U test, and comparisons between times within each group

were performed using the Friedman test. The comparisons of the TS intensity obtained with the VAS

scale were evaluated by using a 2-way repeated measures ANOVA and Tukey’s test.

25

Color changes between groups (∆SGU between base line versus 1 week after the 2nd

bleaching session) were compared by using a t test, and the shade changes were evaluated by using

Student’s t test. In all statistical tests, the significance level was 0.05. We performed all analyses by

using the software SPSS for windows version 20.0 (IBM).

3. Results

We screened 123 participants examined in the dental chair to check if they met the inclusion

and exclusion criteria (Figure 1). The bleaching procedures were implemented exactly as planned and

no modification was performed.

Characteristics of included participants: The baseline color of the volunteers was similar

(control group: 5.9 [1.9]; dexamethasone: 5.6 [2.1]); the mean age, (SD) between volunteers was

similar between the groups (control: 22.5 [2.1] and dexamethasone: 22.3 [2.7]), ranging from 19 to 29

years. Thirty-four percent of the volunteers from the control group, and 23% of the volunteers from

the dexamethasone group were men.

Protocol adherence and dropouts: No discontinuity in both treatment groups was found in the

clinical investigation. All volunteers attended the recall visit 1 week postbleaching.

Tooth Sensitivity: Two volunteers, 1 from each group, took an analgesic to alleviate the

bleaching-induced TS (Tylenol, Janssen Cilag Farmacêutica) in the period from 5 to 7 hours after the

2nd and last clinical bleachings.

Table 2 shows the number of participants who experienced TS during the bleaching regimen

in the control group and dexamethasone group. In this table, it is shown that no significant difference

was observed between groups (p = 0.075). The relative risk, along with the 95% confidence interval, is

also evidence that the use of the experimental drug protocol had no effect on the reduction of TS.

Tables 3 and 4 show that the TS was similar in both groups, at different assessment points, in

both sessions, using both pain scales. It is also seen that the bleaching-induced TS did not last longer

than 48 hours after the bleaching protocol (Tables 3 and 4).

Color Evaluation: Significant whitening was observed in both groups (P < .001). The

descriptive data from bleaching obtained after the 1st and 2nd bleaching sessions can be seen in Table

5. At the end of the bleaching protocol, a whitening of approximately 3 shade guide units was detected

for both groups.

The results of the subjective shade evaluation (VITA Classical: P = 0.27; VITA

Bleachedguide 3D-MASTER: P = 0.68) matched the hypothesis of equality between the groups after

bleaching. The effect size and the confidence interval for the overall mean difference is also shown in

Table 5 and is evidence of no statistical difference between groups.

Adverse effects: In this study, no reports of adverse effects by volunteers were received.

26

4. Discussion

Dental bleaching is a conservative cosmetic treatment, increasingly recommended for

darkened vital teeth, with very favorable and safe results. However, some patients cannot tolerate the

use of trays or wish for a faster result. In this case, the in-office bleaching technique using high

concentrations of hydrogen peroxide (30% -35%) becomes an appropriate alternative. The

effectiveness of this whitening technique is well documented in the literature, with a change in the

color scale ranging from 5 to 8 shade guide units (SGUs) after 2 clinical bleaching sessions

[6,11,12,26]. Nonetheless, several studies have shown that a frequent problem associated with this

technique is increased TS, which often leads to patient withdrawal from treatment [13,20,21,23,36,41].

In this study, 2 calibrated researchers used 2 visual methods of color choice (kappa = 85%).

The colors were analyzed with reference to the VITA Classical and Vita Bleachedguide 3D-MASTER

scales. Although it does not have a linear correlation of value, the Vita Classical scale is frequently

used in bleaching studies [6,36,42]. The VITA Bleachedguide 3D-MASTER scale is younger and has

been organized to encompass color variations to characterize the shadows and to facilitate the

recording of the tooth whitening color by having a subtle and gradual distribution from the lowest to

highest value [43]. Based on the VITA Classical scale, this study showed an effective whitening of

approximately 3 SGUs for both groups, which shows that the product used (Pola Office Plus, SDI -

37% hydrogen peroxide) was effective with the bleaching protocol used. Although these mean values

are lower than the 5 to 8 mean values found in the literature [6,11,12,26], it must be said that many

patients in this stduy had the initial color close to A1, which means that they wouldn’t bleach many

units, and probably, this is the reason for the lower mean values.

Currently, the mechanism responsible for TS after a tooth bleaching procedure is nuclear.

Literature explains this condition with the Hydrodynamic theory [44]. According to this theory, fluid

movement inside dentin tubules is responsible for stimulating receptors in the pulpal dentin area,

resulting in pain. However, Markowitz [28] noted that the mechanism of TS stemming from tooth

bleaching, which occurs in healthy teeth with no other provoking stimulus, differs from the

mechanisms of other forms of TS, which usually occur when stimuli (cold or tactile) contact the

surface of exposed dentin. It has been hypothesized that TS resulting from tooth bleaching occurs

because peroxide penetrates the tooth structure and directly activates a neuronal receptor and not

because of hydrodynamic effects. In addition, alteration stemming from bleaching agents on the

morphological enamel surface (increased surface porosity, depressions and superficial irregularities)

[45,46] could leave the dentin less protected. Although the mechanism of bleaching-induced TS is not

well understood, it seems to result from a reversible inflammatory process due to damage resulting

from hydrogen peroxide in the pulp [28]. This pain is usually mild and resolves within 48 hours after

the protocol [22,26,27]. Nevertheless, in some cases, the bleaching-induced TS can be severe and

responsible for patients’ withdrawal from treatment [28].

27

A recent systematic review, where the authors compared the mean percentage of

sensitivity in home and in-office bleaching techniques, found a significant increase in dental

sensitivity in the in-office bleaching technique compared with the home technique [47]. In another

recent systematic review and meta-analysis, the authors also assessed the risk and intensity of TS

during home and in-office tooth bleaching in adult patients and found no significant difference in

risk/intensity between the techniques [48].

In this study, in the control group, where the bleaching product was used in association with

the desensitizer with potassium nitrate and sodium fluoride, according to the manufacturer's

instructions, a sensitivity risk of 94% was observed, with an average value of sensitivity intensity of

8.09 (17.06) during the 1st whitening session, reaching 11.14 (20.08) in the 1st hour after bleaching

but dropping to close to 0 within the 1st 48 hours. In the 2nd session, these values were slightly higher

(although no statistically significant difference was found when the results of the 2 weeks were

compared with each other), also reaching values close to 0 in the 1st 48 hours. This same trend of

decreasing sensitivity values reaching values close to 0 in the 1st 48 hours was observed in the

experimental group, as well as the trend of higher values in the 2nd bleaching session (Table 4). In this

experimental group, the sensitivity risk was of 80%, which was lower than that of the control group

but without a statistically significant difference (p = 0.075). It should be noted, however, that the

median sensitivity intensity in both groups was between 0 and 1 (absent or mild) in the 2 weeks (Table

3), which means that although the sensitivity was present, it was considered mild and did not prevent

the continuity of bleaching treatment. These values showed that this work is in agreement with the

literature, that is, it was observed that approximately 90% of the patients had some sensitivity

associated with whitening in both groups [20,21,36].

The reduction in bleaching-induced sensitivity has been the goal of several studies, but

the problem has not yet been resolved. Potassium nitrate associated with sodium fluoride has been

used in several ways as a desensitizing agent associated with bleaching techniques. In a recent

systematic review with meta-analysis, it was demonstrated that potassium nitrate associated with

sodium fluoride is able to reduce the sensitivity associated with this technique, but not to eliminate it

completely [29], which was also observed in this study.

In this study, in the control group, it is not possible to assert that the sodium

fluoride/potassium nitrate association was responsible for the sensitivity intensity decrease, and in the

same way, in the experimental group, it was not possible to make the same assertion regarding the

experimental dexamethasone protocol, as we didn’t have a negative control group, without any

dessentizer, or without any drug, because the scientific review committee and the committee for the

protection of human participants in our university did not allow this. However, in fact, this

comparison was already done in other studies [11,22,29,33,34], and other studies [49-51] comparing

other treatments using this same sodium fluoride/potassium nitrate association as a control group have

shown the same tendency. Considering that our objective was to compare the dexamethasone

28

experimental protocol with this “gold standard” treatment (sodium fluoride / potassium nitrate), this

negative control group was really unnecessary.

Non-steroidal anti-inflammatory drugs (NSAIDs) are known to act by suppressing

constitutive cyclooxygenase-1 (COX-1) and induced cyclooxygenase-2 (COX-2). Its use for the

prevention of bleaching-induced sensitivity has been tried in some studies, and the results of the

preventive use of non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of dental

sensitivity resulting from a bleaching treatment were compared in a systematic review with a meta-

analysis [41]. This meta-analysis showed no significant effect of preventive analgesia with the use of

NSAIDs for dental sensitivity after dental bleaching, suggesting the need for further studies in this

área [41].

More recent studies have evaluated the use of steroidal anti-inflammatory drugs, also

known as corticosteroids, which are defined as synthetic hormones that mimic the actions of

endogenous cortisol that the adrenal gland secretes. Its therapeutic effects are generally attributed to

the suppression of multiple mechanisms involved in the inflammatory response, leading to a decrease

in levels of proinflammatory chemical mediators at the site of injury [52].

Except for the replacement therapy of patients with deficiency states of corticoid levels, the

use of corticosteroids is largely empirical [53,54]. Therapeutic principals, such as the disease severity,

side effects and a careful consideration of the risks/benefits for each patient, are considered to design

corticosteroid`s protocols [55]. The rationale behind the protocol used in this study is 1st because

pretreatment with dexamethasone would reduce the production of several inflammatory mediators,

known to sensitize nociceptors. Second, the maximal daily dose of dexamethasone (15 mg by oral

route or 20 mg intravenously) in a short course therapy (up to a week) is unlikely to be harmful [56].

Taken this, we expected that 3 single doses of 8 mg, administrated 48 hours, 24 hours, and on the day

of the clinical bleaching section would inhibit the synthesis of most inflammatory mediators, which

are regularly released after teeth whitening. Therefore, TS would be prevented via dexamethasone`s

antinflammatory effects [57]. So far, posttreatment using steroidal, nonsteroidal or selective

nonsteroidal anti-inflammatory drugs did not completely attenuate bleaching-induced TS [36,58].

Likewise, pretreatment with dexamethasone did not reduce the bleaching-induced TS. This

fact strongly suggests that other mechanisms rather than the ordinary release of inflammatory

mediators or cytokines contribute to TS. As it is well known, dental bleaching causes a chemical-

inciting event within the pulp tissue, which leads to the nerve excitation resulting in pain. Recent

reviews suggested that tooth pain occurs in response to the excitation of a transient receptor potential

cation channel called TRPA1 [59-61]. Although TRPA1 plays a role in TS, it is regulated by TNF-alfa

[62], a transcription factor whose activation should also have been attenuated by our dexamethasone

pretreatment protocol.

TRPA 1 is a classical thermosensory channel belonging to a subfamily of the transient

receptor potential (TRP) channel family, which is activated by several reactive agents, such as

29

hydrogen peroxide [63], and changes in the environmental temperature [64]. During this study, we

noticed that TS scored higher on cold days, even with patients who do not normally feel pain (data not

shown). Further analyses would be important to clarify a possible relationship between cold/hot and

the hydrogen peroxide threshold activation of pulp TRPA1 receptors.

Hydrogen peroxide most likely directly activates TRPA1 and thereby contributes to its

hyperalgesia responses, augmenting the perception of pain. Arachidonic acid metabolites do not

appear to involve direct binding to TRPA1. This is an argument that explains dexamethasone failure in

either preventing or treating TS. Although dental bleaching causes a reversible inflammatory response,

bleaching-induced sensitivity seems to be more related to direct TRPA1 receptor activation. New

approaches should focus on using TRPA1 antagonist substances or analgesics for treatment soon after

bleach-induced TS occurs.

5. Conclusions

The administration preoperatively of dexamethasone, in a protocol of 3 daily doses 8 mg of

the drug, starting 48 hours before an in-office bleaching treatment, does not reduce the incidence or

intensity of bleaching-induced TS.

6. Compliance with Ethical Standards

- Conflict of Interest: Author A declares that she has no conflict of interest. Author B declares that

he has no conflict of interest. Author C declares that he has no conflict of interest. Author D declares

that he has no conflict of interest. Author E declares that she has no conflict of interest. Author F

declares that he has no conflict of interest. Author G declares that he has no conflict of interest. Author

H declares that he has no conflict of interest.

- Funding: This work was supported by National Council for Scientific and Technological

Development (CNPq) and Coordination for the Improvement of Higher Level Personnel (CAPES), in

Brazil.

- Ethical approval: All procedures performed in this study were in accordance with the ethical

standards of the national research committee and with the 1964 Helsinki declaration and its later

amendments or comparable ethical standards.

- Informed consent: Informed consent was obtained from all individual participants included in this

study.

30

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Figure Captions

Figure 1. CONSORT flow diagram of the clinical trial design phases including enrollment and

allocation criteria.

35

TABLE 1

PRODUCT INGREDIENTS

Pola Office + SDI* 37.5% hydrogen peroxide

potassium nitrate

Soothe SDI* potassium nitrate 6.0%

fluoride ions 0.10%

water 89.60%

thickener 4.20%

sodium benzoate 0.10%

Dexamethasone capsules** dexamethasone base 8mg

starch 50%

lactose monohydrate 35%

dibasic calcium phosphate 14%

magnesium stearate 1%

Placebo capsules** starch 50%

lactose monohydrate 35%

dibasic calcium phosphate 14%

magnesium stearate 1%

Placebo gel** carbopol

* SDI, Victoria, Australia

** Handled by Bem Viver laboratory Ltda, registration number 09047030/0001-28, located at Santa

Rosa street, Icarai- Niteroi, RJ, Brazil. Batch of the product: 189155.

36

TABLE 2

Participants who experienced tooth sensitivity during the bleaching regimen in the control group

and dexamethasone group*

TREATMENT

TOOTH SENSITIVITY

(Nº. OF

PARTICIPANTS) ABSOLUTE RISK

RISK RATIO (95%

CONFIDENCE

INTERVAL) Yes No

Control 33 2 0.94 0.24 (0.05 – 1.26)

Dexamethasone 28 7 0.80

* Fischer’s exact test (p= 0.075).

37

TABLE 3

Medians and interquartile (1 and 3 interquartile) ranges of the tooth sensitivity at different assessment points

using the numeric rating scale (NRS).

ASSESSMENT

TIMES

First Session Second Session

Control Dexamethason

e

Compariso

n group Control

Dexamethason

e

Comparison

group

During

bleaching 0 (0-1)A 0 (0-1) A NS 0 (0-1) A 0 (0-1) A NS

Up to 1h after

bleaching 0 (0-1) A 0 (0-1) A NS 0 (0-1) A 1 (0-1) A NS

Up to 24h after

bleaching 0 (0-1) A 0 (0-1) A NS 0 (0-2) A 0 (0-1) A NS

Up to 48h after

bleaching 0 (0-0) B 0 (0-0) B NS 0 (0-0) B 0 (0-0) B NS

* Within each column, significant differences are represented by different uppercase letters.

NS: No significant difference between groups.

38

TABLE 4

Means (standard deviations) of the tooth sensitivity intensity at the different assessment points using visual

analog scales.*

ASSESSMENT

TIMES

First Session Second Session

Control Dexamethasone Compariso

n group Control

Dexamethason

e

Comparison

group

During

bleaching

8.09

(17.06)AB 7.51 (15.46)A NS

14.03

(21.39)A 6.46 (6.34)AB NS

Up to 1h after

bleaching

11.14

(20.08)A 6.31 (12.78)A NS

14.31

(20.13)A 7.57 (13.46)A NS

Up to 24h after

bleaching 8.26 (13.48)A 5.06 (9.86)A NS

16.60

(21.57)A 9.77 (20.55)A NS

Up to 48h after

bleaching 2.91 (9.14)B 0.37 (1.54)B NS 1.91 (5.46)B 1.14 (4.46)B NS

* Within each column, significant differences are represented by different uppercase letters.

NS: No significant difference between groups.

39

TABLE 5

Means (standard deviations) of the change in shade guide units obtained with the VITAL Classical* and

VITA Bleachedguide 3D-Master* at baseline versus each bleaching session and 1 week post-bleaching.

TIME

INTERVAL

COLOR

EVALUATION

TOOL

GROUPS

P

VALUE

MEAN

DIFFERENCE

(95%

CONFIDENCE

INTERVAL)

Control Dexamethasone

Baseline versus 1st

Session

VITA Classical 2.14 (1.52) 1.89 (1.37) 0.46 0.35 (-0.43-0.95)

VITA

Bleachedguide 1.91 (0.95) 1.86 (0.97) 0.81 0.06 (-0.40-0.52)

2nd session versus

1st Session

VITA Classical 0.74 (1.15) 0.71 (1.49) 0.93 0.03 (-0.61-0.66)

VITA

Bleachedguide 1.29 (0.52) 1.23 (0.69) 0.70 0.06 (-0.23-0.35)

Baseline versus

2nd Session

VITA Classical 2.54 (2.39) 2.91 (1.96) 0.48 -0.37 (-1.42-0.67)

VITA

Bleachedguide 3.00 (1.19) 3.2 (1.35) 0.51 -0.20 (-0.81 -0.41)

Baseline versus 1

week after 2nd

session

VITA Classical 2.77 (1.96) 2.26 (1.87) 0.27 0.51 (-0.40-1.43)

VITA

Bleachedguide 3.20 (1.13) 3.09 (1.17) 0.68 0.11 (-0.44 – 0.66)

*Manufactured by VITA Zahnfabrik.

40

4 - CONCLUSÕES

Os autores concluíram que a administração pré-operatória da dexametasona,

no protocolo proposto, não reduz a incidência ou a intensidade da sensibilidade

dentária induzida pelo clareamento.

41

ANEXO A – Comprovantes do envio do artigo

42

ANEXO B- Aprovação do Comitê de Ética

47

ANEXO C- Aprovação Clínical Trials

54

ANEXO D- CONSORT

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