Será o paracetamol eficaz na eliminação da dor após

Seraacute o paracetamol eficaz na eliminaccedilatildeo

da dor apoacutes extracccedilatildeo do terceiro molar

inferior

ANAacuteLISE DA ANALGESIA DO PARACETAMOL COMPARADA Agrave DE

NSAIDrsquoS

SERAacute O PARACETAMOL EFICAZ NA ELIMINACcedilAtildeO DA DOR

APOacuteS EXTRACCcedilAtildeO DO TERCEIRO MOLAR INFERIOR1

Anaacutelise da analgesia do paracetamol comparada agrave de NSAIDrsquos

Catarina Cardoso

Ivo Cavalheiro

Nuno Pinto

Sara Mendes

FACULDADE DE MEDICINA DENTAacuteRIA DA UNIVERSIDADE DE LISBOA

Mestrado Integrado em Medicina Dentaacuteria

Biologia Oral I

2ordm Ano ndash 1ordm Semestre

23 de Dezembro de 2011

1 Este trabalho estaacute escrito segundo as regras do Acordo Ortograacutefico de 1945

RESUMO

Objectivos Investigar a eficaacutecia e os efeitos secundaacuterios do paracetamol

(1000mg) na eliminaccedilatildeo da dor dentaacuteria poacutes-operatoacuteria resultante da extracccedilatildeo de

terceiros molares inferiores comparaacute-la agrave eficaacutecia relativa dos vaacuterios NSAIDrsquos e a

combinaccedilotildees com outros faacutermacos

Materiais e meacutetodos A pesquisa foi realizada em bases de dados secundaacuterias

(Cochrane Database of Systematic Reviews Evidentista CEBD EBD e Lilacs) assim

como em bases de dados primaacuterias (Medline atraveacutes dos motores de busca PubMed e

NICE) entre 7 e 19 de Novembro Os artigos encontrados foram avaliados numa fase

inicial (com base nos seus tiacutetulos e abstracts) para averiguar a sua relevacircncia de acordo

com o seguinte sistema de classificaccedilatildeo adequado provavelmente adequado

inadequado

Resultados Foi encontrado um total de 161 registos incluindo revisotildees

sistemaacuteticas e ensaios cliacutenicos aleatorizados dos quais apenas 31 foram classificados

pelo seu tiacutetulo e abstract como Adequados ou Provavelmente Adequados A anaacutelise

mais aprofundada dos abstracts juntamente com uma leitura transversal dos artigos

resultou em 8 publicaccedilotildees que preenchiam definitivamente os criteacuterios de inclusatildeo e

foram por isso avaliadas com recurso agraves fichas CASP

Conclusotildees Atraveacutes dos estudos analisados conclui-se que o paracetamol eacute uma

analgeacutesico seguro e eficaz dado que apresenta um benefiacutecio estatisticamente

significativo quando comparado a placebo No entanto exibe menor eficaacutecia quando

comparado a outros NSAIDrsquos nomeadamente ibuprofeno e a combinaccedilotildees dos mesmos

(paracetamol+NSAID) Apesar dos melhores resultados alguns NSAIDrsquos manifestam

efeitos secundaacuterios de alta severidade por oposiccedilatildeo aos do paracetamol Revela-se

assim necessaacuterio o desenvolvimento de estudos que investiguem de melhor forma os

efeitos adversos destes faacutermacos e o mecanismo de acccedilatildeo do paracetamol e incluam

outros dados - como custo financeiro e disponibilidade no mercado

Palavras-Chave Paracetamol NSAIDrsquos terceiro molar inferior extracccedilatildeo

dentaacuteria dor poacutes-operatoacuteria aliacutevio da dor Escala Visual Analoacutegica

ABSTRACT

Aims To investigate the efficacy and side effects of paracetamol (1000mg) on

the lower third molar extraction post-operative pain relief to compare it to other

NSAIDrsquos efficacy as well as the combination of both

Methods Searches were conducted in secondary databases (Cochrane Database

of Systematic Reviews Evidentista CEBD EBD and Lilacs) as well as in primary

databases (Medline atraveacutes dos motores de busca PubMed e NICE) between 7 and

November 19 The encountered articles were initially evaluated based on their titles and

abstracts in order to assess their relevance This was done according to a classification

system ldquoadequaterdquo ldquoprobably adequaterdquo ldquoinadequaterdquo

Results A total of 161 records were found including systematic reviews and

randomized clinical trials only 31 were classified as ldquoadequaterdquo or ldquoprobably

adequaterdquo After a more thorough analysis of each abstract in addition to further

reading of the papers only 8 articles fulfilled the inclusion criteria Thus they were

evaluated according to the CASP critical appraisal sheets

Conclusions Paracetamol is a safe and effective analgesic which presents a

statistical significant advantage when compared to a placebo However paracetamol

shows less efficacy when compared to other NSAIDrsquos such as ibuprofen The

combination of paracetamol + other NSAID also shows to be more effective displaying

the additive effect of this compound Although NSAIDrsquos show the best pain relief

scores some can cause severe side effects as opposed to paracetamol Further studies

are needed in order to better investigate the adverse effects of these drugs as well as the

mechanism of action of paracetamol which still remains unclear Other data such as

financial cost and market availability should be approached in future studies

Keywords Paracetamol NSAIDrsquos lower third molar tooth extraction post-operative

pain pain relief Visual Analogic Scale

IacuteNDICE

PERGUNTA FORMULADA PELO PACIENTE 6

QUESTAtildeO PICO 6

OBJECTIVOS 6

INTRODUCcedilAtildeO 7

PESQUISA 12

Criteacuterios de Selecccedilatildeo 12

Tipos de Estudos escolhidos participantes intervenccedilatildeo e de mediccedilatildeo 12

Avaliaccedilatildeo dos Estudos 13

Estrateacutegias de Pesquisa 12

Cochrane Database for Systematic Reviews helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 13

Evidence-Based Dentistry (EBD) helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 14

National Institute of Health and Clinical Excellence (NICE) helliphelliphelliphelliphelliphellip 14

Literatura Latino-Americana e do Caribe em Ciecircncias da Sauacutede (LILACS) 14

PubMed 15

AVALIACcedilAtildeO CRIacuteTICA 17

Revisotildees Sistemaacuteticas 17

Ensaios Cliacutenicos Aleatorizados 28

DISCUSSAtildeO 52

RESPOSTA DADA AO PACIENTE 55

REFEREcircNCIAS BIBLIOGRAacuteFICAS 56

ANEXOS 61

Anexo A ndash Tabela de Artigos Excluiacutedos 61

Anexo B ndash Artigos Incluiacutedos em formato integral 62

PERGUNTA FORMULADA PELO PACIENTE

Apoacutes uma exodontia de um terceiro molar inferior ldquoDoutor natildeo me vai passar

mais nada aleacutem do paracetamol para as dores Eacute eficaz Natildeo vou ter doresrdquo

QUESTAtildeO PICO

Com base na questatildeo apresentada pelo paciente eacute possiacutevel identificar

Populaccedilatildeo ndash Pacientes adultos com pelo menos um terceiro molar inferior

Intervenccedilatildeo ndash administraccedilatildeo poacutes-operatoacuteria de paracetamol (1000g) aquando

duma exodontia do terceiro molar inferior

Comparaccedilatildeo ndash outros analgeacutesicos e NSAIDrsquos (Non-Steroidal Anti-

Inflammatory Drugs) convencionais

Outcome ndash Eliminaccedilatildeo ou atenuaccedilatildeo da dor medida atraveacutes da escala visual

analoacutegica de dor

Em pacientes adultos apoacutes exodontia do 3ordm molar inferior a administraccedilatildeo

de paracetamol eacute mais eficaz na terapecircutica analgeacutesica comparativamente a outros

analgeacutesicos e anti-inflamatoacuterios natildeo esteroacuteides convencionais utilizando uma

escala visual analoacutegica de dor

OBJECTIVOS

Primaacuterios

Investigar a eficaacutecia do paracetamol (1000mg) na eliminaccedilatildeo da dor dentaacuteria

poacutes-operatoacuteria e comparaacute-la com outros NSAIDrsquos comparando os efeitos secundaacuterios

associados a cada faacutermaco

Secundaacuterios

Aferir a eficaacutecia relativa dos vaacuterios NSAIDrsquos bem como combinaccedilotildees de

paracetamol com outros compostos

INTRODUCcedilAtildeO

EXODONTIA DE TERCEIROS MOLARES INFERIORES

A extracccedilatildeo de terceiros molares eacute um procedimento ciruacutergico no campo da

sauacutede oral amplamente praticado e difundido A dor poacutes-operatoacuteria desta intervenccedilatildeo

tornou-se o modelo mais frequentemente usado em ensaios sobre dor aguda por ser um

procedimento comum com dor moderada a severa e com um nuacutemero suficiente de

pacientes para se realizar um estudo de forma relativamente faacutecil (1 2)

Os motivos que conduzem agrave exodontia de terceiros molares devem ser

considerados cuidadosamente natildeo soacute na sua dimensatildeo cliacutenica como no encontro dos

interesses do paciente econoacutemicos e outros Algumas situaccedilotildees constituem uma razatildeo

largamente aceite para a extracccedilatildeo sendo descritas em normas de orientaccedilatildeo cliacutenica

Natildeo se pode excluir poreacutem uma selecccedilatildeo e procura cuidadosa por parte do cliacutenico da

melhor evidecircncia cientiacutefica

Segundo as normas de orientaccedilatildeo cliacutenica NICE a extracccedilatildeo de sisos impactados

deve ser limitada a pacientes que evidenciam patologia como caacuteries irrestauraacuteveis

patologias pulpares ou periapicais natildeo trataacuteveis abcesso e osteomielite reabsorccedilatildeo

internaexterna do dente ou dentes adjacentes fractura dentaacuteria quistos tumores e

outros (3) Terceiros molares impactados mas livres de patologia natildeo devem ser

extraiacutedos pois natildeo haacute evidecircncia de que sugira que traria benefiacutecios para os pacientes

Iria tambeacutem sujeitar pacientes saudaacuteveis aos riscos que acompanha este tipo de

procedimento e os efeitos poacutes-operatoacuterios do mesmo Existe controveacutersia em redor

deste assunto e sobre se existe algum benefiacutecio na extraccedilatildeo profilaacutetica ldquoNo evidence

was found to support or refute routine prophylactic removal of asymptomatic impacted

wisdom teeth in adults There is some reliable evidence that suggests that the

prophylactic removal of asymptomatic impacted wisdom teeth in adolescents neither

reduces nor prevents late incisor crowdingrdquo (4) A extracccedilatildeo de um dente natildeo impactado

deve ser executada quando a natildeo extracccedilatildeo do mesmo eacute ou potencialmente viraacute a

constituir uma situaccedilatildeo patoloacutegica Este procedimento ciruacutergico conduz a um niacutevel

significante de dor poacutes-operatoacuteria sendo esta mais severa nas primeiras doze horas apoacutes

o procedimento com o pico de intensidade nas 6-8 horas poacutes-operatoacuterias (5)

ETIOLOGIA DA DOR

Os tecidos lesados ou traumatizados na sequecircncia da remoccedilatildeo do terceiro molar

conduzem agrave libertaccedilatildeo de mediadores bioquiacutemicos (celulares e soluacuteveis) A inflamaccedilatildeo

aguda surge como resposta ao stress tecidual e passa por um aumento da irrigaccedilatildeo

sanguiacutenea - vasodilataccedilatildeo e aumento de permeabilidade vascular Pode-se enfatizar os

papeacuteis das histamina e a bradiquinina (recruta NO) como mediadores soluacuteveis

importantes na vasodilataccedilatildeo

Os prostanoacuteides ndash moleacuteculas envolvidas nos processos de inflamaccedilatildeo- satildeo

ecosanoacuteides ou seja derivados de precursores de aacutecidos gordos e sintetizados via

cascata do aacutecido araquidoacutenico (6 p 503 7 p 800 8) em condiccedilotildees fisioloacutegicas tecircm

um papel preponderante na citoprotecccedilatildeo da mucosa gaacutestrica hemostase e

hemodinacircmica renal A este grupo pertencem as prostaglandinas prostaciclinas

tromboxanos e leucotrienos Enquanto que as prostaglandinas satildeo sintetizadas a partir

do aacutecido araquidoacutenico por acccedilatildeo de enzimas como as ciclo-oxigenases (COX) os

leucotrienos resultam da acccedilatildeo da lipoxigenase Havendo stress tecidual a membrana

celular eacute danificada conduzindo agrave actividade da enzima fosfolipase Esta ao iniciar a

lipoacutelise possibilita a obtenccedilatildeo do percursor dos prostanoacuteides o aacutecido araquidoacutenico Por

um lado os produtos da acccedilatildeo da lipoxigenase podem estar envolvidos na formaccedilatildeo do

edema por outro os produtos da ciclo-oxigenase nomeadamente prostaglandinas estatildeo

envolvidos no processo de dor e pirexia

A ciclo-oxigenase possui 2 isoenzimas COX-1 e COX-2 (7 p 800)

A COX-1 eacute constitutiva da maioria dos tecidos humanos mas com especial

relevacircncia para mediar a integridade da mucosa gaacutestrica endoteacutelio vascular rins e

plaquetas

A COX-2 eacute expressa apoacutes lesatildeo e aquando a libertaccedilatildeo de mediadores como a

Interleucina-1 o Factor de Activaccedilatildeo de Plaquetas (PAF) ou endotoxinas

lipopolissacaacuterido (LPS) (9) Contribui para o processo inflamatoacuterio e hiperalgesia pois

ao formar prostaglandinas sensibiliza as terminaccedilotildees nervosas locais livres

nociceptivas

PARACETAMOL

O paracetamol eacute uma das drogas mais importantes usadas no tratamento da dor

aguda moderada a severa quando natildeo eacute necessaacuterio um efeito anti-inflamatoacuterio (10)

Classificado como analgeacutesico actua no sistema nervoso pela activaccedilatildeo indirecta de

receptores canabinoacuteides (11) embora este mecanismo ainda natildeo esteja totalmente

esclarecido (12) secundariamente inibe a COX-1 e COX-2 e por consequente a

siacutentese das prostaglandinas Como antipireacutetico age no centro hipotalacircmico que regula a

temperatura produzindo vasodilataccedilatildeo perifeacuterica e aumento do fluxo sanguiacuteneo

diminuindo a temperatura pela sudorese e perda de calor pela pele

O paracetamol eacute usualmente administrado oralmente (10) Apresenta uma meia-

vida de 2-3 horas Apesar de ser comparaacutevel agrave aspirina como analgeacutesico e antipireacutetico

eficaz o paracetamol difere no facto de natildeo possuir propriedades anti-inflamatoacuterias

(10) Difere dos analgeacutesicos opioacuteides porque natildeo provoca euforia nem altera o estado

de humor do doente Da mesma forma que os (NSAIDrsquos) natildeo causa problemas de

dependecircncia toleracircncia e siacutendrome de abstinecircncia Eacute muito utilizado e seguro com a

dosagem recomendada de 4g por dia mas nem sempre oferece um aliacutevio adequado da

dor aguda por si soacute (13)

NSAIDrsquoS

Os NSAIDrsquos satildeo dos agentes terapecircuticos mais utilizados no mundo inteiro

inclui-se neste grupo o ibuprofeno importante no tratamento da dor aguda e croacutenica

(14) Dos inibidores selectivos da COX-2 mais recentes nomeadamente rofecoxib

valdecoxib e celecoxib apenas este uacuteltimo foi comercializado nos EUA devido aos

restantes terem sido associados a eventos tromboacuteticos cardiovasculares (15 pp 277-

281) Apresentam trecircs acccedilotildees principais que resultam da inibiccedilatildeo da COX-2 e da

consequente reduccedilatildeo da siacutentese de prostanoacuteides

Acccedilatildeo anti-inflamatoacuteria a modificaccedilatildeo da resposta inflamatoacuteria ocorre pela

reduccedilatildeo do nordm de prostaglandinas vasodilatadoras (PGE2 prostaciclina)

associada a menor vasodilataccedilatildeo e indirectamente a menos edema No entanto a

acumulaccedilatildeo de ceacutelulas inflamatoacuterias natildeo eacute diminuiacuteda

Efeito analgeacutesico a reduccedilatildeo da siacutentese de prostaglandinas diminui a

sensibilizaccedilatildeo das terminaccedilotildees nervosas nociceptivas a mediadores da

inflamaccedilatildeo (como bradicinina e 5-hidroxitriptamina) provoca tambeacutem a reduccedilatildeo

da vasodilataccedilatildeo e desse modo o aliacutevio da cefaleia

Efeito antipireacutetico deve-se em parte agrave diminuiccedilatildeo da prostaglandina

mediadora a interleucina-1 responsaacutevel pela estimulaccedilatildeo do hipotaacutelamo e

consequente aumento de temperatura ndash febre (10 pp 1056-1061)

Eacute de referir ainda que todos os NSAIDrsquos agrave excepccedilatildeo dos inibidores selectivos da

COX-2 e salicilatos natildeo-acetilados tecircm um efeito inibitoacuterio na agregaccedilatildeo de plaquetas

(15 pp 277-281)

Os efeitos secundaacuterios resultam em grande parte da inibiccedilatildeo da COX-1 Entre

os mais frequentes encontram-se Dispepsia naacuteuseas e voacutemitos associados a lesotildees

gaacutestricas provocadas pela anulaccedilatildeo do efeito protector da prostaglandina sobre a mucosa

gaacutestrica Insuficiecircncia renal Reacccedilotildees cutacircneas Distuacuterbios hepaacuteticos Riscos

cardiovasculares e outros (10)

ESCALAS DE MEDICcedilAtildeO DE DOR - ESCALA VISUAL ANALOacuteGICA

A dor sendo um fenoacutemeno subjectivo compreende um grande conjunto de

componentes - componentes fisioloacutegicos cognitivos sensoriais comportamentais entre

outros Avaliar a dor utilizando uma medida que abranja todas as suas facetas e seja

fidedigna tem-se demonstrado impossiacutevelldquoUm instrumento ideal para a mensuraccedilatildeo da

dor deveria ter propriedades de uma escala de razatildeo fornecer informaccedilatildeo imediata

sobre a fidedignidade do desempenho dos pacientes ser relativamente livre de vieacuteses

ser simples de utilizar com pacientes () demonstrar utilidade tanto para a dor

experimental quanto para a dor cliacutenica permitindo comparaccedilotildees confiaacuteveis entre ambos

os tipos de dorrdquo(16)

A Escala Visual Analoacutegica (VAS) consiste numa mediccedilatildeo da dor em mm (0-

100mm) em que agrave extremidade 0 corresponde ldquonenhuma dorrdquo e agrave extremidade

antagoacutenica ldquopior dor possiacutevelrdquo Eacute uma forma simples eficaz - dentro das limitaccedilotildees - e

faacutecil de reproduzir ldquoou seja pode ser compreendida em distintas situaccedilotildees onde haacute

diferenccedilas culturais ou de linguagem do avaliador cliacutenico ou examinadorrdquo(16)

Para responder agrave questatildeo colocada pelo paciente eacute necessaacuterio a procura da

melhor evidecircncia cientiacutefica integrando-a com o proacuteprio interesse do paciente e a

expertise do cliacutenico Estes objectivos da Medicina Dentaacuteria Baseada na Evidecircncia satildeo

em parte consequecircncia de uma actualizaccedilatildeo constante de praacuteticas cliacutenicas consequentes

de novas evidecircncias cientiacuteficas e com a noccedilatildeo de que nenhum tratamento eacute completo

sem que ldquoas expectativas exigecircncias e direitos legiacutetimos dos pacientes sejam integrados

nos processos de decisatildeo cliacutenica sendo tal facto reconhecidamente essencial para a

melhoria da qualidade de vidardquo(17)

PESQUISA

CRITEacuteRIOS DE SELECCcedilAtildeO

Tipos de Estudos Escolhidos

Para este trabalho foram escolhidos apenas ensaios cliacutenicos aleatorizados cegos

(preferencialmente duplamente cegos) controlados ou natildeo por placebo e revisotildees

sistemaacuteticas

Tipos de participantes

Indiviacuteduos com idade superior a 15 anos

Sujeitos a cirurgia para extracccedilatildeo unilateral ou bilateral do 3ordm molar inferior

Que natildeo estivessem a tomar qualquer outro tipo de medicaccedilatildeo com efeitos

idecircnticos ou semelhantes aos faacutermacos em estudo

Sem patologias orais que provoquem dor moderada a forte ou outras patologias

que afectem a percepccedilatildeo da dor

Tipos de intervenccedilatildeo

Administraccedilatildeo apenas por via oral de

Paracetamol (1000mg) vs placebo

Paracetamol (1000mg) vs outro(s) NSAIDrsquos

Paracetamol ( 1000mg) vs outro(s) NSAIDrsquos vs placebo

Paracetamol (1000mg) + outro(s) NSAIDrsquos

ou Paracetamol (1000mg) + outro(s) NSAIDrsquos vs placebo

Estudos com outros tipos de intervenccedilatildeo natildeo foram incluiacutedos Os estudos que

apenas incluiacuteram o paracetamol sob a forma de proacute-farmaco foram excluiacutedos

Mediccedilatildeo de Resultados

A mediccedilatildeo de resultados foi obtida atraveacutes da escala visual analoacutegica (VAS ndash

visual analogic scale)

Avaliaccedilatildeo dos Estudos

Todos os estudos foram avaliados segundo fichas CASP (Critical Appraisal

Skills Programme) Estas consistem num conjunto de questotildees que permitem avaliar um

artigo cientiacutefico no seu todo para em uacuteltima anaacutelise aferir a sua aplicabilidade validade

e fiabilidade (18) Estas fichas existem para vaacuterios tipos de estudo as CASP utilizadas

neste trabalho foram as referentes a revisotildees sistemaacuteticas e ensaios cliacutenicos

aleatorizados

ESTRATEacuteGIAS DE PESQUISA

Apoacutes cada pesquisa os artigos encontrados foram avaliados numa fase inicial

com base nos seus tiacutetulos e abstracts para averiguar a sua relevacircncia A seguinte escala

foi utilizada adequado possivelmente adequado inadequado Toda a pesquisa foi

efectuada entre 7 e 19 de Novembro de 2011

Primeiramente foram consultadas bases de dados secundaacuterias apoacutes pesquisa

nestas fontes seguiram-se bases de dados primaacuterias

Cochrane Database for Systematic Reviews

Na pesquisa avanccedilada desta base de dados secundaacuteria foi introduzida a seguinte

combinaccedilatildeo de termos utilizando conectores boleanos e seleccionando as opccedilotildees

ldquosearch all textrdquo e ldquoCochrane Database of Systematic Reviewsrdquo

paracetamol AND third molar removal AND pain relief AND analgesicrdquo

Foram encontrados 14 resultados (3 protocolos e 11 revisotildees sistemaacuteticas) dos

quais uma revisatildeo foi categorizada como ldquoadequadardquo

Paracetamol for pain relief after surgical removal of lower wisdom teeth Weil

Hooper (19) Esta revisatildeo foi novamente encontrada na base de dados EBD bem

como na NICE e no PubMed

E outra classificada como ldquopossivelmente adequadardquo mas posteriormente

excluiacuteda (20)

Evidence-Based Dentistry (EBD)

Nesta base de dados foi introduzida a combinaccedilatildeo de termos

ldquoParacetamol OR acetaminophen AND third molar AND painrdquo utilizando os

filtros ldquoBritish Dental Journalrdquo e ldquoEvidence-Based Dentistryrdquo

Foram encontrados 28 resultados dos quais uma revisatildeo foi classificada como

ldquoadequadardquo

Relative efficacy of oral analgesics after third molar extraction ndash a 2011 update

Derry Wiffen (21)

E ainda dois artigos classificados como ldquopossivelmente adequadordquo

An investigation into the comparative efficacy of soluble aspirin and solid

paracetamol in postoperative pain after third molar surgery Seymour

Hawkesford (22)

Relative efficacy of oral analgesics after third molar extraction Barden

Edwards (23)

National Institute of Health and Clinical Excellence (NICE)

Nesta base de dados foi introduzida a seguinte combinaccedilatildeo de termos

ldquoParacetamol and third molar removal and pain and analgesicrdquo

Dos 28 resultados obtidos 1 foi previamente encontrado e classificado (19)

Dos restantes 27 artigos nenhum foi classificado como adequado ou possivelmente

adequado

LILACS

Nesta base de dados primaacuteria foi introduzida a seguinte combinaccedilatildeo de termos

ldquoParacetamol terceiro molar dorrdquo

Dos 3 resultados obtidos um foi classificado como possivelmente adequado mas

posteriormente excluiacutedo (24)

PUBMED

Nesta base de dados primaacuteria foram efectuadas duas pesquisas com termos

diferentes Apenas foram utilizados termos MeSH foram utilizados conectores

boleanos em ambas as pesquisas

Pesquisa 1

Search ((((Acetaminophen[Mesh]) AND Anti-Inflammatory Agents[Mesh])

AND Molar Third[Mesh]) AND Tooth Extraction[Mesh]) AND Pain

Postoperative[Mesh]

Limits only items with abstracts Humans Clinical Trial Meta-Analysis

Randomized Controlled Trial Review Comparative Study Controlled Clinical

Trial English Spanish Portuguese

Foram obtidos 32 resultados dos quais 5 artigos foram classificados como

ldquoadequadosrdquo

Combining paracetamol with a selective cyclooxygenase-2 inhibitor for acute

pain relief after third molar surgery a randomized double-blind placebo-

controlled study Haglund and von Bultzingslowen (25)

Dos restantes quatro artigos um (22) era repetido e os outros trecircs (26-28) foram

posteriormente excluiacutedos

Quatro foram considerados ldquopossivelmente adequadosrdquo dos quais trecircs (29-31)

foram posteriormente excluiacutedos O artigo remanescente foi

Analgesic efficacy of lysine clonixinate paracetamol and dipyrone in lower

third molar extraction a randomized controlled trial (32)

Pesquisa 2

Search (((Acetaminophen[Mesh]) AND Analgesics[Mesh]) AND Molar

Third[Mesh]) AND Tooth Extraction[Mesh]

Randomized Controlled Trial Review English

Obtiveram-se 56 resultados em que sete foram seleccionados como sendo

ldquoadequadosrdquo

Combined acetaminophen and ibuprofen for pain relief after oral surgery in

adults a randomized controlled trial Merry Gibbs (13)

Destes artigos seis (19 22 23 25 28 32) eram repetidos

Oito artigos foram classificados como ldquopossivelmente adequadosrdquo

Onset of analgesia with sodium ibuprofen ibuprofen acid incorporating poloxamer

and acetaminophen--a single-dose double-blind placebo-controlled study in

patients with post-operative dental pain Daniels Reader (33)

Dos oito artigos cinco foram repetidos (26 27 29-31) dois (34 35) foi

posteriormente excluiacutedo

No anexo A encontra-se uma tabela de artigos excluiacutedos cujas razotildees satildeo

discriminadas

Eacute de notar que este tipo de estrateacutegia de pesquisa traz associada grande

quantidade de resultados irrelevantes superior agrave de artigos de interesse mas facilita a

aquisiccedilatildeo de todos os artigos importantes colocando em primeiro plano a sensibilidade

e natildeo a especificidade (36) A utilizaccedilatildeo de conectores boleanos e de filtros especiacuteficos

foi uma forma de minimizar o nuacutemero de resultados natildeo relacionados (17) preservando

os de interesse

AVALIACcedilAtildeO CRIacuteTICA

REVISOtildeES SISTEMAacuteTICAS

Paracetamol for pain relief after surgical removal of lower

wisdom teeth Weil Hooper (19)

1 Did the review ask a clearly-focused question

Sim A populaccedilatildeo em estudo compreende pacientes de qualquer estado de sauacutede

que necessitem de uma exodontia do terceiro molar inferior e que apresentam uma

intensidade de dor basal moderada a forte Foram excluiacutedos pacientes que estivessem a

tomar outro analgeacutesico A intervenccedilatildeo foi baseada em dois aspectos ndash eficaacutecia e efeitos

secundaacuterios

A terapecircutica usada para avaliar a eficaacutecia consistiu na administraccedilatildeo de uma

dose uacutenica de paracetamol por via oral independentemente da formulaccedilatildeo ou do

momento em que o faacutermaco foi tomado

Em relaccedilatildeo aos efeitos secundaacuterios foram incluiacutedos estudos natildeo soacute de dose

uacutenica como tambeacutem de doses muacuteltiplas de acetaminofeno consideraram-se estudos em

que este composto foi tomado ateacute 7 dias apoacutes a primeira toma Para este trabalho apenas

seratildeo considerados os resultados com base na administraccedilatildeo poacutes-operatoacuteria do

paracetamol

Os resultados ndash intensidade da dor e aliacutevio da dor ndash foram medidos usando as

escalas visual analoacutegica categoacuterica verbal numeacuterica verbal global subjectiva de

avaliaccedilatildeo de eficaacutecia e outras categoacutericas Os outcomes derivados do aliacutevio da dor

contabilizados foram total pain relief (TOTPAR) e summed pain intensity difference

(SPID) durante 4 e 6 horas Foram ainda contabilizados os efeitos secundaacuterios

2 Did the review include the right type of study

Os uacutenicos estudos incluiacutedos foram ensaios cliacutenicos aleatorizados duplamente

cegos que comparam o paracetamol a um placebo bem como dosagens diferentes

avaliando efeitos agraves 4 e 6 horas Este tipo de estudo eacute adequado pois implica um baixo

risco de vieacutes

3 Did the reviewers try to identify all relevant studies

Sim Os autores utilizaram estudos de todos os idiomas recorrendo agrave sua

traduccedilatildeo quando necessaacuterio Foram consultadas bases de dados bibliograacuteficas

electroacutenicas The Cochrane Oral Health Grouprsquos Trials Register The Cochrane Central

Register of Controlled Trials The Cochrane Pain Palliative and Supportive Care

Grouprsquos Trials Register MEDLINE EMBASE e Current Controlled Trials Register

Tambeacutem foram realizadas pesquisas manuais em revistas como parte do Cochrane Oral

Health Grouprsquos ongoing journal handsearching programme A pesquisa visou estudos

publicados entre 1966 e 25 de Agosto de 2006

Foram enviadas cartas a autores de ensaios cliacutenicos aleatorizados com vista a

obter estudos natildeo publicados bem como a empresas farmacecircuticas fabricantes de

analgeacutesicos

Os autores deste estudo consultaram ainda referecircncias bibliograacuteficas de papers

reviews e referecircncias pessoais

4 Did the reviewers asses the quality of the included studies

Sim Foi utilizada uma estrateacutegia clara e bem definida para a determinaccedilatildeo dos

estudos a incluir Este processo foi realizado independentemente por dois autores da

revisatildeo ndash natildeo cegos ndash baseando-se em dois criteacuterios centrais atribuiccedilatildeo oculta do

faacutermaco e a existecircncia de um follow-up completo Para estes criteacuterios foi utilizado um

sistema de pontuaccedilatildeo Desta forma a cada estudo foi-lhe atribuiacuteda uma pontuaccedilatildeo

formando-se dois grupos

Baixo risco de vieacutes

Moderado ou alto risco de vieacutes

5 If the results of the studies have been combined was it reasonable to do so

Sim os resultados foram apresentados de forma combinada e loacutegica Em

primeiro lugar foram apresentadas tabelas uma para cada artigoestudo incluiacutedo em

que se encontravam discriminados os meacutetodos participantes intervenccedilotildees resultados e

outras notas Os resultados dos diferentes estudos foram agrupados em 2 outcomes

tendo cada outcome 2 divisotildees

Outcome 1 ndash TOTPAR agraves 4h

A ndash Dosagem de paracetamol ateacute 1000mg vs placebo

B ndash Dosagem de paracetamol igual ou superior a 1000mg vs placebo

Todos estes grupos foram analisados e comparados segundos 2 paracircmetros

Comparaccedilatildeo 1- Medidas de aliacutevio da dor

Comparaccedilatildeo 2- Medidas de intensidade da dor

Tendo em conta todas estas variaacuteveis foram realizadas meta-anaacutelises por

subgrupo (pp 29-40) utilizando graacuteficos forest plot

Anaacutelise 11 ndash Comparaccedilatildeo 1 de A vs B ndash Outcome 1

Anaacutelise 3 ndash Comparaccedilatildeo do nuacutemero de efeitos adversos de paracetamol vs

placebo comparando ainda as duas dosagens diferentes

Valores de heterogeneidade (representados por I2) proacuteximos de 25 indicam

baixa discrepacircncia 50 satildeo indicadores de heterogeneidade moderada e valores

proacuteximos de 75 satildeo sinal de alta heterogeneidade entre os estudos (37)

Olhando para os valores de I2 dois possuem alta heterogeneidade um moderada

e dois baixa Nos grupos que apresentam uma discrepacircncia estatiacutestica significativa dos

resultados a aglutinaccedilatildeo dos mesmos natildeo foi muito bem sucedida Nestes grupos ainda

que a heterogeneidade seja elevada a apresentaccedilatildeo dos resultados de cada estudo foram

correcta e individualmente apresentados Aleacutem deste aspecto os diferentes meacutetodos ndash

dosagem e tempo - foram agrupados exactamente para que as formas de intervenccedilatildeo e

meacutetodos com o menor risco de vieacutes

Tabela 1 ndash Valores de heterogeneidade (I2) de cada anaacutelise

Total de I2

Anaacutelise 11 Anaacutelise 12 Anaacutelise 21 Anaacutelise 22 Anaacutelise 3

76 81 66 29 28

Natildeo foram discutidas as variaccedilotildees nos resultados

6 How are the results presented and what is the main result

A meta-anaacutelise por subgrupos foi realizada com recurso agrave medida de eficaacutecia de

intervenccedilatildeo Risco Relativo (RR) Analisando o graacutefico forest plot os ldquoquadradosrdquo a azul

representam o RR e o poliacutegono (semelhante a um losango) sumariza todas as

informaccedilotildees (provenientes dos vaacuterios estudos) sobre o efeito do paracetamol (38)

ldquoQuando o IC natildeo ultrapassa a linha de nulidade pode-se afirmar que o resultado eacute

estatisticamente significativo Estudos maiores possuem IC mais estreitos ou seja

resultados mais precisos e maior contribuiccedilatildeo para a meta-anaacutelise que tambeacutem eacute repre-

sentada graficamente (quanto maior a aacuterea do quadrado maior o peso) e valor

percentualrdquo (39) A significacircncia aumenta com a distacircncia do poliacutegono da linha de natildeo

efeito

Independentemente do tempo (4 ou 6h) dosagens ateacute 1000mg de paracetamol

apresentam uma pequena discrepacircncia nos resultados sendo que o paracetamol eacute

ligeiramente mais eficaz que o placebo Doses iguais ou superiores a 1000mg de

paracetamol traduzem-se num maior aliacutevio da dor poacutes-operatoacuteria (poliacutegono afastado da

linha de natildeo-efeito)

Em relaccedilatildeo agrave anaacutelise 3 ateacute doses de 1 g de paracetamol nuacutemero de casos de

efeitos adversos eacute muito semelhante entre placebo e a substacircncia activa Para

concentraccedilotildees superiores a 1000 mg o nuacutemero de efeiros adversos eacute superior para

paracetamol Eacute possiacutevel concluir que natildeo haacute uma diferenccedila notoacuteria no nuacutemero de casos

de efeitos adversos O poliacutegono cruza sempre a linha de natildeo efeito

O paracetamol eacute consideravelmente mais eficaz que o placebo no aliacutevio de 50

da dor principalmente em doses iguais ou superiores a 1000mg Natildeo haacute diferenccedila

significativa em relaccedilatildeo aos efeitos adversos

7 How precise are these results

Utilizando um intervalo de confianccedila de 95 e tendo em consideraccedilatildeo que o

poliacutegono natildeo intersecta a linha de natildeo efeito os resultados satildeo precisos (anaacutelise 1 a 2)

Na anaacutelise 3 mesmo com um IC 95 o poliacutegono cruza a linha de natildeo efeito logo natildeo eacute

possiacutevel tirar conclusotildees semelhantes em relaccedilatildeo aos limites inferior e superior do IC

Eacute de notar que a elaboraccedilatildeo de uma meta-anaacutelise contribui para a robustez dos

resultados daiacute provenientes combinar os resultados de cada estudo individual numa

meta-anaacutelise aumenta o poder estatiacutestico gerando resultados mais precisos (40)

8 Can the results be applied to the local population

Sim A extracccedilatildeo de terceiros molares inferiores eacute uma praacutetica cliacutenica comum

em Portugal O paracetamol eacute um analgeacutesico largamente comercializado e administrado

(sendo natildeo sujeito a receita meacutedica) pelo que era possiacutevel reproduzir esta forma de

tratamento

No entanto os estudos incluiacutedos na revisatildeo referem-se a uma dose uacutenica que

embora reproduziacutevel na populaccedilatildeo local seria necessaacuteria uma modificaccedilatildeo do

paradigma cultural em relaccedilatildeo agrave toma de medicamentos

9 Were all important outcomes considered

Natildeo A revisatildeo considera a eficaacutecia do paracetamol vs placebo no aliacutevio da dor

e simultaneamente a ocorrecircncia de efeitos secundaacuterios Satildeo abordados directamente

dois aspectos ndash o da praacutetica cliacutenica e o da investigaccedilatildeo Ambos satildeo relativos ao

profissional de sauacutede e implicitamente ao proacuteprio indiviacuteduo e aos familiares (ao serem

referidas as doses periacuteodos entre tomas e combinaccedilotildees com outros NSAIDrsquos mais

eficazes e simultaneamente seguras)

Poreacutem nada eacute referido em relaccedilatildeo a novas poliacuteticas de sauacutede nomeadamente na

implementaccedilatildeo de uma dose uacutenica culminando numa mudanccedila dos haacutebitos de sauacutede da

comunidade Tambeacutem natildeo foram abordados aspectos econoacutemicos tal como um balanccedilo

entre benefiacutecios e encargos de sauacutede que justifique a utilizaccedilatildeo deste faacutermaco como

tratamento preferencial

10 Should policy or practice change as a result of the evidence contained in this

review

Natildeo Esta revisatildeo demonstra que comparativamente a um placebo o paracetamol

eacute mais eficaz principalmente em doses elevadas e que natildeo haacute diferenccedila estatiacutestica

significativa no nuacutemero de efeitos secundaacuterios Poreacutem natildeo eacute possiacutevel tirar conclusotildees

sobre a dor depois do periacuteodo considerado de 6h Desta forma implementar uma dose

uacutenica de paracetamol a 1000mg seria imprudente sem previamente realizar estudos

complementares sobre a evoluccedilatildeo da dor apoacutes as 6h bem como comparar este faacutermaco

com outros compostos que possam ser igualmente eficazes por um raacutecio custo-benefiacutecio

melhor ou vice-versa

Relative efficacy of oral analgesics after third molar extraction

Barden Edwards (23)

Relative efficacy of oral analgesics after third molar extraction -

a 2011 update Derry Wiffen (21)

A avaliaccedilatildeo feita e disposta abaixo contemplou tanto a revisatildeo sistemaacutetica que

remonta a 2004 como a sua actualizaccedilatildeo de 2011 Uma vez estando inter-relacionados

consideraacutemos pertinente juntar as apreciaccedilotildees destas revisotildees porque caso contraacuterio

perder-se-ia o contexto de ambas

Sim A populaccedilatildeo em estudo comporta pacientes com mais de 15 anos de idade

com uma intensidade de dor basal poacutes-operatoacuteria de moderada a severa apoacutes extracccedilatildeo

de um terceiro molar

A intervenccedilatildeo consistiu no tratamento da dor poacutes-operatoacuteria de intensidade

moderada a severa com doses uacutenicas de analgeacutesicos orais ou placebo sendo que os

analgeacutesicos orais corresponderam a um total de 15 combinaccedilotildees diferentes de faacutermacos

e respectivas dosagens

Os resultados foram obtidos atraveacutes da mediccedilatildeo do aliacutevio total da dor

(TOTPAR) ou da diferenccedila de intensidade da dor (SPID) utilizando uma escala

standard de 5 niacuteveis de aliacutevio da dor uma escala standard de 4 niacuteveis de aliacutevio da dor

ou uma escala visual analoacutegica (VAS) Os efeitos secundaacuterios foram tambeacutem relatados

comparando a proporccedilatildeo de pacientes que apresentaram efeitos generalizados e que

apresentaram efeitos particulares

Actualizaccedilatildeo de 2011

A intervenccedilatildeo consistiu tambeacutem no tratamento da dor poacutes-operatoacuteria de

intensidade moderada a severa com doses uacutenicas de analgeacutesicos orais ou placebo no

entanto os analgeacutesicos utilizados foram diferentes A revisatildeo de 2004 incluiu rofecoxib

and valdecoxib nenhum dos quais se encontra disponiacutevel no mercado Em vez disso

foram utilizadas combinaccedilotildees de ibuprofeno com paracetamol formulaccedilotildees diferentes

de ibuprofeno e diclofenac e etoricoxib

Sim Os estudos que foram incluiacutedos nesta revisatildeo correspondem a ensaios

cliacutenicos aleatorizados duplamente cegos que comparam a eficaacutecia dos diferentes

analgeacutesicos e com placebo na terapecircutica da dor aguda poacutes-operatoacuteria Os grupos

formados possuiacuteam grupos com um miacutenimo de 10 pessoas Em todos os estudos foram

seguidas as guidelines QUORUM e utilizados criteacuterios de inclusatildeo para a dor poacutes-

operatoacuteria em que os resultados satildeo avaliados durante um periacuteodo de 4 a 6 horas apoacutes

medicaccedilatildeo

Sim Os autores da revisatildeo tentaram identificar todos os estudos relevantes

pesquisando nas bases de dados electroacutenicas Cochrane Library Biological Abstracts

MEDLINE PubMed e Oxford Pain Relief Para aleacutem disso consultaram a bibliografia

dos artigos de revisatildeo incluiacutedos de modo a encontrar informaccedilatildeo adicional e possiacuteveis

estudos natildeo publicados os quais apresentam na sua maioria datas de pesquisa que

remontam a 2002 No entanto eacute de mencionar que natildeo contactaram os autores e os

fabricantes para recolha de dados nem procuraram estudos com idiomas diferentes do

inglecircs

Com o passar dos anos os artigos inseridos na revisatildeo foram actualizados de

forma a incluir outros analgeacutesicos e obter ensaios cliacutenicos adicionais e relevantes Desta

forma a actualizaccedilatildeo da revisatildeo sistemaacutetica de 2004 incluiu 35 revisotildees da Cochrane

com 38 anaacutelises realizadas em diferentes analgeacutesicos de dose uacutenica para determinar a

sua eficaacutecia na dor poacutes-operatoacuteria

4 Did the reviewers assess the quality of the included studies

Sim A qualidade dos estudos incluiacutedos foi avaliada vaacuterios autores

independentes e natildeo cegos (pelo facto de estes conhecerem a literatura existente)

utilizando uma escala de qualidade numerada de 1 a 5 e baseada em 3 criteacuterios

distribuiccedilatildeo aleatorizada dos pacientes se os pacientes e os examinadores se

encontravam cegos se houve remoccedilotildees ou desistecircncias durante o estudo A

classificaccedilatildeo maacutexima de um estudo incluiacutedo foi de 5 e a miacutenima foi de 2

Os ensaios cliacutenicos que apresentam uma classificaccedilatildeo igual ou superior a 3

(baixo risco de vieacutes) demonstraram menores efeitos secundaacuterios que os ensaios cliacutenicos

que apresentam uma classificaccedilatildeo igual ou inferior a 2 (alto risco de vieacutes)

Sim Os resultados dos diferentes estudos foram apresentados sob a forma de

tabelas nomeadamente a eficaacutecia dos vaacuterios analgeacutesicos e a ocorrecircncia de efeitos

secundaacuterios foram dispostas em tabelas Aqui eram resumidos os resultados o tipo de

intervenccedilatildeo e respectivo nuacutemero total de pacientes e nordm de estudos realizados

Esta revisatildeo sistemaacutetica natildeo incluiu a realizaccedilatildeo de testes heterogeacuteneos nem a

avaliaccedilatildeo do risco de vieacutes das publicaccedilotildees atraveacutes de forest plots dado que na opiniatildeo

dos autores estas abordagens mostraram-se pouco adequados para este tipo de estudos

No entanto a homogeneidade foi avaliada atraveacutes de um modo visual

A resposta a esta questatildeo eacute claramente afirmativa porque a elevada semelhanccedila

das caracteriacutesticas dos diferentes estudos (meacutetodos utilizados tipo de intervenccedilatildeo e

mediccedilatildeo dos resultados) tornou por um lado inadequada a realizaccedilatildeo uma meta-anaacutelise

para avaliar a heterogeneidade mas por outro adequada a realizaccedilatildeo de uma avaliaccedilatildeo

visual da homogeneidade dos mesmos

Os resultados foram medidos atraveacutes da proporccedilatildeo de pacientes do grupo de

tratamento vs placebo que atingiram pelo menos 50 de maxTOTPAR ou seja aliacutevio

de dor A qual foi utilizada para determinar o benefiacutecio relativo e o NNT bem como o

risco relativo dos diferentes estudos incluiacutedos

Atraveacutes da anaacutelise das tabelas eacute possiacutevel tirar 3 conclusotildees principais

1 A proporccedilatildeo de pacientes que atingiram pelo menos 50 de aliacutevio de dor eacute maior

no grupo de tratamento que no grupo placebo agrave excepccedilatildeo do estudo que utilizou

dihidrocodeiacutena 30mg em que as diferenccedilas natildeo foram estatisticamente relevantes

2 Por comparaccedilatildeo ao paracetamol (independentemente das diferentes dosagens) os

anti-inflamatoacuterios natildeo-esteroacuteides inibidores da COX-2 apresentam um maior

benefiacutecio relativo e necessitam do menor nordm de pacientes tratados para atingirem o

objectivo de 50 de aliacutevio de dor

3 O paracetamol apresenta um maior risco relativo na medida em que insurgem mais

efeitos secundaacuterios nos estudos em que foi administrado por oposiccedilatildeo aos

NSAIDrsquos

Os anti-inflamatoacuterios natildeo-esteroacuteides inibidores da COX-2 satildeo mais eficazes no

tratamento da dor basal poacutes-operatoacuteria moderada a intensa que o paracetamol

Os resultados foram obtidos da mesma forma que na versatildeo de 2004 sendo que

um novo outcome foi considerado ndash tempo meacutedio necessaacuterio para que os pacientes

necessitem de re-medicaccedilatildeo aproximadamente 8 horas Agrave semelhanccedila do que aconteceu

na revisatildeo anterior os dados sobre a dihidrocodeiacutena natildeo foram conclusivos devido agrave

pouca informaccedilatildeo disponiacutevel nos estudos

Os resultados satildeo precisos uma vez que utilizam um intervalo de confianccedila de

95 Eacute de ressalvar que os valores de NNT ou NNH apenas eram calculados quando o

riscobenefiacutecio relativo satildeo significativos isto eacute quando natildeo incluem o valor de 1 No

limite superior do intervalo de confianccedila a intervenccedilatildeo realizada seria a mesma No

entanto dado que o NNH natildeo foi calculado eacute possiacutevel concluir que o risco relativo natildeo

era significativo pelo que permanece uma incerteza se no limite inferior do intervalo de

confianccedila a intervenccedilatildeo realizada seria a mesma

Sim Os resultados da revisatildeo sistemaacutetica podem ser aplicados agrave nossa

populaccedilatildeo local porque os criteacuterios de inclusatildeo utilizados correspondem na sua

maioria a mecanismos fisioloacutegicos caracteriacutesticos do ser humano Para aleacutem disso as

teacutecnicas utilizadas satildeo simples e de faacutecil reproduccedilatildeo na medida em que os faacutermacos

utilizados nos ensaios cliacutenicos estatildeo agrave disposiccedilatildeo dos interessados e os meacutetodos

terapecircuticos baacutesicos

No entanto os estudos incluiacutedos nesta revisatildeo incluiacuteram um tratamento com

uma dose uacutenica de analgeacutesico oral que embora reprodutiacutevel difere do paradigma actual

da nossa populaccedilatildeo (em que haacute a tendecircncia para a auto-medicaccedilatildeo e de recorrer a

diferentes faacutermacos)

Natildeo Os resultados enfatizam a eficaacutecia de vaacuterios analgeacutesicos no aliacutevio de 50

dor em comparaccedilatildeo com placebo Eacute focada ainda o benefiacutecio relativo (95 IC) e o NNT

da mesma problemaacutetica Aleacutem deste conjunto de dados satildeo considerados o nuacutemero de

pacientes com efeitos secundaacuterios risco relativo (95 IC) culminando no caacutelculo do

Contudo natildeo eacute especificado o tipo de efeitos secundaacuterios que podem ser

desencadeados pela toma dos diferentes analgeacutesicos nem aspectos diferenciadores em

analgeacutesicos com eficaacutecia e benefiacutecios idecircnticos (por exemplo custo econoacutemico) Isto

constituiria uma mais-valia para uma escolha mais consciente do analgeacutesico tanto pelos

profissionais como pelos pacientes (individual) e beneficiaria tambeacutem o Sistema

Nacional de Sauacutede (comunidade em geral)

Um dos outcomes considerados semelhante ao que foi abordado na revisatildeo de

2004 foi a percentagem de pacientes com dor moderada (30- 60 mm VAS) ou dor

severa (mais de 60 mm) que obtiveram 50 de aliacutevio de dor Contudo foi adicionado

um novo outcome relevante o tempo necessaacuterio para que metade dos pacientes requeriu

re-medicaccedilatildeo

review

Natildeo Os resultados desta revisatildeo evidenciam a eficaacutecia dos analgeacutesicos

comparativamente a um placebo nomeadamente que o ibuprofeno e o paracetamol

possuem maior maior o benefiacutecioefeito analgeacutesico quanto maior forem as dosagens

Poreacutem natildeo eacute evidecircncia suficiente para mudar o paradigma de tratamento pois ldquoWhat

these comparisons do not do is to tell dentists what to prescriberdquo Satildeo sim uma

importante ferramenta para a tomada de decisotildees que devem ser adaptadas a cada

paciente tendo presente que 80 dos analgeacutesicos prescritos possuem elevados iacutendices

de eficaacutecia e seguranccedila Em adiccedilatildeo nem todos os analgeacutesicos nesta revisatildeo estatildeo

disponiacuteveis no mercado para serem receitados pelos meacutedicos-dentistas

Conclui-se que para que esta revisatildeo fosse pilar basilar nas prescriccedilotildees de

analgeacutesicos teriam de ser apresentadas evidecircncias de benefiacuteciocusto dos analgeacutesicos

com melhores resultados (aspecto econoacutemico e detalhe dos efeitos adversos) Todavia a

informaccedilatildeo presente na mesma sobre a eficaacutecia e efeitos secundaacuterios assim como toda a

bibliografia jaacute existente sobre este assunto eacute uacutetil e deve ser utilizada para tomar inicio agrave

criaccedilatildeo de um formulaacuterio em medicina dentaacuteria

Os resultados obtidos da mesma forma que na revisatildeo anterior natildeo foram

suficientemente relevantes para que as poliacuteticas de sauacutede mudassem No entanto a

quantidade de informaccedilatildeo disponiacutevel sobre analgeacutesicos de dose uacutenica para aliacutevio da dor

poacutes-operatoacuteria eacute grande e bastante acessiacutevel Podem assim servir como boas

ferramentas para a formulaccedilatildeo de poliacuteticas e prescriccedilotildees farmacecircuticas para a populaccedilatildeo

quando existirem dados cliacutenicos mais conclusivos

ENSAIOS CLIacuteNICOS ALEATORIZADOS

Combining paracetamol with a selective cyclooxygenase-2

inhibitor for acute pain relief after third molar surgery a

randomized double-blind placebo-controlled study Haglund and

von Bultzingslowen (25)

1 Did the study ask a clearly-focused question

Sim A populaccedilatildeo compreende indiviacuteduos saudaacuteveis com idade superior a 18

anos peso entre 50 e 120 kg e com necessidade de extrair terceiros molares inferiores

com remoccedilatildeo oacutessea Foram excluiacutedos pacientes intolerantes ao aacutecido acetilsaliciacutelico

paracetamol eou NSAIDrsquos que estivessem a tomar outro tipo de medicaccedilatildeo (excepto

contraceptivos) graacutevidas ou em periacuteodo de amamentaccedilatildeo problemas com drogas ou

aacutelcool Apenas pacientes que reportaram dor moderada a intensa apoacutes a cirurgia foram

incluiacutedos

Existiram quatro grupos de intervenccedilatildeo

Grupo A rofecoxib 50mg + paracetamol 1g dose uacutenica 155 plusmn 37 minutos apoacutes

cirurgia

Grupo B rofecoxib 50mg dose uacutenica 170 plusmn 45 minutos apoacutes cirurgia

Grupo C paracetamol 1g dose uacutenica 184 plusmn 53 minutos apoacutes cirurgia

Grupo D placebo dose uacutenica 161 plusmn 30 minutos apoacutes cirurgia

Os resultados prenderam-se com a intensidade da dor medida atraveacutes da escala

visual analoacutegica (VAS) de 30 em 30 minutos desde a ingestatildeo do faacutermaco durante 8

horas Atraveacutes destas avaliaccedilotildees da dor foi possiacutevel obter valores de

aliacutevio total da dor TOTPAR

soma da diferenccedila de intensidade da dor SPID nas primeiras trecircs horas

soma da diferenccedila de intensidade da dor SPID ateacute agraves 8 horas

Foram obtidos resultados referentes a uma avaliaccedilatildeo global do tratamento feita

4h e 8h apoacutes a toma do faacutermaco O uso de rescue medication foi tomado em conta bem

como o tempo ateacute agrave sua necessidade Foram ainda avaliados eventuais efeitos

secundaacuterios

2 Was this a randomised controlled trial (RCT) and was it appropriately so

Sim A atribuiccedilatildeo de cada tratamento foi cega para todos os pacientes

investigadores e pessoal envolvido Foi levada a cabo a aleatorizaccedilatildeo pela empresa

farmacecircutica responsaacutevel pela produccedilatildeo das caacutepsulas administradas

Natildeo existindo entraves de teor eacutetico ou de disponibilidade de recursos um

ensaio cliacutenico aleatorizado eacute a escolha mais pertinente quando eacute necessaacuterio comparar

dois ou mais tipos de tratamento O facto de existir um grupo de controlo minimiza o

risco de vieacutes

3 Were participants appropriately allocated to intervention and control groups

A colocaccedilatildeo dos pacientes em cada um dos quarto grupos de tratamento foi

concretizada atraveacutes de tabelas de aleatorizaccedilatildeo

4 Were participants staff and study personnel lsquoblindrsquo to participantsrsquo study

Sim Sendo um ensaio cliacutenico duplamente cego tanto o staff investigadores e

pacientes estiveram cegos durante todo o estudo Todas as caacutepsulas eram idecircnticas

sendo que cada embalagem selada continha sempre 6 caacutepsulas Desta forma eacute possiacutevel

garantir que o paciente estaacute cego Sendo cada embalagem feita e selada pela empresa

farmacecircutica eacute igualmente possiacutevel inferir que os investigadores tambeacutem se

encontravam cegos Apenas o investigador principal acedeu aos coacutedigos para fazer os

caacutelculos finais

5 Were all of the participants who entered the trial accounted for at its

conclusion

Os grupos de intervenccedilatildeo foram atribuiacutedos de forma aleatoacuteria e cega os

resultados foram analisados de acordo com o grupo a que inicialmente tinham sido

associados

Inicialmente o desenho do estudo previa 120 participantes

Grupo A n = 40

Grupo B n = 40

Grupo C n = 20

Grupo D n = 20 (controlo)

No entanto no final do estudo foram apurados resultados de 107 indiviacuteduos Isto

deve-se a

Apoacutes a cirurgia alguns pacientes (n = 8) natildeo sentiram dor moderada a forte

no entanto quiseram mesmo assim participar sendo os seus resultados

subtraiacutedos aos caacutelculos

Alguns pacientes (n = 5) foram excluiacutedos sendo que um foi drop-out e os

restantes natildeo entregaram ou preencheram os questionaacuterios pedidos

No final a distribuiccedilatildeo de indiviacuteduos por grupos era a seguinte

Grupo A n = 34

Grupo B n = 36

Grupo C n = 20

Grupo D n = 17

Embora se verifique uma ligeira alteraccedilatildeo natildeo eacute motivo relevante de vieacutes

6 Were the participants in all groups followed up and data collected in the same

Sim Todos os pacientes tiveram acesso aos mesmos questionaacuterios entregues

pelo investigador Em caso de duacutevida ateacute ao final da duraccedilatildeo do estudo (8 horas) o

paciente podia telefonar ao investigador com quaisquer duacutevidas que surgissem Poreacutem

o paciente era responsaacutevel pelo iniacutecio do estudo ao administrar a si mesmo o faacutermaco

em casa no momento em que o fizesse devia telefonar ao investigador para este ter

conhecimento do iniacutecio do estudo Se o paciente natildeo contactasse o investigador ateacute 3

horas apoacutes a cirurgia o investigador contactaria o paciente Os valores maacuteximo e

miacutenimo de tempo entre a cirurgia e iniacutecio do estudo de foram 118 e 237 minutos a este

facto eacute inerente um risco de vieacutes pois nem todos os pacientes estavam na mesma

condiccedilatildeo quando iniciaram o tratamento podendo reflectir-se nos resultados

7 Did the study have enough participants to minimise the play of chance

Sim Os caacutelculos foram efectuados assumindo que existiria uma diferenccedila na

SPID entre grupos A e B de 20 Foram utilizados testes natildeo-parameacutetricos (Mann-

Whitney U-test) sendo definido que pelo menos 22 pacientes deveriam ser incluiacutedos em

cada um destes grupos

Os caacutelculos estatiacutesticos necessaacuterios para a elaboraccedilatildeo dos resultados foram

efectuados no programa Statistical Package for Social Sciences (SPSS) v 12 As

significacircncias entre grupos de tratamento em relaccedilatildeo agraves respostas agrave VAS foram

testadas com t-test de variaacutevel independente em todas as avaliaccedilotildees de dor A mesma

estrateacutegia foi aplicada para a SPID agraves 3 e 8 horas A TOTPAR foi baseada na

assumpccedilatildeo que os resultados satildeo parte de uma escala de intervalos O mesmo teste foi

utilizado para a diferenccedila entre grupos relativamente ao uso de rescue medication Os

testes dos dados provenientes de escalas categoacutericas (PAR e a avaliaccedilatildeo global) foram

realizados atraveacutes de testes natildeo-parameacutetricos (Mann-Whitney U-test)

Intensidade da dor Os resultados favorecem o grupo A ateacute 15h apoacutes o iniacutecio do

tratamento A partir das 2h o grupo A natildeo tem uma eficaacutecia estatisticamente maior que

o grupo B Ambos os grupos tecircm melhores resultados globais que o grupo C O Grupo

D (placebo) eacute notoriamente menos eficaz que todos os outros grupos

Aliacutevio da dor (PAR) Os resultados meacutedios desta afericcedilatildeo satildeo semelhantes aos da

intensidade da dor

TOTPAR Natildeo houve uma diferenccedila significativa entre o grupo A e o grupo B

Ambos foram significativamente melhores que o C todos os grupos de tratamento

activo tiveram melhores resultados que o grupo D (placebo)

SPID Embora o grupo A mostre a maior SPID meacutedia (05 ndash 3h) natildeo foi

estatisticamente diferente do grupo B o grupo C tambeacutem natildeo foi estatisticamente

diferente do grupo B A SPID meacutedia total foi estatisticamente semelhante entre os

grupos A e B mas superior agrave do grupo C O grupo D (placebo) teve resultados

inferiores aos dos restantes grupos

Uso de rescue medication Embora tenha existido um nuacutemero notoriamente

superior de casos entre os grupos A e B comparativamente ao C e ao D esta diferenccedila

natildeo eacute relevante estatisticamente devido ao baixo nuacutemero de pacientes que recorreram a

esta medicaccedilatildeo

Avaliaccedilatildeo global tanto agraves 4 como agraves 8h os grupos A e B receberam avaliaccedilotildees

semelhantes tendo as melhores classificaccedilotildees e sendo significativamente superiores agraves

do grupo C Todos foram melhores que o D (placebo) Agraves 8h as percentagens de

pacientes que avaliaram o tratamento como bom ou excelente foram

Grupo A 90

Grupo B 83

Grupo C 42

No artigo natildeo satildeo mencionados intervalos de confianccedila No entanto nos graacuteficos

referentes agrave intensidade da dor eacute possiacutevel ver as barras correspondentes ao intervalo de

confianccedila Existem sempre que necessaacuterio valores de p associados aos resultados

10 Were all important outcomes considered so the results can be applied

Sim A extracccedilatildeo de terceiros molares em Portugal eacute uma praacutetica cliacutenica comum

pelo que o estudo pode ser facilmente reproduzido desde que haja acesso agrave medicaccedilatildeo

utilizada e que esta esteja em formato idecircntico (para garantir que natildeo existe vieacutes)

Poreacutem o facto de ser utilizada uma dose uacutenica poderaacute natildeo ir de encontro com o padratildeo

actual sendo necessaacuteria uma sensibilizaccedilatildeo do paciente diferente para este meacutetodo

Um facto importante foi referido na discussatildeo deste artigo posteriormente agrave

recolha de dados do mesmo surgiram preocupaccedilotildees seacuterias sobre efeitos nocivos

cardiovasculares em tratamentos de longa duraccedilatildeo com rofecoxib embora estes efeito

secundaacuterios tendam a estar relacionados com as doses e natildeo apenas com a selectividade

COX-2 (8 25) Esta informaccedilatildeo eacute altamente relevante de todos os pontos de vista do

paciente e famiacutelia do profissional de sauacutede e oacutergatildeos legislativos

Tendo em conta este facto seriam necessaacuterios estudos adicionais para aferir o

risco de seguir um tratamento como o visado neste ensaio cliacutenico

Combined acetaminophen and ibuprofen for pain relief after oral

surgery in adults a randomized controlled trial (13)

Sim Foram incluiacutedos pacientes sujeitos a extracccedilatildeo de pelo menos um terceiro

molar inferior Foram excluiacutedos pacientes com idade inferior a 16 anos peso inferior a

50 kg que tivessem tomado NSAIDrsquos (excepto aspirina a 150mg) ou paracetamol 24h

antes da cirurgia entre outros(inserir referencia para a pagina pois sao muitos)

Existiram 3 grupos de intervenccedilatildeo

Grupo A 500mg paracetamol + 150mg ibuprofeno

Grupo B 500mg paracetamol

Grupo C 150mg ibuprofeno

Todos os grupos de intervenccedilatildeo tomaram 2 comprimidos imediatamente antes da

cirurgia e depois 4 comprimidos diariamente (de 6 em 6 horas) durante 48h

Os resultados passaram pela intensidade da dor medida atraveacutes da VAS (mm)

em trecircs momentos distintos antes de tomar qualquer medicaccedilatildeo do estudo

imediatamente apoacutes a cirurgia e de 2 em 2 horas ateacute terminar o periacuteodo de 48 horas A

medida utilizada foi a area under the curve (AUC) dividida pelo tempo resultando em

AUCh Este caacutelculo foi efectuado para encontrar valores ldquomeacutediosrdquo pois houve ligeiras

diferenccedilas no momento da afericcedilatildeo dos valores da VAS Mediu-se tambeacutem o consumo

de rescue medication ao longo das 48 horas

Foram ainda utilizadas escalas categoacutericas de avaliaccedilatildeo global da dor e da

naacuteusea realizadas no final do estudo bem como uma escala VAS para medir os

distuacuterbios no sono apoacutes cada noite

investigadores e pessoal envolvido O responsaacutevel pela aleatorizaccedilatildeo do estudo foi o

estatiacutestico do estudo O estatiacutestico foi a uacutenica pessoa com acesso agraves informaccedilotildees da

atribuiccedilatildeo de tratamento aos pacientes

A colocaccedilatildeo de pacientes em cada um dos trecircs grupos de tratamento foi

aleatorizada A sequecircncia de aleatorizaccedilatildeo foi gerada por computador pelo estatiacutestico

do estudo Foi utilizada uma proporccedilatildeo de 111 para os trecircs grupos de tratamento isto

foi conseguido atraveacutes de permutaccedilatildeo de blocos com estratificaccedilatildeo para o tipo de

anestesia (local ou geral) e centro de estudo A utilizaccedilatildeo da aleatorizaccedilatildeo por

permutaccedilatildeo de blocos assegura uma distribuiccedilatildeo equilibrada por grupos de tratamento

quando o nuacutemero de indiviacuteduos eacute menor que mil (inserir referencia do artigo de

aleatorizajao MJA)

Sim Este ensaio cliacutenico foi duplamente cego Como tal cada tipo de tratamento

consistia em comprimidos idecircnticos colocados num pacote selado as instruccedilotildees sobre

dosagens eram tambeacutem iguais garantindo que o estudo permanecia cego aos

investigadores staff e pacientes prevenindo a existecircncia de vieacuteses

conclusion

Sim O estudo previa um nuacutemero miacutenimo de 120 indiviacuteduos 40 em cada grupo

de tratamento Dos 135 pacientes que concordaram participar apoacutes serem abordados

pelo meacutedico apenas 122 foram incluiacutedos no estudo (os 13 que foram excluiacutedos natildeo

entregaram o diaacuterio de tratamento que lhes foi pedido)

Grupo A n = 40

Grupo B n = 43

Grupo C n = 39

Todos os 122 pacientes incluiacutedos foram seguidos ateacute ao final do estudo

Sim Os pacientes foram abordados primariamente por um cirurgiatildeo e

seguidamente por uma enfermeira responsaacutevel pelo seguimento dos pacientes ao longo

do estudo O seguimento de cada paciente foi realizado de igual forma no hospital e fora

dele onde o contacto era estabelecido por telefone de forma a facilitar a recolha de

informaccedilatildeo levada a cabo por meio da entrega de diaacuterios

Em relaccedilatildeo agrave recolha dos dados relativos agrave dor poacutes-operatoacuteria experienciada os

intervalos de tempo utilizados foram semelhantes (imediatamente antes da

administraccedilatildeo da primeira dose logo apoacutes a cirurgia e de 2 em 2 horas durante um

periacuteodo de 48 horas) e a monitorizaccedilatildeo dos pacientes feita utilizando as mesmas

guidelines

Sim Os investigadores do estudo realizaram a power calculation Estimaram

que eram necessaacuterios 120 participantes distribuiacutedos equitativamente pelos 3 grupos O

power foi de 80 na detecccedilatildeo de diferenccedilas entre os grupos de 9 mm (SD de 14mm)

para mediccedilotildees relativas agrave altura de repouso e os de 13mm (SD de 21mm) e para

mediccedilotildees relativas agrave altura de actividade

Dos 135 pacientes incluiacutedos no estudo 13 natildeo devolveram os seus diaacuterios pelo

que ficaram disponiacuteveis 122 participantes a enquadrar a populaccedilatildeo de tratamento (ITT

population) para anaacutelise dos criteacuterios de comparaccedilatildeo primaacuterios (primary endpoints)

Como o criteacuterio de possuir participantes necessaacuterios foi preenchido os

resultados da comparaccedilatildeo do objectivo primaacuterio deste estudo (mediccedilatildeo da intensidade

meacutedia de dor ao longo do estudo) tecircm uma elevada importacircncia cliacutenica Esta

importacircncia eacute equiparaacutevel aos resultados de estudos publicados anteriormente

Os resultados foram apresentados sob a forma de mediccedilotildees nomeadamente as

principais diferenccedilas (mean differences) entre o paracetamolacetaminofeno ibuprofeno

e combinaccedilatildeo dos dois comparando a eficaacutecia farmacocineacutetica e efeitos secundaacuterios

respectivos a cada um Agraves quais estaacute associada uma taxa de erro de 5 (SEM) ou seja

intervalo de confianccedila de 95 (CI) e um valor de P lt001

Foi realizada a mediccedilatildeo da time-adjusted AUC (AUCh) da VAS que

juntamente com a classificaccedilatildeo global de dor revelou-se substancial e

significativamente menor no grupo que utilizou a combinaccedilatildeo do que nos outros dois

grupos (tanto no periacuteodo de repouso como no periacuteodo de actividade)

Apesar de alguns criteacuterios de comparaccedilatildeo secundaacuterios (secondary endpoints) o

uso de medicaccedilatildeo de resgate apoiarem o uso da combinaccedilatildeo do faacutermaco natildeo possuem

relevacircncia estatiacutestica Aleacutem disso o tipo de anestesia utilizada na cirurgia e o nordm de

dentes extraiacutedos os paracircmetros farmacocineacuteticos e a ocorrecircncia dos efeitos secundaacuterios

natildeo mostraram diferenccedilas significativas entre os 3 grupos de estudo

Os pacientes medicados com a combinaccedilatildeo de paracetamol e ibuprofeno

experienciaram menos dor poacutes-operatoacuteria durante as 48 horas que os pacientes que

usaram os medicamentos isolados

Utilizando um intervalo de confianccedila de 95 e tendo em conta que foi preacute-

definido um valor para P de 005 de forma determinar se os valores obtidos possuem

relevacircncia estatiacutestica ou natildeo os resultados satildeo precisos

Isto mostra que para que a combinaccedilatildeo dos dois medicamentos possa ser

considerada sem incerteza mais adequada que outros meacutetodos de medicaccedilatildeo seriam

necessaacuterios resultados expliacutecitos e com elevada relevacircncia estatiacutestica

Sim O estudo realizado tal como acontece em todos os outros apresenta os

seus pontos fortes e fracos No entanto a pluralidade de criteacuterios utilizados na

comparaccedilatildeo dos vaacuterios grupos de estudo permitiu uma boa percepccedilatildeo da relaccedilatildeo

custobenefiacutecio aqui presente Apesar de certos paracircmetros como a utilizaccedilatildeo de

placebo recrutamento de crianccedilas e avaliaccedilatildeo significativa dos efeitos secundaacuterios natildeo

terem sido explorados estes natildeo apresentam grande peso no que respeita agrave validaccedilatildeo dos

resultados em si Isto acontece pois a bibliografia existente e a praacutetica cliacutenica jaacute nos

permitem deduzir e extrapolar conclusotildees em relaccedilatildeo agravequeles paracircmetros

Deste modo a questatildeo-chave recai sobre o facto de a combinaccedilatildeo de

paracetamol com ibuprofeno ser mais vantajosa e eficaz que a toma de apenas um deles

Caso estes resultados sejam confirmados por estudos de outras entidades a jaacute muito

utilizada combinaccedilatildeo paracetamol+ibuprofeno poderaacute mesmo tornar-se procedimento

padratildeo na terapecircutica da dor aguda moderada (em pacientes sem contra-indicaccedilatildeo para

NSAIDrsquos)

Analgesic efficacy of lysine clonixinate paracetamol and

dipyrone in lower third molar extraction a randomized

controlled trial (32)

Sim A populaccedilatildeo em estudo comporta 90 pacientes entre os 18 e 26 anos de

idade com uma indicaccedilatildeo cliacutenica para extracccedilatildeo de um 3ordm molar inferior impactado

(com classe I e II)

A intervenccedilatildeo consistiu no tratamento da dor apoacutes extracccedilatildeo do 3ordm molar atraveacutes

da medicaccedilatildeo com um dos 3 analgeacutesicos em estudo utilizando 8 comprimidos do

respectivo analgeacutesico a serem tomados 1 hora preacute-cirurgia e a cada 6 horas poacutes-cirurgia

durante um periacuteodo de 24 horas

Os resultados foram obtidos atraveacutes da mediccedilatildeo da intensidade da dor utilizando

a escala visual analoacutegica (VAS) mesmo antes da cirurgia e seguidamente 1 2 4 6 8

12 e 24 horas apoacutes a cirurgia Aleacutem disso para cada uma destas mediccedilotildees os pacientes

tinham de relatar o niacutevel de dor em que se encontravam (percepccedilatildeo da dor) atraveacutes de

uma escala decimal com os seguintes criteacuterios

0 cm Sem dor

01- 3 cm Dor ligeira

31-7 cm Dor moderada

71-10 cm Dor intensa

A presenccedila ou ausecircncia de efeitos secundaacuterios foi tambeacutem uma das

preocupaccedilotildees deste estudo e algo avaliado nos resultados Dado que havia a

possibilidade de ocorrecircncia de agranulocitose anemia anafilaxia e complicaccedilotildees

gastrointestinais

Sim O estudo em questatildeo consiste num ensaio cliacutenico aleatorizado Esta

abordagem foi a mais adequada para a questatildeo colocada uma vez que o objectivo final

eacute comparar a eficaacutecia da lisina clonixinato com o paracetamol e com a dipirona na

analgesia da dor poacutes-operatoacuteria Para obter informaccedilotildees mais completas respeitantes agrave

seguranccedila e eficaacutecia dos faacutermacos comparados eacute necessaacuterio o recrutamento e

aleatorizaccedilatildeo de um determinado nuacutemero de pacientes Eacute necessaacuterio tambeacutem medicaacute-

los medir e avaliar os resultados de forma imparcial e objectiva Desta forma eacute mais

provaacutevel chegar a uma conclusatildeo fidedigna e vaacutelida tanto interna como externamente

Pelas razotildees acima enumeradas a realizaccedilatildeo de um ensaio cliacutenico aleatorizado

foi a melhor abordagem a seguir

Sim Os pacientes foram divididos pelos diferentes grupos de estudo de uma

forma aleatoacuteria utilizando um meacutetodo relativamente simples Os analgeacutesicos foram

repartidos em recipientes brancos opacos e idecircnticos numerados de 1 a 90 Cada

recipiente continha 8 comprimidos de um dos 3 faacutermacos em comparaccedilatildeo (dipirona

500mg paracetamol 750mg lisina clonixinato 125 mg) Por sua vez foi pedido aos

pacientes para retirarem o recipiente agrave sua escolha e ao acaso os quais desconheciam o

seu conteuacutedo

Dos 90 pacientes recrutados de iniacutecio 26 desistiram pelo que os restantes 64

pacientes foram distribuiacutedos por 3 grupos correspondentes a diferentes analgeacutesicos

orais lisina clonixinato composto por 20 indiviacuteduos (8 masculinos 12 femininos)

Paracetamol composto por 23 indiviacuteduos (9M 14F) Dipirona composto por 21

indiviacuteduos (6M 15F)

Natildeo eacute possiacutevel dizer Os pacientes deste estudo estavam lsquocegosrsquo quanto ao grupo

de estudo em que iriam ser colocados O processo de distribuiccedilatildeo dos indiviacuteduos foi

feito de uma forma aleatoacuteria atraveacutes de um meacutetodo bastante simples de escolha de

recipiente

Quanto aos funcionaacuterios e revisores deste estudo o mesmo pode natildeo ter

acontecido pois nenhuma informaccedilatildeo sobre este aspecto eacute mencionada no artigo

conclusion

Sim No estudo realizado os participantes foram distribuiacutedos por 3 grupos um

de estudo ou intervenccedilatildeo onde foi administrado lisina clonixinato e dois de controlo

onde se administrou paracetamol num e dipirona noutro Natildeo houve redistribuiccedilatildeo dos

participantes isto eacute cada participante foi tratado uacutenica e exclusivamente com o faacutermaco

correspondente ao seu grupo

Houve um seguimento dos pacientes durante um periacuteodo de 24 horas de modo a

avaliar a eficaacutecia de cada analgeacutesico na eliminaccedilatildeo da dor poacutes-operatoacuteria de forma

indirecta (quanto maior o aliacutevio de dor ao longo do periacuteodo de estudo maior a eficaacutecia

do respectivo analgeacutesico) Tendo isso em conta os resultados e anaacutelise dos dados foram

realizados em cada grupo e depois comparados com os outros grupos

Os investigadores do estudo poderiam ter formado um grupo placebo e

comparado os seus resultados com os restantes grupos Assim averiguar-se-ia a eficaacutecia

de cada um dos analgeacutesicos e natildeo apenas a eficaacutecia relativa a outros faacutermacos

Sim Os participantes dos diferentes grupos foram seguidos da mesma maneira e

os dados recolhidos de igual forma Os resultados foram avaliados nos mesmos

intervalos de tempo ou seja antes da cirurgia e 1 2 4 6 8 12 e 24 horas apoacutes a

mesma Os pacientes receberam o mesmo tempo de atenccedilatildeo - 24 horas de seguimento e

os dados foram recolhidos utilizando os mesmos paracircmetros a escala visual analoacutegica

para determinar o aliacutevio de dor e a escala decimal para a percepccedilatildeo de dor dos pacientes

e questionaacuterios individuais

Para aleacutem do jaacute referido os investigadores tiveram em atenccedilatildeo a forma como a

cirurgia foi realizada diminuindo o risco de vieacutes

Intervieram 2 cirurgiotildees calibrados entre si na niacutevel da teacutecnica minimizando a

ocorrecircncia de abordagens ciruacutergicas diferentes

o periacuteodo de duraccedilatildeo foi controlado e por isso natildeo influenciou o comportamento

da dor no estudo (meacutedia de 339 minutos com SD plusmn98 min)

Estas cirurgias satildeo bastantes conhecidas e muitas vezes satildeo procedimentos

standard permitindo uma selecccedilatildeo muito mais facilitada e raacutepida de casos cliacutenicos a

incluir no estudo e diminuindo o nuacutemero de eventos de difiacutecil controlo que poderiam

levar a vieacutes dos resultados

Natildeo eacute possiacutevel dizer Dos 90 pacientes inicialmente recrutados para o estudo 26

deles desistiram Os investigadores natildeo referiram o impacto deste nuacutemero de drop-outs

na extrapolaccedilatildeo de conclusotildees a partir dos resultados obtidos Igualmente natildeo foram

mencionados quaisquer caacutelculos que determinassem o nuacutemero necessaacuterio de indiviacuteduos

para o estudo ter validade

Os resultados obtidos no estudo foram categorizados por droga e analisados de

acordo com o desenvolvimento da dor poacutes-operatoacuteria Seguidamente foram

apresentados atraveacutes de mediccedilotildees descritivas da variaccedilatildeo da dor as quais utilizaram

paracircmetros como miacutenimo maacuteximo mean median e desvio-padratildeo (SD)

Por sua vez a anaacutelise dos dados foi feita com os testes de Kruskal-Wallis e de

Friedman onde os resultados satildeo considerados estatisticamente relevantes se

culminarem num valor de lsquoprsquo igual ou inferior a 005 (95 IC) e apresentada utilizando

os mesmos paracircmetros de miacutenimo maacuteximo e SD

O valor de P encontra-se claramente acima do valor de referencia preacute-definido

pelo que os resultados natildeo apresentam relevacircncia estatiacutestica suficiente para aferir que

possuem um melhor outcome que o paracetamol

A lisina clonixinato assim como a dipirona e o paracetamol eacute eficiente no

controlo da dor resultante da extracccedilatildeo de um 3ordmmolar inferior pelo que natildeo apresenta

nenhuma diferenccedila significativa dos outros analgeacutesicos mencionados

Utilizando um intervalo de confianccedila de 95 e tendo em conta que os valores de

P obtidos apoacutes anaacutelise dos resultados se encontrarem abaixo de 001 eacute possiacutevel auferir

que os resultados deste estudo satildeo bastante precisos

Natildeo Os efeitos gerados pela lisina clonoxinato no tratamento da dor derivada de

extracccedilatildeo do 3ordm molar natildeo foram estatisticamente relevantes quando comparados aos do

paracetamol e dipiridona Apesar de as condiccedilotildees pelas quais o estudo foi realizado

serem reprodutiacuteveis na nossa populaccedilatildeo local (tipo de pessoas localizaccedilatildeo e

reprodutibilidade do tratamento) nada eacute referido em relaccedilatildeo a novas poliacuteticas de sauacutede

nomeadamente na implementaccedilatildeo de uma dose uacutenica culminando numa mudanccedila dos

haacutebitos de sauacutede da comunidade Tambeacutem natildeo foram abordados aspectos econoacutemicos

tal como um balanccedilo entre benefiacutecios e encargos de sauacutede que justifique a utilizaccedilatildeo

deste faacutermaco como tratamento preferencial

Onset of analgesia with sodium ibuprofen ibuprofen acidin

corporating poloxamer and acetaminophenmdasha single-dose

double-blind placebo-controlled study in patients with post-

operative dental pain Daniels Reader (33)

Sim A populaccedilatildeo em estudo refere-se a pacientes com idade entre os 16 e os 40

anos apresentando uma intensidade de dor basal poacutes-operatoacuteria moderada a severa O

diagnoacutestico para a extracccedilatildeo poderia ser um dos seguintes pelo menos um 3ordm molar

mandibular indicado para remoccedilatildeo (grau de impactaccedilatildeo superior a 4) ou dois terceiros

molares ipsilaretais com pontuaccedilatildeo de impactaccedilatildeo conjunta natildeo superir a 6

A intervenccedilatildeo traduz-se no tratamento da dor poacutes-ciruacutergica com doses uacutenicas de

diferentes faacutermacos Inicialmente cada participante tem a mesma probabilidade de ser

colocado num dos 4 grupos

A ibuprofeno de soacutedio 2x256 mg (ibuprofeno de soacutedio di-hidratado equivalente a

400 mg de ibuprofeno aacutecido + placebos de ibuprofeno poloxamo e

acetaminofeno

B ibuprofenopoloxacircmero (400mg de Ibuprofeno e 120mg de poloxacircmero

surfactante 407) + placebos de ibuprofeno de soacutedio e paracetamol

C 1000mg acetaminofeno + placebos equivalentes

D placebo para as 3 formas de substacircncias activas

O endpoint primaacuterio consistiu no tempo necessaacuterio para um aliacutevio da dor

perceptiacutevel pelos pacientes Foram considerados inuacutemeros endpoints secundaacuterios (foi

utilizada uma escala categoacuterica e VAS para os endpoints 2 3 e 4)

1 Caacutelculo da AUC e SPRID (0 a 6 horas poacutes-tratamento) e tempo necessaacuterio para

um aliacutevio significativo da dor

2 Aliacutevio total da dor (TOTPAR) SPID e SPRID

3 Aliacutevio da dor e intensidade da mesma em termos individuais (5 minutos - 6

horas)

4 PID ao longo do periacuteodo de estudo e o momento em que este foigt ou igual a 1

5 Instante em que os pacientes recorreram a medicaccedilatildeo de recurso

6 Tempo e proporccedilatildeo de pacientes que sentiram 50 aliacutevio da dor

7 Abstracccedilatildeo agrave dor (1 e 6 horas) e percepccedilatildeo da interferecircncia causada pela dor nas

actividades quotidianas (escala de Ranvier)

8 Avaliaccedilatildeo qualitativa da medicaccedilatildeo tomada pelos dos participantes

Os efeitos adversos foram obtidos atraveacutes da procura de informaccedilatildeo em

documentaccedilatildeo e relacionados (ou natildeo) com a medicaccedilatildeo do estudo pelo investigador

Foi efectuada uma mediccedilatildeo de sinais vitais 6 horas apoacutes a toma e na visita follow-up na

qual tambeacutem foi realizado um exame fiacutesico

Sim O estudo em questatildeo eacute descrito como um ensaio cliacutenico duplamente cego e

controlado com placebo Eacute o tipo de estudo indicado para comparar diferentes formas de

tratamento atraveacutes da divisatildeo dos pacientes por grupos Eacute necessaacuterio ter em

consideraccedilatildeo o aspecto eacutetico de tais tratamentos pois ldquoexposing patients to an

intervention believed to be inferior to current treatment is often thought unethicalrdquo (41)

Para garantir a eacutetica dos tratamentos incluiacutedos o estudo foi conduzido de acordo com a

Declaraccedilatildeo de Helsiacutenquia como referido na Directiva da EU de 200120EC e

concordante com a Conferecircncia Internacional de Harmonizaccedilatildeo (ICH) e a GCP (boa

praacutetica cliacutenica)

Sim Os indiviacuteduos foram divididos aleatoriamente para serem inseridos num

dos 4 grupos de tratamento numa proporccedilatildeo 1111 O meacutetodo de aleatorizaccedilatildeo foi

gerado pelo computador atraveacutes de um randomization Schedule

Para equilibrar a alocaccedilatildeo dos pacientes realizou-se uma estratificaccedilatildeo por sexo

e por intensidade da dor basal O protocolo do estudo foi revisto e aprovado pela

Quorum Review Inc o que leva a querer que a subdivisatildeo foi realmente rigorosa

Os grupos encontram-se equilibrados tanto em nuacutemero como noutras variaacuteveis

particularmente geacutenero intensidade dor basal e idade Deste modo diferenccedilas

reportadas nos resultados natildeo satildeo consequecircncia da heterogeneidade dentro dos grupos

de tratamento

A aleatorizaccedilatildeo dos participantes foi gerada pelo computador O protocolo do

estudo foi posteriormente revisto como anteriormente referido Agrave partida tanto o

investigador e pacientes natildeo interferiram no processo

Foram usados comprimidos para o ibuprofeno de soacutedio ibuprofenopoloxamero

e caacutepsulas para o paracetamol tanto para as formas activas como placebo

conclusion

Sim Os 322 participantes incluiacutedos de 614 inicialmente recrutados 318

completaram o estudo e 321 foram incluiacutedos na populaccedilatildeo ITT (intended do treat)

No grupo ibuprofeno de soacutedio todos os 80 participantes concluiacuteram a anaacutelise

No grupo B dos 80 inicialmente alocados 76 completaram a anaacutelise Um foi

excluiacutedo perdeu-se o follow-up de outro e os restantes natildeo concluiacuteram por

outros motivos

Dos 81 do grupo do paracetamol um natildeo foi incluiacutedo no ITT (falhou em

providenciar os dados da intensidade da dor basal diaacuteria)

No grupo placebo todos os pacientes concluiacuteram o estudo

Os resultados de cada paciente foram analisados agrave luz do grupo de tratamento

em que estes foram colocados

Sim Os participantes permaneceram nos centros de investigaccedilatildeo cliacutenica apoacutes a

toma durante 8-15h Durante as 6 horas apoacutes o tratamento a eficaacutecia foi medida em

intervalos preacute-determinados Para avaliar a existecircncia de efeitos secundaacuterios foi

realizada uma mediccedilatildeo de sinais vitais conduzido um follow-up poacutes-operativo (5 a 12

dias poacutes-cirurgia) e repetida a avaliaccedilatildeo de efeitos adversos Pode-se considerar anaacutelogo

o acompanhamento entre os vaacuterios pacientes poacutes-cirurgia e medicaccedilatildeo pois constituiu

um seguimento proacuteximo maioritariamente presencial e rigoroso

Foram usados dados de estudos preacutevios os quais continham informaccedilatildeo acerca

de AUC e PRID Com estes dados foi determinado que um nuacutemero de 80 pacientes por

grupo providenciaria um power de 90 em detectar diferenccedilas entre os grupos de

tratamento com um niacutevel de significacircncia de 0025 Natildeo foi possiacutevel calcular um power

ldquoformalrdquo para o aliacutevio de dor significativo No entanto a resposta eacute afirmativa para a

questatildeo CASP uma vez que foram realizados esforccedilos para que o nuacutemero das amostras

fosse significativo e correcto

Os resultados satildeo apresentados em termos de percentagens e diferenccedilas meacutedias

(mean differences) alguns com recurso a curvas de Kaplan-Meier (survival curves) Os

efeitos secundaacuterios satildeo apresentados sob a forma de tabela com a percentagem de

pacientes dentro de cada grupo que sofreram os efeitos descritos na mesma

Os grupos A e B exibem resultados substancialmente melhores no que diz

respeito aos seguintes pontos

AUC e SPID satildeo significativamente menores A com 963 e B com 90 face a

C com 675 e D com 25 O tempo para atingir aliacutevio da dor

SPRID Esta eacute semelhante entre os grupos A B e C ateacute aos 45 minutos A partir

deste periacuteodo o ibuprofeno possui uma eficaacutecia superior ao paracetamol

Abstracccedilatildeo agrave dor e percepccedilatildeo da interferecircncia causada pela dor nas actividades

quotidianas (escala de Ranvier)

Utilizaccedilatildeo da medicaccedilatildeo de recurso A com 325 e B com 225 face a C com

438 e D em que a maioria dos pacientes usou a mesma

Avaliaccedilatildeo dos medicamentos por parte dos pacientes (resposta ldquoboardquo ldquomuito

boardquo ou ldquoexcelenterdquo)

No que se refere aos efeitos secundaacuterios 118 da populaccedilatildeo do estudo sofreu

mais efeitos sendo que a maior percentagem ocorreu no grupo do C

Quando comparado com acetaminofeno o ibuprofeno de soacutedio e

Ibuprofenopoloxamero possui uma eficaacutecia analgeacutesica significativamente superior

Nos endpoints primaacuterios as diferenccedilas entre as duas formulaccedilotildees de ibuprofeno e

paracetamol foram avaliadas tendo por base o teste de Wilcoxon rank-sum O hazard

ratio e respectivo IC de 975 foram calculados para as comparaccedilotildees entre os

compostos Os endpoints secundaacuterios que agregavam vaacuterios periacuteodos de tempo foram

calculados atraveacutes da AUC Diferenccedilas entre tratamentos foram avaliadas utilizando

valores de α de 005 o intervalo de confianccedila de 95 (CI) foi calculado por meio dos

paracircmetros do modelo adequado

Eacute introduzido o valor de P que na sua generalidade possui valores reduzidos e

menores que 0005 Considerando a homogeneidade dos grupos o caacutelculo do nuacutemero da

amostra com elevado power e os valores de P podemos concluir que no contexto os

resultados satildeo precisos (42)

Eacute plausiacutevel que a populaccedilatildeo utilizada no estudo fosse semelhante num estudo

anaacutelogo Tanto o local como o proacuteprio tratamento poderiam ser reproduzidos visto que

os compostos em questatildeo satildeo largamente comercializados

Os resultados satildeo importantes para uma escolha mais consciente por parte dos

indiviacuteduos entre tomar paracetamol ou ibuprofeno apoacutes uma cirurgia de um 3ordm molar Eacute

afirmado na discussatildeo deste estudo que o ibuprofeno possui menores efeitos adversos

gastrointestinais que outros NSAIDrsquos Tendo isso em conta pode conduzir a uma

escolha deste composto no tratamento da dor poacutes ciruacutergica por parte dos profissionais

ldquothese findings support a recommendation for this agent as an analgesic of choice for

the treatment of post-operative dental painrdquo A preocupaccedilatildeo pela comunidade em geral

estaacute impliacutecita neste aspecto se possuir menores efeitos secundaacuterios e benefiacutecio superior

eacute melhor para a populaccedilatildeo em geral O custo financeiro destes medicamentos natildeo se

traduz num ponto diferenciador visto que em Portugal existem geneacutericos de ambos

Eacute uma boa base de comparaccedilatildeo entre o paracetamol e ibuprofeno em muitos

aspectos Na procura da melhor evidecircncia e no sentido de a aplicar eacute importante

completar este estudo com outros que nomeadamente se foquem nos efeitos

secundaacuterios

An investigation into the comparative efficacy of soluble aspirin

and solid paracetamol in postoperative pain after third molar

surgery Seymour Hawkesford (22)

Sim O estudo em questatildeo trata-se de um ensaio cliacutenico aleatorizado duplamente

cego e controlado por placebo O seu objectivo central eacute comparar a eficaacutecia da aspirina

soluacutevel agrave do paracetamol soacutelido em pacientes com dor poacutes-operatoacuteria apoacutes extracccedilatildeo do

3ordm molar Foi utilizado um grupo placebo como controlo negativo

Soacute foram incluiacutedos pacientes que necessitavam da extracccedilatildeo do 3ordm molar

saudaacuteveis segundo categoria 1 da American Society of Anaesthesiologists (ASA I) ou agrave

discriccedilatildeo do cirurgiatildeo oral categoria 2 Soacute foram abrangidos pacientes que atingiram o

limiar de dor necessaacuterio ou que requeriram analgeacutesicos ateacute 90 minutos apoacutes a cirurgia

Cada paciente incluiacutedo no estudo foi colocado num dos trecircs grupos de

tratamento

Grupo 1 Aspirina soluacutevel 900mg dose uacutenica

Grupo 2 paracetamol soacutelido 1000mg dose uacutenica

Grupo 3 placebo dose uacutenica

Foi utilizado o meacutetodo de double-dummy ndash assim cada grupo recebeu o seu tipo

de tratamento e um placebo do tratamento alternativo No caso do grupo 3 os pacientes

receberam placebos para os dois tipos de tratamento

Os outcomes passaram pela

Comparaccedilatildeo de medidas de intensidade da dor atraveacutes da escala VAS (mm)

entre os grupos de tratamento aos 10 15 20 e 30 minutos apoacutes a dosagem

inicial

Comparaccedilatildeo da AUC240 com recurso a anaacutelise de co-variacircncia usando o

centro do estudo geacutenero baseline pain intensity duraccedilatildeo da cirurgia e

nuacutemero de molares removidos como co-variaacuteveis

Necessidade de recurso a rescue medication

Impressatildeo geral dos pacientes e enfermeiros sobre a medicaccedilatildeo atraveacutes de

uma regressatildeo binomial logiacutestica (em que um resultado positivo se refere a

uma avaliaccedilatildeo ldquomuito boardquo ou ldquoboardquo)

As comparaccedilotildees feitas foram aspirina vs paracetamol e aspirina vs placebo

Sim O estudo apresentado eacute um RCT por vaacuterias razotildees sendo a mais relevante a

aleatorizaccedilatildeo dos grupos de tratamento em que os pacientes incluiacutedos foram

distribuiacutedos com a mesma probabilidade e aleatoriamente para cada grupo de estudo Os

grupos de tratamento tecircm tamanhos semelhantes e satildeo homogeacuteneos e os pacientes

foram seguidos de forma semelhante - as uacutenicas diferenccedilas residem no tratamento

oferecido

A utilizaccedilatildeo deste tipo de estudo foi loacutegica Um ensaio cliacutenico aleatorizado eacute

ideal para comparar efeitos de determinadas intervenccedilotildees e consequentemente ideal

para comparar eficaacutecia entre medicamentos

Foi realizada uma alocaccedilatildeo aleatoacuteria dos pacientes incluiacutedos assim como uma

aleatorizaccedilatildeo por blocos de cinco para assegurar equiliacutebrio entre grupos de tratamento

ldquoA key advantage of blocked randomization is that treatment groups will be equal in

size and will tend to be uniformly distributed by key outcome-related characteristicsrdquo

Foi ainda efectuada uma aleatorizaccedilatildeo estratificada por geacutenero de modo a

equilibrar nos trecircs grupos o nuacutemero de mulheres e homens e aumentar a credibilidade

das comparaccedilotildees entre os mesmos (proporccedilatildeo MF 21)

Tabela 2 ndash Dados demograacuteficos dos pacientes do estudo

Variaacutevel Aspirina soluacutevel

Paracetamol soacutelido

1000 mg

Placebo

Nuacutemero de pacientes 59 62 32

Raacutecio geacutenero MF 1940 1943 1121

Todos os pacientes incluiacutedos receberam anestesia de acordo com a praacutetica

cliacutenica a extracccedilatildeo dos molares impactados foi realizada seguindo a teacutecnica standard

Estes factores contribuem para a semelhanccedila da forma de tratamento dos 3 grupos Com

estes aspectos em comum a todos os pacientes incluiacutedos em adiccedilatildeo agrave homogeneidade

dos grupos nos seus aspectos demograacuteficos diferenccedilas encontradas nos resultados satildeo

consequecircncias de outros factores

Sim A administraccedilatildeo uacutenica tem a vantagem de natildeo requerer monitorizaccedilatildeo de

um processo ldquodelicadordquo por parte do paciente De facto todo o estudo eacute realizado num

periacuteodo de 4 horas apoacutes a cirurgia e com ajuda de enfermeiros Olhando do ponto de

vista do paciente pode-se consideraacute-lo cego

Se os meacutetodos foram realmente aleatoacuterios o investigador eacute tambeacutem considerado

cego e pode-se afirmar que foram feitos esforccedilos necessaacuterios para o alcanccedilar Tanto a

aspirina soluacutevel como o placebo foram oferecidos sob a forma de uma bebida cor-de-

laranja o paracetamol com substacircncia activa e placebo oferecidos como comprimidos

conclusion

Sim Inicialmente todos os pacientes tinham a mesma probabilidade de serem

incluiacutedos num dos trecircs grupos A distribuiccedilatildeo sendo aleatoacuteria natildeo soacute coloca um

paciente num determinado grupo de tratamento como impossibilita que o mesmo venha

a pertencer a outro O seguimento foi realizado de igual forma para todos os grupos e

intimamente controlado Os resultados foram apresentados separadamente para cada

grupo Dos 167 pacientes foram medicados 153 Dos 14 pacientes natildeo tratados 10 natildeo

desenvolveram dor suficiente para serem incluiacutedos 1 obteve uma reacccedilatildeo adversa agrave

anestesia e 1 natildeo seguiu o protocolo

O grupo da aspirina soluacutevel apresentou melhores resultados que o grupo do

paracetamol e do placebo na medida em que os pacientes reportaram menos dor

apresentou menor intensidade de dor (aos 10 e 30 minutes em comparaccedilatildeo ao

paracetamol e apenas 30 minutos face ao placebo) e os valores de dor global medidos

pela AUC240 foram significativamente menores

Sim A intensidade da dor foi medida frequentemente ao longo de 4 horas

(segundo a VAS) e os pacientes foram informados da possibilidade de tomar medicaccedilatildeo

adicional se necessaacuterio A avaliaccedilatildeo sobre o tratamento dos enfermeiros e dos proacuteprios

pacientes foi tida em consideraccedilatildeo para os resultados

Aleacutem disso ao longo do periacuteodo de investigaccedilatildeo a enfermeira do estudo ficou

responsaacutevel por monitorizar os pacientes e registar a ocorrecircncia de quaisquer eventos

adversos Deste modo eacute muito provaacutevel que todos os pacientes tenham recebido o

mesmo niacutevel de atenccedilatildeo

Natildeo eacute possiacutevel dizer No estudo natildeo eacute referida a utilizaccedilatildeo de power calculations

ou outros meacutetodos para determinar o tamanho da amostra Apenas se pode concluir que

o grupo de controlo negativo tem um menor nuacutemero de pacientes consequecircncia de

desistecircncias ou pelo simples facto de agrave partida se conhecerem os resultados

A intensidade da dor foi medida numa escala VAS aos 10 15 20 e 30 minutos

apoacutes a administraccedilatildeo Foi possiacutevel tirar vaacuterias conclusotildees a partir da observaccedilatildeo dos

resultados

A aspirina demonstrou ser significativamente mais eficaz que o paracetamol ou

placebo embora ateacute aos 15 minutos natildeo seja uma diferenccedila muito expressiva

Relativamente agrave AUC240 experiecircncia global da dor no periacuteodo de 4 horas da

investigaccedilatildeo esta foi significativamente menor para o grupo 1

Natildeo existiu diferenccedila significativa entre os grupos no que diz respeito agrave rescue

medication utilizada No entanto o tempo para a administraccedilatildeo da mesma foi

superior no grupo 1 e 2 em relaccedilatildeo ao grupo placebo

Em relaccedilatildeo agrave impressatildeo global natildeo haacute discrepacircncias consideraacuteveis entre grupo 1

e 2 no que diz respeito agrave percentagem de outcomes positivos (58 e 53

respectivamente) O grupo 3 apresentou apenas 31 de outcomes positivos

A tabela com a percentagem de pacientes que desenvolveram efeitos adversos

para cada grupo mostra que 41 dos pacientes apresentaram efeitos secundaacuterios

nos grupos com tratamento activo no entanto muitos destes estavam

relacionados com o procedimento ciruacutergico

A aspirina soluacutevel 900mg providencia uma analgesia mais significante e raacutepida

que o paracetamol 1000mg no periacuteodo imediato apoacutes a cirurgia do 3ordm molar embora natildeo

seja muito expressiva a percepccedilatildeo desta diferenccedila por parte dos pacientes e enfermeiros

Os resultados satildeo precisos e apresentados atraveacutes de um intervalo de confianccedila

de 95 satildeo tambeacutem apresentados valores de p

Os valores de p satildeo menores que 005 excepto aos 10 e 15 minutos

Para a intensidade da dor ao longo dos 30 minutos e AUC240 da comparaccedilatildeo

aspirina vs placebo a intervenccedilatildeo utilizada seria a mesma tanto no limite superior

como no inferior excepto aos 10 e 15 minutos Na comparaccedilatildeo aspirina soluacutevel vs

paracetamol soacutelido a decisatildeo seria a mesma independentemente dos limites do intervalo

apenas para os minutos 10 20 e 30

O mesmo aconteceria para a medicaccedilatildeo de recurso (outcome C) e a avaliaccedilatildeo do

tratamento por parte dos pacientes e enfermeiros (outcome D)

Pelo intervalo de confianccedila estar presente e pelo facto de os valores de p serem

bastante reduzidos os resultados satildeo precisos ao ponto de ajudarem a suportar uma

decisatildeo

Sim Os pacientes incluiacutedos no estudo o local e o tratamento visados no mesmo

poderiam ser extrapulados e aplicados noutro ambiente O seguimento dos pacientes

durante 4 horas e com ajuda de enfermeiros natildeo se apresenta como muito viaacutevel mas

ainda assim eacute exequiacutevel e seguro

O estudo avalia dados importantes para os profissionais de sauacutede ao afirmar que

a dose (900mg) e a forma (soluacutevel) em que a aspirina eacute tomada conduz a um poder

analgeacutesico superior que o paracetamol No entanto em termos individuais e de poliacuteticas

de sauacutede os efeitos secundaacuterios consequentes da medicaccedilatildeo (excluindo os que se

relacionassem com a cirurgia) deveriam ser completados com estudos suplementares

Segundo este ensaio cliacutenico a incidecircncia de efeitos secundaacuterios natildeo eacute muito

dissemelhante entre aspirina soluacutevel e paracetamol soacutelido nas doses maacuteximas

recomendadas e nestas circunstacircncias a aspirina tem maior poder analgeacutesico Por este

prisma a praacutetica cliacutenica poderia passar pela prescriccedilatildeo de aspirina soluacutevel 900mg para

aliacutevio dor poacutes-operatoacuteria da extracccedilatildeo do terceiro molar Poreacutem eacute necessaacuterio ter em

conta que visa somente a dor nas primeiras quatro horas poacutes-operatoacuterias sendo

importante investigar alternativas eficazes que sejam mais duradouras ou a eficaacutecia e

efeitos secundaacuterios de repetir este tratamento apoacutes as quatro horas iniciais

DISCUSSAtildeO

A partir da anaacutelise feita das revisotildees sistemaacuteticas de Weil (19) e de Barden (23)

conclui-se que o paracetamol eacute uma analgeacutesico seguro e eficaz no tratamento da dor

relativa agrave exodontia de terceiros molares pois apresenta um benefiacutecio estatisticamente

significativo quando comparado a placebo Ambas consideram que os melhores valores

de aliacutevio de dor e da diminuiccedilatildeo da intensidade da mesma satildeo alcanccedilados agraves 4 e 6 horas

apoacutes ingestatildeo do faacutermaco

Com base na primeira revisatildeo acima referida o paracetamol exibe uma dose

uacutenica oacuteptima de 1000mg e um periacuteodo de medicaccedilatildeo apropriado de 8 em 8 horas A

maioria dos artigos incluiacutedos apresenta um risco de vieacutes moderado causado

principalmente pela falta de informaccedilatildeo sobre o mecanismo de alocaccedilatildeo de pacientes

podendo levar a uma descredibilidade dos resultados (36)

Na revisatildeo de Barden (23) a comparaccedilatildeo entre os diferentes NSAIDrsquos

demonstrou que este tipo de faacutermacos e particularmente os inibidores da COX-2

exibem os melhores valores de NNT Atraveacutes de uma comparaccedilatildeo indirecta entre

ibuprofeno vs paracetamol os vaacuterios estudos mostraram que o ibuprofeno apresenta

melhores resultados na analgesia da dor poacutes-operatoacuteria (44)

Os estudos de Seymour (22) de Haglund (25) e de Daniels (33) comparam

diferentes compostos activos a um placebo onde o paracetamol estaacute sempre presente

Todos comprovam que enquanto analgeacutesico apresenta uma eficaacutecia largamente

significativa em termos de aliacutevio da dor (usando a escala VAS) Pelo menos 50 dos

indiviacuteduos incluiacutedos que receberam este faacutermaco avaliaram globalmente o tratamento de

forma positiva Poreacutem todos os artigos que

1 Comparam este composto a outro nomeadamente NSAIDrsquos mostram que estes

tecircm uma eficaacutecia significativamente superior agrave do paracetamol tanto em relaccedilatildeo

a valores mais baixos na escala VAS como subjectivamente na avaliaccedilatildeo global

Cerca de 80 dos indiviacuteduos que tomaram NSAIDrsquos classificaram o tratamento

positivamente (agrave excepccedilatildeo dos estudos (32) e (22)) Reportam ainda os efeitos

adversos mais comuns como tonturas naacuteuseas cefaleia e sonolecircncia que

embora de gravidade reduzida tecircm uma incidecircncia superior no paracetamol que

na aspirina e ibuprofeno

2 Combinam o paracetamol com NSAIDrsquos provam o efeito aditivo daquele bem

como o facto de estas combinaccedilotildees serem mais eficazes que qualquer um dos

faacutermacos em separado (Merry (13) e Haglund (25))

De acordo com os estudos analisados os NSAIDrsquos aparentam ser uma escolha

preferencial face ao paracetamol porque apresentam uma maior eficaacutecia no aliacutevio da dor

apoacutes extracccedilatildeo de terceiros molares embora disponham de propriedades anti-

inflamatoacuterias notoacuterias (e pertinentes no sucesso do tratamento poacutes-operatoacuterio)

O mecanismo de acccedilatildeo do paracetamol necessita de investigaccedilatildeo adicional que

permita uma melhor compreensatildeo e que traga novas respostas na praacutetica cliacutenica Como

aspecto positivo eacute de acrescentar que natildeo existem diferenccedilas estatisticamente

significantes entre o paracetamol e placebo no que diz respeito a efeitos secundaacuterios

(baixo grau de severidade) podendo ser considerado um composto seguro

A revisatildeo de Barden (23) indica que os resultados da eficaacutecia dos NSAIDrsquos

podem atrair os cliacutenicos a aumentar a sua prescriccedilatildeo sem terem em atenccedilatildeo a sua

relaccedilatildeo com o aumento dos efeitos adversos Isto eacute uma situaccedilatildeo insustentaacutevel na

medida em que nas uacuteltimas duas deacutecadas alguns destes medicamentos foram retirados

do mercado devido a eventos adversos graves posteriormente descobertos Um exemplo

eacute o caso do rofecoxib e valdecoxib que produziram acidentes cardiovasculares seacuterios

provavelmente consequentes da dosagem e natildeo da sua selectividade para a COX-2

Os efeitos adversos satildeo um motivo de peso para que os pacientes deixem de

tomar determinada substacircncia ou sejam incapazes de tolerar uma dose eficaz da mesma

Informaccedilotildees complementares que englobassem este aspecto seriam ideais e exequiacuteveis

se os autores de ensaios cliacutenicos lhes dessem maior relevo (45)

Outros dados - como custo financeiro e disponibilidade no mercado - poderiam

ser um auxiacutelio na selecccedilatildeo entre paracetamol e outros medicamentos Eacute de ressalvar

que em Portugal os geneacutericos vieram a baixar os preccedilos de analgeacutesicos e NSAIDrsquos

Medicamentos agrave base de ibuprofeno satildeo dos mais dispendiosos (46)

Os NSAIDrsquos tecircm um problema adicional relacionado com a hemostase ndash inibir a

produccedilatildeo de tromboxano A2 e consequentemente aumentar o risco de hemorragia

prolongada (11) No entanto estes efeitos secundaacuterios estatildeo directamente relacionados

com a dosagem pelo que apenas eacute relevante considerar este aspecto em paciente com

problemas de coagulaccedilatildeo

Conclui-se que embora a toma de paracetamol seja um procedimento seguro e

eficaz existem no mercado compostos com igual seguranccedila e eficaacutecia superior Apesar

de os inibidores da COX-2 serem os compostos mais eficazes abarcam os efeitos

secundaacuterios mais graves pelo que a realizaccedilatildeo de estudos adicionais eacute imperativo no

sentido de colmatar esta falha

RESPOSTA AO PACIENTE

ldquoTendo em conta a evidecircncia cientiacutefica disponiacutevel sobre este assunto e

considerando que natildeo tem problemas gaacutestricos ou de coagulaccedilatildeo sanguiacutenea recomendo

que tome 1g de paracetamol de 8 em 8 horas pois eacute bastante eficaz no aliacutevio da dor

Poreacutem existem outras opccedilotildees como por exemplo combinar o paracetamol a 200mg de

ibuprofeno pode ainda apenas tomar o paracetamol e se sentir necessidade recorrer ao

ibuprofeno 400mg no maacuteximo trecircs vezes ao dia

Tanto o paracetamol como o ibuprofeno tecircm poucos efeitos secundaacuterios e os

mais frequentes satildeo de baixo grau de gravidade Embora existam outros medicamentos

mais eficazes na eliminaccedilatildeo da dor estes tecircm efeitos secundaacuterios mais graves que natildeo

justificam a sua utilizaccedilatildeo

REFEREcircNCIAS BIBLIOGRAacuteFICAS

1 Barden J Edwards JE McQuay HJ Andrew Moore R Pain and analgesic

response after third molar extraction and other postsurgical pain Pain 2004107(1-

2)86-90 Epub 20040113

2 Cooper SA Desjardins PJ The value of the dental impaction pain model in drug

development Methods in molecular biology (Clifton NJ) 2010617175-90 Epub

20100326

3 NICE Guidance on the Extraction of Wisdom Teeth2000 13 December 2011

Available from httppublicationsniceorgukguidance-on-the-extraction-of-wisdom-

teeth-ta1clinical-need-and-practice

4 Mettes Dirk TG Nienhuijs Marloes MEL van der Sanden Wil JM Verdonschot

Emiel H Plasschaert A Interventions for treating asymptomatic impacted wisdom teeth

in adolescents and adults Cochrane Database of Systematic Reviews [Internet] 2005

(2) Available from

httpwwwmrwintersciencewileycomcochraneclsysrevarticlesCD003879frameht

5 Seymour RA Use of analgesics in postoperative dental pain a review Journal

of the Royal Society of Medicine 198477(11)949-54 Epub 19841101

6 Berg JM Tymoczko JL Stryer L Biochemistry 5 ed W H Freeman 2002

1050 p

7 Nelson DL Cox MM Lehninger Principles of Biochemistry 5 ed W H

Freeman 2005 1119 p

8 Sciulli MG Capone ML Tacconelli S Patrignani P The future of traditional

nonsteroidal antiinflammatory drugs and cyclooxygenase-2 inhibitors in the treatment

of inflammation and pain Pharmacological reports PR 200557 Suppl66-85 Epub

20060118

9 Devlin TD Devlins Textbook of Biochemistry 6 ed Hoboken NJ Wiley

2006 1208 p

10 Katzung BG Basical and Clinical Pharmacology 10 ed McGraw-Hill 2006

11 Naclerio-Homem Mg Fau - Deboni MCZ Deboni Mc Fau - Rapoport A

Rapoport A Fau - Chin VKL Chin VK Effects of ketoprofen and diclofenac potassium

on blood coagulation tests after removal of third molars (1936-7163 (Electronic))

12 Toms L McQuay H Derry S Moore R Single dose oral paracetamol

(acetaminophen) for post-operative pain in adults Cochrane Database of Systematic

Reviews 2008(4)

13 Merry AF Gibbs RD Edwards J Ting GS Frampton C Davies E et al

Combined acetaminophen and ibuprofen for pain relief after oral surgery in adults a

randomized controlled trial British journal of anaesthesia 2010104(1)80-8 Epub

20091217

14 Derry C Derry S Moore R McQuay H Single Dose Oral Ibuprofen for Acute

Post-Operative Pain in Adults Cochrane Database of Systematic Reviews 2009(3)

15 Rang HP Dale MM Ritter JM Moore PK Farmacologia 5 ed Elsevier 2003

Elsevier p

16 Scopel E Alencar M Cruz RM Medidas de avaliaccedilatildeo da dor efdeportes

2007(105)

17 Mata AD Marques D Silveira J Marques J Medicina Dentaacuteria Baseada na

Evidecircncia Novas Opccedilotildees para Velhas Praacuteticas Rev Port Estomatol Cir Maxilofac

200849(1)31-7

18 CASP UK [13 Dezembro 2011] Available from httpwwwcasp-

uknetabout-caspabout-casp

19 Weil K Hooper L Afzal Z Esposito M Worthington Helen V van Wijk A et

al Paracetamol for pain relief after surgical removal of lower wisdom teeth Cochrane

Database of Systematic Reviews [Internet] 2007 (3) Available from

20 Toms L Derry S Moore RA McQuay Henry J Single dose oral paracetamol

(acetaminophen) with codeine for postoperative pain in adults Cochrane Database of

Systematic Reviews [Internet] 2009 (1) Available from

21 Derry S Wiffen PJ Moore RA Relative efficacy of oral analgesics after third

molar extraction - a 2011 update Br Dent J 2011211(9)419-20

22 Seymour RA Hawkesford JE Sykes J Stillings M Hill CM An investigation

into the comparative efficacy of soluble aspirin and solid paracetamol in postoperative

pain after third molar surgery Br Dent J 2003194(3)153-7

23 Barden J Edwards JE McQuay HJ Wiffen PJ Moore RA Relative efficacy of

oral analgesics after third molar extraction Br Dent J 2004197(7)407-11

24 Saska S Scartezini GR Souza RFd Hochuli-Vieira E Pereira Filho VA

Gabrielli MAC Cloridrato de tramadolparacetamol no controle da dor poacutes-operatoacuteria

em cirurgias de terceiros molares inclusos

Tramadolacetaminophen in the control of postoperative pain for impacted third molar

surgery Rev cir traumatol buco-maxilo-fac 20099(4)

25 Haglund B von Bultzingslowen I Combining paracetamol with a selective

cyclooxygenase-2 inhibitor for acute pain relief after third molar surgery a randomized

double-blind placebo-controlled study European journal of oral sciences

2006114(4)293-301 Epub 20060817

26 Kubitzek F Ziegler G Gold MS Liu JM Ionescu E Analgesic efficacy of low-

dose diclofenac versus paracetamol and placebo in postoperative dental pain Journal of

orofacial pain 200317(3)237-44 Epub 20031003

27 Bjornsson GA Haanaes HR Skoglund LA A randomized double-blind

crossover trial of paracetamol 1000 mg four times daily vs ibuprofen 600 mg effect on

swelling and other postoperative events after third molar surgery British journal of

clinical pharmacology 200355(4)405-12 Epub 20030419

28 Macleod AG Ashford B Voltz M Williams B Cramond T Gorta L et al

Paracetamol versus paracetamol-codeine in the treatment of post-operative dental pain

a randomized double-blind prospective trial Australian dental journal

200247(2)147-51 Epub 20020726

29 Bjornsson GA Haanaes HR Skoglund LA Ketoprofen 75 mg qid versus

acetaminophen 1000 mg qid for 3 days on swelling pain and other postoperative events

after third-molar surgery Journal of clinical pharmacology 200343(3)305-14 Epub

20030318

30 Chopra D Rehan HS Mehra P Kakkar AK A randomized double-blind

placebo-controlled study comparing the efficacy and safety of paracetamol

serratiopeptidase ibuprofen and betamethasone using the dental impaction pain model

International journal of oral and maxillofacial surgery 200938(4)350-5 Epub

20090127

31 Dolci G Ripari M Pacifici L Umile A Evaluation of piroxicam-beta-

cyclodextrin piroxicam paracetamol and placebo in post-operative oral surgery pain

International journal of clinical pharmacology research 199414(5-6)185-91 Epub

19940101

32 Noronha VR Gurgel GD Alves LC Noman-Ferreira LC Mendonca LL Aguiar

EG et al Analgesic efficacy of lysine clonixinate paracetamol and dipyrone in lower

third molar extraction a randomized controlled trial Medicina oral patologia oral y

cirugia bucal 200914(8)e411-5 Epub 20090506

33 Daniels S Reader S Berry P Goulder M Onset of analgesia with sodium

ibuprofen ibuprofen acid incorporating poloxamer and acetaminophen--a single-dose

double-blind placebo-controlled study in patients with post-operative dental pain

European journal of clinical pharmacology 200965(4)343-53 Epub 20090303

34 Medve RA Wang J Karim R Tramadol and acetaminophen tablets for dental

pain Anesthesia progress 200148(3)79-81 Epub 20011129

35 Bjornsson GA Haanaes HR Skoglund LA Naproxen 500 mg bid versus

acetaminophen 1000 mg qid effect on swelling and other acute postoperative events

after bilateral third molar surgery Journal of clinical pharmacology 200343(8)849-58

Epub 20030905

36 Marques JF Marques D Silveira J Mata AD Revisotildees Sistemaacuteticas o que satildeo

e para que servem Rev Port Estomatol Cir Maxilofac 200849(3)171-8

37 Rodrigues CL Ziegelmann PK Meta-anaacuteliseum guia praacutetico HCPA

201030(4)436-47

38 Alderson P Absence of evidence is not evidence of absence Bmj

2004328(7438)476-7

39 Berwanger O Suzumura EA Buehler AM Oliveira JB Como Avaliar

Criticamente Revisotildees Sistemaacuteticas e Meta-anaacutelises Revista Brasileira de Terapia

Intensiva 200719(4)475-80

40 Noordzij M Zoccali C Dekker FW Jager KJ Adding up the evidence

systematic reviews and meta-analyses Nephron Clinical practice 2011119(4)c310-6

Epub 20111203

41 Sibbald B Roland M Understanding controlled trials Why are randomised

controlled trials important Bmj 1998316(7126)201

42 Primer on Statistical Significance and P Values Effective Clinical Practice

20014(4)183-4

43 Efird J Blocked randomization with randomly selected block sizes International

journal of environmental research and public health 20118(1)15-20 Epub 20110215

44 Cooper S Schachtel B Goldman E Gelb S Cohn P Ibuprofen and

acetaminophen in the relief of acute pain a randomized double blind placebo

controlled study The Journal of Clinical Pharmacology 198929(11)1026-30

45 Edwards JE McQuay HJ Moore RA Collins SL Reporting of Adverse Effects

in Clinical Trials Should Be Improved Lessons from Acute Postoperative Pain Journal

of pain and symptom management 199918(6)427-37

46 Faacutermaco mais vendido versus mais barato Deco Proteste [updated Julho

200919 Dezembro 2011] Available from httpwwwdecoprotesteptservicos-de-

saudefarmaco-mais-vendido-versus-mais-barato-s568081htm

ANEXOS

ANEXO A ndash TABELA DE CARACTERIacuteSTICAS DE ARTIGOS EXCLUIacuteDOS

Artigo Fonte Classificaccedilatildeo

inicial Motivo de Exclusatildeo

Toms Derry (20) Cochrane

Library

Possivelmente

Adequado

Natildeo eacute um estudo sobre

extracccedilatildeo de terceiros molares

Saska Scartezini

(24) LILACS

Possivelmente

adequado

Estudo natildeo visa o tipo de

intervenccedilatildeo considerada

Bjornsson

Haanaes (27) PubMed Adequado

Estudo natildeo se foca na dor poacutes-

operatoacuteria

Kubitzek Ziegler

(26) PubMed Adequado Artigo natildeo disponiacutevel

Macleod

Ashford (28) PubMed Adequado

Bjornsson

Haanaes (29) PubMed

Possivelmente

adequado Artigo natildeo disponiacutevel

Chopra Rehan

(30) PubMed

Possivelmente

adequado

Dolci Ripari (31) PubMed Possivelmente

Medve Wang

(34) PubMed

Possivelmente

adequado

Bjornsson

Haanaes (35) PubMed

Possivelmente

ANEXO B ndash ARTIGOS INCLUIacuteDOS EM FORMATO

INTEGRALi

i Nota os seguintes artigos estatildeo paginados fora do contexto deste trabalho de acordo com a sua

paginaccedilatildeo original

wisdom teeth (Review)

Weil K Hooper L Afzal Z Esposito M Worthington HV van Wijk A Coulthard P

This is a reprint of a Cochrane review prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2008 Issue 4

httpwwwthecochranelibrarycom

Paracetamol for pain relief after surgical removal of lower wisdom teeth (Review)

Copyright copy 2008 The Cochrane Collaboration Published by John Wiley amp Sons Ltd

T A B L E O F C O N T E N T S

1HEADER

1ABSTRACT

2PLAIN LANGUAGE SUMMARY

2BACKGROUND

3OBJECTIVES

3METHODS

5RESULTS

8DISCUSSION

9AUTHORSrsquo CONCLUSIONS

9ACKNOWLEDGEMENTS

10REFERENCES

13CHARACTERISTICS OF STUDIES

30DATA AND ANALYSES

Analysis 11 Comparison 1 50 pain relief using pain relief measures Outcome 1 Paracetamol versus placebo number of

people with at least 50 pain relief at 4 hours 31

Analysis 21 Comparison 2 50 pain relief using pain intensity measures Outcome 1 Paracetamol versus placebo number

of people with at least 50 pain relief at 4 hours 34

Analysis 31 Comparison 3 Number of people with adverse events Outcome 1 Number of patients with adverse events

paracetamol versus placebo 37

38ADDITIONAL TABLES

42APPENDICES

43WHATrsquoS NEW

43HISTORY

43CONTRIBUTIONS OF AUTHORS

43DECLARATIONS OF INTEREST

44SOURCES OF SUPPORT

44INDEX TERMS

iParacetamol for pain relief after surgical removal of lower wisdom teeth (Review)

[Intervention Review]

Paracetamol for pain relief after surgical removal of lowerwisdom teeth

Kiaran Weil1 Lee Hooper2 Zahid Afzal3 Marco Esposito1 Helen V Worthington4 Arjen van Wijk5 Paul Coulthard1

1Department of Oral and Maxillofacial Surgery School of Dentistry The University of Manchester Manchester UK 2School of

Medicine Health Policy amp Practice University of East Anglia Norwich UK 3Oral and Maxillofacial Surgery City Hospital Birming-

ham UK 4Cochrane Oral Health Group MANDEC School of Dentistry The University of Manchester Manchester UK 5Social

Dentistry and Behavioural Sciences ACTA Amsterdam Netherlands

Contact address Kiaran Weil Department of Oral and Maxillofacial Surgery School of Dentistry The University of Manchester

Higher Cambridge Street Manchester M15 6FH UK kiaran_weilhotmailcom

Editorial group Cochrane Oral Health Group

Publication status and date Edited (no change to conclusions) published in Issue 4 2008

Review content assessed as up-to-date 21 May 2007

Citation Weil K Hooper L Afzal Z Esposito M Worthington HV van Wijk A Coulthard P Paracetamol for pain relief af-

ter surgical removal of lower wisdom teeth Cochrane Database of Systematic Reviews 2007 Issue 3 Art No CD004487 DOI

10100214651858CD004487pub2

A B S T R A C T

Background

Paracetamol has been commonly used for the relief of postoperative pain following oral surgery In this review we investigated the

optimal dose of paracetamol and the optimal time for drug administration to provide pain relief taking into account the side effects

of different doses of the drug This will inform dentists and their patients of the best strategy for pain relief after the surgical removal

of wisdom teeth

Objectives

To assess the beneficial and harmful effects of paracetamol for pain relief after surgical removal of lower wisdom teeth compared to

placebo at different doses and administered postoperatively

Search strategy

We searched the Cochrane Oral Health Grouprsquos Trials Register the Cochrane Pain Palliative and Supportive Care Grouprsquos Trials Register

CENTRAL MEDLINE EMBASE and the Current Controlled Trials Register Handsearching included several dental journals We

checked the bibliographies of relevant clinical trials and review articles for studies outside the handsearched journals We wrote to

authors of the identified randomised controlled trials (RCTs) to manufacturers of analgesic pharmaceuticals we searched personal

references in an attempt to identify unpublished or ongoing RCTs No language restriction was applied The last electronic search was

conducted on 24th August 2006

Selection criteria

Randomised parallel group placebo controlled double blind clinical trials of paracetamol for acute pain following third molar surgery

Data collection and analysis

All trials identified were scanned independently and in duplicate by two review authors any disagreements were resolved by discussion

or if necessary a third review author was consulted The proportion of patients with at least 50 pain relief was calculated for both

paracetamol and placebo The number of patients experiencing adverse events andor the total number of adverse events reported were

analysed

1Paracetamol for pain relief after surgical removal of lower wisdom teeth (Review)

Main results

Twenty-one trials met the inclusion criteria A total of 2048 patients were initially enrolled in the trials (1148 received paracetamol

and 892 the placebo) and of these 1968 (96) were included in the meta-analysis (1133 received paracetamol and 835 the placebo)

Paracetamol provided a statistically significant benefit when compared with placebo for pain relief and pain intensity at both 4 and 6

hours Most studies were found to have moderate risk of bias with poorly reported allocation concealment being the main problem

Risk ratio values for pain relief at 4 hours 285 (95 confidence interval (CI) 189 to 429) and at 6 hours 332 (95 CI 188 to 587)

A statistically significant benefit was also found between up to 1000 mg and 1000 mg doses the higher the dose giving greater benefit

for each measure at both time points There was no statistically significant difference between the number of patients who reported

adverse events overall this being 19 in the paracetamol group and 16 in the placebo group

Authorsrsquo conclusions

Paracetamol is a safe effective drug for the treatment of postoperative pain following the surgical removal of lower wisdom teeth

P L A I N L A N G U A G E S U M M A R Y

Paracetamol for pain relief after surgical removal of lower wisdom teeth

The surgical removal of wisdom teeth (third molars) is the most commonly performed surgical procedure undertaken in oral surgery

practice Postoperative complications may include swelling bruising and limited mouth opening but patients are most often concerned

about postoperative pain which may be severe Paracetamol is effective in relieving pain with a low incidence of adverse effects It is one

of the most commonly used analgesics and is widely available without prescription around the world In this review we investigated the

optimal dose of paracetamol and the optimal time for drug administration to provide pain relief after the surgical removal of wisdom

teeth The side effects of different doses of the drug were also explored

Twenty-one trials (with over 2000 participants) were included Paracetamol provided a statistically significant benefit when compared

with placebo for pain relief at both 4 and 6 hours after taking the drug It is most effective at 1000 mg dose and can be taken at six

hourly intervals without compromising safety There was no statistically significant difference between the number of patients who

reported adverse events overall this being 19 in the paracetamol group and 16 in the placebo group It should be noted that most

of the studies were found to have some limitations mainly due to poor reporting of information However the review concludes that

paracetamol is a safe effective drug for the treatment of postoperative pain following the surgical removal of lower wisdom teeth

B A C K G R O U N D

The surgical removal of wisdom teeth is the most commonly per-

formed surgical procedure undertaken in oral surgery practice

Postoperative complications may include swelling bruising and

limited mouth opening but patients are most often concerned

about postoperative pain which may be severe The pain ex-

perienced after oral surgery is a validated and widely used pain

model for the clinical evaluation of analgesic efficacy (Cooper

1976) Tissue damage produced during surgery releases chemicals

that initiate inflammatory pain by activating and sensitising nerve

fibre receptors (Loeser 1999) Chemicals include bradykinin

prostaglandins serotonin and histamine (Dray 1997)

Paracetamol (acetaminophen) is a nonopioid analgesic possessing

antipyretic activity and is effective in relieving pain with a low in-

cidence of adverse effects (Moore 1998) It is one of the most com-

monly used analgesics and is widely available without prescription

around the world Paracetamol is often grouped with the nons-

teroidal anti-inflammatory drug (NSAID) family however it is

considered only to have relatively weak anti-inflammatory activity

(Rang 2003) NSAIDs are assumed largely to produce their anal-

gesia as a result of the inhibition of prostaglandin production by

the enzyme cyclo-oxygenase (Malmberg 1992) The mechanism

of action has not been fully understood Among several theories

it has been suggested that paracetamol is a selective inhibitor of

the newly described COX-3 enzyme a cyclo-oxygenase-1 variant

in the central nervous system This inhibition could represent a

primary central mechanism by which paracetamol decreases pain

and possibly fever (Chandrasekharan 2002) Major evidence has

been accumulated showing that paracetamol inhibits cyclo-oxy-

genase by reducing the higher oxidative state of the cyclo-oxyge-

nase enzyme by reducing oxygen radical co-substrates (Aronoff

2006) Paracetamol has been shown to be an effective analgesic in

the control of postoperative dental pain in a number of clinical

trials (Bentley 1987 Kiersch 1994 Mehlisch 1990) Pain inten-

sity following third molar surgery has been suggested to reach its

maximum between 3 to 5 hours following surgery (Fisher 1988

Seymour 1985) and therefore this pain model is used to test the

efficacy of a single analgesic dose

A recent systematic review (Barden J 2004) has looked at the ef-

ficacy and safety of paracetamol for postoperative pain manage-

ment and has included the findings of studies involving a wide

variety of types of surgery such as gynaecology surgery abdomi-

nal surgery orthopaedic surgery amongst others including the re-

moval of wisdom teeth There is some debate as to whether dental

pain is different from other pain It has been suggested that the

effect of some analgesics including tramadol were worse for dental

pain than for other types of postsurgical pain (Moore 1997)

In this review we investigated the optimal dose of paracetamol and

the optimal time for drug administration to provide pain relief

taking into account the side effects of different doses of the drug

This will inform dentists and their patients of the best strategy for

best pain relief after the surgical removal of wisdom teeth

O B J E C T I V E S

To assess the beneficial and harmful effects of paracetamol for

pain relief after surgical removal of lower wisdom teeth compared

to placebo at different doses and administered preoperatively or

postoperatively

Primary

bull To test the null hypothesis of no difference in the beneficial

and harmful effects between paracetamol and placebo for pain

relief in patients requiring surgical removal of a lower wisdom

tooth or teeth against the alternative hypothesis of a difference

Secondary

and harmful effects between different doses of paracetamol for

pain relief in patients requiring surgical removal of a lower

wisdom tooth or teeth against the alternative hypothesis of a

difference

and harmful effects between different times of administration of

paracetamol for pain relief in patients requiring surgical removal

of a lower wisdom tooth or teeth against the alternative

hypothesis of a difference

M E T H O D S

Criteria for considering studies for this review

Types of studies

All randomised controlled double blind clinical trials

Types of participants

Patients of all health states who required the surgical removal of

a lower wisdom tooth and who had at least had a baseline pain

intensity of moderate to severe pain Patients who also required

removal of an additional tooth or teeth were included Surgery

was undertaken under local anaesthesia intravenous sedation or

general anaesthesia Patients taking concurrent analgesia were ex-

cluded

Types of interventions

Efficacy

bull Paracetamol given as a single dose by mouth in any dose

and in any formulation (for example immediate or slow release)

regardless of when the single dose was given (for example

preoperatively or postoperatively)

Side effects

In order to investigate side effects more thoroughly we included

both single and multiple dose studies

bull Paracetamol given up to 7 days by mouth in any dose and

in any formulation (for example immediate or slow release)

regardless of when the first dose was given (for example

Types of outcome measures

bull Pain intensity (visual analogue scale (VAS) categorical

verbal rating verbal numerical scale global subjective efficacy

ratings and other categorical rating scales)

bull Pain relief (VAS categorical verbal rating verbal numerical

scale global subjective efficacy ratings and other categorical

rating scales) and derived pain relief outcomes extracted will be

total pain relief (TOTPAR) summed pain intensity difference

(SPID) over 4 and 6 hours

bull Side effects (for example hepatic and renal) (binary)

Search methods for identification of studies

To identify studies for inclusion or consideration in this review a

detailed search strategy was developed for each database searched

These were based on the search strategy developed for MEDLINE

but revised appropriately for each database The search strategy

combined a sensitive search strategy for randomised controlled

trials (RCTs) revised from phases 1 and 2 of the Cochrane Sensi-

tive Search Strategy for RCTs (as published in Appendix 5b in the

Cochrane Handbook for Systematic Reviews of Interventions 426

(updated September 2006)) The subject search used a combina-

tion of controlled vocabulary and free text terms based on the

search strategy for searching CENTRAL (see Appendix 1)

Databases to be searched

The Cochrane Oral Health Grouprsquos Trials Register (to 24th August

The Cochrane Central Register of Controlled Trials (CENTRAL)

(The Cochrane Library 2006 Issue 3)

The Cochrane Pain Palliative and Supportive Care Grouprsquos Trials

Register (to 24th August 2006)

MEDLINE (1966 to 24th August 2006)

EMBASE (1980 to 25th August 2006)

Current Controlled Trials Register (wwwcontrolled-trialscom)

(to 24th August 2006)

The bibliographies of papers and review articles were checked for

studies outside the handsearched journals Personal references were

also searched

Language

There were no language restrictions and where necessary transla-

tion into the English language of relevant studies was conducted

Unpublished studies

Authors of RCTs identified were written to in order to obtain

further information about the trial and to attempt to identify

unpublished or ongoing studies We also wrote to manufacturers

of analgesic pharmaceuticals

Handsearching

Several journals relevant to this review were handsearched as part

of the Cochrane Oral Health Grouprsquos ongoing journal hand-

searching programme The list of the dental journals hand-

searched by The Cochrane Collaboration can be found at http

wwwohgcochraneorg

The titles and abstracts (when available) of all reports identified

were scanned independently and in duplicate by two review au-

thors For studies appearing to meet the inclusion criteria or for

which there were insufficient data in the title and abstract to make

a clear decision the full report was obtained and assessed indepen-

dently and in duplicate by two review authors to establish whether

the studies met the inclusion criteria or not Disagreements were

resolved by discussion Where resolution was not possible a third

review author was consulted All studies meeting the inclusion

criteria then underwent quality assessment and data extracted

Studies rejected at this or subsequent stages were recorded in the

Characteristics of excluded studies table and reasons for exclusion

were recorded

Quality assessment

The quality assessment of the included trials was undertaken inde-

pendently and in duplicate by two review authors based on what

is written in the articles

Only double blind trials were included in the review so blinding

was not included in the quality assessment

Two main quality criteria were examined

(1) Allocation concealment recorded as

(A) Adequate -2 points

(B) Unclear - 1 point

(C) Inadequate - 0 points

(2) Completeness of follow up (is there a clear explanation for

withdrawals and drop outs in each treatment group) assessed as

(A) Yes - 1 point

(B) No - 0 points

The agreement for the quality criteria between assessors was de-

termined by Kappa statistics

After taking into account the additional information provided by

the authors of the trials studies were grouped into the following

categories

(A) Low risk of bias - 3 points (plausible bias unlikely to seriously

alter the results) if all criteria were met

(B) Moderate or high risk of bias - 0 to 2 points Moderate risk

of bias - plausible bias that raises some doubt about the results if

one or more criteria are partly met (for example when authors

responded that they had made some attempts to conceal the al-

location of patients to give an explanation for withdrawals but

these attempts were not judged to be ideal these criteria were cat-

egorised as rsquopartlyrsquo) High risk of bias - plausible bias that seriously

weakens confidence in the results if one or more criteria were not

met as described in the Cochrane Handbook for Systematic Reviews

of Interventions 426

We also reported whether the authors of included trials have con-

ducted a sample size calculation

Data extraction

Data were extracted by two review authors independently and

in duplicate using specially designed data extraction forms Any

disagreement was discussed and a third review author consulted

where necessary Authors were contacted for clarification of miss-

ing information Data were excluded until further clarification was

available if agreement could not be reached

For each trial the following data were recorded

bull Year of publication country of origin setting and source of

study funding

bull Details of the participants including demographic

characteristics and criteria for inclusion

bull Details on the study design (parallel group or cross-over

design)

bull Details on the type of intervention

bull Details of the outcomes reported including method of

assessment and time intervals

Data synthesis

From the mean total pain relief (TOTPAR) or summed pain in-

tensity difference (SPID) pain indices reported we computed a

dichotomous outcome variable for the number of patients with

at least 50 pain relief according to the methods outlined in a

Cochrane review (Collins 1999) For each of the three objectives

we examined the appropriateness of different continuous outcome

measurements and these were meta-analysed and reported in the

final review

For dichotomous outcomes the estimate of an intervention was

expressed as risk ratios together with 95 confidence intervals

For continuous outcomes mean differences and 95 confidence

intervals were used to summarise the data for each trial

Clinical heterogeneity was assessed by examining the types of par-

ticipants interventions and outcomes in each study Meta-analyses

were conducted only with studies of similar comparisons report-

ing the same outcome measures Risk ratios were used to combine

dichotomous data and mean differences for continuous data us-

ing random-effects models The significance of any discrepancies

in the estimates of the treatment effects from the different trials

was assessed by means of Cochranrsquos test for heterogeneity and any

heterogeneity investigated

Where both visual analogue scale (VAS) and categorical scales were

used to measure pain intensity or pain relief or both the categorical

data were used in the meta-analysis as this was the most frequently

used scale

Subgroup analyses

Subgroup analyses were planned for studies

bull Where patients underwent surgery with local anaesthesia

alone local anaesthesia and intravenous sedation general

anaesthesia alone and general anaesthesia with local anaesthetic

bull Where different types of formulation of paracetamol were

used for instance immediate release versus slow release

bull Where different doses of paracetamol were used (1000 mg

or more and less than 1000 mg)

bull Where time of administration of paracetamol differs

preoperative versus postoperative

bull Where TOTPAR was calculated using pain relief measures

and pain intensity measures

The difference between studies comparing up to 1000 mg doses

with studies comparing 1000 mg or more was examined by per-

forming random-effects metaregression analyses in Stata version

90 (Stata Corporation USA) using the program Metareg

The results of the metaregressions for comparing the two dose

levels up to 1000 mg and 1000 mg or more are presented in

Additional Table 1

R E S U L T S

Description of studies

See Characteristics of included studies Characteristics of excluded

studies

See Characteristics of included studies and Characteristics of

excluded studies tables

Characteristics of the trial setting and investigators

Of the 67 eligible trials 46 were excluded as shown in the ex-

cluded studies section Of the 21 included studies one was con-

ducted in Denmark (Moller 2000) two in Germany (Kubitzek

2003 Lehnert 1990) one in Italy (Dolci 1994) one in Nor-

way (Skoglund 1991) two in Puerto Rico (Olson 2001 Sunshine

1986) one in Thailand (Vattaraphudej 1986) two in the United

Kingdom (Seymour 1996 Seymour 2003) and 11 in the United

States of America (Cooper 1980 Cooper 1981 Cooper 1988

Cooper 1998 Dionne 1994 Forbes 1984b Forbes 1989 Forbes

1990 Hersh 2000 Kiersch 1994 Mehlisch 1995) Six trials

were conducted at university clinics (Cooper 1998 Hersh 2000

Moller 2000 Olson 2001 Sunshine 1986 Vattaraphudej 1986)

five at private practices (Dionne 1994 Forbes 1984b Forbes

1989 Forbes 1990 Kubitzek 2003) seven did not state a set-

ting (Cooper 1981 Dolci 1994 Kiersch 1994 Mehlisch 1995

Seymour 1996 Seymour 2003 Skoglund 1991) One reported a

single site (Cooper 1988) two reported two sites (Forbes 1989

Seymour 2003) and six specifically stated outpatients (Cooper

1980 Cooper 1988 Forbes 1989 Forbes 1990 Hersh 2000

Lehnert 1990) Seventeen trials were sponsored by industry

(Cooper 1981 Cooper 1988 Cooper 1998 Dionne 1994 Forbes

1984b Forbes 1989 Forbes 1990 Hersh 2000 Kiersch 1994

Kubitzek 2003 Lehnert 1990 Mehlisch 1995 Moller 2000

Olson 2001 Seymour 2003 Skoglund 1991 Sunshine 1986)

one by a university grant (Vattaraphudej 1986) and it was unclear

as whether the remaining three trials (Cooper 1980 Dolci 1994

Seymour 1996) were sponsored but it is likely that they were from

correspondence with some of the authors

Characteristics of interventions

All included interventions were randomised parallel group and

double blind Eleven trials used doses of paracetamol of less than

1000 mg (Cooper 1980 Cooper 1981 Cooper 1988 Dionne

1994 Dolci 1994 Forbes 1984b Forbes 1989 Forbes 1990

Seymour 1996 Sunshine 1986 Vattaraphudej 1986) Eleven tri-

als used doses of 1000 mg (Cooper 1998 Hersh 2000 Kiersch

1994 Kubitzek 2003 Lehnert 1990 Mehlisch 1995 Moller

2000 Olson 2001 Seymour 1996 Seymour 2003 Skoglund

1991) One study (Seymour 1996) used both doses Seven tri-

als used paracetamol in tablet form (Dolci 1994 Forbes 1989

Kubitzek 2003 Mehlisch 1995 Moller 2000 Seymour 2003

Skoglund 1991) Seven trials used capsules (Forbes 1984b Forbes

1989 Forbes 1990 Kiersch 1994 Lehnert 1990 Sunshine 1986

Vattaraphudej 1986) Two trials used caplets (Hersh 2000 Olson

2001) and one trial used effervescent tablets (Moller 2000) Five

trials did not state what formulation was used (Cooper 1980

Cooper 1981 Cooper 1988 Cooper 1998 Dionne 1994) All

trials used placebos in the same formulation as the intervention

Characteristics of outcome measures

For all trials it was possible to calculate the number of patients

with at least 50 total pain relief (TOTPAR) at either 4 hours

6 hours or both Pain intensity was measured in all but one trial

(Kubitzek 2003) pain relief was measured in all but two trials

(Kubitzek 2003 Seymour 2003) Kubitzek 2003 gave a figure for

TOTPAR at six hours and Seymour 2003 measured pain intensity

only Fifteen trials measured pain intensity at 4 hours using a 4-

point categorical scale of 0 to 3 where 0 was no pain at all and 3

was severe pain Five trials measured pain intensity using a visual

analogue scale (VAS) of 0 to 100 mm where 0 was no pain and

100 was the worst pain imaginable Twelve trials measured pain

intensity at 6 hours using a 4-point categorical scale where 0 was

no pain and 3 was severe pain and three trials measured pain

intensity at 6 hours using a VAS of 0 to 100 mm where 0 was no

pain and 100 mm was the worst pain imaginable Sixteen trials

measured pain relief at 4 hours using a 5-point categorical scale

of 0 to 4 where 0 was none and 4 was complete pain relief two

trials measured pain relief at 4 hours using a VAS of 0 to 100 mm

in one trial 0 was none and 100 was complete relief and in the

other trial 0 was complete relief and 100 was no relief (these data

were reversed for statistical purposes) Twelve trials measured pain

relief at 6 hours using a 5-point categorical scale of 0 to 4 where

0 was none and 4 was complete pain relief two trials measured

pain relief at 6 hours using a VAS of 0 to 100 mm in one trial 0

was none and 100 was complete relief and in the other trial 0 was

complete relief and 100 was no relief (these data were reversed for

statistical purposes)

Adverse events and global assessments were recorded in most of

the trials Nineteen trials reported the number of patients with

side effects eight for doses of 1000 mg or more and 15 for doses

of less than 1000 mg Fifteen trials reported the number of adverse

events seven for doses of 1000 mg or more and eight for doses

of less than 1000 mg Fourteen trials recorded global assessment

using a 5-point categorical scale of either 0 to 4 or 1 to 5 where

0 or 1 was poor and 4 or 5 was excellent and four trials used a

4-point categorical scale of 0 to 3 where 0 was poor and 3 was

excellent

Risk of bias in included studies

Details of the quality assessment are presented in Additional Table

2 Seven out of the 21 studies reported adequate concealed al-

location for the remaining studies it was unclear Over half of

the studies (1121) gave clear explanation of withdrawals or drop

outs Taking these two factors into account only three trials were

assessed as being at low risk of bias

Effects of interventions

Comparison 1 Paracetamol versus placebo using

pain relief measurements

(Comparison 1 Outcome 11 amp Comparison 1 Outcome 12)

(Analysis 11 Analysis 12)

There are 16 studies providing pain relief measurements for com-

paring paracetamol versus placebo at 4 hours 11 at doses up to

1000 mg and 5 at doses of 1000 mg Overall there was a highly

statistically significant benefit with the paracetamol with risk ratio

(RR) values for achieving 50 pain relief for all doses of parac-

etamol for 4 hours RR 285 (95 confidence interval (CI) 189

to 429) Chi2 = 6294 degrees of freedom (df ) = 15 P lt 0001

I2 = 76 number needed to treat (to benefit) (NNT) 4 (95

CI 3 to 4) The statistically significant benefit was apparent for

both subgroups with RR for up to 1000 mg 196 (95 CI 134

to 286) Chi2 = 2644 df = 9 P = 0002 I2 = 660 NNT 4

(95 CI 3 to 5) and RR for 1000 mg 456 (95 CI 286 to

727) Chi2 = 544 df = 5 P = 036 I2 = 82 NNT 3 (95

CI 3 to 4) Although both had a statistically significant benefit

over placebo there was a statistically significant difference between

the two subgroups with an enhanced benefit for the higher doses

(metaregression P lt 0001 Additional Table 3) This subgroup

analysis explained some of the heterogeneity in the overall com-

parison however there is still some unexplained heterogeneity be-

tween the trials in the up to 1000 mg dose comparison

paring paracetamol versus placebo at 6 hours 6 doses up to 1000

mg paracetamol and 7 doses of 1000 mg paracetamol Overall

there was a highly statistically significant benefit with the parac-

etamol with RR values for 50 pain relief at 6 hours RR 332

(95 CI 188 to 587) Chi2 = 6335 df = 12 P lt 000001 I2 = 811 NNT 3 (95 CI 3 to 4) The statistically significant

benefit was apparent in both subgroups with RR for up to 1000

mg 189 (95 CI 098 to 367) Chi2 = 1445 df = 5 P = 001

I2 = 654 NNT 6 (95 CI 4 to 10) and RR for 1000 mg

421 (95 CI 297 to 598) Chi2 = 509 df = 6 P = 053 I2 =

0 NNT 3 (95 CI 2 to 3) Although both had a statistically

significant benefit over placebo there was a statistically significant

difference between the two subgroups with an enhanced benefit

for the higher doses (metaregression P lt 0001 Additional Table

3) This subgroup analysis explained some of the heterogeneity in

the overall comparison however there is still some unexplained

heterogeneity between the trials in the up to 1000 mg dose com-

parison

pain intensity difference measurements

There are 18 studies providing pain intensity measurements for

comparing paracetamol versus placebo at 4 hours 10 at doses up

to 1000 mg and 8 at doses of 1000 mg Overall there was a highly

statistically significant benefit with paracetamol with RR values

for 50 pain relief at 4 hours RR 487 (95 CI 283 to 837)

Chi2 = 4973 df = 17 P lt 00001 I2 = 658 NNT 3 (95 CI

3 to 5) The statistically significant benefit was apparent in both

subgroups with RR up to 1000 mg 433 (95 CI 219 to 858)

Chi2 = 2622 df = 9 P = 0002 I2 = 657 NNT 3 (95 CI

3 to 4) and RR for 1000 mg 646 (95 CI 234 to 1785) Chi2 = 2347 df = 7 P = 0001 I2 = 702 NNT 4 (95 CI 3

to 5) Both had a statistically significant benefit over placebo but

there was no statistically significant difference between the two

subgroups (metaregression P = 067 Additional Table 3)

for 50 pain relief RR 341 (95 CI 234 to 497) Chi2 = 1823

df = 13 P = 015 I2 = 287 NNT 4 (95 CI 3 to 4) The

statistically significant benefit was apparent in both groups with

RR up to 1000 mg 267 (95 CI 146 to 490) Chi2 = 705 df

= 5 P = 022 I2 = 291 NNT 5 (95 CI 3 to 7) and RR for

1000 mg 396 (95 CI 252 to 623) Chi2 = 863 df = 7 P =

028 I2 = 189 NNT 3 (95 CI 3 to 4) Both had a statisti-

cally significant benefit over placebo but there was no statistically

significant difference between the two subgroups (metaregression

P = 015 Additional Table 3)

Comparison 3 Number of patients with adverse

events for paracetamol versus placebo

(Comparison 3 Outcome 31) (Analysis 31)

There are 17 studies that reported the number of patients with

adverse events for paracetamol versus placebo 9 studies used less

than 1000 mg and 8 studies used 1000 mg There was no statisti-

cally significant difference in any group For all doses of paraceta-

mol the RR for an adverse event RR 119 (95 CI 090 to 157)

Chi2 = 2073 df = 15 P = 015 I2 = 276 number needed to

treat to harm (NNTH) 33 (95 CI 143 to infinity) For doses of

less than 1000 mg RR 125 (95 CI 069 to 225) Chi2 = 906

df = 7 P = 025 I2 = 228 NNTH 33 (95 CI 143 to infinity)

For 1000 mg paracetamol RR 116 (95 CI 084 to 160) Chi2

= 1096 df = 7 P = 014 I2 = 362 NNTH 33 (95 CI 125

to infinity)

Subgroup analyses

Where patients underwent surgery with local anaesthesia

anaesthesia alone and general anaesthesia with local

anaesthetic

When the data were reviewed it was not possible to do a meta-anal-

ysis Of the 21 included studies 7 did not state what anaesthesia

was used 7 used combinations of anaesthesia but were unclear in

reporting which patients received which anaesthesia 4 used local

anaesthetic only and 3 used general anaesthetic only

Where different types of formulation of paracetamol were

used (immediate release versus slow release)

Most included studies did not report on the formulation other

than to say whether it was tablets capsules or caplets Only one

paper indicated that their study used effervescent tablets (Moller

2000) and their results showed that effervescent tablets gave a faster

onset of pain relief Median value for time to onset of analgesia

was 20 minutes in the effervescent group and 45 minutes in the

tablet group and time to meaningful pain relief was 45 minutes

in the effervescent group and 1 hour in the tablet group However

at the end of a 4-hour period pain relief was better in the tablet

group (44) than the effervescent group (37)

Where different doses of paracetamol were used (1000 mg

This meta-analysis was conducted 11 studies used doses of 1000

mg or more and 11 studies used doses of less than 1000 mg

(Seymour 1996 used both doses)

NNT for lt 1000 mg of paracetamol is 4 (95 CI 3 to 5) at

4 hours and 6 (95 CI 4 to 10) at 6 hours (using pain relief

measurements)

NNT for lt 1000 mg of paracetamol is 3 (95 CI 3 to 4) at 4 hours

and 5 (95 CI 3 to 7) at 6 hours (using intesity measurements)

NNT for 1000 mg of paracetamol is 3 (95 CI 3 to 4) at 4 hours

and 3 (95 CI 2 to 3) at 6 hours (using pain relief measurements)

and 3 (95 CI 3 to 4) at 6 hours (using intensity measurements)

Where time of administration of paracetamol differs

No included study used a preoperative dose as the patients did

not reach moderate or severe pain before the intervention

Where total pain relief (TOTPAR) was calculated using pain

relief measures and pain intensity measures

This meta-analysis was undertaken where the relevant data were

available 16 studies had pain relief data and 17 studies had pain

intensity data

NNT using pain relief scales for lt 1000 mg of paracetamol is 4

(95 CI 3 to 5) at 4 hours and 6 (95 CI 4 to 10) at 6 hours

NNT using pain intensity scales for lt 1000 mg of paracetamol is

3 (95 CI 3 to 4) at 4 hours and 5 (95 CI 3 to 7) at 6 hours

NNT using pain relief scales for 1000 mg of paracetamol is 3 (95

CI 3 to 4) at 4 hours and 3 (95 CI 2 to 3) at 6 hours

NNT using pain intensity scales for 1000 mg of paracetamol is 4

D I S C U S S I O N

The results show paracetamol to be an effective analgesia for use

following third molar surgery The number needed to treat (to

benefit) (NNTs) and number needed to treat to harm (NNTHs)

support the use of 1000 mg as an optimal dose It is effective over

both 4 and 6 hours In considering the use of pain relief or pain

intensity difference as a measure of efficacy it was of interest that

metaregression showed that pain relief scales showed a statistically

significant difference for increased dose and pain intensity did

not It is acknowledged that this review only considered single

dose studies when considering efficacy multidosed studies may be

considered when updating the review The NNTs and NNTHs

found in this review are similar to those recorded by a systematic

review (Barden J 2004) where they investigated paracetamol for

pain involving various types of surgery This would confirm yet

again the value of the third molar pain model showing that dental

pain is comparable with pain from other sources The implemen-

tation of NICE (National Institute for Health and Clinical Excel-

lence) Guidelines for removal of third molars has led to a decrease

in the performance of this surgery which may have an adverse

effect on the number of trials able to use the third molar model

In the United States of America such guidelines have not yet been

adopted It is of interest that in striving to provide evidence based

treatment the opportunity for research using the third molar pain

model may be adversely affected

The data available for adverse events show that NNTH for lt 1000

mg of paracetamol is 33 (143 to infinity) for 1000 mg of parac-

etamol is 33 (125 to infinity) and for all doses 33 (143 to infin-

ity) suggesting it is an extremely safe drug Only one severe ad-

verse event was recorded by any researchers and that was a severe

headache (Olson 2001) two other participants stopped taking

paracetamol because of vomiting However there was a high degree

of inconsistency across the trials in the way that adverse events were

recorded raising the concern that only adverse events considered

by the researchers to be attributable to paracetamol were recorded

with some trials recording many AEs and some reporting none

The diverse way in which adverse events were recorded led to there

being over 20 categories of adverse events The main categories

are shown in Additional Table 4 Of interest are adverse events

where placebo scored more highly than paracetamol which could

suggest that paracetamol may possibly have a beneficial effect eg

dry socket but this would require further investigation As all pa-

tients had surgery and various combinations of local anaesthesia

general anaesthesia and sedation making it difficult to ascertain

which effects are directly related to the intervention However the

results strongly support the use of paracetamol in doses up to 1000

mg as a safe effective analgesia

The efficacy of paracetamol decreases with times and the recom-

mended interval between doses is 8 hours which would suggest

there may be some benefit in a slow release formulation None of

the studies in this trial used a slow release formulation but a trial

(Coulthard 2001) compared sustained release and standard release

formulations of paracetamol and found that the sustained release

was statistically significantly more effective at 6 and 8 hours with

no loss of efficacy at 4 hours Safety for both formulations was

comparable making sustained release paracetamol a safe and ef-

fective choice

The methodology used in the included trials was generally good

This resulted in a large number of participants being included

in this meta-analysis while using only double blind randomised

trials The included trials gave a strong consistent result Many

of the trials were done by researchers with extensive experience

in the field of pain research whose methods have been refined

with experience A large proportion of the trials were done in the

United States and were mostly funded by pharmaceutical com-

panies This seems to be reflected in the methodology However

quality assessment showed there were only three trials with a low

risk of bias and 18 with moderatehigh risk This was mainly the

result of unreported allocation concealment methods In speaking

to some of the authors it is highly likely that the allocation con-

cealment was good in all the trials but that the details were not

well reported Most trials were sponsored by pharmaceutical com-

panies who supplied paracetamol and placebo in identical appear-

ance The reporting of withdrawals and drop outs was sporadic

and even when numbers were cited it was not always clear to which

treatment group the participant had been originally allocated

Mean global assessments (Additional Table 5 Table 6 Table 7

Table 8) all showed higher scores for paracetamol than placebo

It is of interest that despite achieving 50 pain relief participants

did not record 50 on a global assessment scale This again raises

the question of the value of the instruments used to measure the

efficacy of an intervention None of the trials relied on global

assessments as their only measure of efficacy but this information

could be of value to other researchers It raises interesting questions

concerning patientrsquos expectations and the difficulties associated

with quantifying such a subjective experience

A lot of valuable information was gathered incidental to the main

findings in most of the trials So though the topic was concerned

with the use of paracetamol for pain information collected in

many of the trials shed valuable light on subjects such as side effects

measuring instruments and methodology Further appraisal of

the multidisciplinary approach to research a broader view of data

collection and a more accurate reporting of data already collected

could be extremely valuable in the future It would allow research

to be more widely used in various meta-analyses Data from areas

seemingly unrelated to the original null hypothesis eg comparison

of pain relief and pain intensity as a measuring tool adverse event

reporting the significance of global assessments etc could be more

readily available If the third molar trial population does decrease

it would be advantageous to collect as much data as possible from

any trial being undertaken

A U T H O R S rsquo C O N C L U S I O N SImplications for practice

Paracetamol (acetaminophen) is an effective drug to use for post-

operative pain following oral surgery and the reporting of adverse

events shows it to be a safe drug (number needed to treat (to ben-

efit) (NNT) is 3 for 1000 mg of paracetamol at 6 hours number

needed to treat to harm (NNTH) 33) It is most effective at 1000

mg dose and can be taken at six hourly intervals without compro-

mising safety It could be considered more readily by dentist and

patients both as a first choice analgesic or to be taken alternately

with doses of other analgesics such as nonsteroidal anti-inflamma-

tory drugs (NSAIDS)

Implications for research

There is a large body of research in this area and further research

other than as a comparison seems unnecessary However in one

trial (Moller 2000) it was found that an effervescent formulation

appeared to have a faster onset of pain relief which would be

beneficial to patients who are looking for a rapid onset of relief

It may be helpful to undertake some research to confirm these

findings The use of pain relief and pain intensity difference as a

measure of pain relief may be another area for further investigation

It is valuable to have NNTNNTH as a baseline for comparison

with other analgesics Maximizing the third molar pain model

population by multidisciplinary research is another area of interest

highlighted by this review

A C K N O W L E D G E M E N T S

We wish to thank Sylvia Bickley (Cochrane Oral Health Group)

for her assistance with literature searching and Luisa Fernandez

Mauleffinch (Cochrane Oral Health Group) for her help with the

preparation of this review We would also like to thank the follow-

ing referees who reviewed this work at various stages Barry El-

liott Cole Mike Hill Kimito Yamashiro and Lasse Skoglund We

are grateful to Stephen Cooper Donald Mehlisch Philip Moller

Alberto Umile for providing information on their trials and to

Prisana Pripatnanont for translation and information

R E F E R E N C E S

References to studies included in this review

Cooper 1980 published data only

Cooper SA Precheur H Rauch D Rosenheck A Ladov M

Engel J Evaluation of oxycodone and acetaminophen in

treatment of postoperative dental pain Oral Surgery Oral

Medicine and Oral Pathology 198050(6)496ndash501

Cooper SA Breen JF Giuliani RL The relative efficacy of

indoprofen with opiod-analgesic combinations Journal of

Oral Surgery 198139(1)21ndash5

Cooper SA Firestein A Cohn P Double-blind comparison

of meclofenamate sodium with acetaminophen

acetaminophen with codeine and placebo for relief of

postsurgical dental pain The Journal of Clinical Dentistry

19881(2)31ndash4

Cooper SA Reynolds DC Reynolds B Hersh EV Analgesic

efficacy and safety of (R)- ketoprofen in postoperative dental

pain Journal of Clinical Pharmacology 199838(2 Suppl)

11Sndash18S

Dionne 1994 published data only

Dionne RA Snyder J Hargreaves KM Analgesic efficacy

of flurbiprofen in comparison with acetaminophen

acetaminophen plus codeine and placebo after impacted

third molar removal Journal of Oral and Maxillofacial

Surgery 199452(9)919ndash24

Dolci 1994 published data only

Dolci G Ripari M Pacifici L Umile A Evaluation of

piroxicam-beta-cyclodextrin piroxicam paracetamol and

placebo in post-operative oral surgery pain International

Journal of Clinical Pharmacology Research 199414(5-6)

185ndash91

Forbes 1984b published data only

Forbes JA Barkaszi BA Ragland RN Hankle JJ

Analgesic effect of acetaminophen phenyltoloxamine

and their combination in postoperative oral surgery pain

Pharmacotherapy 19844(4)221ndash6

Forbes 1989 published data only

Forbes JA Butterworth GA Burchfield WH Yorio

CC Selinger LR Rosenmertz SK et alEvaluation of

flurbiprofen acetaminophen an acetaminophen-codeine

combination and placebo in postoperative oral surgery

pain Pharmacotherapy 19899(5)322ndash30

Forbes JA Kehm CJ Grodin CD Beaver WT Evaluation

of ketorolac ibuprofen acetaminophen and an

acetaminophen-codeine combination in postoperative

oral surgery pain Pharmacotherapy 199010(6(Pt 2)))

94Sndash105S

Hersh 2000 published data only

Hersh EV Levin LM Cooper SA Doyle G Waksman J

Wedell D et alIbuprofen liquigel for oral surgery pain

Clinical Therapeutics 200022(11)1306ndash18

Kiersch 1994 published data only

Kiersch TA Halladay SC Hormel PC A single-

dose double-blind comparison of naproxen sodium

acetaminophen and placebo in postoperative dental pain

Kubitzek 2003 published data only

Kubitzek F Ziegler G Gold MS Liu JM Ionescu E

Analgesic efficacy of low-dose diclofenac versus paracetamol

and placebo in postoperative dental pain Journal of

Orofacial Pain 200317(3)237ndash44

Lehnert 1990 published data only

Lehnert S Reuther J Wahl G Barthel K [The efficacy of

paracetamol (Tylenol) and acetyl salicylic acid (Aspirin)

in treating postoperative pain] Deutsche Zahnarztliche

Zeitschrift 199045(1)23ndash6

Mehlisch 1995 published data only

Mehlisch DR Jasper RD Brown P Korn SH McCarroll K

Murakami AA Comparative study of ibuprofen lysine and

acetaminophen in patients with postoperative dental pain

Moller 2000 published data only

Moller PL Norholt SE Ganry HE Insuasty JH Vincent

FG Skoglund LA et alTime of onset of analgesia and

analgesic efficacy of effervescent acetaminophen 1000

mg compared to tablet acetominophen 1000 mg in

postoperative dental pain a single-dose double-blind

randomized placebo-controlled study Journal of Clinical

Pharmacology 200040(4)370ndash8

Olson 2001 published data only

Olson NZ Otero AM Marrero I Tirado S Cooper S

Doyle G et alOnset of analgesia for liquigel ibuprofen

400 mg acetaminophen 1000 mg ketoprofen 25 mg

and placebo in the treatment of postoperative dental pain

Journal of Clinical Pharmacology 200141(11)1238ndash47

Seymour 1996 published data only

Seymour RA Kelly PJ Hawkesford JE The efficacy

of ketoprofen and paracetamol (acetaminopen) in

postoperative pain after third molar surgery British Journal

of Clinical Pharmacology 199641(6)581ndash5

Seymour RA Hawkesford JE Sykes J Stillings M Hill

CM An investigation into the comparative efficacy of

soluble aspirin and solid paracetamol in postoperative pain

after third molar surgery British Dental Journal 2003194

(3)153ndash7

Skoglund 1991 published data only

Skoglund LA Skjelbred P Fyllingen G Analgesic efficacy

of acetaminophen 1000 mg acetaminophen 2000 mg and

the combination of acetaminophen 1000 mg and codeine

phosphate 60 mg versus placebo in acute postoperative

Sunshine 1986 published data only

Sunshine A Marrero I Olson N McCormick N Laska

EM Comparative study of flurbiprofen zomepirac sodium

acetaminophen plus codeine and acetaminophen for the

relief of postsurgical dental pain The American Journal of

Medicine 198680(3A)50ndash4

Vattaraphudej 1986 published data only

Vattaraphudej T Thongnoppakao P Koukongviriyapan V

[Comparison of the efficacy of analgesics in pain after oral

surgery] The Journal of the Dental Association of Thailand

198636(6)198ndash206

References to studies excluded from this review

Adame 1979 published data only

Adame C et alPostoperative development of inflammation

after extraction of impacted third molar as a model

for clinical assessment of anti-inflammatory drugs I

Preliminary report Boletin de Estudios Medicos y Biologicos

197930(8)308ndash9

Barden J 2004 published data only

Barden J Edwards J Moore A McQuay H Single dose

oral paracetamol (acetaminophen) for postoperative pain

Cochrane Database of Systematic Reviews 2004 Issue 1

[DOI DOI 10100214651858CD004602]

Becker 1990 published data only

Becker J Beckmann J Bertelt C Gundert-Remy U

Rohmel J Ohlendorf D [Double blind biometric study on

postoperative effects of analgesics] Deutsche Zahnarztliche

Bentley 1987 published data only

Bentley KC Head TW The additive analgesic efficacy of

acetaminophen 1000 mg and codeine 60 mg in dental

pain Clinical Pharmacology and Therapeutics 198742(6)

634ndash40

Breivik 1998 published data only

Breivik EK Bjornsson GA Variation in surgical trauma and

baseline pain intensity effects on assay sensitivity of an

analgesic trial European Journal of Oral Sciences 1998106

(4)844ndash52

Cooper SA Erlichman MC Mardirossian G Double-

blind comparison of an acetaminophen-codeine-caffeine

combination in oral surgery pain Anesthesia Progress 1986

33(3)139ndash42

Cooper SA Schachtel BP Goldman E Gelb S Cohn P

Ibuprofen and acetaminophen in the relief of acute pain

a randomized double-blind placebo-controlled study

Cooper SA Kupperman A The analgesic efficacy of

flurbiprofen compared to acetaminophen with codeine The

Journal of Clinical Dentistry 19912(3)70ndash4

Dionne 1983 (1) published data only

Dionne RA Campbell RA Cooper SA Hall DL

Buckingham B Suppression of postoperative pain by

preoperative administration of ibuprofen in comparison to

placebo acetaminophen and acetaminophen plus codeine

Dionne RA Sisk AL Fox PC Wirdzek PR Gracely

RH Dubner R Suppression of postoperative pain by

preoperative adminsitration of flurbiprofen in comparison

to acetominophen and oxycodone plus acetominophen

Current Therapeutic Research 198334(1)15ndash29

Dionne RA Suppression of dental pain by the preoperative

administration of flurbiprofen The American Journal of

Dolci G Ripari M Pacifici L Umile A [Analgesic efficacy

and the tolerance for piroxicam-beta-cyclodextrin compared

to piroxicam paracetamol and placebo in the treatment of

postextraction dental pain] Minerva Stomatologica 199342

(5)235ndash41

Edwards 2002 published data only

Edwards JE McQuay HJ Moore RA Combination

analgesic efficacy individual patient data meta-analysis

of single-dose oral tramadol plus acetaminophen in

acute postoperative pain Journal of Pain and Symptom

Management 200223(2)121ndash30

Forbes JA Beaver WT White EH White RW Neilson GB

Shackleford RW Diflunisal A new oral analgesic with an

unusually long duration of action JAMA 1982248(17)

2139ndash42

Forbes 1984a published data only

Forbes JA Kolodny AL Chachich BM Beaver WT

Nalbuphine acetaminophen and their combination in

postoperative pain Clinical Pharamacology and Therapeutics

198435(6)843ndash51

Gallardo 1990 published data only

Gallardo F Rossi E Analgesic efficacy of flurbiprofen as

compared to acetaminophen and placebo after periodontal

surgery Journal of Periodontology 199061(4)224ndash7

Gustafsson 1983 published data only

Gustafsson I Nystrom E Quiding H Effect of preoperative

paracetamol on pain after oral surgery European Journal of

Clinical Pharmacology 198324(1)63ndash5

Haanaes 1986 published data only

Haanaes HR Benterud UJ Skoglund LA RF 46-790 versus

paracetamol effect on post-operative pain International

Journal of Clinical Pharmacology Therapy and Toxicology

198624(11)598ndash601

Irvine 1982 published data only

Irvine GH Lutterloch MJ Bowerman JE Comparison

of diflunisal and paracetamol in the management of pain

following wisdom teeth removal British Dental Journal

1982152(1)18ndash20

Laska 1983 published data only

Laska EM Sunshine A Zighelboim I Roure C Marrero

I Wanderling J et alEffect of caffeine on acetaminophen

analgesia Clinical Pharmacology and Therapeutics 198333

(4)498ndash509

Lecointre 1991 published data only

Lecointre C [Efficacy and tolerance of tiaprofenic acid

for extraction complications Results of a randomized

double-blind study tiaprofenic acid versus paracetamol]

LrsquoInformation Dentaire 199173(35)3063ndash6

Liashek 1987 published data only

Liashek P Jr Desjardins PJ Triplett RG Effect of

pretreatment with acetaminophen-propoxyphene for oral

surgery pain Journal of Oral and Maxillofacial Surgery 1987

45(2)99ndash103

Macleod 2002 published data only

Macleod AG Ashford B Voltz M Williams B Cramond T

Gorta L et alParacetamol versus paracetamol-codeine in

the treatment of post-operative dental pain a randomized

double-blind prospective trial Australian Dental Journal

200247(2)147ndash51

Medve 2001 published data only

Medve RA Wang J Karim R Tramadol and acetaminophen

tablets for dental pain Anesthesia Progress 200148(3)

79ndash81

Mehlisch DR Frakes LA A controlled comparative

evaluation of acetaminophen and aspirin in the treatment of

postoperative pain Clinical Therapeutics 19847(1)89ndash97

Mehlisch DR Sollecito WA Helfrick JF Leibold DG

Markowitz R Schow CE Jr et alMulticenter clinical

trial of ibuprofen and acetaminophen in the treatment of

postoperative dental pain Journal of the American Dental

Association 1990121(2)257ndash63

Moore 1986 published data only

Moore PA Werther JR Seldin EB Stevens CM Analgesic

regimens for third molar surgery pharmacologic and

behavioral considerations Journal of the American Dental

Nystrom 1988 published data only

Nystrom E Gustafsson I Quiding H The pain intensity

at analgesic intake and the efficacy of diflunisal in single

doses and effervescent acetaminophen in single and repeated

doses Pharmacotherapy 19888(3)201ndash9

Petersen 1983 published data only

Petersen JK A double-blind cross-over study of the analgesic

and anti-inflammatory effects of dexamethasone and

paracetamol following surgical removal of lower impacted

third molars International Journal of Oral Surgery 198312

(4)266

Quiding 1981 published data only

Quiding H Oksala E Happonen RP Lehtimaki K Ojala

T The visual analog scale in multiple-dose evaluations of

analgesics The Journal of Clinical Pharmacology 198121

(10)424ndash9

Quiding 1982 (1) published data only

Quiding H Oikarinen V Huitfeldt B Koskimo M

Leikomaa H Nyman C An analgesic study with repeated

doses of phenazone phenazone plus dextropropoxyphene

and paracetamol using a visual analogue scale International

Journal of Oral Surgery 198211(5)304ndash9

Quiding H Persson G Ahlstrom U Bangens S Hellem S

Johansson G et alParacetamol plus supplementary doses

of codeine an analgesic study of repeated doses European

Quiding H Oikarinen V Sane J Sjoblad AM Analgesic

efficacy after single and repeated doses of codeine and

acetaminophen Journal of Clinical Pharmacology 198424

(1)27ndash34

Ragot 1991 published data only

Ragot JP [Comparison of analgesic activity of mefenamic

acid and paracetamol in treatment of pain after extraction

of impacted lower 3d molar] LrsquoInformation Dentaire 1991

73(21)1659ndash64

Reijntjes 1987 published data only

Reijntjes RJ Boering G Wesseling H van Rijn LG

Suprofen versus paracetamol after oral surgery International

Journal of Oral and Maxillofacial Surgery 198716(1)45ndash9

Rodrigo 1987 published data only

Rodrigo MR Rosenquist JB Cheung LK Paracetamol

and diflunisal for pain relief following third molar surgery

in Hong Kong Chinese International Journal of Oral and

Maxillofacial Surgery 198716(5)566ndash71

Rodrigo C Chau M Rosenquist J A comparison of

paracetamol and diflunisal for pain control following

3rd molar surgery International Journal of Oral and

Rosen 1985 published data only

Rosen M Absi EG Webster JA Suprofen compared to

dextropropoxyphene hydrochloride and paracetamol

(Cosalgesic) after extraction of wisdom teeth under general

anaesthesia Anaesthesia 198540(7)639ndash41

Sakata 1989 published data only

Sakata LA Rocha B et alEffects of benzydamine after

surgical removal of impacted teeth [Efeitos da benzidamina

apoacutes a extraccedilaumlo de dentes inclusos] Revista da Associacao

Paulista de Cirurgioes Dentistas 198943(4)167ndash70

Selcuk 1996 published data only

Selcuk E Gomel M Bellibas SE Kose T Tuglular I

Comparison of the analgesic effects of diflunisal and

paracetamol in the treatment of postoperative dental pain

International Journal of Clinical Pharmacology Research

199616(2-3)57ndash65

Seymour RA Rawlins MD Pharmacokinetics of parenteral

paracetamol and its analgesic effects in post-operative dental

pain European Journal of Clinical Pharmacology 198120

(3)215ndash8

Seymour RA Analgesic efficacy and plasma concentration

of three analgesics in pain after lower third molar removal

SAAD Digest 19835(7)172ndash88

Skjelbred 1979 published data only

Skjelbred P Lokken P Paracetamol versus placebo effects

on post-operative course European Journal of Clinical

Strom 1990 published data only

Strom C Forsberg O Quiding H Engevall S Larsson

O Analgesic efficacy of acetaminophen sustained release

Van Aken 2004 published data only

Van Aken H Thys L Veekman L Buerkle H Assessing

analgesia in single and repeated administrations of

propacetamol for postoperative pain comparison with

morphine after dental surgery Anesthesia and Analgesia

200498(1)159ndash65

Winter 1983 published data only

Winter L Appleby F Ciccone PE Pigeon JG A double-

blind comparative evaluation of acetaminophen caffeine

and the combination of acetaminophen and caffeine in

outpatients with postoperative oral surgery pain Current

Therapeutic Research 198333(1)115ndash22

Additional references

Aronoff 2006

Aronoff DM Oates JA Boutaud O New insights into

the mechanism of action of acetaminophen Its clinical

pharmacologic characteristics reflect its inhibition of the

two prostaglandin H2 synthases Clinical Pharmacology and

Therapeutics 200679(1)9ndash19

Chandrasekharan 2002

Chandrasekharan NV Dai H Roos KL Evanson NK

Tomsik J Elton TS et alCOX-3 a cyclooxygenase-1 variant

inhibited by acetaminophen and other analgesicantipyretic

drugs cloning structure and expression Proceedings of the

National Academy of Sciences of the United States of America

200299(21)13926ndash31

Collins 1999

Collins SL Moore RA McQuay HJ Wiffen PJ Edwards JE

Single dose oral ibuprofen and diclofenac for postoperative

pain Cochrane Database of Systematic Reviews 1999

Issue 1 [DOI Art No CD001548 DOI 101002

14651858CD001548]

Cooper 1976

Cooper SA Beaver WT A model to evaluate mild analgesics

in oral surgery outpatients Clinical Pharmacology and

Coulthard 2001

Coulthard P Hill CM Frame JW Barry H Ridge BD

Bacon TH Pain control with paracetamol from a sustained

release formulation and a standard release formulation after

third molar surgery a randomised controlled trial British

Dental Journal 2001191(6)319ndash24

Dray 1997

Dray A Kinins and their receptors in hyperalgesia

Canadian Journal of Physiology and Pharmacology 199775

(6)704ndash12

Fisher 1988

Fisher SE Frame JW Rout PG McEntegart DJ Factors

affecting the onset and severity of pain following the surgical

removal of unilateral impacted mandibular third molar

teeth British Dental Journal 1988164(11)351ndash4

Loeser 1999

Loeser JD Melzack R Pain an overview Lancet 1999353

(9164)1607ndash9

Malmberg 1992

Malmberg AB Yaksh TL Antinociceptive effects of spinal

non-steroidal anti-inflammatory agents on the formalin

test in the rat Journal of Pharmacology and Experimental

Therapeutics 1992263136ndash46

Moore 1997

Moore RA McQuay HJ Single-patient data meta-analysis

of 3453 postoperative patients oral tramadol versus

placebo codeine and combination analgesics Pain 199769

(3)287ndash94

Moore 1998

Moore A Collins S Carroll D McQuay H Edwards

J Single dose paracetamol (acetaminophen) with and

without codeine for postoperative pain Cochrane Database

of Systematic Reviews 1998 Issue 4 [DOI Art No

CD001547 DOI 10100214651858CD001547]

Rang 2003

Rang HP Dale MM Ritter JM Moore PK Anti-

inflammatory and immunosuppresant drugs Pharmacology

5th Edition Churchill Livingstone 2003244ndash61

Seymour 1985

Seymour RA Meechan JG Blair GS An investigation into

post-operative pain after third molar surgery under local

analgesia The British Journal of Oral and Maxillofacial

Surgery 198523(6)410ndash8lowast Indicates the major publication for the study

C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Cooper 1980

Methods Randomised parallel group double blind study

Participants 298 participants randomised to 6 groups withdrawals unclear (51 from all groups)

Number randomised to intervention male 13 female 24 mean age 225

Number randomised to placebo male 11 female 27 mean age 235

Number of third molars removed mean for intervention and placebo 19

Baseline pain intensity mean for intervention 241 (moderate 22 severe 15) mean for placebo 242

(moderate 22 severe 16)

Setting - outpatients (USA)

Interventions Paracetamol 500 mg versus placebo

Formulation not stated

Anaesthesia not stated

Outcomes PI at 4 hours categorical scale 0-3 (none - severe)

PR at 4 hours categorical scale 0-4 (none - complete)

Global assessment categorical scale 0-4 (poor - excellent)

Adverse events table

Notes Sponsored unclear

Risk of bias

Item Authorsrsquo judgement Description

Allocation concealment Unclear B - Unclear

Cooper 1981

Number of third molars removed not stated

Baseline pain intensity mean for intervention 22 (moderate 29 severe 9) mean for placebo 23 (moderate

26 severe 11)

Setting not stated (USA)

Anaesthesia LA or GA

Cooper 1981 (Continued)

Total number of adverse events and number of people with adverse events reported

Notes Sponsored by

Adria Laboratories

Risk of bias

Cooper 1988

Number of third molars removed mean for intervention 14 mean for placebo 15

Baseline pain intensity mean for intervention 24 (moderate 21 severe 15) mean for placebo 24 (mod-

erate 25 severe 15)

Setting - outpatients - single site (USA)

Anaesthesia LA or LA and SED

Outcomes PI at 4 hours and 6 hours categorical scale 0-3 (none - severe)

PR at 4 hours and 6 hours categorical scale 0-4 (none - complete)

Total number of adverse events

Notes Sponsored by

Parke-Davis

Risk of bias

Cooper 1998

Participants 177 participants randomised to 4 groups no withdrawals

Baseline pain intensity mean for intervention categorical 23 VAS 603 mean for placebo categorical

22 VAS 628

Setting - Georgetown University Hospital (USA)

Outcomes PI at 4 hours and 6 hours categorical scale 0-3 (none - severe) VAS scale 0-100 mm (none - worst pain

imaginable)

PR at 4 hours and 6 hours categorical scale 0-4 (no relief - complete relief )

Global assessment not stated

Adverse effects table

Notes Sponsored by

Whitehall-Robins

Risk of bias

Dionne 1994

Baseline pain intensity for intervention and placebo not stated

Setting private dental practice (USA)

Anaesthesia LA or LA and SED or GA

Dionne 1994 (Continued)

Notes Sponsored by

Upjohn

Risk of bias

Dolci 1994

Participants 338 participants enrolled in 4 groups withdrawals unclear (40 from all groups)

Number randomised to intervention male 28 female 44 mean age 279 age range 18-49

Number randomised to placebo male 28 female 48 mean age 272 age range 18-45

Baseline pain intensity range for intervention and placebo given together as average 214 (208 - 219)

Setting not stated (Italy)

Formulation tablets

Global assessment categorical 0-4 (negative - very good)

Notes Sponsored - unclear

Risk of bias

Forbes 1984b

Participants 191 participants randomised to 4 groups withdrawals unclear (43 from all groups 164 used in reporting

of adverse events)

Number of third molars removed mean 244

Number randomised to placebo male 21 female 15 mean age 15-32

Forbes 1984b (Continued)

Formulation capsules

Anaesthesia GA

Adverse effects reported as total number of adverse events and number of patients with adverse events

Notes Sponsored by McNeil Consumer Products

Risk of bias

Allocation concealment Yes A - Adequate

Forbes 1989

Participants 107 participants randomised to 5 groups withdrawals unclear (19 from all groups 98 participants used

in reporting of adverse events)

Baseline pain intensity mean for intervention 245 mean for placebo 239

Setting - 2 sites private dental practice outpatients (USA)

Formulation - 1 tablet amp 1 capsule

Anaesthesia LA and GA

Global assessment categorical 0-4 (poor - excellent)

Adverse effects reported by number of patients with adverse events

Notes Sponsored by

Boots Company Ltd GH Besselaar Associates

Risk of bias

Forbes 1989 (Continued)

Forbes 1990

Participants 206 participants randomised to 6 groups

Number randomised to intervention male 20 female 16 (5 withdrawals) mean age 225 age range 16-

Number randomised to placebo male 18 female 16 (4 withdrawals) mean age 2365 age range 16-45

Setting - private dental practice outpatients (USA)

Notes Sponsored by

Syntex Research

Risk of bias

Hersh 2000

Number of third molars removedpatient (11) (26) (35) (451)

Number of wisdom teeth removed per patient (11) (25) (33) (418)

erate 22 severe 5)

Setting - University of Pennsylvania School of Dental Medicine - outpatients (USA)

Hersh 2000 (Continued)

Formulation caplets

Outcomes PI at 4 hours and 6 hours categorical 0-3 (none - severe)

PR at 4 hours and 6 hours categorical 0-4 (no relief - complete relief )

Adverse effects by total number of adverse events and number of patients with adverse events

Notes Sponsored by

Whitehall-Robins

Risk of bias

Kiersch 1994

Participants 232 participants enrolled in 3 groups

Number randomised to intervention 91 withdrawals 4 (2 before and 2 after randomisation) male 72

female 17 mean age 231 age range 15-39

Number randomised to placebo 47 withdrawals 2 male 35 female 10 mean age 247 age range 15-39

Baseline pain intensity mean for intervention and placebo categorical 212 VAS 5835

PR at 4 hours and 6 hours categorical 0-4 (none - complete) VAS 0-100 mm (no pain - worst pain I can

imagine)

Adverse effects reported by total number of adverse events and by number of patients with adverse events

Notes Sponsored by

Syntex Research

Risk of bias

Kiersch 1994 (Continued)

Kubitzek 2003

Number randomised to intervention 78

Number randomised to placebo 84 malefemale 40 male over both groups

Number of third molars removed 1 or 2 for each patient

Baseline pain intensity moderate to severe 65-76 in both groups

Setting dental practice (Germany)

Formulation tablets

Anaesthesia LA

Outcomes PI not stated

PR given as TOTPAR at 6 hours

Adverse effects not stated

Notes Sponsored by

Novartis Consumer Health

Risk of bias

Lehnert 1990

Participants 150 participants randomised to 3 groups 50 to each

Number randomised to intervention 1 withdrawal male 23 female 26 mean age 253 age range 17-52

Number randomised to placebo 2 withdrawals male 24 female 18 mean age 251 age range 18-53

Number of hird molars removed not stated

Setting outpatients (Germany)

Lehnert 1990 (Continued)

Outcomes PI at 6 hours categorical scale 0-3 (no pain - severe)

Adverse effects by number of patients

Notes Sponsored by GH Besselar Associates

Risk of bias

Mehlisch 1995

Participants 240 participants randomised to 3 groups 1 withdrawal from the acetaminophen group

Number randomised to intervention (1 withdrawal) male 30 female 71 mean age 253 age range 15-

Number of third molars removedpatient (10 295 33 43)

Formulation 2 tablets

Adverse events reported by number of patients

Notes Sponsored by

Biomedical Research Group and Merck Research Laboratories

Risk of bias

Moller 2000

Number randomised to Intervention A male 27 female 33 mean age 245

Number randomised to Intervention B male 26 female 34 mean age 262

Number randomised to Placebo A male 21 female 41 mean age 250

Number randomised to Placebo B male 24 female 36 mean age 246

Number of third molars removed per patient in both groups 1

Mean baseline intensity Intervention A categorical 200 (moderate 60) VAS 494

Mean baseline intensity Intervention B categorical 200 (moderate 60) VAS 473

Mean baseline intensity Placebo A categorical 200 (moderate 61 severe 1) VAS 505

Mean baseline intensity Placebo B categorical 200 (moderate 61) VAS 476

Setting Department of Oral and Maxillofacial Surgery Royal Dental College Aarhus (Denmark)

Interventions Intervention A Paracetamol 1000 mg versus Placebo A

Formulation effervescent tablets

Intervention B Paracetamol 1000 mg versus Placebo B

Formulation tablets

Outcomes PI at 4 hours categorical scale 0-3 (none - severe) VAS scale 0-100 mm (no pain - worst possible pain)

PR at 4 hours categorical 0-4 (none - complete)

Notes Sponsored by

Bristol Myers Squibb

Risk of bias

Olson 2001

Number of third molars removedpatient intervention - (11) (264) (31) (40) placebo - (11) (2

38) (30) (40)

4 severe 35)

Setting University of Puerto Rico School of Dentistry (Puerto Rico)

Olson 2001 (Continued)

Formulation caplets

Anaesthesia LA

PR at 4 hours and 6 hours categorical scale 0-4 (none - complete relief )

Notes Sponsored by

Whitehall Robins

Risk of bias

Seymour 1996

Number randomised to intervention A 1 withdrawal male 12 female 28 mean age 238

Number randomised to intervention B 1 withdrawal male 12 female 28 mean age 277 1 withdrawal

Number randomised to placebo 2 withdrawals male 15 female 24 mean age 246

Number of third molars removedpatient not stated

Baseline pain intensity mean for intervention A VAS 549 mean for intervention B VAS 542 mean

for placebo VAS 565

Setting not stated (UK)

Interventions Intervention A paracetamol 500 mg versus placebo

Intervention B paracetamol 1000 mg versus placebo

Anaesthesia GA

Outcomes PI at 6 hours VAS scale 0-100 mm (no pain - unbearable pain)

Global assessment categorical 0 -3 (very good - very poor)

but categories 1 amp 2 and 4 amp 5 not reported separately so unable to include data in tables

Adverse effects - none reported by any participants in any group

Risk of bias

Seymour 1996 (Continued)

Seymour 2003

Participants 167 randomised to 3 groups withdrawals unclear (14 from all groups)

Number of third molars removedpatient intervention - (12) (214) (312) (434) placebo - (13)

(25) (39) (415)

Setting not clear (2 sites Cardiff and Hexham UK)

Formulation tablets

Anaesthesia GA

Outcomes PI at 4 hours VAS scale 0-100 mm (none - worst pain imaginable)

PR not stated

Global assessment categorical scale 1-5 (very poor - very good)

Notes Sponsored by

Reckitt Benckiser Healthcare

Risk of bias

Skoglund 1991

Baseline pain intensity mean for intervention approx 55 mean for placebo approx 45

Setting not stated (Norway)

Formulation tablets

Anaesthesia LA

Skoglund 1991 (Continued)

Outcomes PI at 4 hours and 6 hours VAS scale 0-100 mm (none - pain cannot be worse)

PR at 4 hours and 6 hours VAS scale 0-100 mm (complete relief - no relief ) reversed for statistical analysis

Notes Sponsored by

Apothekernes Laboratorium

Risk of bias

Sunshine 1986

Participants 182 participants randomised to 6 groups no withdrawals (only patients with moderate to severe pain

were randomised)

Setting University of Puerto Rico School of Dentistry Clinic

Anaesthesia LA

PR at 4 hours and 6 hours categorical scale 0-4 (none 0 - complete 100)

Overall improvement 1-7 (very much worse - very much better)

Notes Sponsored by

Upjohn

Risk of bias

Vattaraphudej 1986

Participants 83 enrolled to 4 groups withdrawals unclear (16 from all groups)

Number randomised to intervention male 8 female 8

Number randomised to placebo male 10 female 9

Setting Dept of Oral Surgery Khon Kaen University Thailand

PR at 4 hours categorical scale 0-4 (no relief - total relief )

Adverse effects none reported

Notes Sponsored by Khon Kaen University Thailand Dr Sompong Thongpradith Merck and Russel

Risk of bias

GA - general anaesthetic LA - local anaesthetic PI - pain intensity PR - pain relief SED - sedation TOTPAR - total pain relief VAS

- visual analogue scale

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Adame 1979 Title not in journal quoted unable to find paper

Barden J 2004 Meta-analysis dental papers included individually where appropriate

Becker 1990 Not a third molar study

Bentley 1987 Unable to extract data for third molars only written to authors

Breivik 1998 Dose given at 3 hours postoperatively regardless of baseline pain unable to get 4-hour data Study used for side

effects only

(Continued)

Cooper 1986 Unable to extract third molar data written to authors

Cooper 1991 Unclear if third molars only written to authors

Dionne 1983 (1) Not single dose administered preoperatively

Dionne 1983 (2) Not placebo controlled not single dose administered preoperatively

Dionne 1986 Not placebo controlled

Dolci 1993 The data for the participants in this study are duplicated in Dolci 1994

Edwards 2002 This was a meta-analysis Need to identify source of data to clarify whether third molar studies and exclude

duplication Written to authors

Forbes 1982 Unable to extract third molar data written to authors

Forbes 1984a Not third molar study

Gallardo 1990 Not third molar study (periodontal surgery)

Gustafsson 1983 Patients given either paracetamol preoperatively and placebo postoperatively or vice versa unable to extract

relevant data

Haanaes 1986 Not placebo controlled Study used for side effects only

Irvine 1982 Not placebo controlled

Laska 1983 Not placebo controlled

Lecointre 1991 Not placebo controlled

Liashek 1987 Multiple doses unable to extract single dose data

Macleod 2002 Not placebo controlled

Medve 2001 Only 8-hour SPID and TOTPAR available need 4-hour andor 6-hour to include in review written to authors

Mehlisch 1984 Unable to extract third molar data written to authors

Mehlisch 1990 Unable to extract third molar data

Moore 1986 Multiple doses given unable to extract single dose data

Nystrom 1988 Not placebo controlled

(Continued)

Petersen 1983 Unable to locate complete article

Quiding 1981 Not placebo controlled

Quiding 1982 (1) Not placebo controlled

Quiding 1984 No placebo used

Ragot 1991 Not placebo controlled

Reijntjes 1987 Not placebo controlled

Rodrigo 1987 Mixed parallel and cross-over trial multiple doses unable to extract relevant data

Rodrigo 1989 Not placebo controlled

Rosen 1985 Not placebo controlled multiple doses used unable to extract single dose data

Sakata 1989 Unable to obtain study

Selcuk 1996 Not placebo controlled

Seymour 1981 Cross-over trial baseline pain not stated unable to extract relevant data

Seymour 1983 Acetaminophen administered intravenously

Skjelbred 1979 Multiple doses unable to extract single dose data

Strom 1990 Not placebo controlled

Van Aken 2004 Propacetamol administered intravenously

Winter 1983 Unable to extract third molar data written to authors

SPID - summed pain intensity difference TOTPAR - total pain relief

D A T A A N D A N A L Y S E S

Comparison 1 50 pain relief using pain relief measures

Outcome or subgroup titleNo of

studies

participants Statistical method Effect size

1 Paracetamol versus placebo

number of people with at least

50 pain relief at 4 hours

16 1498 Risk Ratio (M-H Random 95 CI) 285 [189 429]

11 Up to 1000 mg of

paracetamol

12 1000 mg or more 6 788 Risk Ratio (M-H Random 95 CI) 456 [286 727]

21 Up to 1000 mg of

paracetamol

Comparison 2 50 pain relief using pain intensity measures

studies

11 Up to 1000 mg of

paracetamol

21 Up to 1000 mg of

paracetamol

Comparison 3 Number of people with adverse events

studies

1 Number of patients with adverse

events paracetamol versus

placebo

11 Up to 1000 mg of

paracetamol

Analysis 11 Comparison 1 50 pain relief using pain relief measures Outcome 1 Paracetamol versus

placebo number of people with at least 50 pain relief at 4 hours

Review Paracetamol for pain relief after surgical removal of lower wisdom teeth

Outcome 1 Paracetamol versus placebo number of people with at least 50 pain relief at 4 hours

Study or subgroup Paracetamol better Placebo better Risk Ratio Weight Risk Ratio

nN nN M-HRandom95 CI M-HRandom95 CI

1 Up to 1000 mg of paracetamol

Dolci 1994 5472 2576 100 228 [ 161 323 ]

Cooper 1980 1137 1138 82 103 [ 051 207 ]

Forbes 1990 936 134 30 850 [ 114 6357 ]

Forbes 1989 522 023 17 1148 [ 067 19607 ]

Cooper 1988 1636 1240 87 148 [ 081 269 ]

Cooper 1981 2137 637 77 350 [ 160 767 ]

Forbes 1984b 1339 136 30 1200 [ 165 8716 ]

Vattaraphudej 1986 716 219 47 416 [ 100 1726 ]

Sunshine 1986 1830 1530 95 120 [ 076 190 ]

Dionne 1994 2527 1725 102 136 [ 102 182 ]

Subtotal (95 CI) 352 358 667 196 [ 134 286 ]

Total events 179 (Paracetamol better) 90 (Placebo better)

Heterogeneity Tau2 = 018 Chi2 = 2644 df = 9 (P = 0002) I2 =66

Test for overall effect Z = 349 (P = 000048)

2 1000 mg or more

01 02 05 1 2 5 10

Favours placebo Favours paracetamol

(Continued )

( Continued)Study or subgroup Paracetamol better Placebo better Risk Ratio Weight Risk Ratio

Mehlisch 1995 40101 240 49 792 [ 201 3124 ]

Cooper 1998 1850 326 59 312 [ 101 963 ]

Olson 2001 4266 539 74 496 [ 215 1148 ]

Moller 2000 27120 0122 18 5591 [ 345 90627 ]

Hersh 2000 4063 527 75 343 [ 152 773 ]

Kiersch 1994 2589 345 58 421 [ 134 1321 ]

Subtotal (95 CI) 489 299 333 456 [ 286 727 ]

Test for overall effect Z = 637 (P lt 000001)

Total (95 CI) 841 657 1000 285 [ 189 429 ]

Heterogeneity Tau2 = 040 Chi2 = 6294 df = 15 (Plt000001) I2 =76

01 02 05 1 2 5 10

Forbes 1989 322 023 29 730 [ 040 13375 ]

Cooper 1988 1236 940 99 148 [ 071 310 ]

Forbes 1990 736 034 30 1419 [ 084 23928 ]

Dionne 1994 2427 1825 115 123 [ 093 163 ]

Forbes 1984b 1039 036 31 1943 [ 118 31995 ]

Sunshine 1986 1530 1030 104 150 [ 081 279 ]

Subtotal (95 CI) 190 188 407 189 [ 098 367 ]

2 1000 mg or more

Kubitzek 2003 4569 773 99 680 [ 329 1404 ]

Mehlisch 1995 35101 140 49 1386 [ 196 9779 ]

Kiersch 1994 2089 345 79 337 [ 106 1075 ]

Olson 2001 4166 539 94 485 [ 209 1122 ]

Hersh 2000 3563 527 95 300 [ 132 682 ]

Lehnert 1990 2349 640 96 313 [ 141 693 ]

Cooper 1998 1750 326 81 295 [ 095 914 ]

Subtotal (95 CI) 487 290 593 421 [ 297 598 ]

Total (95 CI) 677 478 1000 332 [ 188 587 ]

01 02 05 1 2 5 10

Analysis 21 Comparison 2 50 pain relief using pain intensity measures Outcome 1 Paracetamol versus

Dolci 1994 4972 576 86 1034 [ 437 2449 ]

Seymour 1996 1940 1039 96 185 [ 099 346 ]

Cooper 1980 737 438 74 180 [ 057 563 ]

Forbes 1990 1036 034 28 1986 [ 121 32639 ]

Forbes 1989 622 023 28 1357 [ 081 22736 ]

Cooper 1988 1236 840 90 167 [ 077 361 ]

Sunshine 1986 1830 630 90 300 [ 138 650 ]

Forbes 1984b 1339 036 28 2498 [ 154 40542 ]

Vattaraphudej 1986 616 119 44 713 [ 095 5317 ]

Cooper 1981 1537 037 28 3100 [ 192 49971 ]

Subtotal (95 CI) 365 372 592 433 [ 219 858 ]

2 1000 mg or more

Cooper 1998 1350 026 28 1429 [ 088 23130 ]

Mehlisch 1995 41101 340 75 541 [ 178 1648 ]

Hersh 2000 3663 127 46 1543 [ 223 10685 ]

Skoglund 1991 1632 033 28 3400 [ 213 54391 ]

Seymour 2003 1262 432 78 155 [ 054 442 ]

Seymour 1996 2040 1039 96 195 [ 105 362 ]

Kiersch 1994 989 045 28 971 [ 058 16317 ]

Moller 2000 28120 0122 28 5794 [ 358 93840 ]

Subtotal (95 CI) 557 364 408 646 [ 234 1785 ]

01 02 05 1 2 5 10

(Continued )

Total (95 CI) 922 736 1000 487 [ 283 837 ]

01 02 05 1 2 5 10

Seymour 1996 1840 939 152 195 [ 100 380 ]

Forbes 1989 422 023 16 939 [ 054 16485 ]

Cooper 1988 936 640 105 167 [ 066 422 ]

Forbes 1990 836 032 17 1516 [ 091 25267 ]

Forbes 1984b 1139 036 17 2128 [ 130 34843 ]

Sunshine 1986 1430 530 111 280 [ 115 680 ]

Subtotal (95 CI) 203 200 418 267 [ 146 490 ]

2 1000 mg or more

Hersh 2000 3163 127 33 1329 [ 191 9242 ]

Mehlisch 1995 39101 340 82 515 [ 169 1571 ]

Olson 2001 4266 739 146 355 [ 177 711 ]

01 02 05 1 2 5 10

(Continued )

Seymour 1996 2140 939 157 228 [ 119 433 ]

Cooper 1998 1250 026 17 1324 [ 081 21504 ]

Kiersch 1994 489 045 16 460 [ 025 8361 ]

Lehnert 1990 2449 542 114 411 [ 172 983 ]

Skoglund 1991 1432 033 17 2988 [ 186 48076 ]

Subtotal (95 CI) 490 291 582 396 [ 252 623 ]

Total (95 CI) 693 491 1000 341 [ 234 497 ]

01 02 05 1 2 5 10

Analysis 31 Comparison 3 Number of people with adverse events Outcome 1 Number of patients with

adverse events paracetamol versus placebo

Outcome 1 Number of patients with adverse events paracetamol versus placebo

Study or subgroup Paracetamol more Placebo more Risk Ratio Risk Ratio

Cooper 1980 237 637 033 [ 007 155 ]

Dolci 1994 780 882 090 [ 034 236 ]

Forbes 1990 541 038 1021 [ 058 17873 ]

Forbes 1989 326 226 150 [ 027 825 ]

Sunshine 1986 130 130 100 [ 007 1526 ]

Cooper 1981 1237 438 308 [ 109 869 ]

Dionne 1994 727 525 130 [ 047 356 ]

Vattaraphudej 1986 016 019 00 [ 00 00 ]

Forbes 1984b 143 240 047 [ 004 493 ]

Subtotal (95 CI) 337 335 125 [ 069 225 ]

Total events 38 (Paracetamol more) 28 (Placebo more)

2 1000 mg or more

Olson 2001 1066 239 295 [ 068 1279 ]

Cooper 1998 2550 426 325 [ 127 835 ]

Moller 2000 48120 56122 087 [ 065 117 ]

Seymour 2003 2462 932 138 [ 073 260 ]

Mehlisch 1995 1299 440 121 [ 042 354 ]

Kiersch 1994 2691 1347 103 [ 059 182 ]

Hersh 2000 1263 727 073 [ 032 166 ]

Lehnert 1990 549 440 102 [ 029 355 ]

Subtotal (95 CI) 600 373 116 [ 084 160 ]

Total (95 CI) 937 708 119 [ 090 157 ]

01 02 05 1 2 5 10

Favours treatment Favours control

(Continued )

( Continued)Study or subgroup Paracetamol more Placebo more Risk Ratio Risk Ratio

01 02 05 1 2 5 10

A D D I T I O N A L T A B L E S

Table 1 Number of patients with adverse events (lt 1000 mg ParacetamolPlacebo)

Author Total Paracetamol AEs Paracetamol Total Placebo AEs Placebo

Cooper 1980 37 2 37 6

Cooper 1981 37 12 38 4

Dionne 1994 27 7 25 5

Dolci 1994 80 7 82 8

Forbes 1984b 43 1 40 2

Forbes 1989 26 3 26 2

Forbes 1990 41 5 38 0

Gallardo 1990 15 5 11 3

Seymour 1996 40 0 39 0

Sunshine 1986 30 1 30 1

Vattaraphudej 1986 16 0 19 0

Totals 392 43 385 31

Table 2 Quality assessment

Author Allocation concealment Follow up Total (Max-3)

Cooper 1980 1 0 1

Cooper 1981 1 0 1

Cooper 1988 1 0 1

Cooper 1998 1 1 2

Dionne 1994 1 0 1

Dolci 1994 1 0 1

Forbes 1984b 2 0 2

Forbes 1989 1 0 1

Forbes 1990 2 0 2

Hersh 2000 1 1 2

Kiersch 1994 1 1 2

Kubitzek 2003 1 1 2

Lehnert 1990 1 1 2

Mehlisch 1995 2 1 3

Moller 2000 1 1 2

Olson 2001 2 1 3

Seymour 1996 1 1 2

Seymour 2003 2 0 2

Skoglund 1991 2 0 2

Sunshine 1986 2 1 3

Vattaraphudej 1986 1 1 2

Table 3 Random-effects metaregression lt 1000 mg vs 1000 mg Paracetamol vs Placebo

Outcome Number of studies Slope estimate 95 CI Slope interpretation P value

50 pain relief at 4

hours (using pain re-

lief )

16 094 (036 to 152) more pain relief for

higher doses

50 pain relife at 6

lief )

higher doses

lt0001

50 pain relief at

4 hours (using pain

intensity)

16 023 (-084 to 130) more pain relief for

higher doses

50 pain relief at

6 hours (using pain

intensity)

higher doses

Table 4 List of adverse events

Adverse events Paracetamol Placebo

Nausea 21 11

Vomiting 11 3

Nausea andor vomiting stomach cramps

abdominal pain

Headache 47 31

Drowsiness sleepiness somnolence 36 13

Dizziness fainting syncope 9 4

Bleeding 11 7

Chills flushes fever flu-like symptoms 5 0

Paraesthesia 4 2

Jawache 1 0

Swelling 1 6

Cellulitis 1 0

Table 4 List of adverse events (Continued)

Dry socket 11 12

Surgical complications 6 13

CNS 5 6

GI 12 2

Body as a whole 8 3

Respiratory 2 0

Psychiatric 0 1

Other hiccups hearingvestibular miosis 5 1

Table 5 Global assessment - 5-point scale(lt 1000 mg Paracetamol)

Author Total Paracetamol Global assessment Total Placebo Global assessment

Cooper 1980 37 089 38 089

Cooper 1981 37 192 37 062

Cooper 1988 36 238 40 205

Dionne 1994 27 240 25 200

Dolci 1994 72 210 76 217

Forbes 1984 39 126 36 028

Mean 248 183 252 144

Table 6 Global assessment - 4-point scale (lt 1000 mg Paracetamol)

Forbes 1989 26 100 26 030

Forbes 1990 41 147 38 056

Sunshine 1986 30 120 30 093

Table 6 Global assessment - 4-point scale (lt 1000 mg Paracetamol) (Continued)

Mean 113 131 113 070

Table 7 Global assessment - 5-point scale (1000 mg Paracetamol)

Kiersch 1994 91 130 47 060

Kubitzek 2003 78 198 84 145

Mehlisch 1995 101 157 40 045

Olson 2001 66 281 39 193

Seymour 2003 62 250 32 214

Mean 398 194 242 129

Hersh 2000 63 229 27 085

Moller 2000 120 188 122 154

Mean 183 202 149 141

A P P E N D I C E S

Appendix 1 CENTRAL search strategy

1 MOLAR THIRD single term (MeSH)

2 (wisdom next tooth)

3 (wisdom next teeth)

4 (third near molar)

5 (1 or 2 or 3 or 4)

6 TOOTH EXTRACTION single term (MeSH)

7 (extract near tooth)

8 (extract near teeth)

9 (extract near (third next molar))

10 (extract near (third near molar))

11 (remov near tooth)

12 (remov near teeth)

13 (surgical near remov)

14 (surgery near remov)

15 (surgical near extract)

16 (surgery near extract)

17 (6 or 7 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16)

18 (5 and 17)

W H A T rsquo S N E W

Last assessed as up-to-date 21 May 2007

Date Event Description

31 July 2008 Amended Converted to new review format

H I S T O R Y

Protocol first published Issue 4 2003

Review first published Issue 3 2007

C O N T R I B U T I O N S O F A U T H O R S

Conceiving designing and co-ordinating the review (Kiaran Weil (KW) Paul Coulthard (PC))

Developing search strategy and undertaking searches (Zahid Afzal (ZA) Arjen van Wijk (AJW) KW)

Screening search results and retrieved papers against inclusion criteria (ZA KW) Marco Esposito (ME) Lee Hooper (LH) PC)

Appraising quality (KW ZA)

Extracting data from papers (KW LH Helen Worthington (HW))

Writing to authors for additional information (KW)

Data management for the review and entering data into RevMan (KW)

Analysis and interpretation of data (KW LH HW)

Writing the review (KW)

Providing general advice on the review (ME LH PC HW)

Performing previous work that was the foundation of current study (PC)

D E C L A R A T I O N S O F I N T E R E S T

None known

S O U R C E S O F S U P P O R T

Internal sources

bull The University of Manchester UK

bull The University of Amsterdam Netherlands

External sources

bull No sources of support supplied

I N D E X T E R M S

Medical Subject Headings (MeSH)

Acetaminophen [adverse effects lowasttherapeutic use] Analgesics Non-Narcotic [adverse effects lowasttherapeutic use] Molar Third [lowastsurgery]

Outcome Assessment (Health Care) Pain Postoperative [lowastdrug therapy] Pain Measurement Randomized Controlled Trials as Topic

Tooth Extraction [lowastadverse effects]

MeSH check words

Humans

BRITISH DENTAL JOURNAL VOLUME 197 NO 7 OCTOBER 9 2004 407

Relative efficacy of oral analgesics after thirdmolar extractionJ Barden1 J E Edwards2 H J McQuay3 P J Wiffen4 and R A Moore5

Objectives To compare the relative efficacy of analgesics after thirdmolar extraction from systematic reviews of randomised double blindstudiesData sources Dental trials from systematic reviews of randomiseddouble-blind studies of analgesics in acute painData selection Number of patients with moderate or severe painachieving at least half pain relief over 4 to 6 hours after a single oraldose of analgesicData extraction Independently by two reviewersData synthesis Use of dichotomous information from active andplacebo treatments first to calculate the statistical significance usingrelative risk and then to evaluate the clinical relevance using numberneeded to treat (NNT) Non-steroidal anti-inflammatory drugs (NSAIDs)and cyclo-oxygenase-2 (COX-2) inhibitors had the lowest (best) NNTsfor the outcome of at least half pain relief over 4-6 hours comparedwith placebo With the best performing analgesics 50-70 patients out of100 had good pain relief compared with about 10 out of 100 withplacebo Only paracetamol 600650 mg plus codeine 60 mg wasassociated with any significant increase in any patient experiencing anadverse eventConclusions NSAIDs and COX-2 inhibitors have the lowest (best) NNTsThey may also have fewer adverse effects after third molar surgerythough conclusive evidence is lacking At least 80 of analgesicprescribing by UK dentists is in line with the best available evidence onefficacy and safety

Acute pain has been studied in single dose designs first pro-posed by Beecher and colleagues12 and formalised by Houdeand Wallenstein3 The problem with single trials is that whilethey can demonstrate statistical superiority of analgesic overplacebo variation because of random chance means that if

1Research Associate 2Senior Research Associate 3Professor of Pain Relief 4PrescribingAdvisor 5Research Director Pain Research and Nuffield Department of AnaestheticsUniversity of Oxford Oxford Radcliffe Hospital The Churchill Headington Oxford OX3 7LJ UKCorrespondence to Dr R A MooreE-mail andrewmoorepruoxacuk

Refereed paperReceived 150403 Accepted 121103doi101038sjbdj4811721copy British Dental Journal 2004 197 407ndash411

small they provide a poor estimate of the size of the analgesiceffect4 Combining results from clinically homogeneous trials ina meta-analysis gives an accurate estimate of the extent of theanalgesic effect when sufficient numbers of patients have beenrandomised45

Clinical trials in acute pain normally last 4 to 6 hours becausethat is the duration of effect of most analgesics whether injectedor as tablets and whether simple analgesics NSAIDs or opioidsMeta-analysis in acute pain has concentrated on the use of thearea under the total pain relief versus time curve (TOTPAR)dichotomized into those patients who do or do not achieve atleast half pain relief (at least 50 maximum TOTPAR)6 Thismeasure is the one most frequently reported and it avoids theproblem of reporting continuous pain data as the mean of ahighly skewed distribution7 It has the benefit of being intuitivelymeaningful to patients and professionals as well as being meas-urable

Meta-analyses in acute pain usually combine studies from avariety of pain models and relative efficacy of analgesics inthese studies has been examined6 A majority of studies were inthird molar extraction but any postoperative pain condition islikely to be included In the largest dataset that of aspirin8

pain model (dental or other surgery) made no difference to theNNT

Dentists ask rightly about relative efficacy in dental painThe number of prescription items issued by dentists in Englandwas remarkably consistent between 1998 and 2001 (Table 1)with ibuprofen dihydrocodeine and paracetamol being mostfrequently prescribed This review set out to examine single-dose oral analgesics after third molar extraction from a numberof updated systematic reviews both for the analgesics common-ly prescribed in England and for those for which comparableevidence exists including the newer cyclo-oxygenase-2 selec-tive inhibitors like rofecoxib celecoxib and valdecoxib

METHODSIn all the systematic reviews QUORUM guidelines were fol-lowed9 In the reviews studies for inclusion were soughtthrough searching the Cochrane Library Biological AbstractsMEDLINE PubMed and the Oxford Pain Relief database10 Ref-erence lists and review articles were examined for possible addi-tional references Most had search dates in 2002

This paper reviews the available high quality information on analgesics commonlyprescribed by dentists including COX-2 selective inhibitors

Problems related to chance effects are avoided by combining multiple trials in a meta-analysis

There is good evidence of efficacy for most commonly-prescribed analgesics Standard doses of NSAIDs and COX-2 inhibitors provide the best analgesia and lowest

rate of adverse events

I N B R I E F

RESEARCH

07p407-411qxd 10092004 1518 Page 407

RESEARCH

408 BRITISH DENTAL JOURNAL VOLUME 197 NO 7 OCTOBER 9 2004

References for the reviews are as followsAspirin Edwards et al 19998 additional searching in

2002 found no new studiesCelecoxib An unpublished review being submitted as a

Cochrane ReviewDiclofenac An updated version of a Cochrane review11

Dihydrocodeine A Cochrane review12

Ibuprofen An updated version of a Cochrane review11

Paracetamol An updated version of a Cochrane review13

plus codeineRofecoxib An updated version of a systematic review14

Valdecoxib A systematic review in preparation

Criteria for inclusion for postoperative dental pain werestudy in third molar extraction full journal publication (exceptvaldecoxib which included information from a poster) ran-domised controlled trials which included single dose treatmentgroups of oral analgesic and placebo double blind designbaseline postoperative pain of moderate to severe intensitypatients over 15 years of age at least 10 patients per group andthe pain outcome measures of total pain relief (TOTPAR) orsummed pain intensity difference (SPID) over 4-6 hours or suf-ficient data to allow their calculation Pain measures allowedfor the calculation of TOTPAR or SPID were a standard fivepoint pain relief scale (none slight moderate good complete)a standard four point pain intensity scale (none mild moder-ate severe) or a standard visual analogue scale (VAS) for pain

relief or pain intensity For adverse events the primary out-come sought was the proportion of patients experiencing anyadverse event with secondary outcomes of patients experienc-ing particular adverse events Although adverse events areoften reported inconsistently in acute pain trials15 the outcomeof any patient experiencing any adverse event was the mostconsistently reported

Each report which could possibly be described as a randomisedcontrolled trial was read independently by several authors andscored using a commonly-used three item 1-5 score qualityscale16 Consensus was then achieved The maximum score of anincluded study was 5 and the minimum score was 2 Authors werenot blinded because they already knew the literature This scoringsystem takes account of randomisation blinding and withdrawalsand drop outs Trials that score 3 or more (less biased) have beenshown repeatedly to have lower treatment effects than those scor-ing 2 or less1718

For each trial mean TOTPAR SPID VAS-TOTPAR or VAS-SPIDvalues for each treatment group were converted to maxTOTPARby division into the calculated maximum value19 The proportionof patients in each treatment group who achieved at least 50maxTOTPAR was calculated using valid equations20-22 The num-ber of patients randomised was taken as the basis for calculationsto produce an intention to treat analysis The number of patientswith at least 50 maxTOTPAR was then used to calculate relativebenefit and NNT for analgesic versus placebo The same methodswere used for adverse events where the number needed to harm(NNH) was calculated

Table 1 Numbers of prescription items issued by dentists and dispensed in EnglandAnalgesic 1998 1999 2000 2001

Ibuprofen 400 mg 107200 110400 109000 103900

Dihydrocodeine 30 mg 53700 50300 49100 46700

Ibuprofen 600 mg 34200 39700 40800 42600

Ibuprofen 200 mg 36300 34600 32000 30600

Paracetamol 500 mg 11100 12800 15400 17200

Paracetamol 500 mg soluble 800 1000 900 900

Pethidine 50 mg 1100 900 700 700

Aspirin 300 mg 200 200 200 200

Source DOH statistics division 2002 calendar year January to December

Dihydrocodeine 30 mgParacetamol 300 mg + codeine 30 mg

Paracetamol 600650 mgAspirin 600650 mg

Paracetamol 9751000 mgCelecoxib 200 mg

Paracetamol 600650 mg + codeine 60 mgIbuprofen 200 mgDiclofenac 50 mgRofecoxib 50 mgIbuprofen 400 mgValdecoxib 20 mgDiclofenac 100 mgValdecoxib 40 mgIbuprofen 600 mg

0 10 20 30 40 50 60 70 80 90 10095 confidence interval of the percent ofpatients achieving at least 50 pain relief

Fig 1 The 95confidence interval ofthe proportion ofpatients with at leasthalf pain relief over 4-6hours compared withplacebo in third molarextraction trials

07p407-411qxd 10092004 1519 Page 408

RESEARCH

of patients had at least half pain relief with active treatment in onesmall trial in dental pain (Table 2)

The adverse event outcome of a patient experiencing anyadverse event is shown in Table 3 from 10113 patients in 107 tri-als Of the 15 drug and dose combinations only paracetamol600650 mg plus codeine 60 mg could be statistically distin-guished from placebo in 10 trials and 824 patients The NNH was53 (41 to 74) indicating that five patients had to be treated withparacetamol 600650 mg plus codeine 60 mg for one of them tohave an adverse event that would not have occurred with placeboFor all other drugs and doses there was no difference betweenanalgesic and placebo

DISCUSSIONSystematic review and meta-analysis both depend on two interde-pendent criteria for them to make sense the quality of the compo-nent individual studies and the total size of the sample availablefor analysis

We know that if trials are of poor reporting quality1718 or notrandomised30 or not blind or both31 then the tendency is to over-estimate the benefits of treatment The reviews included here alldemanded that trials should be both randomised and double-blindas a minimum requirement for inclusion

We also know that even if trials are done well small samplesize can lead to an incorrect answer just because of the randomplay of chance4 For these studies we also know just how muchinformation is needed to be 95 confident of an NNT to withplusmn05 units4 With an NNT of 23 it is 400 patients in the compari-son with an NNT of 29 it is 1000 patients and with an NNT of42 it is many more than with 1000 At NNTs of 4 or more evenwith 1000 patients fewer than 75 of trials will be within plusmn05of the overall NNT

The analgesics for which these two criteria were metunequivocally were valdecoxib (combining 20 mg and 40 mg)rofecoxib 50 mg ibuprofen 400 mg diclofenac 50 mg and prob-ably ibuprofen 200 mg For paracetamol the numbers were bor-derline and for diclofenac 100 mg too small to make any safejudgement There is good evidence of good efficacy for the anal-gesics most commonly prescribed by dentists with the excep-tion of dihydrocodeine where there was little evidence in totaland no convincing evidence of efficacy

Relative benefit and relative risk estimates were calculated with95 confidence intervals using a fixed effects model23 Hetero-geneity tests were not used as they have previously been shown tobe unhelpful2425 though homogeneity was examined visually26

Publication bias was not assessed using funnel plots as these testshave been shown to be unhelpful2728 The number needed to treator harm (NNT and NNH) with confidence intervals was calculatedby the method of Cook and Sackett29 from the sum of all eventsand patients for treatment and placebo

Relative benefit or risk was considered to be statistically signifi-cant when the 95 confidence interval did not include 1 NNT val-ues were only calculated when the relative risk or benefit was sta-tistically significant and are reported with the 95 confidenceinterval Calculations were performed using Microsoft Excel 2001on a Power Macintosh G4

RESULTSTable 2 shows the main results from 14150 patients in 155 trials of15 drug and dose combinations against placebo in third molarextractions Of those 15 drug and dose combinations only dihy-drocodeine 30 mg could not be statistically distinguished fromplacebo because there were no trials with any useful informationin third molar extraction Figure 1 shows the proportion ofpatients achieving at least 50 pain relief with treatment Thesmallest sample for any comparison was 136 patients for celecoxib200 mg Only five of the 14 comparisons had more than 1000patients and seven had fewer than 500 patients In all systematicreviews the majority of trials had quality scores of 3 or more

The lowest (best) NNTs were for NSAIDs and COX-2 inhibitorsat standard or high doses For these NNTs could be as low as about2 (meaning that two patients had to be treated with NSAID orCOXIB for one of them to have an outcome of at least half painrelief that would not have occurred with placebo) Valdecoxib 20mg and 40 mg rofecoxib 50 mg ibuprofen 400 mg and diclofenac50 mg and 100 mg all had NNTs below 24 For all of them about60-70 of patients had at least half pain relief with active treat-ment compared with about 10 with placebo

Paracetamol 9751000 mg aspirin 600650 mg and paraceta-mol 600650 mg had NNTs of between 4 and 5 Fewer than 40 ofpatients with paracetamol at these doses had at least half painrelief with active treatment With dihydrocodeine 30 mg only 16

Table 2 Efficacy of analgesics after third molar extraction from systematic reviews of randomised double blind trials

Number () of patientswith at least 50 pain relief

Drug and dose Treatment Placebo Relative benefit Number needed to treat Total patients Total trials(95 CI) (95 CI)

Valdecoxib 40 mg 204279 (73) 19194 (10) 73 (48 to 112) 16 (14 to 17) 473 4

Diclofenac 100 mg 71102 (70) 8102 (8) 89 (45 to 175) 16 (14 to 19) 204 2

Rofecoxib 50 mg 318557 (57) 23262 (9) 66 (44 to 99) 21 (19 to 23) 819 6

Ibuprofen 400 mg 10351835 (56) 1861567 (12) 47 (40 to 54) 22 (21 to 24) 3402 37

Celecoxib 200 mg 3991 (43) 445 (9) 48 (18 to 127) 29 (21 to 48) 136 1

Paracetamol 9751000 mg 226616 (37) 40422 (9) 38 (28 to 52) 37 (31 to 47) 1038 10

Paracetamol 600650 mg + codeine 60 mg 217532 (48) 64380 (19) 25 (19 to 31) 42 (34 to 55) 911 12

Aspirin 600650 mg 6271788 (36) 2551847 (15) 25 (22 to 29) 47 (42 to 54) 3635 46

Dihydrocodeine 30 mg 849 (16) 250 (4) 41 (09 to 18) not calc 99 1

Shaded areas are those analgesics used by dentists in the UK

07p407-411qxd 10092004 1519 Page 409

RESEARCH

With the information available standard doses of NSAIDs andCOX-2 inhibitors provided the best analgesia (Fig 2) NNTs of 2and below are indicative of very effective medicines32 The indirectcomparisons that allow us to arrive at this conclusion are only sus-tainable because the trials have the same design use patients withthe same entry criterion (moderate or severe pain intensity) withstandard measurements made in the same way over the same peri-od of time and with the same output from each trial and oneknown to be legitimate The validity of the indirect comparisonsare buttressed by the dose response of two doses of ibuprofen (400mg was better than 200 mg) and two doses of paracetamol(9751000 mg was better than 600650 mg) where there were cred-ible amounts of information A systematic review of ibuprofenversus paracetamol in dental studies also concluded that ibuprofenwas superior concordant with the indirect comparison33

The adverse event information we have tells us only aboutpatients experiencing any adverse event With the amount ofinformation available it appears that only higher doses ofcodeine with paracetamol resulted in a significantly higher ratefor this outcome than placebo In Table 3 the rate at which thisadverse event occurred with placebo varied greatly between 2

and 52 This variation will be due partly to small sizes4 butalso because we know that methods of collecting adverse eventdata impact significantly on the reported incidence and becausemethods used varied15

Information about specific adverse events is even more difficultto obtain and very large data sets are required to produce infor-mation about for instance gastric irritation with aspirin use8 Ofinterest to dentists might be the rate of alveolitis or dry socket Thisis reported in some of the newer COXIB studies but not in olderstudies There is just too little information to make a judgement

What these comparisons do not do is to tell dentists what toprescribe They and the products of other systematic reviewsshould not be used as rules but rather as evidence-based toolsto help make better policy decisions and decisions about indi-vidual patients Present prescribing practice (Table 1) showsthat for the most part effective and safe analgesics are beingused in 80 of prescriptions The exception is prescribing dihy-drocodeine 30 mg (20 of prescriptions) for which we lack sin-gle dose evidence of efficacy in dental surgery and which couldnot be distinguished from placebo in other conditions againwith little data6

Paracetamol 300 + codeine 30 mgAspirin 600650 mg

Paracteamol 600650 mgParacetamol 600650 + codeine 60 mg

Paracetamol 9751000 mgCelecoxib 200 mgIbuprofen 200 mgDiclofenac 50 mgIbuprofen 400 mgRofecoxib 50 mg

Valdecoxib 20 mgValdecoxib 40 mgDiclofenac 100 mg

1 2 3 4 5 6 7 8 9 1095 confidence interval of the NNT

Fig 2 The 95confidence interval ofthe number needed totreat (NNT) for at leasthalf pain relief over 4-6hours compared withplacebo in third molarextraction trials

Table 3 Patients experiencing any adverse event with analgesics after third molar extraction from systematic reviews of randomised double blind trials

Number () of patientsharmed with

Drug and dose Treatment Placebo Relative risk Number needed to harm Total patients Total trials(95 CI) (95 CI)

Valdecoxib 40 mg 63180 (35) 76144 (53) 06 (05 to 08) not calc 324 3

Diclofenac 100 mg 252 (4) 252 (4) 10 (12 to 68) not calc 104 1

Rofecoxib 50 mg 105314 (33) 48122 (39) 09 (07 to 11) not calc 436 3

Ibuprofen 400 mg 120972 (13) 91805 (12) 11 (08 to 14) not calc 1777 19

Ibuprofen 600 mg no data

Celecoxib 200 mg no data

Paracetamol 9751000 mg 175836 (24) 103464 (20) 11 (09 to 13) not calc 1300 9

Aspirin 600650 mg 1551320 (12) 1681422 (12) 10 (08 to 12) not calc 3031 36

Paracetamol 300 mg + codeine 30 mg 29175 (15) 20124 (16) 09 (06 to 16) not calc 299 3

07p407-411qxd 10092004 1520 Page 410

RESEARCH

Not all the analgesics in this review are presently available forprescribing by dentists at least in the UK The information on effi-cacy on harm and on the amount of information available shouldbe useful in any initiative to develop a prescribing formulary indentistry especially as we have growing confidence in the value ofindirect comparisons34

COMPETING INTERESTSRAM has been a consultant for MSD RAM amp HJM have consulted for variouspharmaceutical companies RAM HJM amp JE have received lecture fees frompharmaceutical companies related to analgesics and other healthcareinterventions All authors have received research support from charitiesgovernment and industry sources at various times but no such support wasreceived for this work No author has any direct stock holding in anypharmaceutical company

AUTHORS CONTRIBUTIONSJB was involved with searching data extraction quality scoring analysis andwriting JE was involved with searching data extraction quality scoring andwriting HJM was involved in analysis and writing RAM was involved in dataextraction quality scoring analysis and writing PW was involved with theoriginal concept with researching prescribing data and writing

The work was supported by Pain Research Funds and the Oxford Pain Relief TrustThe authors would like to thank Frances Fairman of the Cochrane Pain Palliativeand Supportive Care systematic review group for bringing this issue to ourattention The Department of Health Statistics Division provided data onprescribing by dentists

1 Beecher H K Keats A S Mosteller F The effectiveness of oral analgesics (morphinecodeine acetylsalicylic acid) and the problem of placebo lsquoreactorsrsquo and lsquononreactorsrsquo J Pharmacol 1953 109 93-400

2 Beecher H K The measurement of pain Pharmacol Rev 1957 9 59-2103 Houde R W Wallenstein S L Beaver W T Clinical measurement of pain In G De

Stevens (ed) Analgetics pp75-122 New York and London Academic Press 1965 4 Moore R A Gavaghan D Tramegraver M R Collins S L McQuay H J Size is everything mdash

large amounts of information are needed to overcome random effects in estimatingdirection and magnitude of treatment effects Pain 98 78 209-216

5 Ioannidis J P A Lau J Evolution of treatment effects over time Empirical insight fromrecursive cumulative metaanalyses PNAS 2001 98 831-836

6 McQuay H J Moore R A An evidence-based resource for pain relief Oxford OxfordUniversity Press 1998

7 McQuay H J Carroll D Moore R A Variation in the placebo effect in randomisedcontrolled trials of analgesics all is as blind as it seems Pain 1996 64 331-335

8 Edwards J E Oldman A Smith L Wiffen P J Carroll D McQuay H J Moore R A Oralaspirin in postoperative pain a quantitative systematic review Pain 1999 81 289-297

9 Moher D Cook D J Eastwood S Olkin I Rennie D Stroup D F Improving the quality ofreports of meta-analyses of randomised controlled the QUOROM statement Lancet1999 354 1896-1900

10 Jadad A R Carroll D Moore A McQuay H Developing a database of published reportsof randomised clinical trials in pain research Pain 1996 66 239-46

11 Collins S L Moore R A McQuay H J Wiffen P J Edward J S Single dose oral ibuprofenand diclofenac for postoperative pain In The Cochrane Library Issue 4 2000 OxfordUpdate Software

12 Edwards J E McQuay H J Moore R A Single-dose dihydrocodeine for acute

postoperative pain In The Cochrane Library Issue 4 2000 Oxford Update Software13 Moore R A Collins S L Carroll D McQuay H J Edwards J Single dose paracetamol

(acetaminophen) with and without codeine for postoperative pain In The CochraneLibrary Issue 4 2000 Oxford Update Software

14 Barden J Edwards J E McQuay H J Moore R A Rofecoxib in acute postoperative painquantitative systematic review BMC Anesthesiol 2002 2 4httpwwwbiomedcentralcom1471-225324

15 Edwards J E McQuay H J Moore R A Collins S L Reporting of adverse effects inclinical trials should be improved Lessons from acute postoperative pain J PainSympt Manage 1999 18 427-437

16 Jadad A R Moore R A Carroll D et al Assessing the quality of reports of randomizedclinical trials is blinding necessary Control Clin Trials 1996 17 1-12

17 Khan K S Daya S Jadad A R The importance of quality of primary studies inproducing unbiased systematic reviews Arch Intern Med 1996 156 661-666

18 Moher D Pham B Jones A et al Does quality of reports of randomised trials affectestimates of intervention efficacy reported in meta-analyses Lancet 1998 352609-613

19 Cooper S A Single-dose analgesic studies the upside and downside of assaysensitivity In Max M B Portenoy R K and Laska E M (eds) The design of analgesicclinical trials (Advances in Pain Research and Therapy Vol 18) pp117-124 New YorkRaven Press 1991

20 Moore A McQuay H Gavaghan D Deriving dichotomous outcome measures fromcontinuous data in randomised controlled trials of analgesics Pain 1996 66 229-237

21 Moore A McQuay H Gavaghan D Deriving dichotomous outcome measures fromcontinuous data in randomised controlled trials of analgesics Verification fromindependent data Pain 1997 69 127-130

22 Moore A Moore O McQuay H Gavaghan D Deriving dichotomous outcome measuresfrom continuous data in randomised controlled trials of analgesics Use of painintensity and visual analogue scales Pain 1997 69 311-315

23 Morris J A Gardner M J Calculating confidence intervals for relative risk odds ratiosand standardised ratios and rates In Gardner M J and Altman D G(eds) Statistics withconfidence mdash confidence intervals and statistical guidelines pp50-63 LondonBritish Medical Journal 1995

24 Gavaghan D J Moore R A McQuay H J An evaluation of homogeneity tests in meta-analyses in pain using simulations of individual patient data Pain 2000 85 415-424

25 Higgins J Thompson S Deeks J Altman D Statistical heterogeneity in systematicreviews of clinical trials a critical appraisal of guidelines and practice J Health SurvRes Policy 2002 7 51-61

26 LAbbeacute K A Detsky A S ORourke K Meta-analysis in clinical research Ann Intern Med1987 107 224-233

27 Sterne J A Gavaghan D Egger M Publication and related bias in meta-analysispower of statistical tests and prevalence in the literature J Clin Epidemiol 2000 531119-1129

28 Tang J-L Liu J L Y Misleading funnel plot for detection of bias in meta-analysis J ClinEpidemiol 2000 53 477-484

29 Cook R J Sackett D L The number needed to treat a clinically useful measure oftreatment effect Br Med J 1995 310 452-454

30 Carroll D Tramegraver M McQuay H Nye B Moore A Randomization is important instudies with pain outcomes systematic review of transcutaneous electrical nervestimulation in acute postoperative pain Br J Anaesth 1996 77 798-803

31 Schulz K F Chalmers I Hayes R J Altman D G Empirical evidence of bias dimensionsof methodological quality associated with estimates of treatment effects incontrolled trials J Am Med Assoc1995 273 408-412

32 McQuay H J Moore R A Using numerical results from systematic reviews in clinicalpractice Ann Intern Med 1997 126 712-720

33 M Hyllested Jones S Pedersen J L Kehlet H Comparative effect of paracetamolNSAIDs or their combination in postoperative pain management a qualitative reviewBr J Anaesth 2002 88 199-214

34 F Song Altman D G Glenny A M Deeks J J Validity of indirect comparison forestimating efficacy of competing interventions empirical evidence from publishedmeta-analyses Br Med J 2003 326 472-476

07p407-411qxd 10092004 1520 Page 411

Relative efficacy of oral analgesics after third molar extraction ndash a 2011 updateS Derry1 P J Wiffen2 and R A Moore3

and reporting and were all of high meth-odological quality the relative efficacy of different analgesics is justifiable when established against the common comparator of placebo3 Moreover the methods have been extensively examined and validated using individual patient data analyses45

Several approaches can be used to pre-sent results The percentage of patients who benefit with treatment is one approach obviously the higher the number

In 2004 the British Dental Journal carried a review examining analgesic efficacy meas-ured after third molar extractions1 predom-inantly derived from Cochrane reviews of single dose analgesics in established mod-erate or severe pain In the intervening years the reviews on which it was based have been extended to other analgesics and updated to include relevant additional clinical trials performed in the past decade

The culmination of this work has been the publication by the Cochrane Collaboration of an overview of these updated systematic reviews2 The overview included 35 sepa-rate Cochrane Reviews with 38 analyses of single dose oral analgesics tested in acute postoperative pain models with results from about 45000 participants studied in approximately 350 individual studies About 29000 patients contributed data to trials in dental pain

Each individual review reported results for dental studies where data were avail-able overwhelmingly in the third molar extraction pain model Because all of the reviews used identical methods outcomes

This article provides a summary of the efficacy and relative efficacy of 38 different drugs or drug combinations tested in standard postoperative pain trials It will help clinicians and patients make informed choices about analgesia based on pain relief duration of action and adverse events which can then be put into context for the individual patient depending on local availability This article highlights the fact that no single drug is effective in all patients ndash even the best drugs fail to provide good levels of pain relief in at least 30 These patients should try a different analgesic

the better Another way is to look at the number needed to treat (NNT) for one patient to benefit this is the treatment-specific effect and can be expressed as 100(active - placebo) The ideal NNT is 1 where everyone gets better with treatment and no one does with placebo lower numbers are better In dental tri-als where about 10 of patients benefit with placebo the best possible NNT is 100100 - 10 = 11

13Pain Research and Nuffield Division of Anaesthet-ics Department of Clinical Neurosciences University of Oxford The Churchill Hospital Oxford OX3 7LJ 2UK Cochrane Centre Summertown Pavilion 18-24 Middle Way Oxford OX2 7LG Correspondence to R Andrew Moore Email andrewmoorepruoxacuk

Refereed Paper Accepted 12 September 2011 DOI 101038sjbdj2011905 copyBritish Dental Journal 2011 211 419-420

bull Summarises the known evidence on efficacy of oral analgesics in dental pain

bull Describes shorter term pain relief and time needed before remedication

bull Provides an evidential context for making decisions about individual patients or practice guidelines

I N B R I E F

Table 1 Efficacy results in dental pain studies for a range of commonly used analgesics

Drug and dose (mg)Number of

Percent with at least 50 maxi-mum pain relief NNT

Median time to remedication (hr)

Trials Patients Active Placebo

Aspirin 600650 mg 45 3581 36 14 45 (40 to 52) 30

Aspirin 1000 mg 4 436 35 11 42 (32 to 60) no data

Celecoxib 400 mg 4 620 34 3 25 (22 to 29) 84

Diclofenac 50 mg (Na and K) 9 1119 56 19 27 (24 to 31) 43

Diclofenac 50 mg K 5 622 65 16 21 (19 to 24) no data

Etoriocoxib 120 mg 4 500 71 9 16 (15 to 18) gt24

Ibuprofen 400 mg 49 5428 55 12 23 (22 to 24) 56

Ibuprofen 400 mg soluble 9 959 66 10 18 (17 to 20) no data

Ibuprofen 200 mg + paracetamol 500 mg 2 280 74 10 16 (14 to 18) gt8

Naproxen 500550 mg 5 402 61 7 18 (16 to 21) 89

Paracetamol 1000 mg 19 2157 41 10 32 (29 to 36) 39

Note that data for remedication time were not generally available for dental studies separately and the values reported apply to all postoperative conditions though predominantly third molar extraction

BRITISH DENTAL JOURNAL VOLUME 211 NO 9 NOV 12 2011 419

PRACTICE

This brief report describes the main results of interest to dentists using results from the Cochrane overview and from a recent analysis of a combination of ibu-profen and paracetamol5

RESULTSTable 1 reports data for aspirin celecoxib diclofenac etoricoxib ibuprofen ibu-profen plus paracetamol naproxen and paracetamol Widely differing amounts of information were available for individual drugs from as few as 402 patients for nap-roxen 500550 mg and as many as 5428 for ibuprofen 400 mg

One outcome reported is the percentage of patients with initially moderate pain (30-60 mm on a 100 mm VAS) or severe pain (more than 60 mm) who obtained at least 50 of the maximum possible pain relief over a 4-6 hour period after taking the tab-lets This is a high test of efficacy achieved by only about 10 of patients who received no active treatment (placebo) but achieved by 34-74 of those who did get the active drug Ibuprofen 200 mg plus paracetamol 500 mg and etoricoxib 120 mg achieved

response rates above 70 paracetamol 1000 mg achieved only a 41 response rate

Several products had an NNT of about 2 or below the combination of ibupro-fen 200 mg plus paracetamol 500 mg etoricoxib 120 mg ibuprofen 400 mg in a soluble form naproxen 500550 mg and 50 mg of the potassium salt of diclofenac (the sodium salt being much less effective in this assay Fig 1)

A new outcome that some will con-sider relevant is the time required for half the patients to need more analgesia the time to remedication Longer duration is another indicator of greater effect and for a number of analgesics median remedica-tion times are beyond eight hours

DISCUSSIONThe 2004 review included evidence for rofecoxib and valdecoxib neither of which is available today New relevant informa-tion includes data on the ibuprofen plus paracetamol combination different ibu-profen and diclofenac formulations and etoricoxib all of which are among the most efficacious analgesics after third

molar surgery Greater efficacy and longer duration of action tended to go together

For one analgesic relevant to dentistry the evidence is largely silent For dihydrocodeine 30 mg (still commonly used by dentists) only 136 patients were found in trials in dental pain with only 24 obtaining at least 50 maximum pain relief compared with 7 with placebo The resultant NNT was 6 far worse than available for drugs in Table 1 and far worse than ibuprofen 400 mg in the only direct comparison6 The Cochrane overview concluded that the results for dihy-drocodeine were not robust because of the smallness of the data set available and that unpublished results from just 46 patients in zero effect trials would be needed to make any result clinically irrelevant

CONCLUSIONThe amount of evidence available on single dose studies of analgesics in dental pain is large and readily available These results are tools to help formulate policy and pre-scribing for individuals and populations

1 Barden J Edwards J E McQuay H J Wiffen P J Moore R A Relative efficacy of oral analgesics after third molar extraction Br Dent J 2004 197 407ndash411

2 Moore R A Derry S McQuay H J Wiffen P J Single dose oral analgesics for acute postoperative pain in adults Cochrane Database Syst Rev 2011 9 CD008659

3 Song F Altman D G Glenny A M Deeks J J Validity of indirect comparison for estimating efficacy of competing interventions empirical evidence from published meta-analyses BMJ 2003 326 472

4 Moore R A Edwards J E McQuay H J Acute pain individual patient meta-analysis shows the impact of different ways of analysing and presenting results Pain 2005 116 322ndash331

5 Moore R A Straube S Paine J Derry S McQuay H J Minimum efficacy criteria for comparisons between treatments using individual patient meta-analysis of acute pain trials examples of etoricoxib paracetamol ibuprofen and ibuprofenparacetamol combinations after third molar extraction Pain 2011b 152 982ndash989

6 Moore R A Edwards J Derry S McQuay H J Single dose oral dihydrocodeine for acute postop-erative pain Cochrane Database Syst Rev 2000 2 CD002760

Ibuprofen 200mg + paracetamol 500 mg

Ibuprofen 400 mg

Aspirin 600650 mg

Aspirin 1000 mg

Paracetamol 1000

Naproxen 500550

Diclofenac 50 mg (Na and K)

Celecoxib 400 mg

Diclofenac 50 mg K

Ibuprofen 400 mg soluble

Etoriocoxib 120 mg

1 2 3 4 5 6

NNT for at least 50 maximum pain relief (95 CI)

Fig 1 NNTs in dental pain studies for a range of commonly used analgesics

420 BRITISH DENTAL JOURNAL VOLUME 211 NO 9 NOV 12 2011

Combining paracetamol with a selectivecyclooxygenase-2 inhibitor for acutepain relief after third molar surgerya randomized double-blindplacebo-controlled study

Birgitta Haglund12 Inger vonBltzingslccedilwen1

1Public Dental Health Service KarlstadVrmland Sweden 2Department of ClinicalPharmacology Sahlgrenska Academy atGccedilteborg University Sweden

Traditional non-steroidal anti-inflammatory drugs(NSAIDs) [ie non-selective cyclooxygenase (COX)inhibitors such as ibuprofen and diclofenac] have beenwidely used in outpatients for acute pain relief followingoral surgery Their anti-inflammatory and analgesicproperties together with well-established tolerabilitymake them an initial choice for the management of mostforms of mild to moderate pain in outpatients (1 2)However these drugs have well-documented adverseeffects such as gastrointestinal intolerability Further-more they need to be administered several times a dayMore effective and practical pain relief regimes withfewer side-effects are needed for moderate to severe painafter oral surgeryNSAIDs act by inhibiting COX enzymes which are

responsible for the production of prostaglandin fromarachidonic acid This acid emerges from the breakdownof phospholipids in the cell walls of damaged tissue (3)Prostaglandin elicits a number of biological effects someof which contribute to the inflammatory process leading

to pain Multiple COX enzymes have been identifiedCOX-1 is mainly expressed under physiological condi-tions throughout the body for example by platelets (4)and COX-2 is related to inflammation and pain (4ndash6)although COX-1 and COX-2 also have overlappingproperties (7) Improved knowledge on more selectiveCOX enzymes led to the development of specific COX-2inhibitors such as rofecoxib (8) and celecoxib withanalgesic anti-inflammatory and gastroprotective prop-erties Of these drugs rofecoxib has been shown to bemore effective than celecoxib (9ndash11)Rofecoxib has the same analgesic effect as ibuprofen

but with the benefit of a longer duration (9 10 12) It hasa long half-life which makes it suitable for once-dailydosing (12) compared with traditional NSAIDs thatneed to be taken several times per day Rofecoxib hasalso been suggested to be more effective than paracet-amol combined with codeine (13 14) The COX-2inhibitor rofecoxib may be an interesting choice for acutepain relief after oral surgery

Haglund B von Bulzingslowen I Combining paracetamol with a selective cyclooxyge-nase-2 inhibitor for acute pain relief after third molar surgery a randomized double-blind placebo-controlled study Eur J Oral Sci 2006 114 293ndash301 2006 The AuthorsJournal compilation 2006 Eur J Oral Sci

Severe pain after third molar surgery is often encountered and more effective treatmentregimes are warranted The objective of this study was to evaluate if the combinationof paracetamol and rofecoxib a selective cyclooxygenase-2 (COX-2) inhibitorimproves analgesic effects following third molar surgery compared with rofecoxibalone Paracetamol alone was also evaluated Altogether 120 patients with moderate tosevere pain after third molar surgery were given a single postoperative dose of one ofthe following treatments rofecoxib + paracetamol rofecoxib alone paracetamolalone or placebo Patients assessed level of pain and pain relief every 30 min for 8 hafter surgery and made a global evaluation of the medication 4 and 8 h after surgeryParacetamol and rofecoxib combined improved the analgesic effect compared withrofecoxib alone for the first 15 h Rofecoxib alone and the combination of paracet-amol and rofecoxib had a significantly better analgesic effect than paracetamol alonefrom 3 h onwards The early onset of pain relief for the combination of paracetamoland rofecoxib compared with rofecoxib alone could be of great importance whentreating acute pain after third molar surgery After data collection for this studyrofecoxib was withdrawn from the market as a result of reported fatal cardiovascularevents Whether this is relevant for short-term use is unknown but it has to be con-sidered before rofecoxib may be used for pain relief following third molar surgery

Birgitta Haglund Folktandvrden TingvallaBox 577 SE-651 13 Karlstad Sweden

Telefax +46ndash54ndash137435E-mail birgittahaglundlivse

Key words COX-2 inhibitor pain relief para-cetamol randomized trial third molar surgery

Accepted for publication April 2006

2006 The AuthorsJournal compilation 2006 Eur J Oral Sci

European Journal ofOral Sciences

Combining drugs that cause analgesia through differ-ent mechanisms may give additive analgesic effects (15)and lead to dose-sparing effects and improved safety(16) The analgesic mechanism of COX inhibition ispredominantly peripheral Research on paracetamol hasnot been able to delineate a clear mechanism of actionbut it is suggested to lie predominantly in the centralnervous system (17) Some studies indicate that combi-ning a traditional NSAID and paracetamol after oralsurgery may enhance the analgesic effect compared withsingle drug regimes (18 19)The theory of the analgesic effect of traditional

NSAIDs being caused by COX-2 inhibition leads to thethought that an additive effect should be present alsowhen combining rofecoxib and paracetamol The aim ofthis study was therefore to explore in a third molarsurgery pain model (20) if there is an additive analgesiceffect when combining the COX-2 selective inhibitorrofecoxib with paracetamol compared with rofecoxibalone for acute pain relief We also compared the anal-gesic efficiency of rofecoxib and paracetamol becausethis to our knowledge has not been reported followingthird molar surgery

Material and methods

Study design

This study was designed as a multicenter randomizeddouble-blind placebo-controlled study with a single dose ofrofecoxib 50 mg and paracetamol 1 g combined vs rofec-oxib 50 mg alone vs paracetamol 1 g alone vs placebogiven postoperatively to patients stating moderate to severepain after surgical removal of one or two lower third molarsPatients were asked to give written informed consent toparticipate after being told about the procedures A total of120 patients were randomized into four different treatmentgroups as follows 40 patients receiving the combination ofrofecoxib 50 mg and paracetamol 1 g 40 patients receivingrofecoxib 50 mg alone 20 patients receiving paracetamol 1 galone and 20 patients receiving placebo The patientsrsquoevaluations of the treatments were obtained by using aquestionnaire which the patients filled in at home during an8-h study period following intake of the study medicationThe trial was approved by the Regional Ethical Committeeof Medical Research in Orebro Sweden and the MedicalProducts Agency in Uppsala Sweden

Patients

Consecutive patients visiting four general dental practicesand in need of mandibular third molar surgery in accordancewith the National Institutes of Health (NIH) guidelines (21)were screened for enrollment Only patients with thirdmolars needing bone removal were included Other inclusioncriteria were age gt18 yr weight gt50 kg butlt120 kg andan appointment before noon for surgery This was necessaryin order for the patients to have time to fill in the ques-tionnaire for 8 h after intake of the study medication beforebedtime Exclusion criteria were as follows intolerance toacetylsalicylic acid (ASA) paracetamol andor NSAIDsany ongoing medication (except contraceptives) pregnancylactation inadequate contraception alcohol or drug abusePatients with evidence of previous or present cardiovascular

respiratory diabetic hepatic gastric renal neurological orneoplastic diseases were also excluded as were those withongoing pericoronitis or other local oral infections involvingpain Patients with an intake of any analgesics 6 h precedingsurgery was also excluded All patients who met the studycriteria and reported moderate to severe pain after the sur-gery were included in the study

Surgery

The surgery was performed by one of four dentists speciallytrained in dento-alveolar surgery using local anesthesia(lidocaine 20 mg ml)1 plus epinephrine 125 lg ml)1) Theremoval of bone was carried out with a burr under thecooling of saline

Masking randomization and rescue medication

The study medications were masked by being encapsula-ted in identical capsules The capsules contained 50 mg ofrofecoxib 200 mg of paracetamol or placebo All patientswere given a sealed container containing six capsules(Table 1) so that the patients in the different treatmentgroups received the correct amount of medication and stillthe same number of capsules The capsules were manu-factured by Apoteket Production amp Laboratories (APLStockholm Sweden) Randomization of the patients intothe four treatment groups was performed for the group intotal by Apoteket using randomization tables All studypersonnel and participating patients were blinded totreatment assignment for the duration of the study Themain investigator broke the codes for the final calcula-tionsIbuprofen 400 mg was used as a rescue medication in case

patients needed additional analgesia at any time during the8-h study period The rescue medication was kept in aseparate container If patients felt that rescue medicationwas needed they were instructed to wait 90 min if possibleafter intake of their study medication to allow for the studydrug to take effect

Intake of study medication and information about thequestionnaire

After surgery the patients were given their two containerswith study and rescue medications respectively together

Table 1

Distribution of the drug capsules with the different substances percontainer in each study group

Study groups

Rofecoxib50 mg +

paracetamol 1 gRofecoxib50 mg

Paracetamol1 g Placebo

Rofecoxib50 mg

1 1 0 0

Paracetamol200 mg

5 0 5 0

Placebo 0 5 1 6Total no ofcapsules ineach container

6 6 6 6

294 Haglund amp Bultzingslowen

with the questionnaire Routine postoperative informationwas given The patients were instructed to go home and takeno medication before calling the investigator when theyregained full sensibility in the lower lip following the dis-appearance of the local anesthesia If the patient had notcalled the investigatorrsquos mobile phone within 3 h after theend of surgery the investigator called the patientAt the telephone contact the patients were asked to state

their level of pain in the questionnaire using a 3-point scalefrom mild to moderate to severe pain If patients statedmoderate or severe pain they were asked to break the seal ofthe container with their study medication and take all sixcapsules Detailed instructions were provided on how to fill inthe questionnaire To ascertain that patients adhered to theprotocol information was given to contact the investigatorwith any questions regarding medication or other issuesconcerning the studyduring the 8-h postoperative periodThestudy period started at the time of intake of the study medi-cation If patients stated mild pain they were asked if theycould tolerate waiting before taking any medication In suchcases a second telephone contact was made If patients stillstatedmild pain they were asked if it was possible for them toreturn their sealed container with the study medicationPatients who did so were replaced with another patient

Efficacy assessments

The outcome measures of the trial were pain intensity painrelief (PAR) global evaluation score (patientsrsquo overallassessment of the medication) derived summary measuresuse of rescue medication and side-effects experienced allrecorded by the patients in their questionnaire After intakeof the study medication pain intensity and PAR wasassessed by the patient every 30 min for 8 h and the globalevaluation score was measured at 4 and 8 h The startingpoint for each patient was the time for intake of studymedication The final measurement point was the end of theobservation period (ie 8 h later) or the time of intake ofrescue medication If rescue medication was used patientswere asked to assess pain intensity and pain relief and give aglobal evaluation score at the time of intake These scoreswere then used for the rest of the observation period inaccordance with a study by Laska et al (22)Pain intensity was evaluated by the patients using a

horizontal visual analog scale (VAS) of 10 cm marked nopain at 0 and worst possible pain at 10 PAR was meas-ured on a 5-point scale as follows 0 no pain relief 1 somepain relief 2 medium pain relief 3 good pain relief and 4total pain relief Global evaluation score was measured on a4-point scale as follows 0 poor 1 fair 2 good and 3excellent Patients using rescue medication recorded the timeof intake A question about any side-effects experienced wasanswered by yes or no at the end of the study period Ifyes the patients estimated adverse events on a 3-point scale(1 slight 2 moderate 3 severe) and reported what kind ofside-effect was experienced

Analysis

The analgesic effect of the drugs measured every 30 min bypain intensity (VAS) and PAR scores was comparedSummary measures were calculated by the use of the fol-lowing total pain relief (TOTPAR the sum of all PARscores for the whole study period of 05ndash8 h) pain intensitydifference (PID pain intensity at the start minus painintensity at any given observation point) sum of PID for the

05ndash3-h period (SPID05)3 h) and sum of PID for the total05ndash8-h period (SPIDtotal) PID values were not analyzedseparately but used for the calculation of SPIDThe use of rescue medication was compared between the

treatment groups by calculating the percentage of patientsin each group who used rescue Also the mean timebetween intake of the study medication and intake of therescue medication in the different groups was analyzedSide-effects in the treatment groups were compared interms of percentage of patients in each group whoexperienced such problems Median global evaluationscores between the different groups were analyzed as wellas the percentage of patients in each group using the dif-ferent scores

Statistics

The sample size calculations were carried out assuming adifference in SPID outcome between groups using thecombination of rofecoxib + paracetamol and rofecoxibalone amounting to 20 (18) with a power of at least 80and a standard deviation (SD) of 15 using non-para-metric statistics (MannndashWhitney U-test) This calculationestimated that a minimum of 22 patients should be includedin each groupStandard descriptive statistics and tests were used and the

calculations were performed in Statistical Package for SocialSciences (spss) version 12 The principle of last observationcarried forward was used Significances between groupsregarding VAS scores were tested with an independent-samples t-test at each time point for all possible compari-sons as we considered VAS to be a continuous scale inaccordance with Max et al (23) The same applies for thetesting of SPID up to 3 and 8 h The analysis of TOTPARwas based on an assumption that the scores are consideredinterval scaled (23) and significance testing was carried outwith an independent samples t-test The same test was usedfor testing differences between study groups regarding theuse of rescue medication Hypothesis testing of valuesmeasured with categorical ordinal scales (ie PAR andglobal evaluation) was performed with a non-parametrictest (MannndashWhitney U-test) P-values of lt005 were con-sidered statistically significant

Results

Altogether 126 consecutive patients who fulfilled theinclusion criteria gave written informed consent to par-ticipate in the study The majority of the patients whowere asked to participate agreed to do so Patients whodeclined to participate usually did not have a before-noon appointment for the surgery Out of the 126patients six were excluded as they stated their pain asmild at the telephone contacts and were able to returntheir sealed study medication A total of 120 patientsparticipated by taking the randomized study medicationSome patients (n frac14 8) who did not fulfill the criterion ofmoderate to severe pain but nevertheless wanted toparticipate took their study medication but wereexcluded from the calculations Of these patients ahigher proportion was men (75) compared with thestudied population Some patients (n frac14 5) were excludedfor other reasons one patient randomized to the

COX-2 inhibitor and paracetamol after oral surgery 295

rofecoxib group took her rescue medication after only30 min as a result of severe pain and withdrew from thestudy one did not manage to fill in the questionnaireand three did not return their questionnaires althoughthey were repeatedly reminded to do so Final outcomedata were calculated on the following cohort of 107 pa-tients rofecoxib + paracetamol (n frac14 34) rofecoxibalone (n frac1436) paracetamol alone (n frac14 20) and placebo(n frac14 17)The principal investigator and one of the dentists

performed the majority of the operations 43 and 55respectively in total 98 out of 120 The remaining 22operations were performed by the two other dentists oneoperating on 10 and the other on 12 patients as theirstock of patients fulfilling the inclusion criteria wassmaller The principal investigator was in contact withand gave instructions to the 98 patients The 22remaining patients received their instructions from oneof the other two dentists performing the operationsThere were no differences between groups regarding

baseline characteristics and the number of molarsremoved (Tables 2 and 3) In total 56 of the partici-pants were men The mean age of the patients was 27 yr(range 18ndash54) and the mean weight was 73 kg (range 50ndash120) Mean total duration of the surgery was 14 min Intotal 91 patients (85) had one mandibular molar

removed during the operation and 16 (18) had anadditional maxillary molar removed The remaining 16patients (15) had two mandibular molars removed atthe same session (Table 3) There was no difference inpain intensity (VAS) at the start between patients whohad one or two molars removed At the time of intake ofthe study medication 83 of all patients included in theanalysis reported moderate pain and 17 reportedsevere pain There were no major differences in painreported among patients operated on by the differentdentists

Analgesic effect

Pain intensity (VAS) ndash The analgesic effect over the 8-hstudy period recorded by patients using the VAS isshown in Fig 1 Separate curves with confidence inter-vals for study groups are presented in Fig 2 Patientsused the scale from 0 up to 95There was a significant difference in mean VAS score

between the combination group and the rofecoxibgroup at 30 min 1 h and 15 h in favor of thecombination (P lt 005) At 2 h and subsequentlyparacetamol did not show any statistically significantadditive effect when combined with rofecoxib com-pared with rofecoxib aloneWhen comparing rofecoxib and paracetamol after

30 min paracetamol was significantly better regardingeffect on pain intensity (P lt 005) Paracetamol tendedto have a better analgesic effect than rofecoxib (althoughthis was not statistically significant) for another hourafter the starting point From 3 h until the end of thestudy period rofecoxib was significantly better thanparacetamol (P lt 005)Compared with placebo the combination treatment

as well as the single drug treatments resulted in signifi-cantly lower pain intensity scores at all observationpoints except for rofecoxib at 30 min

Pain relief (PAR) ndash The median PAR scores (Fig 3)showed a pattern similar to the mean pain intensityassessment The combination treatment was significantly

Table 2

Baseline characteristics for each study group

Study groups

Rofecoxib +paracetamol(n frac14 34)

Rofecoxib(n frac14 36)

Paracetamol(n frac14 20)

Placebo(n frac14 17)

Gender malefemale 1915 2016 128 98Age (yr) 25 (19ndash35) 26 (18ndash41) 29 (19ndash52) 28 (19ndash54)Weight (kg) 73 plusmn 9 70 plusmn 13 79 plusmn 17 72 plusmn 13Volume of local anesthetic (ml) 54 plusmn 2 58 plusmn 1 56 plusmn 1 56 plusmn 1Length of surgery (min) 13 plusmn 7 15 plusmn 8 13 plusmn 7 15 plusmn 6Time from end of surgery tointake of study medication (min)

155 plusmn 37 170 plusmn 45 184 plusmn 53 161 plusmn 30

Pain intensity (VAS) at the start 51 plusmn 18 54 plusmn 16 51 plusmn 18 46 plusmn 15

Mean (range)Mean plusmn SDVAS visual analog scale

Table 3

Number of mandibular and maxillar third molars removed in eachstudy group

Study groups

1 mandibular 24 24 15 122 mandibulars 5 6 3 21 mandibular+ 1 maxillar

5 6 2 3

better than rofecoxib alone at 30 min (P lt 005) and at1 h (P lt 001) For the rest of the observation periodthere was no significant difference

Between rofecoxib and paracetamol there was a sig-nificant difference in median PAR score in favor ofparacetamol at 30 min and at 1 h (P lt 005) after drug

Placebo

01234567

0 1 2 3 4 5 6 7 8

Paracetamol 1g

01234567

0 1 2 3 4 5 6 7 8

Rofecoxib 50 mg

01234567

0 1 2 3 4 5 6 7 8

Rofecoxib 50 mg+paracetamol 1 g

01234567

0 1 2 3 4 5 6 7 8

Fig 2 Mean pain intensity recorded on a visual analog scale (VAS) and confidence intervals in study groups during the studyperiod of 8 h

0 05 1 15 2 25 3 35 4 45 5 55 6 65 7 75 8

placebo

paracetamol 1g

rofecoxib 50mg

rofecoxib 50mg +paracetamol 1g

Hours from intake of study medication

Fig 1 Mean pain intensity in study groups recorded on a 10-cm visual analog scale (VAS) at each observation point For signifi-cance tests see the Results

placebo

rofecoxib 50mg

rofecoxib 50mg +

05 1 15 2 25 3 35 4 45 5 55 6 65 7 75 8

paracetamol 1g

Fig 3 Median pain relief (PAR) score in study groups at each observation point Pain relief was assessed using the following scale0 no pain relief 1 some pain relief 2 medium pain relief 3 good pain relief and 4 total pain relief For significance tests see theResults

intake There was instead a significant difference in favorof rofecoxib from 25 h (P lt 005) and from 3 h(P lt 001) to the end of the observation period Only atthe observation time-points of 15- and 2-h was there nosignificant difference between the two drugs regardingmedian PAR scoresThe combination treatment and the single treatments

were significantly better than placebo throughout thewhole observation period of 8 h

Total pain relief (TOTPAR) ndash There was no significantdifference in mean TOTPAR between the combinationtreatment group and the rofecoxib-alone group (Table 4)However rofecoxib gave significantly better TOTPARthan paracetamol (P lt 005) All the active treatmentgroups gave better TOTPAR than placebo (P lt 0001)

Sum of pain intensity differences (SPID) ndash The combi-nation group had the highest mean SPID05)3 h scorehowever this was not statistically different from rofecoxibalone (Table 4)No significant difference in SPID0)3 h wasseen between rofecoxib and paracetamol All active treat-ments were significantly better than placebo (P lt 0001)

The mean PID over the whole observation period (iemean SPIDtotal) shows that the combination group didnot differ from the rofecoxib group (Table 4) Therofecoxib group was significantly better than paracet-amol alone (P lt 005) All active treatments weresignificantly better than placebo (P lt 0001)

Use of rescue medication ndash The use of rescue medicationmeasured as the cumulative percentage of patients ineach study group needing analgesic rescue at any timeduring the 8-h observation period is shown in Fig 4There was no significant difference regarding the totalpercentage of patients using rescue when comparing thecombination group with the rofecoxib group (Table 4)Figure 4 indicates a major difference between the rofec-oxib and paracetamol groups This difference is how-ever not significant (P frac14 0055) owing to few patientsneeding rescue medication Both the combination groupand the rofecoxib group used significantly less rescuethan the placebo group (P lt 0001) Paracetamol failedto show a significant difference to placebo regardingpercentage of patients using rescue medication (P frac140066)

Table 4

Summary of efficiency measures

Study groups

Mean TOTPAR05ndash8 h (SE)

452 (20) 409 (27) 287 (44) 91 (27)

Mean SPID05ndash3 h (SE)

182 (19) 151 (18) 111 (34) )32 (23)

Mean SPIDtotal (SE)

526 (59) 515 (60) 208 (96) )101 (57)

Percentage of patients using rescue medication (SE) 88 (49) 167 (63) 400 (112) 706 (114)Mean time (min) to use of rescue medication (SE) 234 (42) 270 (58) 228 (48) 127 (16)Median global evaluation score (0ndash4) at 4 h 2 2 1 0Median global evaluation score (0ndash4) at 8 h 3 2 1 0

P lt 005 vs placebo P lt 001 vs placebo P lt 0001 vs placeboP lt 005 vs paracetamol P lt 001 vs paracetamol P lt 0001 vs paracetamolSE standard error SPID sum of pain intensity differences TOTPAR total pain relief

05 1 15 2 25 3 35 4 45 5 55 6 65 7 75 8

tion placebo

paracetamol 1g

rofecoxib 50mg

Fig 4 Cumulative percentage of patients in each group using rescue medication during the study period of 8 h For significance testssee the Results

There was no statistically significant difference in themean time from intake of study medication to intake ofrescue medication in the different active treatmentgroups However for all active treatments the time wassignificantly longer than for placebo (Table 4)

Side-effects

The majority of all patients 738 reported no adverseevents while 187 experienced side-effects Another75 did not answer this question The majority (789)of the patients with side-effects reported that these wereonly slight while 211 reported moderate side-effectsNo patients reported any severe side-effects No pro-nounced difference was seen between the groupsregarding side-effects The types of side-effects experi-enced are listed in Table 5

Global evaluation

Patientsrsquo median global evaluation scores of their studymedications are shown in Table 4 After 4 h thecombination treatment and rofecoxib alone receivedsimilar evaluations Both groups were significantlybetter than paracetamol (P lt 0001 P lt 001) at thistime All active treatments were significantly betterthan placeboAt 8 h the combination group had the highest score

but the difference from the rofecoxib group was verysmall and not significant (Table 4) Both groups weresignificantly better than paracetamol alone (P lt 0001P lt 001) at 8 h All treatment groups were significantlybetter than placeboThe global evaluation scores are further specified in

Table 6 After 8 h 90 of the patients in the combina-tion group rated their medication as good or excellentFor the rofecoxib group the corresponding value was83 Of the patients treated with paracetamol 42rated their medication as good or excellent after 8 h

Discussion

In this study we showed that for the acute inflammatorypain following third molar surgery there was an additive

analgesic effect when combining rofecoxib with paracet-amol as compared with rofecoxib alone for the first 15 hafter intake After this time point the combination ofrofecoxib and paracetamol gave similar pain relief to thatof the rofecoxib group Paracetamol alone was also moreeffective for the first 15 h while rofecoxib was signifi-cantly better thanparacetamol from3 honwards The factthat rofecoxib and paracetamol were more effective thanplacebo shows that the method used was sensitive enoughto distinguish between different substancesAfter the clinical part of this study was carried out

serious concerns regarding cardiovascular effects of long-term treatment with rofecoxib were raised following re-ports of an increased incidence of myocardial infarctionand stroke among patients treated with rofecoxib in aplacebo-controlled study (24) After a highly significant19-fold increase in the incidence of thrombo-embolicserious adverse events was shown in yet another study(25) rofecoxib was withdrawn from the market Theside-effects of rofecoxib became progressively greaterafter 1 yr of treatment which suggests that the cardio-vascular risk is dose-dependent and not only associatedwith COX-2 selectivity (6) The need for acute pain reliefafter third molar surgery is short and the surgery ismainly performed in otherwise healthy young peopleamong whom the risk for serious cardiovascular events issmall It cannot be ruled out that future further devel-oped selective COX-2 inhibitors may be useful intreating acute pain after third molar surgery in this groupof patients with the advantage of only one dose a dayand minimizing the risk for gastrointestinal symptomsRofecoxib and paracetamol differ in onset time and

patients treated with rofecoxib reach meaningful painrelief after 15 h (8) compared with 05 h for paracet-amol This corresponds well with the results obtained inour study The group treated with paracetamol reportedtheir lowest VAS score by 1 h whereas at this time pointthe rofecoxib group still reported a high VAS scoreThereafter the medium VAS score for the paracetamolgroup increased while patients treated with rofecoxibcontinued to receive good pain relief until the end of theobservation period From these results it is reasonable toassume that the combination grouprsquos significantly betteranalgesic effect between 05 and 1 h compared with

Table 5

Side-effects as stated in patientsrsquo own words

Study groups

Fatigue 4 2 3 2Headache 1 2 ndash 2Fever ndash ndash ndash 1Dizziness 1 ndash 2 ndashStomach pains 1 ndash 1 ndashSickness ndash 1 ndash ndashShivers 1 2 ndash ndashPerspirations ndash 1 ndash ndash

Table 6

Percentage of patients in each study group stating their overallexperience of the study medication at 4 and 8 h

Study groups

Rofecoxib+

paracet-amol

(n frac14 34)Rofecoxib(n frac14 36)

Paracet-amol

(n frac14 20)Placebo(n frac14 17)

4 h 8 h 4 h 8 h 4 h 8 h 4 h 8 h

Poor 0 0 7 6 30 32 75 76Fair 6 10 7 11 40 26 18 18Good 47 32 43 36 15 26 7 6Excellent 47 58 43 47 15 16 0 0

rofecoxib alone was a result of the earlier onset of theeffect of paracetamol The mean VAS scores for thecombination group and the paracetamol group corres-ponds totally at the 30-min observation pointThe peak pain after third molar surgery has been

shown to occur 4ndash6 h postoperatively (26) which coin-cides well with the time for the additive effect of para-cetamol to take effect in our study This supports the useof the combination treatment of rofecoxib and paracet-amol after third molar surgery to gain an early onsetparticularly if pain relief medication is started postop-eratively as it is of great clinical importance to have anearly onset of pain relief when treating acute pain Iftreatment starts pre-operatively the addition of para-cetamol is likely to have less clinical relevance This issupported by a study in which patients were givenrofecoxib and paracetamol before Ear Nose and Throat(ENT) surgery (27) The addition of paracetamol in thatsetting failed to improve the analgesic effects of rofec-oxibRofecoxib and paracetamol also differ in duration

The effect of paracetamol 1 g lasts up to 6 h and the drughas to be administered four times daily while rofecoxib50 mg has an analgesic effect up to 24 h (12) The presentstudy was a single-dose comparison In a normal clinicalsetting another 1 g of paracetamol would probably beprescribed after 6 h which would give another period ofadditive effectThe disparity in effect between rofecoxib and para-

cetamol in the present study from 3 h onwards is inaccordance with the findings of two studies on post-operative pain relief after otolaryngologic surgerycomparing rofecoxib and paracetamol given pre-operatively (11 28) A study regarding inflammatorypain in patients with knee osteoarthritis also showedrofecoxib to be superior to paracetamol (29) The resultof our study from 3 h after baseline and onwards thusconfirms the findings of these studies in a third molarpain modelOur study did not show the same additive effect of

combining rofecoxib and paracetamol as in a study byBreivik et al in which they combined diclofenac andparacetamol (18) These authors demonstrated anadditive effect of paracetamol over the whole studyperiod of 8 h Their study also showed less use of rescuemedication in the combination group compared with thepatients treated with diclofenac alone something alsofound in a study by Matthews et al (19) It would seemreasonable to assume that the additive effect of para-cetamol in our study would be the same as in these twostudies as rofecoxib and ibuprofen have been shown tohave the same analgesic effect following third molarsurgery (9 10 12) and the effects of ibuprofen anddiclofenac are similar (30ndash32) It cannot be ruled out thatthere is a difference in additive effect of paracetamolwhen combining it with rofecoxib compared withdiclofenac This theory is in accordance with the result ofa study by Pickering et al on pain relief after tonsil-lectomy in children in which rofecoxib combined withparacetamol did not significantly alter the need for earlyanalgesia as did ibuprofen combined with paracetamol

(33) Further studies may clarify differences between thetwo drugsIn conclusion the present study indicates that there is

an early additive effect up to 2 h when combiningparacetamol with rofecoxib postoperatively as comparedwith rofecoxib alone which coincides with peak painintensity after the removal of third molars Rofecoxibhad a significantly better analgesic effect than paracet-amol from 3 h onwards Our results indicate that para-cetamol does not enhance the analgesic effect ofrofecoxib over a longer period of time As rofecoxib hasbeen shown to have serious cardiovascular side-effectsfuture studies are needed to determine any serious side-effect during short-term treatment

Acknowledgements ndash This study was supported by grants fromLIV The Country Council of Varmland which made it inde-pendent from all manufacturers of the studied drugs There areno conflicts of interest by any of the authors with any drugcompany We thank Dr Carl-Mauritz Bratt DDS Dr PeterTroberg DDS and Dr Tobias Block DDS for performingsome of the surgery

References1 Cooper SA Five studies on ibuprofen for postsurgical dental

pain Am J Med 1984 77 70ndash772 Dionne RA Campbell RA Cooper SA Hall DL Buck-

ingham B Suppression of postoperative pain by preoperativeadministration of ibuprofen in comparison to placebo acet-aminophen and acetaminophen plus codeine J Clin Pharmacol1983 23 37ndash43

3 Vane JR Inhibition of prostaglandin synthesis as a mechanismof action for the aspirinlike drugs Nature 1971 231 232ndash235

4 Meade EA Smith WL De Witt DL Differential inhibition ofprostaglandin endoperoxide synthase (cyclo-oxygenase) iso-zymes by aspirin and other non-steroidal anti-inflammatorydrugs J Biol Chem 1993 268 6610ndash6614

5 Smith TJ Cyclooxygenase as the principal targets for action ofNSAIDs Rheum Dis Clin North Am 1998 24 501ndash523

6 Sciulli MG Capone ML Tacconelli S Patrignani P Thefuture of traditional nonsteroidal anti-inflammatory drugs andcyclooxygenase-2 inhibitors in the treatment of inflammationand pain Pharmacol Rep 2005 57 66ndash85

7 Spink M Bann S Glickman R Clinical implications of cyclo-oxygenase-2 inhibitors for acute dental pain managementbenefits and risks J Am Dent Assoc 2005 136 1439ndash1448

8 Ehrich EW Dallob A De Lepeleire I Van Hecken ARiendeau D Yuan W Porras A Wittreich J Seibold JRDe Shepper P Mellisch DR Gertz BJ Characterization ofrofecoxib as a cyclooxygenase-2 isoform inhibitor and demon-stration of analgesia in the dental pain model Clin Pharm Ther1999 65 336ndash347

9 Malmstrom K Fricke J Kotey P Kress B Morrisson B Acomparison of rofecoxib versus celecoxib in treating pain afterdental surgery a singlecenter randomized double-blind pla-cebo- and active-comparator-controlled parallel group single-dose study using the dental impaction pain model Clin Ther2002 24 1549ndash1560

10 Malmstrom K Daniels S Kotey P Seidenberg B Desjar-

dins PJ Comparison of rofecoxib and celecoxib two cyclo-oxygenase-2-inhibitors in postoperative dental pain Arandomized placebo- and active-comparator-controlled clinicaltrail Clin Ther 1999 21 1653ndash1663

11 Watcha MF Issioui T Klein KW White PF Costs andeffectiveness of rofecoxib celecoxib and acetaminophen forpreventing pain after ambulatory otolaryngologic surgeryAnesth Analg 2003 96 987ndash994

12 Morrisson BW Christensen S Yuan W Brown J Amlani

S Seidenberg B Analgesic efficacy of the cyclooxygenase-2-specific inhibitor rofecoxib in post-dental surgery pain arandomized controlled trial Clin Ther 1999 21 943ndash953

13 Chang DJ Fricke JR Bird RS Bohidar NR Dobbins TWGeba GP Rofecoxib versus codeineacetaminophen in post-operative dental pain a double-blind randomized placebo-and active comparator-controlled clinical trial Clin Ther 200123 1446ndash1455

14 Chang DJ Desjardins PJ Bird SR Black P Chen EPetruschke RA Geba GP Comparison of rofecoxib and amultidose oxycodoneacetaminophen regimen for the treatmentof acute pain following oral surgery a randomized controlledtrial Curr Med Res Opin 2004 20 939ndash949

15 Berenbaum MC What is synergy Pharmacol Rev 1989 4193ndash141

16 Altman RD A rationale for combining acetaminophen andNSAIDs for mild to moderate pain Clin Exp Rheumatol 200422 110ndash117

17 Bjorkman R Hallman KM Hedner J Hedner T Henning

M Acetaminophen blocks spinal hyperalgesia induced byNMDA and substance P Pain 1994 57 259ndash264

18 Breivik EK Barkvoll P Skovlund E Combining diclofenacwith acetaminophen or acetaminophen-codeine after oral sur-gery a randomized double-blind single-dose study ClinPharmacol Ther 1999 66 625ndash635

19 Matthews RW Scully CM Levers BG The efficacy ofdiclofenac sodium (Voltarol) with and without paracetamol inthe control of post-surgical dental pain Br Dent J 1984 157357ndash359

20 Norholt SE Treatment of acute pain following removal ofmandibular third molars use of the dental pain model inpharmacological research and development of a comparableanimal model Int J Oral Maxillofac Surg 1998 27 1ndash41

21 NIH Consensus Development Conference For Removal OfThird Molars J Oral Surg 1980 38 235ndash236

22 Laska EM Siegel C Sunshine A Onset and durationmeasurement and analysis In Max MB Portenoy RKLaska EM eds Advances in pain research and therapy NewYork Raven Press 1991 691ndash698

23 Max MB Laska EM Single-dose analgesic comparisons InMax MB Portenoy RK Laska EM eds Advances in painresearch and therapy New York Raven Press 1991 55ndash97

24 Bombardier C Laine L Reicin A Shapiro D Burgos-Vargas R Davis B Day R Ferraz MB Hawkey CJHochbergMC Kvien TK Schitzer TJ Comparison of uppergastrointestinal toxicity of rofecoxib and naproxen in patientswith rheumatoid arthritis N Engl J Med 2005 343 1520ndash1528

25 Bresalier RS Sandler RS QuanH Bolognese JA Oxenius

B Horgan K Lines C Riddell R Morton D Lanas AKonstam MA Baron JA Cardiovascular events associatedwith rofecoxib in a colorectal adenoma chemoprevention trialN Engl J Med 2005 17 1092ndash1102

26 Szmyd L Shannon ILMohnac AM Control of postoperativesequelae in impacted third molar surgery J Oral Ther Phar-macol 1965 1 491ndash496

27 Issioui T Klein KW White PF Hu J Skrivanek GDAnalgesic efficacy of rofecoxib alone or in combination withacetaminophen in the ambulatory setting Anesthesiology 200195 A35

28 Issioui T KleinKWhite PWatchaM SkrivanekG JonesSHu J BradleyM Caleb I Cost-efficacy of rofecoxib versusacetaminophen for preventing pain after ambulatory surgeryAnesthesiology 2002 97 931ndash937

29 Geba GP Weaver AL Polis AB Dixon ME Schnitzer TJEfficacy of rofecoxib celecoxib and acetaminophen in osteo-arthritis of the knee a randomized trial JAMA 2002 287 64ndash71

30 Joshi A Parara E Macfarlane TV A double-blind rand-omised controlled clinical trial of the effect of preoperativeibuprofen diclofenac paracetamol with codeine and placebotablets for relief of postoperative pain after removal of impac-ted third molars Br J Oral Maxillofac Surg 2004 42 299ndash306

31 Bakshi R Frenkel G Dietlein G Meurer-Witt B Schn-eider B Sinterhauf U A placebo-controlled comparativeevaluation of diclofenac dispersible versus ibuprofen in post-operative pain after third molar surgery J Clin Pharmacol 199434 225ndash230

32 Ahlstrom U Bakshi R Nilsson P Wahlander L Theanalgesic efficacy of diclofenac dispersible and ibuprofen inpostoperative pain after dental extraction Eur J Clin Pharma-col 1993 44 587ndash588

33 Pickering AE Bridge HS Nolan J Stoddart A Double-blind placebo-controlled analgesic study of ibuprofen orrofecoxib in combination with paracetamol for tonsillectomy inchildren Br J Anaesth 2002 88 72ndash77

Combined acetaminophen and ibuprofen for pain relief after oralsurgery in adults a randomized controlled trial

A F Merry1 2 R D Gibbs3 J Edwards4 G S Ting3 C Frampton5 E Davies1 2

and B J Anderson1

1Department of Anaesthesiology University of Auckland Private Bag 92019 Auckland New Zealand2Department of Anaesthesia Auckland City Hospital Auckland New Zealand 3Oral Health Unit Greenlane

Clinical Centre 214 Greenlane West Epsom Auckland New Zealand 4Oral and Maxillofacial Service Quay

Park Medical Centre 68 Beach Road Auckland Central Auckland New Zealand 5Department of Medicine

Christchurch School of Medicine and Health Sciences University of Otago New Zealand

Corresponding author E-mail amerryaucklandacnz

Background Acetaminophen is often used with a non-steriodal anti-inflammatory drug for

acute pain Hitherto these drugs have had to be given separately typically at different time

intervals Maxigesicw tablets combine acetaminophen and ibuprofen in clinically appropriate

doses to simplify administration and dosage regimen We compared this combination with each

of the constituent drugs for the relief of pain after extraction of third molar teeth

Methods Adults (more than 16 yr) having one or more wisdom teeth removed under general

or local anaesthesia were instructed to take two tablets before operation then two tablets

every 6 h for up to 48 h of (i) a combination of acetaminophen 500 mg and ibuprofen 150 mg

per tablet (Maxigesicw) (ii) acetaminophen 500 mg per tablet alone or (iii) ibuprofen 150 mg

per tablet alone The primary outcome measure was the area under the curve (AUC) of the

100 mm visual analogue scale pain measurements taken for up to 48 h after surgery divided by

time at rest and on activity Pharmacokinetic data were collected in a subset of patients

Results The mean (SEM) time-corrected AUC on rest and activity respectively were combi-

nation group 223 (32) and 284 (34) acetaminophen group 330 (31) and 404 (33) and ibu-

profen group 348 (32) and 402 (34) P001 for each of the four comparisons of combination

vs constituent drug There was no pharmacokinetic interaction between acetaminophen and

ibuprofen administered together

Conclusions Maxigesicw tablets provide superior pain relief after oral surgery to acetamino-

phen or ibuprofen alone

Br J Anaesth 2010 104 80ndash8

Keywords anaesthesia dental analgesia postoperative analgesics non-opioid acetaminophen

analgesics non-opioid ibuprofen non-steroidal anti-inflammatory drugs

Accepted for publication October 16 2009

The relief of pain has been described as a universal human

right but is not always easily achieved1 Opioid analgesics

are effective but have troublesome and potentially danger-

ous side-effects and their potential for abuse may lead to

regulatory and logistical difficulties Non-steroidal anti-

inflammatory drugs (NSAIDs) have fewer regulatory

restrictions but they too have important adverse effects

which are more likely at higher dose or with longer

courses2 Acetaminophen is widely used and is very safe

at the recommended dose of 4 g per day3 but does not

always provide adequate pain relief on its own Combining

analgesics offers the possibility of increasing effectiveness

without increasing dose (and therefore risk)4 5 NSAIDs

are often combined with acetaminophen particularly for

treating postoperative pain6 ndash 10

Prescribing acetaminophen and ibuprofen together is

common in clinical practice6 8 9 11 ndash 13 Ibuprofen has the

advantage of a well-established safety record (particularly

at doses below 15 g per day in adults)14 and in many

countries (including the UK) it is available without

The Author [2010] Published by Oxford University Press on behalf of the British Journal of Anaesthesia

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (httpcreativecommonsorglicensesby-nc25uk)

which permits unrestricted non-commercial use distribution and reproduction in any medium provided the original work is properly cited

British Journal of Anaesthesia 104 (1) 80ndash8 (2010)

doi101093bjaaep338

prescription Typically acetaminophen is given in a dose

regimen of 1 g 6 hourly whereas ibuprofen is given in a

dose of 400 mg 8 hourly3 Compliance with the prescribed

dosing regimen is important for achieving the desired

result with any drug and is often poor with asynchronous

dosing15 A single formulation with a simplified regimen

would probably be appreciated by patients and might

improve compliance

Maxigesicw is a new formulation of acetaminophen 500

mg and ibuprofen 150 mg Taking two tablets 6 hourly

provides the appropriate daily dose of both drugs relatively

simply We have investigated the hypothesis that in adult

patients undergoing a common surgical procedure (extrac-

tion of third molar teeth) this formulation provides

superior analgesia to either of its components alone

Methods

With ethics committee approval we recruited and fol-

lowed up patients between March 2005 and February

2008 Trial registration ANZCTRORGAU (identifier

ACTRN12606000291583)

Setting

This study was conducted at a publicly funded teaching

hospital and a private day-surgical clinic in metropolitan

New Zealand

Participants

We included adults undergoing extraction of at least one

lower wisdom tooth with or without one or more upper

wisdom teeth by one of three participating surgeons We

excluded patients if they were under 16 yr old weighed

50 kg had taken any NSAID (other than aspirin in a

dose of 150 mg daily or less) within 24 h of the operation

had taken acetaminophen or acetaminophen containing

medicines within 12 h of the operation were taking an

angiotensin-converting enzyme inhibitor warfarin steroid

(other than interoperative dexamethasone) or any immu-

nosuppressive drug were intolerant to any NSAID or acet-

aminophen were suffering from a severe local infection

had a history of peptic ulceration asthma or severe hae-

mopoetic renal or hepatic disease were participating in

the investigation of another experimental agent or if the

clinician believed for any other reason that participation in

the study might not be in their best interests

Randomization and blinding

Tablets of identical appearance packaging and dosage

instructions were provided in each of the following formu-

lations (i) acetaminophen 500 mgthornibuprofen 150 mg per

tablet (Maxigesicw Sigma Laboratories Nashik India which

was MHRA approved for manufacturing pharmaceuticals

under GMP) (ii) acetaminophen 500 mg per tablet or

(iii) ibuprofen 150 mg per tablet

Patients were first approached by the surgeon and then

by the study nurse They were given written and verbal

information about the study and invited to participate If

they consented patients were then randomized into one of

the three study groups in a sequential order to receive one

of these formulations in blinded packs The randomization

sequence was computer generated by the study statistician

as a 111 allocation ratio to the three treatments in a

sequence of permuted blocks with stratification for anaes-

thetic type (local or general) and study centre

Stratification by anaesthetic type ensured a balance

between treatments in terms of the number of teeth

extracted as most patients having more than two teeth

extracted have a general anaesthetic Only the statistician

had access to the schedule of patient numbers by drug

allocation Participants and investigators were blinded and

the randomization code was not broken until the final data-

base had been checked and locked

Intervention

Participants were asked to take two tablets of the study

medication before operation (as close as possible to the

start of surgery) and then 4 times a day (as close as poss-

ible to 6 hourly) for up to 48 h after surgery All partici-

pants were given bupivacaine local anaesthetic blocks by

the surgeons For those participants undergoing general

anaesthesia this was induced with propofol and main-

tained with isoflurane and nitrous oxide in oxygen

Monitoring was in accordance with the guidelines of the

Australian and New Zealand College of Anaesthetists16

All extractions were carried out by one of three surgeons

each using his normal technique

If participants required additional postoperative pain

relief while in hospital a rescue dose of fentanyl 10 mg

was given iv as required After discharge to home

codeine was provided (again as rescue medication) in 30

mg tablets one to two to be taken as needed up to

4 hourly

Outcomes

Participants were asked to rate their pain on 100 mm visual

analogue scales (VAS) printed one per double page in a

booklet that they took home Ratings were requested at

baseline (immediately before administration of the first

dose of study medication) after operation (once the partici-

pants were sufficiently awake to respond) and 1ndash2 hourly

thereafter while awake for 48 h The study nurse main-

tained contact with participants by telephone to facilitate

compliance with data collection and the return of diaries

The primary outcome measure was the area under the

curve (AUC) of these VAS ratings divided by time at rest

and on activity The AUC was divided by the period of

the completed assessments to adjust for the fact that some

Combined acetaminophen and ibuprofen for analgesia

patients recorded pain for shorter periods than others This

calculation in effect produces a measure of average pain

intensity over the study period

Secondary efficacy outcome measures were a categorical

global pain rating by the participants taken at the end of the

study period rescue analgesia consumption over the study

period a categorical global rating of nausea by the partici-

pants taken at the end of study period the number of epi-

sodes of vomiting over the study period and a rating of

sleep disturbance on a 100 mm VAS assessed after each

night during the study period In addition participants were

asked to rate their experiences of participating in the study

Sample size estimation

We obtained blood samples from the 38 participants

undergoing general anaesthesia in order to have evaluable

pharmacokinetic data for at least 30 patients The first

sample was obtained 30 min after the first dose of study

medication the second sample at the end of anaesthesia

and additional one or two samples after operation in hospi-

tal The plasma concentration of acetaminophen and ibu-

profen were measured by the sponsor and used to form

individual timendashconcentration profiles The analytical

method used an HPLC-DAD (Diode Array Detector) assay

for the simultaneous determination of acetaminophen and

ibuprofen in plasma Precision and accuracy for acetami-

nophen and ibuprofen assay were validated over the con-

centration range 05ndash50 mg ml21 for both drugs The

intra- and inter-batch precision of the assays at low

medium and high concentrations of acetaminophen and

ibuprofen varied from theoretical values by 15 The

lower limit of quantification for each drug was 05 mg

ml21 The sponsor monitored all data collected during the

study and queries and corrections were made when any

inaccuracies or inconsistencies were identified

We estimated that 120 participants (40 per group) in the

intention-to-treat (ITT) population would provide 80

power to detect differences between the groups of 9 (SD

14) mm in our primary endpoint for resting assessments

and 13 (SD 21) for measures during activity10 17 with a

one-sided type I error rate of 5 These differences equate

to 25 Differences of this magnitude were considered

clinically important and comparable with differences

typical of previous published studies10

Statistical methods

The data were analysed using SPSS version 150 (SPSS

Inc Chicago IL USA) Efficacy analyses were conducted

on an ITT basis with the additional provision that

there were at least three VAS measurements over at

least 12 h available to calculate the primary endpoint All

participants who were randomized into the study were

included in the safety evaluations As the first dose of

study medication was taken before operation while under

the supervision of the surgeon all randomized patients

took at least a single dose of study medication A last

observation carried forward approach was used for those

subjects who left the study prematurely for non-AUC

based variables

We compared the primary endpoint between the combi-

nation group and each of the acetaminophen and ibuprofen

arms at rest and on activity using a general linear model

(GLM) which included terms for treatment the centre and

anaesthetic stratum Additionally to confirm the consist-

ency of the treatment effects across strata the stratum

treatment interaction terms were tested and included in

the final model The analysis was also checked with

number of teeth extracted as an additional factor

Continuous secondary efficacy endpoints were tested for

significance using the same models as used for the

primary endpoint

A one-tailed P005 was pre-specified to indicate stat-

istical significance We required a statistically significant

result favouring the combination from each of the two

planned comparisons with the constituents to define super-

iority for either rest or on activity measures We used one-

tailed tests as there seemed no theoretical or empirical

basis for expecting that combining these analgesics could

result in a reduction in efficacy and because the require-

ment for each of two comparisons to be significant at

P005 is stringent Secondary categorical efficacy end-

points were compared between the groups using x2 tests

and MannndashWhitney U-tests as appropriate

We used non-linear mixed effect models (NONMEM

VI Globomax LLC Hanover MD USA) to estimate

population pharmacokinetics with a Compaq Digital

Fortran Version 66A compiler on an Intel Celeron 333

MHz CPU (Intel Corp Santa Clara CA USA) under MS

Windows XP (Microsoft Corp Seattle WA USA) This

model allows assessment of inter-individual variability

covariance between pharmacokinetic parameters and

residual error We judged the quality of fit of the pharma-

cokinetic model to data using the NONMEM objective

function examination of plots of observed vs predicted

concentrations and visual predictive checks

Results

After initial screening 189 patients were approached 135

agreed to participate One to four teeth were extracted

with local anaesthetic alone in 69 patients and with local

anaesthetic in combination with general anaesthesia in 66

Thirteen patients did not return their patient diaries so

122 patients were included in the evaluable ITT popu-

lation for the analysis of the primary endpoints (Fig 1)

The treatment groups were adequately matched in baseline

patient and clinical characteristics (Table 1) Of those in

Merry et al

the combination group 600 had three or four teeth

extracted compared with 436 for ibuprofen and 535

for acetaminophen

Efficacy

The time-adjusted AUCs were substantially and signifi-

cantly lower at rest and on activity in the combination

group than in either of the other two treatment groups

(Table 2 Figs 2 and 3) with all four P001 The consist-

ency of the treatment effects across strata was confirmed

from the GLM with P-values for the treatment stratum

interaction of 0955 and 0984 for time-adjusted AUCs at

rest and on activity respectively The type of anaesthetic

(local vs general) and number of teeth extracted did not

change the outcome of either analysis

Although all four secondary endpoints favour the com-

bination treatment (Table 3) only the global pain rating

reached statistical significance More participants experi-

enced lsquonilrsquo or lsquomildrsquo pain with the combination (684)

than with either other group this difference was significant

for acetaminophen (375 Pfrac140008) but not for ibupro-

fen (543 Pfrac140263) The use of any rescue medication

also favoured the combination treatment (Table 4) but this

did not reach statistical significance

Pharmacokinetics

There were no significant differences between the combi-

nation group and either constituent group in any of the

estimated pharmacokinetic parameters (Table 5) The

visual predictive plots of individual concentration showed

that 90 of the observations were within the 90 pre-

diction intervals

Twelve participants were given both acetaminophen and

ibuprofen For calculation of the pharmacokinetic vari-

ables a scaling factor was applied to clearance and

volume of distribution in turn for those participants receiv-

ing the combination of acetaminophen and ibuprofen This

scaling factor had no impact on either acetaminophen or

ibuprofen pharmacokinetic parameters indicating that

there was no pharmacokinetic interaction between acetami-

nophen and ibuprofen when administered together

(P005)

Clearance (CLF) and volume of distribution (VF) par-

ameters observed in the study are consistent with those

reported previously (acetaminophen CLFfrac14126ndash210

litre h21 70 kg21 VFfrac14483ndash710 litre 70 kg21 ibupro-

fen CLFfrac1429ndash59 litre h21 70 kg21 VFfrac1464ndash235 litre

70 kg21)18 ndash 20

Adverse effects

The frequency of adverse effects was consistent with the

known effects of the constituent drugs and there were no

Screened(n =189)

Randomized(n =135)

Acetaminophentreatmentgroup(n =47)

Ibuprofentreatment group(n =44)

Combinationtreatment group(n =44)

Patient diariesnot returned(n =4)

Included in theanalysis(n =43)

Fig 1 Flow of participants through trial Not randomized (nfrac1454) (i)

declined to participate (nfrac1415) (ii) did not meet inclusion criteria

(nfrac1414) (iii) other reasons (nfrac1425) other reasons the surgery was

cancelled or rescheduled patient could not be contacted patient was

given the wrong date of the surgery

Table 1 Patient characteristic and baseline information (SD)

Acetaminophen (n547) Ibuprofen (n544) Combination (n544)

Age [mean (range)] (yr) 235 (160ndash404) 237 (168ndash389) 250 (183ndash404)

Weight [mean (SD)] (kg) 713 (156) 808 (201) 711 (135)

Ethnicity [n ()]

Asian 4 (85) 1 (23) 2 (45)

Black 1 (21) 0 (00) 1 (23)

Caucasian 33 (702) 31 (705) 34 (773)

Maori 4 (85) 4 (91) 4 (91)

Pacific Islander 4 (85) 5 (114) 2 (45)

Other 1 (21) 3 (68) 1 (23)

Male [n ()] 13 (277) 21 (477) 13 (295)

Shift workers [n ()] 10 (213) 5 (114) 3 (68)

Preoperative pain scores at rest [mean (SD)] (mm) 19 (51) 21 (52) 26 (68)

Preoperative pain scores on activity [mean (SD)] (mm) 41 (133) 27 (83) 29 (66)

Sleep disturbance for night before surgery as VAS [mean (SD)] (mm) 647 (229) 691 (260) 715 (241)

definitive indications that the adverse event profile is

changed when the two drugs are combined (Table 6)

however the numbers were too small to make meaningful

comparisons between the groups Two participants experi-

enced postoperative bleeding (attributed to surgical

causes) which resolved without readmission to hospital

No gastrointestinal bleeding was reported during the study

Most adverse events were evaluated as mild (574) or

moderate (352) and on review were considered not

related (175) or unlikely to be related (667) to study

medication

General

The majority of participants rated the experience of taking

part in the study as very positive (31) or positive (47)

ActivityRest

Acetaminophen alone

Ibuprofen alone

Combination

Fig 2 Mean (thorn95 CI) mm of time-adjusted AUC (AUCtime) for VAS

at rest and on activity by treatment group

Table 2 Mean (SEM 95 CI) of time-adjusted AUC of visual analogue pain

scores at rest and on activity by treatment group The differences between

combination and each constituent were significant at rest (vs acetaminophen

Pfrac140007 and vs ibuprofen Pfrac140003) and on activity (vs acetaminophen

Pfrac140006 and vs ibuprofen Pfrac140007)

Acetaminophen

(n543)

Ibuprofen (n539) Combination

(n540)

At rest 330 (31 279ndash381) 348 (32 294ndash402) 223 (32 170ndash277)

activity

404 (33 350ndash458) 402 (34 346ndash459) 284 (34 228ndash341)

0 4 8 12 16 20 24 28 32 36 40 44 48

Hours post-surgery

Acetaminophen aloneIbuprofen aloneCombination

Fig 3 Mean (SE) mm VAS out of 100 at rest (A) and on activity (B)

Table 3 Secondary efficacy endpoints by treatment group The only

significant difference was between the global pain ratings for combination and

acetaminophen (Pfrac140008 MannndashWhitney U-test)

Acetaminophen Ibuprofen Combination

Global pain rating [n ()]

Nil 3 (75) 4 (114) 4 (105)

Mild 12 (300) 15 (429) 22 (579)

Moderate 22 (550) 14 (400) 12 (316)

Severe 3 (75) 2 (57) 0 (00)

Global nausea rating [n ()]

Nil 26 (650) 25 (714) 30 (790)

Mild 10 (250) 8 (229) 7 (184)

Moderate 3 (75) 2 (57) 1 (26)

Severe 1 (25) 0 (00) 0 (00)

Vomiting episodes (n) 5 (in 3 subjects) 0 0

Sleep disturbance night

1 vs baseline VAS

[mean (SD)] (mm)

2219 (292) 2174 (229) 2166 (247)

2 vs baseline VAS

[mean (SD)] (mm)

2137 (329) 296 (258) 285 (201)

Table 4 Rescue analgesia by group n () none of these differences were

significant

Rescue analgesic Acetaminophen Ibuprofen Combination

Fentanyl in hospital 5 (116) 9 (237) 6 (154)

Codeine in the first 24 h 21 (4770) 16 (4320) 13 (3250)

Codeine in the second 24 h 22 (5370) 14 (4240) 16 (4210)

Any rescue medication over 48 h 25 (625) 18 (5810) 21 (568)

Table 5 Mean (SD) pharmacokinetic parameters (individual Bayesian

estimates used for descriptive statistics) for a one-compartment first-order

absorption first-order elimination model none of the differences for

combination formulations was significant CLF clearance VF volume of

distribution Tabs absorption half-time Cmax maximum concentration Tmax

time to achieve Cmax

Acetaminophen

alone (n515)

Acetaminophen

in combination(n512)

Ibuprofen

alone(n511)

Ibuprofen in

combination(n512)

CLF (litre

141 (26) 142 (18) 39 (17) 38 (13)

VF (litre) 557 (194) 482 (183) 106 (21) 98 (15)

Tabs (h) 042 (076) 016 (010) 058 (078) 085 (085)

Tmax (h) 109 (112) 064 (031) 116 (090) 144 (093)

Cmax (mg

litre21)

158 (65) 192 (64) 208 (83) 191 (78)

Merry et al

and 19 rated the experience as neutral Four participants

(3) found the experience negative and none rated it as

very negative The ratings were not significantly different

between the study groups

Discussion

We found that patients using the combination of acetami-

nophen and ibuprofen experienced less pain during the

first 48 h after oral surgery than those using the same

daily dosage of either agent alone and we think the differ-

ence was clinically relevant There was no evidence of any

pharmacokinetic interaction between acetaminophen and

ibuprofen Patients receiving ibuprofen alone reported the

lowest frequency of adverse events but the numbers are

too small for meaningful comparisons between the groups

and we saw no cause for concern in any group

Our data are consistent with previous evidence showing

that a combination of ibuprofen and acetaminophen pro-

vides better analgesia than acetaminophen alone8 9 13 21

Note however that two of these studies were in children9 13

so data in adults are relatively limited On the other hand

there are many studies supporting the more general point

that the addition of various NSAIDs improves the pain

relief obtainable from acetaminophen alone More impor-

tantly our data add convincingly to the sparse evidence

supporting the more controversial proposition that this

combination is superior to ibuprofen alone12 In a smaller

study in an orthopaedic pain model (which was positive

for the combination in comparison with acetaminophen)

Dahl and colleagues8 showed no such benefit whereas

Viitanen and colleagues13 (in a paediatric tonsillectomy

study) showed an advantage for the combination only in

the period after discharge from hospital The similarity in

efficacy between ibuprofen and acetaminophen on their

own seen in our study contrasts with the findings of

superior pain relief from ibuprofen after dental surgery by

Cooper and colleagues22 but theirs was a single-dose

Limitations and strengths of the study

Our results are limited to adults and to the doses and

model of pain studied We think our conclusions are likely

to apply to other age groups and other types of pain but

this will require confirmation We have not explored the

optimal dosage of the combination drug but the dosage

used is consistent with current clinical practice The

inclusion of patients who underwent both general and

local anaesthesia implies that our findings are likely to

apply in either case It is not possible to draw firm con-

clusions on the safety of any drug from a study of only 40

participants per group but acetaminophen and ibuprofen

are well established widely used and considered very safe

in appropriate doses3 23 There is no theoretical reason

Table 6 Adverse events and their relationship with study medication as evaluated by the investigators Postoperative pain was noted as a complication in 2 0

and 1 patient in the acetaminophen ibuprofen and combination groups respectively Some individuals experienced more than one adverse event

Relationship System organ class Acetaminophen Ibuprofen Combination Total

Not related Gastrointestinal disorders (numbness of tongue) 1 0 0 1

General disorders and administration site conditions (swollen arm infusion site

phlebitis)

0 0 2 2

Infections and infestations (dry socket alveolitis of jaw) 1 0 1 2

Injury poisoning and procedural complications (bruising of arm postoperative

0 0 2 2

Musculoskeletal and connective tissue disorders ( jaw stiffness) 0 0 1 1

Skin and sc tissue disorders (swelling face) 1 1 0 2

Subtotal 3 1 6 10

Unlikely related Blood and lymphatic system disorders (swollen glands) 1 0 0 1

Ear and labyrinth disorders (pain in ear tinnitus) 2 0 0 2

Gastrointestinal disorders (vomiting nausea stomach cramps dry lips) 6 1 2 9

Injury poisoning and procedural complications (postoperative bleeding) 0 0 1 1

Musculoskeletal and connective tissue disorders ( jaw stiffness aches and pains in

legs jaw pain)

2 0 1 3

Nervous system disorders (headache felt faint sleepy balance difficulty light

headiness dizziness drowsiness lethargic)

6 4 4 14

Psychiatric disorders (disorientation) 0 1 0 1

Respiratory thoracic and mediastinal disorders (sore throat pharyngeal ulceration

hypoventilation coughing)

1 1 2 4

Investigations (body temperature increased) 0 0 1 1

Skin and sc tissue disorders (rash redness of external ear swelling face) 0 1 1 2

Subtotal 18 8 12 38

Possibly related Gastrointestinal disorders (stomach cramps abdominal pain constipation stomach

ache vomiting)

3 0 2 5

General disorders and administration site conditions (fever) 1 0 0 1

Nervous system disorders (sleepy headache) 1 0 1 2

Subtotal 5 0 4 9

Total 26 9 22 57

and no empirical suggestion from our data to suggest that

the combination would be any less safe than the constitu-

ent drugs on their own Our safety data are observational

rather than based on prospective laboratory investigations

but we followed up participants for adverse events for 3

weeks and it seems unlikely that clinically important

harm would have been missed

Pain after oral surgery can persist for several days10 but

we considered 48 h to be a clinically relevant period and

a longer period of study is likely to have resulted in poorer

compliance with data collection

It could be asked whether a more typical (albeit

complex) regimen for ibuprofen alone might have pro-

vided better analgesia than seen with the 4 hourly

approach used here but this seems unlikely particularly

given that our clinical efficacy data were supported by esti-

mates of population pharmacokinetics We had planned to

correlate drug plasma concentration with pain scores but

the drug plasma concentration results were too sparse and

there were too many confounding variables (such as ethni-

city comparators and rescue analgesia) for this to be

undertaken We did demonstrate a lack of interaction

between the constituent drugs when used in combination

and provided evidence that equivalent and predicted blood

concentrations were achieved (the observations of timendash

concentration profile decreased within 90 of prediction

limits for both acetaminophen and ibuprofen) Furthermore

pharmacokinetic parameter estimates observed in the current

study are very similar to those previously reported18 ndash20

The evaluations used in the efficacy analysis have

established construct validity and are appropriate for

parametric analysis24 25

In designing analgesic studies it is an advantage to

minimize the exposure of participants to inadequate

analgesia while controlling for various sources of bias

Some designs incorporate a placebo group but the efficacy

of both ibuprofen26 and acetaminophen27 in comparison

with placebo are well established by previous research

and we would argue that the use of a placebo in this situ-

ation is unnecessary and perhaps even unethical28 There

would be little value in another lsquome toorsquo analgesic unless

it had clear advantages over established agents Therefore

the question of interest lies in the comparisons between

the new agent (Maxigesicw) and the reference standard of

care and in this case we have actually shown superiority to

both of two possible reference standardsmdashacetaminophen

alone and ibuprofen alone One classic approach to analgesic

studies involves treating established acute pain This has the

alleged advantage that pain relief can be assessed (eg by

using AUC to estimate total pain relief or TOTPAR29 30 or

by calculating a pain reduction index per tablet)31 Our

design in contrast follows the widely accepted clinical prac-

tice of anticipating and treating pain before it occurs which

in our unit at least has long been considered best practice

Furthermore rescue medication was readily available and

those requiring it were evenly distributed between the

groups It is notable that most patients did require rescue

medication suggesting that pain after oral surgery can some-

times be severe enough that even the combination of ibupro-

fen and acetaminophen requires supplementation (and it

might be asked whether it would be a good idea for codeine

for example to be added to the combined formulation)

Nevertheless we think it important that the vast majority of

the participants in all groups reported pain scores that were

reasonably low and that all received analgesic regimens

accepted in contemporary practice The predominantly posi-

tive evaluation by participants of their experience in taking

part in the study provides empirical reassurance on this point

(and also other aspects of the conduct of the study)

The treatment of pain is central to medical practice in

hospitals and in primary care If these results are con-

firmed in other settings the already widely used combi-

nation of acetaminophen and ibuprofen may become the

standard of care for the initial management of moderate

acute pain at least for those patients who do not have

contra-indications to NSAIDs Even using the drugs indi-

vidually the dosage regimen studied here is simpler than

that currently recommended and may well improve com-

pliance with and therefore success with this combination

Providing both drugs in one tablet simplifies this regimen

even further and our data confirm that the specific formu-

lation studied here is effective and that there is no inter-

action between its constituent drugs

Conclusions

Doctors treating pain after oral surgery in hospital and at

home and probably pain in many other situations should

consider using acetaminophen and ibuprofen together four

times a day provided there are no contraindications to

either drug and taking into account the known risks of

NSAIDs The combination formulation studied here sim-

plifies this regimen

Funding

This work was supported by AFT Pharmaceuticals Ltd

assisted by New Zealand Trade and Enterprise

Development Grants

Appendix

Declaration of interest

The Department of Anaesthesiology of the University of

Auckland has received payment from AFT

Pharmaceuticals for conducting this study but none of the

investigators has received payment in their personal

capacity

Merry et al

Contributors

AFM BJA CF and Hartley Atkinson designed the

study with input from RDG and JE Hartley Atkinson

obtained funding RDG GST and JE performed the

surgery and contributed to patient recruitment and to the

care of patients during their participation in the study

ED was the study coordinator and was responsible for

patient recruitment and follow-up data collection quality

control and many other logistic aspects of the study The

statistical analysis of clinical data was undertaken by CF

and of the pharmacokinetic data by BJA AFM took

primary responsibility for the manuscript with assistance

from Jennifer Zhang All authors edited and commented

on the manuscript AFM is the guarantor

Chief Executive Officer AFT Pharmaceuticals

Clinical TrialRegulatory Assistant AFT Pharmaceuticals

Ethics approval

This study was approved by the Northern X Regional Ethics

Committee 650 Great South Road Penrose Auckland New

Zealand

Ethics Committee Approval Number AKX0410298

Health Authorities (MEDSAFE) Approval Number

TT50-7316 (458)

Role of the sponsor

The sponsor (AFT Pharmaceuticals Ltd) participated in

the study design and protocol development and provided

logistical support during the trial Monitoring of the

study was performed by the sponsor who also main-

tained the trial database Statistical analyses were

independently performed by the biostatistician and the

results cross-checked by sponsors and investigators The

sponsor assisted with the preparation of the manuscript

and was permitted to review it and to make suggestions

but responsibility for the content of this paper lay with

the academic authors and the style and emphasis is that

of the principle investigator The academic authors had

the explicit right to access all data and publish these

results

Provenance and peer review

This paper was not commissioned informal external peer

review has been obtained before submission to the Journal

Additional contributions

We thank Ms Jenny Rous Pharmacy Manager from the

Mercy Hospital Pharmacy for study drug management

Dr Ralph Richardson Program Manager from Institute of

Environment Science amp Research Limited Wellington in

New Zealand for the plasma sample assays Sally Merry

for proofreading and editing on the manuscript the anaes-

thetists Judy Bent Jack Hill Joanna Rose Joanne Paver

Andrew Warmington and Lisa Chapman at Greenlane

Clinical Centre Kerry Gunn Chris Chambers and

Jonathan Cross at Quay Park Clinic for facilitating the

administration of the study protocol and contributing

substantially to the clinical care of the patients and the

participants for their participation

References1 Cousins MJ Brennan F Carr DB Pain relief a universal human

right Pain 2004 112 1ndash42 Merry A Power I Perioperative NSAIDs towards greater safety

Pain Rev 1995 2 268ndash913 MARTINDALE The Extra Pharmacopoeia London The Royal

Pharmaceutical Society of Great Britain 19964 Mehlisch DR The efficacy of combination analgesic therapy in

relieving dental pain J Am Dent Assoc 2002 133 861ndash71

5 Desmeules J Rollason V Piguet V Dayer P Clinical pharmacologyand rationale of analgesic combinations Eur J Anaesthesiol Suppl2003 20 7ndash11

6 Altman RD A rationale for combining acetaminophen andNSAIDs for mild-to-moderate pain Clin Exp Rheumatol 2004 22

110ndash77 Hyllested M Jones S Pedersen JL Kehlet H Comparative effect

of paracetamol NSAIDs or their combination in postoperativepain management a qualitative review Br J Anaesth 2002 88

199ndash2148 Dahl V Dybvik T Steen T Aune AK Rosenlund EK Raeligder JC

Ibuprofen vs acetaminophen vs ibuprofen and acetaminophenafter arthroscopically assisted anterior cruciate ligament recon-struction Eur J Anaesthesiol 2004 21 471ndash5

9 Gazal G Mackie IC A comparison of paracetamol ibuprofen ortheir combination for pain relief following extractions in childrenunder general anaesthesia a randomized controlled trial Int JPaediatr Dent 2007 17 169ndash77

10 Merry AF Swinburn PF Middleton NG Edwards JL Calder MV

Tenoxicam and paracetamolndashcodeine combination after oralsurgery a prospective randomized double-blind placebo-controlled study Br J Anaesth 1998 81 875ndash80

11 Mitchell A van Zanten SV Inglis K Porter G A randomized con-trolled trial comparing acetaminophen plus ibuprofen versus acet-

aminophen plus codeine plus caffeine after outpatient generalsurgery J Am Coll Surg 2008 206 472ndash9

12 Menhinick KA Gutmann JL Regan JD Taylor SE Buschang PHThe efficacy of pain control following nonsurgical root canal

treatment using ibuprofen or a combination of ibuprofen andacetaminophen in a randomized double-blind placebo-controlledstudy Int Endod J 2004 37 531ndash41

13 Viitanen H Tuominen N Vaaraniemi H Nikanne E Annila PAnalgesic efficacy of rectal acetaminophen and ibuprofen alone

or in combination for paediatric day-case adenoidectomy Br JAnaesth 2003 91 363ndash7

14 Henry D McGettigan P Epidemiology overview of gastrointestinaland renal toxicity of NSAIDs Int J Clin Pract 2003 Suppl (135)43ndash9

15 TGA Medicines Evaluation Committee 2003 Review of non-prescription analgesics Multiple Strength of Oral LiquidsAustralia Therapeutic Goods Administration 2003

16 Australian and New Zealand College of Anaesthetists Monitoringduring anaesthesia (Review P18) Melbourne The College 2008

17 Merry AF Sidebotham DA Middleton NG Calder MV WebsterCS Tenoxicam 20 mg or 40 mg after thoracotomy a prospective

randomized double-blind placebo-controlled study AnaesthIntensive Care 2002 30 160ndash6

18 Davies NM Clinical pharmacokinetics of ibuprofen The first 30years Clin Pharmacokinet 1998 34 101ndash54

19 Prescott LF Pharmacokinetics of paracetamol Paracetamol(Acetaminophen) A Critical Bibliographic Review New York Taylor ampFrancis Inc 2001 205ndash15

20 Rainsford KD The pharmacokinetics of ibuprofen in humans andanimals Ibuprofen A Critical Bibliographic Review London Taylor amp

Francis 1999 92ndash521 Ianiro S Jeansonne B McNeal S Eleazer P The effect of pre-

operative acetaminophen or a combination of acetaminophen andibuprofen on the success of inferior alveolar nerve block forteeth with irreversible pulpitis J Endod 2007 33 11ndash4

22 Cooper SA Schachtel BP Goldman E Gelb S Cohn P Ibuprofenand acetaminophen in the relief of acute pain a randomizeddouble-blind placebo-controlled study J Clin Pharmacol 1989 291026ndash30

23 AHFS Drug Information Bethesda MD American Society of

Health-System Pharmacist 2007

24 Coll AM Ameen JRM Mead D Postoperative pain assessmenttools in day surgery literature review J Adv Nurs 2004 46 124ndash33

25 Philip BK Parametric statistics for evaluation of the visual ana-logue scale Anesth Analg 1990 71 710

26 Schou S Nielsen H Nattestad A et al Analgesic dosendashresponserelationship of ibuprofen 50 100 200 and 400 mg after surgicalremoval of third molars a single-dose randomized placebo-controlled and double-blind study of 304 patients J Clin

Pharmacol 1998 38 447ndash5427 Barden J Edwards J Moore A McQuay H Single dose oral para-

cetamol (acetaminophen) for postoperative pain CochraneDatabase Syst Rev (Online) 2004

28 Anderson B Cranswick N The placebo (I shall please)mdashis it so

pleasing in children Paediatr Anaesth 2005 15 809ndash1329 Australian and New Zealand College of Anaesthetists and Faculty

of Pain Medicine Acute Pain Management Scientific EvidenceAustralian Government National Health and Medical ResearchCouncil 2005

30 Moore RA Edwards JE McQuay HJ Acute pain individualpatient meta-analysis shows the impact of different ways of ana-lysing and presenting results Pain 2005 116 322ndash31

31 Quiding H Oksala E Happonen RP Lehtimaki K Ojala T Thevisual analog scale in multiple-dose evaluations of analgesics J Clin

Pharmacol 1981 21 424ndash9

Merry et al

Med Oral Patol Oral Cir Bucal 2009 Aug 114 (8)e411-5 Lysine Clonixinate paracetamol and dipyrone to control postoperative pain

Journal section Oral Medicine and PathologyPublication Types Research

Analgesic efficacy of Lysine Clonixinate paracetamol and dipyrone in lower third molar extraction A randomized controlled trial

Vladimir-Reimar-Augusto-de Souza Noronha 1 Gladson-de Souza Gurgel 1 Luiz-Ceacutesar-Fonseca Alves 2 Luiz-Claacuteudio Noman-Ferreira 2 Lisette-Lobato Mendonccedila 2 Evandro-Guimaratildees de Aguiar 2 Evandro-Neves Abdo 2

1 Student in Oral and Maxillofacial Surgery and Traummatology Dental School Federal University of Minas Gerais Belo Hori-zonte Brazil2 Senior Lectures of Department of Surgery Pathology and Clinic Dental School Federal University of Minas Gerais Belo Horizonte Brazil

Correspondence Faculdade de Odontologia Universidade Federal de Minas GeraisAv Antonio Carlos 6627Belo Horizonte ndash Minas Gerais - BrasilCEP 31270-901evandroabdogmailcom

Received 18082008Accepted 20032009

Noronha VRA Gurgel GS Alves LCF Noman-Ferreira LC Mendonccedila LL Aguiar EG Abdo EN Analgesic efficacy of lysine clonixinate para-cetamol and dipyrone in lower third molar extraction A randomized con-trolled trial Med Oral Patol Oral Cir Bucal 2009 Aug 114 (8)e411-5 httpwwwmedicinaoralcommedoralfree01v14i8medoralv14i8p412pdf

AbstractObjective The purpose of this study is to compare the analgesic effect of lysine clonixinate paracetamol and dipyrone after lower third molar extraction Material and Methods The sample consisted of 90 individuals with clinical indication for inferior third molars extraction The mean age of the sample was 223 years (DPplusmn25) The individuals received the medication in uni-dentified bottles along with the intake instructions The postoperative pain parameters were measured according to Visual Analogical Scale (VAS) and the data was evaluated using the Kruskal-Wallis Test and Friedman Test with the latter used to test different time intervals for each one of the drugsResults The final sample consisted of 64 individuals including 23 males (459) and 41 females (641) The mean age of the entire sample was 223 years (plusmn25) The average length of the procedures was 339 minutes (plusmn98) The distribution of mean values for this variable showed little variance for the different drugs (p=007) Conclusion Lysine Clonixinate did not show any substantial impact on the postoperative pain control when com-pared to other drugs

Key words Lysine Clonixinate paracetamol dipyrone postoperative pain impacted third molar

Article Number 2409 httpwwwmedicinaoralcomcopy Medicina Oral S L CIF B 96689336 - pISSN 1698-4447 - eISSN 1698-6946eMail medicinamedicinaoralcom Indexed in

-SCI EXPANDED-JOURNAL CITATION REPORTS-Index Medicus MEDLINE PubMed -EMBASE Excerpta Medica-SCOPUS-Indice Meacutedico Espantildeol

Introduction Surgical extraction of third molars is a very usual clini-cal procedure for controlling problems caused by im-pacted tooth and usually is followed by postoperative pain (1) As a result several studies have been published comparing the drugs used to control postoperative pain after surgical removal of third molars (1-4)Lysine Clonixinate is an analgesic that inhibits prostag-landin synthesis A study comparing Lysine Clonixi-nate with Paracetamol on the oral postoperative pain did not find any significantly difference between them (5) In animals Lysine Clonixinate showed a life span of 3 hours and it is recognized as a non-steroid anti-in-flammatory with the shortest life span when compared to other drugs of its category (6)It bonds to plasma proteins in up to 96-98 and its me-tabolism takes place in the liver four different inactive metabolites being derived Seventy-four percent of its excretion is renal and 25 fecal (7) It holds an ex-cellent bio-tolerance and low incidence of collateral ef-fect in the treatment of painful syndrome such as renal neurogenic muscular and tooth pain (89) and migraine (7) The Visual Analogical Scale (VAS) is considered the best and easiest instrument to measure this type of pain The parameters used by VAS determine the intensity of pain as following no pain mild pain moderate pain and severe pain (10-12) The postoperative pain in dentistry should be controlled even before the surgical procedure itself For that many studies suggest the prescription of anti-inflammatory drugs steroids or not or analgesic drugs with some level of anti-inflammatory properties (1314)Paracetamol is a safe effective drug for the treatment of postoperative pain following the surgical removal of lower wisdom tooth (1516) and dipyrone is similar to other analgesics frequently used in the treatment of moderate to severe postoperative pain (17)Although the drugs under test are safe it is possible the occurrence of adverse effect The estimated ex-cess mortality due to community-acquired agranu-locytosis aplastic anemia anaphylaxis and serious upperrsquogastrointestinal complications was 20 per 100 million for paracetamol 25 per 100 million for dipy-rone (18)Regarding the Paracetamol and Dipyrone large use in Brazil Spain and other countries as well (1719) we decided to use them in order to compare the Lysine Clo-nixinate clinic performance The adverse effects due to the use of Lysine Clonixinate could be nausea vomit-ing allergic reactions vertigo and insomnia (9)

Material and MethodsThe sample of 90 individual consisted of all patients under treatment in that semester at the clinic of Oral

Surgery and Oral Traumatology from Federal Univer-sity of Minas Gerais The following conditions were ob-served in order to select the cases (I) individuals with clinical indication for the removal impacted mandibular third molar in Class I or II positioning A or B accord-ing to Pell et al (20) regardless gender race or social class (II) surgeries that would not extend more than 60 minutes (III) age between 18 and 26 years old (IV) absence of allergies to the drugs under test (V) absence of systemic conditions All surgeries were carried out under local anesthesia-Lidocaine 2 with Felipressine 12500 - Novocoreg (SSWhite Artigos Dentais LTDA Rio de Janeiro Brazil)The patients were informed about the purpose of the research project and were asked to give their written consent The research was approved by the local Ethical CommitteeThe drugs tested were bottled in identical opaque white recipient numbered from 1 to 90 Each recipient con-tained eight tablets of either one of the drugs under test (Dipyrone 500mg Paracetamol 750mg Lysine Clonixi-nate 125 mg) The patients themselves chose the recipi-ent at random and they were unaware of its contentEach patient was told to take one tablet from the given recipient one hour before the surgery and another tablet was taken after the surgery in 6 hours intervals after first dose during 24 hours If the pain persisted the pa-tient was given the liberty to take any other drug and the dentist should be informed The assessment of pain was performed according to VAS Pain was measured just after the surgical proce-dure and 1246812 and 24 hours after the operation For each one of the above options they had also to in-form the level of pain according to a decimal scale The criteria used by the authors to assess patientrsquos pain level were 0 cm no pain 01-3 cm light pain 31-7 cm mo-derate pain 71-10 cm intense pain (9) The descriptive analyses are presented in percentages with mean minimum (min) maximum (max) and standard deviation (SD) Kruskal-Wallis and Friedman tests were used and results were considered statistically significant when value of p was less or equal to 005 at least 95 of the confidence

ResultsThe drop-out in the experiment was of twenty-six cases and therefore the sample was reduced to sixty-four The Lysine Clonixinate group was comprised of 20 in-dividuals (8 males and 12 females) The Paracetamol Group was comprised of 23 individuals (9 males and 14 females) and Dipyrone Group was comprised of 21 individuals (6 males and 15 females) The mean age of the entire sample was 223 years (plusmn25) The length of the procedures was in average 339 min-utes (plusmn98) (Table 1) (Table 2) and (Fig 1) depict each

Interval drugdescriptive measurement

Pmin max median mean SD

Right after Lysine clonixinate 000 100 000 020 040 09370

Paracetamol 000 300 000 030 070

Dipyrone 000 100 000 010 040

1 hour afterLysine clonixinate 000 200 100 070 060 08130

Paracetamol 000 300 100 060 070

Dipyrone 000 200 100 070 070

2 hours afterLysine clonixinate 000 200 100 080 070 09310

Paracetamol 000 300 100 080 090

Dipyrone 000 300 100 080 080

Paracetamol 000 200 100 080 070

Dipyrone 000 300 100 100 100

6 horus afterLysine clonixinate 000 200 100 060 060 05330

Paracetamol 000 300 100 080 090

Dipyrone 000 300 000 060 080

Paracetamol 000 200 000 060 080

Dipyrone 000 300 000 040 080

Paracetamol 000 200 000 055 070

Dipyrone 000 300 000 040 090

Paracetamol 000 200 000 040 070

Dipyrone 000 300 000 030 070

Fig 1 Distribution of the scale of pain according to the different time interval for each of the drugs tested

Table 1 Distribution of the variable pain according to VAS in different time period for the tree drugs tested

P refers to Kruskal-Wallis test

one of the VAS parameters distributed according to drugs tested No adverse effect was observed with the drugs tested

DiscussionSixty-four individuals underwent surgical removal of their inferior third molars among them 23 (359) were male and 41 (641) female As reported before by Morin et al (21) the variable gender did not play any important role in the distribution of the variable pain after surgery The mean age was 223 years (SDplusmn25 years) and the sample was quite homogeneous in that aspect which is an advantage for the categorization of pain related to age Age can influence the pain control because third molar surgical extraction in older individuals can be-come troublesome due the cortical bone thickness and bone resilience loss (1) Chiapasco et al (1) reported a decrease in morbidity and postoperative complication of third molars in young patients Olmedo-Gaya et al (14) attributed an increase of pain in older patients due to the more bone density and narrower periodontal liga-ment

The patients underwent all the surgical procedures by 2 surgeons with calibration of the techniques avoiding therefore different approaches The surgeries length was controlled and therefore did not influence the be-havior of pain in this study- 339 min (SDplusmn98 min) Regarding this the authors believe there is no bias con-cerning the time-period of surgery on the results here presentedThe surgery of third molar is a well known procedure It allows a standardization of case selection reducing therefore the number of uncontrolled events that may lead to biasQuestionnaire and VAS were used to obtain the data The data bank was categorized by drug and analyzed according to the development of the postoperative con-dition as presented in (Table 1)The results in this study show no statistically significant difference between the drugs under test for controlling postoperative pain Martiacute et al (5) found similar results comparing Paracetamol and Lysine ClonixinateThe high number of patients without any pain in the postoperative period can be related to the local anesthe-sia The number of patients without pain in the postop-

DescriptionDrug Interval min Max median mean SD p

Lisyne clonixinate

Right after 00 10 00 02 04

lt 0001

1 hour after 00 20 10 07 062 hours after 00 20 10 08 074 hours after 00 20 10 09 076 hours after 00 20 10 06 068 hours after 00 20 05 06 0612 hours after 00 20 00 04 0624 hours after 00 20 00 03 06

Paracetamol

Right after 00 30 00 03 07

lt 0001

Dipyrone

Right after 00 10 00 01 04

lt 0001

Table 2 Distribution of pain perception in the different time intervals after surgery according to VAS

P refers to Friedman test

erative period decreases with the passing of time Four hours after the surgery this percentage was the smallest and it increases slightly on the 6th and 8th hour after surgery reaching its peak with 24 hours The results presented here are similar to those of Olme-do-Gaya et al (14) who found out that the postoperative pain reaches its higher intensity during the first 8 hours after the surgery The moderate postoperative pain is re-ported when the production of pain mediator increases and also when the effect of local anesthesia is fading away After the 8th hour and during the subsequently days the pain decreases progressivelyThe results of this study show that the Lysine Clonixi-nate as well as Dipyrone and Paracetamol are efficient in controlling the postoperative pain in the surgery of inferior impacted third molars Lysine Clonixinate pos-sesses an analgesic activity similar to that of Dipyrone and Paracetamol and did not show any substantial im-pact on the control of postoperative pain when com-pared to those drugs

References1 Chiapasco M De Cicco L Marrone G Side effects and complica-tions associated with third molar surgery Oral Surg Oral Med Oral Pathol 199376412-20 2 Laureano Filho JR Maurette PE Allais M Cotinho M Fernandes C Clinical comparative study of the effectiveness of two dosages of Dexamethasone to control postoperative swelling trismus and pain after the surgical extraction of mandibular impacted third molars Med Oral Patol Oral Cir Bucal 200813E129-32 3 Loacutepez-Carriches C Martiacutenez-Gonzaacutelez JM Donado-Rodriacuteguez M Analgesic efficacy of diclofenac versus methylprednisolone in the control of postoperative pain after surgical removal of lower third molars Med Oral Patol Oral Cir Bucal 200510432-9 4 Esteller-Martiacutenez V Paredes-Garciacutea J Valmaseda-Castelloacuten E Berini-Ayteacutes L Gay-Escoda C Analgesic efficacy of diclofenac sodium versus ibuprofen following surgical extraction of impacted lower third molars Med Oral Patol Oral Cir Bucal 20049448-53 444-8 5 Martiacute ML De los Santos AR Di Girolamo G Gil M Manero EO Fraga C Lysine clonixinate in minor dental surgery double-blind randomized parallel study versus paracetamol Int J Tissue React 199315207-13 6 Gonzaacutelez-Martin G Cattan C Zuntildeiga S Pharmacokinetics of lysine clonixinate in children in postoperative care Int J Clin Phar-macol Ther 199634396-9 7 Krymchantowski AV Peixoto P Higashi R Silva A Jr Schutz V Lysine clonixinate vs naproxen sodium for the acute treatment of mi-graine a double-blind randomized crossover study MedGenMed 2005769 8 Ortiacute E Coirini H Pico JC Site-specific effects of the nonsteroidal anti-inflammatory drug lysine clonixinate on rat brain opioid recep-tors Pharmacology 199958190-9 9 Krymchantowski AV Barbosa JS Cheim C Alves LA Oral lysine clonixinate in the acute treatment of migraine a double-blind place-bo-controlled study Arq Neuropsiquiatr 20015946-9 10 Kremer E Atkinson JH Ignelzi RJ Measurement of pain patient preference does not confound pain measurement Pain 198110241-8 11 Price DD McGrath PA Rafii A Buckingham B The validation of visual analogue scales as ratio scale measures for chronic and ex-perimental pain Pain 19831745-56 12 Collins SL Moore RA McQuay HJ The visual analogue

pain intensity scale what is moderate pain in millimetres Pain 19977295-7 13 Seymour RA Walton JG Pain control after third molar surgery Int J Oral Surg 198413457-85 14 Olmedo-Gaya MV Vallecillo-Capilla M Galvez-Mateos R Rela-tion of patient and surgical variables to postoperative pain and inflam-mation in the extraction of third molars Med Oral 20027360-9 15 Weil K Hooper L Afzal Z Esposito M Worthington HV Van Wijk AJ et al Paracetamol for pain relief after surgical removal of lower wisdom teeth Cochrane Database Syst Rev 20073CD004487 16 Moore A Collins S Carroll D McQuay H Paracetamol with and without codeine in acute pain a quantitative systematic review Pain 199770193-201 17 Edwards JE Meseguer F Faura CC Moore RA McQuay HJ Single-dose dipyrone for acute postoperative pain Cochrane Data-base Syst Rev 20013CD003227 18 Andrade SE Martinez C Walker AM Comparative safety evalu-ation of non-narcotic analgesics J Clin Epidemiol 1998511357-65 19 Lorenzetti BB Ferreira SH Mode of analgesic action of dipy-rone direct antagonism of inflammatory hyperalgesia Eur J Phar-macol 1985114375-81 20 Pell GJ Gregory BT Impacted mandibular third molars clas-sification and modified techniques for removal Dent Digest 193339330-821 Morin C Lund JP Villarroel T Clokie CM Feine JS Differences between the sexes in post-surgical pain Pain 20008579-85

CLINICAL TRIAL

Onset of analgesia with sodium ibuprofen ibuprofen acidincorporating poloxamer and acetaminophenmdasha single-dosedouble-blind placebo-controlled study in patientswith post-operative dental pain

Stephen Daniels amp Sandie Reader amp Phillip Berry amp

Michael Goulder

Received 24 September 2008 Accepted 6 January 2009 Published online 28 February 2009 Springer-Verlag 2009

AbstractObjective To compare the onset of action and efficacy ofsodium ibuprofen (ibuprofen sodium dihydrate) and ibu-profen acid incorporating poloxamer (ibuprofenpoloxamer)with that of acetaminophen and placebo in patients withpost-operative dental painMethods A double-blind randomised placebo-controlledactive comparator two-centre study assessing the analgesicefficacy of sodium ibuprofen (512 mg equivalent to400 mg ibuprofen acid) ibuprofenpoloxamer (containing400 mg ibuprofen acid and 120 mg poloxamer 407)acetaminophen (1000 mg) and placebo in patients withmoderate-to-severe pain after third molar extraction (n=322) Onset of action was assessed using the two-stopwatchtechnique and pain intensity and relief were measuredusing validated traditional descriptor scales

Results Significantly more patients achieved confirmedperceptible pain relief and meaningful pain relief withsodium ibuprofen (963 Plt00001) and ibuprofenpoloxamer (900 P=00005) than with acetaminophen(675) The onset of action of both ibuprofen formula-tions was comparable with that of acetaminophen up to45 min post-dose a marked divergence in onset times infavour of the ibuprofen formulations occurred from45 min onward Mean values for the area under the painrelief and pain intensity differences curve (0ndash6 h) weresignificantly greater for sodium ibuprofen (346) andibuprofen acid (349) than for acetaminophen (225) (Plt0001) Other pain relief and pain intensity endpointsfavoured both ibuprofen formulations over acetamino-phen Distractibility from pain (6 h) was significantlygreater with the ibuprofen formulations than with acet-aminophen (P=0008 for sodium ibuprofen P=003 foribuprofenpoloxamer) In patients receiving ibuprofenpain interfered less with daily activities (at 1 and 6 h)than in those receiving acetaminophen (Ple0015) Bothibuprofen formulations had significantly better meanglobal assessment scores than acetaminophen (Plt0001)Tolerability profiles of the ibuprofen formulations werecomparable with that of acetaminophenConclusions Compared with acetaminophen sodiumibuprofen was associated with significantly greateranalgesic efficacy pain relief in a greater proportion ofpatients and greater patient satisfaction

Keywords Acetaminophen Dental pain

Ibuprofenpoloxamer Impacted teeth Post-operative pain

Sodium ibuprofen

Eur J Clin Pharmacol (2009) 65343ndash353DOI 101007s00228-009-0614-y

S DanielsPremier Research Group Clinical Research Center3200 Red RiverAustin TX 78705 USA

S Reader P Berry ()Reckitt Benckiser Healthcare UKDansom LaneHull HU8 7DS UKe-mail phillipberryreckittbenckisercom

M GoulderWorldwide Clinical Trials UK Ltd Isaac Newton CentreNottingham Science and Technology ParkNottingham NG7 2RH UK

Introduction

Ibuprofen [2-(4-isobutylphenyl) propionic acid] is awidely used non-steroidal anti-inflammatory drug(NSAID) currently licensed and marketed worldwide Itexhibits anti-inflammatory analgesic and antipyreticeffects in humans by working as a potent inhibitor of thecyclooxygenase enzyme system and is used to treat painresulting from a wide variety of ailments There is anextensive amount of published literature describing theefficacy of ibuprofen [1ndash7]

Patients with acute pain require rapid relief from over-the-counter (OTC) analgesics Rapidly absorbed ibuprofenformulations have been developed [8] and it was antici-pated that this rapid absorption would result in early onsetof analgesia This placebo-controlled double-blind rando-mised single-dose study was conducted to measure thetime to onset and degree of analgesia from two investiga-tional ibuprofen formulations The first investigationalibuprofen formulation contains the sodium salt of the drugibuprofen sodium dihydrate (sodium ibuprofen) Theformulation used in this study contains 256 mg of theibuprofen sodium salt equivalent to 200 mg ibuprofen acidIt is well documented that ibuprofen salts such asibuprofen sodium lysine and arginate are more rapidlyabsorbed than formulations of free ibuprofen acid [9] andseveral studies have shown that faster absorbed formula-tions lead to faster onset of analgesia [10ndash12] The saltdissolves rapidly in the gastrointestinal tract leading tofaster absorption Pharmacokinetic analyses show that thetime to peak plasma concentration (Tmax) with ibuprofensodium dihydrate is achieved in approximately 30ndash40 min[8] in contrast to the 1ndash2 h reported for standard ibuprofentablets [13 14] The second investigational ibuprofenformulation contains ibuprofen acid plus the surfactantpoloxamer 407 [from the poloxamer family of polymericnon-ionic surface active agents (ibuprofenpoloxamer)]mdashtoincrease the rate of dissolution of the tablet and enable morerapid absorption relative to standard ibuprofen formula-tions Acetaminophen another widely used OTC analgesicand antipyretic indicated for the same mild-to-moderatepain conditions as ibuprofen was included in the study as areference

The dental pain model was used because it is the mostappropriate model to investigate onset of analgesic actionIt is an established post-surgical pain model that involvesextraction of impacted third molars (wisdom teeth) arelatively consistent surgical technique that predictablyproduces moderate-to-severe pain The model is widelyaccepted and has a proven record of assay sensitivity (ieseparating active drugs from each other as well as fromplacebo) [11 12 15ndash18] The model is sensitive enough todemonstrate a correlation between plasma levels of ibupro-

fen and onset of analgesia with faster absorbed formula-tions such as ibuprofen arginate having a faster clinicalresponse time than standard ibuprofen [11 12 19] Theresults from dental pain studies have been widely extrap-olated to other general pain conditions including mostcommon OTC conditions

Onset of analgesic action was assessed using the two-stopwatch technique [11 12 19] and pain intensity andpain relief at each of the assessment timepoints wereassessed using traditional descriptor scales Exploratoryanalyses were conducted to give additional informationabout the rate of onset of action of the medications and tocompare the extent of relief provided by each of the activeformulations

Both ibuprofen formulations were given at a doseequivalent to 400 mg ibuprofen acid The acetaminophenproduct included in the study was Tylenol Extra Strength(1000 mg) a commercially available product The brandedprinting was removed from the Tylenol caplets to enable amatched placebo to be produced The doses of both drugsare the maximum licensed OTC doses in the USA and mostother countries and they have well-established safety andefficacy profiles

The primary objective of the study was to determine thetime to onset of analgesia following dosing with sodiumibuprofen tablets (2times256 mg ibuprofen sodium dihydrate)and ibuprofen acid tablets incorporating poloxamer (2times200 mg ibuprofen plus 60 mg poloxamer 407) hereafterreferred to as ibuprofenpoloxamer in patients with post-operative dental pain The secondary objective was tocompare the efficacy of the two ibuprofen formulationswith that of 1000 mg acetaminophen and placebo in termsof onset peak and duration of analgesic action

The study was conducted in accordance with theDeclaration of Helsinki [20] as referenced in EU Directive200120EC [21] and complies with International Confer-ence on Harmonisation (ICH) Good Clinical Practice(GCP) and applicable regulatory requirements

Methods

Study design

This study was a randomised double-blind placebo-controlled single-dose parallel-group study using thedental pain model It was conducted in two clinical researchcentres (Austin Texas and San Marcos Texas)

Patients andor their legal guardians provided informedconsent before the conduct of study-related proceduresPatients were screened within the 28 days before surgeryOn the day of surgery patients underwent surgical removalof one partially or full bone impacted mandibular third

344 Eur J Clin Pharmacol (2009) 65343ndash353

molar or two ipsilateral third molars with a total impactionscore of 4 5 or 6

Degree of impaction Points

Erupted 0Soft tissue 1Partial bone 2Complete (full) bone 3Unusual impaction (horizontalinverted or posterior-anterior) 4

Surgery was performed under local anaesthetic (approx-imately 100 mg lidocaine 2 with 110000 epinephrine)with conscious sedation (35 lmin 50 nitrous oxide for15 min) using standard surgical techniques Followingsurgery patients who fulfilled the inclusion criteria regard-ing baseline pain intensity were randomly allocated to oneof four treatment groups (sodium ibuprofen ibuprofenpoloxamer acetaminophen or placebo) in a 1111 ratioaccording to a computer-generated randomisation schedulethat stratified patients by sex and baseline pain intensityAfter dosing patients remained in the centre for 8ndash15 hOnset of action and efficacy assessments were recorded atpre-determined intervals during the 6 h post-dose A post-operative follow-up was conducted 5ndash12 days after surgery

The study protocol and its amendments together with thepatient information and consent documents were reviewedand approved by Quorum Review Inc (Seattle WA)

Patients

Patients were recruited from the Premier Research GroupClinical Research Centers database via advertising andpractitioner referral Eligible patients were males andfemales 16ndash40 years of age with a primary diagnosis of

amp at least one mandibular third molar (with full bonyimpaction and an impaction score of ge4 on a 5-pointscale) indicated for removal

amp two ipsilateral third molars with a combined totalimpaction score no greater than 6

In either case patients were required to have moderate orsevere baseline pain intensity as assessed using a 4-pointcategorical pain intensity scale and confirmed with a visualanalogue scale (VAS) score of ge50 mm but le85 mm (where0=no pain and 100 mm=worst pain)

The main exclusion criteria were history of significantdisease that rendered the patient unsuitable for inclusionsignificant ongoing painful conditions other than thatassociated with third molar surgery any ongoing conditionthat may have interfered with the absorption distributionmetabolism or excretion of study medications history ofallergy gastrointestinal complaints (including ulcers heart-burn dyspepsia and indigestion) migraine headaches

within the last year psychotic illness or drug abuse useof concomitant medication that may have confoundedassessments of pain relief (eg psychotropic drugs anti-depressants or sedative-hypnotics) pregnancylactationingestion of any analgesic or anti-inflammatory drug frommidnight of the night before surgery

Sample size determination

For the primary endpoint data were available for the time toperceptible relief from three studies using ibuprofen arginate[11 12 19] These data suggested that the time to perceptiblerelief would be 9 to 14 min for the two test formulationsassuming a similar onset of action to that of ibuprofen arginateSince it was assumed that the majority of placebo patientswould not achieve meaningful relief it was planned that thetime to confirmed perceptible relief for these patients would becensored at 4 h Although the spread of observations was notprovided for the arginate formulation it was assumed conser-vatively that the standard deviation (SD) for time to confirmedperceptible relief would be 1 h (based on the possible rangebeing 0ndash4 h and covering plusmn 2 SD) Hence this study was highlypowered (gt99) to detect such a large difference for the time toconfirmed perceptible relief using the Wilcoxon test

For the area under the curve (AUC) (pain relief intensitydifference [PRID] from 0 to 6 h) data were available fromtwo previous studies which compared ibuprofen lysine [22]and liquigel [23] ibuprofen with acetaminophen In the formerstudy PRID to 6 h was not provided but the sum of painintensity differences (SPID) to 6 h was given This gave adifference of 251 between ibuprofen lysine and acetamino-phen The within-group SD for acetaminophen was 447Using these data it was calculated that with 80 patients pergroup this study would have a 90 power to detect adifference between the ibuprofen formulations and acetamin-ophen at a significance level of 0025 If the data from theliquigel paper were used for sum of the measures of pain reliefand pain intensity difference (SPRID) to 6 h a slightly higherpower would be achieved It was not possible to performformal power calculations for the second endpoint in the closedtest procedure namely time to meaningful relief

Study and concomitant treatments

Following surgery eligible patients received a single oraldose (four tablets and two caplets) of one of the followingfour study treatments

amp sodium ibuprofen 2times256 mg ibuprofen sodium dihy-drate tablets (each tablet equivalent to 200 mg ibupro-fen acid) plus two matched placebo for ibuprofenpoloxamer tablets plus two matched placebo for 500 mgacetaminophen caplets

Eur J Clin Pharmacol (2009) 65343ndash353 345

amp ibuprofenpoloxamer 2times200 mg ibuprofen acid tabletseach tablet incorporating 60 mg of the surfactantpoloxamer 407 plus two matched placebo for sodiumibuprofen tablets plus two matched placebo for 500 mgacetaminophen caplets

amp acetaminophen 2times500 mg acetaminophen (TylenolExtra Strength) caplets plus two matched placebo forsodium ibuprofen tablets plus two matched placebo foribuprofenpoloxamer tablets

amp placebo two matched placebo for sodium ibuprofentablets plus two matched placebo for ibuprofenpolox-amer tablets plus two matched placebo for 500 mgacetaminophen caplets

Patients were encouraged to wait at least 90 min afterreceiving the study treatment before consuming rescuemedication although rescue medication was available atany time after dosing If rescue medication was neededwithin the first 4 h of dosing an intra-muscular injection ofketorolac tromethamine (60 mg) was administered Ifrescue medication was needed later than 4 h after studydrug administration acetaminophen 500 mghydrocodone5 mg or ketorolac tromethamine was given A prescriptionfor acetaminophen 500 mghydrocodone 5 mg was provid-ed to patients for home use at the time of discharge

The use of intravenous oral or inhaled (nitrous)sedation during surgery was prohibited Analgesic andanti-inflammatory drugs (except for the permitted rescuemedications antibiotics and anaesthetics) were not per-mitted during the 6-h post-dose assessment periodPenicillins macrolide antibiotics clindamycin and topicaltetracycline gelfoam were permitted the use of selectiveserotonin-reuptake inhibitors (SSRIs) and selective nor-epinephrine-reuptake inhibitors (SNRIs) was also accept-able in patients who had maintained a stable dose for atleast 4 weeks prior to the first visit Caffeine-containingfoods and drinks were to be discontinued from midnightprior to surgery until the end of the 6-h post-doseassessment period Ice packs were not allowed for thefirst 3 h after dosing

Efficacy endpoints

Patients were queried at pre-determined intervals by thestudy staff and all pain assessments were recorded by thepatient in their diary

Pain intensity (categorical and VAS)

Pain intensity (PI) was assessed at the following timesbaseline (0 h) and at 5 10 15 20 25 30 35 40 45 60 90120 180 240 300 and 360 min after dosing The PI wasmeasured on a categorical scale in response to the question

ldquoWhat is your pain level at this timerdquo with patient responsechoices of none=0 mild=1 moderate=2 and severe=3 Inaddition patients were also asked to draw a single vertical lineto indicate their current level of PI on the 100-mm VASPatients were randomised to treatment when they rated theirbaseline PI as moderate or severe and the score on the VASwas ge50 mm but le85 mm

Pain relief and pain half-gone

Pain relief (PR) was assessed at the same times as PI (withthe exception of 0 h) in response to the question ldquoHowmuch relief have you had from your starting painrdquo withpatient response choices of none=0 a little=1 some=2 alot=3 and complete=4 In addition patients were alsoasked ldquoIs your starting pain at least half gonerdquo withpatient responses as no=0 or yes=1

Perceptible and meaningful PR

Two stopwatches were started at the time of dosing Eachpatient was instructed ldquoStop the first stopwatch when you firstfeel any pain relief whatsoever This does not mean you feelcompletely better although you might but when you first feelany relief in the pain you have nowrdquo The patient wasinstructed ldquoStop the second stopwatch when the pain relief ismeaningful to yourdquo If the patient did not press thestopwatches within the first 4 h of the treatment period or ifrescue medication was required the patients were no longerrequired to use the stopwatches

Distractibility from pain

Distractibility from pain was assessed at baseline and at 60and 360 min after dosing in response to the question ldquoHoweasy is it for you to distract yourself from your painrdquoPatients responded using a 100-mm VAS scale where 0 =very easy and 100 = impossible

Rainier scale

Patients completed the Rainier scale at baseline and at 60and 360 min after dosing This assessed perceivedfunctional impairment of activities of daily living (ieeating driving sleeping reading working and speaking)Patients rated the perceived pain interference with eachactivity on a scale of 1 to 10 where 1 = would not interfereat all and 10 = would completely interfere

Rescue medication

The time of rescue medication was recorded Patientstaking rescue medication completed all pain intensity and

pain relief assessments immediately before rescue medica-tion and continued to record their pain assessmentsthroughout the 6-h assessment period

Global evaluation

At the end of 6 h or at the time of rescue medication patientswere asked ldquoHow effective do you think the study medicationis as a treatment for painrdquo Response choices were 1 =excellent 2 = very good 3 = good 4 = fair or 5 = poor

The primary efficacy endpoint was the time to firstconfirmed perceptible pain relief There were two keysecondary endpoints (1) the AUC for SPRID from 0 to 6 hand (2) the time to meaningful pain relief

Other secondary endpoints included (1) total pain relief(TOTPAR) SPID (categorical and VAS) SPRID from 0 to4 h (2) TOTPAR SPID (categorical and VAS) from 0 to6 h (3) individual pain relief and pain intensity (categoricaland VAS) readings at each timepoint from 5 min to 6 h (4)peak pain relief and pain intensity difference (PID)(categorical and VAS) throughout the 6-h evaluation period(5) first time at which PID was ge1 (6) time to first use ofrescue medication (7) time to and proportion of patientswith pain half-gone (8) distractibility from pain at baselineand at 1 and 6 h post-dose and perceived pain interferencewith daily activities (Rainier scale) at 1 and 6 h post-dose(9) patientrsquos overall assessment of the medication

Safety assessments

Adverse events (AEs) were assessed by non-directedquestioning recorded in the source documentation andthen assessed by the Investigator with respect to severityand relationship to study medication Vital signs (bloodpressure heart rate and oral temperature) were assessed atscreening baseline (pre-dose) at 6 h post-dose and at thefollow-up visit A physical examination was also conductedat screening and at the follow-up visit 5ndash12 days aftersurgery

Statistical analyses

All calculations and figures were produced using SAS ver91 or S-PLUS 62 (SAS Institute Cary NC) The analysisof the primary endpoints was performed via a closed testprocedure The actual protocol-defined primary endpointwas the time to first confirmed perceptible pain reliefPairwise differences between the two ibuprofen formula-tions and placebo were assessed at a significance level of25 so the overall alpha-level of 5 was maintained Forthe primary endpoint pairwise differences between the twoibuprofen formulations and placebo were assessed using theWilcoxon rank-sum test A sensitivity analysis was also

performed where differences between the ibuprofen for-mulations and placebo were assessed using a Cox regres-sion analysis with treatment group study site gender andbaseline pain intensity (categorical) included in the modelThe hazard ratio and associated 975 confidence intervals(CIs) were calculated for the pairwise comparisons

It was planned that if either of the primary pairwisecomparisons were significant at the 25 level the keysecondary endpoints (SPRID 0ndash6 h and time to meaningfulpain relief) were to be assessed for that formulation under aclosed-test procedure Each endpoint was assessed in theorder specified and only if the previous assessments for thatformulation were significant were the subsequent end-points assessed in a confirmatory sense Once the endpointwas not significant then all subsequent assessments wereconsidered exploratory

Endpoints aggregated over several time points werecalculated using AUC as per the secondary endpointDifferences between the treatments were assessed at atwo-sided alpha of 005 A 95 CI for the pairwisedifferences between the treatments was calculated fromthe parameter estimates of the fitted model The pairwisecomparisons of interest were between each of the ibuprofenformulations and placebo and between each of theibuprofen formulations and acetaminophen For the time-to-event parameters such as time to first (unconfirmed)perceptible pain relief differences between the treatmentgroups were assessed as per the primary endpoint

Differences between each of the two ibuprofen formu-lations and acetaminophen in the key secondary endpointsand in the majority of the other secondary endpoints wereanalysed by analysis of covariance (ANCOVA) includingtreatment group study site gender and baseline painintensity (categorical scale) as factors

All assessments completed after the patient had takenrescue medication were considered to be missing For bothpain relief and pain intensity differences missing valuesbetween two available assessments were linearly interpo-lated Missing readings that could not be interpolated werereplaced with the baseline pain intensity or zero relief

All enrolled patients who received a dose of studymedication were included in the safety population All AEswere listed and tabulated by treatment severity relationshipto therapy and body system according to the MedicalDictionary for Regulatory Activities (MedDRA) Version81

Results

Between June and October 2005 a total of 322 patients(mean age 213 years) were randomised to receive studytreatment Of the 322 randomised patients 318 (988)

completed the study The trial profile including the totalnumber of patients withdrawn and analysed is illustrated inFig 1 A total of 321 patients all of whom were balancedacross treatment groups with respect to baseline demo-graphics pain intensity and clinical characteristics (Table 1)were included in the intent-to-treat (ITT) population

Primary efficacy endpoint

Significantly more patients reported confirmed perceptiblepain relief with sodium ibuprofen (963) and ibuprofenpoloxamer (900) than with acetaminophen (675) (Plt00001 and P=00005 respectively) In the placebo grouponly 259 patients reported confirmed perceptible painrelief KaplanndashMeier median times to confirmed perceptiblepain relief were 170 min for sodium ibuprofen 185 minfor ibuprofenpoloxamer and 201 min for acetaminophen(Fig 2) Median time could not be estimated for placebo asfewer than 50 of patients assigned to this groupexperienced confirmed perceptible pain relief Comparisonsof pairwise differences between the two ibuprofen formu-lations and placebo using Wilcoxon rank-sum tests and Coxregression analysis were highly significant (Plt0001 forboth analyses)

Key secondary efficacy endpoints

Mean SPRID (0ndash6 h) values were 346 349 225 and073 for the sodium ibuprofen ibuprofenpoloxamer

acetaminophen and placebo groups respectively Pair-wise comparisons of ibuprofen and acetaminophen werehighly significant in favour of both ibuprofen formula-tions (Plt0001)

Significantly more patients reported meaningful painrelief with sodium ibuprofen (963) or ibuprofenpolox-amer (900) than with acetaminophen (675) (Plt00001and P=00005 respectively) (Fig 3) Of the patientsreceiving placebo 259 reported meaningful pain reliefThe KaplanndashMeier median times to meaningful relief were451 min (sodium ibuprofen) 447 min (ibuprofenpolox-amer) and 541 min (acetaminophen) Neither of the twoWilcoxon rank-sum comparisons between the ibuprofenformulations and acetaminophen were statistically signifi-cant whereas pairwise comparisons obtained via Coxregression analysis were statistically significantly different(P le 0002) The KaplanndashMeier survival curves were similarfor the ibuprofen and acetaminophen groups up to 45 minbut the degree of separation from 45 min onward wasmarked with more patients achieving meaningful painrelief with ibuprofen

Sitendashtreatment interactions

In general site was a statistically significant factor subjectsfrom the SanMarcos site had less favourable outcomes For theprimary efficacy endpoint and for the key secondary efficacyendpoints of SPRID (0ndash6 h) and time to meaningful pain reliefsite was statistically significantly For all three measures the

Withdrawn from ITT (failure toprovide baseline diary data) 1Withdrawn from ITT (failure toprovide baseline diary data) 1Withdrawn from ITT (failure toprovide baseline diary data) 1

IBUPROFENPOLOXAMER

Total screened 614

Total randomised 322

Excluded prior to surgery (n=240)

Excluded prior to dosing (n=52)

Failure to meet inclusion criteria (n=292)

Allocated to intervention 80

ACETAMINOPHEN

PLACEBO

Completed 80 Completed 81 Completed 81

Total analysed (ITTa) 80 Total analysed (ITTa) 80 Total analysed (ITTa) 81

Completed 76

Withdrew consent 1Lost to follow-up 1Other reasons 2

Withdrawn 0 Withdrawn 0 Withdrawn 0

Total analysed (ITTa) 80

SODIUM IBUPROFEN

Not included in ITT (failure to provide baseline diary data) 1

Fig 1 Flow diagram illustrat-ing patient inclusion and exclu-sion throughout the study ITTIntent to treat aThe ITT popula-tion consisted of all patientswho were randomised whocompleted the baseline efficacyassessments and who had atleast one post-baseline assess-ment (primary efficacy set)

interaction between site and treatment was formally investigat-ed In all cases the interaction term was not statisticallysignificant implying that treatment group responses wereconsistent between the sites

Exploratory secondary efficacy endpoints

Pain relief andor reduction in pain intensity

All summary endpoints related to pain relief andor PIDwere significantly more favourable for the two ibuprofenformulations than for acetaminophen or placebo (Plt0001for both ibuprofen formulations vs acetaminophen orplacebo in all comparisons)

A summary of pain relief scores at specified time pointsfrom 5 min to 6 h is displayed in Fig 4 The superiority of

the two ibuprofen formulations over acetaminophen canclearly be seen from 45 min post-dose onward A summaryof PID (categorical) scores at specified time points from5 min to 6 h is displayed in Fig 5 The superiority of thetwo ibuprofen formulations over acetaminophen can beclearly seen from 60 min post-dose onward

Individual PR and PID

The pain relief and PID (categorical and VAS) scores showthat sodium ibuprofen provided more effective pain reliefthan placebo at 15 min [P=0021 (PR) P=004 (PIDcategorical) P=0036 (PID VAS)] Similarly ibuprofenpoloxamer provided more effective relief than placebo at25 min [P=0002 (PR) P=0002 (PID categorical)] and at20 min [P=0008 (PID VAS)]

Timepoint (mins)

0 50 100 150 200 250

Sodium ibuprofenIbuprofenpoloxamerAcetaminophenPlacebo

Fig 2 KaplanndashMeier curves for time to first confirmed perceptiblepain relief

Timepoint (mins)

0 50 100 150 200 250

Fig 3 KaplanndashMeier curves for time to meaningful pain relief

Table 1 Patient demographics and clinical characteristics at baseline (ITT population)

Baseline patient characteristics Treatment group

Sodium ibuprofen(n=80)

Ibuprofenpoloxamer(n=80)

Acetaminophen(n=80)

Placebo(n=81)

Total(n=321)

Age (years) mean (SD) 214 (388) 214 (360) 212 (443) 211 (408) 213 (399)Sex n ()Male 31 (388) 31 (388) 30 (375) 31 (383) 123 (383)Female 49 (613) 49 (613) 50 (625) 50 (617) 198 (617)

Baseline pain intensity (categorical) n ()Moderate 61 (763) 60 (750) 60 (750) 62 (765) 243 (757)Severe 19 (238) 20 (250) 20 (250) 19 (235) 78 (243)

Baseline pain intensity (VAS) mean (SD)Mean (SD) 6816 (874) 6881 (949) 6703 (932) 6737 (1003) 6784 (939)Range 51ndash85 50ndash89 52ndash84 50ndash85 50ndash89

ITT intent-to-treat SD standard deviation VAS visual analogue scaleTreatment definitions sodium ibuprofen=2times256 mg ibuprofen sodium dihydrate tablets (each tablet equivalent to 200 mg ibuprofen acid)ibuprofenpoloxamer=2times200 mg ibuprofen acid tablets acetaminophen=2times500 mg acetaminophen caplets

First time to PID ge 1

There were no significant differences between the activetreatment groups in the proportion of the time to reportingof PID ge 1

Time to first use of rescue medication

Rescue medication was required by significantly fewerpatients in the sodium ibuprofen group (325) and theibuprofenpoloxamer group (225) than in the acetamin-ophen (438) group Owing to the relatively smallproportion of patients reporting the use of rescue medica-tion KaplanndashMeier median times to first use of rescuemedication could not be calculated The pairwise compar-isons between the two ibuprofen formulations and acet-aminophen were both statistically significant using theWilcoxon rank-sum test with P=0019 and P=0001 forsodium ibuprofen and the ibuprofenpoloxamer formula-tion respectively (Fig 6) The vast majority of patientsrandomised to placebo took rescue medication (827)

Time to and proportion of patients with pain half-gone

The proportion of patients reporting pain half-gone were938 888 75 and 370 for sodium ibuprofenibuprofenpoloxamer acetaminophen and placebo re-spectively The median time to pain half-gone wassimilar for all three active treatment groupsmdash350 min(sodium ibuprofen) 375 min (ibuprofenpoloxamer) and450 min (acetaminophen) The Wilcoxon rank-sumcomparisons between the ibuprofen formulations andacetaminophen were not statistically significant (P=007and P=018 for sodium ibuprofen and ibuprofenpolox-amer respectively) but the two equivalent comparisonswere statistically significant when the Cox regression wasused (P=0013 and P=002 for sodium ibuprofen andibuprofenpoloxamer respectively) This may be explainedin terms of a greater proportion of patients randomised toeither of the ibuprofen formulations reporting the endpointscompared with acetaminophen However as for time tomeaningful relief the separation in onset times in favour ofibuprofen was only apparent from 45 min post-doseonward

Distractibility from pain (VAS)

At 1-h post-dose the mean values for the distractibilityfrom pain (VAS) scores were 290 321 381 and657 mm for sodium ibuprofen ibuprofenpoloxameracetaminophen and placebo respectively Both ibuprofenformations had lower (more favourable) scores thanplacebo (Plt0001) and sodium ibuprofen versus acetamin-ophen was statistically significant (P=0010) whereas theibuprofenpoloxamer versus acetaminophen comparisonswere non-significant (P=0083)

At 6 h post-dose both ibuprofen formulations hadmore favourable distractibility from pain scores thanacetaminophen (P=0008 and P=003 sodium ibuprofen

Timepoint (minutes)

0 15 35 60 90 120 180 240 300 360

Sodium ibuprofen IbuprofenpoloxamerAcetaminophenPlacebo

Fig 5 Mean pain intensity difference (categorical) at each timepoint

Timepoint (mins)

0 50 100 150 200 250

Fig 6 KaplanndashMeier curves for time to first use of rescue medication

Fig 4 Mean pain relief at each timepoint

and ibuprofenpoloxamer respectively) The vast majorityof patients randomised to placebo took rescue medicationso only 14 patients provided valid data within this grouphence this analysis was not performed for the placebogroup

Pain interference with daily activities (Rainier scale)

At 1-h post-dose the mean values on the Rainier scale were188 223 268 and 432 for the sodium ibuprofen ibuprofenpoloxamer acetaminophen and placebo groups respectivelyThe scores were statistically significantly lower for bothibuprofen formulations than for placebo (Plt0001) andacetaminophen [P=0001 (sodium ibuprofen) and P=0015(ibuprofenpoloxamer)] At 6-h post-dose the mean valueswere 151 171 224 and 163 for the sodium ibuprofenibuprofenpoloxamer acetaminophen and placebo groupsrespectively Both ibuprofen formulations maintained signif-icantly lower (more favourable) values on the Rainier scalethan acetaminophen (P=0004 and P=0011 for sodiumibuprofen and ibuprofenpoloxamer) Placebo treatment wasnot analysed for this comparison as only 14 patients in thisgroup provided valid data

Patientrsquos overall assessment of medication as a treatmentfor pain

Significantly more patients in the sodium ibuprofen (813)and ibuprofenpoloxamer (848) groups rated the studymedication as good very good or excellent than in the groupsthat received acetaminophen (538) or placebo (173)Furthermore the mean global assessment scores weresignificantly lower (more favourable) for both ibuprofenformulationsmdash240 (sodium ibuprofen) and 244 (ibuprofenpoloxamer)mdashthan for acetaminophen or for placebo (341 and446 respectively Plt0001)

Safety findings

A total of 118 of all patients had AEs that were consideredby the investigators to be possibly related to study medicationno events were classified as definitely or probably related tostudy treatment Adverse events were experienced by 300238 309 and 296 of patients receiving sodium ibuprofenibuprofenpoloxamer acetaminophen and placebo respec-tively The majority of AEs (73) were mild-to-moderate inseverity and the most frequently reported AEs includednausea headache vomiting and dizziness Adverse eventsoccurring in at least 5 of all patients in any treatment groupare summarised in Table 2 Severe AEs (including vomitingnausea dizziness abdominal pain and headache) occurred atrates of 63 (sodium ibuprofen) 25 (ibuprofenpolox-amer) 123 (acetaminophen) and 99 (placebo) therewere no deaths or withdrawals attributable to AEs during thestudy period There were no significant differences betweenstudy medications in terms of tolerability

Discussion

This placebo-controlled study demonstrated excellent assaysensitivity for every measure of efficacy with bothibuprofen formulations and acetaminophen showing clini-cally and statistically significant analgesia that was superiorto placebo Furthermore the overall analgesic efficacy(duration and total effect) of both ibuprofen formulationswas shown to be superior to acetaminophen

Data from this study showed statistically significant differ-ences between both the ibuprofen test formulations andplacebo for the primary endpoint ie the time to firstconfirmed perceptible pain relief In addition a significantlygreater proportion of patients receiving ibuprofen experiencedconfirmed perceptible pain relief than those receiving acet-

Table 2 Adverse events occurring in gt5 of patients in any treatment group

Sodium ibuprofen (n=80) Ibuprofenpoloxamer (n=80) Acetaminophen (n=81) Placebo (n=81)

Numberof events

Number ofpatients n ()a

Numberof events

Any AE 43 24 (300) 27 19 (238) 41 25 (309) 39 24 (296)GastrointestinalNausea 10 9 (113) 5 5 (63) 8 8 (99) 14 14 (173)Vomiting 2 2 (25) 1 1 (13) 6 6 (74) 8 8 (99)Nervous systemDizziness 4 4 (50) 0 0 (00) 6 5 (62) 5 5 (62)Headache 11 11 (138) 5 4 (50) 4 4 (49) 3 3 (37)

AE Adverse eventTreatment definitions sodium ibuprofen=2times256 mg ibuprofen sodium dihydrate tablets (each tablet equivalent to 200 mg ibuprofen acid)ibuprofenpoloxamer=2times200 mg ibuprofenpoloxamer tablets acetaminophen=2times500 mg acetaminophen capletsa Percentages based on total number of patients per treatment group

aminophen The median time to meaningful pain relief was45 min for both ibuprofen formulations and 54 min foracetaminophen Although a much greater proportion ofpatients reported relief on the two ibuprofen formulationsthe divergence in onset times was only apparent from 45 minpost-dose onward ie there was a much higher proportion ofresponders from 45 min onward for the ibuprofen treatmentsthan for acetaminophen Because of this late divergence theWilcoxon rank-sum test was not sensitive enough to detectsignificant differences whereas the Cox proportional hazardsregression analysis showed significant differences in favour ofibuprofen over acetaminophen In terms of SPRID over 6 hboth ibuprofen test formulations were significantly moreefficacious than acetaminophen

Previous studies using the post-operative dental painmodel have demonstrated that treatment with a differentibuprofen salt formulation ibuprofen arginate (l-argininesalt of ibuprofen) resulted in faster onset times to analgesiaand greater overall efficacy than treatment with conven-tional (standard) ibuprofen [11 12 19] The pharmacoki-netic profile of the ibuprofen sodium formulation used inthis study has been shown to be similar to that of ibuprofenarginate with peak plasma concentrations achieved atapproximately 30ndash40 min compared with 1ndash2 h forstandard ibuprofen [8 13 14] Therefore it was anticipatedthat the rapid absorption associated with sodium ibuprofenwould result in early onset of analgesia similar to thatobserved for ibuprofen arginate This study was notintended nor was it sufficiently powered to compare thetwo ibuprofen formulations

When comparing the median time to meaningful painrelief data from this study with previous studies bothibuprofen test formulations in this study were found to be atthe upper end of the range for ibuprofen arginate andibuprofen lysine data (range 24ndash42 min) [11 12 19 22]ie 451 min (sodium ibuprofen) and 447 min (ibuprofenpoloxamer) In the earlier studies where ibuprofen arginatewas compared with conventional ibuprofen the mediantime to meaningful pain relief obtained for ibuprofenarginate was approximately half that of the conventionalibuprofen [11 12 19] A recent bioavailability study hasalso shown that the Tmax for sodium ibuprofen was lessthan half that of standard ibuprofen (ie 35 min vs 90 minrespectively) [8] Therefore it was not unexpected thatsodium ibuprofen had a fast onset of analgesic effect in thisstudy that was in a similar order of magnitude as thosepreviously reported for faster absorbed formulations

The analyses of secondary endpoints related to degreeof pain relief andor reduction in pain intensity (TOT-PAR SPRID SPID peak PID and peak PR) consistentlyfavoured both ibuprofen formulations over acetamino-phen Only in terms of time to PID of at least 1 werethere no statistically significant differences observed

compared with acetaminophen Measures of analgesicdurationmdashthe proportion of patients taking rescue med-ication and the time to rescue medicationmdashshowed thatthose in the acetaminophen group received rescuemedication sooner than those in either of the twoibuprofen groups This suggests that both ibuprofenformulations had a longer duration of action thanacetaminophen which is in keeping with that previouslyreported for ibuprofen lysine [22] and ibuprofen liquigel[23] In terms of pain relief and PID the timepoint at whicha significant difference was first observed between either ofthe ibuprofen formulations and placebo was 15 min(sodium ibuprofen) a significant difference between eitherof the ibuprofen formulations and acetaminophen was firstobserved at 45 min (sodium ibuprofen) In comparison withpreviously published data studies with ibuprofen arginateand ibuprofen lysine demonstrated significant differences inpain relief and PID between ibuprofen and placebo at 10ndash15 min [11 12 19 23] Furthermore significant differ-ences between ibuprofen lysine and acetaminophen wereobserved at 15 min much sooner than the 45 min observedin our study [22] These differences could be explained bythe different formulations of ibuprofen the fact that adifferent brand of acetaminophen was used in each of therespective studies or the inherent variability associated witha small sample size

Patients in both ibuprofen groups were able to distractthemselves from their pain at 1 and 6 h after dosingsignificantly more easily than those in the placebo andacetaminophen groups (6 h only) Patients in both ibupro-fen groups also reported that pain would interfere with theirdaily activities significantly less than patients in theacetaminophen group Patients in the two ibuprofen groupsrated the study medication as good very good or excellentmore frequently than those in the acetaminophen andplacebo groups

Ibuprofen is a well-tolerated NSAID at low doses [24]However even at prescribed doses ibuprofen is associatedwith the least risk of gastrointestinal complications com-pared with other NSAIDs [25ndash27] No new safety concernswere raised by the current study treatment with singledoses of sodium ibuprofen and ibuprofenpoloxamer werewell tolerated with AE profiles comparable to that ofacetaminophen The most frequently reported AEs consid-ered to be related to study treatment (ie nausea headachevomiting and dizziness) are not unexpected in patientsrecovering from dental surgery

In conclusion these results suggest that compared withacetaminophen both the sodium ibuprofen and ibuprofenacid incorporating poloxamer formulations are more effi-cacious in providing rapid and sustained analgesia and areassociated with pain relief in a greater proportion ofpatients undergoing surgical removal of impacted third

molars Together with the favourable safety profile ofibuprofen these findings support a recommendation forthis agent as an analgesic of choice for the treatment ofpost-operative dental pain

Acknowledgements The authors would like to acknowledgeFranklin S Bonasso DDS and R Dean Jasper DDS (Central OralSurgery Group) Barbara Hernandez MA CCRC Michael Goulder(Worldwide Clinical Trials UK Ltd) for statistical support andVandana Sahajpal PhD and Quyen Chu PhD (Sudler amp HennesseyLondon) for medical writing support

Conflict of interest This study was funded by Reckitt BenckiserGroup plc Stephen Daniels (Premier Research Group ClinicalResearch Centers USA) is the Co-ordinating Investigator SandieReader and Phillip Berry are employees of Reckitt Benckiser Group plc

References

1 Sweetman SC (ed) (2002) Ibuprofen In Martindale the completedrug reference 33rd edn Pharmaceutical Press London

2 Mehlisch DR Sollecito WA Helfrick JF et al (1990) Multicenterclinical trial of ibuprofen and acetaminophen in the treatment ofpostoperative dental pain J Am Dent Assoc 121257ndash263

3 Roy S (1983) A double-blind comparison of propionic acidderivative (ibuprofen) and a fenamate (mefanamic acid) in thetreatment of dysmenorrhoea Obstet Gynecol 61628ndash632

4 Moran M (1991) Double-blind comparison of diclofenac potassi-um ibuprofen and placebo in the treatment of ankle sprain J IntMed Res 19121ndash130

5 Goswick CB (1983) Ibuprofen versus propoxyphene hydrochlo-ride and placebo in acute musculoskeletal trauma Curr Ther ResClin Exp 34685ndash692

6 Schachtel BP Thoden WR (1988) Onset of action of ibuprofenin the treatment of muscle-contraction headache Headache28471ndash474

7 Pearce I Frank GJ Pearce JMS (1983) Ibuprofen compared withacetaminophen in migraine Practitioner 227465ndash467

8 Dewland P Reader S Berry P (2008) Bioavailability of ibuprofenfollowing oral administration of standard ibuprofen sodiumibuprofen or ibuprofen acid incorporating poloxamer in healthyvolunteers Eur J Clin Pharmacol (submitted)

9 Geisslinger G Menzel S Wissel K Brune K (1993) Single dosepharmacokinetics of different formulations of ibuprofen andaspirin Drug Invest 5238ndash242

10 Schleier P Prochnau A Schmidt-Westhausen AM et al (2007)Ibuprofen sodium dihydrate an ibuprofen formulation withimproved absorption characteristics provides faster and great-er pain relief than ibuprofen acid Int J Clin Pharmacol Ther4589ndash97

11 Black P Max MB Desjardins P et al (2002) A randomizeddouble-blind placebo-controlled comparison of the analgesic

efficacy onset of action and tolerability of ibuprofen arginateand ibuprofen in postoperative dental pain Clin Ther241072ndash1089

12 Desjardins P Black P Papageorge M et al (2002) Ibuprofenarginate provides effective relief from postoperative dental painwith a more rapid onset of action than ibuprofen Eur J ClinPharmacol 58387ndash394

13 Albert KS Gernaat CM (1984) Pharmacokinetics of ibuprofenAm J Med 7740ndash46

14 Davies NM (1998) Clinical pharmacokinetics of ibuprofen Thefirst 30 years Clin Pharmacokinet 34101ndash114

15 Cooper SA Precheur H Rauch D et al (1984) The analgesicefficacy of ibuprofen compared to acetaminophen with codeine(abstract) Clin Pharmacol Ther 35232

16 Mehlisch D Frakes L (1984) A controlled comparative evaluationof acetaminophen and aspirin in the treatment of post-operativepain Clin Ther Exerpta Med 789ndash97

17 Mehlisch D Markenson J Schnitzer T (1999) The efficacy ofnonsteroidal anti-inflammatory drugs for acute pain CancerControl 65ndash9

18 Daniels SE Desjardins PJ Talwalker S et al (2002) The analgesicefficacy of valdecoxib vs oxycodoneacetaminophen after oralsurgery J Am Dental Assoc 133611ndash621

19 Mehlisch DR Ardia A Pallotta T (2002) A controlled compar-ative study of ibuprofen arginate versus conventional ibuprofen inthe treatment of postoperative dental pain J Clin Pharmacol42904ndash911

20 World Medical Association (1964) Declaration of HelsinkiEthical principles for medical research involving human patientsAdopted by the 18th WMA General Assembly 1964 and amendedby the 29th 35th 41st and 48th WMA General Assemblies

21 European Parliament and Council of 4 April 2001 (2001)Directive 200120EC of the approximation of the laws regu-lations and administrative provisions of the Member Statesrelating to the implementation of good clinical practice in theconduct of clinical trials on medicinal products for human useOfficial Journal of the European Communities Brussels

22 Mehlisch DR Jasper RD Brown P et al (1995) Comparativestudy of ibuprofen lysine and acetaminophen in patients withpostoperative dental pain Clin Ther 17852ndash860

23 Olson NZ Otero AM Marrero I et al (2001) Onset of analgesiafor liquigel ibuprofen 400 mg acetaminophen 1000 mg ketopro-fen 25 mg and placebo in the treatment of postoperative dentalpain J Clin Pharmacol 411238ndash1247

24 Sachs C (2005) Oral analgesics for acute nonspecific pain AmFam Physician 71913ndash918

25 Doyle G Furey S Berlin R et al (1999) Gastrointestinal safetyand tolerance of ibuprofen at maximum over-the-counter doseAliment Pharmacol Ther 13897ndash906

26 Henry D Lim LL Garcia Rodriguez LA et al (1996) Variability inrisk of gastrointestinal complications with individual non-steroidalanti-inflammatory drugs results of collaborative met-analysis BrMed J 3121563ndash1566

27 Henry D McGettigan P (2003) Epidemiology overview ofgastrointestinal and renal toxicity of NSAIDs Int J Clin Pract13543ndash49

BRITISH DENTAL JOURNAL VOLUME 194 NO 3 FEBRUARY 8 2003 153

RESEARCH

An investigation into the comparative efficacyof soluble aspirin and solid paracetamol inpostoperative pain after third molar surgeryR A Seymour1 J E Hawkesford2 J Sykes3 M Stillings4 and C M Hill5

Objective To compare the efficacy of soluble aspirin 900 mg andparacetamol 1000 mg in patients with postoperative pain after thirdmolar surgeryDesign A randomised placebo controlled double-blind studySetting Day stay units of Oral and Maxillofacial Surgery at CardiffDental Hospital and Hexham General Hospital NorthumberlandSubjects and methods One hundred and sixty-seven (104 female)patients who required the removal of their impacted third molars undergeneral anaesthesiaIntervention In the early postoperative period patients were medicatedwith either a single dose of soluble aspirin 900 mg solid paracetamol1000 mg or placebo Main outcome measures Pain intensity was measured on 100 mmvisual analogue scales at 0 5 10 15 20 30 45 60 90 120 and 240minutes after dosing Other efficacy variables evaluated included time torescue medication and an overall assessment of the study medicationefficacy by the patient on completion of the studyResults One hundred and sixty-seven patients consented to take part inthe study but only 153 were medicated Of the 14 patients not treated10 failed to develop sufficient pain to enter the study two withdrewconsent one had an adverse reaction to the general anaesthetic and onewas a protocol violator Over the four hour investigation period patientstreated with soluble aspirin reported significantly less pain whencompared with those treated with paracetamol (mean difference inAUC0-240 = -2001 95 CI ndash3893 to ndash109 p=0038) and placebo (meandifference in AUC0-240 = -3470 95 CI ndash5719 to ndash1221 p=0003)

1Head of Department Professor of Restorative Dentistry Department of RestorativeDentistry Dental School University of Newcastle Newcastle upon Tyne 2Consultant Oraland Maxillofacial Surgeon Department of Oral and Maxillofacial Surgery NewcastleGeneral Hospital Newcastle upon Tyne 3Clinical Statistician Reckitt Benckiser Healthcare(UK) Hull 4Head of Global Professional Relations Reckitt Benckiser Healthcare (UK) Hull5Consultant Oral and Maxillofacial Surgeon Department of Oral Surgery Dental SchoolUniversity of Wales College of Medicine Cardiff Correspondence to Professor R A Seymour Department of Restorative Dentistry DentalSchool University of Newcastle upon Tyne Framlington Place Newcastle upon TyneEngland NE2 4BWE-mail R A Seymournclacuk

Refereed paperReceived 080302 Accepted 060902copy British Dental Journal 2003 194 153ndash157

Similarly at 20 and 30 minutes after dosing patients in the solubleaspirin group were reporting significantly less pain than those in theparacetamol treatment group (mean difference in pain intensity at 20minutes ndash79 95 CI ndash153 to ndash06 p=0035 at 30 minutes ndash106 95CI ndash186 to ndash26 p=0010) There were no significant differences betweentreatment groups with respect to the number of patients requiringrescue medication however the time to dosing was significantly longerfor those taking soluble aspirin when compared with placebo (hazardratio 234 95 CI 141 to 388 plt0001) Conclusion The findings from this study showed that soluble aspirin900 mg provides significant and more rapid analgesia than paracetamol1000 mg in the early postoperative period after third molar surgery

INTRODUCTIONBoth aspirin (acetylsalicylic acid) and paracetamol (acetamino-phen) are widely available analgesics The drugs are used exten-sively in dentistry either self-prescribed by the patient or recom-mended by the dental surgeon Despite such use there have beenfew comparative studies on these analgesics and the studies pub-lished seem to suggest that the drugs are equi-analgesic1 Morerecent evidence suggests that many factors appear to influence theefficacy of aspirin in postoperative dental pain These include for-mulation dose and plasma concentration of acetylsalicylate2-5

The latter appears to be determined by plasma aspirin esteraseactivity By contrast there is limited information on the efficacy ofparacetamol in postoperative dental pain

Historically there have been many studies comparing the effi-cacy of a whole range of analgesics which have used aspirin as thestandard treatment (positive control) In such studies the formula-tion chosen has invariably been a solid format of the drug This hasled to the impression that aspirin is relatively weak and slow act-ing Previous studies34 have shown that soluble aspirin provides agreater onset of action and is overall more effective than solidaspirin However up to the present time there has been no studycomparing the efficacy of soluble aspirin with solid paracetamolThe present study was designed to investigate whether the superi-ority of soluble aspirin over solid aspirin would be reproducedwhen compared with solid paracetamol The doses chosen for each

This study has shown the benefits of soluble aspirin (900 mg) over solid paracetamol (1000 mg)in the control of postoperative pain after third molar extractions

The aspirin preparation provided an earlier onset of pain relief when compared with paracetamol Most patients in the study did require additional analgesia in the early postoperative period

but the time to remedication was significantly longer in soluble aspirin group whencompared with the placebo

Adverse events due to the medication were few and showed no differences between treatmentgroups

Soluble aspirin 900 mg appears to be a more useful analgesic than paracetamol in the controlof postoperative pain after third molar surgery

I N B R I E F

RESEARCH

154 BRITISH DENTAL JOURNAL VOLUME 194 NO 3 FEBRUARY 8 2003

preparation used in this study is the maximum recommendedwhen purchased as over the counter (OTC) medications

Removal of impacted third molars remains a common dentalsurgical procedure that results in a significant level of postopera-tive pain6 Pain is usually of short duration and reaches its maxi-mum intensity in the early postoperative period7 It is during thistime period that analgesics are frequently prescribed The nature ofthe pain and its duration make the third molar pain model usefulfor evaluation of analgesic efficacy

The overall aim of the present study was to directly compare theefficacy of soluble aspirin with that of solid paracetamol tablets inpatients with postoperative pain after third molar surgery A place-bo group was also used to act as a negative control Within thisoverall remit the primary aim of the study was to compare theonset of efficacy between the two preparations

MATERIAL AND METHODSAdult patients who required the removal of at least one impactedlower third molar were invited to participate in the study Patientswere enrolled from two centres (Cardiff and Hexham) Informedwritten consent was obtained from each patient prior to theirentry into the study which had received ethical approval from theappropriate local Health Authority Ethical Committees Patientsenrolled into the study were fit and healthy and complied with thecriteria of the American Society of Anaesthesiologists categoryone or at the discretion of the dental surgeon category two Allpatients attended a screening clinic prior to their participation inthe study The pre-screening was held up to a maximum of threeweeks before surgery Patients were asked to abstain from takingany analgesics for 24 hours prior to their third molar extractions

Patients underwent the removal of their impacted third molarsunder general anaesthesia The anaesthetic regimen was accord-ing to routine clinical practice at the dental centre and includedinduction with intravenous propofol Muscle relaxation wasachieved with vecuronium atracurium pancurium mivacuriumor suxamethonium Anaesthesia was maintained with nitrousoxide oxygen and either isoflurane enflurane or sevofluranePerioperative analgesia was provided by fentanyl or alfentanyl

Impacted third molars were removed following a standard tech-nique Bone removal was carried out with a drill under saline sprayThe operating time (from first incision to completion of last suture)was recorded for each patient On completion of the surgical proce-dure time was allowed for the patients to recover fully from theeffects of the anaesthetic They were then returned to the wardwhere they were monitored by the study nurse and their pain inten-sity assessed on 100 mm visual analogue scales (VAS) The bound-aries of the scale were marked lsquono painrsquo and lsquoworst pain imaginablersquoWhen patientsrsquo pain intensity reached a level in excess of 30 mm onthe VAS they were randomised to study medication Patients whosepain intensity did not reach the required level or who did notrequest analgesia within 1frac12 hours post-operatively were with-drawn from the study Each eligible patient was randomly allocatedto one of the following treatment groups soluble aspirin (Disprinreg)900 mg solid paracetamol tablets BP 1000 mg or placebo In order

to double-blind the study a double-dummy technique was usedEach patient assigned to receive active soluble aspirin or activesolid paracetamol also received a placebo for the alternative treat-ment and placebo patients received a placebo for both formula-tions Soluble aspirin and the aspirin placebo were presented as anorange drink Paracetamol active and placebo were given as tabletsPatients were randomised to treatment groups in the ratio of 2aspirin2 paracetamol1 placebo The randomisation was stratifiedfor gender A randomisation block size of five was used to ensurebalance between the treatment groups

Pain assessmentThe following measures were used to evaluate efficacya) Pain intensity measures were recorded immediately pre-dose (0

minutes) and at 5 10 15 20 30 45 60 90 120 and 240 minutesafter dosing Onset of analgesia was primarily assessed by painintensity measures at 10 15 20 and 30 minutes

b)Pain intensity over the four hour investigation period The serial VAS measures of the four hour investigation periodwere compiled into a graph of pain (mm) versus time (minutes)The area under the graph (AUC) was calculated using the trape-zoidal method and denoted as AUC240 Such a measure gives anoverall assessment of each patientrsquos pain experience throughoutthe four hour investigation period8

c) Use of rescue medicationIn the event of poor pain control patients were allowed access toalternative analgesia (ibuprofen 400 mg) Patients were encour-aged not to request re-medication in the first hour post-dosingin order to give the study medication time to work For thosetaking additional analgesics the time was recorded and theirlast pre-rescue medication intensity score was extrapolated overthe remaining time points9

d)Overall evaluation At the end of the four hour investigation period (or prior to tak-ing rescue medication) the study nurses and the patients wereasked to provide an overall evaluation of the efficacy of thestudy medication The categories were lsquovery goodrsquo lsquogoodrsquo lsquosatis-factoryrsquo lsquopoorrsquo and lsquovery poorrsquo

Throughout the investigation period a study nurse was respon-sible for monitoring the patients and recording any adverse events

Statistical methodsA previous study in postoperative pain after removal of impactedthird molars4 suggested that mean VAS differences between solu-ble aspirin and placebo and soluble aspirin and solid paracetamolof 26 mm and 14 mm respectively might be anticipated at 20 min-utes post treatment Using a randomisation of 2 soluble aspirin 2paracetamol 1 placebo a total sample size of 150 patients had atleast 80 power to detect this difference

The VAS pain intensity measurements at 10 15 20 and 30minutes after dosing and AUC240 were compared between treat-ment groups using an analysis of covariance using centre gen-der baseline pain intensity operation duration and number of

Table 1 Demographic details of patients who were medicated for the study Where appropriate results are expressed as mean (SD)Variable Soluble aspirin 900 mg Solid paracetamol 1000 mg Placebo

Number of patients 59 62 32Gender ratio MF 1940 1943 1121Age (years) 256 (56) 250 (53) 251 (47)Weight (kg) 702 (16) 719 (145) 743 (149)Mean operating time (mins) 173 (101) 165 (101) 130 (130)Number of molars removed 1 3 (5) 2 (3) 3 (9)[ patients ()] 2 15 (25) 14 (23) 5 (16)

3 11 (19) 12 (19) 9 (28)4 30 (51) 34 (55) 15 (47)

Mean baseline pain score on 100 mm VAS 574 (176) 506 (142) 541 (144)

RESEARCH

in Hexham and the remainder in Cardiff Of the 14 patients nottreated 10 failed to develop sufficient pain to enter the studytwo withdrew consent one had an adverse reaction to the anaes-thesia and one was a protocol violator Demographic details ofthe patients are shown in Table 1 The three groups were bal-anced for demographic variables

The primary aim of the study was to compare the rate of onset ofanalgesia and the 20-minute time was considered to be appropriatefor such an assessment Pain scores as recorded on the VAS at eachtime point are illustrated in Figure 1 and Tables 2a and 2b VASscores decreased in all treatment groups during the first 15 minutespost dosing (Figure 1) At 20 minutes post dosing patients in the sol-

molars removed as covariates Use of rescue medication and thestudy nursesrsquo and patientsrsquo overall impression of their medicationwere analysed using binomial logistic regression with a lsquopositiversquooutcome defined as a response of lsquovery goodrsquo or lsquogoodrsquo Time toadministration of rescue medication was compared betweentreatment groups using Coxrsquos proportional hazard model Com-parisons were performed for soluble aspirin versus solid paraceta-mol and soluble aspirin versus placebo

RESULTSOne hundred and sixty seven patients consented to take part inthe study and 153 were medicated Of these 29 were medicated

0 5 10 15 20 30 45 60 90 120 240

Time (mins)

Soluble AspirinParacetamolPlacebo

Figure 1 Graph to show mean pain scores (mm) versus time (mins) for patients after treatment with placebo solid paracetamol 1000 mg and solubleaspirin 900 mg

Table 2a Summary of efficacy parameters recorded during the investigation period pain scoresBetween treatment comparisons

Variable Soluble aspirin 900 mg Solid paracetamol 1000 mg Placebo Soluble aspirin vs placebo Soluble aspirin vs solid paracetamol

Mean difference (95 CI) p-value Mean difference (95 CI) p-value

Pain score (in mm) 10 mins after dosing 412 (28) 482 (29) 474 (33) -61 (-133 to 10) 0092 -70 (-130 to ndash09) 0024Pain score (in mm) 15 mins after dosing 407 (32) 458 (33) 445 (38) -39 (-120 to 43) 0350 -51 (-120 to 18) 0143Pain score (in mm) 20 mins after dosing 402 (34) 481 (35) 500 (40) -98 (-186 to ndash11) 0028 -79 (-153 to ndash06) 0035Pain score (in mm) 30 mins after dosing 356 (37) 462 (38) 476 (44) -120 (-216 to ndash25) 0014 -106 (-186 to ndash26) 0010Overall pain - AUC240(mmmins) 8001 (871) 10002 (898) 11471 (1035) -3470 (-5719 to ndash1221) 0003 -2001 (-3893 to ndash109) 0038

data presented are adjusted (least squares) mean (standard error of the mean)

Table 2b Summary of efficacy parameters recorded during the investigation period use of escape medicationBetween treatment comparisons

Odds (hazard) ratio (95 CI) p-value Odds (hazard) ratio (95 CI) p-value

Number of patients 48 (81) 46 (74) 29 (91) 0172 (0020 to 1052) 0078 1485 (0455 to 5197) 0518taking escape analgesics

Time (minutes) to 115 (63 - 165) 94 (47 - ++) 64 (42 ndash 117) 234 (141 to 388) lt0001 130 (084 to 203) 0236remedication

data presented are median (Inter Quartile Range)++ Upper quartile cannot be estimated

RESEARCH

uble aspirin group reported significantly less pain than those treatedwith solid paracetamol (p=0035) or placebo (p=0028) Similarlypain intensity was significantly less at 10 and 30 minutes post dos-ing for patients treated with soluble aspirin when compared withsolid paracetamol (p=0024 and 0010 respectively) Pain intensitywas also significantly less for patients treated with soluble aspirinwhen compared with placebo at 30 minutes post dosing (p=0014)but was not significant at 10 minutes post-dosing (p=0092) By con-trast to these findings at 15 minutes after dosing pain scores werenot significantly different between soluble aspirin and placebo(p=0350) or between soluble aspirin and solid paracetamol(p=0143) Overall pain scores as assessed by the AUC240 were sig-nificantly lower in the soluble aspirin group when compared withsolid paracetamol (p=0038) and placebo (p=0003) There was nosignificant centre difference for any of the pain intensity variables

The use of rescue medication and time to requesting such med-ication is also shown in Table 2b There was no significant differ-ence between soluble aspirin and solid paracetamol or placebowith respect to the number of patients requiring rescue medicationduring the four hour investigation period (pgt005) However thetime to administration of rescue medication was significantlylonger for those patients taking soluble aspirin when comparedwith placebo (plt0001) There was no significant difference in timeto rescue medication between the soluble aspirin treated patientsand those treated with solid paracetamol (p=0236) The time toadministration of rescue medication did show a significant centreeffect with those patients enrolled in Cardiff requiring rescueanalgesia at an earlier time point than those in Hexham (plt0001)

The study nursesrsquo and patientsrsquo overall assessment of the effica-cy of the medication is shown in Tables 3a and 3b There was nosignificant difference between soluble aspirin and solid paraceta-mol (p=0285) with respect to the percentage of lsquopositiversquo outcomesassessed by the patients however soluble aspirin was favoured incomparison with placebo (p=0010) Results were similar for thestudy nursesrsquo assessment (p=0387 p=0024)

Adverse events were reported by 41 of patients with a higheroverall incidence in the active treatment groups (Table 4) Many ofthese events were related to the procedure The most commonadverse events were in the central and peripheral nervous system(primarily dizziness) and the gastro-intestinal system (primarilynausea) The incidence of dizziness was similar in the soluble

aspirin and placebo groups (14 and 13 respectively) and wasgreater than in the solid paracetamol group (6) The incidence ofnausea was comparable in the soluble aspirin and solid paraceta-mol groups (15 and 16 respectively) and was greater than thatin the placebo group (6) Gingival bleeding (the only adverseevent recorded under lsquohaemostasisrsquo) had a slightly lower incidencein the soluble aspirin group (8) than in the solid paracetamolgroup (13) and was only slightly higher than that reported in theplacebo group (3) This finding is contrary to any expectationsthat aspirin might exacerbate post-operative bleeding

DISCUSSIONThe present study has shown that soluble aspirin 900 mg is an effec-tive analgesic in the control of postoperative pain after the removalof impacted third molars confirming the evidence from previousstudies34 In addition soluble aspirin provided better pain controlthan solid paracetamol 1000 mg This superior efficacy is reflectedin the overall pain score (Table 2a and Figure 1) and also in the painscores reported during the first 30 minutes post dosing The datasuggest that soluble aspirin is providing a more rapid reduction inpain in the early postoperative period when compared with solidparacetamol If the pain scores are examined in terms of percentagereduction when compared with baseline the results show that solu-ble aspirin is twice as effective as solid paracetamol (at 20 and 30minutes the percentage reduction for soluble aspirin is 310 and406 respectively whilst the figures for solid paracetamol are142 and 204) From the perspective of patient management arapid reduction in pain is an important requisite of any analgesicformulation10 The exception to this pattern is the pain scores at 15minutes post dosing At this time point pain intensity scores aftersoluble aspirin are not significantly different from either placebo orsolid paracetamol mdash the reason for this finding is unclear

Previous comparative efficacy studies between aspirin andparacetamol in postoperative dental pain have revealed somewhatequivocal results11112 The consensus view1 is that both aspirin andparacetamol are both equi-analgesic and equipotent The studiesuse a solid tablet formulation of aspirin at a dose of 650 mg Studiesusing similar methodology have shown that the efficacy of aspirinin postoperative dental pain is related to dose and formulation34

The use of a soluble formulation and the 900 mg dose may explainthe superior efficacy of aspirin in this study

Table 3b Distribution of scores from study nursesrsquo global assessment of the medication (number ())Score Soluble aspirin 900 mg Solid paracetamol 1000 mg Placebo Soluble aspirin vs placebo Soluble aspirin vs solid paracetamol

Odds Ratio (95 CI) p-value Odds Ratio (95 CI) p-value

Positive outcome 32 (54) 32 (52) 10 (31) 2974 (1179 to 7951) 0024 1403 (0655 to 3054) 0387Very good 15 (25) 11 (18) 3 (9)Good 17 (29) 21 (34) 7 (22)Satisfactory 17 (29) 14 (23) 12 (38)Poor 8 (14) 14 (23) 7 (22)Very poor 2 (3) 2 (3) 3 (9)Total 59 62 32

positive outcome = response of lsquovery goodrsquo or lsquogoodrsquo

Table 3a Distribution of scores from patientsrsquo global assessment of the medication (number ())Score Soluble aspirin 900 mg Solid paracetamol 1000 mg Placebo Soluble aspirin vs placebo Soluble aspirin vs solid paracetamol

RESEARCH

The primary aim of this investigation was to compare both anal-gesics with respect to onset of action Early time points were chosenfor this comparison as they represent a suitable period from dosingwhen patients would expect to experience meaningful pain reliefSoluble aspirin was significantly superior to both placebo and solidparacetamol at both 20 and 30 minutes post dosing and there wereindications of superiority as early as at 10 minutes In part this maybe due to the rapid absorption of soluble aspirin and the subsequentpeak concentrations of acetylsalicylate (Tmax) that occurs at thesetime points It has been previously shown that plasma concentra-tions of acetylsalicylate are also important determinants of aspirinrsquosefficacy in postoperative dental pain2 By contrast the absorption ofsolid paracetamol tablets is slow with a Tmax of 60 minutes13 Thusdifferences in pharmacokinetics may account for the differences inonset of analgesia observed in the present study

It is now well established that aspirin exerts both analgesic andanti-inflammatory action by inhibiting prostaglandin synthesis14

Aspirin irreversibly inhibits both cyclo-oxygenase 1 and 2 (Cox-1and Cox-2) by acetylating serine 530 thus preventing the bindingof arachidonic acid to the active sites of the enzyme The pharma-codynamics of paracetamol are uncertain and by comparison withaspirin the drug exhibits weak anti-inflammatory action This lackof a pronounced anti-inflammatory effect may also explain theweaker efficacy of this drug in postoperative dental pain

We can conclude from this study that a single dose of solubleaspirin 900 mg provides significant and more rapid analgesia thansolid paracetamol 1000 mg in the early postoperative period afterthird molar surgery This study confirms the value of soluble aspirinin the management of pain after dental surgical procedures

The authors are grateful to Reckitt Benckiser Healthcare for their support inthis study

1 Cooper S A Comparative analgesic efficacies of aspirin and acetaminophen ArchIntern Med 1981 141 282-285

2 Seymour R A Williams F M Ward A Rawlins M D Aspirin metabolism and efficacyin postoperative dental pain Br J Clin Pharmacol 1984 17 697-701

3 Seymour R A Williams F M Luyk N M et al Comparative efficacy of soluble aspirinand aspirin tablets in postoperative dental pain Eur J Clin Pharmacol 1986 30495-498

4 Holland I S Seymour R A Ward-Booth R P Ord R A Lim K L Hoare R C Anevaluation of different doses of soluble aspirin and aspirin tablets in postoperativedental pain Br J Clin Pharmacol 1988 26 463-468

5 Seymour R A Weldon M Kelly P Nicholson E Hawkesford J E An evaluation ofbuffered aspirin and aspirin tablets in postoperative pain after third molar surgeryBr J Clin Pharmacol 1992 33 395-399

6 Seymour R A Blair G S Wyatt F A Post-operative dental pain and analgesicefficacy Part I Br J Oral Surg 1983 21 290-297

7 Seymour R A Meechan J G Blair G S An investigation into post-operative painafter third molar surgery under local analgesia Br J Oral Maxillofac Surg 1985 23410-418

8 Matthews J N Altman D G Campbell M J Royston P Analysis of serialmeasurements in medical research Br Med J 1990 300 230-235

9 Lasagna L Analgesic methodology a brief history and commentary J ClinPharmacol 1980 20 373-376

10 Meechan J G Seymour R A The use of third molar surgery in clinicalpharmacology Br J Oral Maxillofac Surg 1993 31 360-365

11 Skjelbred P Album B Lokken P Acetylsalicylic acid vs paracetamol effects onpost-operative course Eur J Clin Pharmacol 1977 12 257-264

12 Mehlisch D R Frakes L A A controlled comparative evaluation of acetaminophenand aspirin in the treatment of postoperative pain Clin Ther 1984 7 89-97

13 Muir N Nichols J D Stillings M R Sykes J Comparative bioavailability of aspirinand paracetamol following single dose administration of soluble and plain tabletsCurr Med Res Opin 1997 13 491-500

14 Vane J Botting R Inflammation and the mechanism of action of anti-inflammatory drugs Faseb J 1987 1 89-96

Table 4 Incidence and distribution of adverse events for each treatment groupPercentage of patients reporting events (number of events)

Body system Soluble aspirin (n=59) Solid paracetamol (n=62) Placebo (n=32) Total (n=153)

CNS 20 (14) 8 (5) 19 (6) 15 (25)GI 17 (12) 16 (12) 6 (2) 14 (26)Body as a whole 7 (4) 13 (8) 6 (3) 9 (15)Haemostasis 8 (7) 13 (8) 3 (1) 9 (16)Respiratory 7 (4) 3 (2) 0 (0) 4 (6)Psychiatric 2 (1) 0 (0) 3 (1) 1 (2)Hearingvestibular 0 (0) 2 (1) 0 (0) 1 (1)Skinappendages 2 (1) 0 (0) 0 (0) 1 (1)Vision 2 (1) 0 (0) 0 (0) 1 (1)Total 51 (44) 39 (36) 28 (13) 41 (93)

Abstract

Abstract

Abstract

Abstract

Abstract

Introduction

Methods

Study design

Patients



Efficacy endpoints





Rainier scale

Rescue medication

Global evaluation

Safety assessments


Results












Patientrsquos overall assessment of medication as a treatment for pain

Safety findings

Discussion

References

SERAacute O PARACETAMOL EFICAZ NA ELIMINACcedilAtildeO DA DOR

APOacuteS EXTRACCcedilAtildeO DO TERCEIRO MOLAR INFERIOR1

Anaacutelise da analgesia do paracetamol comparada agrave de NSAIDrsquos

Catarina Cardoso

Ivo Cavalheiro

Nuno Pinto

Sara Mendes

FACULDADE DE MEDICINA DENTAacuteRIA DA UNIVERSIDADE DE LISBOA

Mestrado Integrado em Medicina Dentaacuteria

Biologia Oral I

2ordm Ano ndash 1ordm Semestre

23 de Dezembro de 2011

1 Este trabalho estaacute escrito segundo as regras do Acordo Ortograacutefico de 1945

RESUMO

inadequado

ABSTRACT

IacuteNDICE

QUESTAtildeO PICO 6

OBJECTIVOS 6

PESQUISA 12

PubMed 15

DISCUSSAtildeO 52

ANEXOS 61

QUESTAtildeO PICO

OBJECTIVOS

Primaacuterios

Secundaacuterios

ETIOLOGIA DA DOR

plaquetas

nociceptivas

PARACETAMOL

NSAIDrsquoS

(15 pp 277-281)

PESQUISA

sistemaacuteticas

aleatorizados

excluiacuteda (20)

ldquoadequadardquo

Derry Wiffen (21)

Hawkesford (22)

Edwards (23)

adequado

LILACS

PUBMED

Pesquisa 1

Postoperative[Mesh]

ldquoadequadosrdquo

Pesquisa 2

ldquoadequadosrdquo

discriminadas

os de interesse

secundaacuterios

paracetamol

risco de vieacutes

analgeacutesicos

Total de I2

76 81 66 29 28

efeito

tratamento

review

Barden Edwards (23)

medicaccedilatildeo

inglecircs

NSAIDrsquos

review

incluiacutedos

cirurgia

secundaacuterios

risco de vieacutes

conclusion

associados

Grupo A n = 40

Grupo B n = 40

Grupo C n = 20

deve-se a

Grupo A n = 34

Grupo B n = 36

Grupo C n = 20

Grupo D n = 17

intensidade da dor

Grupo A 90

Grupo B 83

Grupo C 42

aleatorizajao MJA)

conclusion

Grupo A n = 40

Grupo B n = 43

Grupo C n = 39

guidelines

NSAIDrsquos)

(com classe I e II)

0 cm Sem dor

gastrointestinais

seu conteuacutedo

recipiente

conclusion

acetaminofeno

horas)

de tratamento

conclusion

outros motivos

secundaacuterios

tratamento

inicial

oferecido

1000 mg

Placebo

conclusion

resultados

decisatildeo

DISCUSSAtildeO

2)86-90 Epub 20040113

20100326

(2) Available from

1050 p

Freeman 2005 1119 p

20060118

2006 1208 p

Reviews 2008(4)

20091217

Elsevier p

2007(105)

200849(1)31-7

2006114(4)293-301 Epub 20060817

200247(2)147-51 Epub 20020726

20030318

20090127

19940101

Epub 20030905

201030(4)436-47

2004328(7438)476-7

Intensiva 200719(4)475-80

Epub 20111203

20014(4)183-4

ANEXOS

Library

Possivelmente

Adequado

Saska Scartezini

(24) LILACS

Possivelmente

adequado

Bjornsson

operatoacuteria

Kubitzek Ziegler

Macleod

Bjornsson

Haanaes (29) PubMed

Possivelmente

Chopra Rehan

(30) PubMed

Possivelmente

adequado

Medve Wang

(34) PubMed

Possivelmente

adequado

Bjornsson

Haanaes (35) PubMed

Possivelmente

INTEGRALi

2008 Issue 4

1HEADER

1ABSTRACT

2BACKGROUND

3OBJECTIVES

3METHODS

5RESULTS

8DISCUSSION

9ACKNOWLEDGEMENTS

10REFERENCES

30DATA AND ANALYSES

38ADDITIONAL TABLES

42APPENDICES

43WHATrsquoS NEW

43HISTORY

44INDEX TERMS

10100214651858CD004487pub2

A B S T R A C T

Background

of wisdom teeth

Objectives

Search strategy

Selection criteria

analysed

Main results

B A C K G R O U N D

O B J E C T I V E S

postoperatively

Primary

Secondary

difference

M E T H O D S

Types of studies

cluded

Efficacy

Side effects

also searched

Language

Unpublished studies

Handsearching

wwwohgcochraneorg

were recorded

Quality assessment

(A) Yes - 1 point

(B) No - 0 points

categories

Data extraction

study funding

design)

Data synthesis

final review

used scale

Subgroup analyses

Additional Table 1

R E S U L T S

studies

excellent

to 286) Chi2 = 2644 df = 9 P = 0002 I2 = 660 NNT 4

727) Chi2 = 544 df = 5 P = 036 I2 = 82 NNT 3 (95

mg 189 (95 CI 098 to 367) Chi2 = 1445 df = 5 P = 001

421 (95 CI 297 to 598) Chi2 = 509 df = 6 P = 053 I2 =

parison

Chi2 = 4973 df = 17 P lt 00001 I2 = 658 NNT 3 (95 CI

Chi2 = 2622 df = 9 P = 0002 I2 = 657 NNT 3 (95 CI

df = 13 P = 015 I2 = 287 NNT 4 (95 CI 3 to 4) The

1000 mg 396 (95 CI 252 to 623) Chi2 = 863 df = 7 P =

= 1096 df = 7 P = 014 I2 = 362 NNTH 33 (95 CI 125

to infinity)

Subgroup analyses

anaesthetic

measurements)

intensity data

D I S C U S S I O N

fective choice

tory drugs (NSAIDS)

R E F E R E N C E S

19881(2)31ndash4

11Sndash18S

185ndash91

94Sndash105S

(3)153ndash7

198636(6)198ndash206

197930(8)308ndash9

[DOI DOI 10100214651858CD004602]

634ndash40

(4)844ndash52

33(3)139ndash42

(5)235ndash41

2139ndash42

198435(6)843ndash51

198624(11)598ndash601

1982152(1)18ndash20

(4)498ndash509

45(2)99ndash103

200247(2)147ndash51

79ndash81

(4)266

(10)424ndash9

(1)27ndash34

73(21)1659ndash64

199616(2-3)57ndash65

(3)215ndash8

200498(1)159ndash65

Aronoff 2006

200299(21)13926ndash31

Collins 1999

14651858CD001548]

Cooper 1976

Coulthard 2001

Dray 1997

(6)704ndash12

Fisher 1988

Loeser 1999

(9164)1607ndash9

Malmberg 1992

Moore 1997

(3)287ndash94

Moore 1998

CD001547 DOI 10100214651858CD001547]

Rang 2003

Seymour 1985

Cooper 1980

Risk of bias

Cooper 1981

26 severe 11)

Notes Sponsored by

Adria Laboratories

Risk of bias

Cooper 1988

erate 25 severe 15)

Notes Sponsored by

Parke-Davis

Risk of bias

Cooper 1998

22 VAS 628

imaginable)

Notes Sponsored by

Whitehall-Robins

Risk of bias

Dionne 1994

Notes Sponsored by

Upjohn

Risk of bias

Dolci 1994

Formulation tablets

Risk of bias

Forbes 1984b

of adverse events)

Anaesthesia GA

Risk of bias

Forbes 1989

Notes Sponsored by

Risk of bias

Forbes 1990

Notes Sponsored by

Syntex Research

Risk of bias

Hersh 2000

erate 22 severe 5)

Formulation caplets

Notes Sponsored by

Whitehall-Robins

Risk of bias

Kiersch 1994

imagine)

Notes Sponsored by

Syntex Research

Risk of bias

Kubitzek 2003

Formulation tablets

Anaesthesia LA

Notes Sponsored by

Risk of bias

Lehnert 1990

Risk of bias

Mehlisch 1995

Notes Sponsored by

Risk of bias

Moller 2000

Formulation tablets

Notes Sponsored by

Risk of bias

Olson 2001

38) (30) (40)

4 severe 35)

Formulation caplets

Anaesthesia LA

Notes Sponsored by

Whitehall Robins

Risk of bias

Seymour 1996

for placebo VAS 565

Anaesthesia GA

Risk of bias

Seymour 2003

(25) (39) (415)

Formulation tablets

Anaesthesia GA

PR not stated

Notes Sponsored by

Risk of bias

Skoglund 1991

Formulation tablets

Anaesthesia LA

Notes Sponsored by

Risk of bias

Sunshine 1986

were randomised)

Anaesthesia LA

Notes Sponsored by

Upjohn

Risk of bias

Vattaraphudej 1986

Risk of bias

effects only

(Continued)

relevant data

(Continued)

studies

11 Up to 1000 mg of

paracetamol

21 Up to 1000 mg of

paracetamol

studies

11 Up to 1000 mg of

paracetamol

21 Up to 1000 mg of

paracetamol

studies

placebo

11 Up to 1000 mg of

paracetamol

Dolci 1994 5472 2576 100 228 [ 161 323 ]

Cooper 1980 1137 1138 82 103 [ 051 207 ]

Forbes 1990 936 134 30 850 [ 114 6357 ]

Forbes 1989 522 023 17 1148 [ 067 19607 ]

Cooper 1988 1636 1240 87 148 [ 081 269 ]

Cooper 1981 2137 637 77 350 [ 160 767 ]

Forbes 1984b 1339 136 30 1200 [ 165 8716 ]

Vattaraphudej 1986 716 219 47 416 [ 100 1726 ]

Sunshine 1986 1830 1530 95 120 [ 076 190 ]

Dionne 1994 2527 1725 102 136 [ 102 182 ]

Subtotal (95 CI) 352 358 667 196 [ 134 286 ]

2 1000 mg or more

01 02 05 1 2 5 10

(Continued )

Mehlisch 1995 40101 240 49 792 [ 201 3124 ]

Cooper 1998 1850 326 59 312 [ 101 963 ]

Olson 2001 4266 539 74 496 [ 215 1148 ]

Moller 2000 27120 0122 18 5591 [ 345 90627 ]

Hersh 2000 4063 527 75 343 [ 152 773 ]

Kiersch 1994 2589 345 58 421 [ 134 1321 ]

Subtotal (95 CI) 489 299 333 456 [ 286 727 ]

Total (95 CI) 841 657 1000 285 [ 189 429 ]

01 02 05 1 2 5 10

Forbes 1989 322 023 29 730 [ 040 13375 ]

Cooper 1988 1236 940 99 148 [ 071 310 ]

Forbes 1990 736 034 30 1419 [ 084 23928 ]

Dionne 1994 2427 1825 115 123 [ 093 163 ]

Forbes 1984b 1039 036 31 1943 [ 118 31995 ]

Sunshine 1986 1530 1030 104 150 [ 081 279 ]

Subtotal (95 CI) 190 188 407 189 [ 098 367 ]

2 1000 mg or more

Kubitzek 2003 4569 773 99 680 [ 329 1404 ]

Mehlisch 1995 35101 140 49 1386 [ 196 9779 ]

Kiersch 1994 2089 345 79 337 [ 106 1075 ]

Olson 2001 4166 539 94 485 [ 209 1122 ]

Hersh 2000 3563 527 95 300 [ 132 682 ]

Lehnert 1990 2349 640 96 313 [ 141 693 ]

Cooper 1998 1750 326 81 295 [ 095 914 ]

Subtotal (95 CI) 487 290 593 421 [ 297 598 ]

Total (95 CI) 677 478 1000 332 [ 188 587 ]

01 02 05 1 2 5 10

Dolci 1994 4972 576 86 1034 [ 437 2449 ]

Seymour 1996 1940 1039 96 185 [ 099 346 ]

Cooper 1980 737 438 74 180 [ 057 563 ]

Forbes 1990 1036 034 28 1986 [ 121 32639 ]

Forbes 1989 622 023 28 1357 [ 081 22736 ]

Cooper 1988 1236 840 90 167 [ 077 361 ]

Sunshine 1986 1830 630 90 300 [ 138 650 ]

Forbes 1984b 1339 036 28 2498 [ 154 40542 ]

Vattaraphudej 1986 616 119 44 713 [ 095 5317 ]

Cooper 1981 1537 037 28 3100 [ 192 49971 ]

Subtotal (95 CI) 365 372 592 433 [ 219 858 ]

2 1000 mg or more

Cooper 1998 1350 026 28 1429 [ 088 23130 ]

Mehlisch 1995 41101 340 75 541 [ 178 1648 ]

Hersh 2000 3663 127 46 1543 [ 223 10685 ]

Skoglund 1991 1632 033 28 3400 [ 213 54391 ]

Seymour 2003 1262 432 78 155 [ 054 442 ]

Seymour 1996 2040 1039 96 195 [ 105 362 ]

Kiersch 1994 989 045 28 971 [ 058 16317 ]

Moller 2000 28120 0122 28 5794 [ 358 93840 ]

Subtotal (95 CI) 557 364 408 646 [ 234 1785 ]

01 02 05 1 2 5 10

(Continued )

Total (95 CI) 922 736 1000 487 [ 283 837 ]

01 02 05 1 2 5 10

Seymour 1996 1840 939 152 195 [ 100 380 ]

Forbes 1989 422 023 16 939 [ 054 16485 ]

Cooper 1988 936 640 105 167 [ 066 422 ]

Forbes 1990 836 032 17 1516 [ 091 25267 ]

Forbes 1984b 1139 036 17 2128 [ 130 34843 ]

Sunshine 1986 1430 530 111 280 [ 115 680 ]

Subtotal (95 CI) 203 200 418 267 [ 146 490 ]

2 1000 mg or more

Hersh 2000 3163 127 33 1329 [ 191 9242 ]

Mehlisch 1995 39101 340 82 515 [ 169 1571 ]

Olson 2001 4266 739 146 355 [ 177 711 ]

01 02 05 1 2 5 10

(Continued )

Seymour 1996 2140 939 157 228 [ 119 433 ]

Cooper 1998 1250 026 17 1324 [ 081 21504 ]

Kiersch 1994 489 045 16 460 [ 025 8361 ]

Lehnert 1990 2449 542 114 411 [ 172 983 ]

Skoglund 1991 1432 033 17 2988 [ 186 48076 ]

Subtotal (95 CI) 490 291 582 396 [ 252 623 ]

Total (95 CI) 693 491 1000 341 [ 234 497 ]

01 02 05 1 2 5 10

Cooper 1980 237 637 033 [ 007 155 ]

Dolci 1994 780 882 090 [ 034 236 ]

Forbes 1990 541 038 1021 [ 058 17873 ]

Forbes 1989 326 226 150 [ 027 825 ]

Sunshine 1986 130 130 100 [ 007 1526 ]

Cooper 1981 1237 438 308 [ 109 869 ]

Dionne 1994 727 525 130 [ 047 356 ]

Vattaraphudej 1986 016 019 00 [ 00 00 ]

Forbes 1984b 143 240 047 [ 004 493 ]

Subtotal (95 CI) 337 335 125 [ 069 225 ]

2 1000 mg or more

Olson 2001 1066 239 295 [ 068 1279 ]

Cooper 1998 2550 426 325 [ 127 835 ]

Moller 2000 48120 56122 087 [ 065 117 ]

Seymour 2003 2462 932 138 [ 073 260 ]

Mehlisch 1995 1299 440 121 [ 042 354 ]

Kiersch 1994 2691 1347 103 [ 059 182 ]

Hersh 2000 1263 727 073 [ 032 166 ]

Lehnert 1990 549 440 102 [ 029 355 ]

Subtotal (95 CI) 600 373 116 [ 084 160 ]

Total (95 CI) 937 708 119 [ 090 157 ]

01 02 05 1 2 5 10

(Continued )

01 02 05 1 2 5 10

Cooper 1980 37 2 37 6

Cooper 1981 37 12 38 4

Dionne 1994 27 7 25 5

Dolci 1994 80 7 82 8

Forbes 1984b 43 1 40 2

Forbes 1989 26 3 26 2

Forbes 1990 41 5 38 0

Gallardo 1990 15 5 11 3

Seymour 1996 40 0 39 0

Sunshine 1986 30 1 30 1

Totals 392 43 385 31

Cooper 1980 1 0 1

Cooper 1981 1 0 1

Cooper 1988 1 0 1

Cooper 1998 1 1 2

Dionne 1994 1 0 1

Dolci 1994 1 0 1

Forbes 1984b 2 0 2

Forbes 1989 1 0 1

Forbes 1990 2 0 2

Hersh 2000 1 1 2

Kiersch 1994 1 1 2

Kubitzek 2003 1 1 2

Lehnert 1990 1 1 2

Mehlisch 1995 2 1 3

Moller 2000 1 1 2

Olson 2001 2 1 3

Seymour 1996 1 1 2

Seymour 2003 2 0 2

Skoglund 1991 2 0 2

Sunshine 1986 2 1 3

50 pain relief at 4

lief )

higher doses

50 pain relife at 6

lief )

higher doses

lt0001

50 pain relief at

4 hours (using pain

intensity)

higher doses

50 pain relief at

6 hours (using pain

intensity)

higher doses

Nausea 21 11

Vomiting 11 3

abdominal pain

Headache 47 31

Bleeding 11 7

Paraesthesia 4 2

Jawache 1 0

Swelling 1 6

Cellulitis 1 0

Dry socket 11 12

CNS 5 6

GI 12 2

Body as a whole 8 3

Respiratory 2 0

Psychiatric 0 1

Cooper 1980 37 089 38 089

Cooper 1981 37 192 37 062

Cooper 1988 36 238 40 205

Dionne 1994 27 240 25 200

Dolci 1994 72 210 76 217

Forbes 1984 39 126 36 028

Mean 248 183 252 144

Forbes 1989 26 100 26 030

Forbes 1990 41 147 38 056

Sunshine 1986 30 120 30 093

Mean 113 131 113 070

Kiersch 1994 91 130 47 060

Kubitzek 2003 78 198 84 145

Mehlisch 1995 101 157 40 045

Olson 2001 66 281 39 193

Seymour 2003 62 250 32 214

Mean 398 194 242 129

Hersh 2000 63 229 27 085

Moller 2000 120 188 122 154

Mean 183 202 149 141

A P P E N D I C E S

5 (1 or 2 or 3 or 4)

18 (5 and 17)

H I S T O R Y

None known

Internal sources

External sources

I N D E X T E R M S

MeSH check words

Humans

I N B R I E F

RESEARCH

07p407-411qxd 10092004 1518 Page 407

RESEARCH

Ibuprofen 400 mg 107200 110400 109000 103900

Ibuprofen 600 mg 34200 39700 40800 42600

Ibuprofen 200 mg 36300 34600 32000 30600

Paracetamol 500 mg 11100 12800 15400 17200

Pethidine 50 mg 1100 900 700 700

Aspirin 300 mg 200 200 200 200

07p407-411qxd 10092004 1519 Page 408

RESEARCH

Aspirin 600650 mg 6271788 (36) 2551847 (15) 25 (22 to 29) 47 (42 to 54) 3635 46

07p407-411qxd 10092004 1519 Page 409

RESEARCH

07p407-411qxd 10092004 1520 Page 410

RESEARCH

07p407-411qxd 10092004 1520 Page 411

I N B R I E F

Aspirin 600650 mg 45 3581 36 14 45 (40 to 52) 30

Celecoxib 400 mg 4 620 34 3 25 (22 to 29) 84

Ibuprofen 400 mg 49 5428 55 12 23 (22 to 24) 56

Naproxen 500550 mg 5 402 61 7 18 (16 to 21) 89

PRACTICE

Ibuprofen 400 mg

Aspirin 600650 mg

Aspirin 1000 mg

Paracetamol 1000

Naproxen 500550

Celecoxib 400 mg

Diclofenac 50 mg K

Etoriocoxib 120 mg

1 2 3 4 5 6

Study design

Patients

Surgery

Table 1

Study groups

Rofecoxib50 mg +

Rofecoxib50 mg

1 1 0 0

Paracetamol200 mg

5 0 5 0

6 6 6 6

Analysis

Statistics

Results

Analgesic effect

Table 2

Study groups

Table 3

Study groups

5 6 2 3

Placebo

01234567

0 1 2 3 4 5 6 7 8

Paracetamol 1g

01234567

0 1 2 3 4 5 6 7 8

Rofecoxib 50 mg

01234567

0 1 2 3 4 5 6 7 8

01234567

0 1 2 3 4 5 6 7 8

0 05 1 15 2 25 3 35 4 45 5 55 6 65 7 75 8

placebo

paracetamol 1g

rofecoxib 50mg

placebo

rofecoxib 50mg

rofecoxib 50mg +

05 1 15 2 25 3 35 4 45 5 55 6 65 7 75 8

paracetamol 1g

Table 4

Study groups

452 (20) 409 (27) 287 (44) 91 (27)

182 (19) 151 (18) 111 (34) )32 (23)

Mean SPIDtotal (SE)

526 (59) 515 (60) 208 (96) )101 (57)

05 1 15 2 25 3 35 4 45 5 55 6 65 7 75 8

tion placebo

paracetamol 1g

rofecoxib 50mg

Side-effects

Global evaluation

Discussion

Table 5

Study groups

Table 6

Study groups

Rofecoxib+

paracet-amol

Paracet-amol

4 h 8 h 4 h 8 h 4 h 8 h 4 h 8 h

and B J Anderson1

doi101093bjaaep338

improve compliance

Methods

ACTRN12606000291583)

Setting

New Zealand

Participants

Intervention

4 hourly

Outcomes

Statistical methods

based variables

primary endpoint

Results

Merry et al

for acetaminophen

Efficacy

Pharmacokinetics

diction intervals

(P005)

70 kg21)18 ndash 20

Adverse effects

Screened(n =189)

Randomized(n =135)

Weight [mean (SD)] (kg) 713 (156) 808 (201) 711 (135)

Ethnicity [n ()]

Asian 4 (85) 1 (23) 2 (45)

Black 1 (21) 0 (00) 1 (23)

Caucasian 33 (702) 31 (705) 34 (773)

Maori 4 (85) 4 (91) 4 (91)

Other 1 (21) 3 (68) 1 (23)

Male [n ()] 13 (277) 21 (477) 13 (295)

Shift workers [n ()] 10 (213) 5 (114) 3 (68)

medication

General

ActivityRest

Acetaminophen alone

Ibuprofen alone

Combination

Acetaminophen

(n543)

(n540)

activity

0 4 8 12 16 20 24 28 32 36 40 44 48

Hours post-surgery

Nil 3 (75) 4 (114) 4 (105)

Mild 12 (300) 15 (429) 22 (579)

Moderate 22 (550) 14 (400) 12 (316)

Severe 3 (75) 2 (57) 0 (00)

Nil 26 (650) 25 (714) 30 (790)

Mild 10 (250) 8 (229) 7 (184)

Moderate 3 (75) 2 (57) 1 (26)

Severe 1 (25) 0 (00) 0 (00)

1 vs baseline VAS

[mean (SD)] (mm)

2219 (292) 2174 (229) 2166 (247)

2 vs baseline VAS

[mean (SD)] (mm)

2137 (329) 296 (258) 285 (201)

significant

Acetaminophen

alone (n515)

Acetaminophen

Ibuprofen

alone(n511)

Ibuprofen in

combination(n512)

CLF (litre

141 (26) 142 (18) 39 (17) 38 (13)

VF (litre) 557 (194) 482 (183) 106 (21) 98 (15)

Tabs (h) 042 (076) 016 (010) 058 (078) 085 (085)

Tmax (h) 109 (112) 064 (031) 116 (090) 144 (093)

Cmax (mg

litre21)

158 (65) 192 (64) 208 (83) 191 (78)

Merry et al

Discussion

phlebitis)

0 0 2 2

Subtotal 3 1 6 10

legs jaw pain)

2 0 1 3

6 4 4 14

1 1 2 4

Subtotal 18 8 12 38

ache vomiting)

3 0 2 5

Subtotal 5 0 4 9

Total 26 9 22 57

Conclusions

Funding

Development Grants

Appendix

capacity

Merry et al

Contributors

Ethics approval

Zealand

TT50-7316 (458)

Role of the sponsor

results

Merry et al

Paracetamol 000 300 000 030 070

Dipyrone 000 100 000 010 040

Paracetamol 000 300 100 060 070

Dipyrone 000 200 100 070 070

Paracetamol 000 300 100 080 090

Dipyrone 000 300 100 080 080

Paracetamol 000 200 100 080 070

Dipyrone 000 300 100 100 100

Paracetamol 000 300 100 080 090

Dipyrone 000 300 000 060 080

Paracetamol 000 200 000 060 080

Dipyrone 000 300 000 040 080

Paracetamol 000 200 000 055 070

Dipyrone 000 300 000 040 090

Paracetamol 000 200 000 040 070

Dipyrone 000 300 000 030 070

Lisyne clonixinate

Right after 00 10 00 02 04

lt 0001

Paracetamol

Right after 00 30 00 03 07

lt 0001

Dipyrone

Right after 00 10 00 01 04

lt 0001

CLINICAL TRIAL

Michael Goulder

Sodium ibuprofen

Introduction

Methods

Study design

Patients

Efficacy endpoints

Rainier scale

Rescue medication

Global evaluation

Safety assessments

Results

IBUPROFENPOLOXAMER

Total screened 614

ACETAMINOPHEN

PLACEBO

Completed 76

SODIUM IBUPROFEN

Timepoint (mins)

0 50 100 150 200 250

Timepoint (mins)

0 50 100 150 200 250

Acetaminophen(n=80)

Placebo(n=81)

Total(n=321)

Timepoint (minutes)

0 15 35 60 90 120 180 240 300 360

Timepoint (mins)

0 50 100 150 200 250

Safety findings

Discussion

Numberof events

References

RESEARCH

I N B R I E F

RESEARCH

3 11 (19) 12 (19) 9 (28)4 30 (51) 34 (55) 15 (47)

RESEARCH

0 5 10 15 20 30 45 60 90 120 240

Time (mins)

RESEARCH

Abstract

Abstract

Abstract

Abstract

Abstract

Introduction

Methods

Study design

Patients



Efficacy endpoints





Rainier scale

Rescue medication

Global evaluation

Safety assessments


Results













Safety findings

Discussion

References

RESUMO

inadequado

ABSTRACT

IacuteNDICE

QUESTAtildeO PICO 6

OBJECTIVOS 6

PESQUISA 12

PubMed 15

DISCUSSAtildeO 52

ANEXOS 61

QUESTAtildeO PICO

OBJECTIVOS

Primaacuterios

Secundaacuterios

ETIOLOGIA DA DOR

plaquetas

nociceptivas

PARACETAMOL

NSAIDrsquoS

(15 pp 277-281)

PESQUISA

sistemaacuteticas

aleatorizados

excluiacuteda (20)

ldquoadequadardquo

Derry Wiffen (21)

Hawkesford (22)

Edwards (23)

adequado

LILACS

PUBMED

Pesquisa 1

Postoperative[Mesh]

ldquoadequadosrdquo

Pesquisa 2

ldquoadequadosrdquo

discriminadas

os de interesse

secundaacuterios

paracetamol

risco de vieacutes

analgeacutesicos

Total de I2

76 81 66 29 28

efeito

tratamento

review

Barden Edwards (23)

medicaccedilatildeo

inglecircs

NSAIDrsquos

review

incluiacutedos

cirurgia

secundaacuterios

risco de vieacutes

conclusion

associados

Grupo A n = 40

Grupo B n = 40

Grupo C n = 20

deve-se a

Grupo A n = 34

Grupo B n = 36

Grupo C n = 20

Grupo D n = 17

intensidade da dor

Grupo A 90

Grupo B 83

Grupo C 42

aleatorizajao MJA)

conclusion

Grupo A n = 40

Grupo B n = 43

Grupo C n = 39

guidelines

NSAIDrsquos)

(com classe I e II)

0 cm Sem dor

gastrointestinais

seu conteuacutedo

recipiente

conclusion

acetaminofeno

horas)

de tratamento

conclusion

outros motivos

secundaacuterios

tratamento

inicial

oferecido

1000 mg

Placebo

conclusion

resultados

decisatildeo

DISCUSSAtildeO

2)86-90 Epub 20040113

20100326

(2) Available from

1050 p

Freeman 2005 1119 p

20060118

2006 1208 p

Reviews 2008(4)

20091217

Elsevier p

2007(105)

200849(1)31-7

2006114(4)293-301 Epub 20060817

200247(2)147-51 Epub 20020726

20030318

20090127

19940101

Epub 20030905

201030(4)436-47

2004328(7438)476-7

Intensiva 200719(4)475-80

Epub 20111203

20014(4)183-4

ANEXOS

Library

Possivelmente

Adequado

Saska Scartezini

(24) LILACS

Possivelmente

adequado

Bjornsson

operatoacuteria

Kubitzek Ziegler

Macleod

Bjornsson

Haanaes (29) PubMed

Possivelmente

Chopra Rehan

(30) PubMed

Possivelmente

adequado

Medve Wang

(34) PubMed

Possivelmente

adequado

Bjornsson

Haanaes (35) PubMed

Possivelmente

INTEGRALi

2008 Issue 4

1HEADER

1ABSTRACT

2BACKGROUND

3OBJECTIVES

3METHODS

5RESULTS

8DISCUSSION

9ACKNOWLEDGEMENTS

10REFERENCES

30DATA AND ANALYSES

38ADDITIONAL TABLES

42APPENDICES

43WHATrsquoS NEW

43HISTORY

44INDEX TERMS

10100214651858CD004487pub2

A B S T R A C T

Background

of wisdom teeth

Objectives

Search strategy

Selection criteria

analysed

Main results

B A C K G R O U N D

O B J E C T I V E S

postoperatively

Primary

Secondary

difference

M E T H O D S

Types of studies

cluded

Efficacy

Side effects

also searched

Language

Unpublished studies

Handsearching

wwwohgcochraneorg

were recorded

Quality assessment

(A) Yes - 1 point

(B) No - 0 points

categories

Data extraction

study funding

design)

Data synthesis

final review

used scale

Subgroup analyses

Additional Table 1

R E S U L T S

studies

excellent

to 286) Chi2 = 2644 df = 9 P = 0002 I2 = 660 NNT 4

727) Chi2 = 544 df = 5 P = 036 I2 = 82 NNT 3 (95

mg 189 (95 CI 098 to 367) Chi2 = 1445 df = 5 P = 001

421 (95 CI 297 to 598) Chi2 = 509 df = 6 P = 053 I2 =

parison

Chi2 = 4973 df = 17 P lt 00001 I2 = 658 NNT 3 (95 CI

Chi2 = 2622 df = 9 P = 0002 I2 = 657 NNT 3 (95 CI

df = 13 P = 015 I2 = 287 NNT 4 (95 CI 3 to 4) The

1000 mg 396 (95 CI 252 to 623) Chi2 = 863 df = 7 P =

= 1096 df = 7 P = 014 I2 = 362 NNTH 33 (95 CI 125

to infinity)

Subgroup analyses

anaesthetic

measurements)

intensity data

D I S C U S S I O N

fective choice

tory drugs (NSAIDS)

R E F E R E N C E S

19881(2)31ndash4

11Sndash18S

185ndash91

94Sndash105S

(3)153ndash7

198636(6)198ndash206

197930(8)308ndash9

[DOI DOI 10100214651858CD004602]

634ndash40

(4)844ndash52

33(3)139ndash42

(5)235ndash41

2139ndash42

198435(6)843ndash51

198624(11)598ndash601

1982152(1)18ndash20

(4)498ndash509

45(2)99ndash103

200247(2)147ndash51

79ndash81

(4)266

(10)424ndash9

(1)27ndash34

73(21)1659ndash64

199616(2-3)57ndash65

(3)215ndash8

200498(1)159ndash65

Aronoff 2006

200299(21)13926ndash31

Collins 1999

14651858CD001548]

Cooper 1976

Coulthard 2001

Dray 1997

(6)704ndash12

Fisher 1988

Loeser 1999

(9164)1607ndash9

Malmberg 1992

Moore 1997

(3)287ndash94

Moore 1998

CD001547 DOI 10100214651858CD001547]

Rang 2003

Seymour 1985

Cooper 1980

Risk of bias

Cooper 1981

26 severe 11)

Notes Sponsored by

Adria Laboratories

Risk of bias

Cooper 1988

erate 25 severe 15)

Notes Sponsored by

Parke-Davis

Risk of bias

Cooper 1998

22 VAS 628

imaginable)

Notes Sponsored by

Whitehall-Robins

Risk of bias

Dionne 1994

Notes Sponsored by

Upjohn

Risk of bias

Dolci 1994

Formulation tablets

Risk of bias

Forbes 1984b

of adverse events)

Anaesthesia GA

Risk of bias

Forbes 1989

Notes Sponsored by

Risk of bias

Forbes 1990

Notes Sponsored by

Syntex Research

Risk of bias

Hersh 2000

erate 22 severe 5)

Formulation caplets

Notes Sponsored by

Whitehall-Robins

Risk of bias

Kiersch 1994

imagine)

Notes Sponsored by

Syntex Research

Risk of bias

Kubitzek 2003

Formulation tablets

Anaesthesia LA

Notes Sponsored by

Risk of bias

Lehnert 1990

Risk of bias

Mehlisch 1995

Notes Sponsored by

Risk of bias

Moller 2000

Formulation tablets

Notes Sponsored by

Risk of bias

Olson 2001

38) (30) (40)

4 severe 35)

Formulation caplets

Anaesthesia LA

Notes Sponsored by

Whitehall Robins

Risk of bias

Seymour 1996

for placebo VAS 565

Anaesthesia GA

Risk of bias

Seymour 2003

(25) (39) (415)

Formulation tablets

Anaesthesia GA

PR not stated

Notes Sponsored by

Risk of bias

Skoglund 1991

Formulation tablets

Anaesthesia LA

Notes Sponsored by

Risk of bias

Sunshine 1986

were randomised)

Anaesthesia LA

Notes Sponsored by

Upjohn

Risk of bias

Vattaraphudej 1986

Risk of bias

effects only

(Continued)

relevant data

(Continued)

studies

11 Up to 1000 mg of

paracetamol

21 Up to 1000 mg of

paracetamol

studies

11 Up to 1000 mg of

paracetamol

21 Up to 1000 mg of

paracetamol

studies

placebo

11 Up to 1000 mg of

paracetamol

Dolci 1994 5472 2576 100 228 [ 161 323 ]

Cooper 1980 1137 1138 82 103 [ 051 207 ]

Forbes 1990 936 134 30 850 [ 114 6357 ]

Forbes 1989 522 023 17 1148 [ 067 19607 ]

Cooper 1988 1636 1240 87 148 [ 081 269 ]

Cooper 1981 2137 637 77 350 [ 160 767 ]

Forbes 1984b 1339 136 30 1200 [ 165 8716 ]

Vattaraphudej 1986 716 219 47 416 [ 100 1726 ]

Sunshine 1986 1830 1530 95 120 [ 076 190 ]

Dionne 1994 2527 1725 102 136 [ 102 182 ]

Subtotal (95 CI) 352 358 667 196 [ 134 286 ]

2 1000 mg or more

01 02 05 1 2 5 10

(Continued )

Mehlisch 1995 40101 240 49 792 [ 201 3124 ]

Cooper 1998 1850 326 59 312 [ 101 963 ]

Olson 2001 4266 539 74 496 [ 215 1148 ]

Moller 2000 27120 0122 18 5591 [ 345 90627 ]

Hersh 2000 4063 527 75 343 [ 152 773 ]

Kiersch 1994 2589 345 58 421 [ 134 1321 ]

Subtotal (95 CI) 489 299 333 456 [ 286 727 ]

Total (95 CI) 841 657 1000 285 [ 189 429 ]

01 02 05 1 2 5 10

Forbes 1989 322 023 29 730 [ 040 13375 ]

Cooper 1988 1236 940 99 148 [ 071 310 ]

Forbes 1990 736 034 30 1419 [ 084 23928 ]

Dionne 1994 2427 1825 115 123 [ 093 163 ]

Forbes 1984b 1039 036 31 1943 [ 118 31995 ]

Sunshine 1986 1530 1030 104 150 [ 081 279 ]

Subtotal (95 CI) 190 188 407 189 [ 098 367 ]

2 1000 mg or more

Kubitzek 2003 4569 773 99 680 [ 329 1404 ]

Mehlisch 1995 35101 140 49 1386 [ 196 9779 ]

Kiersch 1994 2089 345 79 337 [ 106 1075 ]

Olson 2001 4166 539 94 485 [ 209 1122 ]

Hersh 2000 3563 527 95 300 [ 132 682 ]

Lehnert 1990 2349 640 96 313 [ 141 693 ]

Cooper 1998 1750 326 81 295 [ 095 914 ]

Subtotal (95 CI) 487 290 593 421 [ 297 598 ]

Total (95 CI) 677 478 1000 332 [ 188 587 ]

01 02 05 1 2 5 10

Dolci 1994 4972 576 86 1034 [ 437 2449 ]

Seymour 1996 1940 1039 96 185 [ 099 346 ]

Cooper 1980 737 438 74 180 [ 057 563 ]

Forbes 1990 1036 034 28 1986 [ 121 32639 ]

Forbes 1989 622 023 28 1357 [ 081 22736 ]

Cooper 1988 1236 840 90 167 [ 077 361 ]

Sunshine 1986 1830 630 90 300 [ 138 650 ]

Forbes 1984b 1339 036 28 2498 [ 154 40542 ]

Vattaraphudej 1986 616 119 44 713 [ 095 5317 ]

Cooper 1981 1537 037 28 3100 [ 192 49971 ]

Subtotal (95 CI) 365 372 592 433 [ 219 858 ]

2 1000 mg or more

Cooper 1998 1350 026 28 1429 [ 088 23130 ]

Mehlisch 1995 41101 340 75 541 [ 178 1648 ]

Hersh 2000 3663 127 46 1543 [ 223 10685 ]

Skoglund 1991 1632 033 28 3400 [ 213 54391 ]

Seymour 2003 1262 432 78 155 [ 054 442 ]

Seymour 1996 2040 1039 96 195 [ 105 362 ]

Kiersch 1994 989 045 28 971 [ 058 16317 ]

Moller 2000 28120 0122 28 5794 [ 358 93840 ]

Subtotal (95 CI) 557 364 408 646 [ 234 1785 ]

01 02 05 1 2 5 10

(Continued )

Total (95 CI) 922 736 1000 487 [ 283 837 ]

01 02 05 1 2 5 10

Seymour 1996 1840 939 152 195 [ 100 380 ]

Forbes 1989 422 023 16 939 [ 054 16485 ]

Cooper 1988 936 640 105 167 [ 066 422 ]

Forbes 1990 836 032 17 1516 [ 091 25267 ]

Forbes 1984b 1139 036 17 2128 [ 130 34843 ]

Sunshine 1986 1430 530 111 280 [ 115 680 ]

Subtotal (95 CI) 203 200 418 267 [ 146 490 ]

2 1000 mg or more

Hersh 2000 3163 127 33 1329 [ 191 9242 ]

Mehlisch 1995 39101 340 82 515 [ 169 1571 ]

Olson 2001 4266 739 146 355 [ 177 711 ]

01 02 05 1 2 5 10

(Continued )

Seymour 1996 2140 939 157 228 [ 119 433 ]

Cooper 1998 1250 026 17 1324 [ 081 21504 ]

Kiersch 1994 489 045 16 460 [ 025 8361 ]

Lehnert 1990 2449 542 114 411 [ 172 983 ]

Skoglund 1991 1432 033 17 2988 [ 186 48076 ]

Subtotal (95 CI) 490 291 582 396 [ 252 623 ]

Total (95 CI) 693 491 1000 341 [ 234 497 ]

01 02 05 1 2 5 10

Cooper 1980 237 637 033 [ 007 155 ]

Dolci 1994 780 882 090 [ 034 236 ]

Forbes 1990 541 038 1021 [ 058 17873 ]

Forbes 1989 326 226 150 [ 027 825 ]

Sunshine 1986 130 130 100 [ 007 1526 ]

Cooper 1981 1237 438 308 [ 109 869 ]

Dionne 1994 727 525 130 [ 047 356 ]

Vattaraphudej 1986 016 019 00 [ 00 00 ]

Forbes 1984b 143 240 047 [ 004 493 ]

Subtotal (95 CI) 337 335 125 [ 069 225 ]

2 1000 mg or more

Olson 2001 1066 239 295 [ 068 1279 ]

Cooper 1998 2550 426 325 [ 127 835 ]

Moller 2000 48120 56122 087 [ 065 117 ]

Seymour 2003 2462 932 138 [ 073 260 ]

Mehlisch 1995 1299 440 121 [ 042 354 ]

Kiersch 1994 2691 1347 103 [ 059 182 ]

Hersh 2000 1263 727 073 [ 032 166 ]

Lehnert 1990 549 440 102 [ 029 355 ]

Subtotal (95 CI) 600 373 116 [ 084 160 ]

Total (95 CI) 937 708 119 [ 090 157 ]

01 02 05 1 2 5 10

(Continued )

01 02 05 1 2 5 10

Cooper 1980 37 2 37 6

Cooper 1981 37 12 38 4

Dionne 1994 27 7 25 5

Dolci 1994 80 7 82 8

Forbes 1984b 43 1 40 2

Forbes 1989 26 3 26 2

Forbes 1990 41 5 38 0

Gallardo 1990 15 5 11 3

Seymour 1996 40 0 39 0

Sunshine 1986 30 1 30 1

Totals 392 43 385 31

Cooper 1980 1 0 1

Cooper 1981 1 0 1

Cooper 1988 1 0 1

Cooper 1998 1 1 2

Dionne 1994 1 0 1

Dolci 1994 1 0 1

Forbes 1984b 2 0 2

Forbes 1989 1 0 1

Forbes 1990 2 0 2

Hersh 2000 1 1 2

Kiersch 1994 1 1 2

Kubitzek 2003 1 1 2

Lehnert 1990 1 1 2

Mehlisch 1995 2 1 3

Moller 2000 1 1 2

Olson 2001 2 1 3

Seymour 1996 1 1 2

Seymour 2003 2 0 2

Skoglund 1991 2 0 2

Sunshine 1986 2 1 3

50 pain relief at 4

lief )

higher doses

50 pain relife at 6

lief )

higher doses

lt0001

50 pain relief at

4 hours (using pain

intensity)

higher doses

50 pain relief at

6 hours (using pain

intensity)

higher doses

Nausea 21 11

Vomiting 11 3

abdominal pain

Headache 47 31

Bleeding 11 7

Paraesthesia 4 2

Jawache 1 0

Swelling 1 6

Cellulitis 1 0

Dry socket 11 12

CNS 5 6

GI 12 2

Body as a whole 8 3

Respiratory 2 0

Psychiatric 0 1

Cooper 1980 37 089 38 089

Cooper 1981 37 192 37 062

Cooper 1988 36 238 40 205

Dionne 1994 27 240 25 200

Dolci 1994 72 210 76 217

Forbes 1984 39 126 36 028

Mean 248 183 252 144

Forbes 1989 26 100 26 030

Forbes 1990 41 147 38 056

Sunshine 1986 30 120 30 093

Mean 113 131 113 070

Kiersch 1994 91 130 47 060

Kubitzek 2003 78 198 84 145

Mehlisch 1995 101 157 40 045

Olson 2001 66 281 39 193

Seymour 2003 62 250 32 214

Mean 398 194 242 129

Hersh 2000 63 229 27 085

Moller 2000 120 188 122 154

Mean 183 202 149 141

A P P E N D I C E S

5 (1 or 2 or 3 or 4)

18 (5 and 17)

H I S T O R Y

None known

Internal sources

External sources

I N D E X T E R M S

MeSH check words

Humans

I N B R I E F

RESEARCH

07p407-411qxd 10092004 1518 Page 407

RESEARCH

Ibuprofen 400 mg 107200 110400 109000 103900

Ibuprofen 600 mg 34200 39700 40800 42600

Ibuprofen 200 mg 36300 34600 32000 30600

Paracetamol 500 mg 11100 12800 15400 17200

Pethidine 50 mg 1100 900 700 700

Aspirin 300 mg 200 200 200 200

07p407-411qxd 10092004 1519 Page 408

RESEARCH

Aspirin 600650 mg 6271788 (36) 2551847 (15) 25 (22 to 29) 47 (42 to 54) 3635 46

07p407-411qxd 10092004 1519 Page 409

RESEARCH

07p407-411qxd 10092004 1520 Page 410

RESEARCH

07p407-411qxd 10092004 1520 Page 411

I N B R I E F

Aspirin 600650 mg 45 3581 36 14 45 (40 to 52) 30

Celecoxib 400 mg 4 620 34 3 25 (22 to 29) 84

Ibuprofen 400 mg 49 5428 55 12 23 (22 to 24) 56

Naproxen 500550 mg 5 402 61 7 18 (16 to 21) 89

PRACTICE

Ibuprofen 400 mg

Aspirin 600650 mg

Aspirin 1000 mg

Paracetamol 1000

Naproxen 500550

Celecoxib 400 mg

Diclofenac 50 mg K

Etoriocoxib 120 mg

1 2 3 4 5 6

Study design

Patients

Surgery

Table 1

Study groups

Rofecoxib50 mg +

Rofecoxib50 mg

1 1 0 0

Paracetamol200 mg

5 0 5 0

6 6 6 6

Analysis

Statistics

Results

Analgesic effect

Table 2

Study groups

Table 3

Study groups

5 6 2 3

Placebo

01234567

0 1 2 3 4 5 6 7 8

Paracetamol 1g

01234567

0 1 2 3 4 5 6 7 8

Rofecoxib 50 mg

01234567

0 1 2 3 4 5 6 7 8

01234567

0 1 2 3 4 5 6 7 8

0 05 1 15 2 25 3 35 4 45 5 55 6 65 7 75 8

placebo

paracetamol 1g

rofecoxib 50mg

placebo

rofecoxib 50mg

rofecoxib 50mg +

05 1 15 2 25 3 35 4 45 5 55 6 65 7 75 8

paracetamol 1g

Table 4

Study groups

452 (20) 409 (27) 287 (44) 91 (27)

182 (19) 151 (18) 111 (34) )32 (23)

Mean SPIDtotal (SE)

526 (59) 515 (60) 208 (96) )101 (57)

05 1 15 2 25 3 35 4 45 5 55 6 65 7 75 8

tion placebo

paracetamol 1g

rofecoxib 50mg

Side-effects

Global evaluation

Discussion

Table 5

Study groups

Table 6

Study groups

Rofecoxib+

paracet-amol

Paracet-amol

4 h 8 h 4 h 8 h 4 h 8 h 4 h 8 h

and B J Anderson1

doi101093bjaaep338

improve compliance

Methods

ACTRN12606000291583)

Setting

New Zealand

Participants

Intervention

4 hourly

Outcomes

Statistical methods

based variables

primary endpoint

Results

Merry et al

for acetaminophen

Efficacy

Pharmacokinetics

diction intervals

(P005)

70 kg21)18 ndash 20

Adverse effects

Screened(n =189)

Randomized(n =135)

Weight [mean (SD)] (kg) 713 (156) 808 (201) 711 (135)

Ethnicity [n ()]

Asian 4 (85) 1 (23) 2 (45)

Black 1 (21) 0 (00) 1 (23)

Caucasian 33 (702) 31 (705) 34 (773)

Maori 4 (85) 4 (91) 4 (91)

Other 1 (21) 3 (68) 1 (23)

Male [n ()] 13 (277) 21 (477) 13 (295)

Shift workers [n ()] 10 (213) 5 (114) 3 (68)

medication

General

ActivityRest

Acetaminophen alone

Ibuprofen alone

Combination

Acetaminophen

(n543)

(n540)

activity

0 4 8 12 16 20 24 28 32 36 40 44 48

Hours post-surgery

Nil 3 (75) 4 (114) 4 (105)

Mild 12 (300) 15 (429) 22 (579)

Moderate 22 (550) 14 (400) 12 (316)

Severe 3 (75) 2 (57) 0 (00)

Nil 26 (650) 25 (714) 30 (790)

Mild 10 (250) 8 (229) 7 (184)

Moderate 3 (75) 2 (57) 1 (26)

Severe 1 (25) 0 (00) 0 (00)

1 vs baseline VAS

[mean (SD)] (mm)

2219 (292) 2174 (229) 2166 (247)

2 vs baseline VAS

[mean (SD)] (mm)

2137 (329) 296 (258) 285 (201)

significant

Acetaminophen

alone (n515)

Acetaminophen

Ibuprofen

alone(n511)

Ibuprofen in

combination(n512)

CLF (litre

141 (26) 142 (18) 39 (17) 38 (13)

VF (litre) 557 (194) 482 (183) 106 (21) 98 (15)

Tabs (h) 042 (076) 016 (010) 058 (078) 085 (085)

Tmax (h) 109 (112) 064 (031) 116 (090) 144 (093)

Cmax (mg

litre21)

158 (65) 192 (64) 208 (83) 191 (78)

Merry et al

Discussion

phlebitis)

0 0 2 2

Subtotal 3 1 6 10

legs jaw pain)

2 0 1 3

6 4 4 14

1 1 2 4

Subtotal 18 8 12 38

ache vomiting)

3 0 2 5

Subtotal 5 0 4 9

Total 26 9 22 57

Conclusions

Funding

Development Grants

Appendix

capacity

Merry et al

Contributors

Ethics approval

Zealand

TT50-7316 (458)

Role of the sponsor

results

Merry et al

Paracetamol 000 300 000 030 070

Dipyrone 000 100 000 010 040

Paracetamol 000 300 100 060 070

Dipyrone 000 200 100 070 070

Paracetamol 000 300 100 080 090

Dipyrone 000 300 100 080 080

Paracetamol 000 200 100 080 070

Dipyrone 000 300 100 100 100

Paracetamol 000 300 100 080 090

Dipyrone 000 300 000 060 080

Paracetamol 000 200 000 060 080

Dipyrone 000 300 000 040 080

Paracetamol 000 200 000 055 070

Dipyrone 000 300 000 040 090

Paracetamol 000 200 000 040 070

Dipyrone 000 300 000 030 070

Lisyne clonixinate

Right after 00 10 00 02 04

lt 0001

Paracetamol

Right after 00 30 00 03 07

lt 0001

Dipyrone

Right after 00 10 00 01 04

lt 0001

CLINICAL TRIAL

Michael Goulder

Sodium ibuprofen

Introduction

Methods

Study design

Patients

Efficacy endpoints

Rainier scale

Rescue medication

Global evaluation

Safety assessments

Results

IBUPROFENPOLOXAMER

Total screened 614

ACETAMINOPHEN

PLACEBO

Completed 76

SODIUM IBUPROFEN

Timepoint (mins)

0 50 100 150 200 250

Timepoint (mins)

0 50 100 150 200 250

Acetaminophen(n=80)

Placebo(n=81)

Total(n=321)

Timepoint (minutes)

0 15 35 60 90 120 180 240 300 360

Timepoint (mins)

0 50 100 150 200 250

Safety findings

Discussion

Numberof events

References

RESEARCH

I N B R I E F

RESEARCH

3 11 (19) 12 (19) 9 (28)4 30 (51) 34 (55) 15 (47)

RESEARCH

0 5 10 15 20 30 45 60 90 120 240

Time (mins)

RESEARCH

Abstract

Abstract

Abstract

Abstract

Abstract

Introduction

Methods

Study design

Patients



Efficacy endpoints





Rainier scale

Rescue medication

Global evaluation

Safety assessments


Results













Safety findings

Discussion

References

ABSTRACT

IacuteNDICE

QUESTAtildeO PICO 6

OBJECTIVOS 6

PESQUISA 12

PubMed 15

DISCUSSAtildeO 52

ANEXOS 61

QUESTAtildeO PICO

OBJECTIVOS

Primaacuterios

Secundaacuterios

ETIOLOGIA DA DOR

plaquetas

nociceptivas

PARACETAMOL

NSAIDrsquoS

(15 pp 277-281)

PESQUISA

sistemaacuteticas

aleatorizados

excluiacuteda (20)

ldquoadequadardquo

Derry Wiffen (21)

Hawkesford (22)

Edwards (23)

adequado

LILACS

PUBMED

Pesquisa 1

Postoperative[Mesh]

ldquoadequadosrdquo

Pesquisa 2

ldquoadequadosrdquo

discriminadas

os de interesse

secundaacuterios

paracetamol

risco de vieacutes

analgeacutesicos

Total de I2

76 81 66 29 28

efeito

tratamento

review

Barden Edwards (23)

medicaccedilatildeo

inglecircs

NSAIDrsquos

review

incluiacutedos

cirurgia

secundaacuterios

risco de vieacutes

conclusion

associados

Grupo A n = 40

Grupo B n = 40

Grupo C n = 20

deve-se a

Grupo A n = 34

Grupo B n = 36

Grupo C n = 20

Grupo D n = 17

intensidade da dor

Grupo A 90

Grupo B 83

Grupo C 42

aleatorizajao MJA)

conclusion

Grupo A n = 40

Grupo B n = 43

Grupo C n = 39

guidelines

NSAIDrsquos)

(com classe I e II)

0 cm Sem dor

gastrointestinais

seu conteuacutedo

recipiente

conclusion

acetaminofeno

horas)

de tratamento

conclusion

outros motivos

secundaacuterios

tratamento

inicial

oferecido

1000 mg

Placebo

conclusion

resultados

decisatildeo

DISCUSSAtildeO

2)86-90 Epub 20040113

20100326

(2) Available from

1050 p

Freeman 2005 1119 p

20060118

2006 1208 p

Reviews 2008(4)

20091217

Elsevier p

2007(105)

200849(1)31-7

2006114(4)293-301 Epub 20060817

200247(2)147-51 Epub 20020726

20030318

20090127

19940101

Epub 20030905

201030(4)436-47

2004328(7438)476-7

Intensiva 200719(4)475-80

Epub 20111203

20014(4)183-4

ANEXOS

Library

Possivelmente

Adequado

Saska Scartezini

(24) LILACS

Possivelmente

adequado

Bjornsson

operatoacuteria

Kubitzek Ziegler

Macleod

Bjornsson

Haanaes (29) PubMed

Possivelmente

Chopra Rehan

(30) PubMed

Possivelmente

adequado

Medve Wang

(34) PubMed

Possivelmente

adequado

Bjornsson

Haanaes (35) PubMed

Possivelmente

INTEGRALi

2008 Issue 4

1HEADER

1ABSTRACT

2BACKGROUND

3OBJECTIVES

3METHODS

5RESULTS

8DISCUSSION

9ACKNOWLEDGEMENTS

10REFERENCES

30DATA AND ANALYSES

38ADDITIONAL TABLES

42APPENDICES

43WHATrsquoS NEW

43HISTORY

44INDEX TERMS

10100214651858CD004487pub2

A B S T R A C T

Background

of wisdom teeth

Objectives

Search strategy

Selection criteria

analysed

Main results

B A C K G R O U N D

O B J E C T I V E S

postoperatively

Primary

Secondary

difference

M E T H O D S

Types of studies

cluded

Efficacy

Side effects

also searched

Language

Unpublished studies

Handsearching

wwwohgcochraneorg

were recorded

Quality assessment

(A) Yes - 1 point

(B) No - 0 points

categories

Data extraction

study funding

design)

Data synthesis

final review

used scale

Subgroup analyses

Additional Table 1

R E S U L T S

studies

excellent

to 286) Chi2 = 2644 df = 9 P = 0002 I2 = 660 NNT 4

727) Chi2 = 544 df = 5 P = 036 I2 = 82 NNT 3 (95

mg 189 (95 CI 098 to 367) Chi2 = 1445 df = 5 P = 001

421 (95 CI 297 to 598) Chi2 = 509 df = 6 P = 053 I2 =

parison

Chi2 = 4973 df = 17 P lt 00001 I2 = 658 NNT 3 (95 CI

Chi2 = 2622 df = 9 P = 0002 I2 = 657 NNT 3 (95 CI

df = 13 P = 015 I2 = 287 NNT 4 (95 CI 3 to 4) The

1000 mg 396 (95 CI 252 to 623) Chi2 = 863 df = 7 P =

= 1096 df = 7 P = 014 I2 = 362 NNTH 33 (95 CI 125

to infinity)

Subgroup analyses

anaesthetic

measurements)

intensity data

D I S C U S S I O N

fective choice

tory drugs (NSAIDS)

R E F E R E N C E S

19881(2)31ndash4

11Sndash18S

185ndash91

94Sndash105S

(3)153ndash7

198636(6)198ndash206

197930(8)308ndash9

[DOI DOI 10100214651858CD004602]

634ndash40

(4)844ndash52

33(3)139ndash42

(5)235ndash41

2139ndash42

198435(6)843ndash51

198624(11)598ndash601

1982152(1)18ndash20

(4)498ndash509

45(2)99ndash103

200247(2)147ndash51

79ndash81

(4)266

(10)424ndash9

(1)27ndash34

73(21)1659ndash64

199616(2-3)57ndash65

(3)215ndash8

200498(1)159ndash65

Aronoff 2006

200299(21)13926ndash31

Collins 1999

14651858CD001548]

Cooper 1976

Coulthard 2001

Dray 1997

(6)704ndash12

Fisher 1988

Loeser 1999

(9164)1607ndash9

Malmberg 1992

Moore 1997

(3)287ndash94

Moore 1998

CD001547 DOI 10100214651858CD001547]

Rang 2003

Seymour 1985

Cooper 1980

Risk of bias

Cooper 1981

26 severe 11)

Notes Sponsored by

Adria Laboratories

Risk of bias

Cooper 1988

erate 25 severe 15)

Notes Sponsored by

Parke-Davis

Risk of bias

Cooper 1998

22 VAS 628

imaginable)

Notes Sponsored by

Whitehall-Robins

Risk of bias

Dionne 1994

Notes Sponsored by

Upjohn

Risk of bias

Dolci 1994

Formulation tablets

Risk of bias

Forbes 1984b

of adverse events)

Anaesthesia GA

Risk of bias

Forbes 1989

Notes Sponsored by

Risk of bias

Forbes 1990

Notes Sponsored by

Syntex Research

Risk of bias

Hersh 2000

erate 22 severe 5)

Formulation caplets

Notes Sponsored by

Whitehall-Robins

Risk of bias

Kiersch 1994

imagine)

Notes Sponsored by

Syntex Research

Risk of bias

Kubitzek 2003

Formulation tablets

Anaesthesia LA

Notes Sponsored by

Risk of bias

Lehnert 1990

Risk of bias

Mehlisch 1995

Notes Sponsored by

Risk of bias

Moller 2000

Formulation tablets

Notes Sponsored by

Risk of bias

Olson 2001

38) (30) (40)

4 severe 35)

Formulation caplets

Anaesthesia LA

Notes Sponsored by

Whitehall Robins

Risk of bias

Seymour 1996

for placebo VAS 565

Anaesthesia GA

Risk of bias

Seymour 2003

(25) (39) (415)

Formulation tablets

Anaesthesia GA

PR not stated

Notes Sponsored by

Risk of bias

Skoglund 1991

Formulation tablets

Anaesthesia LA

Notes Sponsored by

Risk of bias

Sunshine 1986

were randomised)

Anaesthesia LA

Notes Sponsored by

Upjohn

Risk of bias

Vattaraphudej 1986

Risk of bias

effects only

(Continued)

relevant data

(Continued)

studies

11 Up to 1000 mg of

paracetamol

21 Up to 1000 mg of

paracetamol

studies

11 Up to 1000 mg of

paracetamol

21 Up to 1000 mg of

paracetamol

studies

placebo

11 Up to 1000 mg of

paracetamol

Dolci 1994 5472 2576 100 228 [ 161 323 ]

Cooper 1980 1137 1138 82 103 [ 051 207 ]

Forbes 1990 936 134 30 850 [ 114 6357 ]

Forbes 1989 522 023 17 1148 [ 067 19607 ]

Cooper 1988 1636 1240 87 148 [ 081 269 ]

Cooper 1981 2137 637 77 350 [ 160 767 ]

Forbes 1984b 1339 136 30 1200 [ 165 8716 ]

Vattaraphudej 1986 716 219 47 416 [ 100 1726 ]

Sunshine 1986 1830 1530 95 120 [ 076 190 ]

Dionne 1994 2527 1725 102 136 [ 102 182 ]

Subtotal (95 CI) 352 358 667 196 [ 134 286 ]

2 1000 mg or more

01 02 05 1 2 5 10

(Continued )

Mehlisch 1995 40101 240 49 792 [ 201 3124 ]

Cooper 1998 1850 326 59 312 [ 101 963 ]

Olson 2001 4266 539 74 496 [ 215 1148 ]

Moller 2000 27120 0122 18 5591 [ 345 90627 ]

Hersh 2000 4063 527 75 343 [ 152 773 ]

Kiersch 1994 2589 345 58 421 [ 134 1321 ]

Subtotal (95 CI) 489 299 333 456 [ 286 727 ]

Total (95 CI) 841 657 1000 285 [ 189 429 ]

01 02 05 1 2 5 10

Forbes 1989 322 023 29 730 [ 040 13375 ]

Cooper 1988 1236 940 99 148 [ 071 310 ]

Forbes 1990 736 034 30 1419 [ 084 23928 ]

Dionne 1994 2427 1825 115 123 [ 093 163 ]

Forbes 1984b 1039 036 31 1943 [ 118 31995 ]

Sunshine 1986 1530 1030 104 150 [ 081 279 ]

Subtotal (95 CI) 190 188 407 189 [ 098 367 ]

2 1000 mg or more

Kubitzek 2003 4569 773 99 680 [ 329 1404 ]

Mehlisch 1995 35101 140 49 1386 [ 196 9779 ]

Kiersch 1994 2089 345 79 337 [ 106 1075 ]

Olson 2001 4166 539 94 485 [ 209 1122 ]

Hersh 2000 3563 527 95 300 [ 132 682 ]

Lehnert 1990 2349 640 96 313 [ 141 693 ]

Cooper 1998 1750 326 81 295 [ 095 914 ]

Subtotal (95 CI) 487 290 593 421 [ 297 598 ]

Total (95 CI) 677 478 1000 332 [ 188 587 ]

01 02 05 1 2 5 10

Dolci 1994 4972 576 86 1034 [ 437 2449 ]

Seymour 1996 1940 1039 96 185 [ 099 346 ]

Cooper 1980 737 438 74 180 [ 057 563 ]

Forbes 1990 1036 034 28 1986 [ 121 32639 ]

Forbes 1989 622 023 28 1357 [ 081 22736 ]

Cooper 1988 1236 840 90 167 [ 077 361 ]

Sunshine 1986 1830 630 90 300 [ 138 650 ]

Forbes 1984b 1339 036 28 2498 [ 154 40542 ]

Vattaraphudej 1986 616 119 44 713 [ 095 5317 ]

Cooper 1981 1537 037 28 3100 [ 192 49971 ]

Subtotal (95 CI) 365 372 592 433 [ 219 858 ]

2 1000 mg or more

Cooper 1998 1350 026 28 1429 [ 088 23130 ]

Mehlisch 1995 41101 340 75 541 [ 178 1648 ]

Hersh 2000 3663 127 46 1543 [ 223 10685 ]

Skoglund 1991 1632 033 28 3400 [ 213 54391 ]

Seymour 2003 1262 432 78 155 [ 054 442 ]

Seymour 1996 2040 1039 96 195 [ 105 362 ]

Kiersch 1994 989 045 28 971 [ 058 16317 ]

Moller 2000 28120 0122 28 5794 [ 358 93840 ]

Subtotal (95 CI) 557 364 408 646 [ 234 1785 ]

01 02 05 1 2 5 10

(Continued )

Total (95 CI) 922 736 1000 487 [ 283 837 ]

01 02 05 1 2 5 10

Seymour 1996 1840 939 152 195 [ 100 380 ]

Forbes 1989 422 023 16 939 [ 054 16485 ]

Cooper 1988 936 640 105 167 [ 066 422 ]

Forbes 1990 836 032 17 1516 [ 091 25267 ]

Forbes 1984b 1139 036 17 2128 [ 130 34843 ]

Sunshine 1986 1430 530 111 280 [ 115 680 ]

Subtotal (95 CI) 203 200 418 267 [ 146 490 ]

2 1000 mg or more

Hersh 2000 3163 127 33 1329 [ 191 9242 ]

Mehlisch 1995 39101 340 82 515 [ 169 1571 ]

Olson 2001 4266 739 146 355 [ 177 711 ]

01 02 05 1 2 5 10

(Continued )

Seymour 1996 2140 939 157 228 [ 119 433 ]

Cooper 1998 1250 026 17 1324 [ 081 21504 ]

Kiersch 1994 489 045 16 460 [ 025 8361 ]

Lehnert 1990 2449 542 114 411 [ 172 983 ]

Skoglund 1991 1432 033 17 2988 [ 186 48076 ]

Subtotal (95 CI) 490 291 582 396 [ 252 623 ]

Total (95 CI) 693 491 1000 341 [ 234 497 ]

01 02 05 1 2 5 10

Cooper 1980 237 637 033 [ 007 155 ]

Dolci 1994 780 882 090 [ 034 236 ]

Forbes 1990 541 038 1021 [ 058 17873 ]

Forbes 1989 326 226 150 [ 027 825 ]

Sunshine 1986 130 130 100 [ 007 1526 ]

Cooper 1981 1237 438 308 [ 109 869 ]

Dionne 1994 727 525 130 [ 047 356 ]

Vattaraphudej 1986 016 019 00 [ 00 00 ]

Forbes 1984b 143 240 047 [ 004 493 ]

Subtotal (95 CI) 337 335 125 [ 069 225 ]

2 1000 mg or more

Olson 2001 1066 239 295 [ 068 1279 ]

Cooper 1998 2550 426 325 [ 127 835 ]

Moller 2000 48120 56122 087 [ 065 117 ]

Seymour 2003 2462 932 138 [ 073 260 ]

Mehlisch 1995 1299 440 121 [ 042 354 ]

Kiersch 1994 2691 1347 103 [ 059 182 ]

Hersh 2000 1263 727 073 [ 032 166 ]

Lehnert 1990 549 440 102 [ 029 355 ]

Subtotal (95 CI) 600 373 116 [ 084 160 ]

Total (95 CI) 937 708 119 [ 090 157 ]

01 02 05 1 2 5 10

(Continued )

01 02 05 1 2 5 10

Cooper 1980 37 2 37 6

Cooper 1981 37 12 38 4

Dionne 1994 27 7 25 5

Dolci 1994 80 7 82 8

Forbes 1984b 43 1 40 2

Forbes 1989 26 3 26 2

Forbes 1990 41 5 38 0

Gallardo 1990 15 5 11 3

Seymour 1996 40 0 39 0

Sunshine 1986 30 1 30 1

Totals 392 43 385 31

Cooper 1980 1 0 1

Cooper 1981 1 0 1

Cooper 1988 1 0 1

Cooper 1998 1 1 2

Dionne 1994 1 0 1

Dolci 1994 1 0 1

Forbes 1984b 2 0 2

Forbes 1989 1 0 1

Forbes 1990 2 0 2

Hersh 2000 1 1 2

Kiersch 1994 1 1 2

Kubitzek 2003 1 1 2

Lehnert 1990 1 1 2

Mehlisch 1995 2 1 3

Moller 2000 1 1 2

Olson 2001 2 1 3

Seymour 1996 1 1 2

Seymour 2003 2 0 2

Skoglund 1991 2 0 2

Sunshine 1986 2 1 3

50 pain relief at 4

lief )

higher doses

50 pain relife at 6

lief )

higher doses

lt0001

50 pain relief at

4 hours (using pain

intensity)

higher doses

50 pain relief at

6 hours (using pain

intensity)

higher doses

Nausea 21 11

Vomiting 11 3

abdominal pain

Headache 47 31

Bleeding 11 7

Paraesthesia 4 2

Jawache 1 0

Swelling 1 6

Cellulitis 1 0

Dry socket 11 12

CNS 5 6

GI 12 2

Body as a whole 8 3

Respiratory 2 0

Psychiatric 0 1

Cooper 1980 37 089 38 089

Cooper 1981 37 192 37 062

Cooper 1988 36 238 40 205

Dionne 1994 27 240 25 200

Dolci 1994 72 210 76 217

Forbes 1984 39 126 36 028

Mean 248 183 252 144

Forbes 1989 26 100 26 030

Forbes 1990 41 147 38 056

Sunshine 1986 30 120 30 093

Mean 113 131 113 070

Kiersch 1994 91 130 47 060

Kubitzek 2003 78 198 84 145

Mehlisch 1995 101 157 40 045

Olson 2001 66 281 39 193

Seymour 2003 62 250 32 214

Mean 398 194 242 129

Hersh 2000 63 229 27 085

Moller 2000 120 188 122 154

Mean 183 202 149 141

A P P E N D I C E S

5 (1 or 2 or 3 or 4)

18 (5 and 17)

H I S T O R Y

None known

Internal sources

External sources

I N D E X T E R M S

MeSH check words

Humans

I N B R I E F

RESEARCH

07p407-411qxd 10092004 1518 Page 407

RESEARCH

Ibuprofen 400 mg 107200 110400 109000 103900

Ibuprofen 600 mg 34200 39700 40800 42600

Ibuprofen 200 mg 36300 34600 32000 30600

Paracetamol 500 mg 11100 12800 15400 17200

Pethidine 50 mg 1100 900 700 700

Aspirin 300 mg 200 200 200 200

07p407-411qxd 10092004 1519 Page 408

RESEARCH

Aspirin 600650 mg 6271788 (36) 2551847 (15) 25 (22 to 29) 47 (42 to 54) 3635 46

07p407-411qxd 10092004 1519 Page 409

RESEARCH

07p407-411qxd 10092004 1520 Page 410

RESEARCH

07p407-411qxd 10092004 1520 Page 411

I N B R I E F

Aspirin 600650 mg 45 3581 36 14 45 (40 to 52) 30

Celecoxib 400 mg 4 620 34 3 25 (22 to 29) 84

Ibuprofen 400 mg 49 5428 55 12 23 (22 to 24) 56

Naproxen 500550 mg 5 402 61 7 18 (16 to 21) 89

PRACTICE

Ibuprofen 400 mg

Aspirin 600650 mg

Aspirin 1000 mg

Paracetamol 1000

Naproxen 500550

Celecoxib 400 mg

Diclofenac 50 mg K

Etoriocoxib 120 mg

1 2 3 4 5 6

Study design

Patients

Surgery

Table 1

Study groups

Rofecoxib50 mg +

Rofecoxib50 mg

1 1 0 0

Paracetamol200 mg

5 0 5 0

6 6 6 6

Analysis

Statistics

Results

Analgesic effect

Table 2

Study groups

Table 3

Study groups

5 6 2 3

Placebo

01234567

0 1 2 3 4 5 6 7 8

Paracetamol 1g

01234567

0 1 2 3 4 5 6 7 8

Rofecoxib 50 mg

01234567

0 1 2 3 4 5 6 7 8

01234567

0 1 2 3 4 5 6 7 8

0 05 1 15 2 25 3 35 4 45 5 55 6 65 7 75 8

placebo

paracetamol 1g

rofecoxib 50mg

placebo

rofecoxib 50mg

rofecoxib 50mg +

05 1 15 2 25 3 35 4 45 5 55 6 65 7 75 8

paracetamol 1g

Table 4

Study groups

452 (20) 409 (27) 287 (44) 91 (27)

182 (19) 151 (18) 111 (34) )32 (23)

Mean SPIDtotal (SE)

526 (59) 515 (60) 208 (96) )101 (57)

05 1 15 2 25 3 35 4 45 5 55 6 65 7 75 8

tion placebo

paracetamol 1g

rofecoxib 50mg

Side-effects

Global evaluation

Discussion

Table 5

Study groups

Table 6

Study groups

Rofecoxib+

paracet-amol

Paracet-amol

4 h 8 h 4 h 8 h 4 h 8 h 4 h 8 h

and B J Anderson1

doi101093bjaaep338

improve compliance

Methods

ACTRN12606000291583)

Setting

New Zealand

Participants

Intervention

4 hourly

Outcomes

Statistical methods

based variables

primary endpoint

Results

Merry et al

for acetaminophen

Efficacy

Pharmacokinetics

diction intervals

(P005)

70 kg21)18 ndash 20

Adverse effects

Screened(n =189)

Randomized(n =135)

Weight [mean (SD)] (kg) 713 (156) 808 (201) 711 (135)

Ethnicity [n ()]

Asian 4 (85) 1 (23) 2 (45)

Black 1 (21) 0 (00) 1 (23)

Caucasian 33 (702) 31 (705) 34 (773)

Maori 4 (85) 4 (91) 4 (91)

Other 1 (21) 3 (68) 1 (23)

Male [n ()] 13 (277) 21 (477) 13 (295)

Shift workers [n ()] 10 (213) 5 (114) 3 (68)

medication

General

ActivityRest

Acetaminophen alone

Ibuprofen alone

Combination

Acetaminophen

(n543)

(n540)

activity

0 4 8 12 16 20 24 28 32 36 40 44 48

Hours post-surgery

Nil 3 (75) 4 (114) 4 (105)

Mild 12 (300) 15 (429) 22 (579)

Moderate 22 (550) 14 (400) 12 (316)

Severe 3 (75) 2 (57) 0 (00)

Nil 26 (650) 25 (714) 30 (790)

Mild 10 (250) 8 (229) 7 (184)

Moderate 3 (75) 2 (57) 1 (26)

Severe 1 (25) 0 (00) 0 (00)

1 vs baseline VAS

[mean (SD)] (mm)

2219 (292) 2174 (229) 2166 (247)

2 vs baseline VAS

[mean (SD)] (mm)

2137 (329) 296 (258) 285 (201)

significant

Acetaminophen

alone (n515)

Acetaminophen

Ibuprofen

alone(n511)

Ibuprofen in

combination(n512)

CLF (litre

141 (26) 142 (18) 39 (17) 38 (13)

VF (litre) 557 (194) 482 (183) 106 (21) 98 (15)

Tabs (h) 042 (076) 016 (010) 058 (078) 085 (085)

Tmax (h) 109 (112) 064 (031) 116 (090) 144 (093)

Cmax (mg

litre21)

158 (65) 192 (64) 208 (83) 191 (78)

Merry et al

Discussion

phlebitis)

0 0 2 2

Subtotal 3 1 6 10

legs jaw pain)

2 0 1 3

6 4 4 14

1 1 2 4

Subtotal 18 8 12 38

ache vomiting)

3 0 2 5

Subtotal 5 0 4 9

Total 26 9 22 57

Conclusions

Funding

Development Grants

Appendix

capacity

Merry et al

Contributors

Ethics approval

Zealand

TT50-7316 (458)

Role of the sponsor

results

Merry et al

Paracetamol 000 300 000 030 070

Dipyrone 000 100 000 010 040

Paracetamol 000 300 100 060 070

Dipyrone 000 200 100 070 070

Paracetamol 000 300 100 080 090

Dipyrone 000 300 100 080 080

Paracetamol 000 200 100 080 070

Dipyrone 000 300 100 100 100

Paracetamol 000 300 100 080 090

Dipyrone 000 300 000 060 080

Paracetamol 000 200 000 060 080

Dipyrone 000 300 000 040 080

Paracetamol 000 200 000 055 070

Dipyrone 000 300 000 040 090

Paracetamol 000 200 000 040 070

Dipyrone 000 300 000 030 070

Lisyne clonixinate

Right after 00 10 00 02 04

lt 0001

Paracetamol

Right after 00 30 00 03 07

lt 0001

Dipyrone

Right after 00 10 00 01 04

lt 0001

CLINICAL TRIAL

Michael Goulder

Sodium ibuprofen

Introduction

Methods

Study design

Patients

Efficacy endpoints

Rainier scale

Rescue medication

Global evaluation

Safety assessments

Results

IBUPROFENPOLOXAMER

Total screened 614

ACETAMINOPHEN

PLACEBO

Completed 76

SODIUM IBUPROFEN

Timepoint (mins)

0 50 100 150 200 250

Timepoint (mins)

0 50 100 150 200 250

Acetaminophen(n=80)

Placebo(n=81)

Total(n=321)

Timepoint (minutes)

0 15 35 60 90 120 180 240 300 360

Timepoint (mins)

0 50 100 150 200 250

Safety findings

Discussion

Numberof events

References

RESEARCH

I N B R I E F

RESEARCH

3 11 (19) 12 (19) 9 (28)4 30 (51) 34 (55) 15 (47)

RESEARCH

0 5 10 15 20 30 45 60 90 120 240

Time (mins)

RESEARCH

Abstract

Abstract

Abstract

Abstract

Abstract

Introduction

Methods

Study design

Patients



Efficacy endpoints





Rainier scale

Rescue medication

Global evaluation

Safety assessments


Results













Safety findings

Discussion

References

IacuteNDICE

QUESTAtildeO PICO 6

OBJECTIVOS 6

PESQUISA 12

PubMed 15

DISCUSSAtildeO 52

ANEXOS 61

QUESTAtildeO PICO

OBJECTIVOS

Primaacuterios

Secundaacuterios

ETIOLOGIA DA DOR

plaquetas

nociceptivas

PARACETAMOL

NSAIDrsquoS

(15 pp 277-281)

PESQUISA

sistemaacuteticas

aleatorizados

excluiacuteda (20)

ldquoadequadardquo

Derry Wiffen (21)

Hawkesford (22)

Edwards (23)

adequado

LILACS

PUBMED

Pesquisa 1

Postoperative[Mesh]

ldquoadequadosrdquo

Pesquisa 2

ldquoadequadosrdquo

discriminadas

os de interesse

secundaacuterios

paracetamol

risco de vieacutes

analgeacutesicos

Total de I2

76 81 66 29 28

efeito

tratamento

review

Barden Edwards (23)

medicaccedilatildeo

inglecircs

NSAIDrsquos

review

incluiacutedos

cirurgia

secundaacuterios

risco de vieacutes

conclusion

associados

Grupo A n = 40

Grupo B n = 40

Grupo C n = 20

deve-se a

Grupo A n = 34

Grupo B n = 36

Grupo C n = 20

Grupo D n = 17

intensidade da dor

Grupo A 90

Grupo B 83

Grupo C 42

aleatorizajao MJA)

conclusion

Grupo A n = 40

Grupo B n = 43

Grupo C n = 39

guidelines

NSAIDrsquos)

(com classe I e II)

0 cm Sem dor

gastrointestinais

seu conteuacutedo

recipiente

conclusion

acetaminofeno

horas)

de tratamento

conclusion

outros motivos

secundaacuterios

tratamento

inicial

oferecido

1000 mg

Placebo

conclusion

resultados

decisatildeo

DISCUSSAtildeO

2)86-90 Epub 20040113

20100326

(2) Available from

1050 p

Freeman 2005 1119 p

20060118

2006 1208 p

Reviews 2008(4)

20091217

Elsevier p

2007(105)

200849(1)31-7

2006114(4)293-301 Epub 20060817

200247(2)147-51 Epub 20020726

20030318

20090127

19940101

Epub 20030905

201030(4)436-47

2004328(7438)476-7

Intensiva 200719(4)475-80

Epub 20111203

20014(4)183-4

ANEXOS

Library

Possivelmente

Adequado

Saska Scartezini

(24) LILACS

Possivelmente

adequado

Bjornsson

operatoacuteria

Kubitzek Ziegler

Macleod

Bjornsson

Haanaes (29) PubMed

Possivelmente

Chopra Rehan

(30) PubMed

Possivelmente

adequado

Medve Wang

(34) PubMed

Possivelmente

adequado

Bjornsson

Haanaes (35) PubMed

Possivelmente

INTEGRALi

2008 Issue 4

1HEADER

1ABSTRACT

2BACKGROUND

3OBJECTIVES

3METHODS

5RESULTS

8DISCUSSION

9ACKNOWLEDGEMENTS

10REFERENCES

30DATA AND ANALYSES

38ADDITIONAL TABLES

42APPENDICES

43WHATrsquoS NEW

43HISTORY

44INDEX TERMS

10100214651858CD004487pub2

A B S T R A C T

Background

of wisdom teeth

Objectives

Search strategy

Selection criteria

analysed

Main results

B A C K G R O U N D

O B J E C T I V E S

postoperatively

Primary

Secondary

difference

M E T H O D S

Types of studies

cluded

Efficacy

Side effects

also searched

Language

Unpublished studies

Handsearching

wwwohgcochraneorg

were recorded

Quality assessment

(A) Yes - 1 point

(B) No - 0 points

categories

Data extraction

study funding

design)

Data synthesis

final review

used scale

Subgroup analyses

Additional Table 1

R E S U L T S

studies

excellent

to 286) Chi2 = 2644 df = 9 P = 0002 I2 = 660 NNT 4

727) Chi2 = 544 df = 5 P = 036 I2 = 82 NNT 3 (95

mg 189 (95 CI 098 to 367) Chi2 = 1445 df = 5 P = 001

421 (95 CI 297 to 598) Chi2 = 509 df = 6 P = 053 I2 =

parison

Chi2 = 4973 df = 17 P lt 00001 I2 = 658 NNT 3 (95 CI

Chi2 = 2622 df = 9 P = 0002 I2 = 657 NNT 3 (95 CI

df = 13 P = 015 I2 = 287 NNT 4 (95 CI 3 to 4) The

1000 mg 396 (95 CI 252 to 623) Chi2 = 863 df = 7 P =

= 1096 df = 7 P = 014 I2 = 362 NNTH 33 (95 CI 125

to infinity)

Subgroup analyses

anaesthetic

measurements)

intensity data

D I S C U S S I O N

fective choice

tory drugs (NSAIDS)

R E F E R E N C E S

19881(2)31ndash4

11Sndash18S

185ndash91

94Sndash105S

(3)153ndash7

198636(6)198ndash206

197930(8)308ndash9

[DOI DOI 10100214651858CD004602]

634ndash40

(4)844ndash52

33(3)139ndash42

(5)235ndash41

2139ndash42

198435(6)843ndash51

198624(11)598ndash601

1982152(1)18ndash20

(4)498ndash509

45(2)99ndash103

200247(2)147ndash51

79ndash81

(4)266

(10)424ndash9

(1)27ndash34

73(21)1659ndash64

199616(2-3)57ndash65

(3)215ndash8

200498(1)159ndash65

Aronoff 2006

200299(21)13926ndash31

Collins 1999

14651858CD001548]

Cooper 1976

Coulthard 2001

Dray 1997

(6)704ndash12

Fisher 1988

Loeser 1999

(9164)1607ndash9

Malmberg 1992

Moore 1997

(3)287ndash94

Moore 1998

CD001547 DOI 10100214651858CD001547]

Rang 2003

Seymour 1985

Cooper 1980

Risk of bias

Cooper 1981

26 severe 11)

Notes Sponsored by

Adria Laboratories

Risk of bias

Cooper 1988

erate 25 severe 15)

Notes Sponsored by

Parke-Davis

Risk of bias

Cooper 1998

22 VAS 628

imaginable)

Notes Sponsored by

Whitehall-Robins

Risk of bias

Dionne 1994

Notes Sponsored by

Upjohn

Risk of bias

Dolci 1994

Formulation tablets

Risk of bias

Forbes 1984b

of adverse events)

Anaesthesia GA

Risk of bias

Forbes 1989

Notes Sponsored by

Risk of bias

Forbes 1990

Notes Sponsored by

Syntex Research

Risk of bias

Hersh 2000

erate 22 severe 5)

Formulation caplets

Notes Sponsored by

Whitehall-Robins

Risk of bias

Kiersch 1994

imagine)

Notes Sponsored by

Syntex Research

Risk of bias

Kubitzek 2003

Formulation tablets

Anaesthesia LA

Notes Sponsored by

Risk of bias

Lehnert 1990

Risk of bias

Mehlisch 1995

Notes Sponsored by

Risk of bias

Moller 2000

Formulation tablets

Notes Sponsored by

Risk of bias

Olson 2001

38) (30) (40)

4 severe 35)

Formulation caplets

Anaesthesia LA

Notes Sponsored by

Whitehall Robins

Risk of bias

Seymour 1996

for placebo VAS 565

Anaesthesia GA

Risk of bias

Seymour 2003

(25) (39) (415)

Formulation tablets

Anaesthesia GA

PR not stated

Notes Sponsored by

Risk of bias

Skoglund 1991

Formulation tablets

Anaesthesia LA

Notes Sponsored by

Risk of bias

Sunshine 1986

were randomised)

Anaesthesia LA

Notes Sponsored by

Upjohn

Risk of bias

Vattaraphudej 1986

Risk of bias

effects only

(Continued)

relevant data

(Continued)

studies

11 Up to 1000 mg of

paracetamol

21 Up to 1000 mg of

paracetamol

studies

11 Up to 1000 mg of

paracetamol

21 Up to 1000 mg of

paracetamol

studies

placebo

11 Up to 1000 mg of

paracetamol

Dolci 1994 5472 2576 100 228 [ 161 323 ]

Cooper 1980 1137 1138 82 103 [ 051 207 ]

Forbes 1990 936 134 30 850 [ 114 6357 ]

Forbes 1989 522 023 17 1148 [ 067 19607 ]

Cooper 1988 1636 1240 87 148 [ 081 269 ]

Cooper 1981 2137 637 77 350 [ 160 767 ]

Forbes 1984b 1339 136 30 1200 [ 165 8716 ]

Vattaraphudej 1986 716 219 47 416 [ 100 1726 ]

Sunshine 1986 1830 1530 95 120 [ 076 190 ]

Dionne 1994 2527 1725 102 136 [ 102 182 ]

Subtotal (95 CI) 352 358 667 196 [ 134 286 ]

2 1000 mg or more

01 02 05 1 2 5 10

(Continued )

Mehlisch 1995 40101 240 49 792 [ 201 3124 ]

Cooper 1998 1850 326 59 312 [ 101 963 ]

Olson 2001 4266 539 74 496 [ 215 1148 ]

Moller 2000 27120 0122 18 5591 [ 345 90627 ]

Hersh 2000 4063 527 75 343 [ 152 773 ]

Kiersch 1994 2589 345 58 421 [ 134 1321 ]

Subtotal (95 CI) 489 299 333 456 [ 286 727 ]

Total (95 CI) 841 657 1000 285 [ 189 429 ]

01 02 05 1 2 5 10

Forbes 1989 322 023 29 730 [ 040 13375 ]

Cooper 1988 1236 940 99 148 [ 071 310 ]

Forbes 1990 736 034 30 1419 [ 084 23928 ]

Dionne 1994 2427 1825 115 123 [ 093 163 ]

Forbes 1984b 1039 036 31 1943 [ 118 31995 ]

Sunshine 1986 1530 1030 104 150 [ 081 279 ]

Subtotal (95 CI) 190 188 407 189 [ 098 367 ]

2 1000 mg or more

Kubitzek 2003 4569 773 99 680 [ 329 1404 ]

Mehlisch 1995 35101 140 49 1386 [ 196 9779 ]

Kiersch 1994 2089 345 79 337 [ 106 1075 ]

Olson 2001 4166 539 94 485 [ 209 1122 ]

Hersh 2000 3563 527 95 300 [ 132 682 ]

Lehnert 1990 2349 640 96 313 [ 141 693 ]

Cooper 1998 1750 326 81 295 [ 095 914 ]

Subtotal (95 CI) 487 290 593 421 [ 297 598 ]

Total (95 CI) 677 478 1000 332 [ 188 587 ]

01 02 05 1 2 5 10

Dolci 1994 4972 576 86 1034 [ 437 2449 ]

Seymour 1996 1940 1039 96 185 [ 099 346 ]

Cooper 1980 737 438 74 180 [ 057 563 ]

Forbes 1990 1036 034 28 1986 [ 121 32639 ]

Forbes 1989 622 023 28 1357 [ 081 22736 ]

Cooper 1988 1236 840 90 167 [ 077 361 ]

Sunshine 1986 1830 630 90 300 [ 138 650 ]

Forbes 1984b 1339 036 28 2498 [ 154 40542 ]

Vattaraphudej 1986 616 119 44 713 [ 095 5317 ]

Cooper 1981 1537 037 28 3100 [ 192 49971 ]

Subtotal (95 CI) 365 372 592 433 [ 219 858 ]

2 1000 mg or more

Cooper 1998 1350 026 28 1429 [ 088 23130 ]

Mehlisch 1995 41101 340 75 541 [ 178 1648 ]

Hersh 2000 3663 127 46 1543 [ 223 10685 ]

Skoglund 1991 1632 033 28 3400 [ 213 54391 ]

Seymour 2003 1262 432 78 155 [ 054 442 ]

Seymour 1996 2040 1039 96 195 [ 105 362 ]

Kiersch 1994 989 045 28 971 [ 058 16317 ]

Moller 2000 28120 0122 28 5794 [ 358 93840 ]

Subtotal (95 CI) 557 364 408 646 [ 234 1785 ]

01 02 05 1 2 5 10

(Continued )

Total (95 CI) 922 736 1000 487 [ 283 837 ]

01 02 05 1 2 5 10

Seymour 1996 1840 939 152 195 [ 100 380 ]

Forbes 1989 422 023 16 939 [ 054 16485 ]

Cooper 1988 936 640 105 167 [ 066 422 ]

Forbes 1990 836 032 17 1516 [ 091 25267 ]

Forbes 1984b 1139 036 17 2128 [ 130 34843 ]

Sunshine 1986 1430 530 111 280 [ 115 680 ]

Subtotal (95 CI) 203 200 418 267 [ 146 490 ]

2 1000 mg or more

Hersh 2000 3163 127 33 1329 [ 191 9242 ]

Mehlisch 1995 39101 340 82 515 [ 169 1571 ]

Olson 2001 4266 739 146 355 [ 177 711 ]

01 02 05 1 2 5 10

(Continued )

Seymour 1996 2140 939 157 228 [ 119 433 ]

Cooper 1998 1250 026 17 1324 [ 081 21504 ]

Kiersch 1994 489 045 16 460 [ 025 8361 ]

Lehnert 1990 2449 542 114 411 [ 172 983 ]

Skoglund 1991 1432 033 17 2988 [ 186 48076 ]

Subtotal (95 CI) 490 291 582 396 [ 252 623 ]

Total (95 CI) 693 491 1000 341 [ 234 497 ]

01 02 05 1 2 5 10

Cooper 1980 237 637 033 [ 007 155 ]

Dolci 1994 780 882 090 [ 034 236 ]

Forbes 1990 541 038 1021 [ 058 17873 ]

Forbes 1989 326 226 150 [ 027 825 ]

Sunshine 1986 130 130 100 [ 007 1526 ]

Cooper 1981 1237 438 308 [ 109 869 ]

Dionne 1994 727 525 130 [ 047 356 ]

Vattaraphudej 1986 016 019 00 [ 00 00 ]

Forbes 1984b 143 240 047 [ 004 493 ]

Subtotal (95 CI) 337 335 125 [ 069 225 ]

2 1000 mg or more

Olson 2001 1066 239 295 [ 068 1279 ]

Cooper 1998 2550 426 325 [ 127 835 ]

Moller 2000 48120 56122 087 [ 065 117 ]

Seymour 2003 2462 932 138 [ 073 260 ]

Mehlisch 1995 1299 440 121 [ 042 354 ]

Kiersch 1994 2691 1347 103 [ 059 182 ]

Hersh 2000 1263 727 073 [ 032 166 ]

Lehnert 1990 549 440 102 [ 029 355 ]

Subtotal (95 CI) 600 373 116 [ 084 160 ]

Total (95 CI) 937 708 119 [ 090 157 ]

01 02 05 1 2 5 10

(Continued )

01 02 05 1 2 5 10

Cooper 1980 37 2 37 6

Cooper 1981 37 12 38 4

Dionne 1994 27 7 25 5

Dolci 1994 80 7 82 8

Forbes 1984b 43 1 40 2

Forbes 1989 26 3 26 2

Forbes 1990 41 5 38 0

Gallardo 1990 15 5 11 3

Seymour 1996 40 0 39 0

Sunshine 1986 30 1 30 1

Totals 392 43 385 31

Cooper 1980 1 0 1

Cooper 1981 1 0 1

Cooper 1988 1 0 1

Cooper 1998 1 1 2

Dionne 1994 1 0 1

Dolci 1994 1 0 1

Forbes 1984b 2 0 2

Forbes 1989 1 0 1

Forbes 1990 2 0 2

Hersh 2000 1 1 2

Kiersch 1994 1 1 2

Kubitzek 2003 1 1 2

Lehnert 1990 1 1 2

Mehlisch 1995 2 1 3

Moller 2000 1 1 2

Olson 2001 2 1 3

Seymour 1996 1 1 2

Seymour 2003 2 0 2

Skoglund 1991 2 0 2

Sunshine 1986 2 1 3

50 pain relief at 4

lief )

higher doses

50 pain relife at 6

lief )

higher doses

lt0001

50 pain relief at

4 hours (using pain

intensity)

higher doses

50 pain relief at

6 hours (using pain

intensity)

higher doses

Nausea 21 11

Vomiting 11 3

abdominal pain

Headache 47 31

Bleeding 11 7

Paraesthesia 4 2

Jawache 1 0

Swelling 1 6

Cellulitis 1 0

Dry socket 11 12

CNS 5 6

GI 12 2

Body as a whole 8 3

Respiratory 2 0

Psychiatric 0 1

Cooper 1980 37 089 38 089

Cooper 1981 37 192 37 062

Cooper 1988 36 238 40 205

Dionne 1994 27 240 25 200

Dolci 1994 72 210 76 217

Forbes 1984 39 126 36 028

Mean 248 183 252 144

Forbes 1989 26 100 26 030

Forbes 1990 41 147 38 056

Sunshine 1986 30 120 30 093

Mean 113 131 113 070

Kiersch 1994 91 130 47 060

Kubitzek 2003 78 198 84 145

Mehlisch 1995 101 157 40 045

Olson 2001 66 281 39 193

Seymour 2003 62 250 32 214

Mean 398 194 242 129

Hersh 2000 63 229 27 085

Moller 2000 120 188 122 154

Mean 183 202 149 141

A P P E N D I C E S

5 (1 or 2 or 3 or 4)

18 (5 and 17)

H I S T O R Y

None known

Internal sources

External sources

I N D E X T E R M S

MeSH check words

Humans

I N B R I E F

RESEARCH

07p407-411qxd 10092004 1518 Page 407

RESEARCH

Ibuprofen 400 mg 107200 110400 109000 103900

Ibuprofen 600 mg 34200 39700 40800 42600

Ibuprofen 200 mg 36300 34600 32000 30600

Paracetamol 500 mg 11100 12800 15400 17200

Pethidine 50 mg 1100 900 700 700

Aspirin 300 mg 200 200 200 200

07p407-411qxd 10092004 1519 Page 408

RESEARCH

Aspirin 600650 mg 6271788 (36) 2551847 (15) 25 (22 to 29) 47 (42 to 54) 3635 46

07p407-411qxd 10092004 1519 Page 409

RESEARCH

07p407-411qxd 10092004 1520 Page 410

RESEARCH

07p407-411qxd 10092004 1520 Page 411

I N B R I E F

Aspirin 600650 mg 45 3581 36 14 45 (40 to 52) 30

Celecoxib 400 mg 4 620 34 3 25 (22 to 29) 84

Ibuprofen 400 mg 49 5428 55 12 23 (22 to 24) 56

Naproxen 500550 mg 5 402 61 7 18 (16 to 21) 89

PRACTICE

Ibuprofen 400 mg

Aspirin 600650 mg

Aspirin 1000 mg

Paracetamol 1000

Naproxen 500550

Celecoxib 400 mg

Diclofenac 50 mg K

Etoriocoxib 120 mg

1 2 3 4 5 6

Study design

Patients

Surgery

Table 1

Study groups

Rofecoxib50 mg +

Rofecoxib50 mg

1 1 0 0

Paracetamol200 mg

5 0 5 0

6 6 6 6

Analysis

Statistics

Results

Analgesic effect

Table 2

Study groups

Table 3

Study groups

5 6 2 3

Placebo

01234567

0 1 2 3 4 5 6 7 8

Paracetamol 1g

01234567

0 1 2 3 4 5 6 7 8

Rofecoxib 50 mg

01234567

0 1 2 3 4 5 6 7 8

01234567

0 1 2 3 4 5 6 7 8

0 05 1 15 2 25 3 35 4 45 5 55 6 65 7 75 8

placebo

paracetamol 1g

rofecoxib 50mg

placebo

rofecoxib 50mg

rofecoxib 50mg +

05 1 15 2 25 3 35 4 45 5 55 6 65 7 75 8

paracetamol 1g

Table 4

Study groups

452 (20) 409 (27) 287 (44) 91 (27)

182 (19) 151 (18) 111 (34) )32 (23)

Mean SPIDtotal (SE)

526 (59) 515 (60) 208 (96) )101 (57)

05 1 15 2 25 3 35 4 45 5 55 6 65 7 75 8

tion placebo

paracetamol 1g

rofecoxib 50mg

Side-effects

Global evaluation

Discussion

Table 5

Study groups

Table 6

Study groups

Rofecoxib+

paracet-amol

Paracet-amol

4 h 8 h 4 h 8 h 4 h 8 h 4 h 8 h

and B J Anderson1

doi101093bjaaep338

improve compliance

Methods

ACTRN12606000291583)

Setting

New Zealand

Participants

Intervention

4 hourly

Outcomes

Statistical methods

based variables

primary endpoint

Results

Merry et al

for acetaminophen

Efficacy

Pharmacokinetics

diction intervals

(P005)

70 kg21)18 ndash 20

Adverse effects

Screened(n =189)

Randomized(n =135)

Weight [mean (SD)] (kg) 713 (156) 808 (201) 711 (135)

Ethnicity [n ()]

Asian 4 (85) 1 (23) 2 (45)

Black 1 (21) 0 (00) 1 (23)

Caucasian 33 (702) 31 (705) 34 (773)

Maori 4 (85) 4 (91) 4 (91)

Other 1 (21) 3 (68) 1 (23)

Male [n ()] 13 (277) 21 (477) 13 (295)

Shift workers [n ()] 10 (213) 5 (114) 3 (68)

medication

General

ActivityRest

Acetaminophen alone

Ibuprofen alone

Combination

Acetaminophen

(n543)

(n540)

activity

0 4 8 12 16 20 24 28 32 36 40 44 48

Hours post-surgery

Nil 3 (75) 4 (114) 4 (105)

Mild 12 (300) 15 (429) 22 (579)

Moderate 22 (550) 14 (400) 12 (316)

Severe 3 (75) 2 (57) 0 (00)

Nil 26 (650) 25 (714) 30 (790)

Mild 10 (250) 8 (229) 7 (184)

Moderate 3 (75) 2 (57) 1 (26)

Severe 1 (25) 0 (00) 0 (00)

1 vs baseline VAS

[mean (SD)] (mm)

2219 (292) 2174 (229) 2166 (247)

2 vs baseline VAS

[mean (SD)] (mm)

2137 (329) 296 (258) 285 (201)

significant

Acetaminophen

alone (n515)

Acetaminophen

Ibuprofen

alone(n511)

Ibuprofen in

combination(n512)

CLF (litre

141 (26) 142 (18) 39 (17) 38 (13)

VF (litre) 557 (194) 482 (183) 106 (21) 98 (15)

Tabs (h) 042 (076) 016 (010) 058 (078) 085 (085)

Tmax (h) 109 (112) 064 (031) 116 (090) 144 (093)

Cmax (mg

litre21)

158 (65) 192 (64) 208 (83) 191 (78)

Merry et al

Discussion

phlebitis)

0 0 2 2

Subtotal 3 1 6 10

legs jaw pain)

2 0 1 3

6 4 4 14

1 1 2 4

Subtotal 18 8 12 38

ache vomiting)

3 0 2 5

Subtotal 5 0 4 9

Total 26 9 22 57

Conclusions

Funding

Development Grants

Appendix

capacity

Merry et al

Contributors

Ethics approval

Zealand

TT50-7316 (458)

Role of the sponsor

results

Merry et al

Paracetamol 000 300 000 030 070

Dipyrone 000 100 000 010 040

Paracetamol 000 300 100 060 070

Dipyrone 000 200 100 070 070

Paracetamol 000 300 100 080 090

Dipyrone 000 300 100 080 080

Paracetamol 000 200 100 080 070

Dipyrone 000 300 100 100 100

Paracetamol 000 300 100 080 090

Dipyrone 000 300 000 060 080

Paracetamol 000 200 000 060 080

Dipyrone 000 300 000 040 080

Paracetamol 000 200 000 055 070

Dipyrone 000 300 000 040 090

Paracetamol 000 200 000 040 070

Dipyrone 000 300 000 030 070

Lisyne clonixinate

Right after 00 10 00 02 04

lt 0001

Paracetamol

Right after 00 30 00 03 07

lt 0001

Dipyrone

Right after 00 10 00 01 04

lt 0001

CLINICAL TRIAL

Michael Goulder

Sodium ibuprofen

Introduction

Methods

Study design

Patients

Efficacy endpoints

Rainier scale

Rescue medication

Global evaluation

Safety assessments

Results

IBUPROFENPOLOXAMER

Total screened 614

ACETAMINOPHEN

PLACEBO

Completed 76

SODIUM IBUPROFEN

Timepoint (mins)

0 50 100 150 200 250

Timepoint (mins)

0 50 100 150 200 250

Acetaminophen(n=80)

Placebo(n=81)

Total(n=321)

Timepoint (minutes)

0 15 35 60 90 120 180 240 300 360

Timepoint (mins)

0 50 100 150 200 250

Safety findings

Discussion

Numberof events

References

RESEARCH

I N B R I E F

RESEARCH

3 11 (19) 12 (19) 9 (28)4 30 (51) 34 (55) 15 (47)

RESEARCH

0 5 10 15 20 30 45 60 90 120 240

Time (mins)

RESEARCH

Abstract

Abstract

Abstract

Abstract

Abstract

Introduction

Methods

Study design

Patients



Efficacy endpoints





Rainier scale

Rescue medication

Global evaluation

Safety assessments


Results













Safety findings

Discussion

References

Documents

Será o paracetamol eficaz na eliminação da dor após