The efficacy of pre-operative oral medication of paracetamol, ibuprofen, and aceclofenac on the success of maxillary infiltration anesthesia in patients

with irreversible pulpitis: A double-blind, randomized controlled clinical trial

Anupama Ramachandran, Sulthan Ibrahim Raja Khan, Deepalakshmi Mohanavelu, and Kumarappan Senthil kumar Abstract Aim: To determine the effect of preoperative administration of paracetamol !ARA", ibuprofen I#$!", or aceclofenac A%&%" on the success of ma'illar( infiltration anesthesia in patients )ith irreversible pulpitis in a double*blinded randomi+ed controlled trial, Materials and Methods: -ne hundred and t)ent( patients )ith irreversible pulpitis of a ma'illar( first molar participated, !atients indicated their pain scores on a .eft !arker visual analo/ scale, after )hich the( )ere randoml( divided into four /roups n 0 12", The subjects received identical capsules containin/ 3222 m/ !ARA, 422 m/ I#$!, 322 m/ A%&% or cellulose po)der placebo, !5A%", 3 h before administration of ma'illar( infiltration anesthesia )ith 67 lidocaine containin/ 3:622,222 epinephrine, Access cavities )ere then prepared and success of anesthesia )as defined as the absence of pain durin/ access preparation and root canal instrumentation, The data )ere anal(+ed usin/ chi*s8uared tests, Results: The success rates in descendin/ order )ere 91,17 I#$!", 927 A%&%", :1,17 !ARA", and 6;,< 7 !5A%", A si/nificant ! = 2,223" difference )as found bet)een the dru/ /roups and the !5A% /roup, %onclusions: !re*operative administration of !ARA, I#$!, and A%&% si/nificantl( improved the efficac( of ma'illar( infiltration anesthesia in patients )ith irreversible pulpitis, Ke()ords: Aceclofenac, ibuprofen, irreversible pulpitis, local anesthesia, ma'illar( infiltration anesthesia, nonsteroidal antiinflammator( dru/s, !aracetamol

INTR !"#TI N Achievin/ profound anesthesia is one of the pre*re8uisites of commencin/ endodontic treatment, Althou/h local anesthetics are hi/hl( effective in producin/ anesthesia in normal tissues, the( commonl( fail in patients )ith inflamed tissues,>3? @or instance, the inferior alveolar nerve block is associated )ith a failure rate of 3<7 in patients )ith normal tissue>6? and AAB437 )ith irreversible pulpitis>1? and 127 failure in ma'illar( infiltration in teeth )ith irreversible pulpitis,>6? Carious reasons cited are decreased tissue p.>A? and activation of nociceptors, includin/ tetrodoto'in and capsaicin*sensitive transient receptor potential vanilloid t(pe 3 TR!C3",><? !rosta/landin*induced sensiti+ation of peripheral nociceptors>;? has been commonl( implicated in anesthesia failure, !rosta/landins !Ds" up*re/ulate a variet( of mechanisms that mi/ht decrease the efficac( of local anesthetics, It alters the kinetics of activit( of the volta/e*/ated sodium channels, resultin/ in increased depolari+ation, activation of &D protein*coupled receptors, namel( !6 or &!1 receptors, )hich are e'pressed on tri/eminal sensor( neurons,>:? The rationale for the pharmacolo/ical mana/ement of pain usin/ ESAIDS is focused on the reduction of chemical inflammator( mediators !Ds" involved in pain, There are numerous published reports>4,9? on increasin/ the efficac( of anesthetics in the mandible but the clinical approaches to achieve successful anesthesia in ma'illar( teeth )ith irreversible pulpitis have not been e'plored sufficientl(, The efficac( of anesthesia close to the site of inflammation can be evaluated better in infiltration injection techni8ues rather than in nerve blocks, The causes for anesthesia failure in mandibular teeth include accessor( innervations of teeth )ith m(loh(oid nerve,>32? cross innervations,>33? and central core theor( in inferior alveolar nerve,>36? These variables are absent in the ma'illar( teeth and hence the( )ere selected for the present stud(, Therefore, the purpose of this prospective, randomi+ed, double*blinded stud( )as to compare the efficac( of oral pre*medication of paracetamol !ARA", ibuprofen I#$!", aceclofenac A%&%", and a placebo !5A%" medication on anesthetic efficac( of ma'illar( infiltration of lidocaine )ith 3:622,222 epinephrine in patients )ith irreversible pulpitis, The null h(pothesis tested )as that there is no si/nificant difference amon/ the four /roups, $AT%RIA&' AN! $%T( !' -ne hundred t)ent( adult patients, )ho reported )ith pain, )ithin the a/e /roup of 62B A2 (ears )ere selected for the stud(, The eli/ibilit( criteria to participate in the clinical trial )ere as follo)s: health( patients ASA I or ASA II" )ith a vital ma'illar( first molar e'periencin/ intermittent or spontaneous pain )hich had a prolon/ed response to cold testin/ )ith &ndo*Ice 3, 3, 3, 6 tetrafluoroethane, .(/enic %orp,, Akron, -." and an

electric pulp tester Kerr, Anal(tic Technolo/( %orp,, Redmond, FA", This )as done to confirm the dia/nosis of irreversible pulpitis, Also, the absence of periapical radiolucenc( on radio/raphs, e'cept for a )idened periodontal li/ament not more than 2,:<B3 mm", and patients )ith the abilit( to understand the use of pain scales )ere selected, Subjects )ho had pulpitis in teeth other than the first ma'illar( molar in the same 8uadrant )ere e'cluded from the stud(, -ther reasons for e'clusion )ere those )ith kno)n aller/( or contraindications to anal/esics: patients )ith a histor( of active peptic ulcer )ithin the precedin/ 36 months, bleedin/ problems or anticoa/ulant use )ithin the last month, opioid, nonopioid anal/esics, steroids, antidepressants, or sedatives use )ithin 36B6A h before administration of the stud( dru/s, The e'cluded patients )ere appropriatel( mana/ed based on their e'istin/ clinical conditions, &thical approval )as sou/ht from the Institutional Revie) #oard and &thical committee of the $niversit(, Informed )ritten consent )as obtained from each subject, Randomi+ation of patients )as done b( simple random samplin/ )ith a linear con/ruential /enerator, Randomi+ed allocation of the patients )as done b( a trained dental h(/ienist )ho )as blinded to the treatment procedures, &ver( patient )as asked to rate hisGher pain on a .eft !arker visual analo/ scale CAS" )ith 3:2*mm line marked )ith various terms describin/ the levels of pain .eft and !arker 394A", The millimeter marks )ere removed from the scale, and the scale )as divided into four cate/ories: no pain corresponded to 2 mmH faint, )eak or mild pain corresponded to 3B<A mmH moderate to severe pain corresponded to <<B33A mmH and stron/, intense, ma'imum possible pain corresponded to more than 33A mm,>31? !atients )ere instructed to place a mark on the line to indicate the painH this mark )as then measured )ith the scale and the score )as recorded, A universit( hospital pharmacist divided 362 empt( capsules of same color and si+e into A bottles: paracetomol !ARA", ibuprofen I#$!", aceclofenac A%&%", and placebo !5A%" /roups, !ARA capsules )ere filled )ith 3222 m/ of paracetamol, I#$! capsules )ith 422 m/ of ibuprofen, A%&% capsules )ith 322 m/ aceclofenac, and !5A% capsules )ith starch, The bottles )ere masked )ith an opa8ue label and )ere randoml( assi/ned a three*di/it alphanumeric value, A trained dental h(/ienist randoml( divided all the patients into four /roups of 12 patients each and /ave one capsule 3 h before the procedure, Topical anesthetic /el 67 lidocaine '(locaine jell(, AstraIeneca, India" )as passivel( placed at the infiltration site for ;2 s usin/ a cotton*tip applicator, A sin/le operator /ave all the injections of 3,4 ml of 67 lidocaine )ith epinephrine 3:622,222 '(locaine 67 )ith epi 3:622,222" usin/ standard dental aspiratin/ s(rin/e fitted )ith a 6:*/au/e, 3,<* inch needle and this operator had no involvement )ith testin/ the outcome, After < min, the tooth in 8uestion )as tested a/ain )ith cold spra(, If the patient felt pain or sensitivit(, the test )as recorded as a failure and eliminated from the stud(, .o)ever, no subjects )ere eliminated in this criterion, A rubber dam )as placed and a standard endodontic access cavit( )as be/un )ith a bur under )ater spra( coolant and pulp

e'tripation done, In the case of pain durin/ the treatment, the procedure )as stopped, and patients )ere asked to rate the pain on .eft !arker CAS, The success of the techni8ue )as defined as the abilit( to access and e'tripate pulp )ithout pain CAS 0 2 mm" or mild discomfortGsensitivit( CAS J <A mm", If the score )as J<A mm, the outcome )as recorded as failure and supplementar( anesthesia )as administered and the procedure )as completed, The post injection CAS scores )ere recorded at the end of the procedure, The findin/s )ere recorded on a Microsoft &'cel sheet Microsoft -ffice &'cel 6221H Microsoft %orp, Redmond, FA" for statistical evaluation b( usin/ the S!SS soft)are, A/e and initial and post*injection pains of the subjects )ere summari+ed b( usin/ means and standard deviations, Multiple comparison anal(sis of variance and post hoc tests )ere used to determine si/nificant differences, Anesthetic success of the !ARA, I#$!, A%&%, and !5A% /roups )as dichotomous in nature and )as anal(+ed b( usin/ chi* s8uare tests, R%'"&T' The Structure of R%T and the number of enrolled in the intention to treat is /iven in >@i/ure 3?, The a/e, /ender, and mean initial CAS scores )ere tabulated >Table 3?, There )ere no si/nificant differences ! = 2,223" bet)een the four /roups, The post*injection CAS scores are /iven in Table 6, There )as si/nificant difference bet)een the !5A% and the three dru/ /roups, I#$! and A%&% /roups demonstrated si/nificantl( lo)er scores than the !ARA /roup, .o)ever, there )as no si/nificant difference bet)een I#$! and A%&% /roups ! = 2,223", The number and percenta/e of patients )ith successful ma'illar( infiltration anesthesia b( the test, and control /roups are presented in Table 6, The percenta/e of successful anesthesia )as as follo)in/: A27 in the control !5A% /roup, )hilst premedication )ith !ARA, I#$!, and A%&% resulted in :1,17, 91,17, and 927, respectivel(, The percenta/e of successful anesthesia )as si/nificantl( hi/her in all the dru/ /roups )hen compared )ith the !5A% /roup ! = 2,223",

@i/ure 3 @lo) chart of R%T

Table 3 comparison of a/e, /ender, and initial heft parker visual analo/ue scale scores amon/ the four /roups

Table 6 %omparison of percenta/e of inferior alveolar treatment /roup nerve block amon/ the four /roups

!I'#"''I N In irreversible pulpitis, breakdo)n of dama/ed cell membranes and release of arachidonic acid AA" occurs, This AA is acted on b( c(clo'(/enase %-K" en+(me and /ets converted into 62*carbon chain molecules called eicosanoids, These are converted b( cell*specific isomerases and s(nthases to produce five biolo/icall( active !Ds: !DD6, !D&6, !D@6a, prostac(clin !DI6", and thrombo'ane A6 T'A6", These !Ds sensiti+e nerve endin/s to brad(kinins and histamines and cause the allod(nia and h(peral/esia associated )ith inflammation,>3A?

The success rates of local anesthesia have been found to be )orse in patients )ith inflamed pulpal tissues,>3<? Eumerous reports>3;,3:? su//est that activation of nociceptors b( inflammator( mediators such as !Ds are a major cause of increased failure of anesthesia, !eripheral terminals of nociceptors e'press certain protein receptors )hich can detect chemical and ph(sical stimuli, Inflammator( mediators such as prosta/landins produce their effects b( bindin/ to these various protein receptors resultin/ in activation of various ion channels e'pressed on peripheral terminals, These mediators reduce the threshold for activation of nociceptor neurons to a point that a minor stimulus mi/ht fire the neurons, The primar( action of local anesthetics in producin/ a conduction block is to decrease the permeabilit( of volta/e*/ated sodium channels to sodium ions, There are at least nine different subt(pes of sodium channels, Eociceptors e'press a tetrodoto'in*resistant TTK*R" class of volta/e*/ated sodium channels that are relativel( resistant to local anesthetics and are sensiti+ed b( prosta/landins, These TTK*R channels are of t)o specific isoforms Eav3,4 and Eav3,9 )hich pla( a ke( role in the /eneration and maintenance of inflammator( pain, !rosta/landins not onl( alter the kinetics of the channelsL activit(, resultin/ in increased depolari+ation, but the actual TTK* R channels themselves are e'pressed at hi/her levels,>34? In a recent stud(, Fells et al,>39? usin/ immunoreactivit( found si/nificantl( increased levels of the TTK*R channels of Eav3,9 isoform in painful, inflamed teeth compared )ith as(mptomatic dental pulps, Therefore, it can be concluded that b( reducin/ the amount of prosta/landins, TTK*R channels become less active thereb( increasin/ the anesthetic success, Acetaminophen, aceclofenac, and ibuprofen are relativel( safe, fast*actin/ anal/esics that also control inflammation, !aracetamol has been used clinicall( for over a half of a centur( and remains the most popular anal/esicGantip(retic used in children )ith its proven safet( and efficac(,>62? The efficac( of ibuprofen a propionic acid derivative" in postoperative dental pain is also )ell established, Aceclofenac phen(lacetic acid derivative" has anti*inflammator( properties similar to those of diclofenac and of indomethacin, In clinical studies, it has been sho)n to treat dental pain effectivel(,>63? Eielsen et al,>66? sho)ed that 422 m/ ibuprofen )as superior to A22 m/ in a stud( of laser*induced pain, Sko/lund et al,>61? compared 3,222 m/ and 6,222 m/ acetaminophen and reported total anal/esia )ith 3,222 m/, .ence, 3,222 m/ of acetaminophen, 422 m/ of ibuprofen, and 322 m/ of aceclofenac )ere chosen for this stud(, !remedication )as /iven 3 h before the procedure to allo) ESAIDs to achieve satisfactor( plasma concentration, The CAS is to be methodolo/icall( sound, conceptuall( simple, eas( to administer, and unobtrusivse to the respondent, A combined metric scale .eft*!arker" for pain measurement that provides the subject )ith multiple cues mi/ht improve communication and concordance bet)een scales for individual pain determination,>31? Similar methodolo/( )as follo)ed b( other researchers>31,3<?

The results of the stud( sho) that the increase in anesthetic effect of lidocaine )as statisticall( si/nificant in all the three dru/ /roups compared to the placebo /roup, Similar results )ere found b( Ianiro et al,>9? The mechanism of action of most ESAIDs results b( acet(latin/ the c(cloo'(/enase en+(me, )hich in turn inhibits the s(nthesis of prosta/landins, Thus, ESAIDs nonspecificall( prevent both the %-K*3 and %-K*6 isoen+(mes from formin/ arachidonic acid metabolites, #ecause there is induction of %-K*6 at sites of inflammation, it is believed that the therapeutic properties of ESAIDs account primaril( for the inhibition of %-K*6,>6A? Fhile ibuprofen and aceclofenac are both ESAIDs, the( have different chemical structures, Ibubrufen is a non*selective %-K inhibitor and aceclofenac is a selective %-K*6 inhibitor, Ibuprofen also inhibits the mi/ration and other functions of leucoc(tes, )hile aceclofenac reduces intracellular concentrations of free arachidonate in leucoc(tes, Althou/h the action of acetaminophen is unkno)n, it has been su//ested that it interferes )ith inflammation b( diminishin/ the s(nthesis of prosta/landins possibl( !D@6", An alternative e'planation is that a !D.S variant %-K*1" e'ists in the central nervous s(stem %ES", and that this variant is e'8uisitel( sensitive to !ARA,>6<? This premise also needs further inspection, The I#$! and A%&% /roup demonstrated better anal/esic effect than the !ARA /roup, This could be because !ARA has a )eak anal/esicGanti*inflammator( effect and a stron/ antip(retic effect, Also, the suppression of !Ds at the inflammator( site appears to be at a minor level and the predominant mechanisms lar/el( responsible for !ARAMs anal/esic activit( are located in the %ES,>62? In the present stud(, there )as no si/nificant difference bet)een the I#$! and A%&% /roups as both the dru/s inhibit %-K*6 en+(me )hich pla(s a major role in inflammation, .o)ever, further research is needed in this direction, A further clinical trial )ith a lar/er sample si+e )ould stren/then the results of the present stud(,

# N#&"'I N -ral pre*medication )ith 422 m/ I#$!, 322 m/ A%&%, and 3222 m/ !ARA resulted in si/nificantl( hi/her percenta/e of successful ma'illar( infiltration anesthesia in patients )ith irreversible pulpitis,