diplopiannt

FullTerms&Conditionsofaccessandusecanbefoundathttps://www.
tandfonline.
com/action/journalInformationjournalCode=ieop20ExpertOpiniononPharmacotherapyISSN:1465-6566(Print)1744-7666(Online)Journalhomepage:https://www.
tandfonline.
com/loi/ieop20MedicalmanagementoftrigeminalneuropathicpainsJoannaMZakrzewskaTocitethisarticle:JoannaMZakrzewska(2010)Medicalmanagementoftrigeminalneuropathicpains,ExpertOpiniononPharmacotherapy,11:8,1239-1254,DOI:10.
1517/14656561003767449Tolinktothisarticle:https://doi.
org/10.
1517/14656561003767449Publishedonline:29Apr2010.
SubmityourarticletothisjournalArticleviews:3610Citingarticles:60Viewcitingarticles1.
Background2.
Trigeminalneuralgia3.
Glossopharyngealneuralgia4.
Traumaticallyinducedneuralgia,trigeminalneuropathicpainandatypicalodontalgia5.
Burningmouthsyndrome6.
Conclusion7.
ExpertopinionReviewMedicalmanagementoftrigeminalneuropathicpainsJoannaMZakrzewskaEastmanDentalHospital,OralMedicineDepartment,London,UKImportanceofthefield:Althoughtrigeminalneuralgiahastraditionallybeenconsideredtheprimeneuralgicconditioninthefaceregion,otherformsofneuropathicpainarenowbeingmorefrequentlyrecognizedandrequirerecognitionandadifferentmanagementapproach.
Areascoveredinthisreview:Thisreviewprincipallycoversmedicalmanage-mentoftrigeminalneuralgia;butalsoincludedisglossopharyngealneural-gia,trigeminalneuropathicpain(atypicalodontalgia)andburningmouthsyndrome.
Systematicreviewsandguidelineswillbediscussed.
Whatthereaderwillgain:Anupdatewillbeprovidedofdrugtherapyfortheserelativelyrarefacialpains.
Takehomemessage:Trigeminalneuralgiacontinuestobebestmanagedusinganticonvulsantdrugs,theprimaryonesbeingcarbamazepineandoxcar-bazepine;baclofenmaybehelpfuland,ofthenewlyemergingdrugs,prega-balinhaspotential.
Glossopharyngealneuralgiaremainsmanagedinthesamewayastrigeminalneuralgia.
Trigeminalneuropathicpainisprobablybestmanagedaccordingtoguidelinesusedforthemanagementofneuro-pathicpain,whichincludetheuseoftricyclicantidepressants,gabapentin,pre-gabalin,duloxetine,venalafaxineandtopicallidocaine.
Burningmouthsyndromeisaneuropathicpainmanagedinitiallywithtopicalclonazepamandthenwithotherneuropathicdrugs.
Patientsneedtobeinvolvedintheirmanagement.
Keywords:antidepressants,antiepilepticdrugs,burningmouthsyndrome,glossopharyngealneuralgia,neuropathicpain,trigeminalneuralgiaExpertOpin.
Pharmacother.
(2010)11(8):1239-12541.
BackgroundThemostwidelyrecognizedneuropathicpainofthefaceistrigeminalneuralgia.
Othersthatalsooccurincludeglossopharyngealneuralgia,postherpeticneuralgiaandtherelativelynewlyemergingtrigeminalneuropathicpainpossiblythesameasatypicalodontalgiaalsoneedtobeconsidered.
Thereisalsoincreasingevidencethatburningmouthsyndromeisaneuropathicpain.
Agroupofconditionscalledthetrigeminalautonomiccephalgias(TAC)formadistinctsubgroupofneuralgiform-typepainsprincipallyaffectingthefirstdivisionofthetrigeminalnerve.
Theseincludeconditionsknownasclusterheadache,paroxysmalhemicrania,shortunilateralneuralgiformpainwithconjunctivalinjectionandtearing(SUNCT)andthemorerecentlyusedterminologyshortunilateralneuralgiformpainwithautonomic(SUNA)symptoms.
ThelastprobablyencompassthemorestrictcriteriaofSUNCT[1].
TheTACsarenotcoveredbythisreview.
LookingthroughtheInternationalHeadacheSocietyclassification[2],amultitudeofotherneuralgiashavebeenidentified.
Theevidencefortheirexistenceasdistinctentitiesisscant,andeventhebest-knowntrigeminalneuralgiahasnotbeenformallyvalidatedbycase-controlseries[3].
Severalpromisingtargetsfortreatmenthavebeenidentified,suchassodiumandcalciumchannels,glutamatereceptors,monoaminesandneurotrophicfactors,and10.
1517/146565610037674492010InformaUKLtdISSN1465-65661239Allrightsreserved:reproductioninwholeorinpartnotpermittedithasthereforebeensuggestedthatamoremechanism-basedapproachshouldbetakentomanagementofthesecon-ditions[4].
However,atpresenttreatmentisofteninsufficientwhenusingthismethodologyandFinnerupetal.
[5]suggestthatthisisbecausewestilllackvalidandreliabletoolstoassessneuropathicpainanddonotunderstandthemecha-nismsofindividualconditions.
Theemergenceofseveralscreeningtoolsbasedonverbaldescriptors,withorwithoutbedsidetesting,toattempttodiagnoseneuropathicpaininrecentyearsisevidenceoftheincreasingattemptstopheno-typethesepatientsmoreaccurately[6].
Thesetoolshaverarelybeenusedinfacialpainconditions.
2.
Trigeminalneuralgia2.
1OverviewAreviewoftrigeminalneuralgiaanditstreatmentswaslastpublishedinExpertOpinionin2003[7].
Thisarticleupdatesthematerialinthatreview.
Trigeminalneuralgiaisdefinedasaunilateral,severe,short-lastingpainoftheface[2,8].
Thevastmajorityofcasesareofunknownaetiologyandtherarerformsareduetosec-ondarycausessuchasbenignandmalignanttumours,demy-lination(suchasoccursinmultiplesclerosis)andrarearteriovascularmalformations.
EpidemiologicalstudiesthatweremainlydoneintheUSduringthe1990ssuggestedthatthisconditionwasrare,withanannualincidenceintheUSof4--6per100,000patients,thatitoccurredinthe50--70yearsagegroupandwasmorecommoninwomenthanmen[9].
However,morerecentstudiescarriedoutinresearchprimary-carepracticesbothintheUKandinHollandsuggestthatgeneralmedicalpractitionersarediag-nosingtrigeminalneuralgiamuchmorefrequently,withinci-dencerateof28per100,000[10,11].
IsuspecttheremaybeanelementofmisdiagnosisandsomeofthesecaseswillbedentalpainsoroneoftheTACs,asteachingonfacialpainamongmedicalpractitionersisvirtuallynon-existentandmisdiagno-sisiseasy[12].
LargerEuropeanstudieslookingattheburdenofneuropathicpainacrosssixEuropeancountriesshowedthatof602patients,14%hadtrigeminalneuralgia[13].
Theywentontoshowthatthemeanageofthese82patientswithtrigeminalneuralgiawas62yearsandthattherewasapredominanceoffemales(67%)[14].
Interestingly,theyalsoreportedonthetreatmentsofthesepatients,comparingthedrugsthatthephysicianreportedtheyusedwithpatientreports:aswouldbeexpected,therewerediscrepancies.
Justoverhalfthepatients--55%--wereprescribedoneortwoantiepilepticdrugs,ofwhichcarbamazepinewasusedin54%ofcases,gabapentinin29%andavarietyofothersintherest.
However,46%werestillusingstandardanalgesicdrugsand26%wereusingantidepressantdrugs.
Upto40%ofpatientsreportedthattheyusedparacetamoland17%usedherbs,vitaminsandsupplements.
Themajorityofthepatientshadusedtheirdrugsforover3years.
Yetitiswellknownthatcarbamazepineisahighlyeffectivedrug,withanumberneededtotreat(NNT),dependingonthereviewoneuses,ofaround1.
9[95%confidenceinterval(CI)1.
4--2.
8]and--especiallyearlyinthehistory--givesnotjust50%painreliefbutvirtually100%.
IntheUK,carbamazepineisthedrugoffirstchoiceoftheBritishNationalFormularyandinguidancetoGPsintheirClinicalKnowledgeSumma-ries.
Thisthereforebegsthequestion,arethesepatientsmisdiagnosedoraretheybeingofferedsuboptimalcareduetoignoranceofhealthcarepractitionersEuropeanstudieshaveshownthat,generally,chronicpainisvastlyundertreated[15].
Althoughitisnowrecognizedthatriskfactorsfortrigemi-nalneuralgiaincludemultiplesclerosisandhypertension,thereisstillverylittledatatodeterminetheprognosisforthesepatientsandtherehavebeennocomparativestudieslookingatoutcomesofpatientswhohavebeenmedicallymanagedasopposedtothosemanagedsurgically.
Overall,itappearsthatrelapseisassociatedwithincreasedintensityofpain;however,althoughthistendstooccur,therearegroupsofpatientsinwhomtheintensityofthepainseemstoremainfairlysteady.
Therearefewdatatodeterminewhethertoler-ancetodrugsdevelops.
ThediagnosticclinicalfeaturesoftrigeminalneuralgiaareillustratedinFigure1.
Expertsworkinginthefieldoftrigeminalneuralgiarecog-nizeaform,oftentermed'atypicaltrigeminalneuralgia',inwhichpatientsnotonlyhavetheclassicfeaturesoftrigeminalneuralgiabutalsoreportabackgroundburning,dulltypeofpainthatdoesnotappeartobeasresponsivetoanticonvulsanttherapyastheclassictrigeminalneuralgia[16];itmayinfacthaveadifferentaetiology.
Anaccuratehistoryofthepainisextremelyimportantasthiscanalterdrugmanagement.
TheaetiologyandpathophysiologyoftrigeminalneuralgiahasremaineddifficulttodetermineandthemostwidelyacceptedtheoryisthatofDevoretal.
[17]:theignitionhypoth-esis.
Thereisnowincreasingevidencethatchangesoccurnotonlyperipherallybutalsocentrally,andthatthesecentralchangesmightbemorefrequentinpatientswhosufferfromatypicaltrigeminalneuralgia[18].
Obermannetal.
[18]haveshowninasmallgroupofpatientsthattheremaybeArticlehighlights.
.
TherearefewhighqualityRCTsofdrugsusedalltheseconditions.
.
Carbamazepineandoxcarbazepinearethefirstlinedrugsfortrigeminalneuralgiaandglossopharyngealneuralgia.
.
Trigeminalneuropathicpainalsocalledatypicalodontalgiaismanagedusingneuropathictypedrugs.
.
Burningsyndromeislikelytobeaneuropathicpain.
.
Managementbeginswitheducationandfirstlinedrugistopicalclonazepamfollowedbyotherneuropathictypedrugs.
Thisboxsummariseskeypointscontainedinthearticle.
Medicalmanagementoftrigeminalneuropathicpains1240ExpertOpin.
Pharmacother.
(2010)11(8)overactivationofthecentralfacilitationoftrigeminalnocicep-tiveprocessing.
Ithasoftenbeensuggestedthattheatypicalformfollowsonfromclassictrigeminalneuralgia,andyetthiscounterssomerecentepidemiologicalstudiesbasedonapatientledsurveyinover6000patientsinwhomtheageofonsetofclassictrigeminalneuralgiaislaterthanthatofatyp-icaltrigeminalneuralgiaandtheseatypicalfeaturesarereportedatthestartoftheconditionnotjustinlaterstages(Vellyetal.
,unpublisheddata).
Antiepilepticdrugs(AED)havebeenusedsincethe1860sandpossiblyrelatetotheobservationthattheintermittencyoftheattacksofpainweresimilartoepilepsyandthatthereforethemechanismscouldbesimilarandpatientswouldrespondtothesetypesofdrug.
In1942,phenytoinwasfirstreportedasbeingeffective,butthiswassoonsupersededbycarbamaz-epine,theuseofwhichintrigeminalneuralgiawasfirstreportedin1962.
Sincethen,manyAEDs,andotherdrugs,havebeenusedforthemanagementoftrigeminalneuralgia.
Therehavenowbeenavarietyofsystematicreviews,bothwithintheCochranecollaborationandwithout,toevaluatetheuseofthesedrugs[19-23].
Thesehaveledtothepublicationofinternationalguidelines[24,25].
Giventherarityoftheconditionanditspeculiarfeatureofunpredictableremissionperiods,ithasbeendifficulttoperformrobustrandomizedcontrolledtrials(RCTs).
ReviewshaveshownthatmanyhaveflawedmethodologyanddonotfollowtheCONSORT(ConsolidatedStandardsofReportingTrials;http://www.
consort-statement.
org)guidelinesforreportingoftrials(Figure2).
JornsandZakrzewska[26]havehighlightedthesedifficultiesandhaveputforwardsomesuggestionsformorerobustdesignsofsuchtrials:.
Carefulphenotypingofpatients,payingparticularatten-tiontothecharacterofpain,durationofdiseaseandpastdrugsandresponses.
.
Useofenhancement-enrichedstudiesratherthantheconventionalcross-overandparallelstudies.
.
Clearstatementsonprimaryandsecondaryoutcomemeasures.
.
Useofpowercalculations.
Onlyveryrecentpublishedtrialsfollowtheserecommenda-tionsandmostoutcomemeasuresarebasedpurelyonavisualanaloguescaleofpainintensity.
TheIMMACTgroup[27]hassuggestedawiderrangeofoutcomemeasures,includingqual-ityoflife,physicalfunctioningandemotionalfunctioning;theall-importanttolerabilityandsafetyshouldalsobereported.
Currently,onlyonetrialontrigeminalneuralgia,usingIVimmunoglobulinislistedintheUKClinicalTrialsRegister.
Thewebsitehttp://public.
ukcrn.
org.
uk,liststrialsthatfulfilthecriteriaforRCTsandhaveethicalapproval.
2.
2MethodsTheauthorregularlyupdatesareviewinClinicalEvidence.
Theeditorialteamdevelopedthesearchstrategy,runsthesearchesandensuresthatauthorscriticallyappraisealltheidentifiedstudiesusingtheirmethodologyforqualityscor-ing[23].
Currently,searcheshavebeencarriedonanupdateofaCochranereviewonnon-epilepticdrugsintrigeminalneuralgia[22]andthishasalsobeenusedtoidentifyallthehigh-qualitystudies.
RCTsvaryinsizefrom341patientstojustthreepatients.
Table1liststhedrugsusedinRCTswithmorethan10patients.
Sharp,shootingElectric,lightningTerrifyingUnbearableModeratetosevereUnilateral97%TrigeminalareaRarefirstdivisionLighttouchevokedSpontaneousMaybetriggerspotsCharacterseveritySiteTimingperiodicityProvokingAssociatedfactorsParoxysmalAcuteonsetNNTSideeffectsNNHCommentsonuseBaclofenMusclerelaxant,GABAbreceptoragonistFrommetal.
1984:R*,D-B,C-Obaclofen-10patientsFrommetal.
1987R,D-B,C-OracemicvsL-baclofen,15patientsParekhetal.
1989:R,D-B,PbaclofenvsCBZvscombination,30patients50--80mgGoodbutnotpossibletodetermineNNTAtaxia,lethargy,fatigue,nausea,vomiting,lossofmuscletoneBewarerapidwithdrawalMaybeusefulinpatientswithmultiplesclerosisorwithallergiestoCBZCarbamazepine(CBZ)ActsonNa+channelsandblocksL-typeCa2+channelsCampbell1966:R,D-B,C-O,70patientsKillian&Fromm1968:R,D-B,initiallyC-O,followedbyclosedlabelextension,24patientsNicol1969:R,D-B,modifiedC-O,followedbyclosed-labelextension300--1000mgNNT1.
9(95%CI1.
4--2.
8)butlosesefficacywithtimeDrowsiness,ataxia,headaches,nausea,vomiting,constipation,blurredvision,rash,introduceslowly,druginteractionsNNH3.
7(CI2.
4--7.
8).
ForminorsideeffectsNeedscarefulmonitoringespeciallyifpatientsareonotherdrugsGabapentin(GBP)andropivacain(ROP)Gabapentin:Ca2+channela2dligand,elevatesGABA.
ropivacain:blocksNa+channelsLemosetal.
2008:R,singleB,P,36patients,12GBP,12ROP,12GBP+ROPfollowedbyopen-label12monthsGBP300--900mgROPweeklyintriggerarea,max4InsufficientpaincontrolonROPaloneGBP+ROP:NNT2.
4(95%CI:1.
46--8.
49)at4weeksSedation,ataxia,dizziness,oedemaShorttrial,shortdurationofdiseasesmall.
OpenstudieshaveneededtousemuchhigherdosesLamotrigineActsbothonNa+andCa2+channels,altersreleaseofglutamateandaspartateZakrzewskaetal.
1997:R,D-B,C-O,addon14patients200--400mgGoodwhenaddedtootherAEDNNT2.
1(1.
3--6.
1)Dizziness,drowsiness,constipation,ataxia,diplopia,irritability,rapiddoseescalationleadstorashesShorttrialwithnofollow-upandnoindicationifeffectiveasmonotherapy.
TheneedforslowescalationprecludesitfromacuteuseOxcarbazepine(OXC)KetoderivativeofCBZsosameactionLiebel2001:R,D-B,PG48patientsvsCBZBeydounetal.
2000,2002:R,D-B,PG,130patients,includedmeta-analysisvsCBZ300--1200mgEqualtoCBZImprovedtolerabilitywhencomparedtoCBZVertigo,fatigue,dizziness,nausea,hyponatraemiainhighdoses,nomajordruginteractionsEffectivedrugusedasprimarydrugofchoiceinScandinaviancountriesClomipramineCarasso1979:R*,single--B,P,18patientsvsamitriptyline20--75mgSomeimprovementNonestatedVerypoorqualitystudy,notused*poorrandomization.
AED:Anti-epilepticdrug;C-O:Cross-overdesign;D-B:Doubleblind;NNH:Numberneededtoharm;NNT:Numberneededtotreat;P:Parallelgroups,R:Randomized.
ZakrzewskaExpertOpin.
Pharmacother.
(2010)11(8)1243Table1.
Drugsusedintrigeminalneuralgiawhichhavebeenevaluatedinrandomizedcontrolledtrials(RCTs)(continued).
Drug/therapyMechanismofactionTrialdetailsDailydoserangeEfficacyNNTSideeffectsNNHCommentsonusePimozideDopaminereceptorantagonistLechinetal.
1989:R,D-B,C-O,48patientsvsCBZ4--12gExcellentSeveresideeffectsExtrapyramidal;tremor,rigidity,memorylossSideeffectslimititsuseProparacainehydrochloride0.
5%eyedropsNotentirelyclear.
MayinhibitNa+ionfluxesKondziolkaetal.
1994:R,D-B,C-O,47patients2dropsof0.
5%solutionfor20minIneffectiveNilNoclinicaluseSumatriptanActivation%-HTreceptorsKanaietal.
2006:R,D-B,C-O,24patients3mgsubcutaneousTransientriseinbloodpressure,fatigue,nauseaEffectstooshorttermtobeofclinicaluseTocainideNa+channelblockerLindstrom&Lindblom1987:R,D-B,C-O-12patientsvsCBZ60mg/kgAseffectiveasCBZRash,nausea,paraesthesia,aplasticanemiaItsseveresideeffectsprecludeitsroutineuseTizanidinea-adrenoceptoragonistFromm1993:R*,D-B,C-O,11patientsVilmingetal.
1986:R*,D-B,P,12patientsvsCBZ6--18mgIneffectiveDrowsiness,dizziness,altersliverenzymesNoclinicaluse*poorrandomization.
AED:Anti-epilepticdrug;C-O:Cross-overdesign;D-B:Doubleblind;NNH:Numberneededtoharm;NNT:Numberneededtotreat;P:Parallelgroups,R:Randomized.
Medicalmanagementoftrigeminalneuropathicpains1244ExpertOpin.
Pharmacother.
(2010)11(8)2.
2.
3GabapentinThisAEDhasbeenusedextensivelyinRCTsofneuropathicpainandisproventobeofvalue.
Itisthereforenotsurprisingthatithasbeenreportedintrigeminalneuralgiainseveralopenstudies[38,39]andreviewed[40,41].
OnlyoneRCTuseditincombinationwithropivacain[42].
Althoughconsiderableeffortwasplacedonallocationconcealmentandrandomiza-tion,thestudywasonlysingleblindedaspatientsknewwhethertheyreceivedaninjection.
Thestudywasextendedbeyond28daysforupto6months.
Thecombinationpatientshadthebestoutcomeandwereabletouselowertotaldailydosesofgabapentin.
Thedosesusedwerelow--upto900mgdaily--incomparisonwithopen-labelstudies,inwhichupto3600mgwereused.
Althoughqualityoflifewasreported,therearenodetailsofadverseevents,withjustamentioninthediscussionthatthecombinedtreatmentgrouphadnone.
2.
2.
4LamotrigineThisdrughasbeenreportedinsmallcaseseries[43,44]buthasbeenusedinonlyonesmallRCT,whereitwasaddedtoexistingsub-effectivetherapy[45].
AlthoughtheNNThasbeencalculatedat2.
1andthe95%confidencelimitsarewide(1.
3--6.
1),itseffectivenessasastand-alonedrughasnotbeenfullyevaluated.
Itisessentialtoescalatethedoseveryslowly.
2.
2.
5OxcarbazepineTheketoderivativeofcarbamazepinedoesnotpassthroughthelivercytochromesystemandsoresultsinfewersideeffectsanddruginteractionsthancarbamazepine.
Unfortunately,theRCTsandmeta-analysis[46-48]remainasabstractsanditisimpossibletogetfurtherinformationtoevaluatethesetrialscomprehensively.
Theycomparedcarbamazepinetooxcarba-zepineandshowedequalefficacy:88%receivedapainreduction>50%buttolerabilitywasbetterwithoxcarbaze-pine.
Threecasereports[49-51]showsimilarefficacy.
Along-termcohortstudyonpatientswithoxcarbazepineshowthatwithtimethediseasebecomesmoresevereandsurgerybecomesthetreatmentofchoice[52].
2.
2.
6OthersmallrandomizedcontrolledstudiesDextromethorphan[53]andtopiramate[54]werebothevalu-atedinanRCTinvolvingthreepatients,whichistoosmalltoprovideanymeaningfuldata.
Eyedrops[55]andstreptomy-cininjectionswithlidocaine[56],whenassessedinRCTs,showednoeffect.
Tocainade[57]wascomparedwithcarba-mazepineinasmallstudyandwasshowntohavethesameeffectivenessbutmoreadverseeffects.
AnothertwosmallRCTswithtizanidineshowedthisdrugtohaveresultssimilartocarbamazepine[58,59].
Arecentnovelapproachissubcutaneoussumatriptan[60].
Thepremisewasthattheremightbearolefora5-HTrecep-torintrigeminalneuralgia.
Patientshadtocomeoffalltheirneuralgicmedicationsfor12hpriortothetrialcommencingandtheoutcomemeasurewaswhetherthepaincouldbetriggered15minaftertheinjection.
Theeffectpersistedforonly8h.
Theauthorssuggestthattheintranasalspraycouldbeusedtocontrolsevereevokedattacksofpain.
2.
3DrugsusedincaseseriestrigeminalneuralgiaMostAEDshavebeenusedandreportedincaseseriesfortri-geminalneuralgia,includingphentyoin[61-63],valproicacid[64],clonazepam[65-68]andfelbamate[69](Table2).
Morerobustcasestudieshaveshowedthatleviteracetam,althoughhavingverygoodtolerability,isnoteffectiveintrigeminalneuralgia[70].
Awell-designedcohortstudyusingpregablinindosesof150--600mgdailyin53patientsoveraperiodof1yearshowspromise.
Pregablinhasbeenfoundtobeparticularlyusefulinthosepatientswhodidnotreportotherconcomitantfacialpain[71].
AstudyinprimarycarebyaSpanishgroupshowedthatpregablinwascosteffectiveasitseffectivenessreducedotherhealthcarecosts[72].
ThesideeffectsprofilewassimilartootherAEDsbutwaslessmarked,i.
e.
,dizziness,tiredness,headacheandperipheraloedema.
ItsadvantageoverotherAEDsisthatitcanbeusedonatwice-dailydosageschemeandcanbetitratedrapidly.
BothstudiesshowedthattheresultswerenotsustainedandotherAEDswereneededlater.
Topicalcapsaicinhasalsobeenreported[73,74]butitispainfultoputonespeciallyifthepainistriggeredbytouch.
Althoughtrigeminalneuralgiaisconsideredtobeduetoneurovascularcompression,asmall,open-labelstudyusinghumanpooledimmunoglobulininchronicpainpatientsshowedthat,ofthegroupsresponding,thebestresultswereseeninpatientswithtrigeminalneuralgia,withfouroutofsixpatientshavingmorethan70%painrelief[75].
ThisisnowgoingtobetestedinanRCTthathasbeensetupandisontheclinicaltrialsregister[76].
Areportofthreecasessuggeststhataninfusionoffosphenytoinmightbeusefulinacutecases[69].
Patientswithtrigeminalneuralgiaandmultiplesclerosisaredifficulttotreatanddonotrespondwelltoconven-tionalAEDs.
Onthebasisof11patients,Khan[77]andSolaroetal.
[78]proposeeithergabapentinonitsownorthecombinationoflow-dosegabapentinwitheitherlamotrigineorcarbamazepine.
TheDMKGgroup[79]evaluatedmiso-prostolin14patientsandshowedbenefitintheshortterm.
Topiramatewasfoundtobeeffectiveinsixpatients[80].
3.
Glossopharyngealneuralgia3.
1OverviewTheInternationalAssociationfortheStudyofPaindefinesglossopharyngealneuralgiaasasuddenseverebriefrecurrentpaininthedistributionoftheglossopharyngealnerve[8].
Inmostcases,thisconditionisidiopathicbutsomeinstancesmightbeduetosymptomaticcauses,againcompressionofthenervebytumoursormalformations.
Glossopharyngealpainisalsoasevere,transient,sharp,stabbingpainbutitsZakrzewskaExpertOpin.
Pharmacother.
(2010)11(8)1245distributionisalongtherouteoftheglossopharyngealnerveandsoitisfeltintheear,atthebaseofthetongue,attheton-sillarfossaandbeneaththeangleofthejaw.
Thepaincanalsobefeltintheauricularandpharyngealbranchesofthevagusnerve.
Itisprovokedbylighttouchactivitiessuchasswallow-ing,talkingorcoughing.
Patientswillsufferfromepisodesofpainlastingforweeksormonths,andthenhaveperiodsofremission.
Theattacksthemselvesalsolastfornomorethan2min.
Thepainagainisunilateral.
Glossopharyngealneuralgiaisevenrarer,withanincidencerateof0.
7per100,000,andithasbeenreportedascoexistingwithtrigeminalneuralgia[81].
Itoccursinolderagegroupsandseemstopredominateinwomen.
Therearenodataonprognosisbut,judgingbythefewreportsofsurgicaltreat-ment,itwouldappearthatpatientshavealessseverehistorythanthosewithtrigeminalneuralgia.
Therearenotrialsreportingtheuseofanydrugsinglossopharyngealneuralgia.
Thelargestreviewofpatientswithtrigeminalneuralgia,byRushton[82],suggestedthesamedrugsasfortrigeminalneural-giaandhalfofthepatientseventuallyunderwentsurgicalman-agement.
Otherdrugshavebeenreportedmainlyassingle-casereports:pregabalin[83],lamotrigine[84],oxcarbazepine[85],carbamazepine[86],gabapentin[87].
4.
Traumaticallyinducedneuralgia,trigeminalneuropathicpainandatypicalodontalgia4.
1OverviewItisnowincreasinglyrecognizedthattraumatothetrigeminalnervecanresultnotjustinneuropathybutalsolong-termneuropathicpain.
ManycasespreviouslydiagnosedasatypicalfacialpainareprobablycasesthatinfactbelongtoTable2.
Drugsusedincaseseriesonlyfortrigeminalneuralgia.
DrugdailydosageOutcomereportedineachstudySideeffects/withdrawals(noofsideeffectsinreports)CommentsRef.
Capsaicin3gfor21--28days6/12complete,4/12partial,4/12relapses,1/5partial,4/5nilorlittleBurningsensation(NS)Rubontheskin,temporaryreliefinmajority,avoidcontactwiththeeyeFuscoetal.
1992Epsteinetal.
1994Clonazepam2--8mg5/7goodresult,13/19excellentorgood,10/25excellent,6/25good,64%complete/partialLethargy,fatigue,dizziness,personalitychange(5/5,4/19,22/25)Drowsinessisverysevereanddoserelated.
ThromocytopeniacanoccurCaccia1975Chandra1976Court&Kase1976Smirne&Scarlato1997Felbamate800--1200mgdaily3/3improvedNausea,insomnia,inepilepsystudiescancauseaplasticanaemiaDuetopotentialseveresideeffectsnotofclinicaluseCheshire1995Leviteracetam1000--4000mgdaily10weeks4/10goodresultusingavarietyofoutcomemeasures1drowsy,1tiredness,1diarrhoeaEfficacylowinseverecases,verygoodtolerabilitycomparedtootherAEDJornsZakrzewska2009Phenytoin200--300mg4/4excellent,8/20excellent,6/20partial,4/5excellent,1/5partialAtaxia,lethargy,nausea,headache,behaviouralchanges(1/4,NS,NS)Folatedeficiencyinprolongeduse,gingivalhypertrophy,canbeusedintravenouslyforimmediateeffectIannoneetal.
1958Braham&Saia1960Chinitzetal.
1966Pregablin150--600mgdailyfor1year39/53had>50%improvement,14/53noresponse,overall59%responsein6519%dizziness,15%tiredness,4%headaches,2%peripheraloedemaIncludedpatientswithotherfacialpainswhodidlesswell.
ResultswerenotsustainedandotherAEDswereneededlaterinbothstudies.
Obermannetal.
2008Perezetal.
2009Valproicacid600--2000mg9/20excellent/good,4/20goodifusedwithotherdrugs3/20noresponse,4/10excellent/good,6/10poorbutifusedasaddon10/10goodIrritability,restlessness,tremor,confusion,nausea(1/20,NS)Rashandwithprolongedusealopecia,weightgain,increaseefficacywithadditionofbaclofenPeirisetal.
1980Desaietal.
1991AED:Anti-epilepticdrugs;NS:Notstated.
Medicalmanagementoftrigeminalneuropathicpains1246ExpertOpin.
Pharmacother.
(2010)11(8)thisgroup.
Carefulneurophysiologicalandqualitativephysio-logicaltestingcandistinguishtheseconditions,whichcouldbeofimportanceinmanagement[88].
Thereisalsothehighlyspecificcondition'atypicalodontalgia',whichisdefinedaspaininatooth,oratooth-bearingarea,whichisnotrelatedtoanydentalcauseandagainisoftenmistakenastoothacheandtreatedwithmultipledentaltreatments[12].
Thesepainsmayinfactconstituteasub-setoftrigeminalneuropathicpainandhavebeenwellcharacterizedbyBaad-Hansen[89]andListetal.
[90].
Neurophysiologicaltestingshowsthatthesepatientshaveperipheralandcentralsensitizationchangesbutthereisalsosomeevidencefornociceptivechanges,whichmightthereforebeimportantinthechoiceofdrugs[91]Cur-rently,therearenodataontheepidemiologyofneuropathicpainbutithasbeensuggestedthatariskfactorforthiscouldbeinadequateanaesthesiaduringdentalprocedures,asthisincreasestheriskforpotentialcentralsensitization.
Asany-whereelseinthebody,traumaandcompressionofsensorynervescanresultinlongtermneuropathicpain.
TheclinicalfeaturesoftrigeminalneuropathicpainareshownintheFigure3.
4.
2ManagementInareviewofclinicalmanagementofatypicalodontalgia,Baad-Hansen[89]suggeststhatmostofthemanagementisbasedonexpertopinionandcasereports.
Mostexpertsrec-ommendtheuseoftricyclicantidepressantsbuttheanticon-vulsants,suchasphenytoin,carbamazepine,pregabalinandgabapentin,havealsobeenproposed.
Topicalanalgesicssuchaslidocaineorcapsaicinhavebeenputforwardasfirst-linetreatmentsduetotheirlackofsystemicside-effects.
Therehasonlybeenonespecificrandomizedcontroltrialofman-agementofatypicalodontalgia.
Listetal.
[91]performedarandomizedcross-overstudyin35patientswithatypicalodontalgia,whichinvolvedeitherinjectionoflidocainewithadrenalinornormalsaline.
Thosereceivingthelocalanaes-theticweremorelikelytoachievepainreliefbutthiswasnotcomplete,suggestingthatthepainofatypicalodontalgiaisnotpurelydependentonperipheralafferentinputsandthattheremaybemorecentralsensitization.
Thiswouldpotentiallyindicatethatuseoftopicallidocaineintheformofpatchesorgelswouldbeinsufficienttogivecompletepainrelief.
Therehasbeenamovetotailorthetreatmentofneuropathicpainmoretothemechanismsinvolvedandsototargetspecificareas,suchassodiumandcalciumchannels,glutamaterecep-tors,monoaminesandneurotrophicfactors.
However,asyetthereisinsufficientdetailonmanyofthesepainmechanismstobeabletoputthemintocategories.
Thereisincreasingevi-dencethatinmanycasesthereissomeoverlapbetweenneuro-pathicpainandnociceptivepainandhencedrugssuchastheopiodsmaybeusefulasaddonmedications.
Treatmentoftri-geminalneuropathicpainisbasedonextrapolationfromthedataonneuropathicpainusingavarietyofthedifferentguidelinesthatarenowinplace,thesearesummarizedinTable3.
O'ConnorandDworkin[92]haverecentlyreviewedalltheguidelinesonneuropathicpain,includingtheEuropeanFed-erationofNeurologicalSocietyguidelinesEFNS(Attaletal.
[93]),theCanadianguidelines[94]andthoseproducedbytheNeuropathicSpecialInterestGroupNeuPSIG[95].
Theynotethatthemajordifferencesrelatetothoseareasinwhichthereisalackofevidence.
Thereisconsensusinallthreeguidelinesthattricyclicantipressantsandcalciumchannelblockers(gabapentinandpregablin)shouldbefirst-linedrugs.
TheSSRIs/SSNRIsduloxetineandvenalafaxinearealsocon-sideredfirstlinebytheNeuSigguidelines,butsecondlinebytheCanadianandEFNguidelines.
Topicallidocaineisadvo-catedasfirstlineinperipheralneuropathicpainbytheNeu-PSIGandEFNSguidelines.
OpioidsandtramdadolareallsecondoreventhirdlineintheCanadianones.
Despitethisreasonablebodyofevidence,patientsinprimarycarecon-tinuetobepoorlymanagedandopioidsareusedmuchmorefrequentlythantheguidelineswouldsuggest[96].
Thereisaneedforindividualizationofmedicationbasedonotherco-morbiditiesandtheuseofothermedications.
Attentionisdrawntothefactthatthereisalackoflong-termcohortstudiesandhead-to-headcomparisonsbetweendifferentmedicationsandcombinationsofmedications.
Tri-alsalsosuggestthathigherdosesdonotalwaysresultinimprovedefficacybutdoresultinincreasedsideeffects.
Themajorityofthedrugsneedtobeslowlyescalatedandusedforseveralweeksbeforetheyaredeemedineffective.
5.
Burningmouthsyndrome5.
1OverviewBurningmouthsyndrome(BMS),orstomatodynia,isdefinedasachronic,idiopathicoralmucosalpain/discomfortinwhichnoclinicallesionsorsystemicdiseasesareidentified.
ItsprincipalfeaturesareindicatedinFigure4.
Itisimportanttoexcludeothercauses--bothlocalandsystemic--thatcancauseburningespeciallydrugs,suchastheACEinhibitors.
Itisparticularlycommoninperi-menpausalwomenwhoareoftentoldthatthisisduetopsychologicalcause.
However,thereisnowanincreasingbodyofevidencetoshowthatthereareneuropathicelementstothispain[97]andthereareseveralRCTsandsystematicreviewsonthistopic:.
Worldworkshopinoralmedicine[98].
.
ClinicalEvidence(www.
clinicalevidence.
bmj.
com)[99].
.
Cochranesystematicreviewonthistopic[100].
ThewholetopichasbeenwellcoveredbyWodaandGrushkainarecentchapteronthistopic[97].
ThetreatmentsusedinBMSaresummarizedinTable4.
OftheRCTs,itwouldappearthatclonazepamusedtopicallymaybehelpfulaswellascognitivebehaviourtherapy.
Manypatientswhoaregivenaphysiologicalexplanationfortheirpain,andreassurancethattheyarenotdevelopingcancer,learntocopewiththeirsymptomsanddonotrequiredrugtherapy.
ZakrzewskaExpertOpin.
Pharmacother.
(2010)11(8)12476.
ConclusionSeveralneuropathicpainconditionsoccurinthefaceandmouth,themajorityofwhicharetreatedlikeotherneuro-pathicpainsusingdrugssuchastricyclicantidepressants,gabapentinandpregablin.
However,patientswithtrigeminalneuralgiarespondbesttoAEDssuchascarbamazepineandoxcarbazepine.
7.
ExpertopinionAmajorproblemencounteredbyallpractisingcliniciansistryingtoextrapolatethefindingsfromRCTs,asmanypatientshaveotherco-morbitiesandpsychosocialproblemsthatcanhaveaprofoundeffectontheirresponsetodrugther-apy.
ItisimportanttoensurethatthedrugsareusedinthedosagesthathavebeenusedinthetrialsasoftenpatientsareBurningAching,throbbingMildtomoderateNeuro-anatomicalLocal/widspreadOftentoothbearingareaLighttouchevokedAllodyniaLidocainetopicalgivesreliefCharacterseveritySiteTimingperiodicityProvokingAssociatedfactorsContinuousYearsHistoryoftraumaFigure3.
Clinicalfeaturesoftrigeminalneuropathicpain.
Table3.
SummaryofdrugsusedinneuropathicpainbasedonareviewoftheO'ConnerandDworkinguidelines,whichcouldbeusedintrigeminalneuropathicpain.
MedicationclassDailydose-average-rangeUseSideeffectsCommentsTricyclicantidepressants:nortiptyline50mg(25--150mg)Minimum6--8weeksnocteSedation,drymouth,weightgainImprovesdepression,lowcost,usewithcareincardiacdisease,glaucomaCanuselowerdoseswithgoodresponseSSNRIs:duloxetine60mg(30--120mg)4weekstwicedailyNauseaImprovesdepression,careinthosewithhepaticorrenalproblems,takingtramadolSSNRI:velafaxine225mg(75--225mg)4--6weeksdailyNauseaSmallRCTinatypicalfacialpainnobenefitCalciumchannelblocker:gabapentin3000mg(600--3600mg)3--8weeksthreetimesadaySedation,ataxia,dizziness,oedemaImprovessleep,fewdruginteractionsCareinrenaldysfunctionCalciumchannelblocker:pregablin600mg(300--600mg)4weeks,twicedailyDizziness,tiredness,headaches,peripheraloedemaImprovesanxiety,sleepCareinrenaldysfunctionTopical:5%lidocainepatch3patchesformaximum12h12hatanyonetimeLocalerythema,rashOnlyifextraoralpainandallodyniapresentRCT:Randomizedcontrolledtrial.
Medicalmanagementoftrigeminalneuropathicpains1248ExpertOpin.
Pharmacother.
(2010)11(8)givensuboptimaldosagesandsothedrugsareperceivedtobeineffective.
7.
1TrigeminalneuralgiaThereislittledoubtastotheefficacyofcarbamazepineinthemanagementoftrigeminalneuralgia.
Thedrugishighlyeffec-tive,providesexcellentpainreliefwithinafewdays,especiallyinitially,butitswidespreadsideeffectsanddruginteractionsmakeitacomplexdrugtouseinclinicalpractise.
Oxcarbazepine,therefore,isaveryusefulalternativeasithassimilarefficacytocarbamazepinebutgreatlyimprovedtolerabilityandrelativelackofinteractionwithotherdrugs.
Havingusedbothdrugsforover20yearsinlargecohortsofstudies,Iaminnodoubtthatoxcarbazepineisbettertoler-atedandpatientsparticularlyfindthereductionincognitiveimpairmenttoimprovetheirqualityoflife.
Lamotrigineisausefuldruginpatientswhodevelopaller-giestocarbamazepineandoxcarbazepine,buttheneedforslowescalationtoreduceskinreactionsmeansitisnotusefulforacutecases.
ItmightalsobeusefulinthosepatientswhohavebeenmistakenlydiagnosedastrigeminalneuralgiabutinfacthaveSUNCTorSUNA.
AlthoughIhaveusedgabapentinasathird-linedrug,Ihavehaddisappointingresultswithitandhavehadtousemuchhigherdosagesthanthosereportedintherandomi-zedcontrolledtrial[42].
Althoughthesideeffectsofgaba-pentinarequotedasbeinglow,weightgainandoedemaseemtobemorefrequentlyreportedthanwhenusingotheranticonvulsants.
Pregabalinappearstobeapromisingdruginthatitcanbeescalatedmorerapidlythangabapentin,canbeusedonatwicedailydosageschemeandappearstohavesomeeffectonreducinganxietyoftenpresentinthesepatients.
Ifinditofmorevalueinpatientswithtrigeminalneuropathicpainthantrigeminalneuralgia.
Thereareveryfewdatatosupporttheuseofpolypharmacybutifpatientswithtrigeminalneuralgiareportthattheyalsohaveadull,burning,achingbackgroundpainthenIoftenwillincludeatricyclicantidepressantsuchasnortriptylineindosesaround40mgnocte.
Oncepatientshavegainedconfi-denceinmanagingtheirdrugregimen,theyareveryreluctanttochangetootherdrugsastheyfearthatachangeovercouldescalatetheirsymptoms,whichisamajorcauseforlackofrecruitmenttoourIVGstudy[76].
Inouropentrialofleviteracetam[70]therewasaverymarkedimprovementinsideeffects,evenwhenusedinhighdoses,butthedrugwasdisappointinglynon-effectiveinseverecasesoftrigeminalneuralgia.
Anydrugthatwastoreplacecarbamazepineasthegoldstandardforthetreatmentoftrigeminalneuralgiawouldneedtohavethefollowingminimalcharacteristics:1)Aseffectiveintermsofpainrelief.
2)Improvedtherapeuticindex(i.
e.
,lesstoxicinrelationtoitsobservedbenefits).
3)Simplepharmacokineticcharacteristicsbothinrelationtotheprescribingofthedrugandpatientcompliance.
Ofspecialimportancewouldbetheabilitytoescalatethedrugrapidly.
4)Shouldnotinteractwithotherdrugswhichmaybeco-prescribedasmanyofthesepatientsareelderlyandhaveotherco-morbidities.
BurningTinglingAbnormaltactilesensationsMildtomoderateBilateralTongueinmostcasesLips,palate,pharynxStressAlteredtasteDisturbedsalivationSensorychangesCharacterseveritySiteTimingperiodicityProvokingAssociatedfactorsContinuousMaybeintermittentYearsFigure4.
Clinicalfeaturesofburningmouthsyndrome.
ZakrzewskaExpertOpin.
Pharmacother.
(2010)11(8)12497.
2GlossopharyngealneuralgiaGlossopharyngealneuralgiaisbestmanagedwiththeuseofcarbamazepine,butquicklychangingtooxcarbazepineifthereareanyissuessurroundingsideeffectsanddruginteractions.
IhavenothadanyexperienceinusinganyoftheotherdrugsasIhavefoundoneorotherofthesedrugstobeeffectiveinmydozenorsocases.
7.
3TrigeminalneuropathicpainTheincreasingrecognitionofthisconditionputsincreasingchallengesonclinicianstomanagethispain.
Atopicalapproachistheuseoflidocaineorcapsaicinpatches,orevenclonazepam,asusedinburningmouthsyndrome.
Itmaypro-videsomebenefit,especiallyifthepainisprovokedbylighttouchactivitiesandinterfereswithsleep.
Somepatientshavefoundthattheadvantageofhavingagoodnight'ssleepena-blesthemtocopebetterwiththeirneuropathicpainthrough-outtheday.
However,asthetrialshaveshown,itishighlylikelythattrigeminalneuropathicpainalsoresultsincentralchangesandthereforethereisarequirementforsystematicdrugs.
Nortriptyline,ofteninlowerdosesthanrecommendedintheguidelines,seemstoresultina30%painreduction.
Pregabalinappearstobeespeciallyusefulinpatientswhoalsoshowhighlevelofanxiety.
Topicallidocainemayagainbeusefulinthosepatientswhosesleepisinterruptedduetotheallodynia.
7.
4PatienteducationPatienteducationiscrucial,themorepatientswhounder-standtheirconditionandhowthedrugsworkforthem,themoreeffectivethedrugsbecome.
Patientsarekeentohavethisinformation,asseenbythesizeoftheirsupportgroups(www.
tna.
org.
uk,www.
fpa-support.
org)andageneralwill-ingnesstopublishbooksonthistopic(e.
g.
,Insights--factsandstoriesbehindtrigeminalneuralgia[101]).
Patientsareoftenreferredtomeasmedicalfailuresbutitisoftenasmuchthephysician'sfaultasthepatient'sthatthepainisnotbeingcontrolled.
ManypatientswithBMS,whenreassuredandTable4.
Drugsusedinburningmouthsyndromebasedontableinref.
[97].
Drug/therapyDailydoserangeUseEfficacyNNTSideeffectsCommentsProveninRCTsAntioxidantalphalipoicacid200--600mgDailyfor3monthsInearliertrialsNNT1.
6--3.
3NilreportedSeveralstudiesfromsamecentre,notalldoubleblindandnewerRCTshowsnobenefitClonazepam1--3mgtopical0.
25--1mgsystemicTopicallysuckfor3minfor2weeksSystemicnoctefewweeksTopical10/16stillsomebenefitat6/12LimitedbenefitNilsignificantiftopicalbutsystemicallydrowsinessTopicalusereportedasRCTfor14days,openlabelfollowup6monthsSystemicusecasereportsBenzydaminetopical0.
15%solution15ml3timesdailyNoteffectivewhenusedinRCTNilHigh-qualityRCTCapsaicinsystemic0.
25%capsule3timesdailyfor1monthNNT1--2Gastricpainin32%increaseovertimePoor-qualitytrial,sideeffectslimititsuseTrazodone200mgDailyNoeffectDrowsinessanddizzinessHigh-qualityRCTnotusedclinicallyAmisulprideParoxetineSertraline50mg20mg50mgDailydosageforfewweeksAlleffectivenoNNTMild,non-specificNoplacebocontrol,poorRCT,notusedclinicallyCommonlyusedbutnoRCTGabapentin300--2400mg3--8weeks3timesadayLimitedAtaxia,dizziness,drowsiness,nausea,headache,weightgainImprovessleep,fewdruginteractionsCareinrenaldysfunctionNortiptyline20--50mgNocte6--8weeksMaybeeffectiveSedation,drymouth,weightgainImprovesdepression,lowcost,usewithcareincardiacdisease,glaucomaPregablin100--300mg4weeks,twicedailyMaybeeffectiveDizziness,tiredness,headaches,weightgainImprovesanxiety,sleepCareinrenaldysfunctionRCT:Randomizedcontrolledtrial.
Medicalmanagementoftrigeminalneuropathicpains1250ExpertOpin.
Pharmacother.
(2010)11(8)givenanexplanation,willmanagewithoutdrugtherapy.
Patientswithtrigeminalneuralgianeedtotaketheirmedica-tionbeforemealtimesorwashing,asthesearetheprimetimeswhentheirpainisevoked,andyetmanyhavethebeliefthatdrugsshouldbetakenaftermealstoreducesideeffects.
Itneedstobemadeclearwhichdrugsneedtobetakenonafre-quentdosageschemeandwhichcanbetakentwicedaily.
Thekeepingofdiariesforshortperiodsisusefulifapatientistogainanunderstandingofhisorherindividualresponsetothedrugsandthentobeabletotakecontrol.
Thisisespeciallyimportantinpatientswithintermittentpain,suchastrigemi-nalneuralgia,astheyneedtobeabletobothescalateanddecreasetheirdrugsdependentontheperiodicityofthepain.
7.
5FuturedirectionsKatzetal.
[102]lookedatclinicaltrialoutcomesinneuropathicpaintoidentifyfactorsleadingtopositiveornegativeout-comes.
Thisstudyagainprovidesimpetusforfutureresearch,suggestingtheneedfordecreasingplaceboresponserates,lookingatdifferenttrialdesignsandatenrolmentoflargernumbersofsubjects.
Straubeetal.
[103]reviewedthevalueofenhancementenrichmentenrolmentstudiesinpotentialtrialsofpregabalinandgabapentininneuropathicpain.
Thesetypesofstudyenableapilotstudytobecarriedoutinitiallyandthosepatientswhorespondtothedrugtherapyarethenenrolledintoarandomizedcontrolledtrial.
Theoutcomemeasureisthespeedwithwhichpatientsdropoutofthestudy,whichintheoryshouldbefasterforthosegiventhepla-cebo.
Theysuggestthatnogreatbenefitwasfoundincurrentstudiesbutthat,iffutureresearchersaretousethismethodol-ogythenanyenrichmentmustdescribeboththeprocessandtheextentofenrichment;onlytimewilltellwhetherthismethodologymaybeuseful.
Thereisaneedforhead-to-headcomparisonsoftherangeofdrugsavailable;itwouldseemfromdataavailablethatnewerdrugsappeartoprovidethesamepainreliefprofilebutareassociatedwithfewersideeffects.
Mechanism-basedtreatmentsareprobablythewayforwardasweincreasinglyrecognizethatneuropathicpainismultifactorialandmorethanonemechanismmightbeinvolved.
Thus,acombinationofdrugsthatactondifferentsitesmightbeneeded.
Futuretrialsmightneedtoconsidertheadditionofsecond-linedrugsoropioidsoncemaximumreliefhasbeenobtainedwithfirst-linedrugs.
Thereisalsosomeevidencethattheremaybeanimmunologicalresponsetoneuropathicpain,asearlyworkbyGoebeletal.
[75]suggested,andtheongoingRCTofintra-venousimmunoglobulinintrigeminalneuralgiamayshowothermechanismstobeinvolved,especiallyinthosepatientswhoareintractableanddonothaveneurocompression.
Thefindingsfromtrialsneedtoberapidlycommunicatedtoprimarycareasnumerousstudieshaveshownhowinade-quatelychronicpainpatientsaremanaged[15,14,96]andpatienteducationneedstobehighontheagenda.
Letusbearinmindthatourfutureresearchneedstobepatientcentredandthat,atpresent,ourpatientscontinuetostruggleonthedrugsweprescribe.
ThisisaptlyexpressedbyBettyPrice,apatientwithtrigeminalneuralgiawhowrites[101]:"ThereisamedicineyoucantakeButit'snotthecureItmaymakeyoudrowsyItmaymakeyousickNowhewasnotkiddingForthisitquicklydidTherearemorepillstotakeAndthere'snomiraclefixWelldayshavecomeandgoneThenauseaisstillthesameIfeelI'mfightingabattleWithlittlecoastingalongtheway.
"DeclarationofinterestJ.
ZakrzewskahasreceivedinvestigatorledgrantfromUCBPharmaforstudyonleviteracetam.
ThisworkwasundertakenatUCL/UCLHTwhoreceivedaproportionoffundingfromtheDepartmentofHealth'sNIHRBiomedicalResearchCentrefundingscheme.
ZakrzewskaExpertOpin.
Pharmacother.
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BrJClinPharmacol2008;66:266-75AffiliationJoannaMZakrzewskaBDSMBBChirMDFDSRCS(Eng)FFDRSCI(OralMed)FFPMRCAFHEAConsultantHonoraryProfessor,EastmanDentalHospital,OralMedicineDepartment,UCLHNHSFoundationHospital,256Gray'sInnRoad,LondonWC1X8LD,UKTel:+442079151195;Fax:+442079151105;E-mail:j.
zakrzewska@ucl.
ac.
ukMedicalmanagementoftrigeminalneuropathicpains1254ExpertOpin.
Pharmacother.
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