Original Article

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Introduction

Pain isa familiarcomplaintbypatientsseekinghelp from theirphysician.Patientscomplainingofdifferentdegreeofpainareseenindailyrheumatologicpractice.Chronicpainisdefinedaspainlastinglongerthan3to6monthsthatmaycausevaryingdegreeofphysicaldysfunctionandtriggerdifferentpsychological

Prevalence of neuropathic pain in patients with rheumatoid arthritis Te-Cheng Chung1, Jeng-Hsien Yen1,2, Tsan-Teng Ou1,2, Hong-Wen Liu1,2, Wen-Chan Tsai1,2

1Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan2Kaohsiung Medical University, Kaohsiung, Taiwan

Correspondingauthor:Wen-ChanTsai,M.D.,Ph.D.SectionofAllergy,ImmunologyandRheumatology,KaohsiungMedicalUniversityHospital,Kaohsiung,TaiwanTel:+886-7-3121101ext6088,Fax:+886-7-3221505E-mail:d740094@kmu.edu.twReceived: August 1, 2008Revised: November 4, 2008Accepted: November 7, 2008

Objective:Tostudytheprevalenceofpossibleneuropathicpaininpatientswithrheumatoidarthritis(RA)inadditiontoinvestigatingthecorrelationbetweendiseasedurationandoccurrenceofneuropathicpain.Methods:AquestionnairecontainingBriefPainInventorybyDr.CleelandtranslatedintoChinesewasgiventopatientswithRAintherheumatologicoutpatientdepartmentfromMarch2008toJune2008inatertiarycenterinsouthernTaiwan.Objectivesensorytestingwasalsocarriedoutwithresultsrecordedinthequestionnaire.Latestlevelofserologicalmarkersforinflammation,erythrocytesedimentationrateandC-reactiveprotein,ofthepatientweredocumentedforinvestigationonpossiblecorrelation.Results:Onehundredpatients fulfilling the1987 revisedcriteriaof theAmericanCollegeofRheumatologyforRAparticipated.Twenty-fivepatientswereexcludedduetoinsufficientbackgroundinformationforanalysis.Oftheseventy-fivepatientsanalyzed,femalepatientspredominated(62female,84%),meanagewas55.64years,averagediseasedurationwas11.08years,and67/75(89.33%)ofthepatientsreportedpainwithinoneweekpriortotheclinicvisit. Amongthesixty-sevenpatientscomplainingofpain,theyratedtheirworstpainintensityas5.74(range1to10)onanumericratingscale,withleastpainintensityas1.78(range0to9),andpainintensitymostofthetimeas3.54(ranged0to10).Amongthe67RApatientscomplainingofpainuponquery,theiraveragediseasedurationwas11.19years;allodyniaandalteredpinprickthresholdwerefoundin40patients(59.70%)and47patients(70.15%),respectively.Conclusion:Reviewoftheliteraturestatesallodyniaandalteredpinprickthresholdtobepathognomonicofneuropathicpain.53ofthe67patients(79.10%)complainingofpainshowedpositiveforatleastoneobjectivesensorytest.Nearly80%ofpatientshaveneuropathicpain.OurstudyfoundthatdiseasedurationofRAdoesnotcorrelatewellwithoccurrenceofallodyniaoralteredpinprickthreshold.Patientswith2-yeardurationofRAmaydemonstrateapositiveresultforbothallodyniaandalteredpinprickthreshold;however,eightoutofourseventy-fivestudysubjects(10.1%)withovera10-yeardiseaseduration(range10-40years)werenegativeforboth.

Key words:Neuropathicpain,rheumatoidarthritis,allodynia,alteredpinprickthreshold

Formosan Journal of Rheumatology 2009;23:�9-24

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Neuropathic pain in RA

conditions ranging fromanxiety, depression, andpersonalitychangesthatimpairedthepatient’squalityof life [1].Clinically, thebestknownexamplesofneuropathicpainhavebeenobservedinpatientswithdiabeticneuropathy,post-herpeticneuralgia,trigeminalneuralgia,phantomlimbpain,nervecompressionandentrapmentneuropathy,post-strokeneuropathicpain,andmultiplesclerosis…etc.Patientswithrheumatoidarthritis (RA)experiencedvaryingdegreesofpainanddifferenttypesofsensorydeficit[1,2].However,neuropathicpaininpatientswithRAislessreportedinTaiwan,possiblyduetolackofdefinitediagnosticcriteriaandstandardizedtestinginstrumentsfor thiscomplexcondition.Westartedout to investigate theprevalenceofpossibleneuropathicpaininpatientswithRA;correlationbetweendiseasedurationofRAandoccurrenceofneuropathicpainwerealsostudied.

TheInternationalAssociationfortheStudyofPain(IASP)definesneuropathicpainas“paininitiatedorcausedbyaprimarylesionordysfunctioninthenervoussystem”[3].Somehavearguedthisdefinitionhaslimitedpracticalvalueforeitherclinicalorepidemiologicalclassificationfor thewideanddiverseetiologiesofneuropathicpain. Frequently,patientsusedtermsas“tingling,burning,numbness…etc”insteadof“pain”todescribewhattheyexperiencedthatdisturbedtheirdailylifeactivities.Physiciansmayraisesuspicionofpossibleneuropathicpainiftheirpatientsdemonstratedsignssuchasallodynia(painduetoastimulusthatdoesnotnormallyprovokepain),hyperalgesia(apainfulsensationofabnormalseverity followinganoxiousstimulusandrepresentsanexaggeratedresponsetothesamemodalitystimulus),hyperpathia(characterizedbytemporalabnormalitiessuchasincreasedreactiontoastimulusandspatialabnormalitiessuchaspainprovokedinlegwhenarmisstimulated),autonomicdysfunction(skincolor, temperature,sweatingmaybealteredininvolvedarea).Bothallodyniaandhyperalgesiaarereported tobepathognomonicofneuropathicpain.Therefore, thepresenceofneuropathicpaincanbeinferredonly, identifyingpossibleneuropathicpain,insteadofmakingadefinitediagnosis [4].StudiesconductedintheUnitedKingdomandtheU.S.A.havedevelopedDouleurNeuropathique4(DN4)and theLeedsAssessmentofNeuropathicSymptomsandSigns(LANSS),whichincludesaself-completeversion,theS-LANSS,toidentifypatientswithpossibleneuropathicpain.Nonetheless,validation(translationandback-translation)oftheoriginal(English)LANSS-scalehasnotyetbeencarriedoutinChinese-speakingcountries.Validatedinstrumentavailableforpainevaluationin

TaiwanoriginatedfromtheworkofGeretal.in1999[5].Theyconductedthevalidationof theBriefPainInventory(BPI)formulatedbyCleelandetal.of thePainResearchGroupoftheWHOCollaboratingCentreforSymptomEvaluationinCancerCarein1983[6].BriefPainInventoryhasbeenvalidatedintoadozenversionsandlanguages; it isoneof themostwidelyused instrumentsforpainevaluation.BPIappliedapredominantlynumericratingscale(NRS)toevaluatetheseverityofpain,“0”asnopainand“10”as theworstpainimaginable;patientscanpickanumberinbetweentorepresenttheirpainintensity.Becausepainissubjective,objectivesensorytestingviacottonwoolbrushingandpinprick thresholdexaminationovertenderareascontrastedtonon-tenderareasofthesamepatientwasperformedwithresultsdocumentedinourquestionnairecontainingvalidatedBPIinMandarin.

Methods

Initially,aquestionnairecontainingvalidatedBPIbyGerLPetal.alongwithobjectivesensorytestingonallodyniaandalteredpinprickthresholdwasdevised;thequestionnairewassenttoourInstitutionalReviewBoardforapproval.ThequestionnairewasadministeredtopatientsoftherheumatologicoutpatientdepartmentfromMarchtoJulyof2008.Onehundredpatientsfulfillingthe1987revisedcriteriaof theAmericanCollegeofRheumatologyforRA[7]signedinformedconsentsandansweredthequestionsalongwiththesensorytest.Twenty-fivepatientswereexcludedduetoinsufficientbackgroundinformationforanalysis.

Results

Oftheseventy-fivepatientsanalyzed,femalepatientspredominated(62female,84%),meanage55.64years(Fig.1A),averagediseaseduration11.08years(Fig.1B),67/75(89.33%)patientsstatedtheyexperiencedpainwithinoneweekpriortotheclinicvisit.Amongthesixty-sevenpatientscomplainingofpain,theyratedtheirworstpainintensityas5.74(range1to10)onthenumericratingscale,withleastpainintensityas1.78(range0to9),painintensitymostofthetimeas3.54(ranged0 to10),pain intensityuponqueryas2.55(ranged0to10),occurrenceofallodyniaas40in67(59.70%),andoccurrenceofalteredpinprickthresholdas47in67(70.15%).89.10%(53/67)ofpatientswerepositiveforatleastoneobjectivesensorytest.

Serumlevelof inflammatorymarkersC-reactive

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protein(CRP)anderythrocytesedimentationrate(ESR)wereavailable in59and69patients, respectively;averageserumlevelof inflammatorymarkerswereCRP8.63mg/LandESR30.74mm/hour,respectively.Amongthe67RApatientscomplainingofpainuponquery, their average serum level of inflammatorymarkers,ifavailable,wereCRP9.46mg/L(n=51)andESR15.63mm/hour(n=61),respectively;theiraveragediseasedurationwas11.19years.Serum levelsofinflammatorymarkersdonotcorrelatewithoccurrenceofallodyniaandalteredpinprickthreshold(Fig.2and3).

Inthe8patientswhodidnotexperiencepainwithinoneweekprior toquery, theoccurrenceofallodyniaandalteredpinprickthresholdwere3/8(37.5%)and3/8(37.5%),respectively.Theiraveragediseasedurationwas10.125years.Bothallodyniaandalteredpinprickthresholdwerepresentinthethreepatients,theiraveragediseaseduration,serumlevelofinflammatorymarkerswere3.67years,CRP0.89mg/L(range0.58-1.2mg/L)andESR17.33mm/hour(range12-25mm/hour),respectively.

Nearly90%(67outofseventy-fivepatients)ofourFigure 1. Age distributions (�A) and distributions of disease duration (�B) among the patients with RA.

Figure 2. The correlations between ESR and occurrence of altered pinprick threshold (2A) and allodynia (2B). Group �: no pain in one week, Group 2: presence of pain in one week.Abbreviations: ESR = erythrocyte sendimentation rate; APT = altered pinprick threshold.

Figure 3. The correlations between CRP and occurrence of altered pinprick threshold (3A) and allodynia (3B). Group �: no pain in one week, Group 2: presence of pain in one week.Abbreviations: CRP = C-reactive protein; APT = altered pinprick threshold.

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studiedsubjectscomplainedofpainwithinoneweekpriortohisorherclinicvisit;amongthem,about60%(n=40)ofpatientsdemonstratedallodynia,and70%(n=47)showedalteredpinprickthreshold.53ofthe67patients(79.10%)complainingofpaindemonstratedpositiveforatleastoneobjectivesensorytest(cottonwoolbrushingorsafetypinprickthreshold).Assumingallodyniaoralteredpinprickthresholdweresensitiveandspecificforneuropathicpain,about80%ofourpatientscomplainingofpainmayhavepossibleneuropathicpain.

OurstudyfoundthatdiseasedurationofRAdoesnotcorrelatewellwithoccurrenceofallodyniaoralteredpinprickthreshold.Patientswith2-yeardurationofRAmaydemonstrateapositiveresultforbothallodyniaandalteredpinprickthreshold;however,eightoutofourseventy-fivestudysubjects(10.1%)withover10-yeardiseaseduration(range10-40years)werenegativeforboth.

Discussion

Rheumatologists seepatientswithpain in theireverydaypractice.With treatment, somepatientsachievedsatisfactorypainreliefandresumedtheirdailylifeactivity;thoselessfortunateonesrespondedpoorlytotreatmentandcausedabsencefrom,ifnot lossof,workforthemselvesandtheirfamilies.Theeconomicimpactbypatientswithchronicpainishugebecausetheytendtoworklessandearnless[1].Chronicpainsuchasdiabeticneuropathy[8],post-herpeticneuralgia,phantomlimbpain,andpost-strokeneuropathicpainareconditionswithneuropathiccomponentandmuchcomplexity thatrendersneuropathicpaindifficult todiagnose.Pathophysiologicalmechanismsbetweennociceptiveandneuropathicpainmayoverlap,therefore,many instruments for pain assessment havebeendeveloped[9].Westerncountrieshave longrealizedthe impactchronicpaincanexertonpublichealth,andmanyresourceshavebeeninvestedinstudiesonpain[10-13].RAis themostcommoninflammatoryarthritisafflicting1%ofthegeneralpopulationwithgreaterfemaleinvolvement,female/maleratio2:1to4:1[1].Itisnotsurprisingtofindfemalepredominanceinourstudy.FlareofRAmayaccompanylocalfindingof inflammation(erythema,warmth,swelling,pain)alongwithelevationof inflammatorymarker (CRPandESR).However, it isnotunusual toencounterpatientswithRAcomplainingofpainwithoutclinicalsignsof inflammatoryflare.Numbnessandburningsensationwere themost frequentlycomplainedof

symptoms.MichaelBennett,editorofNeuropathicPainbyOxfordPainManagementLibrary,hasstatedthatneuropathicpaincanonlybeinferredinsteadofbeingobjectivelyidentifiedatpresent.Acausalrelationshipbetweenneuropathyandpainofthepatientawaitstobeestablished[4].

Neuropathic componentmay be suspected inpatientswithchronicpainthatdoesnotrespondwellto traditionalremediesfornociceptivepain.Correctidentificationofneuropathicpainandappropriatemedicationmayprovidebetterreliefofsymptoms.Weare interested in theprevalenceofneuropathicpainamongRApatientsandthecorrelationbetweendiseasedurationofRAandoccurrenceofneuropathicpain.89.33%(n=67)ofourRApatientscomplainedofpainwithinoneweekpriortohisorhervisitand79.10%(n=53)ofthesepatientswithpaindemonstratedpositiveresultonatleastoneobjectivesensorytesting,signifyinghighpercentageofpossibleneuropathicpainamongrheumatoidarthriticpatients.However,diseasedurationdoesnotcorrelatewellwithoccurrenceofneuropathicpain.

Fromthe2006NationalInstituteonDisabilityandRehabilitationResearch(NIDRR)SpinalCordInjury(SCI)MeasuresMeeting,evidence-basedreviewforclinicalpracticeonpainevaluationsuggested thatcottonwoolandhigh-thresholdvonFreyfilamenttobeappliedontestingformechanicalallodyniaandhyper/hypoalgesia,respectively[13].VonFreyfilamentsarerelativelyexpensive(SomedicofSwedenoffersonesetofvonFreyfilamentsatroughlyUS$650)andarenotusedinmostclinicalsettingshereinTaiwan.Onthecontrary,a23Gneedlemountedinsideasyringebarrelmaybeusedtodetecthyper/hypoalgesiainmostclinicalpractice,anditisreadilyavailable[4].

Absenceofgoldstandardondiagnosisofneuropathicpainhashampered its sequential developmentofeffectivetreatmentandevaluation.Agroupofspecialistsmadeupofneurologists,scientists,neurophysiologistsandneurosurgeonsestablishedataskforceandrevisedIASPdefinitiononneuropathicpainafter intensivereview of the literature and frequent consensusconferencing;agradingsystemcomposedoffourcriteriaforneuropathicpainwasproposed[14].AnotherItaliangroupperformedaprospectivestudycollecting124patientswithsensoryneuropathyfromareferrednumberof486patientsforevaluation;spontaneousremissionofneuropathicpainoccurred in10.9%ofpatientswithsmallfiberneuropathywhile30.4%ofpatientsexperienced furtherdeterioration [15].Only afterconsensusonthedefinitionanddiagnosisofneuropathic

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painbecomesavailable,willscientificresearchprogressanduncover theneuropathologyofsuchacomplexcondition;thenmoreeffectivetreatmentbeprovidedtoourpatients.

Ourstudyis limitedbyitssmallsizeandlackofprospective follow-upof eachpatient’s condition.Additionally,assumptionofallodyniaand/oralteredpinprickthresholdtobepathognomonicofneuropathicpainmayoversimplifythiscomplexandchallengingdisease.Moresophisticatedstudydesignenrollinglargernumbersofpatientsareneededforbetterunderstandingofneuropathicpainamongpatients,thusbettercarecanbeprovidedforthem.

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3.MerskeyH,BogdukN.Classificationofchronicpain.Seattle:IASPPress,1994.

4.BennettM.Neuropathicpain,1sted.NewYork,Oxford,2007:25-35.

5.GerLP,HoST,SunWZ,WangMS,CleelandCS.ValidationoftheBriefPainInventoryinaTaiwanesepopulation.JPainSymptomManage1999;18:316-22.

6.DautRL,CleelandCS,FlaneryRC.Developmentof theWisconsinBriefPainQuestionnairetoassesspainincancerandotherdiseases.Pain1983;17:197-210.

7.ArnettFC,EdworthySM,BlochDA,McShaneDJ,FriesJF,CooperNS,etal.TheAmericanRheumatismAssociation1987revisedcriteriafor theclassificationofRheumatoidArthritis.ArthritisRheum1988;31:315-24.

8.ColeBE.Diabeticperipheralneuropathicpain:recognitionandmanagement.PainMed2007;8Suppl2:S27-32.

9.BreivikH,BorchgrevinkPC,AllenSM,RosselandLA,RomundstadL,HalsEK,etal.Assessmentofpain.BrJAnaesth2008;101:17-24.

10.HallGC,CarrollD,McQuayHJ.Primarycareincidenceandtreatmentoffourneuropathicconditions:adescriptivestudy,2002-2005.BMCFamPract2008;9:26.

11.SommerC,GeisC,HaanpääM,SerraJ,TanE,CruccuG.Questionnaireonneuropathicpain:aEuropeanneurologistsurvey.NeurolSci2007;28:136-41.

12.HansG,MasquelierE,DeCockP.Thediagnosis andmanagementofneuropathicpainindailypracticeinBelgium:anobservationalstudy.BMCPublicHealth2007;7:170.

13.BryceTN,BudhCN,CardenasDD,DijkersM,FelixER,FinnerupNB,etal.Painafterspinalcordinjury:anevidence-basedreviewforclinicalpracticeandresearch.ReportoftheNationalInstituteonDisabilityandRehabilitationResearchSpinalCordInjuryMeasuresmeeting.JSpinalCordMed2007;30:421-40.

14.TreedeRD,JensenTS,CampbellJN,CruccuG,DostrovskyJO,GriffinJW,etal.Neuropathicpain:redefinitionandagradingsystemforclinicalandresearchpurposes.Neurology2008;70:1630-5.

15.DevigiliG,TugnoliV,PenzaP,CamozziF,LombardiR,MelliG,etal.Thediagnosticcriteriaforsmallfiberneuropathy:fromsymptomstoneuropathology.Brain2008;131:1912-25

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神經性疼痛在類風濕性關節炎的盛行率

鍾德正 歐燦騰 顏正賢 林育志 劉宏文 蔡文展

高雄醫學大學附設醫院 過敏免疫風濕科

目的：研究在類風濕性關節炎病人中，發生神經性疼痛的比例；同時，也調查罹病時間長短和發生

神經性疼痛的關係。方法：將葛魯蘋教授翻譯的BriefPain Inventory (BPI，原作者Dr.Cleeland) 以

問卷調查的方式在南部某醫學中心過敏免疫風濕科門診調查類風濕性關節炎病人的神經性疼痛盛

行率；感覺神經測試也一併記錄在問卷中。病人之發炎指數紅血球沈降速率 (ESR) 和C-反應蛋白

(CRP) 也記錄在問卷中，以研究這兩者之間是否有相關。問卷調查時間自2008年三月起至六月底

止。結果：一百位符合1987年美國風濕病學院類風濕性關節炎診斷標準的病人接受問卷調查；其中

25人因資料不足而排除。75個病人資料進行統計。其中以女性病人佔多數 (62位女性，84%)，平均

年齡為55.64歲，平均罹病時間為11.08年，近九成病人 (67/75,89.33%) 陳述在求診前一週內出現疼

痛情形。在這65位病人，以0為“不痛＂到10為“這輩子沒這麼痛過＂的疼痛指數量表，他們最痛

的疼痛指數平均為5.74分 (範圍從1分到10分)，最輕微的疼痛平均為1.78分 (範圍從0分到9分)，過去

一週大部分時間的疼痛指數為3.54分 (範圍從0分到10分)。在67位有陳述疼痛病人，他們的平均罹

病時間是11.19年；其中40位 (59.70%) 病人出現allodynia，47位 (70.15%) 病人出現alteredpinprick

threshold。結論：文獻指出allodynia及alteredpinprickthreshold和神經性疼痛的強烈相關性，在我們

類風濕性關節炎合併疼痛的病人中出現神經性疼痛的比例達79.10%(53/67)。然而，罹病時間的長

短和神經性疼痛的表現並沒有正相關。

關鍵詞：神經性疼痛，類風濕性關節炎，allodynia，alteredpinprickthreshold