PainMedicine2010;11:1500–1503WileyPeriodicals,Inc.

BRIEFRESEARCHREPORT

OxycodoneintheLong-TermTreatmentofChronicPainRelatedtoSclerodermaSkinUlcers

DiliaGiuggioli,MD,AndreinaManfredi,MD,MicheleColaci,MD,andClodoveoFerri,MD

Rheumatology Unit,Chairof Rheumatology,DepartmentofInternalMedicine,UniversityofModenaeReggioEmilia,MedicalSchool,Modena,Italy

Reprintrequeststo:ClodoveoFerri,MD,CattedradiReumatologia,PoliclinicodiModena,ViadelPozzo,71,41100Modena,Italy.Tel:+340594222279;Fax:

+340594224178;E-mail:.

Abstract

Objective.Todemonstratetheefficacyandsafetyoflong-termtherapywithoxycodoneinseverepainofsclerodermaskinulcers.

Design.Openstudy.

SettingandPatients.Twenty-nineconsecutivepatients,referredtoourRheumatologyUnitduring2006,affectedbysystemicsclerosiscomplicatedbypainfullong-standingskinulcersenteredinthestudy.Inallcases,painwasclassifiedassevereaccordingtoWorldHealthOrganizationguidelines,andoxycodonechloridrate(Oxycontin®;Mundip-harmaPharmaceuticals,Milan,Italy)wasadminis-tratedatthedosageof10–20mgtwicedailyfora

meanperiodof7.9±3.2standarddeviationmonths.

OutcomeMeasures.Toevaluatetheefficacyandsafetyofopioidtherapy,thefollowingparameterswererecordedatstandardtimeintervals:visualanalogscale(VAS)pain,Pittsburghsleepqualityindex(PSQI),hoursofsleeppernight,HealthAssessmentQuestionnaire-Disabilityindex,analge-sicsuse(rescuetherapy),sideeffects,vitalsigns,routinelaboratoryassessment.

Results.After 1 month of therapy, all patients

experiencedreliefofpain(VASdecreasedfrom93.8±8.72to56.7±10.4,P0.0001),andbetter

qualityofsleep(totalhoursofsleepincreasedfrom 3.68±1.28 to 5.27±0.75, P0.0001; PSQI

decreased from 9.72±3.95 to 3.37±1.04,P0.0001).Theseparametersfurtherimprovedafter 3 months of therapy and remained stable

duringthefollow-up;moreover,anincreaseofdailydosageofoxycodonewasnever required.Theobservedsideeffectswerealwaystransientandmild;onlyconstipation,whenpresent,waspersistent.

Conclusion.Oxycodoneshowedtobeeffectiveandsafeinthetreatmentofpainduetoseveresclero-dermaskinulcers;contemporarily,itmarkedlyimprovedthepatient’scompliancetolocalwoundcareprocedures.

KeyWords.Oxycodone;Pain;SkinUlcers;Sys-temicSclerosis;Scleroderma

Introduction

SystemicSclerosis(SSc)isanautoimmunedisease,char-acterizedbyprogressivefibrosisoftheskinandinternalorgansduetodiffuseimmune-mediatedmicroangiopathy[1].Skin ulcers representone of the mostfrequent com-plicationsofthedisease;theyareslow-healingischemiclesions,characterizedbyseverechronicpain,oftenresis-tanttotraditionaltreatments.Moreover,theyarefrequentlycomplicatedbyinfections,gangrene,andconsequentamputation,whichseverelyaffectthequalityoflifeofthesepatientsandareresponsiblefordisability.Systemictherapy(i.e.,calcium-channelblockers,prostanoids,anti-endothelinreceptors)maylimittheincidenceofsmallulcers,whereastheyarescarcelyeffectiveonmostsevereskinlesions.Thepainreliefprovidedbystandardtherapy(i.e.,nonsteroidalanti-inflammatorydrugs[NSAIDs],tra-madol)isofteninadequateordoselimitedbysideeffects.

Moreover,paincontrolisfundamentalforthewoundcareproceduresinSScpatients,increasingtreatmentadher-enceandcompliancetoskinulcersdressingchanges.

Opioidshavebeendefinedeffectiveandsafeinthetreat-mentofchroniccancerpain[2];theirefficacywasdem-onstratedeveninchronicnoncancerpainconditions[3].However,theuseoforalopioidsinSScpatientswaslimitedtotramadol[4].Amongopioidanalgesics,theoxy-codone,derivedfromalkaloidthebaine,wasdescribedasadrugwellabsorbedorally,withhigherbioavailabilitythanmorphine[5].

Thisopenstudyevaluatedtheefficacyandsafetyofoxy-codoneassupportivetherapyinseverepainrelatedtosclerodermaskinulcers.

PatientsandMethods

Twenty-nineSScpatients(24womenand5men;meanage52.3±12.9standarddeviation[SD]years),referredtoourRheumatologyUnitduring2006,wereconsecutivelyincludedinthestudy.AllpatientssatisfiedthepreliminaryAmericanCollegeofRheumatol-ogy(ACR)classificationcriteriaforSSc[6].Inallcases,thediseasewascomplicatedbylong-standing,painfulskinulcersresistanttobothNSAIDsandtramadoltherapy,atthemaximumrecommendeddoses.Painwasclassifiedassevere,accordingtoWorldHealthOrganizationguidelinesinallsubjects[7].Theoxyc-odonechloridrate(Oxycontin®controlled-releasetablets;MundipharmaPharmaceuticals)wastakentwiceadaytoassure24hourspaincontrol.Atthebeginning,thelowestdoseofmedication(10mgtwicedaily)wasadministeredinallcases,andprogressivelyadjustedinordertoobtainacompletepainrelief.Allpatientscon-tinuedsystemic(calcium-channelblockersand/orpros-tanoids)andlocal(surgicaldebridementandmoistdressing)standardtherapiesforskinsclerodermaulcers.

Patientshavebeenprovidedwith a diary to recordthefollowingsymptomsdaily:self-evaluationofpainatthesametimeintheevening,usingavisualanalogscale(VAS)[8],eventualuseofotheranalgesics,hoursofsleeppernight,eventualsideeffects.HealthAssessmentQuestionnaire-DisabilityIndex(HAQ-DI)[9]wasadministratedbaselineand attheend of treatment,whilePittsburghSleepQualityIndex(PSQI)question-naire[10]wasadministratedbaseline,after1month,andattheendofthetreatment.Thelatterself-ratequestionnaireisaneffectivetoolabletodifferentiatepoorfromgoodsleepersbymeasuringbothqualityandquantityofsleep,thereforeitwaspreviouslyusedinpatientswithchronicnoncancerpain[11]andfibromy-algia[12].

Safetyofoxycodonewasevaluatedbypatient’srecordsofsideeffects,whilevitalsignsandlaboratoryparametervariationsweremonitoredateachmonthlyvisit.

AlldatawereanalyzedbypairedStudent’st-test.

Results

Allpatientstreatedwithoxycodoneexperiencedasignifi-cantreductionoftheskinulcers-relatedpain.Onthewhole,meanoxycodonedosagevariedfrom20to40mg/day,administeredforaperiodof7.9±3.2SDmonths.Afterthefirstmonthoftherapy,painVASdecreasedfrom93.8±8.72to56.7±10.4(P0.0001),totalhoursof

sleep increased from 3.68±1.28 to 5.27±0.75(P0.0001),whilePSQIdecreased,from9.72±3.95to

3.37±1.04(P0.0001),suggestingabetterqualityofsleep.Additionalanalgesictherapywasnecessaryin11/29:6/11assumedNSAIDs,2/11morphine,3/11paracetamolpluscodeine.

After3monthsoftherapy,furtherclinicalimprovementwasobserved:thepainVASreducedto42.9±14.9,themeantotalhoursofsleeppernightwas6.10±0.85andthePSQI3.37±1.04.Eightpatientsneededadditionaltherapy:NSAIDsin5/8andparacetamolpluscodeinein3/8.TheHAQ-DIdecreasedfrom1.1±0.67(baseline)to

1.46±0.46atthelastpatients’evaluation,whencom-pletereliefofthepainwasobtainedandoxycodonewasdiscontinued.

Of interest, withoxycodonetreatmentthepatient’scom-pliancetothelocalwoundmanagement,speciallytosur-gicaldebridement,markedlyimproved.Inaddition,weobservedaprogressivereductionofpatient’sanalgesicconsumptionduringtheulcertreatments.

Nopatientexperiencedsevereadverseeventsrelatedtothetreatment,neitherphysicalexaminationnorlaboratoryparameteralterationswerenoticedduringtheentireperiodofobservation.Mildsideeffects,namelyitch,nausea,and/ordizziness,werereferredby9/29(31%)patients,while15subjects(51.7%)reportedconstipationafter1monthoftreatment.Thislattersymptomwascon-trolledwithpsylliumfibersupplementationand,onlyinsomecases,withlaxatives.

Finally,nopatientpresentedtheabstinencephenomenonaftertreatmentdiscontinuation.

Discussion

Theresultsofourpreliminarystudysuggestedthatlong-termtreatmentwithoxycodonerepresentanimportantapproachtothesclerodermaskinulcers,responsibleforseverechronicpainandmarkedreduc-tionofpatients’qualityoflife.Inaddition,thetreatmentwaswelltoleratedandpermittedabetterlocalmanage-mentofulcers,mainlywithregardstothesurgicaldebridement.

Adequatepaincontrolisaprimarygoalinthemanage-mentofSScpatientscomplicatedbyskinulcers,butstandardizedanalgesicstrategiesarenotavailableforthiscondition.Opioidsareacceptedandusedforthetreatmentofmoderatetoseverepaininchroniccancerandnoncancerpain[2,3].Thisstudypreliminaryevalu-atedtheeffectofoxycodoneinpatientswithpainful,long-lastingsclerodermaskinulcers,withoutimportantsideeffects.

Oxycodonemayrepresentanidealanalgesicdrugforthetreatmentofnonmalignantchronicpain,frequentlyobservedinseveralrheumaticdiseases,becauseofthelongdurationofaction,minimalsideeffects[13],andreasonablecosts.

Giuggiolietal.

Theusefulnessofoxycodonetherapyinreducingchronicrheumaticpainwith onlymild toxicitywas firstlydemon-stratedin1998byStevenetal.[14],andconfirmedbyJamisonetal.inpatientswithchronicnoncancerbackpain[15].Amorerecentrandomized,controlledtrialwithoxycodoneinpatientswithosteoarthritisandmoderatetoseverepain,resistanttostandardtherapy,demonstratedasignificantpaincontrolandimprovementofphysicalactivity[16].

Chronicpainmanagementinsclerodermapatientsispoorlyinvestigated,eventhoughitisacommonsymptom,mainlyinpatientswithskinulcers[17,18];Georgesetal.demonstrated that sclerodermadigitalulcersmayinfluencebothmentalandphysicalcompo-nentscoreofSF-36,severelyaffectingthepatient’squalityoflife,particularlyforresistantchronic pain[19].

Theusefulnessofanalgesicsubstancesappliedtopicallytopainfulskinlesionscomplicatingdifferentconditions,includingscleroderma,hasbeeninvestigated,namelytheuseofcreamcontainingbenzydamineinpatientswithpressuresoresandamixtureofdiamorphineinpressuresoresormalignantskinulcerations[20,21].Theseobser-vationswerenotconfirmedbyrecentrandomized,con-trolledtrialevaluatingtheeffectoftopicalmorphineinchronicskinlesions[22].

Similarly,inourpreviousclinicalexperiencetopicalopioidsscarcelyaffectedpainfulsclerodermaskinlesions.Moreover,asthepainfromskinulcers isoftenresistanttoconventionalanalgesictherapy(NSAIDs,tramadol),anaggressivetherapeuticapproachisrequired.

Inconclusion,ourstudysuggeststhatlong-termuseoforaloxycodoneiseffectiveandsafeinmaintaininganal-gesiainpatientswithsclerodermaskinulcers;notsec-ondarilyitmaybecrucialforanadequatelocalwoundcare.

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