Treatment of Diabetic Neuropathy

28/5/2015 Treatmentofdiabeticneuropathy

http://www.uptodate.com.scihub.org/contents/treatmentofdiabeticneuropathy?topicKey=NEURO%2F5280&elapsedTimeMs=2&source=preview&sear 1/20

OfficialreprintfromUpToDate www.uptodate.com.scihub.org2015UpToDate

AuthorsEvaLFeldman,MD,PhDDavidKMcCulloch,MD

SectionEditorsJeremyMShefner,MD,PhDDavidMNathan,MD

DeputyEditorJohnFDashe,MD,PhD

Treatmentofdiabeticneuropathy

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.Literaturereviewcurrentthrough:Apr2015.|Thistopiclastupdated:Jan15,2015.

INTRODUCTIONPeripheralandautonomicneuropathiesareamajorcauseofmorbidityinpatientswithdiabetesmellitus.(See"Clinicalmanifestationsanddiagnosisofdiabeticpolyneuropathy"and"Diabeticautonomicneuropathy".)

Thetreatmentofdiabeticperipheralneuropathywillbereviewedhere.Therearethreemainelementsinthetreatmentregimen:

GLYCEMICCONTROLFORESTABLISHEDNEUROPATHYOptimalglucosecontrolisimportantforthepreventionofdiabeticneuropathy,atleastinpatientswithtype1diabetesmellitus(see"Pathogenesisandpreventionofdiabeticpolyneuropathy").InthelongitudinalfollowupinthelargeDiabetesControlandComplicationsTrial/EpidemiologyofDiabetesInterventionsandComplications(DCCT/EDIC)trialoftype1patients,glucosecontrolamelioratedtheonsetofneuropathyaswellasprogressionofsurrogateelectrophysiologicmarkersofneuropathy(figure1)[1,2].ApracticestatementissuedbytheAmericanDiabetesAssociationin2005recommendedthatthefirststepinthemanagementofpatientswithsymptomaticdiabeticpolyneuropathyshouldbetoaimforstableandoptimalglycemiccontrol[3].Ina2012systematicreview,enhancedglucosecontrolledtostatisticallysignificantimprovementsinsurrogatemeasuresofneuropathy,includingnerveconductionvelocityandvibrationperceptionthresholds[4].Thesedatasupportthepossibilityofsymptomaticimprovement.Inaddition,clinicalexperiencesuggeststhatvigorousglycemiccontrolisassociatedwithimprovementinsymptomsforpatientswhodevelopacutepainfuldiabeticneuropathyafteraperiodofextremehyperglycemiasuchasdiabeticketoacidosis.Nevertheless,establishedsymptomaticdiabeticneuropathyisgenerallynotreversibleevenwithintensiveglucosecontrol,emphasizingtheimportanceofprevention.(See"Pathogenesisandpreventionofdiabeticpolyneuropathy",sectionon'Prevention'.)

Findingsfromasmallobservationalstudysuggestbutdonotestablishthatsurgicaltreatment(ie,gastricbypass)ofobesepatientswithtype2diabetescanleadtoshorttermimprovementinbothglycemiccontrolanddiabeticneuropathysymptoms[5].Datafromlargerandmorerigorousstudiesarenecessarytodeterminewhetherthisapproachprovideslongtermbenefitforpatientswithobesityrelatedtype2diabetesandneuropathy.

FOOTCAREWecombinegoodglucosecontrolwithfootcare.Onadailybasis,patientsneedtoinspecttheirfeetforthepresenceofdryorcrackingskin,fissures,plantarcallusformation,andsignsofearlyinfectionbetweenthetoesandaroundthetoenails.Regularfootexaminationsbythephysiciantodetectearlyneuropathyarealsoanessentialcomponentofthetreatmentofdiabeticpatients.(See"Evaluationofthediabeticfoot".)

Onceapatienthasdiabeticneuropathy,footcareisevenmoreimportanttopreventulceration,infection,andamputation.(See"Managementofdiabeticfootlesions".)

PAINFULDIABETICNEUROPATHYOnlyasmallfractionofpatientswithdiabeticpolyneuropathyhavepainfulsymptoms.Patientswithpainfuldiabeticneuropathyshouldbetreatedwithasystematic,stepwiseapproach[3].Beforeinitiatingtherapy,itisimportanttoconfirmthatthepainisduetoneuropathy.The

GlycemiccontrolFootcareTreatmentofpain

SciHub



diagnosisofdiabeticpolyneuropathyisreviewedherebrieflyanddiscussedindetailseparately.(See"Clinicalmanifestationsanddiagnosisofdiabeticpolyneuropathy".)

Theonsetofseverepaininthefeetandlowerlimbscanbeverydistressinganddisabling.Adisclesionshouldbeconsideredifthepainhasdevelopedinrelationtorecenttraumaoritsonsetisabrupt.Inaddition,painduetodiscdiseaseismoreoftenunilateralthanpainrelatedtoperipheralneuropathy.(See"Approachtothediagnosisandevaluationoflowbackpaininadults".)

Intheabsenceofthesefeatures,thedifferentialdiagnosisisneuropathyorperipheralvasculardisease.Thephysicalexaminationmaybehelpful(decreasedsensationorlossofdeeptendonreflexes),butthesesignsofneuropathydonotnecessarilymeanthatthepainisduetotheneuropathy.Severalcluesthatthepatienthasneuropathicpainarethelocationofpain(feetmorethancalves),thequalityofthepain,andthetimingofpain(presentatrest,improveswithwalking)(table1).Eachofthesefeaturesisdifferentfromthoseofthepainduetoischemicvasculardisease.

Althoughuncommoncomparedwithsymmetricdiabeticpolyneuropathy,thereareseveralothertypesofacutepainfuldiabeticneuropathysyndromes.Theseare:

Ingeneral,theseconditionsarecharacterizedbysevereneuropathicpain,autonomicdysfunction,andapotentiallyreversiblecoursethatmaylastformanymonths.(See"Epidemiologyandclassificationofdiabeticneuropathy",sectionon'Acutepainfuldiabeticneuropathies'.)

Finally,diabeticamyotrophytypicallyoccursinpatientswithtype2diabetesmellitus.Thetraditionalfeaturesincludetheacute,asymmetric,focalonsetofpainfollowedbyweaknessinvolvingtheproximalleg,withassociatedautonomicfailureandweightloss.Progressionoccursovermonthsandisfollowedbypartialrecoveryinmostpatients.(See"Diabeticamyotrophyandidiopathiclumbosacralradiculoplexusneuropathy".)

SpontaneousresolutionOncethediagnosisofpainfuldiabeticpolyneuropathyisestablished,thepatientshouldbeinformedthattheconditionissometimesselflimited.Inaprospectivestudyof29patients,forexample,painremittedwithin12monthsin16patients(55percent)[6].Remissionwasmorelikelyiftheonsetofsymptomshadfollowedasuddenmetabolicchange(eitheranepisodeofdiabeticketoacidosisoroccasionallyanimprovementinglycemiccontrol),whenthedurationofdiabeteswasrelativelyshort,orwhenmarkedweightlossprecededtheonsetofpain[1].

Themechanismsresponsiblefortheresolutionofpainarenotunderstood.Proposedmechanismsincludealteredperceptionofpain,furtherdeteriorationofthenervesothatitnolongerrespondstostimulation(sothatthepatientisatevengreaterriskfromtrauma),orimprovementinnervefunction.Asanexample,aneuronmayspontaneouslyfireandcausepainwhileitisbeingdamagedorwhileitisrecovering.Thus,inapatientwhohaspoorglycemiccontrol,thenervesmaybestarvedofnutrients,leadingtoacutebutreversiblenerveinjury.Ontheotherhand,apreviouslysilent(anesthetic)nervemayrecoverduringimprovedglycemiccontrol,leadingtospontaneousfiringandtheperceptionofpain.

PAINCONTROLTreatmentsthatarebeneficialforpainfuldiabeticneuropathyincludeanumberofantidepressants(eg,amitriptyline,duloxetine,venlafaxine),anticonvulsants(eg,pregabalin,sodiumvalproate),andcapsaicincream[7].Othertreatmentsthatmaybebeneficialincludelidocainepatch,alphalipoicacid,isosorbidedinitratetopicalspray,andtranscutaneouselectricalnervestimulation.Thesupportingevidencefortheseinterventionsisreviewedinthesectionsthatfollow,asareguidelinerecommendations(see'Guidelines'below)andourapproachtotreatment(see'Choiceoftherapy'below).

AntidepressantsThereisevidencefromrandomizedcontrolledtrialsthattricyclicdrugs(mainlyamitriptyline)andtheantidepressantsduloxetineandvenlafaxinearebeneficialforreducingpainassociatedwithdiabeticneuropathy.

TricyclicdrugsSeveraltricyclicantidepressantdrugs(butnotselectiveserotoninreuptakeinhibitors)

TreatmentinducedneuropathyofdiabetesthatpresentsinthesettingofrapidglycemiccontrolDiabeticneuropathythatoccursinthesettingofunintendedsevereweightloss(diabeticneuropathiccachexia)

Diabeticneuropathythatisseenwithintentionalweightloss(diabeticanorexia)



havebeenfoundindoubleblind,randomizedcontrolledtrialstoimprovesymptomsinpatientswithpainfuldiabeticneuropathy[811].Tricyclicsmayactbyalteringthecentralperceptionofpain.Thetherapeuticeffectusuallyoccurssooner(withinsixweeks)andatlowerdosesthanistypicalwhenthesedrugsaregivenforthetreatmentofdepression.

Thesepointsareillustratedbythefollowingtrials:

Weuseeitheramitriptylineordesipramineinpatientswithseverepain.Thisclassofdrugscanbeaddedtopregabalinoranticonvulsantsbutnottoduloxetine.Thestartingdoseofdesipramineis25mg,takenatbedtime.Thedosecanbeincreasedtoamaximumof200mg/dayoverafewweeks.

Thechoiceofaspecificdrugmayvary:

Commonsideeffectsoftricyclicantidepressantsincludedrymouthandsomnolence.Wesuggestinitiatingtricyclictherapywithadoseatbedtime.Urinaryretentionmayoccur,especiallyinmenwithenlargedprostates.

DuloxetineAsystematicreviewpublishedin2014concludedthatduloxetine,adualserotoninandnorepinephrinereuptakeinhibitor,iseffectivefortreatingpainindiabeticpolyneuropathy[13].Thebenefitofduloxetinewasestablishedinthree12weekrandomized,blinded,controlledtrialsinvolving1102subjects[1416].Inthesetrials,painimprovementoccurredsignificantlymorefrequentlywithduloxetine60or120mgdailythanwithplacebo(47and48percent,versus29percentwithplacebo).Painimprovementwasnotedasearlyasthefirstweekoftreatmentandcontinuedforthedurationofthestudies.Duloxetineshowedrapidonsetofactionandsustainedbenefit,anditwasalsoeffectiveinrelievingpainatnight.The120mgdailydosewasnotaswelltoleratedas60mgdaily,althoughbothwerebeneficial.

Whileduloxetinewasmoreeffectivethanplacebo,allthreetrialswereofrelativelyshortduration,andthelongtermeffectivenessandsafetyofduloxetineisuncertain[17].Furthermore,inclinicaltrialsevaluatingpainfuldiabeticpolyneuropathy,duloxetinetreatmentresultedinmodestincreasesinfastingplasmaglucose[18].Althoughcomparativetrialsarefew,amitriptylineappearstobeaseffectiveasduloxetineforthetreatmentofpainfuldiabeticneuropathy,andislessexpensive.(See'Tricyclicdrugs'above.)

Themostcommonreportedsideeffectsofduloxetinewerenausea,somnolence,dizziness,decreasedappetite,andconstipation.Hotflashesanderectiledysfunctionwerealsoreportedinfrequently.

Inaplacebocontrolled,doubleblind,randomizedcrossovertrial,amitriptylineanddesipraminewereequallyeffectiveandsuperiortofluoxetineorplacebo[9].Thebenefitofthetricyclicdrugswasnotedwithintwoweeksandcontinuedtoincreaseatsixweeks(figure2).Desipraminehadsomewhatfewersideeffectsthanamitriptyline,particularlydrymouth(table2).Theaverageeffectivedose,titratedoversixweekstoachievecontrolofsymptoms,was111mg/dayfordesipramineand105mg/dayforamitriptyline.Therewasnocorrelationbetweenreliefofpain,dosage,orplasmadrugconcentrations,suggestingthattheclinicalresponseandtolerabilityofsideeffectsarethebestguidestodosetitration.

Arandomized,blindedcrossovertrialof58adultswithpainfuldiabeticneuropathythatcomparedamitriptyline(10to50mgdaily)andduloxetine(20to60mgdaily)givenatbedtimefoundasignificantimprovementinpainwithbothmedicationscomparedwithpretreatmentbaseline[12].Agoodoutcome,definedasamedianpainscorereductionof>50percent,wasreportedatasimilarrateforamitriptylineandduloxetine(55versus59percent),andthedifferencewasnotsignificant.Drymouthwassignificantlymorefrequentwithamitriptylinecomparedwithduloxetine(55versus24percent),whileconstipationwasnonsignificantlymorefrequentwithduloxetine(37versus17percent).

Wefrequentlysubstitutenortriptylineforamitriptylineifanticholinergicsideeffectsareaproblem.

Someexpertsusenortriptylineasfirstlinebecauseithasfeweranticholinergicsideeffectsthanamitriptyline.

Amitriptylineandnortriptylinearebothcontraindicatedinpatientswithcardiacdisease.Inthesepatients,weconsultwiththepatient'scardiologistandgiveeitherdoxepin,theleastcardiotoxictricyclicantidepressant,orantidepressantdrugsunrelatedtothetricyclicfamilysuchduloxetineorvenlafaxine.



Becausenauseaiscommon,patientsareencouragedtotakethedrugonafullstomach.Duloxetineshouldnotbetakenwithotherserotoninornorepinephrineuptakeinhibitorsbutcanbecombinedwithanticonvulsanttherapy.

VenlafaxineInarandomizedcontrolledtrial,extendedrelease(ER)venlafaxinewasevaluatedin244patientswithpainfuldiabeticneuropathy[19].Atsixweeks,treatmentwithERvenlafaxineathigher(150to225mgdaily)butnotlower(75mgdaily)doseswasassociatedwithsignificantbenefitintheprimaryoutcomemeasuresofpainintensityandpainreliefcomparedwithplacebo.Thestrengthofthisfindingislimitedbytheshortdurationofthistrial.Nauseaandsomnolencewerethemostcommonsideeffectsofvenlafaxine,andbloodpressureandcardiacrhythmchangesoccurredmoreoftenwithvenlafaxinetreatmentthanwithplacebo.

AnticonvulsantsBothnewer(pregabalin)andolder(valproate)anticonvulsantsmaybeusefulfortreatingpainfuldiabeticpolyneuropathy(DPN).Theutilityofgabapentinisuncertain.

PregabalinPregabalinisanalpha2deltaligandthatisstructurallyrelatedtogabapentinbutwithoutknownactivityatGABAorbenzodiazepinereceptors[20].Itappearstoactasapresynapticinhibitorofthereleaseofexcitatoryneurotransmittersincludingglutamate,substanceP,andcalcitoningenerelatedpeptide(CGRP)[21,22].

Theeffectivenessofpregabalinforthetreatmentofpainfuldiabeticneuropathywasevaluatedinapooledanalysisofsevenrandomizedclinicaltrials,of5to13weeksduration,withatotalof1510patientsintheintentiontotreatpopulation[23].Thefollowingobservationswerereported:

Pregabalinisstartedat50mgtwiceaday(total100mg/day)andisthenslowlyincreasedto150mgtwotimesaday(total300mg/day,themaximumdoseapprovedbytheFDAfordiabetesassociatedneuropathicpain)overaweekormore.Itcanalsobeadministered100mgthreetimesaday.

Pregabalincancauseanumberofsideeffects,includingdizziness,vertigo,incoordination,ataxia,diplopia,blurredvision,sedation,andconfusion[24].ItmaybehabitformingandisclassifiedasaScheduleVdrugintheUnitedStates.Itisgenerallyheldthatmoreclinicalexperiencewiththedrugwilldelineateifitsefficacyoutweighsitspotentialhabitformingclassification.

GabapentinThereiscontroversyregardingtheeffectivenessofgabapentinforthetreatmentofpainfuldiabeticneuropathy:

Giventhattheavailableevidenceisincomplete,theroleofgabapentinforthetreatmentofpainfuldiabeticneuropathyiscontroversial.Someexpertsnolongerusegabapentinforpainfuldiabeticneuropathy,believingit

Comparedwithplacebo,pregabalintreatmentattotaldailydosesof150,300,and600mgresultedinastatisticallysignificantreductioninthemeanpainscore,theprimaryendpointofallincludedstudies.Themediantimetoasustained1pointimprovementonan11pointpainscoreforpregabalin(at150mg,300mg,and600mg)andplacebowas13,5,4,and60days,respectively.

Withhigherdoses,therewasacleardoserelatedincreaseineffectiveness,andanincreaseintheincidenceofmostadverseevents.

Themostcommonadverseeventsweredizziness,somnolence,andperipheraledema.Theincidenceofclinicallymeaningfulweightgain(definedasa7percentweightincreasefrombaselinetoendpoint)wassignificantlyhigherforpatientsassignedtopregabalinthanforthoseassignedtoplacebo(2.0to3.9percentversus0.7percent),butweightgaindidnotaffectdiabetescontrol.

Inasystematicreview,withdatafromsixtrialsand1277participants,theproportionofpatientsachievingatleasta50percentpainintensityreductionwassignificantlyhigherwithgabapentin(dosedat1200mgdaily)comparedwithplacebo(38versus21percent,relativerisk1.9,95%CI1.52.3)[25].Alloftheevidencewasconsidered"secondtier"withpotentiallyimportantresidualbiases.

Theexistenceofunpublishedrandomizedcontrolledtrialsevaluatinggabapentinforthetreatmentofpainfuldiabeticneuropathyhasraisedsignificantconcernsthatgabapentinisnotmoreeffectivethanplacebo[2527],andareviewofpublishedandunpublishedtrialscalledintoquestiontheefficacyofgabapentin[27].



tobenobetterthanplacebo.However,theclinicalexperienceofotherexpertsandthepublisheddatafromrandomizedtrialssuggestthatgabapentinhasarole.

Typicalstartingdosesforgabapentinare300to600mgthreetimesdailythedrugcanbetitratedslowlyupto900mgfourtimesdaily.Themajorsideeffectsofgabapentinaresomnolence,dizziness,andataxia.

OtheranticonvulsantsValproicacid(500to1200mgdaily)waseffectiveforreducingpainindiabeticneuropathyintwosmallplacebocontrolledtrialsfromasinglecenter[28,29].However,itshouldnotbeusedtotreatdiabeticneuropathyinwomenofchildbearingpotentialbecauseofteratogeniceffects.Carbamazepinemayalsohavesomebenefit,butithasnotbeenevaluatedinmodernrandomizedtrialsforthetreatmentofpainfuldiabeticneuropathy[30,31].Asystematicreviewthatanalyzeddatafromthreerandomizedtrialsconcludedthattopiramateisnoteffectiveforpainfuldiabeticpolyneuropathy[32].

CapsaicincreamCapsaicinisanaturallyoccurringcomponentofmanyhotpeppersandcausesanalgesiathroughlocaldepletionofsubstanceP.Itisavailableinacreamfortopicalapplication.Inrandomizedtrialsinpatientswithpainfuldiabeticneuropathy,capsaicinhasbeenassociatedwithmodestbutstatisticallysignificantimprovementinpaincomparedwithplacebo[3336].

Weaddcapsaicin(0.075percentappliedtopicallyfourtimesdaily)forpatientswithsymptomaticpainfuldiabeticpolyneuropathywhoarerefractorytoorintolerantofantidepressants(eg,amitriptyline,duloxetine,venlafaxine)oranticonvulsants(eg,pregabalin)discussedabove.Localburningandskinirritationcanoccur,butthisbecomeslessofaproblemwithcontinueduse.Nevertheless,manypatientsareunabletotoleratethelocalburningpain,whichisexacerbatedbycontactwithwarmwaterandhotweather[36].

AnestheticdrugsAsystematicreviewpublishedin2011concludedthattheevidencefortheeffectivenessofmexiletineisconflicting[36].Thehighestqualitytrialevaluatedfoundnosignificantbenefitofmexiletinecomparedwithplacebo[37].However,othertrialssuggestedbenefit[38,39].

Anopenlabeltrialfoundthatapplicationofuptofourlidocainepatches(5percent)forupto18hoursperdaysignificantlyimprovedpainandqualityofliferatingsin56patientswithpainfuldiabeticneuropathy[40].Arandomizedtrialisnecessarytoconfirmtheseresults.

AlphalipoicacidOneofthemechanismsimplicatedinthepathogenesisofdiabeticneuropathyisincreasedoxidativestress.Asaresult,antioxidantshavebeenstudiedfortheirpotentialtodiminishoxidativestress,improvetheunderlyingpathophysiologyofneuropathy,andreducepain.(See"Pathogenesisandpreventionofdiabeticpolyneuropathy".)

Alphalipoicacid(ALA),apotentantioxidant,hasbeenassociatedwithbenefitforsymptomaticdiabeticneuropathyinseveralprospective,placebocontrolledstudies[4144].IntheSYDNEY1trial,dailyintravenousALAforthreeweekswasassociatedwithreducedpain,paresthesia,andnumbness[42].

IntheSYDNEY2trial,181patientswithdiabetesandsymptomaticdistalsymmetricpolyneuropathywererandomlyassignedtooneofthreedosesoforallyadministeredALA(600,1200,or1800mgdaily)ortoplaceboforfiveweeks[44].Thefollowingobservationswerereported:

Thestrengthofthesefindingsislimitedbytheshortdurationofthistrial[44].Therearenolongtermstudiesthatassesstheaffectofalphalipoicacidonprogressionofneuropathy.

AllthreedosesoforalALAtreatmentwereassociatedwithastatisticallysignificantreductionintheprimaryoutcomemeasure,theneuropathytotalsymptomscore(asummationofstabbingpain,burningpain,paresthesia,andasleepnumbness),comparedwithplacebo[44].ThebenefitofALAdidnotdifferbydose.

Aclinicallymeaningfulresponse,definedas50percentreductioninneuropathicsymptoms,wasobservedin50to62percentofpatientstreatedwithALAversus26percentwithplacebo,adifferencethatwasstatisticallysignificant.

TheoptimaldoseofALAwas600mgoncedaily,ashigherdoseswerelimitedbyincreasingadverseevents(nausea,vomiting,andvertigo)withoutincreasingefficacy.



However,baseduponthesedata,wesuggesttreatmentwithoralALA600mgoncedailyforpatientswithsymptomaticpainfuldiabeticpolyneuropathywhoarerefractorytoorintolerantofantidepressants(eg,amitriptyline,duloxetine,venlafaxine)oranticonvulsants(eg,pregabalin)thathavebeenestablishedasbeneficialforthiscondition.

OpioidsAnumberofopioidshavebeenstudiedforthetreatmentofpainfuldiabeticneuropathy.

ThetrialssupportingtheefficacyofopioidssuchastramadolandoxycodoneCRarealllimitedbyshorttermfollowup[4751].A2009systematicreviewofopioidsforchronicnoncancerpainfoundapaucityofevidenceregardingthelongtermeffectivenessandrisksofsuchtreatment,includingthepotentialforopioidabuse,addiction,andoverdose[51].Similarly,a2013systematicreviewnotedthattheavailablerandomizedcontrolledtrialsofopioidsforneuropathicpaindidnotclearlyaddresstheissuesofabuseandaddiction[52].Inacohortstudyofover9900patientsprescribedlongtermopioidtherapyfornonmalignantpain,theuseofhigherdoseregimenswasassociatedwithanincreasedriskofopioidoverdose[53].Becauseoftheseissues,someexpertshavestoppedusingopioidsaltogetherforthetreatmentofpainfuldiabeticneuropathy.Wesuggestnotusingopioidsforthetreatmentofpainfuldiabeticneuropathybecauseofthelackofevidenceregardinglongtermeffectiveness,andbecauseofthepotentialfortolerance,addiction,andoverdose.

CombinationtherapyResultsfromsmalltrialssuggestthatthetreatmentofneuropathicpainwithcombinationsofdrugsfromdifferentmedicationclassesismodestlymoreeffectivethanmonotherapy.

Inbothreports,thebenefitofcombinationtreatmentwassmallbutstatisticallysignificant.

ElectricalnervestimulationAlthoughdataarelimited,a2010statementfromtheAmericanAcademyofNeurology(AAN)assessingtheuseofTENSforpaininneurologicdisordersconcludedthatTENSisprobablyeffectiveforreducingpainfromdiabeticpolyneuropathy[56],baseduponthefollowingevidence:

Dextromethorphan,aweaksigmaopioidreceptoragonistandanNmethylDaspartate(NMDA)receptorantagonist,wasmoderatelybeneficialcomparedwithplacebointwosmalltrialsforreducingpaininpatientswithdiabeticneuropathy[45,46].

Intwosmallrandomized,doubleblindtrialstramadol,atanaveragedoseof210mg/day,wasmoreeffectivethanplaceboforrelievingpain[47,48].Themostfrequentadverseeffectswerenausea,constipation,headache,andsomnolence.

Controlledrelease(CR)oxycodoneatadailydoseof10to60mgappearsbeeffectiveandsafeforthetreatmentofpainfuldiabeticpolyneuropathy,asshownintworandomizedclinicaltrials[49,50].Inthelargerofthesetrialsinvolving159patients,oxycodoneCRatanaveragedoseof37mgdaily(range10to99mgdaily)providedmorepainreliefthanplacebo[50].

Inasinglecenterrandomizedtrialof44patientswithneuropathicpain(amajoritywithdiabeticpolyneuropathy),gabapentincombinedwithmorphinewasmoreeffectivethaneitheragentaloneforreducingthemeanintensityofpainduringweekfouroftreatmentatthemaximumtolerateddailydose(mean,gabapentin1705mgandmorphine34mgincombination)[54].Constipation,sedation,anddrymouthwerethemostfrequentsideeffectsofthecombinationtherapy.

Asimilarsinglecenterrandomizedtrialof47patients(mostwithdiabeticpolyneuropathy)foundthatthecombinationofnortriptylinewithgabapentinwasmoreeffectivethaneitheragentaloneforreducingthemeanintensityofdailypainduringweekfouroftreatmentatthemaximumtolerateddailydose(mean,nortriptyline50mgandgabapentin2180mgincombination)[55].

Onetrialassigned31patientswithchronicpainfuldiabeticneuropathytoeitherTENSorshamtreatmenttothelegsfor30minutesdailyforfourweeks[57].Symptomaticimprovement(ofatleastonegradeonauniquezerotofivescale)occurredin15of18patients(83percent)withTENStreatment,comparedwithfiveof13patients(38percent)whoreceivedshamtreatment(oddsratio6,95%CI1.133.4)[57].

Anothertrialevaluated19patientswithmildtomoderatesymptomaticdiabeticpolyneuropathy[58].Comparedwithshamtreatment,activetreatmentwithTENSledtoastatisticallysignificantreductionintotalsymptomscoreatsixandtwelveweeks.Inaddition,TENStherapywasassociatedwitha



Asubsequent2011guidelinefromtheAANevaluatingthetreatmentofpainfuldiabeticneuropathyconcludedthatpercutaneouselectricalnervestimulationisprobablyeffective[36],baseduponthreesmalltrials[5961].However,thepercutaneoustechniquesevaluatedinthe2011AANguidelinearenotwidelyavailableinclinicalpractice.

OtherinterventionsSeveralotherapproacheshavebeentriedinpatientswithpainfuldiabeticneuropathy.

AcetylLcarnitineAcetylLcarnitine(ALC),theacetylatedesteroftheaminoacidLcarnitine,hasbeenevaluatedinpatientswithdiabeticperipheralneuropathy[62].Indatafromtworandomizedcontrolledtrialsofidenticaldesign,anintentiontotreatanalysisof1257patientswithdiabeticpolyneuropathyfoundthatALC1000mg(butnot500mg)threetimesdailycomparedwithplacebowasassociatedwithsignificantimprovementinpainscoresinoneofthestudiesandinthecombinedcohort[63].ThebenefitofALCrequiresconfirmation,particularlysincesignificantimprovementwasnotseeninbothtrialsoratthelowerdoseofALC.

IsosorbideAplacebocontrolledpilotstudyofisosorbidedinitratetopicalsprayin22diabeticpatientsreportedasignificantreductioninoverallneuropathicpainandburningsensationinthetreatmentgroup[64].

NSAIDsNonsteroidalantiinflammatorydrugs(NSAIDs)areeffectiveinpatientswithmusculoskeletalorjointabnormalitiessecondarytolongstandingneuropathythejointdeformitiesmayactuallybetheprimarysourceofpain(see"Musculoskeletalcomplicationsindiabetesmellitus").Bothibuprofen(600mgfourtimesdaily)andsulindac(200mgtwicedaily)canleadtosubstantialpainreliefinpatientswithdiabeticneuropathy[65].

ThereisatheoreticalconcernthatNSAIDsmayimpairnervecirculationandworsennerveinjuryduetoinhibitionofprostacyclinsynthesis.Cautioususeofthisclassofdrugsiswarranteduntilthispossibilityisfullyevaluated.

SpinalcordstimulationSpinalcordstimulationisaninvasivemethodinvolvingimplantableelectrodesthatdeliverelectricalstimulationtothedorsalcolumnsofthespinalcord.Preliminarydatafromasmallopenlabeltrialsuggestthatspinalcordstimulationreducespainforpatientswithrefractorypainfuldiabeticneuropathyaffectingthelegs[66].Furthertrialsareneededtoconfirmtheefficacyofthisapproach.

GuidelinesTheAmericanAcademyofNeurology(AAN)performedasystematicreviewandpublishedguidelinesin2011forthetreatmentofpainfuldiabeticneuropathy[36].Thefollowingobservationsweremade:

statisticallysignificantbutmodestimprovementinpainonthevisualanalogscaleatsixweeks.

Pregabalin(300to600mgdaily)wasregardedaseffective[36].

Anumberoftreatmentswereregardedasprobablyeffective[36]:

Gabapentin,900to3600mgdailySodiumvalproate,500to1200mgdailyAmitriptyline,25to100mgdailyDuloxetine,60to120mgdailyVenlafaxine,75to225mgdailyDextromethorphan,400mgdailyMorphinesulphate,titratedto120mgdailyOxycodone,mean37mgdaily,maximum120mgdailyTramadol,210mgdailyCapsaicin,0.075percentfourtimesdailyIsosorbidedinitratesprayPercutaneouselectricalnervestimulationforthreetofourweeks

Lidocainepatchwasregardedaspossiblyeffective[36].

TreatmentsregardedasprobablynoteffectivebytheAANwereoxcarbazepine,lamotrigine,lacosamide,clonidine,pentoxifylline,mexiletine,magneticfieldtreatment,lowintensitylasertherapy,andReikitherapy[36].



Amanagementalgorithmoutlinedbyastatementpublishedin2005fromtheAmericanDiabetesAssociation(ADA)recommendedtreatmentinsequentialstepsorderedasfollows[3]:

TheADAstatementnotedthatnonpharmacologic,topical,orphysicaltherapiesmightbeusefulatanystage.Thesemeasuresincludeacupuncture,capsaicin,glyceryltrinitratesprayorpatches,andothertherapies[3,67].

ChoiceoftherapyWesuggestusingoneoftheantidepressants(eg,amitriptyline,duloxetine,venlafaxine)oranticonvulsants(eg,pregabalin)discussedaboveasinitialtherapyforpatientswithpainfuldiabeticneuropathy.Theavailableevidencesuggeststhattheseagentshavesimilarmodestbenefit,thoughfewhighqualitycomparativetrialshavebeendone[12,68,69].Amongtheseoptions,weprefertostartwithamitriptyline,particularlyinyoungerhealthierpatients,becauseofitseffectivenessandlowcost.Patientswhofailtoimprovewithareasonabletrialofoneoftheseagentscanbeswitchedtomonotherapywithanotheragent.(See'Antidepressants'aboveand'Anticonvulsants'above.)

Forpatientswhodonotimproveononedrug,wesuggestcombinationtherapyemployingtwodrugsfromdifferentmedicationclassesasthenextstepinthetreatmentparadigm.Forpatientswhoareunabletotolerateanyofthesedrugs,alternativetreatmentsincludecapsaicincream,lidocainepatch,alphalipoicacid,isosorbidedinitratetopicalspray,andtranscutaneouselectricalnervestimulation.(See'Capsaicincream'aboveand'Anestheticdrugs'aboveand'Alphalipoicacid'aboveand'Opioids'aboveand'Combinationtherapy'aboveand'Electricalnervestimulation'above.)

Theuseofopioidsforchronicnonmalignantpainiscontroversial.Wesuggestnotusingopioidsforthetreatmentofpainfuldiabeticneuropathybecauseofthelackofevidenceregardinglongtermeffectiveness,andbecauseofthepotentialforopioidtolerance,addiction,andoverdose.However,otherexpertsbelievethatopioidshavearoleinthemanagementofpainfuldiabeticneuropathydespitetheseconcerns[36].(See'Opioids'above.)

Thetreatmentoptionsandsuggesteddosesaresummarizedinthetable(table3).

Theroleofglycemiccontrolinestablisheddiabeticneuropathyisuncertain.However,strictglycemiccontrolisassociatedwithareducedriskofmicrovascularcomplicationsinpatientswithtype2diabetes,andintensivetherapymayreducetheriskofmacrovascularcomplicationsinsuchpatients.Inaddition,tightglycemiccontrolisassociatedwithareductioninmicrovascularandmacrovascularcomplicationsforpatientswithtype1diabetes.Theseissuesarediscussedindetailseparately.(See"Glycemiccontrolandvascularcomplicationsintype2diabetesmellitus"and"Glycemiccontrolandvascularcomplicationsintype1diabetesmellitus".)

NONGLYCEMICMEASURESMultifactorialriskfactorreductionandaldosereductaseinhibitorsarepotentialstrategiesfortreatingdiabeticneuropathy.

MultifactorialriskfactorreductionThepotentialefficacyofintensivecombinedtherapyinpatientswithtype2diabetesandmicroalbuminuriawasexaminedintheStenotype2trial[70].Inthisprospectivestudy,160patientswererandomlyassignedtostandardormultifactorialintensivetherapy.Theintensiveregimenconsistedofbehavioraltherapy(includingadviceconcerningdiet,exercise,andsmokingcessation)andpharmacologicintervention(consistingoftheadministrationofmultipleagentstoattainseveralaggressivetherapeuticgoals)(table4).Diabeticautonomicandperipheralneuropathywerepresentatbaselinein28and34percent,respectively.

Atameanfollowupof7.8years,therewasasignificantlylowerrateofprogressionofautonomicneuropathyintheintensivetherapygroup(30versus54percent,relativerisk0.37),butnoslowingofprogressionofperipheralneuropathy[70].

ExcludenondiabeticetiologiesStabilizeglycemiccontrol(insulinnotalwaysrequiredintype2diabetes)Tricyclicdrugs(eg,amitriptyline25to150mgbeforebed)Anticonvulsants(eg,gabapentin,typicaldose1.8g/day)Opioidoropioidlikedrugs(eg,tramadolorcontrolledreleaseoxycodone)Considerpainclinicreferral



Thedetailsoftheprotocolandoverallresultsofthisstudyarediscussedelsewhere.(See"Overviewofmedicalcareinadultswithdiabetesmellitus",sectionon'Multifactorialriskfactorreduction'.)

AldosereductaseinhibitorsInadditiontoloweringbloodglucoseconcentrations,anotherpotentialapproachistominimizethetoxicityofhyperglycemia.Tothedegreethatsorbitolaccumulationmayplayaroleindiabeticneuropathy,useofanaldosereductaseinhibitortopreventsorbitolformationmightbebeneficial.

Intheavailablestudiesofthisunapprovedclassofmedications,aldosereductaseinhibitorshaveproducedinconsistentbenefitsindiabeticneuropathy.Theevidenceispresentedindetailseparately.(See"Aldosereductaseinhibitorsinthepreventionofdiabeticcomplications",sectionon'Neuropathy'.)

SurgicaldecompressionSurgicaldecompressionofmultipleperipheralnerves(calledtheDellonprocedure)isanalternative,controversialmethodfortreatingdiabeticpolyneuropathy[71].Thepurportedrationaleforsurgicaldecompressionisbasedonthenotionthatthemetabolicstressofdiabetesrendersperipheralnervessusceptibletocompressiveinjuryatsitesofpotentialnerveentrapment[7274],andthatcompressiveinjuryofmultipleperipheralnervesiswhatleadstosymptomsinmostpatients[75].

However,therearenoadequatelydesignedtrialstosupporttheuseofsurgicaldecompressionofmultipleperipheralnervesasatreatmentforsymptomaticdiabeticpolyneuropathy[72].Therefore,thistreatmentisnotrecommended.

INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5 to6gradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10 to12 gradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortablewithsomemedicaljargon.

Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon"patientinfo"andthekeyword(s)ofinterest.)

SUMMARYANDRECOMMENDATIONS

th th

th th

Basicstopics(see"Patientinformation:Nervedamagecausedbydiabetes(TheBasics)"and"Patientinformation:Neuropathicpain(TheBasics)")

BeyondtheBasicstopics(see"Patientinformation:Diabeticneuropathy(BeyondtheBasics)")

Optimalglucosecontrolisconsideredthecornerstoneforthetreatmentofdiabetesanditscomplications.Intensiveglucosecontrolhasbeenshowntopreventthedevelopmentofperipheralneuropathy.However,whethernearnormalglycemiccontrolcanameliorateestablishedsymptomaticdiabeticneuropathy,andpainfulneuropathyinparticular,isnotasclear.(See'Glycemiccontrolforestablishedneuropathy'above.)

Forpatientswithdiabeticneuropathy,footcareisimportanttopreventulceration,infection,andamputation.(See'Footcare'aboveand"Managementofdiabeticfootlesions".)

Onlyasmallfractionofpatientswithdiabeticpolyneuropathyhavepainfulsymptoms.Inaddition,thepainassociatedwithdiabeticpolyneuropathyisoftenselflimitedevidencefromasmallprospectivestudysuggeststhatresolutionoccursover12monthsinapproximatelyonehalfofpatients.(See'Painfuldiabeticneuropathy'aboveand'Spontaneousresolution'above.)

Forpatientswithpainfuldiabeticneuropathy,wesuggestinitialtherapyusingeitheramitriptylineorvenlafaxine(Grade2B),orduloxetineorpregabalin(Grade2A).Amongtheseoptions,weprefertostartwithamitriptyline,particularlyinyoungerhealthierpatients,becauseofitseffectivenessandlowcost.Forpatientswhodonotimproveononedrug,wesuggestcombinationtherapyemployingtwodrugsfromdifferentmedicationclasses(Grade2C).Forpatientswhoareunabletotolerateanyofthesedrugs,alternativetreatmentsincludecapsaicincream,lidocainepatch,alphalipoicacid,isosorbidedinitratetopicalspray,andtranscutaneouselectricalnervestimulation.(See'Paincontrol'aboveand'Choiceof


http://www.uptodate.com.scihub.org/contents/treatmentofdiabeticneuropathy?topicKey=NEURO%2F5280&elapsedTimeMs=2&source=preview&sea 10/20

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

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72. TherapeuticsandTechnologyAssessmentSubcommitteeoftheAmericanAcademyofNeurology,ChaudhryV,StevensJC,etal.PracticeAdvisory:utilityofsurgicaldecompressionfortreatmentofdiabeticneuropathy:reportoftheTherapeuticsandTechnologyAssessmentSubcommitteeoftheAmericanAcademyofNeurology.Neurology200666:1805.

73. UptonAR,McComasAJ.Thedoublecrushinnerveentrapmentsyndromes.Lancet19732:359.74. DellonAL,MackinnonSE,SeilerWA4th.Susceptibilityofthediabeticnervetochroniccompression.

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Surg199126:259.

Topic5280Version18.0



GRAPHICS

Benefitofglycemiccontrolinestablisheddiabeticneuropathy

Image

Histogramofperonealmotornerveconductionvelocitiesafterfiveyearsofconventional(bluebars)orintensive(redbars)insulintreatmentforpatientswithpossibleordefiniteneuropathyintheprimaryprevention(upperpanel)orsecondaryintervention(lowerpanel)cohorts.Nerveconductionvelocitywassignificantlyhigherinbothintensivetherapygroups.

Datafrom:EffectofintensivediabetestreatmentonnerveconductionintheDiabetesControlandComplicationsTrial.AnnNeurol199538:869.

Graphic70945Version4.0



Clinicalfeaturesofdiabeticneuropathy

Characteristic Favorsneuropathy

Favorsvasculardisease

Siteofpain Feetmorethancalves Calves,thighs,andbuttocksmorethanfeet

Qualityofpain Sharp,superficial,burning,tingling

Deepache

Presentatrest Common Rare

Effectofwalking Painimproves Painmadeworse

Painworseinbed Yes No

Precededbyrecentchangeinglycemiccontrol

Sometimes No

Clinicalfeaturestohelpdistinguishthepainindiabeticneuropathyfromthatwithperipheralvasculardiseaseandintermittentclaudication.




Tricyclicdrugsimprovepainindiabeticneuropathy

Meanchangesinpainscore(anegativevalueindicatesimprovement)inpatientswithpainfuldiabeticneuropathywhoweretreatedwithplacebo(n=15),fluoxetine(n=12),desipramine(n=18),oramitriptyline(n=12).Drugtherapywasbegunatweekoneafteroneweekofobservation.Desipramineandamitriptylinewereequallybeneficialandmoreeffectivethanfluoxetineorplacebo.

DatafromMaxMB,LynchSA,MuirJ,etal,NEnglJMed1992326:1250.




Sideeffectsofdrugsusedfordiabeticneuropathy

Sideeffect Amitriptyline Desipramine Fluoxetine Placebo

Drymouth 63 32 11 35

Fatigue 34 34 13 17

Headache 21 11 24 9

Constipation 8 21 2 7

Palpitations 13 3 2 0

Anysymptoms 81 76 63 68

Percentageofpatientsreportingsideeffectsduringtreatmentwithamitripyline,desipramine,fluoxetine,orplacebo.




Treatmentoptionsforpainfuldiabeticneuropathy

Antidepressants

Tricyclics

Amitriptyline25to100mgatnight

Nortriptyline25to100mgatnight

Doxepin25to100mgatnight

Others

Duloxetine60to120mgdaily

Venlafaxine75to225mgdaily

AnticonvulsantsPregabalin300to600mgdaily

Sodiumvalproate500to1200mgdaily

OthersCapsaicintopicalcream0.075percent

Lidocainepatch

Alphalipoicacid600mgoncedaily

Isosorbidedinitratespray

Transcutaneouselectricalnervestimulation(TENS)




TreatmentgoalsintheStenotype2diabetesstudy

Standard Intensive

Systolicbloodpressure(mmHg)



Disclosures:EvaLFeldman,MD,PhDNothingtodisclose.DavidKMcCulloch,MDNothingtodisclose.JeremyMShefner,MD,PhDGrant/ResearchSupport:Cytokinetics,Inc.[ALS]GlaxoSmithKline.Consultant/AdvisoryBoard:BiogenIdec[ALS]Cytokinetics,Inc.[ALS]Kinemed[ALS]VoyagerTherapeutics[ALS]ISISPharmaceuticals[SMA].DavidMNathan,MDNothingtodisclose.JohnFDashe,MD,PhDNothingtodisclose.Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.Conflictofinterestpolicy

Disclosures

Treatment of Diabetic Neuropathy

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