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Treatmentofdiabeticneuropathy

OfficialreprintfromUpToDate
www.uptodate.com.scihub.org2015UpToDate

Treatmentofdiabeticneuropathy
Authors
EvaLFeldman,MD,PhD
DavidKMcCulloch,MD

SectionEditors
JeremyMShefner,MD,
PhD
DavidMNathan,MD

DeputyEditor
JohnFDashe,MD,PhD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.

Literaturereviewcurrentthrough:Apr2015.|Thistopiclastupdated:Jan15,2015.

INTRODUCTIONPeripheralandautonomicneuropathiesareamajorcauseofmorbidityinpatientswith
diabetesmellitus.(See"Clinicalmanifestationsanddiagnosisofdiabeticpolyneuropathy"and"Diabetic
autonomicneuropathy".)
Thetreatmentofdiabeticperipheralneuropathywillbereviewedhere.Therearethreemainelementsinthe
treatmentregimen:
Glycemiccontrol
Footcare
Treatmentofpain
GLYCEMICCONTROLFORESTABLISHEDNEUROPATHYOptimalglucosecontrolisimportantforthe
preventionofdiabeticneuropathy,atleastinpatientswithtype1diabetesmellitus(see"Pathogenesisand
preventionofdiabeticpolyneuropathy").InthelongitudinalfollowupinthelargeDiabetesControland
ComplicationsTrial/EpidemiologyofDiabetesInterventionsandComplications(DCCT/EDIC)trialoftype1
patients,glucosecontrolamelioratedtheonsetofneuropathyaswellasprogressionofsurrogate
electrophysiologicmarkersofneuropathy(figure1)[1,2].ApracticestatementissuedbytheAmerican
DiabetesAssociationin2005recommendedthatthefirststepinthemanagementofpatientswithsymptomatic
diabeticpolyneuropathyshouldbetoaimforstableandoptimalglycemiccontrol[3].Ina2012systematic
review,enhancedglucosecontrolledtostatisticallysignificantimprovementsinsurrogatemeasuresof
neuropathy,includingnerveconductionvelocityandvibrationperceptionthresholds[4].Thesedatasupportthe
possibilityofsymptomaticimprovement.Inaddition,clinicalexperiencesuggeststhatvigorousglycemic
controlisassociatedwithimprovementinsymptomsforpatientswhodevelopacutepainfuldiabetic
neuropathyafteraperiodofextremehyperglycemiasuchasdiabeticketoacidosis.Nevertheless,established
symptomaticdiabeticneuropathyisgenerallynotreversibleevenwithintensiveglucosecontrol,emphasizing
theimportanceofprevention.(See"Pathogenesisandpreventionofdiabeticpolyneuropathy",sectionon
'Prevention'.)
Findingsfromasmallobservationalstudysuggestbutdonotestablishthatsurgicaltreatment(ie,gastric
bypass)ofobesepatientswithtype2diabetescanleadtoshorttermimprovementinbothglycemiccontrol
anddiabeticneuropathysymptoms[5].Datafromlargerandmorerigorousstudiesarenecessarytodetermine
whetherthisapproachprovideslongtermbenefitforpatientswithobesityrelatedtype2diabetesand
neuropathy.
FOOTCAREWecombinegoodglucosecontrolwithfootcare.Onadailybasis,patientsneedtoinspect
theirfeetforthepresenceofdryorcrackingskin,fissures,plantarcallusformation,andsignsofearlyinfection
betweenthetoesandaroundthetoenails.Regularfootexaminationsbythephysiciantodetectearly
neuropathyarealsoanessentialcomponentofthetreatmentofdiabeticpatients.(See"Evaluationofthe
diabeticfoot".)
Onceapatienthasdiabeticneuropathy,footcareisevenmoreimportanttopreventulceration,infection,and
amputation.(See"Managementofdiabeticfootlesions".)

SciHub

PAINFULDIABETICNEUROPATHYOnlyasmallfractionofpatientswithdiabeticpolyneuropathyhave
painfulsymptoms.Patientswithpainfuldiabeticneuropathyshouldbetreatedwithasystematic,stepwise
approach[3].Beforeinitiatingtherapy,itisimportanttoconfirmthatthepainisduetoneuropathy.The
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diagnosisofdiabeticpolyneuropathyisreviewedherebrieflyanddiscussedindetailseparately.(See"Clinical
manifestationsanddiagnosisofdiabeticpolyneuropathy".)
Theonsetofseverepaininthefeetandlowerlimbscanbeverydistressinganddisabling.Adisclesionshould
beconsideredifthepainhasdevelopedinrelationtorecenttraumaoritsonsetisabrupt.Inaddition,paindue
todiscdiseaseismoreoftenunilateralthanpainrelatedtoperipheralneuropathy.(See"Approachtothe
diagnosisandevaluationoflowbackpaininadults".)
Intheabsenceofthesefeatures,thedifferentialdiagnosisisneuropathyorperipheralvasculardisease.The
physicalexaminationmaybehelpful(decreasedsensationorlossofdeeptendonreflexes),butthesesignsof
neuropathydonotnecessarilymeanthatthepainisduetotheneuropathy.Severalcluesthatthepatienthas
neuropathicpainarethelocationofpain(feetmorethancalves),thequalityofthepain,andthetimingofpain
(presentatrest,improveswithwalking)(table1).Eachofthesefeaturesisdifferentfromthoseofthepaindue
toischemicvasculardisease.
Althoughuncommoncomparedwithsymmetricdiabeticpolyneuropathy,thereareseveralothertypesofacute
painfuldiabeticneuropathysyndromes.Theseare:
Treatmentinducedneuropathyofdiabetesthatpresentsinthesettingofrapidglycemiccontrol
Diabeticneuropathythatoccursinthesettingofunintendedsevereweightloss(diabeticneuropathic
cachexia)
Diabeticneuropathythatisseenwithintentionalweightloss(diabeticanorexia)
Ingeneral,theseconditionsarecharacterizedbysevereneuropathicpain,autonomicdysfunction,anda
potentiallyreversiblecoursethatmaylastformanymonths.(See"Epidemiologyandclassificationofdiabetic
neuropathy",sectionon'Acutepainfuldiabeticneuropathies'.)
Finally,diabeticamyotrophytypicallyoccursinpatientswithtype2diabetesmellitus.Thetraditionalfeatures
includetheacute,asymmetric,focalonsetofpainfollowedbyweaknessinvolvingtheproximalleg,with
associatedautonomicfailureandweightloss.Progressionoccursovermonthsandisfollowedbypartial
recoveryinmostpatients.(See"Diabeticamyotrophyandidiopathiclumbosacralradiculoplexusneuropathy".)
SpontaneousresolutionOncethediagnosisofpainfuldiabeticpolyneuropathyisestablished,thepatient
shouldbeinformedthattheconditionissometimesselflimited.Inaprospectivestudyof29patients,for
example,painremittedwithin12monthsin16patients(55percent)[6].Remissionwasmorelikelyiftheonset
ofsymptomshadfollowedasuddenmetabolicchange(eitheranepisodeofdiabeticketoacidosisor
occasionallyanimprovementinglycemiccontrol),whenthedurationofdiabeteswasrelativelyshort,orwhen
markedweightlossprecededtheonsetofpain[1].
Themechanismsresponsiblefortheresolutionofpainarenotunderstood.Proposedmechanismsinclude
alteredperceptionofpain,furtherdeteriorationofthenervesothatitnolongerrespondstostimulation(sothat
thepatientisatevengreaterriskfromtrauma),orimprovementinnervefunction.Asanexample,aneuron
mayspontaneouslyfireandcausepainwhileitisbeingdamagedorwhileitisrecovering.Thus,inapatient
whohaspoorglycemiccontrol,thenervesmaybestarvedofnutrients,leadingtoacutebutreversiblenerve
injury.Ontheotherhand,apreviouslysilent(anesthetic)nervemayrecoverduringimprovedglycemiccontrol,
leadingtospontaneousfiringandtheperceptionofpain.
PAINCONTROLTreatmentsthatarebeneficialforpainfuldiabeticneuropathyincludeanumberof
antidepressants(eg,amitriptyline,duloxetine,venlafaxine),anticonvulsants(eg,pregabalin,sodiumvalproate),
andcapsaicincream[7].Othertreatmentsthatmaybebeneficialincludelidocainepatch,alphalipoicacid,
isosorbidedinitratetopicalspray,andtranscutaneouselectricalnervestimulation.Thesupportingevidencefor
theseinterventionsisreviewedinthesectionsthatfollow,asareguidelinerecommendations(see'Guidelines'
below)andourapproachtotreatment(see'Choiceoftherapy'below).
AntidepressantsThereisevidencefromrandomizedcontrolledtrialsthattricyclicdrugs(mainly
amitriptyline)andtheantidepressantsduloxetineandvenlafaxinearebeneficialforreducingpainassociated
withdiabeticneuropathy.
TricyclicdrugsSeveraltricyclicantidepressantdrugs(butnotselectiveserotoninreuptakeinhibitors)
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havebeenfoundindoubleblind,randomizedcontrolledtrialstoimprovesymptomsinpatientswithpainful
diabeticneuropathy[811].Tricyclicsmayactbyalteringthecentralperceptionofpain.Thetherapeuticeffect
usuallyoccurssooner(withinsixweeks)andatlowerdosesthanistypicalwhenthesedrugsaregivenforthe
treatmentofdepression.
Thesepointsareillustratedbythefollowingtrials:
Inaplacebocontrolled,doubleblind,randomizedcrossovertrial,amitriptylineanddesipraminewere
equallyeffectiveandsuperiortofluoxetineorplacebo[9].Thebenefitofthetricyclicdrugswasnoted
withintwoweeksandcontinuedtoincreaseatsixweeks(figure2).Desipraminehadsomewhatfewer
sideeffectsthanamitriptyline,particularlydrymouth(table2).Theaverageeffectivedose,titratedover
sixweekstoachievecontrolofsymptoms,was111mg/dayfordesipramineand105mg/dayfor
amitriptyline.Therewasnocorrelationbetweenreliefofpain,dosage,orplasmadrugconcentrations,
suggestingthattheclinicalresponseandtolerabilityofsideeffectsarethebestguidestodosetitration.
Arandomized,blindedcrossovertrialof58adultswithpainfuldiabeticneuropathythatcompared
amitriptyline(10to50mgdaily)andduloxetine(20to60mgdaily)givenatbedtimefoundasignificant
improvementinpainwithbothmedicationscomparedwithpretreatmentbaseline[12].Agoodoutcome,
definedasamedianpainscorereductionof>50percent,wasreportedatasimilarrateforamitriptyline
andduloxetine(55versus59percent),andthedifferencewasnotsignificant.Drymouthwassignificantly
morefrequentwithamitriptylinecomparedwithduloxetine(55versus24percent),whileconstipationwas
nonsignificantlymorefrequentwithduloxetine(37versus17percent).
Weuseeitheramitriptylineordesipramineinpatientswithseverepain.Thisclassofdrugscanbeaddedto
pregabalinoranticonvulsantsbutnottoduloxetine.Thestartingdoseofdesipramineis25mg,takenat
bedtime.Thedosecanbeincreasedtoamaximumof200mg/dayoverafewweeks.
Thechoiceofaspecificdrugmayvary:
Wefrequentlysubstitutenortriptylineforamitriptylineifanticholinergicsideeffectsareaproblem.
Someexpertsusenortriptylineasfirstlinebecauseithasfeweranticholinergicsideeffectsthan
amitriptyline.
Amitriptylineandnortriptylinearebothcontraindicatedinpatientswithcardiacdisease.Inthesepatients,
weconsultwiththepatient'scardiologistandgiveeitherdoxepin,theleastcardiotoxictricyclic
antidepressant,orantidepressantdrugsunrelatedtothetricyclicfamilysuchduloxetineorvenlafaxine.
Commonsideeffectsoftricyclicantidepressantsincludedrymouthandsomnolence.Wesuggestinitiating
tricyclictherapywithadoseatbedtime.Urinaryretentionmayoccur,especiallyinmenwithenlarged
prostates.
DuloxetineAsystematicreviewpublishedin2014concludedthatduloxetine,adualserotoninand
norepinephrinereuptakeinhibitor,iseffectivefortreatingpainindiabeticpolyneuropathy[13].Thebenefitof
duloxetinewasestablishedinthree12weekrandomized,blinded,controlledtrialsinvolving1102subjects[14
16].Inthesetrials,painimprovementoccurredsignificantlymorefrequentlywithduloxetine60or120mgdaily
thanwithplacebo(47and48percent,versus29percentwithplacebo).Painimprovementwasnotedasearly
asthefirstweekoftreatmentandcontinuedforthedurationofthestudies.Duloxetineshowedrapidonsetof
actionandsustainedbenefit,anditwasalsoeffectiveinrelievingpainatnight.The120mgdailydosewasnot
aswelltoleratedas60mgdaily,althoughbothwerebeneficial.
Whileduloxetinewasmoreeffectivethanplacebo,allthreetrialswereofrelativelyshortduration,andthelong
termeffectivenessandsafetyofduloxetineisuncertain[17].Furthermore,inclinicaltrialsevaluatingpainful
diabeticpolyneuropathy,duloxetinetreatmentresultedinmodestincreasesinfastingplasmaglucose[18].
Althoughcomparativetrialsarefew,amitriptylineappearstobeaseffectiveasduloxetineforthetreatmentof
painfuldiabeticneuropathy,andislessexpensive.(See'Tricyclicdrugs'above.)
Themostcommonreportedsideeffectsofduloxetinewerenausea,somnolence,dizziness,decreased
appetite,andconstipation.Hotflashesanderectiledysfunctionwerealsoreportedinfrequently.
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Becausenauseaiscommon,patientsareencouragedtotakethedrugonafullstomach.Duloxetineshouldnot
betakenwithotherserotoninornorepinephrineuptakeinhibitorsbutcanbecombinedwithanticonvulsant
therapy.
VenlafaxineInarandomizedcontrolledtrial,extendedrelease(ER)venlafaxinewasevaluatedin244
patientswithpainfuldiabeticneuropathy[19].Atsixweeks,treatmentwithERvenlafaxineathigher(150to
225mgdaily)butnotlower(75mgdaily)doseswasassociatedwithsignificantbenefitintheprimaryoutcome
measuresofpainintensityandpainreliefcomparedwithplacebo.Thestrengthofthisfindingislimitedbythe
shortdurationofthistrial.Nauseaandsomnolencewerethemostcommonsideeffectsofvenlafaxine,and
bloodpressureandcardiacrhythmchangesoccurredmoreoftenwithvenlafaxinetreatmentthanwithplacebo.
AnticonvulsantsBothnewer(pregabalin)andolder(valproate)anticonvulsantsmaybeusefulfortreating
painfuldiabeticpolyneuropathy(DPN).Theutilityofgabapentinisuncertain.
PregabalinPregabalinisanalpha2deltaligandthatisstructurallyrelatedtogabapentinbutwithout
knownactivityatGABAorbenzodiazepinereceptors[20].Itappearstoactasapresynapticinhibitorofthe
releaseofexcitatoryneurotransmittersincludingglutamate,substanceP,andcalcitoningenerelatedpeptide
(CGRP)[21,22].
Theeffectivenessofpregabalinforthetreatmentofpainfuldiabeticneuropathywasevaluatedinapooled
analysisofsevenrandomizedclinicaltrials,of5to13weeksduration,withatotalof1510patientsinthe
intentiontotreatpopulation[23].Thefollowingobservationswerereported:
Comparedwithplacebo,pregabalintreatmentattotaldailydosesof150,300,and600mgresultedina
statisticallysignificantreductioninthemeanpainscore,theprimaryendpointofallincludedstudies.The
mediantimetoasustained1pointimprovementonan11pointpainscoreforpregabalin(at150mg,300
mg,and600mg)andplacebowas13,5,4,and60days,respectively.
Withhigherdoses,therewasacleardoserelatedincreaseineffectiveness,andanincreaseinthe
incidenceofmostadverseevents.
Themostcommonadverseeventsweredizziness,somnolence,andperipheraledema.Theincidenceof
clinicallymeaningfulweightgain(definedasa7percentweightincreasefrombaselinetoendpoint)was
significantlyhigherforpatientsassignedtopregabalinthanforthoseassignedtoplacebo(2.0to3.9
percentversus0.7percent),butweightgaindidnotaffectdiabetescontrol.
Pregabalinisstartedat50mgtwiceaday(total100mg/day)andisthenslowlyincreasedto150mgtwotimes
aday(total300mg/day,themaximumdoseapprovedbytheFDAfordiabetesassociatedneuropathicpain)
overaweekormore.Itcanalsobeadministered100mgthreetimesaday.
Pregabalincancauseanumberofsideeffects,includingdizziness,vertigo,incoordination,ataxia,diplopia,
blurredvision,sedation,andconfusion[24].ItmaybehabitformingandisclassifiedasaScheduleVdrugin
theUnitedStates.Itisgenerallyheldthatmoreclinicalexperiencewiththedrugwilldelineateifitsefficacy
outweighsitspotentialhabitformingclassification.
GabapentinThereiscontroversyregardingtheeffectivenessofgabapentinforthetreatmentofpainful
diabeticneuropathy:
Inasystematicreview,withdatafromsixtrialsand1277participants,theproportionofpatients
achievingatleasta50percentpainintensityreductionwassignificantlyhigherwithgabapentin(dosedat
1200mgdaily)comparedwithplacebo(38versus21percent,relativerisk1.9,95%CI1.52.3)[25].All
oftheevidencewasconsidered"secondtier"withpotentiallyimportantresidualbiases.
Theexistenceofunpublishedrandomizedcontrolledtrialsevaluatinggabapentinforthetreatmentof
painfuldiabeticneuropathyhasraisedsignificantconcernsthatgabapentinisnotmoreeffectivethan
placebo[2527],andareviewofpublishedandunpublishedtrialscalledintoquestiontheefficacyof
gabapentin[27].
Giventhattheavailableevidenceisincomplete,theroleofgabapentinforthetreatmentofpainfuldiabetic
neuropathyiscontroversial.Someexpertsnolongerusegabapentinforpainfuldiabeticneuropathy,believingit
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tobenobetterthanplacebo.However,theclinicalexperienceofotherexpertsandthepublisheddatafrom
randomizedtrialssuggestthatgabapentinhasarole.
Typicalstartingdosesforgabapentinare300to600mgthreetimesdailythedrugcanbetitratedslowlyupto
900mgfourtimesdaily.Themajorsideeffectsofgabapentinaresomnolence,dizziness,andataxia.
OtheranticonvulsantsValproicacid(500to1200mgdaily)waseffectiveforreducingpainindiabetic
neuropathyintwosmallplacebocontrolledtrialsfromasinglecenter[28,29].However,itshouldnotbeusedto
treatdiabeticneuropathyinwomenofchildbearingpotentialbecauseofteratogeniceffects.Carbamazepine
mayalsohavesomebenefit,butithasnotbeenevaluatedinmodernrandomizedtrialsforthetreatmentof
painfuldiabeticneuropathy[30,31].Asystematicreviewthatanalyzeddatafromthreerandomizedtrials
concludedthattopiramateisnoteffectiveforpainfuldiabeticpolyneuropathy[32].
CapsaicincreamCapsaicinisanaturallyoccurringcomponentofmanyhotpeppersandcausesanalgesia
throughlocaldepletionofsubstanceP.Itisavailableinacreamfortopicalapplication.Inrandomizedtrialsin
patientswithpainfuldiabeticneuropathy,capsaicinhasbeenassociatedwithmodestbutstatistically
significantimprovementinpaincomparedwithplacebo[3336].
Weaddcapsaicin(0.075percentappliedtopicallyfourtimesdaily)forpatientswithsymptomaticpainful
diabeticpolyneuropathywhoarerefractorytoorintolerantofantidepressants(eg,amitriptyline,duloxetine,
venlafaxine)oranticonvulsants(eg,pregabalin)discussedabove.Localburningandskinirritationcanoccur,
butthisbecomeslessofaproblemwithcontinueduse.Nevertheless,manypatientsareunabletotoleratethe
localburningpain,whichisexacerbatedbycontactwithwarmwaterandhotweather[36].
AnestheticdrugsAsystematicreviewpublishedin2011concludedthattheevidencefortheeffectiveness
ofmexiletineisconflicting[36].Thehighestqualitytrialevaluatedfoundnosignificantbenefitofmexiletine
comparedwithplacebo[37].However,othertrialssuggestedbenefit[38,39].
Anopenlabeltrialfoundthatapplicationofuptofourlidocainepatches(5percent)forupto18hoursperday
significantlyimprovedpainandqualityofliferatingsin56patientswithpainfuldiabeticneuropathy[40].A
randomizedtrialisnecessarytoconfirmtheseresults.
AlphalipoicacidOneofthemechanismsimplicatedinthepathogenesisofdiabeticneuropathyis
increasedoxidativestress.Asaresult,antioxidantshavebeenstudiedfortheirpotentialtodiminishoxidative
stress,improvetheunderlyingpathophysiologyofneuropathy,andreducepain.(See"Pathogenesisand
preventionofdiabeticpolyneuropathy".)
Alphalipoicacid(ALA),apotentantioxidant,hasbeenassociatedwithbenefitforsymptomaticdiabetic
neuropathyinseveralprospective,placebocontrolledstudies[4144].IntheSYDNEY1trial,dailyintravenous
ALAforthreeweekswasassociatedwithreducedpain,paresthesia,andnumbness[42].
IntheSYDNEY2trial,181patientswithdiabetesandsymptomaticdistalsymmetricpolyneuropathywere
randomlyassignedtooneofthreedosesoforallyadministeredALA(600,1200,or1800mgdaily)ortoplacebo
forfiveweeks[44].Thefollowingobservationswerereported:
AllthreedosesoforalALAtreatmentwereassociatedwithastatisticallysignificantreductioninthe
primaryoutcomemeasure,theneuropathytotalsymptomscore(asummationofstabbingpain,burning
pain,paresthesia,andasleepnumbness),comparedwithplacebo[44].ThebenefitofALAdidnotdiffer
bydose.
Aclinicallymeaningfulresponse,definedas50percentreductioninneuropathicsymptoms,was
observedin50to62percentofpatientstreatedwithALAversus26percentwithplacebo,adifference
thatwasstatisticallysignificant.
TheoptimaldoseofALAwas600mgoncedaily,ashigherdoseswerelimitedbyincreasingadverse
events(nausea,vomiting,andvertigo)withoutincreasingefficacy.
Thestrengthofthesefindingsislimitedbytheshortdurationofthistrial[44].Therearenolongtermstudies
thatassesstheaffectofalphalipoicacidonprogressionofneuropathy.
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However,baseduponthesedata,wesuggesttreatmentwithoralALA600mgoncedailyforpatientswith
symptomaticpainfuldiabeticpolyneuropathywhoarerefractorytoorintolerantofantidepressants(eg,
amitriptyline,duloxetine,venlafaxine)oranticonvulsants(eg,pregabalin)thathavebeenestablishedas
beneficialforthiscondition.
OpioidsAnumberofopioidshavebeenstudiedforthetreatmentofpainfuldiabeticneuropathy.
Dextromethorphan,aweaksigmaopioidreceptoragonistandanNmethylDaspartate(NMDA)receptor
antagonist,wasmoderatelybeneficialcomparedwithplacebointwosmalltrialsforreducingpainin
patientswithdiabeticneuropathy[45,46].
Intwosmallrandomized,doubleblindtrialstramadol,atanaveragedoseof210mg/day,wasmore
effectivethanplaceboforrelievingpain[47,48].Themostfrequentadverseeffectswerenausea,
constipation,headache,andsomnolence.
Controlledrelease(CR)oxycodoneatadailydoseof10to60mgappearsbeeffectiveandsafeforthe
treatmentofpainfuldiabeticpolyneuropathy,asshownintworandomizedclinicaltrials[49,50].Inthe
largerofthesetrialsinvolving159patients,oxycodoneCRatanaveragedoseof37mgdaily(range10to
99mgdaily)providedmorepainreliefthanplacebo[50].
ThetrialssupportingtheefficacyofopioidssuchastramadolandoxycodoneCRarealllimitedbyshortterm
followup[4751].A2009systematicreviewofopioidsforchronicnoncancerpainfoundapaucityofevidence
regardingthelongtermeffectivenessandrisksofsuchtreatment,includingthepotentialforopioidabuse,
addiction,andoverdose[51].Similarly,a2013systematicreviewnotedthattheavailablerandomized
controlledtrialsofopioidsforneuropathicpaindidnotclearlyaddresstheissuesofabuseandaddiction[52].In
acohortstudyofover9900patientsprescribedlongtermopioidtherapyfornonmalignantpain,theuseof
higherdoseregimenswasassociatedwithanincreasedriskofopioidoverdose[53].Becauseoftheseissues,
someexpertshavestoppedusingopioidsaltogetherforthetreatmentofpainfuldiabeticneuropathy.We
suggestnotusingopioidsforthetreatmentofpainfuldiabeticneuropathybecauseofthelackofevidence
regardinglongtermeffectiveness,andbecauseofthepotentialfortolerance,addiction,andoverdose.
CombinationtherapyResultsfromsmalltrialssuggestthatthetreatmentofneuropathicpainwith
combinationsofdrugsfromdifferentmedicationclassesismodestlymoreeffectivethanmonotherapy.
Inasinglecenterrandomizedtrialof44patientswithneuropathicpain(amajoritywithdiabetic
polyneuropathy),gabapentincombinedwithmorphinewasmoreeffectivethaneitheragentalonefor
reducingthemeanintensityofpainduringweekfouroftreatmentatthemaximumtolerateddailydose
(mean,gabapentin1705mgandmorphine34mgincombination)[54].Constipation,sedation,anddry
mouthwerethemostfrequentsideeffectsofthecombinationtherapy.
Asimilarsinglecenterrandomizedtrialof47patients(mostwithdiabeticpolyneuropathy)foundthatthe
combinationofnortriptylinewithgabapentinwasmoreeffectivethaneitheragentaloneforreducingthe
meanintensityofdailypainduringweekfouroftreatmentatthemaximumtolerateddailydose(mean,
nortriptyline50mgandgabapentin2180mgincombination)[55].
Inbothreports,thebenefitofcombinationtreatmentwassmallbutstatisticallysignificant.
ElectricalnervestimulationAlthoughdataarelimited,a2010statementfromtheAmericanAcademyof
Neurology(AAN)assessingtheuseofTENSforpaininneurologicdisordersconcludedthatTENSisprobably
effectiveforreducingpainfromdiabeticpolyneuropathy[56],baseduponthefollowingevidence:
Onetrialassigned31patientswithchronicpainfuldiabeticneuropathytoeitherTENSorshamtreatment
tothelegsfor30minutesdailyforfourweeks[57].Symptomaticimprovement(ofatleastonegradeona
uniquezerotofivescale)occurredin15of18patients(83percent)withTENStreatment,comparedwith
fiveof13patients(38percent)whoreceivedshamtreatment(oddsratio6,95%CI1.133.4)[57].
Anothertrialevaluated19patientswithmildtomoderatesymptomaticdiabeticpolyneuropathy[58].
Comparedwithshamtreatment,activetreatmentwithTENSledtoastatisticallysignificantreductionin
totalsymptomscoreatsixandtwelveweeks.Inaddition,TENStherapywasassociatedwitha
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statisticallysignificantbutmodestimprovementinpainonthevisualanalogscaleatsixweeks.
Asubsequent2011guidelinefromtheAANevaluatingthetreatmentofpainfuldiabeticneuropathyconcluded
thatpercutaneouselectricalnervestimulationisprobablyeffective[36],baseduponthreesmalltrials[5961].
However,thepercutaneoustechniquesevaluatedinthe2011AANguidelinearenotwidelyavailableinclinical
practice.
OtherinterventionsSeveralotherapproacheshavebeentriedinpatientswithpainfuldiabeticneuropathy.
AcetylLcarnitineAcetylLcarnitine(ALC),theacetylatedesteroftheaminoacidLcarnitine,hasbeen
evaluatedinpatientswithdiabeticperipheralneuropathy[62].Indatafromtworandomizedcontrolledtrialsof
identicaldesign,anintentiontotreatanalysisof1257patientswithdiabeticpolyneuropathyfoundthatALC
1000mg(butnot500mg)threetimesdailycomparedwithplacebowasassociatedwithsignificant
improvementinpainscoresinoneofthestudiesandinthecombinedcohort[63].ThebenefitofALCrequires
confirmation,particularlysincesignificantimprovementwasnotseeninbothtrialsoratthelowerdoseofALC.
IsosorbideAplacebocontrolledpilotstudyofisosorbidedinitratetopicalsprayin22diabeticpatients
reportedasignificantreductioninoverallneuropathicpainandburningsensationinthetreatmentgroup[64].
NSAIDsNonsteroidalantiinflammatorydrugs(NSAIDs)areeffectiveinpatientswithmusculoskeletalor
jointabnormalitiessecondarytolongstandingneuropathythejointdeformitiesmayactuallybetheprimary
sourceofpain(see"Musculoskeletalcomplicationsindiabetesmellitus").Bothibuprofen(600mgfourtimes
daily)andsulindac(200mgtwicedaily)canleadtosubstantialpainreliefinpatientswithdiabeticneuropathy
[65].
ThereisatheoreticalconcernthatNSAIDsmayimpairnervecirculationandworsennerveinjurydueto
inhibitionofprostacyclinsynthesis.Cautioususeofthisclassofdrugsiswarranteduntilthispossibilityisfully
evaluated.
SpinalcordstimulationSpinalcordstimulationisaninvasivemethodinvolvingimplantableelectrodes
thatdeliverelectricalstimulationtothedorsalcolumnsofthespinalcord.Preliminarydatafromasmallopen
labeltrialsuggestthatspinalcordstimulationreducespainforpatientswithrefractorypainfuldiabetic
neuropathyaffectingthelegs[66].Furthertrialsareneededtoconfirmtheefficacyofthisapproach.
GuidelinesTheAmericanAcademyofNeurology(AAN)performedasystematicreviewandpublished
guidelinesin2011forthetreatmentofpainfuldiabeticneuropathy[36].Thefollowingobservationsweremade:
Pregabalin(300to600mgdaily)wasregardedaseffective[36].
Anumberoftreatmentswereregardedasprobablyeffective[36]:

Gabapentin,900to3600mgdaily
Sodiumvalproate,500to1200mgdaily
Amitriptyline,25to100mgdaily
Duloxetine,60to120mgdaily
Venlafaxine,75to225mgdaily
Dextromethorphan,400mgdaily
Morphinesulphate,titratedto120mgdaily
Oxycodone,mean37mgdaily,maximum120mgdaily
Tramadol,210mgdaily
Capsaicin,0.075percentfourtimesdaily
Isosorbidedinitratespray
Percutaneouselectricalnervestimulationforthreetofourweeks

Lidocainepatchwasregardedaspossiblyeffective[36].
TreatmentsregardedasprobablynoteffectivebytheAANwereoxcarbazepine,lamotrigine,
lacosamide,clonidine,pentoxifylline,mexiletine,magneticfieldtreatment,lowintensitylasertherapy,and
Reikitherapy[36].
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Amanagementalgorithmoutlinedbyastatementpublishedin2005fromtheAmericanDiabetesAssociation
(ADA)recommendedtreatmentinsequentialstepsorderedasfollows[3]:

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

TheADAstatementnotedthatnonpharmacologic,topical,orphysicaltherapiesmightbeusefulatanystage.
Thesemeasuresincludeacupuncture,capsaicin,glyceryltrinitratesprayorpatches,andothertherapies[3,67].
ChoiceoftherapyWesuggestusingoneoftheantidepressants(eg,amitriptyline,duloxetine,venlafaxine)
oranticonvulsants(eg,pregabalin)discussedaboveasinitialtherapyforpatientswithpainfuldiabetic
neuropathy.Theavailableevidencesuggeststhattheseagentshavesimilarmodestbenefit,thoughfewhigh
qualitycomparativetrialshavebeendone[12,68,69].Amongtheseoptions,weprefertostartwith
amitriptyline,particularlyinyoungerhealthierpatients,becauseofitseffectivenessandlowcost.Patientswho
failtoimprovewithareasonabletrialofoneoftheseagentscanbeswitchedtomonotherapywithanother
agent.(See'Antidepressants'aboveand'Anticonvulsants'above.)
Forpatientswhodonotimproveononedrug,wesuggestcombinationtherapyemployingtwodrugsfrom
differentmedicationclassesasthenextstepinthetreatmentparadigm.Forpatientswhoareunabletotolerate
anyofthesedrugs,alternativetreatmentsincludecapsaicincream,lidocainepatch,alphalipoicacid,
isosorbidedinitratetopicalspray,andtranscutaneouselectricalnervestimulation.(See'Capsaicincream'
aboveand'Anestheticdrugs'aboveand'Alphalipoicacid'aboveand'Opioids'aboveand'Combination
therapy'aboveand'Electricalnervestimulation'above.)
Theuseofopioidsforchronicnonmalignantpainiscontroversial.Wesuggestnotusingopioidsforthe
treatmentofpainfuldiabeticneuropathybecauseofthelackofevidenceregardinglongtermeffectiveness,and
becauseofthepotentialforopioidtolerance,addiction,andoverdose.However,otherexpertsbelievethat
opioidshavearoleinthemanagementofpainfuldiabeticneuropathydespitetheseconcerns[36].(See
'Opioids'above.)
Thetreatmentoptionsandsuggesteddosesaresummarizedinthetable(table3).
Theroleofglycemiccontrolinestablisheddiabeticneuropathyisuncertain.However,strictglycemiccontrolis
associatedwithareducedriskofmicrovascularcomplicationsinpatientswithtype2diabetes,andintensive
therapymayreducetheriskofmacrovascularcomplicationsinsuchpatients.Inaddition,tightglycemiccontrol
isassociatedwithareductioninmicrovascularandmacrovascularcomplicationsforpatientswithtype1
diabetes.Theseissuesarediscussedindetailseparately.(See"Glycemiccontrolandvascularcomplications
intype2diabetesmellitus"and"Glycemiccontrolandvascularcomplicationsintype1diabetesmellitus".)
NONGLYCEMICMEASURESMultifactorialriskfactorreductionandaldosereductaseinhibitorsare
potentialstrategiesfortreatingdiabeticneuropathy.
MultifactorialriskfactorreductionThepotentialefficacyofintensivecombinedtherapyinpatientswith
type2diabetesandmicroalbuminuriawasexaminedintheStenotype2trial[70].Inthisprospectivestudy,
160patientswererandomlyassignedtostandardormultifactorialintensivetherapy.Theintensiveregimen
consistedofbehavioraltherapy(includingadviceconcerningdiet,exercise,andsmokingcessation)and
pharmacologicintervention(consistingoftheadministrationofmultipleagentstoattainseveralaggressive
therapeuticgoals)(table4).Diabeticautonomicandperipheralneuropathywerepresentatbaselinein28and
34percent,respectively.
Atameanfollowupof7.8years,therewasasignificantlylowerrateofprogressionofautonomicneuropathyin
theintensivetherapygroup(30versus54percent,relativerisk0.37),butnoslowingofprogressionof
peripheralneuropathy[70].
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Thedetailsoftheprotocolandoverallresultsofthisstudyarediscussedelsewhere.(See"Overviewof
medicalcareinadultswithdiabetesmellitus",sectionon'Multifactorialriskfactorreduction'.)
AldosereductaseinhibitorsInadditiontoloweringbloodglucoseconcentrations,anotherpotential
approachistominimizethetoxicityofhyperglycemia.Tothedegreethatsorbitolaccumulationmayplayarole
indiabeticneuropathy,useofanaldosereductaseinhibitortopreventsorbitolformationmightbebeneficial.
Intheavailablestudiesofthisunapprovedclassofmedications,aldosereductaseinhibitorshaveproduced
inconsistentbenefitsindiabeticneuropathy.Theevidenceispresentedindetailseparately.(See"Aldose
reductaseinhibitorsinthepreventionofdiabeticcomplications",sectionon'Neuropathy'.)
SurgicaldecompressionSurgicaldecompressionofmultipleperipheralnerves(calledtheDellon
procedure)isanalternative,controversialmethodfortreatingdiabeticpolyneuropathy[71].Thepurported
rationaleforsurgicaldecompressionisbasedonthenotionthatthemetabolicstressofdiabetesrenders
peripheralnervessusceptibletocompressiveinjuryatsitesofpotentialnerveentrapment[7274],andthat
compressiveinjuryofmultipleperipheralnervesiswhatleadstosymptomsinmostpatients[75].
However,therearenoadequatelydesignedtrialstosupporttheuseofsurgicaldecompressionofmultiple
peripheralnervesasatreatmentforsymptomaticdiabeticpolyneuropathy[72].Therefore,thistreatmentisnot
recommended.
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"
and"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6th
gradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagiven
condition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoread
materials.BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.
Thesearticlesarewrittenatthe10thto12thgradereadinglevelandarebestforpatientswhowantindepth
informationandarecomfortablewithsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
"patientinfo"andthekeyword(s)ofinterest.)
Basicstopics(see"Patientinformation:Nervedamagecausedbydiabetes(TheBasics)"and"Patient
information:Neuropathicpain(TheBasics)")
BeyondtheBasicstopics(see"Patientinformation:Diabeticneuropathy(BeyondtheBasics)")
SUMMARYANDRECOMMENDATIONS
Optimalglucosecontrolisconsideredthecornerstoneforthetreatmentofdiabetesanditscomplications.
Intensiveglucosecontrolhasbeenshowntopreventthedevelopmentofperipheralneuropathy.However,
whethernearnormalglycemiccontrolcanameliorateestablishedsymptomaticdiabeticneuropathy,and
painfulneuropathyinparticular,isnotasclear.(See'Glycemiccontrolforestablishedneuropathy'above.)
Forpatientswithdiabeticneuropathy,footcareisimportanttopreventulceration,infection,and
amputation.(See'Footcare'aboveand"Managementofdiabeticfootlesions".)
Onlyasmallfractionofpatientswithdiabeticpolyneuropathyhavepainfulsymptoms.Inaddition,the
painassociatedwithdiabeticpolyneuropathyisoftenselflimitedevidencefromasmallprospective
studysuggeststhatresolutionoccursover12monthsinapproximatelyonehalfofpatients.(See'Painful
diabeticneuropathy'aboveand'Spontaneousresolution'above.)
Forpatientswithpainfuldiabeticneuropathy,wesuggestinitialtherapyusingeitheramitriptylineor
venlafaxine(Grade2B),orduloxetineorpregabalin(Grade2A).Amongtheseoptions,weprefertostart
withamitriptyline,particularlyinyoungerhealthierpatients,becauseofitseffectivenessandlowcost.For
patientswhodonotimproveononedrug,wesuggestcombinationtherapyemployingtwodrugsfrom
differentmedicationclasses(Grade2C).Forpatientswhoareunabletotolerateanyofthesedrugs,
alternativetreatmentsincludecapsaicincream,lidocainepatch,alphalipoicacid,isosorbidedinitrate
topicalspray,andtranscutaneouselectricalnervestimulation.(See'Paincontrol'aboveand'Choiceof
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therapy'above.)
Theuseofopioidsforchronicnonmalignantpainiscontroversial.Wesuggestnotusingopioidsforthe
treatmentofpainfuldiabeticneuropathy(Grade2C).(See'Opioids'above.)
Nonglycemicinterventions(eg,multifactorialriskfactorreductionandaldosereductaseinhibitors)are
underinvestigationfortreatingorpreventingdiabeticneuropathy.(See'Nonglycemicmeasures'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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72. TherapeuticsandTechnologyAssessmentSubcommitteeoftheAmericanAcademyofNeurology,
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GRAPHICS
Benefitofglycemiccontrolinestablisheddiabetic
neuropathy
Image

Histogramofperonealmotornerveconductionvelocitiesafterfive
yearsofconventional(bluebars)orintensive(redbars)insulin
treatmentforpatientswithpossibleordefiniteneuropathyinthe
primaryprevention(upperpanel)orsecondaryintervention(lower
panel)cohorts.Nerveconductionvelocitywassignificantlyhigherin
bothintensivetherapygroups.
Datafrom:Effectofintensivediabetestreatmentonnerveconductioninthe
DiabetesControlandComplicationsTrial.AnnNeurol199538:869.
Graphic70945Version4.0

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Clinicalfeaturesofdiabeticneuropathy
Favors
neuropathy

Characteristic

Favorsvascular
disease

Siteofpain

Feetmorethancalves

Calves,thighs,andbuttocks
morethanfeet

Qualityofpain

Sharp,superficial,
burning,tingling

Deepache

Presentatrest

Common

Rare

Effectofwalking

Painimproves

Painmadeworse

Painworseinbed

Yes

No

Precededbyrecentchangein
glycemiccontrol

Sometimes

No

Clinicalfeaturestohelpdistinguishthepainindiabeticneuropathyfromthatwith
peripheralvasculardiseaseandintermittentclaudication.
Graphic72373Version1.0

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Tricyclicdrugsimprovepainindiabeticneuropathy

Meanchangesinpainscore(anegativevalueindicatesimprovement)
inpatientswithpainfuldiabeticneuropathywhoweretreatedwith
placebo(n=15),fluoxetine(n=12),desipramine(n=18),or
amitriptyline(n=12).Drugtherapywasbegunatweekoneafterone
weekofobservation.Desipramineandamitriptylinewereequally
beneficialandmoreeffectivethanfluoxetineorplacebo.
DatafromMaxMB,LynchSA,MuirJ,etal,NEnglJMed1992326:1250.
Graphic55889Version2.0

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Sideeffectsofdrugsusedfordiabeticneuropathy
Sideeffect

Amitriptyline

Desipramine

Fluoxetine

Placebo

Drymouth

63

32

11

35

Fatigue

34

34

13

17

Headache

21

11

24

Constipation

21

Palpitations

13

Anysymptoms

81

76

63

68

Percentageofpatientsreportingsideeffectsduringtreatmentwithamitripyline,
desipramine,fluoxetine,orplacebo.
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Treatmentoptionsforpainfuldiabeticneuropathy
Antidepressants
Tricyclics
Amitriptyline25to100mgatnight
Nortriptyline25to100mgatnight
Doxepin25to100mgatnight
Others
Duloxetine60to120mgdaily
Venlafaxine75to225mgdaily

Anticonvulsants
Pregabalin300to600mgdaily
Sodiumvalproate500to1200mgdaily

Others
Capsaicintopicalcream0.075percent
Lidocainepatch
Alphalipoicacid600mgoncedaily
Isosorbidedinitratespray
Transcutaneouselectricalnervestimulation(TENS)
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TreatmentgoalsintheStenotype2diabetesstudy

Standard

Intensive

Systolicbloodpressure(mmHg)

<160

<140

Diastolicbloodpressure(mmHg)

<95

<85

HbA1c(percent)

<7.5

<6.5

Serumtriglycerides(mg/dL)

<194

<150

Serumtotalcholesterol(mg/dL)

<250

<193

SerumHDLcholesterol(mg/dL)

>35

>42

ACEinhibitortherapyindependentofbloodpressure

No

Yes

Aspirintherapyinpatientswithknownischemia

Yes

Yes

Aspirintherapyinpatientswithperipheralvasculardisease

No

Yes

Toconvertserumtriglyceridevaluestommol/Lmultiplyby0.011,andtoconvertserum
cholesterolvaluestommol/Lmultiplyby0.026.
GaedeP,VedelP,ParvingHH,PedersenO.Intensifiedmultifactorialinterventioninpatientswithtype
2diabetesmellitusandmicroalbuminuria:theStenotype2randomisedstudy.Lancet1999
353:617.
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Disclosures
Disclosures:EvaLFeldman,MD,PhDNothingtodisclose.DavidKMcCulloch,MDNothingto
disclose.JeremyMShefner,MD,PhDGrant/ResearchSupport:Cytokinetics,Inc.[ALS]Glaxo
SmithKline.Consultant/AdvisoryBoard:BiogenIdec[ALS]Cytokinetics,Inc.[ALS]Kinemed[ALS]
VoyagerTherapeutics[ALS]ISISPharmaceuticals[SMA].DavidMNathan,MDNothingtodisclose.
JohnFDashe,MD,PhDNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,these
areaddressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsfor
referencestobeprovidedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofall
authorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

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