Botulinum Toxin for the Treatment of Neuropathic Pain

15 Pages·2017·0.62 MB·English

toxins
Review
Botulinum Toxin for the Treatment of
Neuropathic Pain
JungHyunPark1andHueJungPark2,*
1 DepartmentofAnaesthesiology&PainMedicine,IncheonSt.Mary’sHospital,CollegeofMedicine,
TheCatholicUniversityofKorea,Incheon21431,Korea;[email protected]
2 DepartmentofAnaesthesiology&PainMedicine,SeoulSt.Mary’sHospital,CollegeofMedicine,
TheCatholicUniversityofKorea,Seoul06591,Korea
* Correspondence:[email protected].;Tel.:[phone]or+82-2258-6157
AcademicEditor:StevePeigneur
Received:10August2017;Accepted:21August2017;Published:24August2017
Abstract: Botulinum toxin (BoNT) has been used as a treatment for excessive muscle stiffness,
spasticity, and dystonia. BoNT for approximately 40 years, and has recently been used to treat
various types of neuropathic pain. The mechanism by which BoNT acts on neuropathic pain
involvesinhibitingthereleaseofinflammatorymediatorsandperipheralneurotransmittersfrom
sensory nerves. Recent journals have demonstrated that BoNT is effective for neuropathic pain,
suchaspostherpeticneuralgia,trigeminalneuralgia,andperipheralneuralgia. Thepurposeofthis
reviewistosummarizetheexperimentalandclinicalevidenceofthemechanismbywhichBoNT
acts on various types of neuropathic pain and describe why BoNT can be applied as treatment.
ThePubMeddatabasewassearchedfrom1988toMay2017. Recentstudieshavedemonstratedthat
BoNTinjectionsareeffectivetreatmentsforpost-herpeticneuralgia,diabeticneuropathy,trigeminal
neuralgia,andintractableneuropathicpain,suchaspoststrokepainandspinalcordinjury.
Keywords: botulinumtoxin;neuropathicpain;neuropathicpaintreatment
1. Introduction
Botulinumtoxin(BoNT)hasbeenusedfordecadesinthetreatmentofdiseases,suchasdystonia
orseizures,andcosmetictreatments. BoNTisusefulinconditionssuchasstrabismusbecauseitcauses
longlastingbutreversibleparalysisviatheadministrationofsmallamountslocally[1,2]. AsBoNT
purificationtechnologydevelops,therangeofuseofthisdrughasbeenexpanded,andthenumber
of Food and Drug Administration (FDA)-approval diseases has also increased. Common to these
applicationsisthefactthatBoNTisabsorbedfromtheneuromuscularjunctionorparasympatheticaxon
terminaltothemotorneuronterminalbecausethetoxinisresponsibleforthereleaseofacetylcholine.
Itisimportanttonotethattheseeffectsarenotsystematicallyredistributedbutonlylocalized.Numerous
reportssuggestthatlocaladministrationofBoNThasasignificanteffectonneuropathicpain.
Foralongtime,theanalgesiceffectofBotulinumtoxinA(BoNT-A)wasconsideredtobedue
to the effect of muscle relaxation [3–5]. However, recent studies using BoNT in neuropathic pain
modelshavedemonstratedthatBoNThasananalgesiceffectindependentofmusclerelaxationby
demonstratingdissociationofthedurationofmusclerelaxationanddurationofpainrelief[6].
Inthispaper,weinvestigatethemechanismofBoNTinneuropathicpainbyexaminingtheeffects
ofthe drugforintractable neuropathicpains, such aspostherpeticneuralgia, diabeticneuropathy,
complexregionalpainsyndrome,trigeminalneuralgia,phantomlimbpain,spinalcordinjury-induced
neuropathicpain,andcentralpoststrokepain.
Toxins2017,9,260;doi:10.3390/toxins9090260 www.mdpi.com/journal/toxins
Toxins2017,9,260 2of15
2. StructureofBotulinumToxin
BoNTisproteingroupproducedbyanaerobicbacteriacalledClostridiumbotulinum,whichhas
approximately40subtypes. However,sevenserotypesaretypicallynotedbasedonantigenspecificity.
BotulinumtoxinA(BoNT-A)andB(BoNT-B)arethemostcommonlyuseddrugs.Particularly,BoNT-A
typehasamolecularweightofapproximately900,000. BoNT-Aisadoublechainprotein. Thelight
chain(LC)isactive,whereastheheavychain(HC)isnotactive. BoNTbindstotheacceptoratthe
nerveendandentersthenerveendingbyreceptor-mediatedendocytosis. LCbindstotheexogenous
proteininvolvedinexocytosisandbreaksdownthepeptidebondoftheproteintransportertoblock
exocytosisandacetylcholinesecretion. TheC-terminalreceptor-bindingdomain,whichconstitutes
theheavychainofBoNT,bindstogangliosidereceptorsandspecificproteinsonthecellmembrane.
ThisbindinginducesendocytosisofHC-LC.Ingeneral,acetylcholinebindingtotheacetylcholine
receptorofthemotorendplateisnecessaryformusclecontraction. Atthistime, theacetylcholine
exocytosisprocessisnecessaryinpresynapticmembrane. Thenormalacetylcholineexocytosisprocess
requiresthreeproteins: thesynaptosomalassociatedprotein-25kDa(SNAP-25),syntaxin,andthe
vesicle-associatedmembraneprotein(VAMP)/synaptobrevininthepresynapticmembrane. These
proteinsarecalledsolubleN-ethylmaleimide(SNARE)proteins. Asazinc-dependentendoprotease,
theLCofBoNTcleavesintracellularSNARE.ThiscleavageinterfereswithSNARE-mediatedprotein
transportandtransmitterrelease, blockingmuscleinnervationattheneuromuscularjunctionand
resultinginflaccidparalysis[7,8]. ThiseffectofBoNTLCisdependentontheserotype,butitpersists
fromdaystomonths[9,10].
BoNT-AandBoNT-Bareeffectiveinneuropathicpain. Micecanbetreatedwithnerveligationto
inducemononeuropathyandcisplatintoinducepolyneuropathy. BoNT-Bimprovesallodyniaand
hyperalgesia [11]. A clinically reported case report demonstrates that BoNT-B improves pain and
symptomsincomplexregionalpainsyndrome(CRPS)patientswithalumbarsympatheticblock[12].
3. MechanismofActionofBotulinumToxinforNeuropathicPain(ExperimentalStudy)
BoNT also reduces and alters neuropathic pain in several animal models via the following
mechanisms. BoNTinhibitsthesecretionofpainmediators(substanceP,glutamate,andcalcitonin
generelatedprotein(CGRP))fromthenerveendingsanddorsalrootganglions(DRG),reduceslocal
inflammationaroundthenerveendings,deactivatesthesodiumchannel,andexhibitsaxonaltransport.
WewillreviewthevariousmechanismsbywhichBoNTreducesneuropathicpain(Figure1).
3.1. BoNTInhibitstheReleaseofPainMediatorsfromthePeripheralNerveTerminal,DRG,andSpinal
CordNeuron
TheeffectofBoNTonthesecretionofsensoryneurotransmittershasbeendocumentedinseveral
animal models. BoNT reduces normal CGRP release and capsaicin-induced DOA secretion and
has additional effects on the TRPV1 pathway [13]. According to Meng et al., in a rat trigeminal
ganglionsensorypeptidergicneuroncellculturemodel,BoNTcleavesneuronalSNAREandblocks
neurotransmittersecretion[14]. Durhametal. alsoreportedaprophylacticadvantageinmigraine
headaches via blocking the release of neuropeptides, such as CGRP from the trigeminal ganglion
neuronalculture[15].
Fanetal. demonstratedthatBoNTsignificantlyreducesTRPV1proteinlevels. Severalstudies
demonstratedthatTRPV1playsacrucialroleinarthritispain,andthisarticleexaminedthecausal
relationship between the antinociceptive effect of BoNT and the expression of TRPV1 in DRG of
ratswitharthriticpain. NosignificantchangesinTRPV1mRNAlevelswereobservedviaRT-PCR
performedwithdifferentBoNTdoses(1,3,and10U);However,BoNTorTRPV1proteinlevelswere
significantlydecreased. ThispaperdemonstratestheantinociceptivemechanismofBoNTbyreducing
TRPV1expressionbyinhibitingplasmamembranetraffickingafterintra-articularadministration[16].
ToTxoixnisns2 021071,79, ,92, 62060 33o off1 154

Figure 1. (A) Noxious stimuli cause inflammation through the release of neuropeptides and
Figure 1. (A) Noxious stimuli cause inflammation through the release of neuropeptides and
inflammatorymediators,whichcancauseperipheralsensitization. ThisactionalsooccursinDRG,
inflammatory mediators, which can cause peripheral sensitization. This action also occurs in DRG,
dorsal horn of spinal cord and can lead to central sensitization. Botulinum toxin (BoNT) inhibits
dorsal horn of spinal cord and can lead to central sensitization. Botulinum toxin (BoNT) inhibits the
thereleaseofpainmediatorsinperipheralnerveterminal, DRG,andspinalcordneuron, thereby
release of pain mediators in peripheral nerve terminal, DRG, and spinal cord neuron, thereby
reducing the inflammatory response and preventing the development of peripheral and central
reducing the inflammatory response and preventing the development of peripheral and central
sensitization. Symbols; SP, substance P; CGRP, calcitonin gene related protein; DRG, dorsal root
sensitization. Symbols; SP, substance P; CGRP, calcitonin gene related protein; DRG, dorsal root
ganglion;(B)ThehyperexcitabilityandspontaneousactionpotentialmediatedbytheNachannelin
ganglion; (B) The hyperexcitability and spontaneous action potential mediated by the Na channel in
peripheralsensoryneuroncontributetothepathophysiologyofneuropathicpain.BoNTcancontrol
npeeurriopphaethraicl speaninsobryy bnleouckroinng ctohnetNriabuchtea nton ethl;e( Cp)aSthoompehoyfstiholeoBgoyN oTf napeupreoapratothriect rpoagirna.d BeotNraTns cpaonr tcaolnotnrgol
neuropathic pain by blocking the Na channel; (C) Some of the BoNT appear to retrograde transport
theaxons.SNAP-25iscleavedinthedorsalhornofthespinalcordandcentralnucleiafterasmallamount
oaflBoonNg Tthies aadxmonins.i sStNerAedPt-o25t hies pcleeraipvheder yin,t htheere dboyrbsaolo shtoinrng tohfe trheet rsopgirnaadle ctorradn sapnodrt coefnBtroaNl Tn.uclei after a
small amount of BoNT is administered to the periphery, thereby boosting the retrograde transport of
3.2. BoBNoNTTR. educesInflammation
3.2. BCoyNclTo pRhedouspcehsa Imnfildamem(CaYtiPon) wasinjectedintothebladderofratstoinduceCYP-inducedcystitis,
and HCL was injected into the bladder to induce acute injury. The bladder was harvested and
Cyclophosphamide (CYP) was injected into the bladder of rats to induce CYP-induced cystitis,
comparedwiththeShamgroup. ThecellswereculturedinasolutioncontainingBoNTtocompare
and HCL was injected into the bladder to induce acute injury. The bladder was harvested and
neurotransmitters. CGRP and substance P were significantly increased in the acute injury group
compared with the Sham group. The cells were cultured in a solution containing BoNT to compare
compared with the control group, and substance P was significantly increased in the CYP-induced
neurotransmitters. CGRP and substance P were significantly increased in the acute injury group
cystitisgroup.AfterexposuretoBoNT,neurotransmitterlevelsweresignificantlyreduced.Inthisarticle,
compared with the control group, and substance P was significantly increased in the CYP-induced
we found that BoNT has an anti-inflammatory effect on chronic inflammation and acute injury [17].
cystitis group. After exposure to BoNT, neurotransmitter levels were significantly reduced. In this
Inachronicarthritisdogmodel,intraarticularBoNTinjectionsareeffectiveforupto12weeks[18,19].
article, we found that BoNT has an anti-inflammatory effect on chronic inflammation and acute
The anti-inflammatory effect of BoNT reduces the release of peripheral neurotransmitters and
injury [17]. In a chronic arthritis dog model, intraarticular BoNT injections are effective for up to 12
inflammatorymediators.
weeks [18,19]. The anti-inflammatory effect of BoNT reduces the release of peripheral
However, the effects are debated. Rojecky et al. injected carrageenan and capsaicin into the
neurotransmitters and inflammatory mediators.
hindpaw of the rat, and rats were treated with BoNT five days before injection. No significant
However, the effects are debated. Rojecky et al. injected carrageenan and capsaicin into the
differencesinedemaandplasmaproteinextravasationwerenotedbetweenthegroupinjectedwith
hindpaw of the rat, and rats were treated with BoNT five days before injection. No significant
BoNT and the group without BoNT [20]. In addition, Sycha et al. reported that the BoNT group
differences in edema and plasma protein extravasation were noted between the group injected with
and the control group had no direct effect on acute, noninflammatory pain in the group treated
BoNT and the group without BoNT [20]. In addition, Sycha et al. reported that the BoNT group and
with BoNT upon skin exposure to Ultraviolet B [21]. Chuang et al. measured cyclooxygenase-2
the control group had no direct effect on acute, noninflammatory pain in the group treated with
(COX-2)levelsinthecapsaicin-inducedprostatitismodel. COX-2isakeyenzymethatisanimportant
BoNT upon skin exposure to Ultraviolet B [21]. Chuang et al. measured cyclooxygenase-2 (COX-2)
mediatorofinflammationandpain. COX-2expressionwasinducedasassessedbyWesternblotting
levels in the capsaicin-induced prostatitis model. COX-2 is a key enzyme that is an important
mediator of inflammation and pain. COX-2 expression was induced as assessed by Western blotting
Toxins2017,9,260 4of15
orimmunostaining. Inflammationwasinduceduponinjectionofcapsaicinintotheprostateofan
adultmalerat. Anothergroupwaspretreatedwith20UBoNToneweekbeforeinjectionofcapsaicin.
TheexpressionofCOX-2wasreducedinspinalsensoryandmotorneuronsandtheprostateinthe
pretreatmentgroup[22].
BoNT also decreases local inflammation around the nerve terminal. According to the report
of Cui et al., BoNT was administered to the footpads in formalin-inflammatory pain model rats.
Theantinociceptiveeffectstarted5hafterBoNTtreatmentandpersistedforgreaterthan12days.
Inaddition,edemawasreduced,butnolocalizedmuscleweaknesswasobserved. Formalin-induced
glutamatereleasewasalsosignificantlyreduced. Thisfindingdemonstratesthatlocalinflammation
aroundthenerveendingsisreducedintheabsenceofobviousmuscleweakness[23].
3.3. BoNTDeactivatesSodiumChannels
BoNTalsodeactivatesthesodiumchannel. Nacurrentstimulatesnumerouscellularfunctions,
such as transmission, secretion, contraction, and sensation. BoNT-A changes the Na current of
a neuronal excitable membrane, which is different from that of local anesthetics, tetrodotoxin,
and antiepileptic drugs that completely control the Na current via a concentration-dependent
manner[24].
3.4. BoNTExhibitsAxonalTransport
BoNTexhibitsaxonaltransportfunctionfromtheperipherytotheCNS,andadministeringBoNT
tothefacialandtrigeminalnervecausesSNAP-25cleavageinthecentralnuclei. Inaddition,asmall
amountofBoNTwasinjectedintothehindlimb,confirmingthecleavageoftheSNAP-25intheventral
hornandthedorsalhornoftheipsilateralspinalcord,therebydemonstratingtheretrogradeaxonal
transportfunctionofBoNT[25]. Inaddition,theBoNTeffectonbothsideshasbeenreportedafter
injectingBoNTononeside[26–28]. Inanimalstudies,theanti-nociceptiveeffectofBoNTwasstudied
inpaclitaxel-inducedperipheralneuropathy. Thewithdrawalnociceptivereflexwasreducedafter
paclitaxelinjectionintothehindpawoftherat.BoNTwasinjectedintooneside,buttheanalgesiceffect
wasobservedonbothsides. Diffusionintobloodcirculationmayaffectthecentralnervoussystem,
butthedosewastoolowtocausesystemicsideeffects. BoNTisalsotoolargetopasstheBBB,sothe
theorythatBoNTistransmittedfromtheperipherytothecentralnervoussystemthroughtheaxonis
possible[28].Topreventretrogradeaxonaltransport,Rojeckyetal.confirmedtheantinociceptiveeffect
ofunilateraltransportoftheaxonictransportblockercolchicineintheipsilateralsciaticnerve[26],
whichalsodemonstratedtheretrogradeaxonaltransportofBoNT.
However,thisnotioniscontroversial. Tangetal. injected125I-radiolabeledfreeBoNTintothe
gastrocnemiusmuscleofratsandrabbiteyelidsandobservedBoNTinvarioustissuesatdifferenttime
points. Inbothrabbitsandrats,systemiceffectswereabsent,andmostofthetoxinsremainedinthe
injectionsite. TheauthorsconcludedthatmostoftheBoNTremainedneartheinjectionsiteanddid
notcausesystemictoxicity[29].
WhetherBoNTistransportedretrogradefromtheinjectionsiteremainscontroversial. However,
retrogradeaxonaltransporthasbeendemonstratedinnumerouspapers. Marinellietal. analyzed
the expression of cl-SNAP-25 from the nerve endings of the hind paw to the spinal cord after
applyingBoNTtotheperiphery. Immunostainedcl-SNAP-25wasdetectedinalltissues. Additional
experimentswereperformedtoassesswhetherthegrowthstateofSchwanncellsinteractswithBoNTs.
Asaresult,BoNTregulatedtheproliferationofSchwanncellstoinhibitacetylcholinerelease. This
resultdemonstratesretrogradetraffickingofBoNT[30].
Toxins2017,9,260 5of15
4. ClinicalStudyofBotulinumToxinforNeuropathicPain
4.1. TrigeminalNeuralgia
AreviewoftheefficacyofBotulinumtoxin(BoNT)ontrigeminalneuralgia(TN)hasbeenreported
inapproximately11cases,includingthreeRCTpapers. Thisreviewincludesthelargestnumberof
clinicaltrialsforneuropathicpainforBoNT.Inarandomized,double-blind,placebo-controlledstudy
of42patients,Wuetal.performedaparalleldesignwithintradermalorsubmucosalinjectionof75Uof
BoNT-Ain22patients. Twentypatientsinthecontrolgroupreceived1.5mLsaline. IntheBoNTgroup,
68.8%ofpatientshadavisualanalogscale(VAS)reductionofgreaterthan50%. Inthecontrolgroup,
aVASreductionofgreaterthan50%wasnotedin15%ofthepatients[31]. Inaddition,arandomized,
double-blind,placebo-controlledstudywasperformedin84adultswithTNbyZhangetal.28control
subjectsweretreatedwithsaline,27with25UBoNT-A,and29with75UBoNT-A.Theresponserates
inthe25Uand75Ugroupswere70.4%and86.2%,respectively,whichweresignificantlydifferent
from the control group (32.1%). However, no significant differences were noted between the two
groups[32]. AccordingtoZunigaetal.,20patientsreceived50UofBoNT-A,and16controlsreceived
thesamedoseofsaline. VASwas4.9vs. 6.63attwomonthsfollow-up. Nosignificantdifferenceswere
notedbetweenthetwogroups. Atthreemonths,therewasasignificantdifferenceat4.75vs. 6.94[33].
Prospective,open,andcaseseriesfortrigeminalneuralgiaarereportedinthreestudies.According
toBohlulietal.,15TNpatientswereadministered50–100UofBoNT-Ainthetriggerzonewithout
anyspecialinjectionmode. AllpatientsreportedareductioninpainfrequencyandVASscore[34].
Zunigaetal. reported12trigeminalneuralgiapatientswhounderwentsubcutaneousinjectioninthe
triggerzone,andareductioninVASlastinggreaterthantwomonthswasnotedin10patients[35].
Turketal. alsoreportedthatinjectionof50UBoNT-Aat1.5–2cmdeptharoundthezygomaticarch
wasperformedineightpatients,andtheincidenceofpainandVASwerereducedinallpatients[36].
TheabovepapersaresummarizedinTable1.
Table1.Botulinumtoxinfortrigeminalneuralgia.
Numberof MethodofInjection(Total
StudyDesign Result Reference
Patients Volume)
Randomized 50%VASreduction68.8%
Intradermal,submucosal
double-blind, 42 (Botulinumtoxin(BoNT)group) [31]
(75U/saline1.5mL)
placebo-controlled 15%(Control)
Randomized, 84(27BoNT25U, Visualanalogscale(VAS)
Intradermal,submucosal
double-blind, 29BoNT75U, reduction70.4%(25U)vs. [32]
(25U/75U/saline1mL)
placebo-controlled 28control) 86.2%(75U)vs.32.1%(Control)
Randomized, VAS(BoNTvs.Control)4.9vs.
36(20BoNT, Intramuscular
double-blind, 6.63(2months)4.75vs. [33]
16control) (50U/saline1mL)
placebo-controlled 6.94(3months)
Prospective,open, Injectedatthetriggerzones Allpatientsimprovedfrequency
15 [34]
caseseries (50–100U) andseverityofpainattacks
Prospective,open, VASreducedlastingmorethan
12 Subcutaneous(20–50U) [35]
caseseries 2monthsin10patients.
Aroundzygomaticarch,
Prospective,open, IncidenceofpainandVASwere
8 1.5–2cmdepth [36]
caseseries reducedinallpatients.
(50Uperpoint,total100U)
4.2. PostherpeticNeuralgia
TwoBoNTRCTsforpostherpeticneuralgia(PHN)havebeenreported. Xiaoetal. performeda
randomized,double-blind,placebo-controlledstudyof60patientswithPHN.Thefollowingstudy
groupswereincluded: theBoNTgroup,0.5%lidocainegroup,and0.9%salinegroup. Thesepatients
weretreated5U/mLBoNT-A,0.5%lidocaineand0.9%salineintheaffecteddermatome,respectively.
Follow-up was performed at one day, seven days, and three months after drug administration.
TheBoNTgroupexhibitedsignificantlyimprovedVASandsleepqualitycomparedwiththeother
Toxins2017,9,260 6of15
twogroups[37]. Inaddition,Apallaetal. performedarandomized,double-blind,placebo-controlled
studyon30adultswithPHN,andtheaffectedsitesweredividedintoachessboardof5UBoNT-A
perinjection. Thirteenofthe15patientshadaVASreductionofatleast50%lastingapproximately
16 weeks and a significantly reduced the sleep score [38]. Previously, there were reports on the
antinocicepticeffectofBoNT.Liuetal. reportedthattheVASdecreasedfrom10to1afterBoNT-A
injectionintothelesion,andtheeffectpersistedfor52days[39]. Sotiriouetal. reportedassesseda
caseseriesofthreepatients. Theaffectedsitewasdividedintoachessboardformusingatotalof100U
BoNT-Awith5Uinjectedateachpoint. TheVASstartedtodecreaseinthreedaysandcontinuedto
decreaseforgreaterthantwomonths[40]. ThesepapersaresummarizedinTable2.
Table2.Botulinumtoxinforpostherpeticneuralgia.
Numberof MethodofInjection
StudyDesign Result Reference
Patients (TotalVolume)
SubcutaneousBoNT5U, SignificantlyVASpain
Randomized,double-blind,
60 0.5%lidocaine, scorewasdecreasedand [37]
placebo-controlled
0.9%salinepersite sleeptimeimproved
Randomized,double-blind, Dividedintochessboard 50%VASreductionof
30 [38]
placebo-controlled 5Upersite 13patients
VASdecreasefrom10to1
Casereport 1 Fanpatterninjection100U [39]
Lastedfor52days
Dividedintochessboard VASdecreaseand
Caseseries 3 [40]
5Upersite(100U) continuedto2months
4.3. Post-SurgicalNeuralgia
FourreportsontheefficacyofBoNTonpost-surgicalneuralgia,includingRCTarticles,havebeen
published. RCTarticlesincludepost-herpeticneuralgiaandpost-traumaticneuralgia. Accordingto
Ranouxetal.,29patientswithfocalpainfulneuropathyandmechanicalallodyniawereincludedina
randomized,double-blind,placebo-controlledstudy. Upto20–190UBoNT-Awasinjectedintothe
painsiteintradermally. TheinjectionsreducedVAS,burningsensation,andallodynicbrushsensitivity
andimprovedQOL[41]. Layeequeetal. alsoobservedpostoperativepain. In48breastcancerpatients
subjecttomastectomy,22patientsweretreatedwithBoNT-Ainthepectoralismajor,serratusanterior,
and rectus abdominis muscle, and 26 control group patients were not treated. The group treated
withBoNTreportedimprovedpost-operativepain,andpost-operativeanalgesicusewassignificantly
reduced. Inaddition,thetissueexpanderwasremovedfromonepatientintheBoNTgroupandfive
patientsinthecontrolgroup. TheBoNTgroupdidnotcomplainofanyparticularcomplications[42].
AcasereportdescribedsatisfactoryresultsfromsubcutaneousinjectionofBoNT-Aina67-year-old
patientwithpost-thoracotomypainformorethantwoyearspostoperatively.Thepainsitewasdivided
into1-squarecentimeter. Then,2.5UofBoNT-Awasinjectedintothemiddle,and100UBoNT-Awas
administeredintotal. Thepatientreportedimprovedpainafterfivedays,andpainreliefpersistedfor
upto12weeks[43]. AccordingtoRostamietal.,eightcancerpatientswithpersistentfocalpainwere
treatedwithsurgeryorradiotherapy. BoNT-Awasinjectedintramuscularlyorsubcutaneouslyintothe
localizedpainarea. AllpatientsreportedsignificantVASimprovement,andasignificantimprovement
inQOLwasalsonoted[44]. TheabovestudiesaredescribedinTable3.
Toxins2017,9,260 7of15
Table3.Botulinumtoxinforpost-surgicalneuralgia.
MethodofInjection(Total
StudyDesign NumberofPatients Result Reference
Volume)
Randomized, 29(4Postherpeticneuralgia, DecreaseVAS,neuropathic
double-blind, 25Post-traumatic, Intradermal(20–190U) naturepainandimprovein [41]
placebo-controlled post-surgicalneuropathy) qualityoflife
Prospective,
Post-operativepainand
non-randomized, 48(22BoNT,26control) Intramuscular(100U) [42]
analgesicusewasreduced
placebo-controlled
SubcutaneousAffectedzone Improvementinpainwas
wasdrawnwithdivisionsof about50%asmeasuredon
Casereport 1 [43]
approximately1cm2, theVASandpersistedat
2.5Upersite(100U) 12weeks
Intramuscular,subcutaneous AllpatientshadVAS
Pilot,prospective 8 [44]
(100U) improvement
4.4. DiabeticNeuropathy
Tworandomized,double-blind,placebo-controlledstudiesusedBoNTforpaincontrolofdiabetic
neuropathy (DN). In a study of 20 DN patients, Yuan et al. reported that 4 U of BoNT-A per site
(total50U)wasadministeredtothedorsumoffoot,and44%ofpatientshadaclearreductioninVAS
lastingthreemonthsandimprovedsleepquality[45]. Ghasemietal. conductedastudysimilarto
the previous paper, except that the BoNT dose was 8–10 U per site in 40 DN patients. A decrease
inneuropathicpainscore(NPS)andDouleurNeuropathique4(DN4)scoreswerereportedinthat
study [46]. A meta-analysis of these two articles concluded that DN has a significant association
betweenBoNTandpainrelief[47]. TheabovepapersaredescribedinTable4.
Table4.Botulinumtoxinfordiabeticneuropathy.
No.of MethodofInjection
StudyDesign Result Reference
Patients (TotalVolume)
Randomized,
44.4%oftheBoNTgroup
double-blind, Intradermal4Upersiteatdorsum
20 experiencedareductionof [45]
placebo-controlled, offoot(50Upereachfoot)
VASwithin3months.
cross-overtrial
Randomized, Intradermal,dorsumofthefoot, Decreaseinneuropathic
double-blind, 40 inagriddistributionpattern,total painscoreandDouleur [46]
placebo-controlled 12sites8–10Upersite Neuropathique4
4.5. OccipitalNeuralgia
Kapuraletal. retrospectivelyanalyzedsixpatientsinjectedwith50UBoNT-Aintheoccipital
nerveandfoundthattheVASwassignificantlyreduced. Fivepatientsexhibitedpainrelieflasting
greaterthanfourweeks[48]. Tayloretal. reportedthat100UofBoNT-Awasadministeredtothe
occipitalprotuberanceintheprospective,open,andcaseseries. Improvementinsharp/shootingpain
wasnoted,butnodefiniteimprovementindull/achingpainwasindicated[49]. Occipitalneuralgia
hasbeenassessedinonlytwocaseserieswithoutanRCTarticle,sothesestudiesareinsufficientto
provetheeffectivenessofBoNT.TheabovepapersarealsodescribedinTable5.
Toxins2017,9,260 8of15
Table5.Botulinumtoxinforoccipitalneuralgia.
No.of MethodofInjection
StudyDesign Result Reference
Patients (TotalVolume)
Occipitalnerveblock50U SignificantVASreductionand
Caseseries 6 [48]
foreachblock(100U) painrelieflasting>4weeks
Improvementinsharp/shooting
Prospective,open, Greaterandlesseroccipital
6 pain,nodefiniteimprovement [49]
caseseries nerveblock(100U)
indull/achingpain
4.6. CarpalTunnelSyndrome
Breuer et al. conducted a randomized, double-blind, placebo-controlled study of 20 patients.
Inthisstudy,2,500UofBoNT-Borsalinewasinjectedintohypothenamuscleandtentoriumassociated
withcarpaltunnel. Tinglingsensation,pain,andpainrelatedtoimprovedsleepwerenoted,butthere
wasnosignificantdifferencecomparedwiththecontrolgroup[50]. Inaprospective,open,pilotstudy
offivepatients,atotalof30UofBoNT-Awasinjectedintracarpally. Ofthefivepatients,threereported
insignificantpainrelief,andnonehadelectrophysiologicalchanges[51]. Theseresultssuggestthatthe
useofBoNTincarpaltunnelsyndromeisnoteffective. ThesepapersaredescribedinTable6.
Table6.Botulinumtoxinforcarpaltunnelsyndrome.
No.of MethodofInjection
StudyDesign Result Reference
Patients (TotalVolume)
Randomized,
Intramuscular,hypothena Nosignificantdifference
double-blind, 20 [50]
muscle,tentorium(2500U) comparedtothecontrolgroup
placebo-controlled
Threepatientsinsignificant
Prospective, Intracapal30Uforeach
5 reducedpain,nonehad [51]
open,pilot carpaltunnel(60U)
electrophysiologicalchange.
4.7. CRPS
Safarpouretal. reportedthattwopatientswithCRPShadareductionofCRPSandmyofascial
painwiththeintramuscularadministrationof20UBoNT-Apersiteandtriggerpointinjection[52].
Theyalsoperformedrandomized,prospective,double-blind,placebo-controlled,open-labelextension
studiesofBoNTinCRPSpatients. FourteenpatientswithCRPSweredividedintotheBoNTgroup
(n = 8) and control group (n = 6). A total of 40–200 U (5 U per point) BoNT was administered to
theaffectedareawithallodynia. Nodifferencewasfoundbetweentheinterventionalgroupandthe
placebogroup,andthisstudywasterminatedearlyduetotheintoleranceofBoNT[53]. Inanother
study,lumbarsympatheticblockwasperformedinarandomized,double-blind,placebo-controlled
crossoverstudy. PatientsreceivedstandardLSGBononeside,and10mLof0.5%bupivacainewas
used. Thesamepatientwasinjectedwithacrossover(anotherside)injectionof75UBoNT-Ain10mL
of0.5%bupivacaine.Thecontrolgrouphasamedianof10days,whereastheBoNTgrouphasamedian
of71days[54]. InacaseseriespublishedbyChoietal.,twopatientswhoexperiencedshort-term
effectsonthelumbarsympatheticblockwereinjectedwith5000UofBoNT-Bin0.25%levobupivacaine
withalumbarsympatheticblock. VAS,allodynia,edema,coldness,andanalgesicdrugusagewere
reduced[12]. Inaprospective,opencaseseriesof11patientswithCRPSsymptomsinupperlimb
girdlemuscles,atotalof300UofBoNT-Awasadministeredtothepain-relatedmusclesat25–50U.
AllpatientsexhibitedimprovedVAS,allodynia,hyperalgesia,andskincolorafter6–12weeks[55].
Inaretrospective,uncontrolled,unblendedstudyof37patients,asaresultofadministeringatotalof
100UofBoNT-A(10–20Uperpainsite),97%ofpatientsreportedpainreduction,andtheaverage
painscoredecreasedby43%[56]. Exceptforonenegativestudy,positiveresultshavebeenpublished.
Toxins2017,9,260 9of15
However,thesestudiesincludealowclasspapers,andtheeffectofBoNTinCRPSpatientshasnot
beenproven. ThesepapersaresummarizedinTable7.
Table7.Botulinumtoxinforcomplexregionalpainsyndrome(CRPS).
Numberof MethodofInjection
StudyDesign Result Reference
Patients (TotalVolume)
IntramuscularTrigger ReductionofCRPSpainand
Caseseries 2 [52]
point20Upersite myofascialpain
Randomized,
prospective, Intradermal,subcutaneous NodifferencebetweenBoNT
14(8BoNTgroup,
double-blind, Allodyniaarea5Upersite groupandplacebogroup, [53]
6controlgroup)
placebo-controlled, (40–200U) terminatedstudyearly.
andopen-labelextension
Randomized, Lumbarsympatheticblock
Longerdurationofpain
double-blind, 75UBoNT+0.5%
9(18cases) reduction(BoNTvs. [54]
placebo-controlled bupivacaine/0.5%
control/71daysvs.10days)
crossover bupivacaine
Lumbarsympatheticblock
VASandCRPSsymptoms
Caseseries 2 5000UBoNT-B+0.25% [12]
werereduced.
levobupivacaine
AllpatientshadimprovedVAS,
Prospective, Affectedsite,
11 allodynia,hyperalgesia,and [55]
opencaseseries 25–50Upersite(300U)
skincolorafter6to12weeks
Retrospective, Affectedsite, The97%patientsreducedpain.
37 [56]
uncontrolled,unblended 10–20Upersite(100U) (averagepainreductionof43%)
4.8. PhantomLimbPain
Inaprospective,randomized,double-blindpilotstudy,14patientswithphantomlimbpainwere
treatedwith50Upersiteforatotalof250–300UBoNT-A.Inaddition,alidocaineanddepomedrol
mixturewasadministeredatthefocaltenderpoint. VASwasassessedmonthlyinpatientsbeforeand
sixmonthsaftertreatment. Bothgroupsreportedimprovedpain. TheBoNTgrouphadanadvantage
overpaincontrolduringthe3–6months,butphantomlimbpainwasnotcompletelyalleviated[57].
ThereisacasereportinwhichtheeffectofBoNTwaseffectiveinreducingphantomlimbpainfor
greaterthan12months. Intotal,25UofBoNT-Awasinjectedintothetriggerpointofthestumpat
foursites,andthepatientwasabletoreducethepainmedicationgiventhatthepainwassignificantly
eliminated[58]. TheeffectofBoNTonphantomlimbpaincannotbeverifiedbecauseonlylow-grade
studiesonphantomlimbpainhavebeenreported. TheabovepapersarealsolistedinTable8.
Table8.Botulinumtoxinforphantomlimbpain.
No.of
StudyDesign MethodofInjection(TotalVolume) Result Reference
Patients
Bothgroupsimprovedpainand
Prospective, Intramuscular/cutaneous/subcutaneous/ BoNTgrouphadanadvantageover
randomized, 14 neuroma(EMGguidance)50Upersite paincontrolduring3–6monthsbut [57]
double-blind,pilot (250–300U) couldnotcompletelychange
phantomlimbpain.
Phantompain,painmedicationcould
EMGguidanceintopointswithstrong bereduced,thegaitbecamemore
Caseseries 3 [58]
fasciculation(500U) stableandtheartificiallimbwas
bettertolerated.
4.9. SpinalCordInjury-InducedNeuropathicPain
In a study of 40 patients with spinal cord injury-induced neuropathic pain, a randomized,
double-blind,placebo-controlleddesignwasused. IntheBoNTgroup,200UBoNT-Awasdivided
into 40 sites, and 4 mL of saline was administered to the control group in a similar manner. Pain
intensitieswereassessedusingVAS,theKoreanversionoftheshort-formMcGillPainQuestionnaire
Toxins2017,9,260 10of15
(SF-MPQ),andtheKoreanversionoftheWorldHealthOrganizationQualityofLife(WHOQOL-BREF)
questionnaire. Thesameprocedurewasperformedatbaselineandfourandeightweeks. TheBoNT
group exhibited a statistically significant decrease in VAS at four and eight weeks compared with
theplacebogroup, andSF-MPQwasalsosignificantlyreducedcomparedwiththeplacebogroup.
However, there was no significant difference between the control group and the BoNT group in
the Korean version of the WHOQOL-BREF, which assesses physical health, psychological social
relationship,andenvironmentaldomains[59].Asimilarpaperwaspublishedin2017,andarandomized,
double-blind,placebo-controlledstudywasperformedin44patientswithspinalcordinjury-induced
neuropathicpain.TheBoNTgroupreceived200UofBoNT-Aatthepainsite,andthecontrolgroup
receivedthesameamountofsalineatthepainsite. Unliketheabovepaper,patientsreceivedthesame
treatmentoncedailyforeightweeks. TheprimaryoutcomeofpainwasmeasuredonaVASscale,
andthesecondaryoutcomewasmeasuredbytheSF-MPQandtheWHOQOL-BREFquestionnaire.
At four and eight weeks, both primary and secondary outcomes were measured and evaluated.
Noadverseeffectwasnotedinbothgroups. VASandSF-MPQweresignificantlydecreasedinthe
BoNTgroupcomparedwithplacebogroupatfourandeightweeks,respectively. Thedifferencefrom
theabovepaperisthattheWHOQOL-BREFalsoexhibitedastatisticallysignificantdecreasecompared
withtheplacebogroup[60].
Inaddition,therehavebeenseveralcasereportsofneuropathicpainassociatedwithspinalcord
injury. Jabbari et al. reported that two patients who had burning pain and allodynia after spinal
cordinjuryinjectedwith5UofBoNT-Aat16–20sitesinthepainsitemaintainedsignificantVAS
reductionforgreaterthanthreemonths[61]. Hanetal. mentionedthat20UofBoNT-Awasinjected
into10painfulareasinpatientswithspinalcordinjuries,andVASwasdecreasedfrom96to23[62].
TheuseofBoNTforspinalcordinjuryisconsideredtobeeffectivebasedonastatisticallysignificant
RCTjournalreport. ThesepapersarelistedinTable9.
Table9.Botulinumtoxinforspinalcordinjury-inducedneuropathicpain.
Numberof MethodofInjection
StudyDesign Result Reference
Patients (TotalVolume)
Randomized,double-blind, SignificantlyVASwas
40 Subcutaneous(200U) [59]
placebo-controlled decreasedat4and8weeks.
Randomized,double-blind, Subcutaneous(200U) SignificantlyVASwas
44 [60]
placebo-controlled Oncedailyfor8weeks decreasedat4and8weeks.
Subcutaneous5UofBoNT SignificantVASreduction
Case 2 [61]
at16–20sites formorethan3months
Subcutaneous20Uof
Case 1 VASdecreasedfrom96to23. [62]
BoNTat10sites
4.10. CentralPoststrokePain
PoststrokepatientsoftenuseBoNTduetopoststrokespasticity. However,somerecentreports
havereportedthatBoNTisusedforcentralpoststrokepaincontrol. Shippenetal. injectedBoNTin
patientswithelbowflexorspasticitywithcentralpoststrokepain. Thepatientshadsevereneuropathic
painatthesiteofthespasticityandreceived100UBoNT-AofBicepsBrachii,75UBrachialisand
25UBrachioradialis. Afterthesecondday,thepainwasreduced,andthespasticitywasimproved
one week after administration. The patients repeat BoNT every three months to control pain [63].
Barbosaetal. alsopublishedacasereportinwhichananalgesiceffectwasobtainedusingBoNT-A
inpatientswithcentralpoststrokepain. Intwopatientswithstroke,injectionofBoNT-A200Uinto
theaffectedareaunderEMGguidanceresultedinadecreaseinNRSaftera3-monthfollow-up[64].
Arandomized,double-blind,placebo-controlledtrialof273patientswithpoststrokespasticitywas
performed. In total, 74.3% of the patients had stroke-related pain, and 47.3% were suffering from
greaterthanNRS4. Patientsweredividedintotwogroups: BoNT-Aandstandardcarevs. placebo
andstandardcare. Thedegreeofpainwascompared12weeksfromthebaseline,andtheBoNTgroup