Treatment of Painful Peripheral Neuropathies Thomas H Brannagan III, MD Peripheral Neuropathy Center Weill Medical College of Cornell Uni

ersity INTRODUCTION Peripheral neuropathy is a common pro!lem and for some patients, pain is a disa!ling component of the neuropathy" The first goal in e aluating patients #ith painful peripheral neuropathies is to identify the cause, #ith the hope of identifying treatment to re erse ner e damage" There are a large num!er of disorders that may !e associated #ith a painful peripheral neuropathy" $Ta!le %& When neuropathic pain is present, it is appropriate to treat this concurrently, during the e aluation, as #ell as during the treatment of the neuropathy, if identified is in process" 'or some types of neuropathy, there are no a aila!le treatments for the underlying disorder, and therapy for neuropathic pain, if present may !e the only treatment a aila!le" Pain can !e classified !roadly as t#o types" Nocicepti e pain is protecti e and is a normal response to tissue in(ury, ser ing to #arn of the presence of in(ury" There is also sensiti)ation of peripheral nociceptors and central ner ous system changes, #hich protect the damaged area !y a oiding contact" Neuropathic pain is a pathologic or maladapti e pain, #hich results from damage to the ner ous system, producing pain in the a!sence of stimulation of nociceptors or inappropriate response to stimulation of nociceptors" Nocicepti e and neuropathic pain are not synonymous #ith acute and chronic pain" 'or instance, rheumatoid arthritis is a chronic pain, #hich is nocicepti e pain" * herniated disc can cause acute sciatic pain, #hich is neuropathic" Patients #ith neuropathic pain typically descri!e !urning, lancinating, sta!!ing, cramping, aching and sometimes ice+li,e pain" It can !e paro-ysmal or constant" .n e-amination hyperalgesia, allodynia or hyperpathia are sometimes elicited" The normal path#ays in ol ed in the transmission of pain !egin #ith stimulation of nociceptors including those that respond to chemical irritant stimuli such as /0%, D0*1IC, P234 and no-ious heat stimuli such as /0% and /05%" 1ignals resulting from intense mechanical and thermal stimulate * delta fi!er nociceptors and intense mechanical ,thermal and chemical stimuli stimulate polymodal C nociceptors" *fferent fi!ers synapse in 0e-ed6s lamina I, II and / in the spinal cord, #hich is the first le el of modulation" .piate receptors and interneurons are present at the dorsal horn" There are are also descending inputs from the hypothalamus, peria7ueductal gray" .piods, norepineprhine and serotonin ha e modulatory effects on pain transmission"

MECHANISMS OF NEUROPATHIC PAIN Why certain neuropathies cause pain is un,no#n, !ut there has !een increasing ,no#ledge a!out the mechanism of pain" The gate theory of pain proposed that the su!stantia gelatinosa acted as a gate allo#ing pain transmission to proceed and that the inhi!itory affect of the su!stantia gelatinosa is increased !y large diameter fi!ers" Central descending influence #as also postulated" 8Mel)ac, and Wall %9:;<Though specifics of this theory ha e !een sho#n to !e incorrect, the !asic premise of central modification of pain perception at the dorsal horn and other parts of the central ner ous system is still held" Dyc, et al 8Dyck et al" %9=:<, noted that neuropathic pain #as related to the rate and ,ind of ner e fi!er degeneration" It is not related simply to the ratio of remaining large and small ner e fi!ers" Bro#n et al noted that unmyelinated and small myelinated fi!ers #ere most prominently in ol ed and unmyelinated ner e fi!er sprouting #as e ident in painful dia!etic neuropathy" 8Bro#n et al" %9=:< *nimal models of pain ha e added to the understanding of neuropathic pain" There are > commonly used animal models, #hich include the chronic constricti e in(ury $CCI& model, the partial ner e transection, spinal ner e transection model and the spared ner e model" 8?im and Chung %992@1elt)er et al" %99A@Bennett and 3ie %9BB@Decosterd and Woolf 2AAA<The chronic constricti e in(ury model is produced !y a loosely constricti e ligature around the sciatic ner e" 8Bennett and 3ie%9BB< *lmost all of *+C fi!ers die, as do the ma(ority of *D fi!ers" * large percentage of C fi!ers persist" The partial ner e transection model in ol es tightly ligating and transecting %E4 to F of of the rat sciatic ner e" The spinal ner e transection model in ol es tight ligation and transection of the 5; and 5: ner e roots" This affects ;AG of the sural and saphenous ner e fi!ers" The spared ner e model in ol es a lesion of 2 of the 4 terminal !ranches of the sciatic ner e $ti!ial and peroneal& intact, lea ing the sural ner e intact" 8Decosterd and Woolf2AAA<There is partial deafferentation !ut not differential in ol ement of ner e fi!ers, in these three models" Heat hyperalgesia, mechano+hyperalgesia, mechano+allodynia and cold+allodynia may !e o!ser ed and !eha ioral changes consistent #ith spontaneous pain such as limping and guarding the hind pa# are seen" Both peripheral and central mechanisms ha e !een o!ser ed in animal models" *fter ner e in(ury there are spontaneous discharges of ner e fi!ers, neuromas and dorsal root ganglion" This has !een seen in traumatic ner e in(ury models , as #ell as models of peripheral neuropathy from dia!etes and hea y metal into-ication" Increased e-pression of sodium channels are seen in neuroma6s in humans and animal models" The density of sodium channel e-pression correlates #ith the degree of pain" 8Hngland et al" %99:< Changes in sodium channel e-pression are seen and may contri!ute to ner e e-cita!ility and spontaneous pain" 8Wa-man et al" %999@Craner MJ et al" 2AA2<" These spontaneous discharges !y themsel es can cause pain, !ut they also ha e additional affects" C fi!er afferents trigger cell death of neurons in the dorsal horn, #here

inhi!itory interneurons are concentrated, possi!ly through an e-citoto-ic mechanism" This may result in increased pain transmission"" $81ugimoto et al" %9B9@1ugimoto et al" %99A@5aird and Bennett %992< C fi!er afferents release glutamate and synapse on 2nd order neurons and ha e e-citatory affects" Ilutamate synapses at *MP* receptors #hich depolari)es the mem!rane" This depolari)ation releases the inhi!ition of the NMD* receptor !y the magnesium ions and there is an influ- of calcium" 1econd order neurons are gradually depolari)ed and responses are amplified and this changes the response of neurons to su!se7uent input" T#o processes that are distinct occur at the dorsal horn #hich are designated J#indupK and Jcentral sensiti)ation"K Windup up results from repetiti e C fi!er firing at lo# fre7uencies that result in a progressi e !uildup of the amplitude of the response of the dorsal horn neuron, only during the repetiti e train" Central sensiti)ation is an a!normal sensiti ity #ith a spread of hypersensiti ity to unin(ured sites and pain resulting from stimulation of lo# threshold * mechanoreceptors" Central sensiti)ation follo#s a !rief high fre7uency input and the increased response to su!se7uent inputs is prolonged" Both can !e !loc,ed !y NMD* receptor antagonists" Central sensiti)ation can result from #indup" This is a result of the calcium influ- through the NMD* receptor follo#ing depolari)ation of the dorsal horn mem!rane" The intracellular calcium acti ated a num!er of ,inases of #hich protein ,inase C $P?C& is li,ely important" P?C enhances the NMD* receptor , #hich results in su!se7uent glutamate !inding of the NMD* receptor generating an in#ard current" Though #indup can result in central sensiti)ation it is not necessary for central sensiti)ation to occur" 8Woolf and 1alter 2AAA@Woolf %99:< 1imilar o!ser ations had pre iously !een noted !y Denny+Bro#n #ho descri!ed an enlarged and hypersensiti e dermatomal region in primates #hen se ering the surrounding ner e roots distal to the dorsal root ganglion compared #ith se ering pro-imal to the D0I" This suggested plasticity of the dorsal horn neurons secondary to input from the D0I" 8?ir, and Denny+Bro#n %9=A@?ir, and Denny+Bro#n%9=A@Denny+ Bro#n et al" %9=4< Ner e in(ury also results in sprouting of myelinated fi!ers into lamina II of the dorsal horn, #hich under normal circumstances recei es only C fi!er input" 8Mannion et al" %99:<This may result in allodynia" There is a genetic influence on the e-perience of neuropathic pain though it is poorly delineated" There are ariations on the e-pression of pain !eha iors seen in different strains of animals" 8De or and 0a!er %99A< * recent study noted that ;:G of patients #ith painful dia!etic neuropathy had a relati e #ith painful dia!etic neuropathy suggesting a genetic component"8Ialer et al" 2AAA< The relati e importance of these arious mechanisms is not clearly ,no#n, ho#e er there is potentially multiple sites for inter ention in treating painful neuropathies"

Medications Tricyclic anti+depressants ha e !een !eneficial in controlled studies of neuropathic pain" 8Ma- %99;<They !loc, the reupta,e of norepinephrine and serotonin and are thought to modulate descending inhi!itory path#ays" There !enefit #ith neuropathic pain is independent of their effect on depression" 8Max et al" %9B=< Patients #ho are not depressed can respond and lo#er doses than are used to treat depression are effecti e to treat neuropathic pain" Tricyclic anti+depressants can !loc, oltage dependent sodium channels and this may contri!ute to their efficacy to treat neuropathic pain" 8Brau et al" 2AA%< They are typically started at a dose of %A+2; mg at night and titrated as tolerated up to a dose of %;A mg if necessary" 1ide effects include dry mouth, cardiac arrhythmias, urinary retention and se-ual dysfunction" /enlafa-ine has fe#er side effects and has also !een reported to !enefit neuropathy pain" 8*nsari 2AAA< The selecti e serotinin reupta,e inhi!itors $110I& ha e !een less effecti e for treatment of neuropathic pain" 'luo-etine #as not effecti e in clinical trials" 8Max et al" %992<Paro-etine and Citalopram !een reported to !e effecti e" 81indrup et al" %992@1indrup et al" %99A< *nticon ulsants ha e also !een studied in neuropathic pain" Both phenytoin $Dilantin& and car!ame)apine $Tegretol& ha e !een !eneficial in trials of dia!etic neuropathy" 8Chadda /1 %9=B@0ull et al" %9:9<They act as sodium channel !loc,ers" Both medications ha e fre7uent side effects that are #ell ,no#n" Iapapentin $Neurontin&, !inding site alpha delta Ca channel" It is though to act at a spinal site of action" 83iao and Bennett %99:< Controlled studies in dia!etic neuropathy, post+herpetic neuralgia and other neuropathic pain states" 8Bac,on(a et al" %99B< 1tarting doses are usually%AAmg tid or 4AAmg 7hs" Unless the drug is not tolerated or a dose of :AA mg tid has !een tried it should not !e considered a treatment failure" .ften higher doses pro ide more !enefit" 1ide effects include dro#siness, fogginess, leg edema" Ia!apentin is cleared !y the ,idneys and there are not significant drug interactions" The dosing should !e ad(usted in renal insufficiency and failure" 5amotrigine $5amictal& is a sodium channel !loc,er, #hich also inhi!its glutamate release" It has reduced cold allodynia in the CCI model" 8Hunter et al" %99=<5amotrigine is effecti e in controlled studies in dia!etic, HI/ associated painful neuropathy, post+herpetic neuralgia, and trigeminal neuralgia"81impson et al" 2AAA@Hisen!erg et al" 2AA%<" I6 e found lamotrigine to cause less dro#siness or di))iness than most other medications used for neuropathic pain and though these symptoms ha e !een seen during epilepsy trials, they #ere not seen more commonly than place!o in 2 recent trials of neuropathy pain" 0ash is a side effect and a 1te ens Lohnson syndrome may occur" This is less fre7uent #hen the medication is titrated slo#ly" The rash is less common #ith a slo# titration" The follo#ing titration schedule has !een used for

neuropathic painM 2;mg 7d for 2 #ee,s, 2; mg !id for the ne-t 2 #ee,s, ;A mg !id for the ne-t 2 #ee,s, %AAmg !id for 2 #ee,s" If the patient is also ta,ing alproate #hich inhi!its the meta!olism of lamotrigine, a dose of 2; mg 7od is recommended as an initial dose" .-car!a)epine $Trileptal& is similar in structure to car!ame)apine, !ut lac,s the %A,%% epo-ide, #hich is thought to !e responsi!le for !etter tolera!ility" *utoinduction does not occur and rash and drug interactions are less fre7uent than #ith car!ame)apine" Hyponatremia does occur" 8Na,r)e#s,a and Patsalos %9B9< Dou!le !lind place!o controlled studies of me-ilitine ha e !een negati e, ho#e er su!groups #ith sta!!ing and !urning pain had !enefit" *nother study noted !enefit in night time pain #ith the :=; mg dose, !ut not the lo#er doses of >;A mg or 22; mg" Topiramate $Topama-& sho#ed !enefit in animal models and preliminary studies and anecdotal reports of dia!etic neuropathy and neuropathic pain" 8Hd#ards et al" 2AAA@Potter and Hd#ards %99B<Though the results ha e not !een pu!lished Lohnson O Lohnson announced that the results of clinical trials in dia!etic neuropathy pain #ere not positi e $0euter 9E%BE2AA%&" De-tromorthorphan is a lo# affinity NMD* antigonist" It has !een !eneficial in animal studies and painful neuropathies" 1ide effects are fre7uent and it is poorly tolerated" 8Nelson et al" %99=< De-tromethorphan in com!ination #ith other medications as #ell as more selecti e NMD* receptor antagonists that may ha e less side effects are !eing pursued"8Boyce et al" %999< Clonidine an alpha+2 agonist, as a transdermal patch #as successfully used in a su!set of patients #ith painful dia!etic neuropathy using an enrolled enrichment design" Ti)anidine, also an alpha+2 agonist, reduces thermal hyperalgesia in the CCI rat model and has !een successful in open la!el studies in neuropathic pain"8Hord et al" 2AA%@1emenchu, and 1herman 2AAA!< Tramodol $Ultram& has !een effecti e in studies of painful dia!etic neuropathy" 8Harati et al" %99B< 1ide effects include nausea, headache, constipation, somnolence and sei)ures" 5idoderm is !eneficial for post+herpetic neuralgia" The dose of %+4 patches for %2 hours, #ith %2 hours off the patch" It has !een !eneficial in other forms of neuropathic pain" 8De ers and Ialer 2AAA< Based on small preliminary and anecdotal series, as #ell as animal data, other medications including )onisamide and le etiracetam may !e !eneficial" 8Bac,on(a 2AA2@1emenchu, and 1herman 2AAAa@Hord et al2AA%< HI/ painful neuropathy is a particularly difficult syndrome to treat" Controlled studies of amitriptyline, me-ilitine, and acupuncture ha e !een negati e" 81hlay et al" %99B@?ie!urtz et al" %99B<Ia!apentin has !een reported to !e successful, though

re7uiring higher doses" 8Ne#shan %99B< Phenytoin and car!ame)apine as P>;A inducers should !e a oided as they can induce the meta!olism of the protease inhi!itors and ma,e them ineffecti e" 80omanelli et al" 2AAA<5amotrigine has !een successful in !linded place!o controlled studies" T#o consecuti e studies ho#e er pro ided conflicting data #ith the first suggesting that there #as no !enefit a!o e place!o in patients ta,ing neuroto-ic dideo-ynucleotide anti+retro irals compared #ith those patient not ta,ing neuroto-ic antiretro irals and the second study sho#ed the opposite" 81impson et al" 2AA2@1impson et al2AAA< 1ince se eral different mechanisms are in ol ed in neuropathic pain, treatment directed against the mechanism of pain #ould !e desira!le and has !een proposed" Une7ui ocally identifying mechanisms at #or, to date has !een difficult in patients" 'or instance the symptom of allodynia may occur from peripheral sensiti)ation or central sensiti)ation" 8Woolf et al" %99B< It is a commonly held !elief that tricyclic anti+ depressants are more effecti e against !urning pain and anti+con ulsants are more effecti e against paro-ysmal sta!!ing pain" In clinical trials ho#e er this has not !een demonstrated"" 1electi e affects in animal models ha e !een demonstrated" 'or e-ample de-trorphan reduces heat hyperalgesia, !ut has no effect on mechanical allodynia in the CCI model" 8Tal and Bennett %99>< Ho# this correlates to treatment of people #ith neuropathic pain is still e ol ing" In the future coc,tails targeting different mechanisms at #or, in patients #ith peripheral neuropathies may !e possi!le" 0eference 5ist *nsari *" The efficacy of ne#er antidepressants in the treatment of chronic painM * re ie# of current literature" Har ard 0e ie# of Psychiatry 2AAA@ =M 2;=+2==" Bac,on(a M, Beydoun *, Hd#ards ?0 et al" Ia!apentin for the symptomatic treatment of painful neuropathy in patients #ith dia!etes mellitus + * randomi)ed controlled trial" Lama+Lournal of the *merican Medical *ssociation %99B@ 2BAM %B4%+%B4:" Bac,on(a MM" Use of anticon ulsants for treatment of neuropathic pain" Neurology 2AA2@ ;9M 1%>+1%=" Bennett IL, 3ie P?" * Peripheral Mononeuropathy in 0at That Produces Disorders of Pain 1ensation 5i,e Those 1een in Man" Pain %9BB@ 44M B=+%A=" Boyce 1, Wyatt *, We!! L? et al" 1electi e NMD* N02B antagonists induce antinociception #ithout motor dysfunctionM correlation #ith restricted localisation of N02B su!unit in dorsal horn" Neuropharmacology %999@ 4BM :%%+:24" Brau MH, Dreimann M, .lsche#s,i *, /ogel W, Hempelmann I" Hffect of drugs used for neuropathic pain management on tetrodoto-in+resistant NaQ currents in rat sensory neurons" *nesthesiology 2AA%@ 9>M %4=+%>>"

Bro#n ML, Martin L0, *s!ury *?" Painful Dia!etic Neuropathy + Morphometric 1tudy" *rchi es of Neurology %9=:@ 44M %:>+%=%" Chadda /1, Mathur M1" Dou!le !lind study of the effects of diphenylhydantoin sodium on dia!etic neuropathy" L"*ssoc"Physiol"India 2:, >A4" %9=B" Craner ML, ?lein LP, 0enganathan M, Blac,, L" *", and Wa-man, 1" I" Changes of sodium channel e-pression in e-perimental painful dia!etic neuropathy" *nnals of Neurology ;2, =B:+=92" 2AA2" Decosterd I, Woolf CL" 1pared ner e in(uryM an animal model of persistent peripheral neuropathic pain" Pain 2AAA@ B=M %>9+%;B" Denny+Bro#n D, ?ir, HL, Panagisa#a N" Tract of 5issauer in 0elation to 1ensory Transmission in Dorsal Horn of 1pinal+Cord in Maca7ue Mon,ey" Lournal of Comparati e Neurology %9=4@ %;%M %=;+%99" De ers *, Ialer B1" Topical lidocaine patch relie es a ariety of neuropathic pain conditionsM *n open+la!el study" Clinical Lournal of Pain 2AAA@ %:M 2A;+2AB" De or M, 0a!er P" Herita!ility of 1ymptoms in *n H-perimental+Model of Neuropathic Pain" Pain %99A@ >2M ;%+:=" Dyc, PL, 5am!ert HH, .!rien PC" Pain in Peripheral Neuropathy 0elated to 0ate and ?ind of 'i!er Degeneration" Neurology %9=:@ 2:M >::+>=%" Hd#ards ?0, Ilant) ML, Button L, Norton L*, Whitta,er T, Cross N" Hfficacy and safety of topiramate in the treatment of painful dia!etic neuropathyM * dou!le+!lind, place!o controlled study" Neurology 2AAA@ ;>M *B%" Hisen!erg H, 5urie P, Bra,er C, Daoud D, Ishay *" 5amotrigine reduces painful dia!etic neuropathy + * randomi)ed, controlled study" Neurology 2AA%@ ;=M ;A;+;A9" Hngland LD, Happel 5T, ?line DI et al" 1odium channel accumulation in humans #ith painful neuromas" Neurology %99:@ >=M 2=2+2=:" Ialer B1, Iianas *, Lensen MP" Painful dia!etic polyneuropathyM epidemiology, pain description, and 7uality of life" Dia!etes 0esearch and Clinical Practice 2AAA@ >=M %24+ %2B" Harati P, Iooch C, 1#enson M et al" Dou!le+!lind randomi)ed trial of tramadol for the treatment of the pain of dia!etic neuropathy" Neurology %99B@ ;AM %B>2+%B>:" Hord *H, Chalfoun *I, Denson DD, *)e edo MI" 1ystemic ti)anidine hydrochloride $Nanafle- $TM&& relie es thermal hyperalgesia in rats #ith an e-perimental mononeuropathy" *nesthesia and *nalgesia 2AA%@ 94M %4%A+%4%;"

Hunter LC, Iogas ?0, Hedley 50 et al" The effect of no el anti+epileptic drugs in rat e-perimental models of acute and chronic pain" Huropean Lournal of Pharmacology %99=@ 42>M %;4+%:A" ?ie!urt) ?, 1impson D, Piannoutsos C et al" * randomi)ed trial of amitriptyline and me-iletine for painful neuropathy in HI/ infection" Neurology %99B@ ;%M %:B2+%:BB" ?im 1H, Chung LM" *n H-perimental+Model for Peripheral Neuropathy Produced !y 1egmental 1pinal Ner e 5igation in the 0at" Pain %992@ ;AM 4;;+4:4" ?ir, HL, Denny+Bro#n D" 'unctional /ariation in Dermatomes in Maca7ue Mon,ey 'ollo#ing Dorsal 0oot 5esions" Lournal of Comparati e Neurology %9=A@ %49M 4A=+O" 5aird LM*, Bennett IL" Dorsal+0oot Potentials and *fferent Input to the 1pinal+Cord in 0ats #ith *n H-perimental Peripheral Neuropathy" Brain 0esearch %992@ ;B>M %B%+%9A" Mannion 0L, Dou!ell TP, Coggeshall 0H, Woolf CL" Collateral sprouting of unin(ured primary afferent *+fi!ers into the superficial dorsal horn of the adult rat spinal cord after topical capsaicin treatment to the sciatic ner e" Lournal of Neuroscience %99:@ %:M ;%B9+ ;%9;" Ma- MB" Thirteen consecuti e #ell+designed randomi)ed trials sho# that antidepressants reduce pain in dia!etic neuropathy and postherpetic neuralgia" Pain 'orum %99;@ >M 2>B+2;4" Ma- MB, Culnane M, 1chafer 1C et al" *mitriptyline 0elie es Dia!etic Neuropathy Pain in Patients #ith Normal .r Depressed Mood" Neurology %9B=@ 4=M ;B9+;9:" Ma- MB, 5ynch 1*, Muir L, 1hoaf 1H, 1moller B, Du!ner 0" Hffects of Desipramine, *mitriptyline, and 'luo-etine on Pain in Dia!etic Neuropathy" Ne# Hngland Lournal of Medicine %992@ 42:M %2;A+%2;:" Mel)ac, 0, Wall PD" Pain Mechanisms + * Ne# Theory" 1cience %9:;@ %;AM 9=%+O" Nelson ?*, Par, ?M, 0o!ino it) H, Tsigos C, Ma- MB" High+dose oral de-tromethorphan ersus place!o in painful dia!etic neuropathy and postherpetic neuralgia" Neurology %99=@ >BM %2%2+%2%B" Ne#shan I" HI/ neuropathy treated #ith ga!apentin" *ids %99B@ %2M 2%9+22%" Potter D, Hd#ards ?0" Potential role of topiramate in relief of neuropathic pain" Neurology %99B@ ;AM *2;;" 0omanelli ', Lennings H0, Nath *, 0yan M, Berger L" Therapeutic dilemma + The use of anticon ulsants in HI/+positi e indi iduals" Neurology 2AAA@ ;>M %>A>+%>A="

0ull L*, Rui!rera 0, I.NN*5HN"H, C*1T*NHD".5" 1ymptomatic Treatment of Peripheral Dia!etic Neuropathy #ith Car!ama)epine $Tegretol& + Dou!le Blind Crosso er Trial" Dia!etologia %9:9@ ;M 2%;+O" 1elt)er N, Du!ner 0, 1hir P" * No el Beha ioral+Model of Neuropathic Pain Disorders Produced in 0ats !y Partial 1ciatic+Ner e In(ury" Pain %99A@ >4M 2A;+2%B" 1emenchu, M0, 1herman 1" Hffecti eness of ti)anidine in neuropathic painM *n open+ la!el study" Lournal of Pain 2AAAa@ %M 2B;+292" 1emenchu, M0, 1herman 1" Hffecti eness of ti)anidine in neuropathic painM *n open+ la!el study" Lournal of Pain 2AAA!@ %M 2B;+292" 1hlay LC, Chaloner ?, Ma- MB et al" *cupuncture and amitriptyline for pain due to HI/+related peripheral neuropathy + * randomi)ed controlled trial" Lama+Lournal of the *merican Medical *ssociation %99B@ 2BAM %;9A+%;9;" 1impson DM, Mc*rthur LC, .lney 0, 0oss D, Barrett P, Baird BL" * multicenter, dou!le+!lind, randomi)ed, place!o+controlled e aluation of lamotrigine in adult su!(ects #ith painful HI/+associated peripheral neuropathy" Neurology 2AA2@ ;BM *>A=" 1impson DM, .lney 0, Mc*rthur LC, ?ahn *, Iod!old L, H!el+'rommer ?N" * place!o+controlled trial of lamotrigine for painful HI/+associated neuropathy" Neurology 2AAA@ ;>M 2%%;+2%%9" 1indrup 1H, B(erre U, De(gaard *, Brosen ?, *aes(orgensen T, Iram 5'" The 1electi e 1erotonin 0eupta,e Inhi!itor Citalopram 0elie es the 1ymptoms of Dia!etic Neuropathy" Clinical Pharmacology O Therapeutics %992@ ;2M ;>=+;;2" 1indrup 1H, Iram 5', Brosen ?, Hsho( ., Mogensen H'" The 1electi e 1erotonin 0eupta,e Inhi!itor Paro-etine Is Hffecti e in the Treatment of Dia!etic Neuropathy 1ymptoms" Pain %99A@ >2M %4;+%>>" 1ugimoto T, Bennett IL, ?a(ander ?C" 1trychnine+Hnhanced Transsynaptic Degeneration of Dorsal Horn Neurons in 0ats #ith *n H-perimental Painful Peripheral Neuropathy" Neuroscience 5etters %9B9@ 9BM %49+%>4" 1ugimoto T, Bennett IL, ?a(ander ?C" Transsynaptic Degeneration in the 1uperficial Dorsal Horn *fter 1ciatic+Ner e In(ury + Hffects of * Chronic Constriction In(ury, Transection, and 1trychnine" Pain %99A@ >2M 2A;+2%4" Tal M, Bennett IL" Neuropathic Pain 1ensations *re Differentially 1ensiti e to De-trorphan" Neuroreport %99>@ ;M %>4B+%>>A" Wa-man 1I, Cummins T0, Di!+Ha(( 1, '(ell L, Blac, L*" 1odium channels, e-cita!ility of primary sensory neurons, and the molecular !asis of pain" Muscle O Ner e %999@ 22M %%==+%%B="

Woolf CL" Windup and central sensiti)ation are not e7ui alent" Pain %99:@ ::M %A;+%AB" Woolf CL, Bennett IL, Doherty M et al" To#ards a mechanism+!ased classification of painS Pain %99B@ ==M 22=+229" Woolf CL, Mannion 0L" Neuropathic painM aetiology, symptoms, mechanisms, and management" 5ancet %999@ 4;4M %9;9+%9:>" Woolf CL, 1alter MW" Neuroscience + Neuronal plasticityM Increasing the gain in pain" 1cience 2AAA@ 2BBM %=:;+%=:B" 3iao, P" ?" and Bennett, I" L" Ia!apentin has an anti+nocicepti e effect mediated ia a spinal site of action in a rat model of painful peripheral neuropathy" *nalgesia 2, 2:=+ 2=4" %99:" Na,r)e#s,a LM, Patsalos PN" .-car!a)epine+a ne# drug in the management of intracta!le trigeminal neuralgia" L Neurol Neurosurg Psychiatry %9B9@ ;2M >=2+>=:"

Ta!le % Painful peripheral neuropathies Dia!etes mellitus HI/ *myloidosis 'a!ry6s disease Celiac disease Hereditary sensory neuropathy Ideopathic To-ic neuropathies Dideo-ynucleotide antiretro irals *ntineoplastic agents $ incristine, ta-ol& Isonia)id *lcohol Pyrido-ine $B:& *utoimmune *nti+sulfatide anti!ody neuropathies Neuropathy associated #ith monoclonal gammopathy 1(ogren6s disease 5upus /asculitic neuropathy

Ta!le 2 Potential mechanisms of neuropathic pain 1odium channel accumulation, redistri!ution, altered e-pression Central sensiti)ation Peripheral sensiti)ation T+receptor e-pression 1ympathetic sprouting Increased transmission 0educed inhi!ition

Modified from 8Woolf and Mannion %999<

Ta!le 4 Medications used to treat neuropathic pain Medication Antidepressants *mitriptyline nortriptylene enlafa-ine Anticonvulsants Ia!apentin 5amotrigine .-car!a)epine Topiramate Other medications me-ilitine Tramodol 5idocaine patch ;G %;A mg 7d 2;mg P. 7d anecdotal, su!group analysis of PCT PCT U Dia!etic neuropathy nauseaE omiting, palpitations, chest pain sei)ures, nausea, headache, constipation, somnolence application site reactions %AAmg tid 2; mg 7d =; mg 7hs %;+2; mg P. 7hs PCT + Dia!etic neuropathy, post+herpetic neuralgia PCT + HI/ neuropathy, dia!etic neuropathy anecdotal reports + trigeminal neuralgia anecdotal reports U dia!etic neuropathy, neuropathic pain somnolence, fatigue, pedal edema 1te ens+Lohnson rash gastrointestinal, ata-ia, hyponatremia, rash somnolence,#ord+finding difficulties, ,idney stones %A+2; mg 7hs %A+2; mg 7hs 4="; mg 7d PCT U dia!etic neuropathy anecdotal reports anecdotal reports U neuropathy, post+herpetic neuralgia arrhythmia, urinary retention, se-ual dysfunction less somnolence and orthostatic hypotension than amitriptyline hypertension, se-ual dysfunction, nausea 1tarting doses Data studies supporting the use 1elected 1ide effects

% patch for %2 hours PCT U post+herpetic neuralgia

5egendM PCT U place!o controlled trials