Anexa 18

Ghidul EFNS de tratament farmacologic n durerea neuropatic

N. Attala,b, G. Cruccua,c, M. Haanpa,d, P. Hanssona,e, T.S. Jensena,f, T. Nur !""o#, C. Sa pa!o$, S. S!ndrup!, P. %!en& a EFNS Panel Neuropathic Pain; bINSERM U-792, Centre d E!aluation et de "raite#ent de la $ouleur, %&pital '#broi(e Par), 'P-%P and Uni!er(it) *er(aille(-Saint-+uentin, ,oulo-ne-,illancourt, France; c $epart#ent o. Neurolo-ical Science(, /a Sapien0a Uni!er(it1, Ro#e, Ital1;
d $epart#ent( o. 'nae(the(iolo-1 and Neuro(ur-er1, Pain Clinic, %el(in2i %o(pital, e %el(in2i, $epart#ent o. Molecular Medicine and Sur-er1, Sec tion o.Uni!er(it1 Clinical Pain Re(earch and Pain Finland; Center, $epart#ent o. Neuro(ur-er1, 3arolin(2a In( ti tute, Uni!er(it1 %o(pital, Stoc2hol#, S4eden;

$epart#ent - o. Neurolo-1 and $ani(h Pain Re(earch Center, 'arhu( Uni!er(it1 %o(pital, 'arhu(, $en#ar2; Pain Re(earch In( titute, $i!i(ion o. ti Neurolo-ical Science, School o. Clinical Science(, Uni!er(it1 o. /i!erpool, /i!erpool, U3; hIn( tuto de Far#acolo-ia e "erapeu tica 5eral, i 7 /i(bon School o. Medicine, Uni!er(it1 o. /i(bon, Portu-al; $epart#ent o. Re!ie4 Neurolo-1, 6den(e Uni!er(it1 %o(pital, 6den(e, $en#ar2; and /i(bon, Cochrane Pain 8 Pallia ti!e Care 5roup, 69.ord, U3
.

Cuvinte cheie: durere central', durere neuropat!c', s! pto e de durere, neuropat!e dureroas', trata( ent far acolo#!c, ne)ral#!e post$erpet!c', cal!ta( tea )!e*!!, ne)ral#!e tr!#e !nal'. Trata entul durer!! neuropat!ce r' +ne nesat!sf'c'tor, de,! a crescut ult nu 'rul stud!!lor -n acest do en!u. Co !tetul de .edac( *!onare /0NS a ur 'r!t s' e)alue1e do)e1!le de&a ex!stente despre trata entul far acolo#!c al durer!! neuropat!ce. Stud!!le au fost clas!f!cate dup' et!olo( #!a afec*!un!lor. S(a apelat la stud!! de clasa 2 ,! 22, dar s( au luat -n cons!derare ,! stud!! de clas' a! !c' -n cond!*!!le -n care nu ex!stau alte do)e1!. Au fost e)a( luate doar terap!!le real!1ab!le pentru un pac!ent a bulator. Au fost c'utate efectele asupra se nelor ,! s! pto elor durer!!, cal!t'*!! )!e*!! ,! co orb!d!( t'*!lor. Ma&or!tatea stud!!lor rando !1ate controlate au !nclus pac!en*! cu ne)ral#!e post$erpet!c' ,! pol!neuropat!e dureroas', -n spec!al de cau1' d!abet!c'. Aceste stud!! au ofer!t do)e1! de n!)el A pentru ef!cac!tatea ant!depres!)elor tr!c!cl!ce, #abapent!ne!, pre#abal!ne! ,! op!o!delor, cu un nu 'r are de stud!! de clasa 2, ur ate de 3!doca!na top!c' ,! ant!( depres!)ele a! no!, 4enlafax!na ,! 5uloxet!na. 6n nu 'r !c de stud!! controlate s(au concentrat asu( pra durer!! centrale, ne)ral#!e! tr!#e !nale, altor cau1e per!fer!ce de durere neuropat' ,! durer!! neuropate de et!olo#!e ult!pl'. Pr!nc!palele cau1e per!fer!ce de durere neuropat' r'spund s! !lar la ant!depres!)e tr!c!cl!ce, #abapent!n' ,! pre#abal!n', dar unele afec*!un!, cu ar f! neuropat!a H24 sunt a! refractare. Sunt prea pu*!ne stud!! despre dure( rea central', terap!a de co b!nare ,! co para*!! d!recte. Pentru stud!!le )!!toare, no! reco and' ur 'r!rea cal!t'*!! )!e*!! ,! a se nelor ,! s! pto elor durer!! cu etode standard!1ate. GENERALI !"I #I $%IEC I&E 1

7n c!uda nu 'rulu! -n cre,tere de stud!! rando( !1ate placebo(controlate despre durerea neuropa( t' -n ult! !! an!, trata entul ed!cal al aceste!a es( te departe de a f! sat!sf'c'tor, a! pu*!n de &u 'tate d!ntre pac!en*! at!n#+nd un benef!c!u se n!f!cat!) sub terap!e far acolo#!c' 81,9:. Stud!!le controlate rando !1ate ;.C< -n #eneral au !nclus pac!en*! clas!f!ca*! -n func*!e de et!olo#!e. Ma&or!tatea stu( d!!lor s(au concentrat pe ne)ral#!a post$erpet!c' ,! pol!neuropat!a dureroas', -n t! p ce foarte pu*!ne s(au ocupat de alte durer! neuropate, cu ar f!= ne)ral#!a tr!#e !nal', durerea central', rad!culopat!! dureroase ;despre aceast' ult! ' patolo#!e nu ex!st' n!c! un stud!u rando !1at controlat<. .ecent au fost propuse terap!! care )!1ea1' ecan!s ele durer!! 8>,?:, dar r' +n -n cont!nuare destul de d!f!c!l de apl!cat -n pract!ca cl!n!c' 8@( A:. 5e,! eta(anal!1ele sau b!lan*ur!le s!ste at!ce despre trata entul -n durerea neuropat' au fost recent publ!cate 81,9,8(11:, ex!st' -nc' o l!ps' a con( sensur!lor pr!)!nd #$!dur!le de terap!e -n durerea neuropat'. Acest lucru se poate datora $etero#en!( t'*!! acestu! t!p de durere dator!t' et!olo#!e!, s! pto( elor, se nelor ,! ecan!s elor de producere. Bb!ect!)ele Co !tetulu! de .edac*!onare au fost= ;1< s' exa !ne1e toate stud!!le rando !1at con( trolate efectuate -n d!fer!te cond!*!! pr!)!nd durerea neuropat'C ;9< s' e)alue1e efectele ed!ca entelor asupra s! pto elor, cal!t'*!! )!e*!! ,! so nulu! deter( !nate de durere, precu ,! reac*!!le ad)erseC ;>< s' propun' reco and'r! ba1ate pe re1ultatele acestor stud!! cu scopul de a a&uta cl!n!c!en!! -n ale#erea lor terapeut!c' pentru d!fer!te t!pur! de durere neuropat'C ;?< s' propun' no! stud!! care ar putea clar!f!ca aspectele nere1ol)ate. 'E $(E A consultat b!bl!oteca Coc$rane, !ar atunc! c+nd aceasta nu ne(a putut furn!1a !nfor a*!!le necesare le#ate de o anu !t' cond!*!e a durer!! neuropate sau un ed!ca ent presupus a f! act!) -n durerea neuropat', a ext!ns c'ut'r!le cu M/532N/ )er!f!c+nd eta(anal!1e, art!cole ,! raport'r! cl!n!ce. Pentru a ne folos! de cele a! no! !nfor a*!!, a cerut co pan!!lor far aceut!ce produc'toare de ed!ca ente cu ! portan*' -n aceast' patolo#!e s' ne furn!1e1e stud!! -nc' nepubl!cate ;Anexa A<. Pentru a putea furn!1a neurolo#!lor !nd!ca*!! clare pr!)!nd trata entul pentru cele a! stud!ate t!pur! de durere neuropat', Co !tetul de .edac*!o( nare a dec!s s' redacte1e cap!tole separate pentru pol!neuropat!!le dureroase, ne)ral#!a post$erpet!c', ne)ral#!a tr!#e !nal', durerea de t!p central, !n&u( r!!le 'du)e! sp!n'r!!, durerea post( stro"e ,! sclero1' ult!pl', dar s' furn!1e1e !nfor a*!! ,! despre cele( lalte t!pur! de durere neuropat' a! pu*!n stud!ate ;posttrau at!c', postc$!rur#!cal', durerea e ( brulu! fanto ', s!ndro ul Gu!llan(Darre<. 0!ecare cap!tol a fost atr!bu!t pentru do! autor! a! Co !tetulu! de .edac*!onare. Cla)ificarea dove*ilor Clas!f!carea do)e1!lor ,! reco and'r!lor au fost -n acord cu standardele /0NS 819:. 9

7n part!cular, clasa 2 se refer' nu doar la stud!! adec)ate prospect!)e rando !1ate controlate, c! ,! la b!lan*ur! s!ste( at!ce. Criterii de includere +i e,cludere Stud!!le !ncluse au -ndepl!n!t ur 'toarele cr!te( r!!= ;1< stud!! rando !1ate sau non( rando !1ate controlate de clasa 2 sau 22C ;9< d! !nuarea durer!! a fost cons!derat' scopul pr! ar ,! a fost e)aluat' cu scale de )al!d!tateC ;>< !n! 1E pac!en*! !nclu,!C ;?< durata trata entul ,! ur 'r!rea pac!en*!lor clar spe( c!f!cateC ;@< e)aluarea trata entulu! pentru cel pu*!n 1 s'pt' +n'C ;F< trata ent fe1ab!l pentru un pac!ent a bulator ;ad !n!strarea !ntra)enoas', subcutanat' sau !ntratecal' sau blocur!le ner)oase nu au fost luate -n cons!derare<C ;A< e)aluarea ed!( ca entelor ut!l!1ate curent sau a celor aflate -n fa1a cl!n!c' 222 de de1)oltareC ;8< !ncluderea pac!en*!lor cu durere secundar' une! le1!un!Gbol! def!n!te a s!ste ulu! ner)os 81>: sau ne)ral#!e tr!#e !nal' !d!opat!c'C ;H< traducerea co plet' a lucr'r!! -n en#le1', france1', dane1', f!nlande1', #er an', !tal!an', portu#$e1', span!ol'. Cr!ter!!le de excludere au fost= ser!! dupl!cate de pac!en*!, stud!! necontrolate, durere f'r' e)!den( *!erea une! le1!un! ner)oase ;cu ar f! durerea fac!al' at!p!c', C.PS t!p 2 sau lo bal#!a<, re1ultate ne)al!date sau necon)en*!onale, !nter)en*!! non( far acolo#!ce, terap!! care ac*!onea1' d!rect asupra bol!!. Informa-ii )electate din )tudii A extras d!n art!colele care au -ndepl!n!t cr!te( r!!le noastre de c'utare, !nfor a*!! despre ef!cac!tatea terap!!lor ,! reac*!!le ad)erse, dar ,! efectele lor asupra s! pto elor ,! se nelor durer!!, cal!t'*!! )!e*!!, st'r!! afect!)e. A f'cut refer!n*' la eta( anal!1ele recente atunc! c+nd aceste stud!! nu au furn!1at !nfor a*!! le#ate de aceste aspecte. A folos!t nu 'rul necesar de pac!en*! ce trebu!e tra( ta*! ;NNT< pentru a ob*!ne r'spunsul la un ed!ca ent, cu un !nter)al de conf!den*' de H@I pentru stud!!le de clasa 2 sau 22 pentru a c+,t!#a !nfor a*!! pr!)!nd ef!cac!tatea unu! ed!ca ent. Aceste )alor! au fost calculate pentru no!le stud!! sau extrase d!n eta( anal!1ele recente real!1ate de e br!! Co !tetulu! de .edact!onare 89,H,1?: sau d!n ba1a de date Coc$rane 811,1@(1A:. Nu a ut!l!1at ,! nu 'rul de pac!en*! ce trebu!e )'t' a*! dator!t' l!pse! de cr!ter!! un!for e pentru stab!l!rea e)en! entelor de le1are 89:. RE./L A E 0olineuropatia dureroa) Pol!neuropat!a dureroas' este o cau1' co un' de durere neuropat'. Pol!neuropat!a d!abet!c' este exe plul clas!c. Pac!en*!! se pre1!nt' -n #eneral cu durer! spontane sau pro)ocate de d!)er,! st! ul! cu o d!str!bu*!e s! etr!c' ,! d!stal' 818:. 5e,! unul sau a! ulte s! pto e dureroase caracter!st!ce neuropat!e! apar la a&or!tatea pac!en*!lor, cel a! frec)ent s! pto a fost durerea profund' 818:. Pol!neuropat!a dureroas' d!abet!c' ,! non(d!abet!c' au s! pto atolo#!e ,! r'spuns terapeut!c ase 'n'toare ;clasa 2< 81H:. S!n#urele excep*!! sunt neuropat!a >

H24 ,! neuropat!a !ndus' de c$! !oterap!e, care sunt descr!se separat. 'ntidepre(i!ele Ant!depres!)ele au fost recent re)!1u!te -n dou' eta(anal!1e de clasa 2 pentru durerea neuropat', !nclu1+nd pol!neuropat!a dureroas'. 5o)e1! le#ate de ef!cac!tatea ant!depres!)elor tr!c!cl!ce ;A !tr!pt!l!na, Clo !pra !na, 5es!pra !na, 2 !pra !na, Tabelul 1< ex!st' -nc' de acu >E de an!, c+nd au fost !ntroduse pentru pr! a dat' -n terap!a pl!neuropat!e! dure( roase. Ma&or!tatea datelor sur)!n d!n stud!! !c! -ncruc!,ate de clasa 2 sau 22, care pot supraest! a ef!cac!tatea lor.
Tabelul 1. Mecanismele de aciune predominante ale principalelor medicamente Medicament Mecanism de aciune A !tr!pt!l!na Ant!depres!) tr!c!cl!c, !n$!b' recaptarea de onoa !ne Capsa!c!na ;top!c< 5epolar!1ea1' e brana ner)oas' pr!ntr(un receptor )an!lo!d de t!p 1, !n!*!al st! ulea1' apo! bloc$ea1' f!brele ner)oase d!n p!ele Carba a1ep!na Dloc$ea1' canalele de sod!u )olta&(dependente Clo !pra !na Ant!depres!) tr!c!cl!c, !n$!b' recaptarea de onoa !ne 5es!pra !na Ant!depres!) tr!c!cl!c, !n$!b' recaptarea de noradrenal!n' 5extro etorfan Anta#on!st NM5A 5uloxet!na 2n$!b' recaptarea de seroton!n'(noradrenal!n' Se lea#' de subun!tatea J9K a canalelor pres!napt!ce de calc!u )olta&(dependente Gabapent!na cu reducerea el!ber'r!! pres!napt!ce de ed!ator! 2 !pra !na Ant!depres!) tr!c!cl!c, !n$!b' recaptarea de onoa !ne 3!doca!na ;top!c< Dloc$ea1' canalele de sod!u per!fer!ce 3a otr!#!na 2n$!b' canalele de sod!u )olta&(dependente pres!napt!ce ,! reduce el!berarea pres!napt!c' de ed!ator! Me ant!na Anta#on!st NM5A Nortr!pt!l!na 2n$!b' recaptarea de noradrenal!n' Bxcarba1ep!na Dloc$ea1' canalele de sod!u ,! calc!u )olta&(dependente Bx!codona A#on!st al receptor!lor op!o!1! L Se lea#' de subun!tatea J9K a canalelor pres!napt!ce de calc!u )olta&(dependente Pre#abal!na cu reducerea el!ber'r!! pres!napt!ce de ed!ator! Tetra$!drocanab!no A#on!st al receptor!lor canab!no!1! CD1 ,! CD9 Top!ra at Dloc$ea1' canalele de sod!u )olta&(dependente ,! !n$!b' el!berarea #luta atulu! pr!n ac*!une asupra receptor!lor AMPAG"a!nat Tra adol A#on!st al receptor!lor op!o!1! L ,! !n$!b!tor al recapt'r!! de onoa !ne 4alproat Cre,te el!berarea de GADA la n!)elul cre!erulu! 4enlafax!na SN.2, !n$!b' recaptarea de seroton!n'(noradrenal!n'

NNT pentru ant!depres!)ele tr!c!cl!ce -n pol!neuropat!a dureroas' este 9.1 ;C2 1.8(9.F< pentru ed!ca ente care !n$!b' recaptarea de sero( ton!n' ,! noradrenal!n' ,! 9.@ ;C2 1.H(>.F< 81?:. 7ntr(un stud!u, A !tr!pt!l!na a fost u,or, dar se n!f!cat!) a! ef!c!ent' dec+t Maprot!l!na ;clasa 2< 89E:, -n t! p ce un alt stud!u a e,uat s' arate d!feren*e -ntre Clo !pra !na ,! 5es!pra !na ;clasa 2< 891:. 2n$!b!tor!! select!)! de recaptare a seroton!ne! ;SS.2< sau M!anser!na deter !n' efect cl!n!c !nor sau !nsuf!c!ent de d! !nuare a durer!! -n ? stud!! de clasa 2 811,1?:, -n t! p de !n$!b!tor!! de recaptare de se( roton!n'(noradrenal!n' ;SN.2<, cu ar f! 4enlafax!na ;1@E(99@ #G1!<;clasa 2=99,9>< sau 5uloxet!na ;FE( 19E #G1!<;clasa 2=9?,9@<, sunt ef!c!en*!, de,! efectele lor sunt oderate. 7ntr(un stud!u co parat!) de >> de pac!en*!, 4enlafax!na a fost a! pu*!n ef!c!ent' dec+t 2 !pra !na -n ceea ce pr!)e,te propor*!a de pac!en*! ce au r'spuns ;clasa 2= 9><. Cu do1e adec)ate, NNT a fost ?.F ;C2 9.H(1E.F< pentru 4enlafax!na ;1@E(99@ #G1!< ,! @.9 ;C2 >.A(8.@< pentru 5uloxet!na ;FE( 19E #G1!<. 'ntiepilepticele 5ou' stud!! !c! dublu(orb -ncruc!,ate, publ!cate acu >E de an!, au raportat un ! portant efect al Carba a1ep!ne! -n pol!enuropat!a dureroas' d!abe( t!c', dar etodele nu se r!d!c' la standardele de ast'1! ;clasa 222= 9F,9A<. 6n stud!u !c dublu(orb cu 1F pac!en*! raportea1' ef!cac!tate s! !lar' -ntre Carba a1ep!na ,! Nortr!pt!l!n(0lufena1!na, dar nu( 'rul de pac!en*! este prea !c pentru a ar'ta o d!feren*' ;clasa 22= 98<. 5atele despre Bxcarba1ep!na au fost e)a1!)e -n pol!neuropat!a dureroas' &udec+nd dup' abstractele con#resulu! /0NS d!n 9EE?, cu c+te)a stud!! ne#at!)e nepubl!cate. Cu toate acestea, un stud!u recent dublu(orb controlat placebo cu durata de 1F s'pt'( +n!, ar'ta c' Bxcarba1ep!na ;>EE(18EE #G1!< a a)ut un efect benef!c odest, dar se n!f!cat!) pen( tru pac!en*!! cu pol!neuropat!e dureroas' d!abet!c' cu NNTM@.H ;C2 >.9(?9.9< ;clasa 22=9H<. 3a otr!#!na are ef!c!en*' se n!f!cat!)' cu NNTM?.E ;C2 9.1(?9< la pac!en*!! cu pol!neuropat!e dure( roas' d!abet!c' ;clasa 2= >E<. Top!ra atul a e,uat -n a a el!ora durerea d!n pol!neuropat!a d!abet!c' -n > stud!! controlate ar! ;clasa 2= >1<, !ar un altul a ar'tat un efect odest cu NNTMA.? ;?.9(98.@< ;clasa 2= >9<. Pentru ca datele despre 4alproat sunt contro)ersate cu 9 stud!! po1!t!)e ;NNTM1.@C C2 1.9(9.9< ;clasa 22= >>,>?< ,! unul ne#at!) ;clasa 2= >@<, poten*!alul lu! -n pol!neuropat!a dureroas' trebu!e clar!f!cat. Ant!ep!lept!cele cu cele a! bune do)e1! pentru ef!cac!tatea -n pol!neuropat!a dureroas' sunt Gaba( pent!nul ;19EE(>FEE #G1!< ,! Pre#abal!nul ;1@E(FEE #G1!< ;clasa 2=>F(>H:. Aceste ed!ca ente a e( l!orea1' durerea d!n pol!neuropat!a d!abet!c' con( s!stent de(a lun#ul a! ultor stud!! ;NNTM>.H, C2 >.9(@.1<. Ma&or!tatea stud!!lor !n!*!ale despre Pre#abal!n au fost ne#at!)e pentru c' ele au !nclus pac!en*! nerespons!)! la Gabapent!n, dar alte 9 stud!! recente de clasa 2 rando !1ate controlate, f'r' acest cr!ter!u, au raportat ef!cac!tate s! !lar' @

8?E,?1:. 6n s!n#ur stud!u a co parat Gabapent!nul ;18EE #G1!< cu A !tr!pt!l!na ;A@ #G1!<. 5ator!t' nu 'rulu! prea !c de pac!en*!, d!feren*a de ef!cac!tate ,! tolerab!l!tate -ntre aceste dou' ed!ca ente nu a putut f! stab!l!t' ;clasa 22= ?9<. 7ntr(un stud!u nepubl!cat care a co parat Pre#abal!na ,! A !tr!pt!l!na cu placebo, A !tr!pt!l!na, ,! nu Pre#abal!na, a fost se n!f!cat!) a! ef!c!ent' dec+t placebo ;clasa 22<. 6pioidele Bx!codona ;do1a ed!e >A(FE #G1! cu l! !te 1E(HH #G1!<, s!n#urul op!o!d folos!t -n pol!neuropat!a dureroas', este ef!c!ent cu NNTM9.F ;C2 1.H(?.1< ;clasa 2= ?>,??<. Pac!en*!! care au a! pr! !t op!o!de -n antecedente au putut part!c!pa la aceste stud!!, ceea ce e pos!b!l s' f! crescut propor*!a de r'spunsur! po1!t!)e ,! s' f! redus rata efectelor ad)erse. Tra a( dolul 9EE(?EE #G1!, cu efecte op!o!de ,! onoa !( ner#!ce, are ef!cac!tate -n pol!neuropat!a dureroas' cu NNTM>.? ;C2 9.>(F.?< ;clasa 2= ?@,?F<. 'ltele Mex!let!na ;ant!ar!t !c< nu a ar'tat un efect se n!f!cat!) -n ? stud!! de clasa 2(22 -n pol!neuropat!a dureroas'. Capsa!c!na apl!cat' local a furn!1at re1ultate d!screpante de(a lun#ul a @ stud!! de clasa 2(22 care nu au e)!den*!at a el!orarea durer!! se n!( f!cat!) 89:. Sen1a*!a !ntens' de arsur' la locul apl!c'r!! scade destul de ult co pl!an*a. Me ant!na ;anata( #on!st NM5A< nu a ar'tat ef!cac!tate con)!n#'toare -n pol!neuropat!a dureroas' ;clasa 2= ?A<, -n t! p ce a el!orare -n durere a ar'tat 5extro etorfanul -n 9 stud!! !c! ;clasa 22= ?A,?8<. /f!cac!tatea 3e)odope! a fost raportat' -ntr(un stud!u !c rando !1at controlat ;clasa 22= ?H<. Alte ed!ca ente -ncercate -n pol!( neuropat!a dureroas' ;Asp!r!na, A2NS, Clon!d!na apl!cat' local< au ef!cac!tate l! !tat' sau absent' pe ba1a stud!!lor de clas' 2(22. Neuropatia a(ociat: cu in.ec;ia %I* <i neuropatia indu(: de chi#ioterapie 5ou' stud!! rando !1ate controlate nu au ar'tat benef!c!u terapeut!c d!n parte 3a otr!#!ne! ;>EE( FEE #G1!< la pac!en*!! cu neuropat!e H24(asoc!at', except+nd sub#rupur!le de pac!en*! care pr! eau conco !tent a#ent ant!retro)!ral ;clasa 2G22= @E,@1<= stud!ul cu cel a! are nu 'r de pac!en*! ;99A< care a folos!t rando !1are strat!f!cat', a ar'tat ef!( cac!tate pentru #rupul care pr! ea a#ent ant!re( tro)!ral ,! a ar'tat efect placebo -nalt -n #rupul care nu pr! ea a#ent ant!retro)!ral 8@1:, -n t! p ce stud!ul a! !c a de onstrat efecte benef!ce -n #rupul care nu pr! ea a#ent ant!retro)!ral 8@E:. 7ntr(un stud!u -ncruc!,at rando !1at controlat, Gabapent!na ;p+n' la 9?EE #G1!< a a el!orat durerea ,! so nul -n aceea,! 'sur' ca ,! placebo ;clasa 22= @9<. /x!st' do)e1!, d!n stud!! de clasa 2G22, c' A !tr!pt!l!na 8@>,@?:, 3!doca!na local' 8@@:, Mex!let!na 8@?,@F: ,! Capsa!c!na nu au ef!cac!tate. 6n stud!u de clasa 22 rando !1at controlat, efec( tuat pentru pac!en*!! cu neuropat!e F

!ndus' de C!s( plat!n, a raportat un !c benef!c!u d!n partea Notr!pt!l!ne! ;1EE #G1!< asupra durer!! ,! pareste1!!lor, dar area l! !tare a acestu! stud!u este d!st!nc*!a d!f!c!l' -ntre durere ,! pareste1!! 8@8:. "erapii co#binate 5ou' stud!! rando !1at controlate au stud!at terap!a co b!nat'. Cel a! are, care a !nclus ,! pa( c!en*! cu ne)ral#!e post$erpet!c', a de onstrat efectele s!ner#!ce ale Gabapent!nulu! ,! Morf!ne!, cu !nstalarea anal#e1!e! la do1e a! !c! d!n f!ecare ed!ca ent, dar efectul ad!*!onal al co b!na*!e! a fost sc'1ut ;clasa 2= @H<. 6n alt stud!u a ar'tat super!or!tatea co b!na*!e! Gabapent!n(4enlafax!n' asupra durer!!, st'r!! afect!)e ,! cal!t'*!! )!e*!! -n co para*!e cu Gabapent!n plus placebo, dar stud!ul a a)ut un nu 'r prea !c de pac!en*! ;11< ;clasa 22= >H<. Recomandri Terap!!le cu ef!cac!tate stab!l!t' pe ba1a stud!!lor de clasa 2 -n pol!neuropat!a dureroas' ;except+nd neuropat!a H24(asoc!at'< sunt ant!depres!)ele tr!( c!cl!ce, 5uloxet!na, 4enlafax!na, Gabapent!nul, Pre( #abal!nul, op!o!dele ,! Tra adolul ;n!)el A de reco andare<. Ant!depres!)ele tr!c!cl!ce ;A !tr!p( t!l!na ,! 2 !pra !na< -n do1e adec)ate par s' a!b' cea a! are ef!cac!tate pe ba1a NNT, dar ulte d!ntre stud!!le !c! pot supraaprec!a ef!cac!tatea. No! reco and' ant!depres!)ele tr!c!cl!ce sau Gabapent!nul c' pr! a ale#ere. SN.2 ;5uloxet!na ,! 4enlafax!na< sunt cons!derate terap!! de l!n!a a doua pentru c' au ef!cac!tate oderat', dar sunt a! s!#ure ,! au a! pu*!ne contra!nd!ca*!! dec+t ant!de( pres!)ele tr!c!cl!ce ,! ar trebu! preferate acestora la pac!en*!! cu factor! de r!sc card!o)ascular. Bp!o!dele ,! 3a otr!#!na sunt terap!! de l!n!a a doua sau a tre!a. Terap!!le cu ef!cac!tate !n! ' sunt= Capsa!c!na, Mex!let!na, Bxcarba1ep!na, SS.2, Top!ra atul ;n!)elul A<, Me ant!na, M!anser!na ,! Clon!d!na local' ;n!)elul D<. 7n ceea ce pr!)e,te Carba a1ep!na, o)e!le sunt l! !tate ;n!)elul C<, la fel ,! pentru 5extro etorfan ,! 3e)odopa. Pentru 4alproat p+n' acu s(au ob*!nut re1ultate d!screpante. Pol!neuropat!a H24(asoc!at' a fost refractar' la a&or!tatea acestor ed!ca ente. Acest aspect probab!l c' se datorea1' unu! ecan!s aparte de producere a durer!! sau unu! r'spuns placebo -nalt, obser)at -n a&or!tatea stud!!lor. 5oar 3a otr!#!na a fost raportat' ca f!!nd ef!c!ent' la pac!en*!! care pr! esc a#ent ant!retro)!ral -ntr(un stud!u de clasa 2, dar un alt stud!u a! !c de clasa 22 a raportat re1ultate total opuse ;n!)el D<. Nevralgia po)therpetic Ne)ral#!a post$erpet!c' este o consec!n*' du( reroas' a $erpesulu! 1oster. Ce! a! ! portan*! factor! de r!sc pentru ne)ral#!a post$erpet!c' sunt )+rsta -na!ntat' ,! durerea acut' se)er'. Pac!en*!! cu ne)ral#!e post$erpet!c' descr!u durere cu carac( ter A

de arsur' constant', durere !nter !tent' cu caracter lanc!nant ,! alod!n!e ;-n peste HEI d!ntre ca1ur!<. Pentru f!ecare !nd!)!d, or!care d!n co po( nente poate f! a! e)!dent' 8FE:. 'ntidepre(i!ele A !tr!pt!l!na ;F@(1EE #G1!<, Nortr!pt!l!na ;8H #G1!<, 5es!pra !na ;F@(A> #G1!< sunt ef!c!ente -n ne)ral#!a post$erpet!c' pe ba1a a tre! stud!! de clasa 2(22 placebo( controlate cu NNTM9.F ;C2 9.1(>.@< ;clasa 2= 8,H<. 7n dou' stud!! !c! co parat!)e, ant!depres!)ul Maprot!l!na a fost #'s!t ca f!!nd a! pu*!n ef!c!ent dec+t A !tr!pt!l!na ;clasa 22= F1< ,! Nortr!pt!l!na la fel de ef!c!ent' c' A !tr!pt!l!na, dar a! b!ne tolerat' ;clasa 22= F9<. Nu ex!st' stud!! rando !1ate controlate despre ef!cac!tatea SS.2 sau SN.2 -n ne)ral#!a post$erpet!c'. 'ntiepilepticele Gabapent!na ;18EE(>FEE #G1!< ;clasa 2= F>,F?< ,! Pre#abal!na ;1@E(FEE #G1!< ;clasa 2= F@,FF< s(au ar'tat constant a f! ef!c!ente -n ne)ral#!a post$erpet!c' cu un NNT de ?.? ;C2 >.>(F.1< pentru Gabapent!n ,! ?.H ;C2 >.A(A.F< pentru Pre#abal!n ;clasa 2= H<. .ecent, au fost raportate foarte bune re1ultate cu 4alproatul cu un NNTM9.1 ;C2 1.?( ?.9< ;clasa 22=FF<. "erapii topice Apl!ca*!! repetate de 3!doca!n' patc$ ;@I< au de( onstrat ef!cac!tate -n ne)ral#!a post$erpet!c' cu alod!n!e -n tre! stud!! placebo(controlate, toate cu durat' scurt' de desf',urare ;p+n' la > s'pt' +n!< ;clasa 22= F8(AE<. 6n stud!u cu >9 de pac!en*! nu a raportat n!)elele ba1ale de durere ,! a ut!l!1at o -n( rolare - bo#'*!t' ;doar pac!en*!! cu a el!orare cl!( n!c' la trata entul desc$!s ;Nopen(labelO< cu l!doca( !n' top!c' au fost ,! recruta*!<. 5ou' stud!! 8FH,AE: au fost anal!1e post($oc cu !nfor a*!! pro)en!te d!n stud!! a! lar#! care au !nclus ult!ple et!olo#!! de durere neuropat' ;clasa 22= A1< !nclus!) ne)ral#!a post$erpet!c' 8F8:. Capsa!c!na apl!cat' top!c E.EA@I a fost #'s!t' ca f!!nd ef!c!ent', de,! -ntr(un #rad !c, -n dou' stud!! paralele rando !1ate controlate ,! cau1ea1' frec)ent sen1a*!e de arsur' ;clasa 2= A9,A><. 6pioide Bx!codona, Morf!na ,! Metadona au a)ut ef!cac!( tate -n ne)ral#!a post$erpet!c' -n dou' stud!! -ncru( c!,ate placebo(controlate rando !1ate ;clasa 2= A?,A@<. 6n stud!u paralel necontrolat placebo a raportat ef!cac!tate a! are a do1elor ar! de 3e)orfanol co parat!) cu do1ele !c! la pac!en*!! cu ne)ral#!e post$erpet!c' ;clasa 2=AF<. NNT pentru op!o!dele putern!ce -n ne)ral#!a post$erpet!c' este 9.A ;C2 9.1(>.A< ;clasa 2= H<. 7ntr(un stud!u care a co parat Morf!na cu el!berare lent' ;H1 #G1!, l!( !te 1@(99@ #G1!< ,! Metadon' ;1@ #G1!< cu ant!( depres!)ele tr!c!cl!ce ,! placebo, a el!orarea durer!! a fost se n!f!cat!) a! are cu Morf!na co parat!) cu Nortr!pt!l!na, -n t! p ce efectul anal#e1!c al Metadone! a fost ase 'n'tor cu al ant!depres!)elor tr!c!cl!ce 8A@:. Au fost a! ulte -ntrerupr! de trata ent pentru op!o!de dec+t pentru ant!depres!)e tr!c!cl!ce, dar deter!orarea 8

co#n!t!)' a fost obser)at' doar pentru ant!depres!)ele tr!c!cl!ce. Tra adolul ;do1' ed!e 9A@ #G1! p+n' la ?EE #G1!< a ar'tat ef!cac!tate oderat' cu NNTM?.8 ;C2 9.F(9F.H< ;clasa 2= AA<, stud!u -n care au fost !nclu,! doar pac!en*!! cu durere de a! pu*!n de un an, de aceea un!! pac!en*! s(au a el!orat spontan, ceea ce a crescut rata de r'spuns placebo. 'lte terapii Anta#on!,t!! NM5A ;5extro etorfan, Me ant!( na< ,! ben1od!a1ep!nele ;3ora1epa < sunt !nef!c!ente -n ne)ral#!a post$erpet!c' ;clasa 2G22= ?A,?8,A8,AH<. Recomandri Med!ca entele ef!c!ente -n ne)ral#!a post$erpet!c' sunt= ant!depres!)ele tr!c!cl!ce, Gabapent!na, Pre#abal!na ,! op!o!dele ;n!)el A, clasa 2<. Med!ca ente cu ef!cac!tate a! !c' sunt= Capsa!c!na, Tra adolul, 3!doca!na top!c ,! 4alproatul ;n!)el D<. No! reco and' ant!depres!)ele tr!c!cl!ce sau Gaba( pent!na GPre#abal!na ca pr! a l!n!e terapeut!c'. 3!doca!na apl!cat' top!c a fost e)aluat' doar la pac!en*!! cu alod!n!e -n stud!! de scurt' durat', care au ut!l!1at o recrutare - bo#'*!t' sau au fost anal!1e post( $oc der!)ate d!n stud!! a! ar!. 5ator!t' tolerab!l!t'*!! foarte bune, acest trata ent poate f! preferat la )+rstn!c!, a! ales la ce! cu alod!n!e ,! ar!e restr+ns' de durere. Bp!o!dele ar trebu! reco andate c' terap!e de l!n!a a doua d!n cau1a reac*!!lor ad)erse. Mex!let!na, 3ora1epa ul ,! anta#on!,t!! NM5A au ef!cac!tate slab' sau sunt !nef!c!ente ;n!)el A<. Nevralgia trigeminal Ne)ral#!a tr!#e !nal' ;NT< t!p!c' se caracter!1ea1' pr!n durere parox!st!c' cu atacur! scurte, ap'rute brusc, ase 'n'toare ,ocur!lor electr!ce. 5urerea poate f! spontan' sau deter !nat' de d!fer!*! st! ul! care ac*!onea1' la n!)el fac!al sau !ntraoral ;1one tr!##er<. NT se - parte -n= clas!c' ;c+nd este secundar' une! co pres!! )asculare a ner)ulu! tr!#e en la n!)elul un#$!ulu! cerebelopont!n sau c+nd nu se poate dep!sta o cau1' a durer!!< ,! s! pto at!c' ;c+nd ex!st' o le1!une la n!)elul un#$!ulu! cerebelopont!n= as' tu oral', sclero1' ult!pl'<. Pac!en*!! cu NT s! pto at!c' r'spund a! pu*!n la terap!e 88E: 'ntiepilepticele 0en!to!na a fost pr! ul ed!ca ent folos!t -n NT, cu re1ultate po1!t!)e, dar ex!st' doar stud!! de clasa 24 despre acest aspect 881:. Carba a1ep!na ;9EE(19EE #G1!< a fost stud!at' -n ur ' cu ?E de an! -n tre! stud!! placebo(controlate, care au !nclus un total de 1@E de pac!en*!, cu un NNTM1.8 ;1.>( 9.9<, stud!! de clasa 22(222 81F,81: ,! a a)ut efect at+t pe frec)en*a, c+t ,! pe !ntens!tatea parox!s elor 889:. 6t!l!1area Carba a1ep!ne! este co pl!cat' de far acoc!net!ca e! ,! uneor! de reac*!!le ad)erse se)ere, -n spec!al la )+rstn!c!. Cu toate acestea, H

ef!cac!tatea e! foarte bun' -n NT co pensea1' tolerab!l!tatea sc'1ut'. Bxcarba1ep!na este folos!t' ca trata ent !n!*!al -n NT 88>:. /ste preferat' Carba a1ep!ne! dator!t' tolerab!l!t'*!! a! ar! ;clasa 2= 8?<. Tre! stud!! dublu( orb rando !1ate controlate au co parat Bxcarba( 1ep!na ;do1a ed!e 1E8> #G1!< cu Carba a1ep!na ;do1a ed!e A>? #G1!< ;No)art!s, Dasel, SP!t1erland<. 5oar unul d!n ele a fost publ!cat -n extenso ;clasa 22= 8@<. 7n eta(anal!1ele acestor stud!!, !nclu1+nd 1>E de pac!en*!, re1ultatele au fost s! !lare pentru cele dou' ed!ca ente ;88I d!ntre pac!en*! au ob*!nut o reducere a atacur!lor cu Q @EI< ;clasa 22= 8F<. Aceste stud!! nu au fost controlate placebo ,! doar unul publ!cat !n extenso este -n acord cu cr!ter!!le /0NS. /f!cac!tatea Carba a1ep!ne! ,! Bxcarba1ep!ne! scade cu t! pul ;clasa 2= 81<. 3a otr!#!na ;?EE #G1!< a fost ef!c!ent' ca tera( p!e ad!*!onal' pe un !ndex co po1!t de ef!cac!tate la 1? pac!en*! ;clasa 22= 8A<. Nu s(au ob*!nut re1ultate stat!st!ce -n ceea ce pr!)e,te !ntens!tatea ,! frec)en*a parox!s elor. Alte ant!ep!lept!ce ;Clona1epa , Gabapent!n, 4alproat< au fost raportate ca f!!nd ef!c!ente -n stud!! !c! necontrolate de clasa 24. 'lte #edica#ente Stud!! !c! de clasa 22 ;1E(1@ pac!en*!< au ar'tat c' Daclofenul reduce nu 'rul de atacur! 888,8H:. Toca!n!da ,! P! o1!da au fost raportate ca f!!nd la fel de ef!c!ente sau a! ef!c!ente dec+t Carba a1ep!na ;clasa 22= HE,H1<, dar ele nu se a! folosesc. "erapii ine.iciente 2nclude aneste1!a top!c' oftal !c' ;clasa 2= H9< ,! Capsa!c!na top!c' ;clasa 222= H><. T!1an!d!na este a! pu*!n ef!c!ent' dec+t Carba a1ep!na ;clasa 22G222= H?,H@<.

"erapii de co#binare Terap!!le co b!nate pot f! ef!c!ente, pol!terap!a cu ono( terap!a 8HF:.

dar nu ex!st' stud!! care s' co pare

Nevralgia trigeminal )imptomatic 3a otr!#!na, Gabapent!na ,! Top!ra atul au fost raportate ca f!!nd ef!c!ente -n stud!! de clasa 24 -n NT asoc!at' cu SM. Toate stud!!le le#ate de NT sn( dar' une! tu or! de un#$! cerebelopont!n au !nd!cat trata entul c$!rur#!cal. Recomandri Cele dou' ed!ca ente cel a! frec)ent folo( s!te -n NT !d!opat!c' sunt Carba a1ep!na ;9EE(19EE #G1!< ;n!)el A< ,! Bxcarba1ep!na ;FEE(18EE #G1!< ;n!)el D<. Bxcarba1ep!na are a! pu*!ne do)e1! dec+t Carba a1ep!na, dar este a! s!#ur'. Daclofenul ,! 3a otr!#!na au doar do)e1! de n!)el C. No! reco( and' ca pr! ' 1E

op*!une terapeut!c' Carba( a1ep!na sau Bxcarba1ep!na. Pentru c' NT de ob!ce! durea1' toat' )!a*a cu per!oade de re !s!une co plet' sau par*!al' ,! per!oade de recurent', pac!en*!! trebu!e educa*! s'(,! adapte1e do1ele frec)en*e! atacur!lor. Nu ex!st' do)e1! c' terap!a de co b!nare este a)anta&oas'. 3a pac!en*!! non(res( pons!)! la trata entul ed!cal, !nter)en*!!le c$!rur( #!cale au a)ut re1ultate excelente. Mul*! pac!en*! nu tolerea1' testarea far acolo#!c' cu durata de c+te)a s'pt' +n! ,! au ne)o!e de trata ent neuroc$!rur#!cal. Daclofenul ,! 3a otr!#!na sunt reco andate atunc! c+nd pac!en*!! sunt refractar! la Carba a1ep!na sau Bx( carba1ep!na sau c+nd refu1' !nter)en*!a c$!rur#!cal'. 7ncura&' stud!!le controlate -n NT s! pto( at!c'. (urerea central 5urerea central' sau durerea neuropat!c' de t!p central se datorea1' une! le1!un! -n s!ste ul ner( )os central. Poate f! consec!n*a unu! acc!dent )as( cular cerebral, sclero1e! ult!ple, trau at!s elor sp!nale sau altor et!olo#!! 8HA:. 5urerea poate a)ea d!fer!te caractere= arsur', -n*ep'tur', ap'sare ,! deseor! se -nso*e,te de d!seste1!e, $!peral#e1!e sau alod!n!e, a! ales la per!at sau rece 8HA,H8:. 'ntidepre(i!ele triciclice A !tr!pt!l!na a fost stud!at' -n durerea post(A4C ,! post(trau at!s e sp!nale. 3a 1@ pac!en*! cu durere post(A4C, A !tr!pt!l!na A@ #G1! a fost super!oar' efectulu! placebo ;NNTM1.AC C2 1.9(>.1< ,! Carba a1ep!ne! ;8EE #G1!<, aceasta d!n ur ' a)+nd efect ase 'n'tor cu cel placebo ;clasa 2=HH<. 7ntr( un stud!u lar# de pac!en*! cu durere posttrau a( t!s e sp!nale ;nM8?<, A !tr!pt!l!na ;do1a ed!e de @@ #G1!< a fost !nef!c!ent', dar l!psa efectulu! se poate datora e)alu'r!! !nadec)ate a durer!! neuro( pat!ce ;clasa 2= 1EE<= scopul pr! ar a fost durerea #lobal', ,! doar anal!1a pr!n re#res!e s(a ut!l!1at pentru a aprec!a dac' efectul a !tr!pt!l!ne! a fost !nfluen*at de pre1en*a durer!! neuropat!ce. 'ntiepilepticele 7ntr(un stud!u de clasa 2 cu >E de pac!en*! cu durere post(A4C, 3a otr!#!na ;9EE #G1!< a redus se n!f!cat!) !ntens!tatea durer!! co parat!) cu placebo 81E1:. 3a pac!en*!! cu trau at!s e ale 'du)e! sp!n'r!!, 3a otr!#!na ;p+n' la ?EE #G1!< nu a deter !nat un efect se n!f!cat!) asupra durer!! spontane sau pro)ocate, dar un efect a fost obser)at -ntr(o anal!1' post($oc la pac!en*!! cu trau at!s e !nco plete ale 'du)e! sp!n'r!! ;clasa 2= 1E9<. 7ntr(un stud!u !c -ncruc!,at de 9E de pac!en*! cu durere -n ur a trau at!s elor 'du)e! sp!n'r!!, Gabapent!na ;p+n' la >FEE #G1!< a a)ut ef!c!en*' se n!f!cat!)' ;clasa 22= 1E><. Pre#abal!na ;do1a ed!e ?FE #G1!< a fost se n!f!cat!) ef!c!ent -ntr( un stud!u lar# ;nM1>A< de clasa 2 paralel rando !1at controlat ;Pf!1er<. 7ntr(un stud!u rando !1at controlat le#at de tra( u at!s ele 'du)e! sp!n'r!!, nu a fost )reo d!fe( ren*' -ntre 4alproat ;p+n' la 9?EE #G1! t! p de > s'pt' +n!< ,! placebo ;clasa 22= 1E?<. 11

6pioidele /x!st' un s!n#ur stud!u rando !1at controlat despre op!o!de, -n afec*!un! ale s!ste ulu! ner)os central sau per!fer!c care deter !n' durere ;et!olo#!! ult!ple<C 3e)orfanol -n do1' are ;8.H #G1!< a fost a! ef!c!ent dec+t -n do1a !c' ;9.A #G1!< la pac!en*!! cu durere central', dar nu a ex!stat un #rup placebo ;clasa 2= AF<. Nu au ex!stat d!feren*e pentru pac!en*!! cu trau at!s e sp!nale, sclero1' ult!pl', ne)ral#!a post$erpet!c' sau pol!neuropat!a dure( roas', dar pac!en*!! cu le1!un! cerebrale au renun*at a! frec)ent la ed!ca*!e d!n cau1a efectelor ad( )erse. 'ltele 7ntr(un stud!u !c -ncruc!,at cu 11 pac!en*! cu trau at!s e sp!nale, Mex!let!na ;?@E #G1!< nu a fost a! bun dec+t placebo ;clasa 22= 1E@<. 5o1ele prea !c! ,! nu 'rul redus de pac!en*! ar putea &uca un rol -n re1ultatele acestu! stud!u. Trata entul canab!no!d a fost stud!at recent -n dou' stud!! rando !1ate controlate despre durere la pac!en*!! cu sclero1' ult!pl'. 7ntr(un stud!u cu 9? de pac!en*!, 5ronab!nol ;tetra$!drocanab!nol, THC< @(1E #G1!, t! p de > s'pt' +n!, a fost super!or efectulu! placebo cu un NNTM>.? ;C2 1.8(9>.?< ;clasa 2= 1EF< asupra durer!! ,! parox!s elor dureroase, dar nu ,! asupra ecan!s elor alod!n!e!. Canab!no!dele ad !n!strate sub for ' de spraR oral ;9.A # THC ,! 9.@ # Canab!d!ol< sunt -ntr(un stud!u cl!n!c de fa1a 222 pentru durerea d!n SM. 6n stud!u paralel placebo( controlat care a !nclus FF de pac!en*! a ar'tat efecte benef!ce asupra durer!! ,! so nulu! ;do1a ed!e de ad !n!str'r! ale spraR(ulu! H.F, l! !te 9(9@< cu un NNTM>.A ;C2 9.9(1>< ;clasa 2= 1EA<. Pac!en*!! !nclu,! au a)ut f!e durere neuropat!c', f!e durere deter !( nat' de spas , !ar anal!1ele post($oc au !nd!cat un efect a! bun pentru pac!en*!! cu spas e usculare dureroase. Recomandri 3u+nd -n cons!derare nu 'rul !c de stud!! ran( do !1at(controlate -n durerea central' ,! nu 'rul !c de pac!en*! !nclu,!, trata entul se ba1ea1' pe pr!nc!p!! #enerale ale durer!! neuropat!ce per!fer!ce. /x!st' do)e1! de n!)el D pentru ut!l!1area 3a otr!( #!ne!, Gabapent!ne!, Pre#abal!ne! ;stud!u nepubl!cat< sau ant!depres!)elor tr!c!cl!ce pentru durerea post( A4C sau durerea d!n trau at!s e sp!nale. N!)elul de e)!den*' este sc'1ut pentru op!o!de -n l!psa stud!!lor cu control placebo ;n!)el C<. /x!st' do)e1! de n!)el D -n ceea ce pr!)e,te !nef!c!en*a 4alproatulu! ,! Mex!let!ne! -n durerea d!n trau at!s ele sp!nale. 7n durerea central' asoc!at' cu SM, canab!no!dele au ar'tat ef!c!en*' se n!f!cat!)' ;n!)el A<, dar pot r!d!ca proble e le#ate de s!#uran*'. 5e aceea, no! reco and' -ncercarea !n!*!al' a altor ed!ca ente ef!c!ente -n durerea central'. Condi-ii de durere neuropatic mai pu-in )tudiate Stud!!le rando !1at controlate despre cond!*!!le neuropat!ce a! pu*!n stud!ate s(au refer!t la can( cere !nf!ltrat!)e, e brul fanto ', le1!une ner)oas' postc$!rur#!cal' sau posttrau at!c', s!ndro ul 19

Gu!llan(Darre sau et!olo#!! ult!ple ale durer!! neuropat!ce. 5e,! ulte stud!! rando !1ate controlate au fost efectuate -n do en!ul lo bal#!e!, n!c! unul nu a cons!derat durerea rad!cular' ca ob!ect!) pr! ar. 7n ceea ce pr!)e,te s!ndroa ele cron!ce de durere rad!cular', a&or!tatea stud!!lor au !nclus pac!en*! cu C.PS 2 sau au ut!l!1at blocada ner)!lor s! pat!c! ;clasa 2= 1E8<. $urerea neuropatic: datorat: in.iltr:rii canceroa(e Gabapent!na ;p+n' la 18EE #G1!< asoc!at' cu op!o!de au !ndus efecte benef!ce odeste asupra durer!! ,! d!seste1!e! -ntr( un stud!u are ;nM191< de clasa 2 rando !1at controlat 81EH:C Gabapent!na a fost -n #eneral b!ne tolerat', f'r' d!feren*e fa*' de placebo atunc! c+nd a fost retras'. 6n stud!u .C cu do1' !c' de A !tr!pt!l!n' ;>E(@E #G1!< -n co b!( na*!e cu op!o!de pentru 1E 1!le a raportat un efect odest asupra durer!! ax! e dar nu ,! asupra durer!! ed!!. $urerea neuropatic: po(tchirur-ical: (au po(ttrau#atic: Tre! stud!! au fost efectuate -n durerea post as( tecto !e ,! unul -n durerea !xt' postc$!rur#!cal' le#at' de cancer. 6n stud!u !c ;nM1@< de clasa 22 a ar'tat ef!c!en*a A !tr!pt!l!ne! ;9@(1EE #G1!< -n durere, so n ,! act!)!t'*! 1!ln!ce 8111:C efectele ad)erse au cau1at patru retra#er! ,! a&or!tatea pac!en*!lor au -ntrerupt trata entul dup' stud!u. 7ntr(un stud!u !c ;nM1>< de clasa 22 .C, carac( ter!1at pr!ntr(un re arcab!l r'spuns placebo, do1e !c! de 4enlafax!n' ;>A.@(A@ #G1!< a a)ut efect pe durerea ax! al', dar nu pe durerea ed!e 8119:. Capsa!c!na top!c' ;E.EA@I< a fost raportat' ca f!!nd -n #eneral ef!c!ent' -ntr(un stud!u lar# de clasa 2 -n durerea postc$!rur#!cal' 811>:, -n t! p ce -ntr(un stud!u !c de clasa 22 cu pac!en*! cu durere post( astecto !e, a a)ut efecte ne#at!)e asupra durer!! pers!stente ,! efecte po1!t!)e asupra durer!! exa( cerbate ,! !ntens!t'*!! durer!! 811?:. A +ndou' stud!!le au folos!t placebo, ceea ce poate deter !na o eroare s!ste at!c' dator!t' sen1a*!e! de arsur' pe care o !nduce Capsa!c!na. /x!st' do)e1! -n ceea ce pr!)e,te !nef!c!en*a Propranololulu! -n le1!un!le ner)oase posttrau at!ce ;clasa 22= 11@< sau a spraR(ulu! canab!no!d -n durerea d!n le1!un!le pr!n s ul#ere a plexulu! bra$!al ;clasa 2= 11F<. $urerea #e#brului .anto#: 7ntr(un stud!u !c ;nM1H< de clasa 22 TC, Gabapent!na t!trat' p+n' la 9?EE #G1! a fost ef!c!enta pe durere, dar nu ,! pe starea afect!)', so n sau act!)!t'*! 1!ln!ce 811A:. Morf!na sulfatat' ;AE(>EE #G1!< a fost ef!c!ent' -ntr(un stud!u !c ;nM19< de clasa 22 .C, dar a&or!tatea pac!en*!lor ,! terapeu*!lor au recunoscut trata entul act!), ceea ce a descoper!t controlul orb al stud!ulu!. /x!st' do)e1! -n ceea ce pr!)e,te !nef!c!en*a Me ant!ne! >E #G1! ;clasa 2= 11H< sau A !tr!pt!l!ne! 19@ #G1! ;clasa 22= 19E<. 1>

Sindro#ul 5uillan-,arre 5ou' stud!! de clasa 22 .C de durat' scurt' ;A 1!le< au ut!l!1at Gabapent!na co b!nat' cu op!o!dele. Gabapent!na a fost super!oar' efectulu! placebo -ntr(un stud!u ;nM18C 191< ,! super!or Carba a1ep!ne! -ntr(un altul ;nM>FC 199<, cu reducere rap!d' ;9(> 1!le< a durer!! ,! consu ulu! de op!o!de. B cercetare s!ste at!c' a unu! #rup de consens sus*!ne ut!l!1area Gabapent!ne! sau Carba a1ep!ne! -n un!t'*!le de terap!e !ntens!)' -n fa1' acut' a bol!!, -n t! p ce op!o!dele pot f! folos!te, dar neces!t' on!tor!1are atent' a efectelor ad)erse 819>: $urerile neuropatice de etiolo-ie #ultipl: Stud!! despre durerea neuropat!c' de et!lo#!e ult!pl' au !nclus o propor*!e are de pac!en*! cu C.PS ;co plex re#!onal pa!n sRndro e< sau rad!culopat!e. Pentru pac!en*!! cu durere neuropat!c' per!fer!c' ex!st' do)e1! pentru ef!cac!tatea ant!( depres!)elor Duprop!on 1@E # ;clasa 2= 19?<, Clo !( pra !na ;clasa 22= 19@,19F<, Nortr!pt!l!na ;clasa 22= 19@<C Carba a1ep!na ;clasa 22= 19A< ,! 3!doca!na top!c' 8A1:. .e1ultate d!screpante au fost raportate pentru Mex!let!na ;clasa 2= 198,19H< cu efecte po1!( t!)e asupra ecan!s elor alod!n!e! 819H:. .e1ultatele cu anata#on!stul NM5A, .!lu1ol, au fost ne#at!)e -ntr(un stud!u ;clasa 22= 1>E<. 6n alt stud!u a ar'tat re1ultate ne#at!)e pentru do1e f!xe de Morf!n' ;clasa 22= 19A<. Patru stud!! .C au exa !nat efectele op!o!delor 8AF:, 5extro orfanulu! ;re1ulate ne#at!)eC clasa 22= 1>1<, Gabapent!ne! ;clasa 22= 1>9< sau canab!no!dulu! CT> ;re1ultate po1!t!)eC clasa 2= 1>>< la pac!en*!! curere neuropat!c' de et!olo#!e ult!pl' per!fer!c' sau central'. Stud!ul cu Gabapent!n' a fost po1!t!) doar -n unele aspecte ale durer!! cu caracter de arsur' ,! $!peral#e1!e!, dar nu ,! asupra durer!! lanc!nanteC aceste re1ultate slabe se pot datora !ncluder!! unu! #rup lar# de pac!en*! f'r' do)e1! de le1!une ner)oas' ;C.PS t!p 2<, care pot f! refractar! la acest ed!ca ent. 7n dou' stud!! de clasa 222, -n care et!olo#!a nu a fost en*!onat' deloc, unul cu 3a otr!#!na 9EE #G1! a fost ne#at!), !ar cel'lalt cu Capsa!c!na s!n#ur' sau -n co b!na*!e cu 5oxep!na top!c' a a)ut re1ultate po1!t!)e pe c+te)a d!ntre s! pto ele dureroase 81>?,1>@:. Recomandri Cele c+te)a cond!*!! neuropat!ce a! pu*!n stud!ate ;durerea e brulu! fanto ', durerea neuropat!c' postc$!rur#!cal', s!ndro ul Gu!llan(Darre< par s' a!b' r'spuns terapeut!c s! !lar pentru a&or!tatea ed!ca( entelor folos!te -n celelalte cond!*!! neuropat!ce ;ex= ant!depres!)ele tr!c!cl!ce, Gabapent!na, op!o!dele<, dar re1ultatele se ba1ea1' pe un nu 'r !c de stud!! de clasa 22.C cu pu*!n! pac!en*! ;n!)el D<. 5urerea neuro( pat!c' datorat' !nf!ltr'r!! canceroase pare a f! cea a! refractar' la terap!a ed!ca entoas', probab!l pentru c' este o afec*!une pro#res!)'. Efecte a)upra )emnelor +i )imptomelor durerii 5e,! a&or!tatea stud!!lor !n!*!ale au cons!derat durerea neuropat!c' ca f!!nd o 1?

ent!tate un!for ', stud!!le no! au e)aluat d!fer!te s! pto e ,! se ne ale durer!! pro)ocate. Ant!depres!)ele tr!c!cl!ce ,! SN.2 au ac*!une s! !lar' asupra durer!! pers!stente ,! parox!st!ce -n pol!neuropat!a dureroas' ,! ne( )ral#!a post$erpet!c' ;clasa 2G22= 9>,9?,F1,F9<. /fectele ant!depres!)elor asupra se nelor ,! s! pto( elor durer!! pro)ocate sunt contro)ersate, cu efecte slabe asupra alod!n!e! co parat!) cu durerea spontan' ;clasa 2G22= 9>,9@,1>F,1>A<, dar efecte po1!t!)e asupra durer!! pro)ocate de per!at ;clasa 22= F1,F9< sau pres!une ;clasa 2= 9><. Bx!codona ,! Tra adolul au fost raportate ca a el!or+nd durerea cont!nu', durerea parox!st!c' ,! s! pto ele durer!! pro)ocate ;de at!n#ere< -n tre! stud!! controlate -n pol!neuropat!a dureroas' ,! ne)ral#!a post$erpet!c' ;clasa 2= ?>,?F,A?<. 3a otr!#!na a fost raportat' ca f!!nd ef!c!en*a pe alod!n!a pro)ocat' de fr!#, dar nu ,! asupra alod!n!e! ecan!ce d!n durerea central' post(A4C ;clasa 2= 1E1<. /fectele Gabapent!ne! asupra s! pto elor d!st!ncte de durere au fost !n)est!#ate -ntr(un stud!u lar# cu pac!en*! cu ult!ple et!olo#!! de durere neuropat', dar stud!ul a a)ut a! ulte l! !t'r! ;)e1! Cond!*!!le de durere neuropat' a! pu*!n stud!ate<. 7n ne)ral#!a tr!#e !nal', Carba a1ep!na a fost ef!c!ent' at+t -n atacur!le spontane, c+t ,! -n cele pro)ocate ;clasa 22= 89<, !ar Carba a1ep!na ,! Bxcarba1ep!na au a)ut ef!c!en*' e#al' asupra durer!! deter !nat' de tr!##er!, cu ar f! +ncatul sau b'utul ;clasa 2= 1>8<. 6n b!lan* s!ste at!c al stud!!lor .C raportea1' c' de,! Bxcarba1ep!na a redus nu 'rul de atacur! spontane la a&or!tatea pac!en*!lor, nu a !nfluentat durerea pro)ocat' de tr!##er! -n ?9I d!ntre ca1ur! ;clasa 2 S.= 1>H<. /f!cac!tatea 3!doca!ne! top!ce a fost raportat' pentru d!)erse s! pto e ;arsur', durere surd', durere pro)ocat' de st! ul! tact!l!< ;clasa 22= FH<, cu un efect slab pe se nele alod!n!e! ecan!ce co ( parat! cu durerea -n desf',urare ;clasa 22= A1<. Surpr!n1'tor, acest ed!ca ent s(a do)ed!t recent ca f!!nd a! ef!c!ent -n alod!n!a pac!en*!lor cu ne)ral#!e post$erpet!c' ,! afectarea func*!e! noc!cept!)e co parat!) cu ce! f'r' afectare sen1!t!)' ;clasa 22= AE<. 5!n o ent ce nu eroase ed!ca ente par s' a!b' ef!cac!tate d!fer!t' pe )ar!ate s! pto e ,! se ne ale durer!! neuropat!ce ;date ob*!nute -n #eneral d!n stud!! !c!<, aceste date trebu!e con( f!r ate de stud!! lar#! cu etode de )al!dare standard!1ate 81?E:. Efecte a)upra calit-ii vie-ii +i comor1idit-ilor 7n #eneral, cal!tatea )!e*!! este afectat' la pac!en*!! cu durere neuropat!c'. 5oar stud!! recente au exa !nat adec)at efectele d!fer!telor ed!ca( ente asupra cal!t'*!! )!e*!!, so nulu! ,! co orb!( d!t'*!lor ;0!#.1<. /fecte se n!f!cat!)e asupra cal!t'*!! )!e*!!, !nclus!) so nul, au fost raportate pentru Gabapent!na ,! Pre#abal!na -ntr(un stud!u lar# de clasa 2 -n pol!neuropat!a dureroas', ne)ral#!a post( $erpet!c' sau trau at!s ele sp!nale 8>F(>H,@H,F>(FF,1>9C Pf!1er:, pentru 5uloxet!na -n pol!neuropat!a dureroas' 89?:, ;clasa 2< ,! pentru canab!no!de -n SM 81EF, clasa 2: ;n!)el A<. 6n alt stud!u nu a -nre#!strat efecte se n!f!cat!)e asupra cal!t'*!! )!e*!! pr!n ut!l!( 1area Pre#abal!ne!, 1@

dar a notat efecte po1!t!)e asupra so nulu! 8?E, clasa 2:. Pre#abal!na=
Pre#abal!n GDP Cannab!no!ds 5uloxet!ne Bp!o!ds BxcarbaRep!ne 1 9 > ? @ F A Nu ber of .CTs 8 H 1E Ne#at!) Po1!t!)

Figura 1. Calitatea vieii/comorbiditi. Nu#:rul (tudiilor rando#i0ate, controlate de cla(a I <i II, care au ar:tat re0ultate po0iti!e >alb= (au ne-ati!e >ne-ru= cu pri!ire la #:(ur:tori ale calit:;ii !ie;ii?di(po0i;iei@ $ou: (tudii cu pre-abalin: >AB= (au o9carba0epin: >29= au a!ut re0ultate ne-ati!e pri!ind cele #ai #ulte #odalit:;i de #:(urare ale calit:;ii !ie;ii?di(po0i;iei, dar au ar:tat e.ecte po0iti!e a(upra (o#nului@ "rei (tudii adi;ionale cu lidocain: aplicat: topic >7C=, pre-abalin: >AC= (au canabinoi0i >CB7= au e!aluat doar (o#nul >nu (unt ar:tate aici@

Gabapent!na au a)ut efecte po1!t!)e asupra st'r!! afect!)e ;clasa 2= >F,>8,F>,FF< ;n!)el A<. Bp!o!dele putern!ce sau Tra adolul nu au - ( bun't'*!t cal!tatea )!e*!! sau starea afect!)' -n stud!! .C ;clasa 2= ??,?@,A?,AF,AA< cu excep*!a a dou' stud!! ;clasa 2= ?>,@H< ;n!)el D<. 6n stud!u cu Bx!codon' -n pol!neuropat!a dureroas' nu a raportat efecte asu( pra cal!t'*!! )!e*!! sau st'r!! afect!)e, dar a a)ut efecte po1!t!)e asupra so nulu! 89H, clasa 22:. 6n stud!u cu 3!doca!na top!c' 8A1, clasa 22: nu a -nre#!strat efecte benef!ce asupra cal!t'*!! so nulu! -n durerea neuropa( t!c' de et!olo#!e ult!pl' ;n!)el D<. Reac-ii adver)e +i indica-ii de utili*are 7n aceast' sec*!une, a pre1entat cele a! ! ( portante efecte ad)erse ale ed!ca entelor ut!l!( 1ate obser)ate -n a! ulte stud!! despre durerea neuropat!c' ,! !nd!ca*!! pract!ce pentru ut!l!1are. 'ntidepre(i!ele triciclice Cele a! co une reac*!! ad)erse sunt= usc'c!unea ucoase! bucale, const!pa*!e, transp!ra*!e, a e*eal', tulbur'r! de )edere, palp!ta*!!, $!potens!une ortostat!c', sedare ,! tulbur'r! de !c*!une. Ant!depres!)e tr!c!cl!ce a! select!)e, cu ar f! Nortr!pt!l!na, sunt a! b!ne tolerate dec+t cele neselect!)e, cu a! pu*!ne efecte ant!col!ner#!ce ,! sedat!)e ; clasa 22 C F9 <. A fost se nalat' o pos!b!l' le#atur' -ntre ant!depres!)ele tr!c!cl!ce ! oarte sub!t' card!ac' C un stud!u ep!de !olo#!c recent a ar'tat o uoar' cretere a r!sculu! de oarte sub!t' la ce! care au pr! !t ant!depres!)e tr!c!cl!ce peste 1EE #G 1! 81?1:. 5e aceea, se reco and' aten!e -n ut!l!Rarea acestora la )+rstn!c! ! la ce! cu factor! de r!sc card!o)ascular 81,1?:. Ant!depres!)ele tr!c!cl!ce ar trebu! !n!!ate la do1e !c! ;1E(9@ #G1! -n do1' un!c' seara la culcare< ,! t!trate lent, pe 'sura toleran*e!. 5o1ele ef!c!ente )ar!a1' de la un pac!ent la altul, do1a ed!e pentru A !tr!pt!l!n' f!!nd de A@ #G1!. /x!st' contro)erse -n ceea ce pr!)e,te do1area n!)elulu! plas at!c al ant!depres!)elor tr!c!cl!ce ;clasa 2 S.= 1?,1>A, clasa 22= 1?9<. 1F

SNRI 2n$!b!tor!! recapt'r!! de seroton!na ! noradrenal!n' ;5uloxet!na, 4enlafax!na< sunt a! s!#ur! dec+t ant!( depres!)ele tr!c!cl!ce ,! sunt o op*!une a! bun' dec+t acestea la pac!en*!! cu boal' card!ac'. .!scul relat!) pentru efecte ad)erse este a! !c ,! nu este ne)o!e de on!tor!1area n!)elulu! plas at!c. Cele a! co une reac*!! ad)erse ale 5uloxet!ne! au fost= #rea*', )'rs'tur', const!pa*!e, so nolen*', usc'c!u( nea ucoase! bucale, transp!ra*!e, anorex!e, slab!c!u( ne 89?,9@, clasa 2:. 5e,! ! ed!ata el!berare a 4enlafa( x!ne! este asoc!at' cu reac*!! ad)erse ale SNC ,! s! pto e so at!ce, cu ar f! a#!ta*!e, d!aree, cre,( terea en1! elor $epat!ce, $!pertens!une, $!pona( tre !e ;clasa 2 S.= 1?><, for ulele cu el!berare prelun#!t' sunt a! u,or de tolerat, pr!nc!palele reac*!! secundare f!!nd cele #astro!ntest!nale ;clasa 2= 99,9><. 7ntr(un stud!u de co para*!e, 4enlafax!na ;99@ #G1!< nu a fost super!oar' 2 !pra !ne! ;1@E #G1!< *!n+nd cont de tolerab!l!tate ,! reac*!! ad)erse 89>:. 5o1a opt! ' pentru 5uloxet!na este FE #G1!C do1a de 19E #G1! nu este a! ef!c!ent' dec+t cea de FE #G1!, !ar do1a de 9E #G1! este !nef!c!ent' 89?,9@:. 5o1e ar! de 4enlafax!n' ;1@E(99@ #G1!< au fost raportate ca f!!nd ef!c!ente -n t! p ce do1ele !c! ;A@ #G1!< nu au ef!c!en*' ;clasa 2G22= AF,119<. Carba#a0epina?69carba0epina Carba a1ep!na deter !n' frec)ent reac*!! ad)erse care !nclude sedare, a e*eal', tulbur'r! de ers. /n1! ele $epat!ce, celulele san#!une, plac$e ele ,! natre !a trebu!e on!tor!1ate cel pu*!n -npr! ul an de terap!e d!n cau1a r!sculu! de $epat!t', de reac*!! anapla1!ce sau de $!ponatre !e. 2nduc*!a s!ste ulu! en1! at!c !cro1o al poate !nfluen*a etabol!1area altor ed!ca ente. 7n contrast cu Carba a1ep!na, Bxcarba1ep!na nu deter !n' !nduc*!e en1! at!c' ,! ex!st' r!sc sc'1ut de aler#!e cutanat' -ncruc!,at'. 7n pr! ele lun! de trata ent trebu!e on!tor!1at' natre !a, pentru c' ,! Bxcarba1ep!na !nduce $!ponatre !e, a! ales la b'tr+n! ;FI d!n @? de pac!en*!< ;clasa 2 S.= 8?<. 7n ceea ce pr!)e,te alte efecte ad)erse, de,! Bxcarba1ep!na are o toleran*' a! bun' 88F,1>8, 1>H: nu ex!st' do)e1! cons!stente de clasa 2. 7ntr(un stud!u recent cu pac!en*! cu pol!neuropat!e dure( roas' d!abet!c', 9A,@I d!ntre pac!en*!! care pr! eau Bxcarba1ep!n' au -ntrerupt trata entul d!n cau1a efectelor secundare centrale ,! #astro!ntest!nale ;co parat!) cu 8I -n #rupul placebo< ;clasa 22= 9H<. A bele ed!ca ente trebu!e !n!*!ate -n do1e !c! ,! lent crescute p+n' de)!n ef!c!ente sau nu a! pot f! tolerate. 5o1ele ef!c!ente sunt= 9EE(19EE #G 1! pentru Carba a1ep!n' ,! FEE(18EE #G1! pentru Bxcarba1ep!n'. 5abapentina?Pre-abalina Cele a! co une reac*!! ad)erse sunt= a e*eal', so nolen*', ede ul per!fer!c, usc'c!unea ucoa( selor ;frec)en*a s! !lar' pentru a bele ed!ca ente<. 7n t! p ce Gabapent!na este tolerat' ,! la do1e ar! ;Q9?EE #G1!< ;clasa 2 S.= 1@,1A<, efectele secundare ale Pre#abal!ne! se sc$! b' ult cu do1a= la 1@E(>EE #G1! 1A

are acela,! efect ca ,! placebo ;clasa 2= >A,?E<, -n t! p ce la FEE #G1! rata de -ntrerupere a terap!e! a&un#e la 9EI ;clasa 2= ?9,F@<. 5o1ele ef!c!ente pentru Gabapent!n' sunt 19EE( >FEE #G1!, !ar pentru Pre#abal!na 1@E(FEE #G1!. Gabapent!na neces!t' t!trare !nd!)!dual' lent' cu o do1' !n!*!al' de >EE #G1! ;sau a! pu*!n la )+rstn!c!<, -n t! p ce Pre#abal!na poate f! t!trat' a! rap!d ,! are un debut a! precoce al efectulu! ;S1 s'pt'( +n'<. Gabapent!na se ad !n!strea1' de > or!G1!, -n t! p de Pre#abal!na se ad !n!strea1' de 9 or!G1!. /a#otri-ina 3a otr!#!na este -n #eneral b!ne tolerat'. .eac*!!le ad)erse !nclud= a e*eal', #rea*', cefalee ,! oboseal' ;clasa 2=>E,>H,1E1,1E9<. Poate produce reac*!! aler#!ce cutanate se)ere. 7ntr(o eta(anal!1' ce a colectat !nfor a*!! de la @A9 de pac!en*!, HI au -ntrerupt ed!ca*!a d!n cau1a efectelor ad)erse a&ore ;cel a! co un ras$(ul< ;clasa 2= 1??<. Pentru a !n! al!1a apar!*!a ras$(ulu! cutanat, se reco( and' t!trarea lent' a do1elor ,! trebu!e e)!tat' asoc!erea cu 4alproatul. Terap!a se -ncepe cu 9@ #G 1! ,! se cre,te cu 9@ # Gs'pt' +n'. 5o1ele anal#e( 1!ce ale 3a otr!#!ne! sunt 9EE(?EE #G1!. 6pioidele?"ra#adolul Cele a! co une reac*!! ad)erse ale op!o!delor sunt const!pa*!a, sedarea, #rea*a, a e*eala ,! )'rs'( tura. .!scul de deter!orare co#n!t!)' a fost raportat c' f!!nd ne#l!&ab!l ;clasa 2= A@,AF<, de,! Morf!na afec( tea1' aten*!a la do1e foarte ar! ;p+n' la >EE #G 1!< ;clasa 22= 118<. Prof!lul reac*!!lor ad)erse ale op!o!( delor -n durerea neuropat' a fost raportat ca f!!nd bun, a! ales pentru Bx!codon' ;clasa 2= ?>,??,A?(AF<, uneor!, -n od surpr!n1'tor, cu o rat' de -ntrerupere a ed!ca*!e! s! !lar' cu cea a #rupulu! placebo. Cu toate acestea, a! pu*!n de 9EI d!ntre pac!en*! cont!nu' op!o!dele dup' 1 an, d!n cau1a balan*e! ne( fa)orab!le -ntre ef!cac!tate ,! efecte ad)erse ;clasa 2 S.= @<, !ar stud!!le .C au fost prea scurte pentru a furn!1a do)e1! despre toleran*' ,! dependen*'. 7n acord cu reco and'r!le europene recente, op!o!dele trebu!e cons!derate terap!e de a doua l!n!e pentru pac!en*!! cu durere cron!c' non(canceroas' 81?@:. 5o1ele trebu!e t!trate !nd!)!dual -n func*!e de ef!c!en*' ,! reac*!! secundare. 5o1ele ef!c!ente au fost de 1E( 19E #G1! pentru Bx!codon' ,! 1@(>EE #G1! pentru Morf!n'. Tra adolul poate deter !na a e*eal', usc'( c!unea ucoaselor, #rea*', const!pa*!e, so nolen*', cu ult a! ulte -ntreruper! de terap!e dec+t placebo ;clasa 2= ?F,AF<. /x!st' un r!sc crescut de cr!1e ep!lept!ce la pac!en*!! cu !stor!c de ep!leps!e sau ce! care pr! esc ed!ca*!e ant!ep!lept!c'. S!n( dro ul seroton!ner#!c ;)ar!ate co b!na*!! de !oclo( nus, r!#!d!tate, $!perreflex!e, tre or, confu1!e, a#!ta( *!e, co ', !nstab!l!tate autono ', febr', #rea*', d!aree, flus$ ,! rar rabdo !ol!1' ,! oarte< poate ap'rea dac' Tra adolul este ut!l!1at -n co b!na*!e cu alte ed!ca ente seroton!ner#!ce ;-n part!cular SS.2<. Tra adolul trebu!e !n!*!at -n do1e !c!, a! ales la pac!en*!! )+rstn!c! 18

;@E #G1!< ,! apo! t!trat -n l! !ta toleran*e!. 5o1ele ef!c!ente sunt de 9EE(?EE #G1!. 6t!l!1area 3!doca!ne! patc$ este foarte s!#ur' cu absorb*!e s!ste !c' redus' ,! efecte ad)erse localeu,oare ;reac*!! cutanate< ;clasa 22= F8,FH<. Pentru a acoper! ar!a dureroas' pot f! folos!te p+n' la ? patc$ur!G1!. T!trarea nu este necesar'. Canab!no!dele au fost -n #eneral b!ne tolerate -n do1e !c! ;1E #G1! pentru 5ronab!nol< ,! cu t!trare lent'. .eac*!!le ad)erse sunt a e*eal', usc'c!unea ucoaselor ,! sedarea ;clasa 2= 1EF,1EA<. /x!st' un stud!u care a -nre#!strat afectarea se n!f!cat!)' a e or!e! dup' ut!l!1area canab!no!delor sub for ' de spraR 81EA:. Pr!n ut!l!1area pe ter en lun#, cre,te r!scul de dependen*' f!1!c' ,! toleran*'. Recomandri finale Ale#erea ed!ca*!e! de pr! ' l!n!e -n durerea neuropat' trebu!e s' *!n' sea a nu nu a! de ef!cac!tatea relat!)' ba1at' pe stud!!le de co para*!e d!rect' -ntre ed!ca ente, dar ,! de raportul ef!( c!en*'Gs!#uran*'. /fectul asupra d!fer!telor s! pto( e ale durer!!, co orb!d!t'*!lor ,! cal!t'*!! )!e*!! trebu!e docu entat. Aceste aspecte au fost stud!ate -n pu*!ne stud!! ,! pentru pu*!ne ed!ca ente, !ar e)aluarea se nelor ,! s! pto elor a folos!t uneor! etode !nadec)ate ,! ne)al!date 81?E:. /fectele ed!ca entelor -n afec*!un! per!fer!ce neuropate d!fer!te pot a)ea s! !lar!t'*!, except+nd pol!neuropat!a H24 ,! ne)ral#!a tr!#e !nal'. 5urerea central' a fost a! pu*!n stud!at'. 5e aceea, ur '( toarele reco and'r! se refer' -n spec!al la durerea neuropat!c' per!fer!c'. .eco and'r!le pr!)!nd alte cond!*!! pot f! #'s!te -n Tabelul 9. Med!ca entele reco andate ca pr! ' l!n!e de terap!e sunt ant!depres!)ele tr!c!cl!ce, #abapent!na ,! pre#abal!na ;n!)el A, a! ulte stud!! de clasa 2<. Ant!depres!)ele tr!c!cl!ce par a! ef!c!ente &udec+nd dup' NNT, dar este pos!b!l ca aceste date s' f! fost supraest! ate, !ar super!or!tatea lor nu a fost conf!r( at' de stud!! co parat!)e. /le pot a)ea efecte secundare card!ace ,! trebu!e folos!te cu aten*!e la pac!en*!! )+rstn!c!. Terap!a de l!n!a a doua !nclude= 3!doca!na top!c', SN.2 ;4enlafax!na ,! 5uloxet!na<, 3a otr!#!na ,! Tra adolul. 3!doca!na top!c' poate f! preferat' la un!! pac!en*! cu ne)ral#!e post$erpet!c' sau neuropat!e focal', a! ales la )+rstn!c!. Contrar aspectelor le#ate de ef!cac!tatea lor slab' -n durerea neuropat!c' 81?A:, op!o!dele s(au do)ed!t ef!c!ente -n a! ulte stud!! de clasa 2 -n d!fer!te cond!*!! neuropate ;n!)el A<, dar ar trebu! propuse doar ca terap!e de l!n!a a doua sau a tre!a -n durerea cron!c' non( canceroas' 81?@:. Nu ex!st' suf!c!ente do)e1! despre ut!l!1area Carba a1ep!ne!, Bxcarba1ep!ne! ;cu excep*!a ne)ral#!e! tr!#e !nale<, Capsa!c!ne! ;except+nd ne)ral#!a post$erpet!c'<, Mex!let!ne!, anat#on!st!lor NM5A, SS.2, Top!ra atulu!. 7n c!uda folos!r!! de lun#' durat' a 4alproatulu! -n ep!leps!e, stud!! .C recente de clasa 22 au pre1entat re1ultate contro)ersate despre ut!l!1area lu! -n durerea ne( uropat'. 4alproatul are ne)o!e de alte stud!! pentru a stab!l! n!)elur!le de reco andare. 7n ceea ce pr!)e,te co orb!d!t'*!le ,! cal!tatea )!e*!!, doar Gabapent!na, Pre#abal!na ,! 5uloxet!na au fost adec)at stud!ate cu efecte po1!t!)e ,! de aceea ar 1H

putea f! reco andate pac!en*!lor cu ! ( pact se)er al durer!! asupra cal!t'*!! )!e*!! sau co or( b!d!t'*!lor ;n!)el A<. Bp!o!dele nu au a)ut efect asupra acestor aspecte. 7n ceea ce pr!)e,te se nele ,! s! pto ele durer!!, doar ant!depres!)ele ,! op!( o!deleGTra adolul au fost ef!c!ente pe durerea cont!nu' sau parox!st!c', -n t! p ce efecte pe alo( d!n!a !ndus' de per!a& au fost raportate pentru 3!doca!na top!c' ,! op!o1!GTra adol ;n!)el D<. 6t!l!( 1area 3!doca!ne! top!ce poate f! preferat' la pac!en*!! cu alod!n!e ecan!c'. Terap!!le co b!nate pot f! propuse atunc! c+nd onoterap!a nu este sat!sf'c'toare ,! trebu!e pre( ferate ed!ca entele cu ecan!s e de ac*!une co ple entare. P+n' acu s(a do)ed!t ef!c!ent' co b!na*!a Gabapent!nGMorf!n' ;n!)el A<. A propus ur 'toarele strate#!! pentru stud!!le )!!toare= ;1< /f!cac!tatea ar trebu! ur 'r!t' pr!n cr!( ter!! standard!1ate ,! acceptate !nterna*!onal 81>8:C ;9< trebu!e ob*!nute cr!ter!! un!)ersale ,! !dent!ce -n ceea ce pr!)e,te efectele d'un'toareC ;>< stud!! co parat!)e pentru d!fer!te ed!ca ente ,! d!fer!te ecan!s e ,! t!pur! de durere per !t alc'tu!rea unu! al#or!t pentru terap!a durer!!C ;?< ra*!unea terap!e! co b!nate ur ea1' a f! stab!l!t'. 4re s' ul*u ! ur 'toarelor co pan!! pen( tru c' ne(au furn!1at docu entare despre stud!!le efectuate pentru d!)erse ed!ca ente= Cep$alon, /ndo, 0orest P$ar aceut!cals, JanssenTJo$nson, 3undbec", No)art!s, Pf!1er, Sc$Part1 P$ar a, 6CD P$ar a ,! %Ret$. A)e cuno,t!n*' c' a! ulte stud!! ! portante sunt -n curs de desf',urare ,! se a,teapt' apar!*!a unor no! ed!ca ente cu do)e1! adec)ate. Ne propune s' re-nno! aceste #$!dur! peste 9 an!.
Tabelul 2. Clasificarea dovezilor despre medicamentele folosite n polineuropatia dureroas nevralgia post!erpetic nevralgia trigeminal "i durerea central cu recomandrile de prima "i a doua linie terapeutic
Condi-ia durereoa) Nivelul A Nivelul % Nivelul C )au re*ultate )la1e2 di)crepante pentru nivelul A2% Capsa!c!na top!c Carba a1ep!na 3e)odopa Mex!let!na Anta#on!,t! NM5A Bxcarba1ep!na SS.2 Top!ra at 4alproat Anta#on!,t! NM5A 3ora1epa , Mex!let!na Daclofen 3a otr!#!na Recomandri de prim linie terapeutic Recomandri de linia a doua terapeutic

Pol!neuropat!a Gabapent!na 3a otr!#!na dureroas' Bp!o!de Pre#abal!na SN.2 ATC Tra adol

Gabapent!na 3a otr!#!na Pre#abal!na ATC Bp!o!de SN.2 Tra adol

Ne)ral#!a post$erpet!c'

Gabapent!na Bp!o!de Pre#abal!na ATC Carba a1ep!na

Ne)ral#!a tr!#e !nal'

Capsa!c!na top!c 3!doca!na top!c Tra adol, 4alproat Bxcarba1ep!na

Gabapent!na Pre#abal!na 3!doca!na top!c ATC Bxcarba1ep!na Carba a1ep!na

Capsa!c!na Bp!o!de Tra adol 4alproat C$!rur#!e

9E

5urerea central'

Canab!no!de Gabapent!na Pre#abal!na A !tr!pt!l!na 3a otr!#!na

Mex!let!na, Bp!o!de

A !tr!pt!l!na Gabapent!na Pre#abal!na

Canab!no!de 3a otr!#!na Bp!o!de

(ECLARA"A C$NFLIC EL$R (E IN ERESE 6r 'tor!! autor! au efectuat stud!! sau au fost consulta*! de ur 'toarele co pan!! far aceut!ce= NA= GlaxoS !t$Ul!ne, Grunent$al, No)art!s, Pf!1er, P!erre 0abre, Sanof!( A)ent!sC GC= GlaxoS !t$Ul!ne, 3undbec", Janssen, No)art!s, Pf!1erC MH= Janssen( C!la#, Merc", Mund!p$ar a, Br#anon, Br!on, Pf!1er, Sanof!C PH= D!osc$Part1, GlaxoS !t$Ul!ne, 3undbec", Pf!1erC TSJ= /l! 3!llR, GlaxoS !t$Ul!ne, Grunent$al, 3undbec", Neurosearc$, Pf!1erC TN= Aller#an, Astra( Venaca, GlaxoS !t$Ul!ne, G%P$ar a, Napp, No)art!s, Pf!1er, .eno)!s, Sc$Part1P$ar aC SS= /l! 3!llR, GlaxoS !t$Ul!ne, Grunent$al, 3undbec", No)art!s, P!erre 0abre, 6CD P$ar a. Ce!lal*! autor! nu au n! !c de declarat. Ane,a A: Mon!tor!1area co pan!!lor far ace( ut!ce care au fost contactate ;). etodolo#!e<= Cep$alon, /lan, /ndo, 0orest P$ar aceut!cals, GSU, G% P$ar a, Janssen T Jo$nson, 3!llR, 3undbec", NePron, No)art!s, Pf!1er, Sc$Par1 P$ar a, S!# aTau, 6CD P$ar a, %allace 3aborator!es, %Ret$. Co pan!! care au a)ut ater!ale rele)ante pe care le(au tr! !s autor!lor= Cep$alon, /ndo, 0orest P$ar aceut!cals, JanssenTJo$nson, 3undbec", No)art!s, Pf!1er, Sc$Par1 P$ar a, 6CD P$ar a, %Ret$. Ane,a %: 3!sta de acron! e A25S, acWu!red ! unodef!c!encR sRndro eC CDV,carba a1ep!neC C2, conf!dence !nter)alsC CP, central pa!nC C.PS, co plex re#!onal pa!n sRndro eC /M3A, eutect!c !xture of local anaest$et!cs ;l!do( ca!ne and pr!loca!ne<C GADA, #a a(a !nobutRr!c ac!dC GDP, #abapent!nC 3TG, la otr!#!neC MS, ult!( ple scleros!sC NM5A, N( et$Rl(5( aspartateC NNH, nu ber needed to $ar C NNT, nu ber needed to treatC NSA25, nonstero!dal ant!(!nfla atorR dru#C BXC, oxcarba1ep!neC PHN, post$erpet!c neural#!aC PPN, pa!nful polRneuropat$RC .CT, rando !1ed controlled tr!alC SC2, sp!nal cord !n&urRC SN.2, seroton!n( noradrenal!n reupta"e !n$!b!tor ant!depressantsC S., sRste at!c re)!eP or etaanalRs!sC SS.2, select!)e seroton!n reupta"e !n$!b!tor ant!depressantsC TCA, tr!cRcl!c ant!de( pressantsC TN, tr!#e !nal neural#!aC 4AS, )!sual analo#ue scale. %I%LI$GRAFIE 91

1. 5Por"!n .H, Dac"on&a M, .oPbot$a MC, et al. Ad)ances !n neuropat$!c pa!n= d!a#nos!s, ec$an!s s, and treat ent reco endat!ons. Arc$!)es of Neurolo#R 9EE>aC FE= 1@9?Y1@>?. 9. 0!nnerup ND, Btto M, McZuaR HJ, et al. Al#or!t$ for neuropat$!c pa!n treat ent= an e)!dence based proposal. Pa!n 9EE@C 118= 98HY>E@. >. Daron .. Neuropat$!c pa!n. T$e lon# pat$ fro ec$an!s s to ec$an!s (based treat ent. Anaest$et!st 9EEEC ?H= >A>Y>8F. ?. %oolf CJ, Max MD. Mec$an!s (based pa!n d!a#nos!s= !ssues for anal#es!c dru# de)elop ent. Anest$es!olo#R 9EE1C H@= 9?1Y9?H. @. Attal N. C$ron!c neuropat$!c pa!n= ec$an!s s and treat ent. Cl!n!cal Journal of Pa!n 9EEEC 1F;Suppl. ><= S118YS1>E. F. Hansson P. 5!ff!cult!es !n strat!fR!n# neuropat$!c pa!n bR ec$an!s s. /uropean Journal of Pa!n 9EE>C A= >@>Y>@A. A. Jensen TS, Daron .. Translat!on of sR pto s and s!#ns !nto ec$an!s s !n neuropat$!c pa!n. Pa!n 9EE>C 1E9= 1Y8. 8. 5ub!ns"R .M, Uabban! H, /l(C$a ! V, et al. Zual!tR Standards Subco !ttee of t$e A er!can Acade R of Neurolo#R. Pract!ce para eter= treat ent of post$erpet!c neural#!a= an e)!dence(based report of t$e Zual!tR Standards Subco !ttee of t$e A er!can Acade R of Neurolo#R. Neurolo#R 9EE?C F>= H@HYHF@. H. He penstall U, Nur !""o TJ, Jo$nson .%, et al. Anal#es!c t$erapR !n post$erpet!c neural#!a= a Wuant!tat!)e sRste at!c re)!eP. P3oS Med!c!ne 9EE@C 9= F98YF??. 1E. Adr!aensen H, Pla#$"! 3, Mat$!eu C, et al. Cr!t!cal re)!eP of oral dru# treat ents for d!abet!c neuropat$!c pa!n(cl!n!cal outco es based on eff!cacR and safetR data fro placebo(controlled and d!rect co parat!)e stud!es. 5!abetesGMetabol!s .esearc$ and .e)!ePs 9EE@C 91= 9>1Y9?E. 11. Saarto T, %!ffen P. Ant!depressants for neuropat$!c pa!n. Coc$rane 5atabase of SRste !c .e)!ePs 9EE@C 9E= C5EE@?@?. 19. Dra!n!n M, Darnes M, Daron JC, et al. Gu!del!ne Standards Subco !ttee of t$e /0NS Sc!ent!f!c Co !ttee. Gu!dance for t$e preparat!on of neurolo#!cal ana#e ent #u!del!nes bR /0NS sc!ent!f!c tas" forces Y re)!sed reco endat!ons. /uropean Journal of Neurolo#R 9EE?C 11= @AAY@81. 1>. .as ussen P4, S!ndrup SH, Jensen TS, et al. SR pto s and s!#ns !n pat!ents P!t$ suspected neuropat$!c pa!n. Pa!n 9EE?C 11E= ?F1Y?FH. 1?. S!ndrup SH, Btto M, 0!nnerup ND, et al. Ant!depressants !n t$e treat ent of neuropat$!c pa!n. Das!c and Cl!n!cal P$ar acolo#R and T$erapR 9EE@C HF= >HHY?EH. 1@. %!ffen P, McZuaR H, /dPards J, et al. Gabapent!n for acute and c$ron!c pa!n. Coc$rane 5atabase SRste at!c .e)!ePs 9EE@aC 9E= C5EE@?@9. 1F. %!ffen P, McZuaR H, Moore .. Carba a1ep!ne for acute and c$ron!c pa!n. Coc$rane 5atabase SRste at!c .e)!ePs 9EE@bC 9E= C5EE@?@1. 1A. %!ffen P, Coll!ns S, McZuaR H, et al. Ant!con)ulsant dru#s for acute and c$ron!c pa!n. Coc$rane 5atabase SRste at!c .e)!ePs 9EE@cC 9E= C5EE11>>. 99

18. Btto M, Da" S, Dac$ 0%, et al. Pa!n p$eno ena and poss!ble ec$an!s s !n pat!ents P!t$ pa!nful polRneuropat$R. Pa!n 9EE>C 1E1= 18AY1H9. 1H. S!ndrup SH, Jensen TS. P$ar acolo#!c treat ent of pa!n !n polRneuropat$R. Neurolo#R 9EEEC @@= H1@YH9E. 9E. 4ret$e M, Do!)!e J, ArnW)!st H, et al. A co par!son a a !tr!ptRl!ne and aprot!l!ne !n t$e treat ent of pa!nful polRneuropat$R !n d!abet!cs and nond!abet!cs. Cl!n!cal Journal of Pa!n 1HHAC 1>= >1>Y>9> ;class 2<. 91. S!ndrup SH, Gra 30, S"&old T, et al. Clo !pra !ne )s des!pra !ne )s placebo !n t$e treat ent of d!abet!c neuropat$R sR pto s. A double(bl!nd cross(o)er studR. Dr!t!s$ Journal of Cl!n!cal P$ar acolo#R 1HHEC >E= F8>YFH1 ;class 2<. 99. .oPbot$a MC, Gol! 4, Uun1 N., et al. 4enlafax!ne extended release !n t$e treat ent of pa!nful d!abet!c neuropat$R= a double(bl!nd, placebo(controlled studR. Pa!n 9EE?C 11E= FHAYAEF ;class 2<. 9>. S!ndrup SH, Dac$ 0%, Madsen C, et al. 4enlafax!ne )ersus ! !pra !ne !n pa!nful polRneuropat$R. A rando !1ed, controlled tr!al. Neurolo#R 9EE>C FE= 198?Y198H ;class 2<. 9?. Goldste!n 5J, 3u [, 5et"e MJ, et al. 5uloxet!ne )ersus placebo !n pat!ents P!t$ pa!nful d!abet!c neuropat$R. Pa!n 9EE@C 11F= 1EHY118 ;class 2<. 9@. .as"!n J, Pr!tc$ett [3, %an# 0, et al. A double(bl!nd, rando !1ed ult!center tr!al co par!n# duloxet!ne P!t$ placebo !n t$e ana#e ent of d!abet!c per!p$eral neuropat$!c pa!n. Pa!n Med!c!ne 9EE@C F= >?FY>@F ;class 2<. 9F. .ull JA, Zu!brera ., Gon1ale1(M!llan H, et al. SR pto at!c treat ent of per!p$eral d!abet!c neuropat$R P!t$ carba a1ep!ne ;Te#retol<= double bl!nd crosso)er tr!al. 5!abetolo#!a 1HFHC @= 91@Y918 ;class 222<. 9A. %!lton T5. Te#retol !n t$e treat ent of d!abet!c neuropat$R. Sout$ Afr!can Med!cal Journal 1HA?C ?8= 8FHY8A9 ;class 222<. 98. Go e1(Pere1 0J, C$o1a ., .!os JM, et al. Nortr!ptRl!ne( flup$ena1!ne )s. carba a1ep!ne !n t$e sR pto at!c treat ent of d!abet!c neuropat$R. Arc$!)es of Med!cal .esearc$ 1HHFC 9A= @9@Y@9H ;class 22<. 9H. 5o#ra S, DeRdoun S, Ma11ola J, et al. Bxcarba1ep!ne !n pa!nful d!abet!c neuropat$R= a rando !1ed, placebocontrolled studR. /uropean Journal of Pa!n 9EE@C H= @?>Y@@? ;class 22<. >E. /!senber# /, 3ur!e [, Dra"er C, et al. 3a otr!#!ne reduces pa!nful d!abet!c neuropat$R= a rando !1ed, controlled studR. Neurolo#R 9EE1C @A= @E@Y@EH ;class 2<. >1. T$!enel 6, Neto %, Sc$Pabe SU, et al. Top!ra ate 5!abet!c Neuropat$!c Pa!n StudR Group. Top!ra ate !n pa!nful d!abet!c polRneuropat$R= f!nd!n#s fro t$ree double(bl!nd placebo(controlled tr!als. Acta Neurolo#!ca Scand!na)!ca 9EE?C 11E= 991Y9>1. >9. .as"!n P, 5onofr!o P5, .osent$al N., et al. Top!ra ate )s placebo !n pa!nful d!abet!c polRneuropat$R= anal#es!c and etabol!c effects. Neurolo#R 9EE?C F>= 8F@Y 8A> ;class 2<. 9>

>>. Uoc$ar 5U, Ja!n N, A#arPal .P, et al. Sod!u )alproate !n t$e ana#e ent of pa!nful polRneuropat$R !n tRpe 9 d!abetes Y a rando !1ed placebo controlled studR. Acta Neurolo#!ca Scand!na)!ca 9EE9C 1EF= 9?8Y9@9 ;class 22<. >?. Uoc$ar 5U, .aPat N, A#raPal .P, et al. Sod!u )alproate for pa!nful d!abet!c neuropat$R= a rando !sed double(bl!nd placebo(controlled studR. T$e ZuarterlR Journal of Med!c!ne 9EE?C HA= >>Y>8 ;class 22<. >@. Btto M, Dac$ 0%, Jensen TS, et al. 4alpro!c ac!d $as no effect on pa!n !n polRneuropat$R= a rando !1ed controlled tr!al. Neurolo#R 9EE?C F9= 98@Y988 ;class 2<. >F. Dac"on&a M, DeRdoun A, /dPards U., et al. Gabapent!n for t$e sR pto at!c treat ent of pa!nful neuropat$R !n pat!ents P!t$ d!abetes ell!tus= a rando !1ed controlled tr!al. T$e Journal of t$e A er!can Med!cal Assoc!at!on 1HH8C 98E= 18>1Y 18>F ;class 2<. >A. 3esser H, S$ar a 6, 3aMoreaux 3, et al. Pre#abal!n rel!e)es sR pto s of pa!nful d!abet!c neuropat$R. Neurolo#R 9EE?C F>= 91E?Y911E ;class 2<. >8. .osenstoc" J, Tuc$ ann M, 3aMoreaux 3, et al. Pre#abal!n for t$e treat ent of pa!nful d!abet!c per!p$eral neuropat$R= a double(bl!nd, placebo(controlled tr!al. Pa!n 9EE?C 11E= F98YF>8 ;class 2<. >H. S! pson 5A. Gabapent!n and )enlafax!ne for t$e treat ent of pa!nful d!abet!c neuropat$R. Journal of Cl!n!cal Neuro uscular 5!sease 9EE1C >= @>YF9 ;class 22<. ?E. .!c$ter .%, PortenoR ., S$ar a 6, et al. .el!ef of d!abet!c per!p$eral neuropat$R P!t$ pre#abal!n= a rando !sed placebo(controlled tr!al. Journal of Pa!n 9EE@C F= 9@>Y9FE ;class 2<. ?1. 0reRn$a#en ., Stro&e" U, Gr!es!n# T, et al. /ff!cacR of pre#abal!n !n neuropat$!c pa!n e)aluated !n a 19(Pee", rando !sed, double(bl!nd, ult!centre, placebo( controlled tr!al of flex!ble( and f!xed(dose re#! ens. Pa!n 9EE@C 11@= 9@?Y9F> ;class 2<. ?9. Morello CM, 3ec"band SG, Stoner CP, et al. .ando !1ed double(bl!nd studR co par!n# t$e eff!cacR of #abapent!n P!t$ a !tr!ptRl!ne on d!abet!c per!p$eral neuropat$R pa!n. Arc$!)es of 2nternal Med!c!ne 1HHHC 1@H= 1H>1Y1H>A ;class 22<. ?>. %atson CP, Moul!n 5, %att(%atson J, et al. Controlled(release oxRcodone rel!e)es neuropat$!c pa!n= a rando !1ed ontrolled tr!al !n pa!nful d!abet!c neuropat$R. Pa!n 9EE>C 1E@= A1YA8 ;class 2<. ??. G! bel JS, .!c$rds P, PortenoR .U. Controlled(release oxRcodone for pa!n !n d!abet!c neuropat$R.Arando !1ed controlled tr!al. Neurolo#R 9EE>C FE= H9AYH>? ;class 2<. ?@. Harat! [, Gooc$ C, SPenson M, et al. 5ouble(bl!nd rando !1ed tr!al of tra adol for t$e treat ent of d!abet!c neuropat$R. Neurolo#R 1HH8C @E= 18?9Y18?F ;class2<. ?F. S!ndrup SH, Andersen G, Madsen C, et al. Tra adol rel!e)es pa!n and allodRn!a !n polRneuropat$R= a rando !sed, double(bl!nd, controlled tr!al. Pa!n 1HHHC 8>= 8@Y HE ;class 2<. ?A. San# CN, Doo$er S, G!lron 2, et al. 5extro et$orp$an and e ant!ne !n pa!nful d!abet!c neuropat$R and post$erpet!c 9?

neural#!a. /ff!cacR and dose(response tr!als. Anest$es!olo#R 9EE9C HF= 1E@>Y1EF1 ;class 2<. ?8. Nelson UA, Par" UM, .ob!no)!t1 /, et al. H!#$(dose oral dextro et$orp$an )ersus placebo !n pa!nful d!abet!c neuropat$R and post$erpet!c neural#!a. Neurolo#R 1HHAC ?8= 1919Y1918 ;class 2<. ?H. /rtas M, Sa#duRu A, Arac N, et al. 6se of le)odopa to rel!e)e pa!n fro pa!nful sR etr!cal d!abet!c polRneuropat$R. Pa!n 1HH8C A@= 9@AY9@H ;class 22<. @E. S! pson 5M, BlneR ., McArt$ur JC, et al. A placebo(controlled tr!al of la otr!#!ne for pa!nful H24assoc!ated neuropat$R. Neurolo#R 9EEEC @?= 911@Y911H ;class 22<. @1. S! pson 5M, McArt$ur JC, BlneR ., et al. 3a otr!#!ne for H24(assoc!ated pa!nful sensorR neuropat$!es= a placebo(controlled tr!al. Neurolo#R 9EE>C FE= 1@E8Y 1@1? ;class 2<. @9. Ha$n U, Arendt G, Draun JS. Ger an Neuro(A25S %or"!n# Group. A placebo( controlled tr!al of #abapent!n for pa!nful H24(assoc!ated sensorR neuropat$!es. Journal of Neurolo#R 9EE?C 9@1= 19FEY19FF ;class 22<. @>. S$laR JC, C$aloner U, Max MD, et al. Acupuncture and a !tr!ptRl!ne for pa!n due to H24(related per!p$eral neuropat$R= a rando !1ed controlled tr!al. TerrR De!rn Co un!tR Pro#ra s for Cl!n!cal .esearc$ on A25S. T$e Journal of A er!can Med!cal Assoc!at!on 1HH8C 98E= 1@HEY1@H@ ;class 2<. @?. U!eburt1 U, S! pson 5, [!annoutsos C, et al. A rando !1ed tr!al of a !tr!ptRl!ne and ex!let!ne for pa!nful neuropat$R !n H24 !nfect!on. Protocol Tea . Neurolo#R 1HH8C 9?9= 1F89Y1F88 ;class 2<. @@. /stan!slao 3, Carter U, McArt$ur J, et al. T$e 3!doder (H24 Neuropat$R Group. 3!doca!ne #el for H24(assoc!ated d!stal sR etr!c polRneuropat$R. Journal of AcWu!red 2 une 5ef!c!encR SRndro es 9EE?C @= 1@8?Y1@8F ;class 22<. @F. Ue per CA, Uent G, Durton S, 5eres!ns"! SC. Mex!let!ne for H24(!nfected pat!ents P!t$ pa!nful per!p$eral neuropat$R= a double(bl!nd, placebo(controlled, crosso)er treat ent tr!al. Journal of AcWu!red 2 une 5ef!c!encR SRndro es and Hu an .etro)!rolo#R 1HH8C 1H= >FAY >A9 ;class 2<. @A. Pa!ce JA, 0errans C/, 3as$leR 0., et al. Top!cal capsa!c!n !n t$e ana#e ent of H24(assoc!ated per!p$eral neuropat$R. Journal of Pa!n and SR pto Mana#e ent 9EEEC 1H= ?@Y@9 ;class 2<. @8. Ha ac" J/, M!c$ala" JC, 3opr!n1! C3, et al. P$ase 222 e)aluat!on of nortr!ptRl!ne for alle)!at!on of sR pto s of c!s(plat!nu (!nduced per!p$eral neuropat$R. Pa!n 9EE9C H8= 1H@Y9E> ;class 22<. @H. G!lron 2, Da!leR JM, Tu 5, et al. Morp$!ne, #abapent!n, or t$e!r co b!nat!on for neuropat$!c pa!n. NeP /n#land Journal of Med!c!ne 9EE@C >@9= 1>9?Y1>>? ;class 2<. FE. Nur !""o T, DoPs$er 5. So atosensorR f!nd!n#s !n post$erpet!c neural#!a. Journal of Neurolo#R, Neurosur#erR and PsRc$!atrR 1HHEC @>= 1>@Y1?1. F1. %atson CP, C$!p an M, .eed U, et al. A !tr!ptRl!ne )ersus aprot!l!ne !n post$erpet!c neural#!a= a rando !1ed, double(bl!nd, crosso)er tr!al. Pa!n 1HH9C ?8= 9HY>F ;class 22<. 9@

F9. %atson CP, 4ern!c$ 3, C$!p an M, et al. Nortr!ptRl!ne )ersus a !tr!ptRl!ne !n post$erpet!c neural#!a= a rando !1ed tr!al. Neurolo#R 1HH8C @1= 11FFY11A1 ;class 22<. F>. .oPbot$a MC, Harden N, StaceR D, et al. Gabapent!n for treat ent of post$erpet!c neural#!a. T$e Journal of A er!can Med!cal Assoc!at!on 1HH8C 98E= 18>AY18?> ;class 2<. F?. .!ce ASC, Maton S. Post Herpet!c Neural#!a StudR Group. Gabapent!n !n post$erpet!c neural#!aC a rando !sed, double(bl!nd, controlled studR. Pa!n 9EE1C H?= 91@Y99? ;class 2<. F@. 5Por"!n .H, Corb!n A/, [oun# JP Jr, et al. Pre#abal!n for t$e treat ent of post$erpet!c neural#!a= a rando !1ed, placebo(controlled tr!al. Neurolo#R 9EE>bC FE= 19A?Y198> ;class 2<. FF. SabatoPs"! ., Gal)e1 ., C$errR 5A, et al. Pre#abal!n reduces pa!n and ! pro)es sleep and ood d!sturbances !n pat!ents P!t$ post($erpet!c neural#!a= results of a rando !sed, placebo(controlled cl!n!cal tr!al. Pa!n 9EE?C 1EH= 9FY>@ ;class 2<. FA. Uoc$ar 5U, Gar# P, Du b .A et al. 5!)alproex sod!u !n t$e ana#e ent of post($erpet!c neural#!a= a rando !1ed double(bl!nd placebo(controlled studR. ZuarterlR Journal of Med!c!ne 9EE@C H8= 9HY>? ;class 22<. F8. Galer DS, .oPbot$a MC, Perander J, et al. Top!cal l!doca!ne patc$ rel!e)es post$erpet!c neural#!a ore effect!)elR t$an a )e$!cle top!cal patc$= results of an enr!c$ed enroll ent studR. Pa!n 1HHHC 8E= @>>Y@>8 ;class 22<. FH. Galer DS, Jensen MP, Ma T, et al. T$e l!doca!ne patc$ @I effect!)elR treats all neuropat$!c pa!n Wual!t!es= results of a rando !1ed, double(bl!nd, )e$!cle(controlled, >(Pee" eff!cacR studR P!t$ use of t$e neuropat$!c pa!n scale. Cl!n!cal Journal of Pa!n 9EE9C @= 9HAY>E1 ;class 22<. AE. %asner G, Ule!nert A, D!nder A, et al. Post$erpet!c neural#!a= top!cal l!doca!ne !s effect!)e !n noc!ceptordepr!)ed s"!n. Journal of Neurolo#R 9EE@C 9@9= FAAYF8F ;class 22<. A1. Me!er T, %asner G, 0aust M, et al. /ff!cacR of l!doca!ne patc$ @I !n t$e treat ent of focal per!p$eral neuropat$!c pa!n sRndro es= a rando !1ed, double(bl!nd, placebocontrolled studR. Pa!n 9EE>C 1EF= 1@1Y1@8 ;class 22<. A9. Dernste!n J/, Uor an NJ, D!c"ers 5., et al. Top!cal capsa!c!n treat ent of c$ron!c post$erpet!c neural#!a. Journal of t$e A er!can Acade R of 5er atolo#R 1H8HC 91= 9F@Y9AE ;class 22<. A>. %atson CP, TRler U3, D!c"ers 5., et al. A rando !1ed )e$!cle(controlled tr!al of top!cal capsa!c!n !n t$e treat ent of post$erpet!c neural#!a. Cl!n!cal T$erapeut!cs 1HH>C 1@= @1EY@9F ;class 2<. A?. %atson CP, Dabul N. /ff!cacR of oxRcodone !n neuropat$!c pa!n= a rando !1ed tr!al !n post$erpet!c neural#!a. Neurolo#R 1HH8C @E= 18>AY18?1 ;class 2<. A@. .a&a SN, HaRt$ornPa!te JA, Pappa#allo M, et al. Bp!o!ds )ersus ant!depressants !n post$erpet!c neural#!a. Neurolo#R 9EE9C @H= 1E1@Y1E91 ;class 2<. 9F

AF. .oPbot$a MC, TP!ll!n# 3, 5a)!es PS, et al. Bral op!o!d t$erapR for c$ron!c per!p$eral and central neuropat$!c pa!n. NeP /n#land Journal of Med!c!ne 9EE>C >?8= 199>Y19>9 ;class 22<. AA. Doureau 0, 3e#all!c!er P, Uab!r(A$ ad! M. Tra adol !n post($erpet!c neural#!a= a rando !1ed, double(bl!nd, placebo(controlled tr!al. Pa!n 9EE>C 1E?= >9>Y>>1 ;class 2<. A8. /!senber# /, Ule!ser A, 5ortort A, et al. T$e NM5A ;N( et$Rl(5(aspartate< receptor anta#on!st e ant!ne !n t$e treat ent of post$erpet!c neural#!a= a doublebl!nd, placebo(controlled studR. /uropean Journal of Pa!n 1HH8C 9= >91Y>9A ;class 22<. AH. Max MD, Sc$afer SC, Culnane M, et al. A !tr!ptRl!ne, but not lora1epa , rel!e)es post$erpet!c neural#!a. Neurolo#R 1H88C >8= 1?9AY1?>9 ;class 22<. 8E. Cruccu G, Tru!n! A. Tr!#e !nal neural#!a and orofac!al pa!ns. 2n= Pappa#allo M, ed. T$e Neurolo#!cal Das!s of Pa!n. NeP [or"= McGraP(H!ll, 9EE@= ?E1Y?1?. 81. S!ndrup SH, Jensen TS. P$ar acot$erapR of tr!#e !nal neural#!a. Cl!n!cal Journal of Pa!n 9EE9C 18= 99Y9A. 89. Ca pbell 0G, Gra$a JG, and V!l"$a UJ. Cl!n!cal tr!al of carba a1ep!ne ;te#retol< !n tr!#e !nal neural#!a. Journal of Neurolo#R, Neurosur#erR and PsRc$!atrR 1HFFC 9H= 9F@Y9FA. 8>. Jensen TS. Ant!con)ulsants !n neuropat$!c pa!n= rat!onale and cl!n!cal e)!dence. /uropean Journal of Pa!n 9EE9C F;Suppl. A<= F1YF8. 8?. UutluaR /, McCa#ue U, 5\Sou1a J, et al. SafetR and tolerab!l!tR of oxcarba1ep!ne !n elderlR pat!ents P!t$ ep!lepsR. /p!lepsR T De$a)!or 9EE>C ?= 1A@Y 18E. 8@. 3!ebel JT, Men#er N, 3an#o$r H. Bxcarba1ep!ne !n der De$andlun# der Tr!#e !nus neural#!e. Ner)en$e!l"unde 9EE1C 9E= ?F1Y?F@ ;class 22<. 8F. DeRdoun A. SafetR and eff!cacR of oxcarba1ep!ne= results of rando !1ed, double( bl!nd tr!als. P$ar acot$erapR 9EEEC 9E= 1@9SY1@8S. 8A. Va"r1ePs"a JM, C$aud$rR V, Nur !""o TJ, et al. 3a otr!#!ne ;la !ctal< !n refractorR tr!#e !nal neural#!a= results fro a double(bl!nd placebo controlled crosso)er tr!al. Pa!n 1HHAC A>= 99>Y9>E ;class 22<. 88. 0ro GH, Terrence C0, C$att$a AS. Daclofen !n t$e treat ent of tr!#e !nal neural#!a= double(bl!nd studR and lon#(ter folloP(up. Annals of Neurolo#R 1H8?C 1@= 9?EY9?? ;class 22<. 8H. 0ro GH, Terrence C0. Co par!son of 3(baclofen and race !c baclofen !n tr!#e !nal neural#!a. Neurolo#R 1H8AC >A= 1A9@Y1A98 ;class 22<. HE. 3!ndstro P, 3!ndblo 6. T$e anal#es!c effect of toca!n!de !n tr!#e !nal neural#!a. Pa!n 1H8AC 98= ?@Y@E ;class 22<. H1. 3ec$!n 0, )an der 5!&s D, 3ec$!n M/, et al. P! o1!de t$erapR for tr!#e !nal neural#!a. Arc$!)es of Neurolo#R 1H8HC ?F= HFEYHF> ;class 22<. H9. Uond1!ol"a 5, 3e leR T, Uestle J., et al. T$e effect of s!n#le(appl!cat!on top!cal op$t$al !c anest$es!a !n pat!ents P!t$ tr!#e !nal neural#!a. A rando !1ed 9A

doublebl!nd placebo(controlled tr!al. Journal of Neurosur#erR 1HH?C 8E= HH>YHHA ;class 2<. H>. /pste!n JD, Marcoe JH. Top!cal appl!cat!on of capsa!c!n for treat ent of oral neuropat$!c pa!n and tr!#e !nal neural#!a. Bral Sur#erR, Bral Med!c!ne, and Bral Pat$olo#R 1HH?< AA= 1>@Y1?E ;class 222<. H?. 4!l !n# ST, 3Rber# T, 3ataste X. T!1an!d!ne !n t$e ana#e ent of tr!#e !nal neural#!a. Cep$alal#!a 1H8FC F= 181Y189 ;class 222<. H@. 0ro GH, Au entado 5, Terrence C0. A cl!n!cal and exper! ental !n)est!#at!on of t$e effects of t!1an!d!ne !n tr!#e !nal neural#!a. Pa!n 1HH>C @>= 9F@Y 9A1 ;class 2<. HF. Nur !""o TJ, /ldr!d#e P.. Tr!#e !nal neural#!a Ypat$op$Rs!olo#R, d!a#nos!s and current treat ent. Dr!t!s$ Journal of Anaest$es!a 9EE1C 8A= 11AY1>9. HA. Do!)!e J. Central pa!n. 2n= MacMa$on SD, Uolt1enbur# M ;eds<, %all and Mel1ac"\s Textboo" of Pa!n. C$urc$!ll 3!)!n#stone= /lse)!er, 9EE@= 1E@AY1EA@. H8. Attal N, Dou$ass!ra 5. Central neuropat$!c pa!n. 2n= Pappa#allo M, ed. T$e Neurolo#!cal Das!s of Pa!n. McGraP(H!ll, NeP [or", 9EE@= >E1Y>1H. HH. 3e!&on G, Do!)!e J. Central post(stro"e pa!n Y a controlled tr!al of a !tr!ptRl!ne and carba a1ep!ne. Pa!n 1H8HC >F= 9AY>F ;class 2<. 1EE. Cardenas 55, %ar s CA, Turner JA, et al. /ff!cacR of a !tr!ptRl!ne for rel!ef of pa!n !n sp!nal cord !n&urR= results of a rando !1ed controlled tr!al. Pa!n 9EE9C HF= >F@Y>A> ;class 2<. 1E1. 4ester#aard U, Andersen G, Gottrup H, et al. 3a otr!#!ne for central poststro"e pa!n= a rando !1ed controlled tr!al. Neurolo#R 9EE1C @F= 18?Y1HE ;class 2<. 1E9. 0!nnerup ND, S!ndrup SH, Dac$ 0%, et al. 3a otr!#!ne !n sp!nal cord !n&urR pa!n= a rando !1ed controlled tr!al. Pa!n 9EE9C HF= >A@Y>8> ;class 2<. 1E>. 3e)endo#lu 0, B#un CB, B1erb!l B, et al. Gabapent!n !s a f!rst l!ne dru# for t$e treat ent of neuropat$!c pa!n !n sp!nal cord !n&urR. Sp!ne 9EE?C 9H= A?>YA@1 ;class 22<. 1E?. 5rePes AM, Andreasen A, Poulsen 3H. 4alproate for treat ent of c$ron!c central pa!n after sp!nal cord !n&urR. A double(bl!nd cross(o)er studR. Paraple#!a 1HH?C >9= @F@Y@FH ;class 22<. 1E@. C$!ou(Tan 0[, Tuel SM, Jo$nson JC, et al. /ffect of ex!let!ne on sp!nal cord !n&urR dRsest$et!c pa!n. A er!can Journal of P$Rs!cal Med!c!ne and .e$ab!l!tat!on 1HHFC A@= 8?Y8A ;class 2<. 1EF. S)endsen UD, Jensen TS, Dac$ 0%. T$e cannab!no!d dronab!nol reduces central pa!n !n Mult!ple Scleros!s. A rando !sed double(bl!nd placebo controlled cross(o)er tr!al. Dr!t!s$ Med!cal Journal 9EE?C >9H= 9@>Y9F1 ;class 2<. 1EA. .o# 5J, Nur !""o TJ, 0r!ede T, et al. .ando !1ed, controlled tr!al of cannab!s( based ed!c!ne !n central pa!n !n ult!ple scleros!s. Neurolo#R 9EE@C F@= 819Y81H ;class 2<. 1E8. U!n#erR %S. A cr!t!cal re)!eP of controlled cl!n!cal tr!als for per!p$eral neuropat$!c pa!n and co plex re#!onal pa!n sRndro es. Pa!n 1HHAC A>= 19>Y1>H. 98

1EH. Caracen! A, Vecca /, Done11! C, et al. Gabapent!n for neuropat$!c cancer pa!n= a rando !1ed controlled tr!al fro t$e Gabapent!n Cancer Pa!n StudR Group. Journal of Cl!n!cal Bncolo#R 9EE?C 99= 9HEHY9H1A. 11E. Mercadante S, Arcur! /, T!rell! %, et al. A !tr!ptRl!ne !n neuropat$!c cancer pa!n !n pat!ents on orp$!ne t$erapR= a rando !1ed placebo(controlled, double(bl!nd crosso)er studR. Tu or! 9EE9C 88= 9>HY9?9 ;class 22<. 111. Ualso /, Tas ut$ T, Neu)onen PJ. A !tr!ptRl!ne effect!)elR rel!e)es neuropat$!c pa!n folloP!n# treat ent of breast cancer. Pa!n 1HHFC F?= 9H>Y>E9 ;class 22<. 119. Tas ut$ T, Hartel D, Ualso /. 4enlafax!ne !n neuropat$!c pa!n folloP!n# treat ent of breast cancer. /uropean Journal of Pa!n 9EE9C F= 1AY9? ;class 22<. 11>. /ll!son N, 3opr!n1! C3, Uu#ler J, et al. P$ase 222 placebocontrolled tr!al of capsa!c!n crea !n t$e ana#e ent of sur#!cal neuropat$!c pa!n !n cancer pat!ents. Journal of Cl!n!cal Bncolo#R 1HHAC 1@= 9HA?Y9H8E ;class 2<. 11?. %atson CP, /)ans .J. T$e post astecto R pa!n sRndro e and top!cal capsa!c!n= a rando !1ed tr!al. Pa!n 1HH9C @1= >A@Y>AH ;class 22<. 11@. Scadd!n# J%, %all P5, ParrR CD, et al. Cl!n!cal tr!al of propranolol !n post( trau at!c neural#!a. Pa!n 1H89C 1?= 98>Y9H9 ;class 22<. 11F. Der an JS, SR onds C, D!rc$ .. /ff!cacR of tPo cannab!s based ed!c!nal extracts for rel!ef of central neuropat$!c pa!n fro brac$!al plexus a)uls!on= results of a rando !sed controlled tr!al. Pa!n 9EE?C 119= 9HHY>EF ;class 2<. 11A. Done M, Cr!tc$leR P, Du##R 5J. Gabapent!n !n posta putat!on p$anto l! b pa!n= A rando !1ed, doublebl!nd, placebo(controlled, cross(o)er studR. .e#!onal Anest$es!a and Pa!n Med!c!ne 9EE9C 9A= ?81Y?8F ;class 22<. 118. Huse /, 3arb!# %, 0lor H, D!rbau er N. T$e effect of op!o!ds on p$anto l! b pa!n and cort!cal reor#an!1at!on. Pa!n 9EE1C HE= ?AY@@. Journal of Cl!n!cal Bncolo#RC 99= 9HEHY9H1A ;class 22<. 11H. Ma!er C, 5ertP!n"el ., Mansour!an N, et al. /ff!cacR of t$e NM5A(receptor anta#on!st e ant!ne !n pat!ents P!t$ c$ron!c p$anto l! b pa!n Y results of a rando !1ed double(bl!nded, placebo(controlled tr!al. Pa!n 9EE>C 1E>= 9AAY98> ;class 2<. 19E. .ob!nson 3., C1ern!ec"! JM, /$de 5M, et al. Tr!al of a !tr!ptRl!ne for rel!ef of pa!n !n a putees= results of a rando !1ed controlled studR. Arc$!)es of P$Rs!cal Med!c!ne and .e$ab!l!tat!on 9EE?C 8@= 1YF ;class 22<. 191. PandeR CU, Dose N, Gar# G, et al. Gabapent!n for t$e treat ent of pa!n !n Gu!lla!nYDarre sRndro e= a doublebl!nded, placebo(controlled, crosso)er studR. Anest$es!a and Anal#es!a 9EE9C H@= 1A1HY1A9> ;class 22<. 199. PandeR CU, .a1a M, Tr!pat$! M, et al. T$e co parat!)e e)aluat!on of #abapent!n and carba a1ep!ne for pa!n ana#e ent !n Gu!lla!n(Darre sRndro e 9H

pat!ents !n t$e !ntens!)e care un!t. Anest$es!a and Anal#es!a 9EE@C 1E1=99EY99@ ;class 22<. 19>. Hu#$es .A, %!&d!c"s /0, Denson /, et al. Mult!d!sc!pl!narR Consensus Group. Support!)e care for pat!ents P!t$ Gu!lla!n(Darre sRndro e. Arc$!)es of Neurolo#R 9EE@C F9= 11H?Y11H8. 19?. Se enc$u" M., S$er an S, 5a)!s D. 5ouble(bl!nd, rando !1ed tr!al of buprop!on S. for t$e treat ent of neuropat$!c pa!n. Neurolo#R 9EE1C @A= 1@8>Y1@88 ;class 2<. 19@. Panera! A/, Mon1a G, Mo)!l!a P, et al. A rando !1ed, P!t$!n(pat!ent, cross( o)er, placebo(controlled tr!al on t$e eff!cacR and tolerab!l!tR of t$e tr!cRcl!c ant!depressants c$lor! !pra !ne and nortr!ptRl!ne !n central pa!n. Acta Neurolo#!ca Scand!na)!ca 1HHEC 89= >?Y>8 ;class 22<. 19F. 3an#o$r H5, Sto$r M, Petruc$ 0. An open and doublebl!nd cross(o)er studR on t$e eff!cacR of clo !pra !ne ;Anafran!l< !n pat!ents P!t$ pa!nful ono( and polRneuropat$!es. /uropean Neurolo#R 1H89C 91= >EHY>1A ;class 22<. 19A. Har"e H, Greten"ort P, 3adle!f H6, .a$ an S, Har"e B. T$e response of neuropat$!c pa!n and pa!n !n co plex re#!onal pa!n sRndro e 2 to carba a1ep!ne and susta!ned(release orp$!ne !n pat!ents pretreated P!t$ sp!nal cord st! ulat!on= a double(bl!nded rando !1ed studR. Anest$es!a and Anal#es!a 9EE1C H9= ?88Y?H@ ;class 22<. 198. C$abal C, Jacobson 3, Mar!ano A, et al. T$e use of oral ex!let!ne for t$e treat ent of pa!n after per!p$eral ner)e !n&urR. Anest$es!olo#R 1HH9C AF= @1>Y@1A ;class 2<. 19H. %allace MS, Ma#nuson S, .!d#ePaR D. /ff!cacR of oral ex!let!ne for neuropat$!c pa!n P!t$ allodRn!a= a doublebl!nd, placebo(controlled, crosso)er studR. .e#!onal Anest$es!a and Pa!n Med!c!ne 9EEEC 9@= ?@HY?FA ;class 2<. 1>E. Galer DS, TP!ll!n# 33, Harle J, et al. 3ac" of eff!cacR of r!lu1ole !n t$e treat ent of per!p$eral neuropat$!c pa!n cond!t!ons. Neurolo#R 9EE@C @@= HA1YHA@ ;class 22<. 1>1. McZuaR HJ, Carroll 5, Jadad A., et al. 5extro et$orp$an for t$e treat ent of neuropat$!c pa!n= a doublebl!nd rando !sed controlled crosso)er tr!al P!t$ !nte#ral n(of(1 des!#n. Pa!n 1HH?C @H= 19AY1>> ;class 22<. 1>9. Serpell MG. Neuropat$!c pa!n studR #roup. Gabapent!n !n neuropat$!c pa!n sRndro es= a rando !sed, doublebl!nd, placebo(controlled tr!al. Pa!n 9EE9C HH= @@AY@FF ;class 22<. 1>>. Uarst M, Sal! U, Durste!n S, Conrad 2, HoR 2, Sc$ne!der 6. Anal#es!c effect of t$e sRnt$et!c cannab!no!d CT(> on c$ron!c neuropat$!c pa!n= a rando !1ed controlled tr!al. Journal of t$e A er!can Med!cal Assoc!at!on 9EE>C 9HE= 1A@AY1AF9. 1>?. McCleane GJ. 9EE # da!lR of la otr!#!ne $as no anal#es!c effect !n neuropat$!c pa!n= a rando !sed, double(bl!nd, placebo controlled tr!al. Pa!n 1HHHC 8>=1E@Y1EA ;class 222<. >E

1>@. McCleane G. Top!cal appl!cat!on of doxep!n $Rdroc$lor!de, capsa!c!n and a co b!nat!on of bot$ produces anal#es!a !n c$ron!c $u an neuropat$!c pa!n= a rando !1ed, double(bl!nd, placebo(controlled studR. Dr!t!s$ Journal of Cl!n!cal P$ar acolo#R 9EEEC ?H= @A?Y@AH ;class 222<. 1>F. Max MD, U!s$ore(Uu ar ., Sc$afer SC, et al. /ff!cacR of des!pra !ne !n pa!nful d!abet!c neuropat$R= a placebocontrolled tr!al. Pa!n 1HH1C ?@= >YH ;class 2<. 1>A. U!s$ore(Uu ar ., Max MD, Sc$afer SC, et al. 5es!pra !ne rel!e)es post$erpet!c neural#!a. Cl!n!cal P$ar acolo#R and t$erapeut!cs 1HHEC ?A= >E@Y>19 ;class 22<. 1>8. DeRdoun A. Cl!n!cal use of tr!cRcl!c ant!con)ulsants !n pa!nful neuropat$!es and b!polar d!sorders. /p!lepsR T De$a)!or 9EE9C >= S18YS99. 1>H. Carra1ana /, M!"os$!ba /. .at!onale and e)!dence for t$e use of oxcarba1ep!ne !n neuropat$!c pa!n. Journal of Pa!n and SR pto Mana#e ent 9EE>C 9@= S>1YS>@. 1?E. Cruccu G, Anand P, Attal N, et al. /0NS #u!del!nes on neuropat$!c pa!n assess ent. /uropean Journal of Neurolo#R 9EE?C 11= 1@>Y1F9. 1?1. .aR %A, Mered!t$ S, T$apa PD, et al. CRcl!c ant!depressants and t$e r!s" of sudden card!ac deat$. Cl!n!cal P$ar acolo#R and T$erapeut!cs 9EE?C A@= 9>?Y9?1. 1?9. %atson CP, /)ans .J, .eed U, et al. A !trRpt!l!ne )ersus placebo !n post( $erpet!c neural#!a. Neurolo#R 1H89C >9= FA1YFA> ;class 22<. 1?>. 5e#ner 5, Gro$ ann ., Uropp S et al. Se)ere ad)erse dru# react!ons of ant!depressants= results of t$e Ger an ult!center dru# sur)e!llance pro#ra AMSP. P$ar acopsRc$!atrR 9EE?C >A;Suppl. 1<= S>HYS?@. 1??. Detts T, GoodP!n G, %!t$ers .M, et al. Hu an safetR of la otr!#!ne. /p!leps!a 1HH1C >9;Suppl. 9<= S1AYS91. 1?@. Ualso /, Allan 3, 5elle !&n P3 et al. .eco endat!ons for us!n# op!o!ds !n c$ron!c non(cancer pa!n. /uropean Journal of Pa!n 9EE>C A= >81Y>8F. 1?F. S!ndrup SH, Jensen TS. /ff!cacR of p$ar acolo#!cal treat ents of neuropat$!c pa!n= an update and effect related to ec$an!s of act!on. Pa!n 1HHHC 8>= >8HY?EE. 1?A. McZuaR HJ. Neuropat$!c pa!n= e)!dence atters. /uropean Journal of Pa!n 9EE9C F;Suppl. A<= 11Y18.

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