Side Effects of It Opioids

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M a r k A . C h a n c y M D

Review Art ic leSide effects of intrathe-ca l and epidura l op io ids

The purpo se o f this article is to review the l i terature on theside effects of intrathecal an d epidural opioids. English-languageart ic les were ident i f ied through a MEDLINE search andthrou gh review o f the bibliographies of identif ied articles. Withthe increasing uti l ization o f intrathecal an d epidur al opioidsin h um ans dur ing the 1980s , a wide var iety o f c l in ical ly re levantside effects hav e bee n rep orted. The fo ur classic side effectsare pruritus, nause a an d vomiting, urinar y retention, an d res-piratory depression. Num erous o ther s ide e ffects have a lso be endescr ibed. Most s ide e f fec ts are dose-dependent and may bemo re co mm on i f the opioid i s adminis tered in trathecaily . S ideef fec ts are less comm on in pat ients chronical ly expose d to e i therintrathecal, epidural, or systemic opioids. So m e side effects aremediated via interaction with specific opioid receptors whileothers are not. I t is conclu ded that the introduction o f intrath-e c a l and e p i dur a l op i o i d s mar k s one o f t he mos t i mpor t an tbreakthroughs in pain ma nage men t in the last two decades.However, a wide variety of clinically relevant non-nociceptiveside effects ma y occur. All physicians uti lizing intrathecal an depidural opioids m ust be aw are o f these s ide e ffects, fo r whi lemo st are minor, others are potentially lethal.Ce travail consti tue un surv ol de la l i t t$rature porta nt su r leseffets secondaires des morphiniques sous-arachnogdiens et ~pi-durau:c. Les articles en langu e anglaise on t ~t~ identif ids grace?: une recherche sur Medline et une revue des bibliographiesdes articles trouv$s de cette faf on . Av ec l 'uti lisation croissantedes morphiniques sous-arachno~diens e t ~piduraux d$but6eclans les anr~es 80, on a d~cr i t avec per t inence u ne grand evaridt6 d'effets secondaires convaincants. I_~ q uatres effets se-

Key wordsA N A L G E S I A : pos t ope r a t i ve ;ANALGESIA: m orp hin e, fentany l , sufen tanil .From the Department of Anesthesiology, Foster G. M eGawHospital , Loyola Un iversity Medical Center , 2160 South FirstAvenue, M aywood , I l l inois 60153.

Address correspondence to: Dr. Mark A. Chaney,Department of Anesthesiology, Foster G. M eGaw Hospital ,Loyola U niversity Medical Cen ter , 2160 South First Av enue,Mayw ood, I l l inois 60153.

Accepted or publ icat ion 9th June , 1995.

condaires classiques son t le prurit , les nausdes et les vomis-semen ts, la rktention urinaire et ia ddpression respiratoire; cene sont toutefois pas les seuls effets secondaires rapport~s. Laplupart d dpenden t de la dose e t sont p lus f rrqu ents lorsquele morphinique est administr~ par la voie sous-arachno~dienne.Les effets second_aires surv ienne nt m oin s so uve nt c hez lea pa-t ients exposds de fa f on chronique ~ des morph iniques sous-arachnoi 'd iens , 6pidurau x o u sys tdmiques . Qu elquev uns des e f -

fet s secondaires rrsultent .de l' interaction de r~cepteurs mo rphi-nique s sprcifiques m ais pa s tous. Les auteurs concluent q ueHntroduction des mo rphin iques sous-arachno?diens et dpidu-rau x reprrsente la pere~e la plu s im portan te des de ux dernib.resdrcennies dans le domaine du traitement de la douleur. Ce-pendant, des effets secondaires multiples de nature non-nociceptive so nt susceptiblea de survenir. Tous lea mk decin sutil isateurs de morphinique sous-arachnoMiens et ~pidurauxdoivent connat tre ces e f fe t s secondaires qu i sont mineu rs pou rla plupart, alors qu e d'autres so nt pote ntiellem ent idtaux.

Pur e a n t i noe i c e p t i on wi t hou t s i de e f f e c t s ha s l ong be e na n e l u s ive goa l. I n t he 1970s, t he d i s c ove r y o f h i gh l y s pe -c i f i c op i o i d r e c e p t o r s i n t he c e n t r a l ne r vous s y s t e m , i npa r t i c u l a r t he i r e x i s t e nc e i n t he s p i na l c o r d , c r e a t e d ne we n t hus i a s m f o r t he pos s i b l e r e a l i z a t i on o f t h i s goa l . Sub -s e que n t de m o ns t r a t i on t ha t s m a l l a m oun t s o f in t r a the c a lo r e p i d u r a l o p i o i d s p r o d u c e d p r o f o u n d a n t i n o c i c e p t i o non l y he i gh t e ne d e n t hus i a s m . How e ve r , wi t h i nc r e a si ngun i ve r s a l a pp l i c a t i on o f t he t e c hn i que i n hum a ns i n t he1980s , a w i de va r i e t y o f c l i n i c a ll y r e l e va n t n on - noc i e e p t i ves i de e f fe c t s ha ve be e n r e po r t e d , t,2 Be c a u s e o f t he p r o f o unda n t i noc i c e p t i on ob t a i ne d a nd de s p i t e t he non - noc i c e p t i ves i de e f f e c t s , s p i na l a pp l i c a t i on o f op i o i d s r e m a i ns ve r ypop u l a r a nd e f f e ct ive i n t he tr e a t m e n t o f m a n y pa i n s t a te s .

O p i o i d s a r e p e r h a p s t h e o l d e s t a n d m o s t s t u d i e d o fd r ugs . Op i um us e , f o r i t s e upho r i c e f f e c t s , c a n be t r a c e dba c k ove r 4000 y r a nd i t s r e s p i r a t o r y de p r e s s a n t e f f e c t sw e r e f i r s t n o t e d a p p r o x i m a t e l y 6 0 0 y r a g o . I t w a s n o tun t i l 1971 , howe ve r , tha t h i gh l y s pe c i f ic op i o i d r e c e p t o r swe r e d i s c ove r e d . 3 I n 1973 , op i o i d r e c e p t o r s w e r e l oc a l i z e di n m a m m a l i a n b r a i n 4 a n d i n 1 9 76 th e y w e r e f o u n d t oe x i s t in p r i m a t e s p i na l c o r d . s Al s o i n 1976 , Ya ks h a ndRudy f i r s t de m ons t r a t e d t he e f f e c t i ve ne s s o f i n t r a t he c a l

C A N J A N A E S T H 1 9 9 5 / 4 2 : I 0 / p p S 91 - 90 3


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8 92 C A N A D I A N J O U R N A L O F A N A E S T H E S I A

o p i o i d s i n a b o l i s h in g e x p e r i m e n t a l p a i n i n a n a n i m a lmo de l . 6 I n 1979 , i n i ti a l r epo r t s o f i n t r a t heca l 7 and ep i -d u r a l s u s e o f m o r p h i n e i n h u m a n s a p p e a r e d i n t h e l it -e r a t u r e .

I n t r a th e c a l a n d e p i d u r a l o p i o id s p r o d u c e p r o f o u n d s e g -m e n t a l a n t i n o c i c e p t io n i n d o se s m u c h s m a l l e r t h a n w o u l db e r e q u i r e d f o r c o m p a r a b l e a n t i n o c i c e p t i o n i f a d m i n i s -t e r e d s y s t e m i c a l l y . A n t i n o c i c e p t i o n m a y b e p r o l o n g e d ;w h e n m o r p h i n e i s u t i l i z e d , i t m a y p e r s i s t f o r d a y s f o l -l owi ng a s i ng l e i n j ec ti on . 9 Unl i ke t he r e sponse t o l oca la n a e s t h e t i c s , t h e r e i s n o m o t o r , s e n s o r y , o r a u t o n o m i cb l o c k a d e . P a r a l y s i s a n d h y p o t e n s i o n , t h e r e f o r e , a r e a b -sen t . Anot he r c r i t i ca l advan t age ove r l oca l anaes t he t i c si s t he ava i l ab i li t y o f a spec i f i c op i o i d r ecep t or an t ago ni s t ,n a l o x o n e .P h m n a c o k i n e f i c s o f i n t m t h e c a l a n d e p i d ur a l o p i o i d sS i d e e f f e ct s o f i n t r a t h e c a l a n d e p i d u r a l o p i o i d s a r e c a u s e db y p r e s e n c e o f t h e d r u g i n e i t h e r c e r e b m s p i n a l f l u i d o rb l o o d . T h e r e f o r e , f o ll o w i n g a d m i n i s t r a t io n o f i n t r a th e c a lan d e p i dura l op i o i ds , s i de e f f ec t s w i ll be p ro foun dl y a f -f e c te d b y t h e i r p h a r m a c o k i n e t i c b e h a v i o u r . F e n t a n y l a n dsufen t an i l a r e , r e spec t i ve l y , approx i ma t e l y 800 and 1600t i m e s a s l i p i d - s o l u b l e a s m o r p h i n e . W h e n a d m i n i s t e r e di n t r a t heca l l y o r ep i duraUy, t he r e for e , morph i ne wi l l ex -h i b i t s lo w e r o n s e t a n d l o n g e r d u r a t i o n o f a n t i n o c i c e p ti o nand a h i g he r i nc i dence o f som e s i de e f fec ts .

I n t r a th e e a l a d m i n i s tr a t io n o f o p i o i d s i m m e d i a t e l y p r o -d u c e s h i g h c e r e b r o s p i n a l f l u i d c o n c e n t r a t io n s o f d r u g t h a ta r e d o s e - d ep e n d e n t .~ ~ V a s c u l a r r e a b s o r p t i o n o f o p i o i d sf o l lo w i n g i n tr a t h e c a l a d m i n i s t r a t io n d o e s o c c u r t o s o m edegree , b u t i s c li n i ca l ly i r r e levan t , n -13 F en t any l an d su-f en t an i l pene t r a t e t he sp i na l cord qu i ck l y , l eav i ng l i t t l ed r u g t o a s c e n d c e p h a l a d i n c e r e b r o s p i n a l f l u i d . I n c o n -W as t, mo rph i n e pen e t r a t e s t he sp i na l co rd s l owl y , a l l owi ngc o n s i d e r a b le a m o u n t s o f d r u g t o a s c e n d c e p h a l a d i n c e r e -b r o s p i n a l f l u i d . F o l l o w i n g l u m b a r i n t r a t h e c a l m o r p h i n eadmi n i s t r a t i on , apprec i ab l e ce rv i ca l ce r ebrosp i na l f l u i deoneen t r a t i ons occur one t o f i ve hour s a f t e r i n j ec t i on ,w h i l e c e r v i c a l c e r e b r o s p i n a l f l u i d c o n c e n t r a t i o n s o f ah i gh l y l ipoph il ic op i o i ds , s i mi l a r l y adm i n i s t e r ed , a r e m i n-i ma l . 14.15 T h e und er l y i ng ca use o f a scens i on o f m orp h i nei s b u l k f l o w o f e e r e b r o s p i n a l f lu i d . C e r e b r o s p i n a l f l u i da s c e n d s i n a c e p h a l a d d i r e c t i o n f r o m t h e l u m b a r r e g i o n ,r e a c h i n g t h e c i s t e r n a m a g n a b y o n e o r t w o h o u r s a n dt he fo ur t h and l a t e r a l ven t ri c l e s by t h r ee t o s i x hour s . 16A l t h o u g h c o u g h i n g , s n e e z i n g , o r s t r a i n i n g c a n a f f e c tm o v e m e n t o f c e r e b r o s p i n a l f l u i d , b o d y p o s i t i o n d o e sno t . 16 Hi gh l y l ipoph il ic op i o i ds a r e r e m oved f r om ce r e -b r o s p i n a l f l u i d r a p i d l y s e c o n d a r y t o v a s c u l a r r e a b s o r p t io nand sp i na l cord p ene t r a t i on . 17 In co n t r a s t , morp h i ne p e r -s is ts i n c e r e b r o s p i n a l f l u id f o r p r o l o n g e d p e r i o d s a n d m a yd e p e n d o n r e a b s o r p t i o n t h r o u g h a r a c h n o i d g r a n u l a t i o n s

TA BL E I S ide effects of in tratheeal and epidural opioid sP ru r i tu sN aus ea and vomi t ingUrin ary retent ionRespiratory depress ionMe ntal s tatus changesCentral nervoussystemexcitationHyperalgesiaHerpes s im plex labial is v irus react ivat ionN eona ta l morb id itySexu al dysfunctionOcu lar dysfunctionGastrointestinal y s f u n c t i o nT h c r m o r e g u l a t o r y y s f u n c t i o nW a t e r r e t e n t io nC a r d i a c y s r h y t h m i aH a i r l o ssNeurotoxici tyAnaphylaxis

fo r e l i mi na t i on . Zs T h e t e rm i na l e l i mi na t i on ha l f - li f e o fmorph i ne i n ce r ebrosp i na l f l u i d i s s i mi l a r t o t ha t i nplasm a, tw o to fou r hours . 10,17

E p i d u r a l a d m i n i s t r a ti o n o f o p i o i d s a l s o p r o d u c e s c o n -s i d e r a b l e c e r e b r o s p i n a l f l u i d c o n c e n t r a t i o n s o f d r u g .P e n e t r a t i o n o f t h e d u r a i s c o n s id e r a b l y i n f lu e n c e d b y l i-p o p hi li ci ty , b u t m o l e c u l a r w e i g h t m a y a l s o p l a y a n i m -por t a n t r o l e . 19 F o l l owi ng ep i dura l adm i n i s t r a t ion , ce r e -b r o s p i n a l f l u i d c o n c e n t r a t io n s o f f e n t a n y l p e a k i n 1 0 to2 0 r a i n 2 ~ w h i l e s u f e n t a n i l c o n c e n t r a ti o n s p e a k i n a b o u ts i x m i nu t es . 21 In con t r a s t , ce r e brosp i na l f l u i d co ncen t r a -t io n s o f m o r p h i n e , f o l lo w i n g e p i d u r a l a d m i n i s tr a t io n ,p e a k i n o n e t o f o u r h o u r s . ~ ,z 3 F u r t h e r m o r e , o n l y a b o u t3 % o f t h e d o s e o f m o r p h i n e a d m i n i s t e r e d e p i d u r a l l yc r o s se s th e d u r a t o e n t e r c e r e b r o s p i n a l f l u i d . Z ~ T h e e p i -d u r a l s p a c e c o n t a i n s a n e x t e n si v e v e n o u s p l e x u s . T h e r e -fo r e , vascu l a r r eabsorp t i on fo l l owi ng ep i dura l admi n i s t r a -t i on o f op i o i ds i s ex tens ive . E p i dura l ad mi n i s t r a t i on o fm o r p h i n e , f e n t a n y l, o r s u f e n t a n il p r o d u c e s o p i o i d b l o o dc o n c e n t r a t io n s t h a t a r e s i m i l a r t o a n i n t r a m u s c u l a r i n -j e c t io n o f a n e q u i v a l e n t d o s e . F o l lo w i n g e p i d u r a l a d m i n -i s t ra t i on , f en t any l b l ood co ncen t r a t i ons pea k a t ab ou t f i vet o t e n m i n u t e s ~ ; -s w h i l e s u f e n ta n l l b l o o d c o n c e n t r a t io n spea k even f a s te r . =3~6 In con t r a s t , b l ood conc en t r a t i ons o fm o r p h i n e f o ll ow i ng e p i d u r a l a d m i n i s t r a t io n p e a k a t a b o u t1 0 to 1 5 m il l. ~ 7 ; sSide e f fec t s o f in tra theezd and ep idura l op io idsS i de e f f ec t s o f i n t r a t heca l and ep i dura l op i o i ds a r e l i s t edi n T ab l e I . T h e fou r c la s si c s i de e f fec t s a r e p ru r i t us , n an -s e a a n d v o m i t i n g , u r i n a r y r e t e n t i o n , a n d r e s p i r a t o r y d e -p r e s si o n . N u m e r o u s o t h e r s i d e e ff e c ts h a v e a l s o b e e n d e -sc r i bed . I n gene ra l , mos t s i de e f f ec t s o f i n t r a t heca l and


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Chancy: SPIN AL OPIOIDS 893e p i d u r a l o p i o i d s a r e d o s e - d e p e n d e n t a n d m a y b e m o r ec o m m on i f t he op i o i d i s a dm i n i s t e r e d i n tr at hec a ll y. S i dee f f e c t s a r e l e s s c om m on i n pa t i e n t s c h r on i c a l l y e xpos e dto e i ther in t ra theca l , ep idura l , or sys temic opioids .29 Somes i de e f f e c t s a r e m e d i a t e d v i a i n t e r a c t i on wi t h s pe c i f i cop i o i d r e c e p t o r s wh i l e o t he r s a r e no t .

Op i o i d i n t e r a c t i on i n t he s ubs t a n t i a ge l a t i nos a m a y t husi n i ti a te a n " i t c h r e f l e x" t h r ough i nd i r e c t a c t ion o n t het r ige m i na l nuc l e us . ~ P r u r i t u s m a y be a c li n ic a l s y m p t omi n pa t i e n t s who e xpe r i e nc e s e ns o r y m odu l a t i on d i s t u r b -ances ; exam ples inc lude mu l t ip le sc le ros i s , 4s d iabe te s , ~sand di f fe rent ia l neura l b loc kad e . 47

P r u r i t u sThe m o s t c om m o n s i de e f f e c t o f in t r a the c a l a nd e p i du r a lop i o i d s i s p r u r i t u s . I t m a y be ge ne r a l i z e d bu t i s m or el ike l y to be l oc a l iz e d t o t he f a c e , ne c k , o r u ppe r t ho r a x . 1 ,2Th e i nc i de nc e va r i e s wi de ly , f r om 0 t o 100% , a nd i t iso f t e n e l ic i te d on l y a f t e r d i r e c t que s t ion i ng . Se ve r e p r u r i t u si s r a r e , oc c u r r i ng i n on l y a bou t 1% o f pa t i en t s . P r u r i t u sus ua l l y oc c u r s wi t h i n a fe w hou r s o f in j e c t ion a nd m a ypr e c e de t he ons e t o f a n f inoc i c c p t ion . 3~ The i nc i de nc em a y 32 o r m a y no t 3~ be r e l a te d t o t he do s e o f op i o i d a d -m i n i s t e r e d , m a y be h i ghe r whe n t he i n t m t he c a l r ou t e i su t i li z e d 33 a nd i s l ow e r f o l l owi ng s ubs e qu e n t dos e s . 29 P r u -r i tus i s more l ike ly to occur in obs te t r i c pa t i ent s32 whichm a y r e s u l t f r om a n i n t e r a c t i on o f oe s t r oge n wi t h op i o i drec ep tors . 34,35

A l t h o u g h o p i o i d s m a y l i b e r a t e h i s t a m i n e f r o m m a s tc e l l s , t h i s doe s no t a ppe a r t o be t he m e c ha n i s m unde r -l y i ng p r u r i t u s . Op i o i d s c a n p r oduc e na l oxone - r e ve r s i b l ep r u r i t u s w i t hou t a f f e c ti ng p l a s m a h i s t a m i ne c onc e n t r a -t ions . 36 Fu r ther mo re , rash fo l low ing in t ra theca l an d ep i -du r a l op i o i d a dm i n i s t r a t i on i s ve r y r a r e . 37 Pa r a dox i c a l l y ,a n t i h i s ta m i ne s m a y be e f f e c t ive t r e a t m e n t f o r p r u r i tu s ,l ike ly secondary to the i r seda t ive e f fec t s . Prur i tus a l sodoe s no t . a ppe a r t o be r e l a t e d t o s y s t e m i c a bs o r p t i on o fopio id . 31

Pr u r i t u s i nd uc e d b y i n t r a the c a l a nd e p i du r a l op i o i d si s l ike l y due t o c e ph a l a d m i g r a t ion o f t he d r ug i n c e r e -b r os p i na l f l u i d a nd s ubs e que n t i n t e r a c t i on wi t h t he t r i -ge m i na l nuc l e us l oc a t e d s upe r f ic i a l ly i n t he m e du l l a . -38Op i o i d r e c e p t o r s a r e p r e s e n t i n t he t r i ge m i na l nuc l e usa nd t r i ge m i na l ne r ve r oo t s . 39 I n f a c t , t he m os t c om m onl oc a t i on o f i nduc e d p r u r i t u s i s i n t he f a c i a l a r e a s i nne r -va t e d by t he t r ige m i na l ne r ve . 38 An i m a l s t ud i e s s uppo r tt he c onc e p t o f a n " i t c h c e n t r e " l oc a t e d i n t he l owe r m e -du l l a 4~a nd i nd i c a t e t ha t t he t r ige m i na l n uc l e us i s invo l ve din the i t ch re f lex . 41 In jec t ion of o pioid in to the c i s te rnac e r e b e ll o m e d u l l a ri s o f e a t s p r o m o t e s i t c h i n g : ~ I n h u -m a n s , na l ox one ha s be e n u s e d s uc c e s s f u l ly i n tr e a t m e n to f i n t r a c t a b l e i d i opa t h i c p r u r i t u s 42 a nd c e r e b r a l t um our sinfdt ra t ing the four th vent r i c le cause i t ching in fac ia l a reasi n n e r v a te d b y t h e t r ig e m i n a l n e r v e : 3

Al t e r e d c e n t r a l ne r vou s s y s t e m pe r c e p t i on o f pa i n m a ya l s o p l a y a r o l e i n p r u r i t u s i nduc e d by i n t r a t he c a l a nde p i du r a l op i o i d s . 44 The t r ige m i na l nuc l e us de s c e nds i n t ot he c e r v i c a l r e g i on o f t he s p i na l c o r d a nd be c o m e s c on -t i nuous wi t h t he s ubs t a n t i a ge l a t i nos a o f t he do r s a l ho r n .

N a u s e a a n d v o m i ti n gThe i nc i de nc e o f na us e a a nd vom i t i ng f o l l owi ng i n t r a t h -e c a l a nd e p i du r a l op i o i d s i s a pp r ox i m a t e l y 30% . Al -t hough t he unde r l y i ng m e c ha n i s m i s no t r e l a t e d t o s y s -t e m i c a b s o r p t i on o f d r ug , 31 t he i nc i de nc e o f na us e a a ndvom i t i ng f o l lowi ng i n t r a ve nous op i o i d s i s the s a m e . l ;N a u s e a u s u a l ly o c c u r s w i t h in f o u r h o u r s o f i n je c ti o n a n dvom i t ing soon thereaf te r . 31 Th e inc idence may 3~ orm ay no t 32 ,5~be r e l a t e d t o t he dos e o f op i o i d a dm i n i s t e r e da nd m a y be h i ghe r whe n i n t r a t he c a l m or ph i ne i s u t i -l iz e d. J,2 Na us e a a nd vom i t ing a r e m o r e f r e que n t i nwo m e n t ha n i n m e n e xpe r i e nc i ng pa i n . 50 Pa r a dox i c a l l y ,f o r r e a s ons unkn ow n , t he e p i du r a l a dm i n i s t r a t i on o fop i o i d s m a y de c r e a s e t he i nc i de nc e o f pe r i ope r a t i ve na u -s e a a n d vom i t i ng . 51

N a u s e a a n d v o m i t in g i n d u c e d b y i n t ra t h ec a l a n d e p i-du r a l op i o i d s a r e l ike l y t he r e s u l t o f c e pha l a d m i g r a t i ono f d r ug i n c e r e b r os p i na l f l u i d a nd s ubs e que n t i n t e r a c t i onwi t h op i o i d r e c e p t o r s l oc a t e d i n t he a r e a pos t r e m a . 39,52Se ns i t iz a t i on o f t he ve s t i bu l a r s y s t e m t o m o t i on 53 a ndde c r e a s e d ga s t r i c e m p t y i ng34 p r oduc e d by op i o i d s m a ya l s o p l a y a r o l e i n na us e a a nd vom i t i ng i nduc e d by i n -t r a t he c a l a nd e p i du r a l op i o i d s .U r i n a r y retentionThe i nc i de nc e o f u r i na r y r e t e n t i on f o l l owi ng i n t r a t he c a la nd e p i du r a l op i o i d s va r i e s wi de l y , f r om 0 t o 80% , a n doc c u r s m o s t o f t e n i n you ng m a l e vo l un t e e r s . 2,3~ Th e i n -c i de nc e i s no t r e l a t e d t o t he dos e o f op i o i d a dm i n i s -t e r e d 3~176 a nd m a y be h i ghe r whe n in t r a t he c a l m or -ph i ne i s u t il iz e d . 33 The unde r l y i ng m e c ha n i s m i s no tr e l a t e d t o s y s t e m i c a bs o r p t i on o f d r ug . 3~ Ur i n a r y r e t e n -t i on f o l lowi ng in t r a t he c a l a n d e p i du r a l op i o i d s i s m u c hm o r e c o m m o n t h a n a f t e r i n t r a v e n o u s o r i n t r a m u s c u l a ra dm i n i s t r a t i on o f e qu i va l e n t dos e s o f op i o i d . 55-57Ur i n a r y r e t e n t i on induc e d b y i n t r at he c a l a nd e p i du r a lop i o i d s i s l i ke l y r e l a t e d t o i n t e r a c t i on wi t h op i o i d r e c e p -tors loc a ted in the sacra l sp ina l co rd . 55 Th is in te ra c t ionp r om ot e s i nh i b i ti on o f s a c r a l pa r a s ym pa t he t i c ne r vou ss y s t e m o u t f l o w w h i c h c a u s e s d e t n t s o r m u s c l e r e l a x a t io na nd a n i nc r e a s e i n m a x i m a l b l a dde r c a pa c i t y l e a d i ng t ou r i na r y r e t e n t i on . I n hum a ns , e p i du r a l m or ph i ne c a us e sm a r ke d d e t r u s o r m us c l e r e la xa t i on w i t h i n 15 r n i n o f i n -j e c t i on t ha t pe r s i s t s f o r up t o 16 h r a nd i s r e a d i ly r e ve r s e dwi t h n a l oxone . 5 s End oge n ous op i o i d s l i ke l y p l a y a n i m -po r t a n t r o l e i n no r m a l c on t r o l o f b l a dde r f unc t i on v i a


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8 9 4 C A N A D I A N J O U R N A L O F A N A E S T H E S I Am o d u l a t i o n o f p a r a s y m p a t h e t i c n e r v o u s s y s t e m o u t f l o wat th e sac ra l sp ina l cor d leve l . 5s-6~R e s p i r a to r y d e p r e s s io nT h e m o s t f e a r e d s i d e e f f e c t o f i n t r a t h e c a l a n d e p i d u r a lo p i o i d s i s r e s p i r a t o r y d e p r e s s io n . 6 2 O n l y f o u r m o n t h s a f t e ri n i t i a l u t i l i T a t i o n o f i n t r a t h e c a l a n d e p i d u r a l o p i o i d s i nh u m a n s , f i f e -t h r e a t e n in g re s p i r a t o r y d e p r e s s i o n w a s r e -p o r t e d . 6 3-6 5 C l i n i c a l ly i m p o r t a n t r e s p i r a t o r y d e p r e s s i o nh a s b e e n r e p o r t e d f o l l o w i n g in t r a t h e c a l m o r p h i n e , 6 6 e p i -d u r a l m o r p h i n e , s ~ i n t r a th e c a l f e n t a n y l , 67 e p i d u r a l f e n -t a ny l ,6 8 i n t r a t h e c a l s u f e n t a n i l , 69 a n d e p i d u r a l s u f e n t a n i l . 7 ~R e s p i r a t o r y d e p r e s s io n m a y o c c u r w i t h i n m i n u t e s o f in -j e c t i o n o f o p i o i d o r m a y b e d e l a y e d f o r h o u r s . T h e i n -c i d e n c e o f r e s p i r a t o r y d e p r e s s i o n d e p e n d s o n h o w i t i sd e f m e d . 71 T h e i n c i d e n c e o f r e s p i r a t o r y d e p r e s s i o n r e q u i r -i n g i n t e r v e n t i o n f o l l o w i n g c o n v e n t i o n a l d o s e s o f i n t r a t h -e c a l a n d e p i d u r a l o p i o i d s i s a p p r o x i m a t e l y 1 % , w h i c hi s t h e s a m e a s t h a t f o l l o w i n g c o n v e n t i o n a l d o s i n g o f i n -t r a m u s c u l a r a n d i n t r a v e n o u s o p i o i d s . 3 2 . 3 3 , 5 0 , 6 6 , 7 2

E a r l y r e s p i r a t o r y d e p r e s s i o n o c e u r s w i t h i n t w o h o u r so f i n j e c t io n o f o p i o i d . M o s t r e p o r t s o f c li n i c a ll y i m p o r t a n te a r l y r e s p i r a t o r y d e p r e s s i o n i n v o l v e a d m i n i s t r a t i o n o f e p i -du ra l f en tany l o r ep idu ra l sufen tani126 ,68 ,70 ,73 ,74 nd i s ve r yr a r e f o l l o w i n g t h e i n t r a t h e e a l u s e o f f e n t a n y l o r s u f e n -t a n i l. 67,69 R e s p i r a t o r y d e p r e s s i o n i n d u c e d b y e p i d u r a l f e n -t a n y l a n d s u f e n t a n i l l i k e l y r e s u l t s f r o m s y s t e m i c a b s o r p -t i o n o f d r u g , s i nc e b l o o d c o n c e n t r a t io n o f o p i o i d i sp r o p o r t i o n a l t o t h e m a g n i t u d e o f r e s p i r a t o r y d e p r e s -s io n .2 6 ,7 3 H o w e v e r , c e p h a l a d m i g r a t i o n o f o p i o i d i n c e r e -b r o s p i n a l f l u i d m a y a l s o i n i t i a t e e a r l y r e s p i r a t o r y d e p r e s -s i o n . F o l l o w i n g e p i d u r a l a d m i n i s t r a t i o n o f s u f e n t a n i l,c i s t e r n a l c e r e b r o s p i n a l f l u i d c o n c e n t r a t i o n s o f o p i o i d a r em e a s u r a b l e w i t h i n o n e m i n u t e . 21 A p n o e a w i t h i n o n e m i n -u t e o f i n je c t io n o f e p i d u r a l s u f e n ta n i l h a s b e e n r e p o r t e d . "A l t h o u g h s e n s i t i v e t e s t s o f r e s p i r a t o r y d e p r e s s i o n r e v e a lt h a t e p i d u r a l m o r p h i n e i n d u c e s e a r l y r e s p i r a t o r y d e p r e s -s i o n , i t i s c l i n i c a l l y i r r e l e v a n t . 7 6,7 7 C l i n i c a l l y i m p o r t a n te a r l y r e s p i r a t o r y d e p r e s s i o n f o l lo w i n g i n tr a t h e c a l u s e o fm o r p h i n e h a s n e v e r b e e n d e s c r i b ed .

D e l a y e d r e s p i r a t o r y d e p r e s s i o n o c c u r s m o r e t h a n t w oh o u r s a f t e r i n j e c t i o n o f o p i o i d . A l l r e p o r t s o f c li n i c a ll yr e l e v a n t d e l a y e d r e s p i r a t o r y d e p r e s s i o n i n v o l v e a d m i n i s -t r a t i o n o f i n t r a t h e c a l o r e p i d u r a l m o r p h i n e . s o ,6 6 C l i n i c a l l yi m p o r t a n t d e l a y e d r e s p i r a t o r y d e p r e s s i o n f o ll o w i n g a s i n -g l e i n j e c t i o n o f i n t r a t h e e a l o r e p i d u r a l f e n t a n y l o r s u f e n -t a n i l h a s n e v e r b e e n d e s c r i b e d . H o w e v e r , c o n t i n u o u s i n -f u s i o n s o r r e p e a t e d d o s e s o f a l i p o p h i l i c o p i o i d m a yp o s s i b l y i n i t ia t e c l i n i c a ll y r e l e v a n t d e l a y e d r e s p i r a t o r y d e -p r e s s i o n . 73 D e l a y e d r e s p i r a t o r y d e p r e s s i o n r e s u l ts f r o me e p h a l a d m i g r a t i o n o f o p i o i d i n c e r e b r o s p i n a l f l u i d a n ds u b s e q u e n t i n t e r a c t i o n w i t h o p i o i d r e c e p t o r s l o c a t e d i nt h e v e n t r a l m e d u l l a . V S H i g h c o n c e n t r a t i o n s o f o p i o i d r e -

TA B LE I I F ac to r s inc reas ing r i s k o f r e s p i r a to r y dep r es s ionHigh dosesof opioidRepeateddoses of opioidIntratheealutilizationMorphineIntravenous edativesAdvancedag eCo-ex it ing diseaseLac k o f op io id to le ranceThoracic epidural p lacementGeneral anaes thes iaIncreased nt rathorac ic pressurePatien t pos i t ion

c e p t o r s e x i s t i n t h e v e n t r a l m e d u l l a a n d a r e i m p o r t a n ti n n o r m a l r e g u l a ti o n o f r e s p i ra t io n . 79 M i n u t e a m o u n t so f o p i o i d d i r e c t l y a p p l i e d t o t h e m e d u l l a i n d u c e s i g n i f -i c a n t r e s p i r a t o r y d e p r e s s i o n . S ~ F o l l o w i n g l u m b a r i n t r a t h -e c a l m o r p h i n e a d m i n i s t r a t i o n , r e s p i r a t o r y d e p r e s s i o n i sm a x i m a l w h e n p e a k c o n c e n t r a t i o n o f m o r p h i n e i s a t -t a i n e d i n t h e m e d u l l a . s l D e l a y e d r e s p i r a t o r y d e p r e s s i o nc h a r a c t e r is t i c al l y o c c u r s 6 t o 1 2 h r f o l l o w i n g i n t ra t h e c a lo r e p i d u r a l a d m i n i s t r a t i o n o f m o r p h i n e y e t m a y p e r s i s t24 hr . 30,76,77

D e t e c t i o n o f r e s p i r a t o r y d e p r e s s i o n i n d u c e d b y i n t r a t h -e c a l a n d e p i d u r a l o p i o i d s m a y b e d i f t i e u l t . C l a s s i c b r a -d y p n o e a m a y 33 o r m a y n o t 72 b e p r e s e n t a n d h y p e r c a r b i am a y d e v e l o p d e s p i t e a n o r m a l r e s p i r a t o r y r a t e . s 2 B r a d y p -n o e a a p p e a r s t o b e a m o r e r e l i a b l e c li n i c a l s i g n o f e a r lyr e s p i r a t o r y d e p r e s s i o n f o l l o w i n g in t r a t h e c a l o r e p i d u r a lu s e o f f e n t a n y l o r s u f e n t a n il . 67,68,70,73 P u l s e o x i m e t r y m a yb e v a l u a b l e 3 ~ b u t m u s t b e i n t e r p r e t e d c a u t i o u s l y i f s u p -p l e m e n t a l o x y g e n is b e i n g a d m i n i s t e r e d , s3 T h e m o s t r e -l i a b l e c l i n i c a l s i g n o f r e s p i r a t o r y d e p r e s s i o n a p p e a r s t ob e a d e p r e s s e d l e v e l o f c o n s c i o u s n e s s , p o s s i b l y c a u s e db y h y p er ea rb ia .6 2 .7 2 ,s 2 I n h a l a t i o n o f c a r b o n d i o x i d e m i x -t u r e s b y h e a l t h y v o l u n t e e r s c a u s e s s o m n o l e n c e a n d l o s so f c o n s c i o u s n e s s a t P a C O 2 o f 8 0 m m H g . 8 4 C h a r a c t e r -i s t i c a l l y , e a r l y r e s p i r a t o r y d e p r e s s i o n d e v e l o p s r a p i d l y ,w h e r e a s , d e l a y e d r e s p i r a t o r y d e p r e s s i o n d e v e l o p s s l o w l ya n d p r o g r e s s i v e ly ) ~ P r o t o c o l s f o r m o n i t o r i n g t h e d e v e l-o p m e n t o f r e s p i r a t o r y d e p r e s s i o n f o l l o w i n g i n t r a t h e c a la n d e p i d u r a l o p i o id s v a r y a m o n g i n s ti t u ti o n s . M o s t a s se s sp a t i e n t s h o u r l y f o r f o u r t o s i x h o u r s i f f e n t a n y l o r s u -f e n t a n i l h a s b e e n a d m i n i s t e r e d a n d f o r 1 8 t o 2 4 h r a f t e rm o r p h i n e . 72 C l i n i c a ll y i m p o r t a n t r e s p i r a t o r y d e p r e s s i o nd e v e l o p i n g 2 4 h r a f t e r th e l a s t i n j e c t io n o f i n t r a t h e c a l o re p i d u r a l m o r p h i n e h a s n e v e r b e e n d e s c r ib e d .C e r t a i n f a c t o r s a r e k n o w n t o i n c r e a s e t h e r i s k o f r e s-p i r a t o r y d e p r e s s i o n fo l l o w i n g i n t r a t h e c a l a n d e p i d u r a lo p i o i d s ( T a b l e I I ) . C o n c o m i t a n t u s e o f a n y i n t r a v e n o u ss e d a t iv e i n c r e a se s t h e r i s k a n d s h o u l d b e a v o i d e d , i f p o s -s i b l e . C o u g h i n g m a y a f f e c t m o v e m e n t o f c e r e b r o s p i n a l


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Chaney: SPIN AL OPIOIDS 895f l u i d 16 a nd m a y b e a s s oc i a t e d w i t h t he de ve l opm e n t o fr e s p i r a t o r y d e p r e s s ion . 77 AlthO Ugh b o d y p o s i ti o n d o e s no ta f f e c t m ov e m e n t o f e e r e b r os p i na l f l u id , 16 i t m a y85 o r m a yno t 86 i nc r e a s e t he r i s k o f r e s p i r a t o r y de p r e s s i on . O bs t e t r i cpa t i e n t s a ppe a r t o be a t l e s s r i s k f o r r e s p i r a t o r y de p r e s -s i on , pe r ha p s be c a us e o f inc r e a s e d b l ood c on c e n t r a t i onof proges terone , a respi ra tory s t imulant .87M e n t a l s t a t u s c h a n g e sS e d a t i o n , t h e m o s t c o m m o n m e n t a l s t a t u s c h a n g e f o l -l owi ng in t r a t he c a l a nd e p i du r a l op i o i d s , oc c u r s f r e que n t l yw i t h a l l o p i o i d s b u t i s m o s t c o m m o n l y a s s o c i a t e d w i t ht he u s e o f s u f e n ta n i l. 88 Th e de g r e e o f s e da t i on a ppe a r st o be r e l a t e d t o t he d os e o f op i o i d a dm i n i s t e r e d . 30,49 Ce n -t ra l n e r v o u s s y s t e m d e p r e ss i o n m a y b e p r o f o u n d a n dc om a ha s be e n de s c r i be d . 89,s0 An y t i m e s e da t i on oc c u r sf o l lowi ng i n tr a t he c a l o r e p i du r a l a dm i n i s t ra t i on o fop i o i d s , r e s p i r a t o r y de p r e s s i on m us t be s u s p e c t e d . 9 t

M e nt a l s t a t u s c ha nge s o t he r t ha n s e da t i on m a y a l s ooc c u r a f t e r i n t r a t he c a l a nd e p i du r a l op i o i d s . Na l oxone -revers ib le par ano id psyc hos i s 92 an d ca ta tonia 33,93 havebe e n r e po r t e d . Ot he r s ha ve de s c r i be d t he de ve l opm e n to f e upho r i a , a nx i e t y , a nd ha l l uc ina t i ons . 66

M e n t a l s t a t u s c ha nge c a us e d by i n t r a t he c a l a nd e p i -du r a l o p i o i d s l i ke ly r e s u l t s f r om c e pha l a d m i g r a t i on o fd r ug i n c e r e b r os p i na l f l u i d a nd s ubs e que n t i n t e r a c t i onwi t h op i o i d r e c e p t o r s loc a t e d i n t he b r a i n . Pos s i b l e m e c h -a n i s m s i nc l ude i n t e r a c t i ons wi t h op i o i d r e c e p t o r s l oc a t e di n t he t ha l a m us , l i m b i c s y s t e m , a n d c e r e b r a l c o r t e x . 94O t h e r b e h a v i o u r a l c h a n g e s m a y b e c a u s e d b y i n t er a c ti o nwi t h op i o i d r e c e p t o r s l oc a t e d i n t he a m ygda l a . 39 O f i n -t e r e s t, a n i m a l s t ud i e s i nd i c a te t ha t op i o i d r e c e p t o r s i n t heb r a i n m a y p l a y a r o l e in c e r t a i n f o r m s o f m e n t a l i ll ne s s. 95C entra l nervous sys tem exc i ta t ionTon i c m us c l e r i g i d it y r e s e m b l i ng s e i z u r e a c t iv i t y is a we l lkno wn s i de e f f e c t o f l a r ge dos e s o f i n t ra ve nous op io ids . 96Ra r e l y , s i m i l a r a c t i v i t y m a y be obs e r ve d f o l l owi ng a d -m i n i s t r a ti on o f i n tr a t he c a l o r e p i du r a l op i o i d s . M yoc l on i ca c t i v i t y f o l l owi ng bo t h i n t r a t he c a l a nd e p i du r a l op i o i d shas bee n rep or ted . 97,98 M usc le r ig id i ty has a l so b een ob -served af te r adm inis t ra t ion of epidura l m orph ine 93,99 an dint ra theca l sufentani l , l~176 ee p t endo n ref lexes m ay be-c om e hy pe r t on i c f o l l owi ng e p idu r a l m or ph i ne . ~~ I n a n -i m a l s , l a rge dos e s o f i n t r a the c a l op i o i d s i nduc e h i nd l i m bstiffn ess an d rigidity. 102,103

Th e m e c ha n i s m o f c en t r a l ne r vou s s y s t e m e xc it a t ionc a us e d b y i n t r a the c a l a nd e p i du r a l op i o i d s doe s no t a p -pe a r t o b e m e d i a t e d by o p i o i d r e c e p t o rs . 102 A s p i na l c o r dm e c ha n i s m m a y b e i nvo l ve d to4 bu t c e pha l a d m i g r a t i ono f op i o i d i n c e r e b r os p i na l f l u i d a nd s ubs e que n t i n t e r -a c t i on wi t h non - op i o i d r e c e p t o r s i n t he b r a i n s t e m o r ba s a lga ng l i a i s m o r e l ik e l y . 9 6 I n a n i m a l s , a dm i n i s t r a t i on o f

op i o i d s i n t o t he c e r e b r a l ve n t r i c l e s i nduc e s be ha v i ou r a lexc i tat ion th at is no t re versib le with nalo xo ne. ~05,106T h ec e n t r a l ne r vous s y s t e m e xc i t a t i on m a y be c a us e d by t hea b i l i t y o f o p i o i d s t o b l o c k g l y c i n e o r g a m m a - a m i n o -butyr ic ac id-media ted inhibi t ion . 107Al t hough l a r ge dos e s o f op i o i d s r e l i a b l y i nduc e s e i z u r eac t iv i ty in animals , c l in ica l ly re levant doses of in t rave-nous , i n t r a t he e a l , o r e p i du r a l op i o i d s ha ve ne ve r be e nobs e r ve d t o i nduc e ge ne r a l i z e d c o r t i c a l s e i z u r e a c t i v i t yi n hum a ns . 96Hyperalges iaPa r a dox i c a l l y , l a r ge dos e s o f in t r a the c a l m or p h i ne wi l lcause hyperalgesia in laboratory animals. 103,J07-109H y p e r -a l ge s i a ha s a l s o be e n r e po r t e d i n r e f r a c t o r y c a nc e r pa i npa t i e n t s a dm i n i s t e r e d l a r ge dos e s o f i n t ra t he c a l m or -phine. 110,"Hyp e r a l ge s i a c a us e d b y in t r a the c a l m or ph i ne i s no t m e -d i a t e d by op i o i d r e c e p t o r s a nd i s no t a f f e c t e d by e ve nlarge do ses of nal ox on e, t03,107-109Al t e r a t i on o f s p i na l c o r dc o d i n g o f s e n so r y in f o r m a t io n v i a a n o n - o p i o i d r e c e p t o rm ech anis m m ay play a ro le . 103.109 Hy pera lg es ia m ay bec a u s e d b y t h e a b i l i t y o f m o r p h i n e t o b l o c k g l y c i n e o rg a m m a - a m i n o b u t y r i c a c i d - m e d i a t e d i n h i b i t i o n . 107,108C o n j u g a t e d m e t a b o l i te s o f m o r p h i n e , s e v e ra l h u n d r e dt i m e s m or e po t e n t a t p r oduc i ng be ha v i ou r a l e xc i t a t i on ,m a y a l s o be i nvo l ve d . ~~ Un l i ke m o r ph i ne , op i o i d s t ha td o n o t u n d e r g o c o n j u g a t i o n a r e i n c a p a b l e o f p ro d u c i n ghype ra lges ia . 38H erp es s im plex l ab ia l i s v i rus reac t iva t ionA l i nk e x is t s be t w e e n t he u s e o f e p i du r a l m or ph i ne i nobs t e t r i c pa t i e n t s a nd r e a c t i va t i on o f he r pe s s i m p l e x l a -b ia l i s v i rus . 112,113Re a c t i va t i on o f the he r p e s v i r u s t yp i c a l l yoc c u r s t w o t o f i ve da ys a f t e r e p idu r a l a dm i n i s t r a ti on o fop i o i d , r e, H4 M a n i f e s t a t i on o f s ym pt om s c ha r a c t e r i s ti c a l lyoc c u r s i n t he s a m e s e ns o r y i nne r va t i on a r e a a s t he p r i -m a r y i n f e c t i on , wh i c h i s u s ua l l y f a c i a l a r e a s i nne r va t e dby t he t r i ge m i na l n e r ve . " 3 A s i m i l a r l ink be t we e n t heus e o f i n t r a t he c a l op i o i d s i n young pa t i e n t s a nd r e a c -t i va ti on o f t he he r pe s v i r u s ha s be e n s ugge s t e d . I tS ,H6 Atp r e s e n t , no e v i de nc e e x i s t s s uppo r t i ng a l i nk be t we e n u s eo f a n y o t h e r o p i o i d b y a n y o t h e r r o u t e a n d r e a c t i v a t i o nof he rpes s implex l abia l i s v i rus . 112

T h e u n d e r l y i n g m e c h a n i s m c a u s i n g h e r p e s v i r u s r e a c -t i va t i on l i ke l y i nvo l ve s c e pha l a d m i g r a t i on o f op i o i d i nc e r e b r os p i na l f l u i d a nd s ubs e que n t i n t e r a c t i on wi t h t het r igernina l nuc leu s . 117 Re act iva t io n o f the herp es v i rusm a y be i n i t i a t e d by s t i m u l a t i on o f op i o i d r e c e p t o r s l o -c a t e d i n t he t r i ge m i na l nuc l e us , whe r e t he v i r u s i s knownto res ide in l a tent form . j l3 I t ching, wi th a ssoc ia ted me -c ha n i c a l i r r it a t ion o f t he s k i n , i nduc e d by i n t r a the c a l o re p i du r a l op i o i d s , m a y a l s o i nd i r e c t l y r e a c t i va t e t he l a t e n t


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8 96 C A N A D I A N J OU R N A L O F A N A E S T H E S I Aherpes v i ius . 112-114 ,1 j7 ,118 t i s i n t e r es t i ng t o no t e t ha t t hem o s t c o m m o n a r e a s o f b o t h p r u r it u s a n d r e a ct iv a ti o no f h e r p e s v i r u s f o l lo w i n g i n tr a t h e c a l a n d e p i d u r a l o p i o i d si s in f a c i a l a re a s i n n e r v a t e d b y t h e t r i g e m i n a l n e rv e . P h y s -i o lo g i c al c h a n g e s n o r m a l l y a s s o c i a t e d w i t h p r e g n a n c y , i n -e l u d i n g d e p r e s s io n o f s o m e a s p e c t s o f c e l l- m e d i a t e d im -m u n i t y a n d a l t e r a t i o n s i n h o r m o n e l e v e l s , m a y a l s o b ei nvo l ved i n r eac t i va t i on o f t he h e rpes v i rus , t l8 M o s t l i kel y ,t h e u n d e r l y i n g m e c h a n i s m c a u s i n g h e r p e s s i m p l e x l a b ia -l i s v i rus r eac t i va t i on i s mul t i f ae t o r i a l and may i nvo l vea ll , so m e , o r n o n e o f t h e a b o v e p r o p o s e d m e c h a -n i sms . H3,HaN e o n a t a l m orbidi tyN e o n a t a l m o r b i d i t y i s p o s s i b l e w h e n i n t r a t h e c a l o r e p i -dura l op i o i ds a r e used i n obs t e t r i c pa t i en t s f o r pa i n r e l i e fd u r i n g l a b o u r o r C a e s a r e a n s ec ti on . F o l lo w i n g i n tr a t h e c a lo r e p i d u r a l a d m i n i s t r a t i o n o f o p i o i d t o t h e m o t h e r , v a s -cu l a r r e ,absorp t ion o f d ru g occu r s . Onc e p r esen t i n them a t e r n a l b l o o d , t h e o p i o i d m a y t h e n b e t r a n s f e rr e d a c r o s st h e p l a c e n t a t o t h e f e t u s . I m m e d i a t e l y a ft e r b ir t h , n e o n a t a lb l o o d c o n c e n t r a t i o n s o f o p i o i d a r e d e t e c t a b l e f o l l o w i n gm a t e r n a l a d m i n i s t r a t i o n o f i n t r a t h e c a l m o r p h i n e , H9 epi -du ral m orp hin e, 12~ epid ural fentan yl , 121'j22 an d epid uralsuf en t an i l , lZ~ C l i n i ca l l y i m por t a n t r e sp i r a t o ry depres s i onh a s d e v e l o p e d i n n e o n a t e s f o l lo w i n g a d m i n i s t r a ti o n o f e p i -d u r a l m o r p h i n e 12~ a n d e p i d u r a l f e n t a n y l m t o t h e m o t h e r .F u r t h e r m o r e , n e u r o l o g i c a l si gn s o f d r u g - i n d u c e d d e p r e s -s i o n i n n e o n a t e s h a v e b e e n o b s e r v e d f o l lo w i n g e p i d u r a lsuf en t an i l , m How ever , mul t i p l e i nves t ga f i ons i nvo l v i ngl a r g e n u m b e r s o f p a t i e n t s h a v e r e v e a l e d t h a t i n t r a t h e c a la n d e p i d u r a l o p io i d s a r e s a fe f o r t h e m o t h e r a n d n e o n a t eprov ided th at co nve nt ion al doses a re used . ~ 'J l9 '12Zm't~ 129

T h e u s e o f i n tr a t h e e a l o r e p i d u r a l o p i o i d s i n o b s t e t ri cp a t ie n t s m a y a f f e c t t h e n e o n a t e i n w a y s o t h e r t h a n p l a -cen t a l t r ans f e r o f d rug . F or a va r i e t y o f r easons , i n t r a t h -e c a l m o r p h i n e m a y e i t h e r i n h i b i t 130.131 or en ha nc e 132 thep r o g r e s s o f l a b o u r. F o l lo w i n g a d m i n i s tr a t io n o f e p i d u r a lf en t any l o r ep i du ra l su f en t an i l t o ob s t e t r ic pa t i en t s , b r eas tm i l k co ncen t r a t i on o f op i o i d i s neg li g ib l e. 133Sexual d ys func t ionI n h e a l t h y m a l e v o l u n t e e r s , a d m i n i s t r a t i o n o f e p i d u r a lm o r p h i n e m a y l e a d t o s u s t a i n e d e r e c t i o n a n d i n a b i l i t yt o e j acu l a t e . 55,1~ In m a l e r a t s , i n t r a t heca l m orph i ne i n -c r e a s e s w h i le i n t ra t h e c a l n a l o x o n e d e c r e a s e s t h e n u m b e rof i n t romi s s i ons p r i o r t o o rgasm . J35 T h ese p ro pe r t i e s m aym a k e i n t r a t h e c a l o r e p i d u r a l o p i o id s v i a b l e t re a t m e n t o p -t ions for pre m atu re e jacu lat ion. 13s,136 Ere ct ion i s un de rt h e i n f l u e n c e o f t h e p a r a s y m p a t h e t i c n e r v o u s s y s t e mw h e r e a s e j a c u l a ti o n a n d t e r m i n a t i o n o f e r e c t i o n a r e u n d e rt h e i n f l u e n c e o f t h e s y m p a t h e t i c n e r v o u s s y s te m . 136 T h e r e -f o r e , s u s t a in e d e r e c t i o n a n d i n a b i li ty t o e j a c u l a te m a y b e

s e c o n d a r y to a n o p i o i d - in d u c e d d e c r e a s e in s y m p a t h e t i cne rvo us sys t em r esponse t o s exua l s t i mul a t i on . ~36 I t ap -pea r s t ha t t h i s e f f ec t occur s i n t he sp i na l cord , f o r sus -t a i ned e r ec t i on and i nab i l i t y t o e j acu l a t e i s no t obse rvedi n m a l e s a d m i n i s t e r e d i n t r a v e n o u s o r i n t r a m u s c u l a ropioids.55,134,J3s

In f emal e r a t s , i n t r a t heca l morph i ne i nh i b i t s whi l e i n -t r a t heca l na l ox one enha nces s exua l r ecep ti v it y . ~35 Op i o i dsm a y a l s o i n h i b i t o v u l a t i o n i n r a ts . ~37 A m e n o r r h o e a a n ds t e r i l i t y a r e c o m m o n l y o b s e r v e d i n h u m a n f e m a l e m o r -ph ine addicts . 138O c u l a r dysfunctionNal oxone- r eve r s i b l e nys t agrnus has been r epor t ed fo l l ow-i ng adm i n i s t r a t i on o f i n t r a t heca l m orp h i ne 139 and ep i -dura l morph i ne .14~ A na l oxone- r eve r s i b l e M 6ni ~ re - l i kes y n d r o m e h a s a l s o b e e n r e p o r t e d f o l lo w i n g a d m i n i s t ra t i o nof ep i du ra l m orph i ne . 141 Ver ti go ha s been obse rved a f t e ru s e o f e p i d u r a l m o r p h i n e , t42 T h e t i m e c o u r s e o f s y m p t o md e v e l o p m e n t a n d t h e f a c t t h a t t h e y a r e n a l o x o n e -r e v e rs i b le i n d ic a t e c e p h a l a d m i g r a t io n o f o p i o i d i n c e r e -b r o s p i n a l f l u i d a n d s u b s e q u e n t i n t e r a c t i o n w i t h o p i o i dr ecep t or s i n t he b r a i n i s l i ke ly inv olv ed . 14L142

L i k e i n t r a v e n o u s o p i o i d s , i n t r a t h e c a l a n d e p i d u r a lop i o i ds m ay i n i ti a t e mi os is . W hen mi os i s occu r s f o l lowi ngadm i n i s t r a t i on o f i n t r a t heca l o r ep i dura l op i o i ds , it i n -d i c a te s d r u g i s p r e s e n t i n c e r e b r o s p i n a l f l u id a t t h e m i d -b r a i n l e v e l a n d t h u s m a y b e a n e a r l y w a r n i n g s i g n o fim pen din g re spi ra tory depre ss ion. 143,z44Gas t ro i n t e s t i na l dysfunctionI n t r a v e n o u s a n d i n t r a m u s c u l a r o p i o i d s a r e k n o w n f o rt he i r ab i l i t y t o a l t e r gas t ro i n t e s t i na l mot i l i t y . I n t r a t heca la n d e p i d u r a l o p i o i d s m a y a l s o d e la y g a s tr i c e m p t y i n g a n dpro lon g intes t inal t ransi t t ime. 54,102 In hu m an volu nteers ,a d m i n i s tr a t io n o f e p i d u r a l m o r p h i n e d e l a y s g a st r ic e m p -tying.145 I n m i c e , i n t r a t h e c a l m o r p h i n e c a u s e s d o s e -d e p e n d e n t , n a l o x o n e - r e v e r s i b l e p r o l o n g a t i o n o f s m a l lbow el t r ans i t t i me . ~ P a t i en t s adm i n i s t e r ed i n t r a t heca l o re p i d u r a l o p i o id s m a y e x h i b i t si g n s a n d s y m p t o m s o f i le u sw h i c h m a y , i n tu r n , l e a d t o n a u s e a a n d v o m it in g . 54'97'102'145T he cause o f t he dec r ease i n gas t ro i n t e s t i na l mot i l i t y f o l -l owi ng i n t r a t heca l o r ep i dura l op i o i ds i s no t r e l a t ed t os y s t e m i c a b s o rp t i o n o f d r u g 145 a n d a p p e a r s t o b e c a u s e db y i n t e r a c t io n w i t h o p i o i d r e c e p t o r s lo c a t e d i n t h e s p i n a lc o rd . 145,146Therm oregula torydys func t ionO p i o i d s i n d u c e a l te r a ti o n s i n b o d y t e m p e r a t u r e , a n e f f e c tt h a t d e p e n d s o n s p ec ie s, r o u t e o f a d m i n i s tr a t io n , d o s a g e ,an d am bi en t t em pera t u r e . 147,14s In r a t s , i n t r a t he ca l m or -p h i n e c a u s e s a d o s e - d e p e n d e n t , n a l o x o n e - re v e r s i b le i n -c r e a s e i n b o d y t e m p e r a t u r e , w h i c h a p p e a r s t o b e c a u s e d


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Chaney: SPINALOPIOIDS 897by interaction with opioid receptors located in the spinalcor d . 149 However, a lterations in body temperature mayalso be initiated by cephalad migration of drug in cere-brospinal fluid and subsequent interaction with opioidreceptors located in the hypothalamus. In animals, ad-ministration of opioid into the cerebral ventricles maycause hyper thermia o r h y p o t h e r m i a . 9 5,1 5~ In humans ,administration of epidural sufentanil may induce hypo-thermia, an effect likely caused by the abili ty of the opioidto dec rease shiv ering . 152-154Water re tent ionOliguria an d w ater retention leading to peripheral oed em ahave been reported following administration of intrathecalan d epidural mo rphine. 97,155 Th e w ate r retention is likelycaused by release of vasopressin, stimulated by eephaladmigration o f opioid in cerebrospinal fluid and subsequ entinteraction with opioid receptors located in the posteriorpituitary. The posterior pituitary does possess opioid re-ceptors ~56 an d release o f vasopressin is stim ulated in an-imals ad ministered opioid s. 157 In h um ans , administrationof epidural m orphine stimulates release of vasopressin de-spite effective analgesia. 155Ca r d i a c dysrhythmiaNew left bundle branch b lock has occurred in on e patient45 rain after receiving an inadvertent overdose of epi-dura l morphine. 15s Five min utes after intravenous nal-oxone, the lef t bundle branch block disappeared and th eECG reverted to the patient's usual pattern.Hair lossUnexplained ha ir loss, resembling alopecia areata, h as oc-curred in one patient after receiving epidural morphinefor three days. 159 Th e hair loss was associated with wide-spread itching.NeurotoxicityDam age to the sp inal cord may occur fo llowing admin-istration o f intrathecal or epidural op ioids. Afte r intrath-ecal injection of mo rphine, 2.5 m g, the cerebrospinal fluidconcentration of d rug is 4000 times that seen af ter intra-veno us injection o f 1.0 n ag. kg -~. 160 In s h e e p , e p i d u r a lmo rphin e causes spinal cord necrosis 161 and intrathecalsufentanil induces inf lam mato ry changes in the m en-inges. 162 In cats, intratheca l sufentan il induces in flam m a-tory changes in the spinal cord. 103 Furt herm ore, theseanimals exhibited hindlimb dysfunction in the form ofstiffn ess a nd we akn ess. 103,z61,m62 n mo nke ys, ho we ver, n ospinal co rd dam age w as detected following administrationof intrathecal morphine. 163 In hum ans, intrathecal mo r-phine 33'97'164 and epidural m o r p h i n e 33 have been impli-cated as possible causes of spinal cord damage. Clinical

manifestations in these patients included sensory andmotor neurological dysfunction,33,]64myoclonic spasms, 97paresis, 33 and paralysis. 97 O n the oth er h and , adminis-tration of large doses of intrathecal morphine for pro-longed periods of t ime has proved to b e saf e . 29,j65,m66In -trathecal morphine has been administered for as long as90 days and epidural morphine for as long as 450 dayswith out problems. 29 Inad verten t overdose of epiduralmorph ine h as also occurred without sequela , t5s Post-mortem examination of spinal cords from patients whohad received prolonged infusions of intrathecal morphinerevealed no dam age. ~65 In sum mary , spinal cord dam agefollowing administration of intrathecal or epidural op ioidsmay occur but is extremely rare if conventional dosesof opioids a re utilized.

The spinal cord possesses only marginal blood f lowan d is susceptible to ischaemia if vasoconstriction occurs.Several studies have demonstrated opioid receptor-mediated effects on blood vessels in vitro. 167 Althoughno studies have been performed in humans, i t appearsfrom animal studies that intrathecal m orphine does n o taffect spinal cord blood flow. =

Som e opioid preparations c on tain preservatives which,if injected intrathecally or epidurally, may cause spinalcord damage. ~69,=70 In hu ma ns, inad verte nt use of dru gswith p reservatives has cause d paralysis following intrath-eca l 171 an d epidu ral m injection.

AnaphylaxisTrue anaphylaxis foUowingadministration of opioids, byany route, is extremely late. R has been reported oncefollow ing administration o f epidural fentanyl. 1~3 A pre -vious exposure to fentanyl was documented and hyper-sensitivity was later con firme d by intradermal testing.Tr e a t m e n t a n d p r o p h y l a x i s o f s i d e e f f e c tsEssentially, all side effects of intrathecal and epiduralopioids are m edia ted via opioid receptors. Treatment,therefore, involves administration of an opioid receptorantagonist , usually naloxone. The most common clini-cally enco untered side effects (pruritus, nausea and vom -iting, urinary retention, respiratory depression) are allreadily antagonized with administration of naloxone. U n-fortunately, w hen antagonizing side effects with n aloxone,analgesia m ay 174-176 or may no t 5~ be preserved. Ad -ministration of an opioid agonist-antagonlst to treat sideeffects instead o f an opioid antagonist ma y preserve anal-gesia, t79,~so D uri ng treatm ent of respira tory depressioncaused by intrathecal or epidural morphine, i t m ay reap-pear la ter if only a single dose o f naloxon e is uf il iTed,mslOral nalaex one, a long-acting opioid antagonist, ma y beuseful if one wants to avoid the t ime an d expense involvedin ma intain ing a nalo xon e infusion. 182 Even th oug h nal-


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898 CANADIAN JOURNAL OF ANAESTHESIAoxone crosses the placenta , i t appears to cause no neo-nata l morbidi ty and thus may be ut i l i7ed to t rea t s ideeffec ts in obste t r ic pa t ients . Is3 Drugs other than opioidreceptor antagonists have been used to t rea t s ide effec tsof in t ra thecal and epidura l opioids wi th occasional sue-cess. Ant iemet ics are of ten useful in t rea t ing nause a an dvomi t ing ye t unwan ted seda t i on may aggrava t e r e sp i ra -tory depression. ~

Prophy lac ti c admin i s t r a t ion o f o p io id r ecep to r an t ag -onists has occasional ly been effec t ive in decreasing theincidence of so me side effec ts . H owever, the dose o f na l -oxon e tha t wi ll antagonize side effec ts wh i le a t the sam et ime preserve analgesia i s uncer ta in a t best . 3o M ost phy-sic ians be lieve th a t p rophylac t ic administ ra t ion o f opioidantagonists to decrease the inc idence of s ide effec ts i sno t j u s t if i ed and t r ea tmen t shou ld be r e se rved fo r t hosepat ients w ho man ifest sym ptom s, n9,t85 In theory, in t ra th-ecal or epidura l administ ra t ion of an opioid agonist -antagonist should be associa ted wi th a lower inc idenceof s ide effec ts than a pure opioid agonist s imi lar ly ad-ministered. However , th is m ay 76 or ma y n ot ls~ occu r a ndanalgesia i s infer ior to th a t pro duced by o pioid agonists .Oth er drugs" have b een u sed p rophylac t ica l ly in a t tem ptsto decrease the inc idence of s ide effec ts of in t ra thecaland epidura l opioids w i th occasional success. Prophylac-t ic t ransdermal scopolamine decreases the inc idence ofnausea and vomi t i ng a ssoc i a t ed wi th ep idura l mor -phine.S3.187S u m m a r yThe int roduct ion of in t ra thecal and epidura l opioidsmarks one o f t he mos t impor t an t b reak th roughs i n pa inman agem ent i n t he l a s t two decades. Pro foun d segmenta lan t inoc i cep tion is ob t a ined wi th doses m uch sma l l e r t hanwo uld be requi red i f adm inistered systemical ly . However,a wide v ar ie ty of c l inica l ly re levant non -noeieept ive sideeffec ts ma y occur . Al l physic ians ut il iz ing int ra thecal andepidura l opioids must be aware of the non-nocicept iveside effec ts for whi le some are minor , o thers are poten-tially lethal.References

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