ALCOHOL WITHDRAWAL: PATHOPHYSIOLOGY, DIAGNOSIS ANDTREATMENT Carlos A. Hernandez-A !la,M.D. De"ar#$en# o% Ps&'(!a#r&)n! ers!#& o% Conne'#!'*# S'(ool o% Med!'!

ne Al'o(ol Med!'al S'(olarsPro+ra$ Prepared: April 2005 I. INTRODUCTION A. Alcohol Dependence (AD), ma or ca!"e o# mor$ali$% and mor&idi$% '. (ore $han 2)* o# AD pa$ien$" in clinical "e$$in+" ha,e Alcohol -i$hdra.al (A-) C. A- o#$en pre"en$" a" an/ie$% and in"omnia. (i"dia+no"i" can &e deadl% D. Topic" $o &e co,ered: 0pidemiolo+% Pa$hoph%"iolo+% Clinical Pic$!re and Dia+no"i" Trea$men$ Slide1 Slide2

II. 0PID0(IO1O23 A. 0pidemiolo+% o# Alcohol U"e Di"order" (AUD):4 45.* million ha,e alcohol a&!"e or dependence 4* 5 o# men and6 5 o# .omen o,er a+e 47 (ore #re8!en$ amon+ 0!ropean9American" 459*05 o# primar% care and ho"pi$ali:ed pa$ien$" 605 $ra!ma pa$ien$" ha,e &lood alcohol le,el" ('A1) 400 m+)dl Slide3

'. Alcohol U"e Di"order" (AUD") can &ede#ined:2 a. 4. Alcohol A&!"e:

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&. ;i+ni#ican$ impairmen$)di"$re"" in a 429mon$h period c. Dia+no"i" re8!ire" 4< o# #ollo.in+: d. e. #. i. =ail!re $o #!l#ill ma or o&li+a$ion" ii.>a:ardo!" ac$i,i$ie" d!rin+ in$o/ica$ion iii.1e+al pro&lem"

i,.;ocial)in$erper"onal pro&lem" 2. Alcohol Dependence (AD): +. ;i+ni#ican$ impairmen$)di"$re"" in a 429mon$h period h. Dia+no"i" re8!ire" *< o# #ollo.in+: i. . ?. l. m. n. o. i. Tolerance ii. W!#(dra,al iii.1ar+er amo!n$" #or lon+er period $han in$ended i,.Per"i"$en$ de"ire and !n"!cce""#!l a$$emp$" $o c!$ do.n ,. 0/ce""i,e $ime "pen$ drin?in+ alcohol ,i. Ac$i,i$ie" +i,en !p d!e $o drin?in+ ,ii. Con$in!ed !"e de"pi$e pro&lem"

C. 0pidemiolo+% o# Alcohol -i$hdra.al (A-):*,6,5,@ A- "%mp$om" a##ec$ !p $o A0 5 o# AD pa$ien$"

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(ore #re8!en$ in $he elderl% No +ender or e$hnic di##erence" 755 o# pa$ien$" .i$h A- e/perience mild9$o9modera$e "%mp$om" 455 "e,ere "%mp$om" .i$h complica$in+ condi$ion": a.;ei:!re", 405 o# $he ca"e" &.Deliri!m Tremen", 55 i.In $he pa"$, mor$ali$% ra$e .a" 459255 ii.C!rren$l% 45

III. PAT>OP>3;IO1O23 O= A1CO>O1-IT>DRA-A1 A. Alcohol e##ec$" in $he &rain:A Slide6

4. Baria&le e##ec$" a" a #!nc$ion o# d!ra$ion o# admini"$ra$ion 2. No "in+le "i$e o# ac$ion *. A##ec$" m!l$iple ne!ro$ran"mi$$er "%"$em": a. 2l!$ama$e and a"par$a$e &. 2A'A c. Dopamine d. Noradrenaline e. Cor$ico$ropin9relea"in+9#ac$or

'. 0/ci$a$or% ne!ro$ran"mi$$er "%"$em" and A-:7

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2l!$ama$e: (ain e/ci$a$or% ne!ro$ran"mi$$er Ac$i,a$eN(DA recep$or" and ,ol$a+e9opera$in+ channel": Calci!m in#l!/ ne!ronal e/ci$a&ili$% 0/ce""i,e ac$i,a$ion "ei:!re", ne!ro$o/ici$% and cell dea$h 0##ec$" o# drin?in+ on e/ci$a$or% ne!ro$ran"mi""ion: 7 Alcohol an$a+oni:e" N(DA recep$or" Chronic drin?in+ and $olerance $o alcohol are a""ocia$ed .i$h compen"a$or%: N(DA recep$or" n!m&er Calci!m (Ca) channel"

*.0/ci$a$or% ne!ro$ran"mi""ion d!rin+ A-: 7

Slide8

a. Roden$" "ho. +l!$ama$e ) a"par$a$e in &rain re+ion" rela$ed $o: i.Re.ard (e.+. ;$ria$!m and N!cle!" Acc!m&en" CNACD) ii. Alcoholco+ni$i,e di"$!r&ance" and A- "ei:!re" (e.+. >ippocamp!") &. Pa$ien$" "ho. 2l!$ama$e in cere&ro"pinal #l!id (C;=) c. In "!mmar%:D!rin+ A- $here i" e/ci$a$or% ne!ro$ran"mi""ion

C. Inhi&i$or%ne!ro$ran"mi""ion and A-: E

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2A'A: a. (aininhi&i$or% ne!ro$ran"mi$$er &. Ac$i,a$e"recep$or9opera$ed FC1 channel" i. (em&raneh%per9polari:a$ion ("$a&ili$%) ii.Ne!ronal e/ci$a&ili$% 0##ec$" o# drin?in+ on 2A'A: E a. Ac!$e alcohol 2A'AA recep$or#!nc$ion &Chronic drin?in+ 2A'AA recep$or "en"i$i,i$% $olerance *. 2A'A and A-:E a. D!rin+ A- 2A'AArecep$or remain" impaired &. Repea$ed A-#!r$her impair" 2A'AA recep$or ne!ronal e/ci$a&ili$%(e.+. ne!ronal G?indlin+H) A- "ei:!re" and deliri!m c. In "!mmar%,chan+e" in 2A'A ne!ro$ran"mi""ion d!rin+ A- $ran"la$e: i. Impairmen$ o#ne!ronal inhi&i$or% mechani"m" ii. An/ie$%,"%mpa$he$icac$i,i$% and "ei:!re"

0. Dopamine (DA):40 (ainne!ro$ran"mi$$er media$in+ re.ard:

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a. Relea"ed &%$he Ben$ro$e+men$al area (BTA) in$o $he NAC &. Occ!r" inan$icipa$ion and d!rin+ re.ardin+ "$im!li (i.e., #ood, "e/) 0##ec$" o# drin?in+ on DA: 40

a. Ac!$e alcohol DA in NAC &. Chronic drin?in+ and $olerance DAin NAC

*. DA and A-: 40 i. DAde#ici$ in NAC

Slide11

ii. Ne+a$i,emood" (i.e., d%"phoria, anhedonia or lo"" o# a&ili$% $o en o% pre,io!"l% re.ardin+ac$i,i$ie") ii. Rea""!min+drin?in+ re,er"e" DA de#ici$ i,. Drin?in+relie,e" ne+a$i,e mood" (i.e., ne+a$i,e rein#orcin+). 6. -hen A- i"complica$ed .i$h deliri!m and hall!cina$ion": i.DAand homo,anilic acid in C;= ii.2A'Aac$i,i$% lead" $o DA 5. In "!mmar%,d!rin+ A-: i. DA de#ici$ in$he NAC media$e" ne+a$i,e mood "$a$e" ii. >o.e,er,deliri!m and hall!cina$ion" are a""ocia$ed .i$h DA

=. O$herNe!ro$ran"mi$$er ;%"$em":

Slide12

4. Norepinephrine and me$ho/%969h%dro/%phenil+l%col ((>P2):44 a. Pla"ma concen$ra$ion" correla$e .i$h 'P, p!l"e, $remor" and diaphore"i" &. 29adrenorecep$or re+!la$ion o# norepinephrine relea"e

2. Cor$ico$ropin9relea"in+9#ac$or (CR=): 42, 4* a. 1on+ la"$in+ CR= le,el" in C;= and am%+dale &. CR=R4 recep$or "en"i$i,i$% i. An/io+enic9li?ere"pon"e ii. CR=R4an$a+oni"$" &loc? $hi" e##ec$ iii. ;$re"" "en"i$i,i$% e,en a#$er ac!$e A- "%mp$om" "!&"ide

A-Pa$hoph%"iolo+%: Ie% I""!e":A 'rainhomeo"$a"i" re#lec$" a &alance &e$.een: 0/ci$a$or% Inhi&i$or% ne!ro$ran"mi""ion Ne!roadap$a$ion:

Slide13

Chronic drin?in+ ne!roadap$a$ion $o main$ain homeo"$a"i" Allo." &rain #!nc$ionin+ .hile di"$!r&ed &% alcohol D!rin+ A- ne!roadap$i,e mechani"m" are o!$ o# &alance: Ne!ronal o,ere/ci$a$ion a!$onomic h%perac$i,i$%and "ei:!re" Re.ard de#ici$ ne+a$i,e mood "$a$e" and !r+e" $o drin?

2. 2ene$ic" o# Alcohol -i$hdra.al:A""ocia$ion ;$!die": 4. AD pa$ien$" di##er in A-predi"po"i$ion e,en drin?in+ "imilar amo!n$"46

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2. There i" a predi"po"i$ion $ocomplica$ion" o# hea,% drin?in+ (e.+., alcoholic li,er di"ea"e) independen$#rom +ene" predi"po"in+ $o AD45,4@

*. 0,idence o# +ene$ic #ac$or"con#errin+ predi"po"i$ion $o A-: a.2ene$ic line" o# roden$" prone $o A- "ei:!re"4A &.>!man +ene ,arian$" (e.+., allele") a""ocia$ed .i$h A- "ei:!re" and deliri!m: i. AE allele o#DA $ran"por$er, DA clearance DA47 ii. ;hor$ alleleo# 59>T $ran"por$er, 59>T clearance46 iii. A4 allele o#$he DRD2, DRD2 den"i$% depre""ion d!rin+ A-4E

IB. DIA2NO;I; AND 0BA1UATION A. A- Dia+no"$icCri$eria (D;(9IB):2 4. ;e,eri$% ma% &e,aria&le: mild $o li#e $hrea$enin+ 2. 'e+in" a #e.ho!r" or da%" (492) a#$er ce""a$ion or red!c$ion o# prolon+ed drin?in+ *. ;%mp$om" ca!"e"i+ni#ican$ di"$re"" or impairmen$ 6. I" no$ d!e $oano$her medical or men$al di"order 5. Dia+no"i": 2<o#: a.A!$onomic h%perac$i,i$% (e.+., ".ea$in+ or p!l"e J 400) &.>and $remor c. In"omnia d. Na!"ea or,omi$in+ e. Tran"ien$,i"!al, $ac$ile or a!di$or% hall!cina$ion" or ill!"ion" #. A+i$a$ion +. An/ie$% Slide15

h. 2rand mal"ei:!re"

'. Op$imalA""e""men$ o# A- re8!ire": Comple$ehi"$or%, ph%"ical, and men$al "$a$!" e/am 1a&ora$or%$e"$ ;$andardi:eda""e""men$"

Slide16

C. >i"$or% andPh%"ical: 4. Predic$or" o#A- "e,eri$%: a. Older a+e &. ;e,eri$%o# drin?in+ and hi+h $olerance c. N!m&er o# A- epi"ode" and de$o/i#ica$ion" d. >i"$or% o#pre,io!" A- "ei:!re" o# deliri!m $remen" e. Pre"ence o# A- "%mp$om" de"pi$e hi+h 'A1 #. (a or medical or "!r+ical pro&lem" +. Concomi$an$"eda$i,e)h%pno$ic !"e

Slide17

2. Ph%"ical and men$al "$a$!" e/am: a.;i+n" "!++e"$i,e o# chronic alcohol drin?in+: i.2eneral: Under.ei+h$, chronic #a$i+!e

ii. 2I:D%"pep"ia, +a"$ri$i", hepa$i$i" or li,er cirrho"i" "$i+ma$a ( a!ndice, &leedin+ $ime, a"ci$i", 2I &leedin+, "pider an+ioma", &r!i"e") iii.Imm!nolo+ical: Oppor$!ni"$ic in#ec$ion" i,.Cardio,a"c!lar: >%per$en"ion, cardiom%opa$h%, arrh%$hmia ,. O"$eoporo"i"and pa$holo+ical #rac$!re" ,i.Ne!rop"%chia$ric: Ne!ropa$h%, "ei:!re", deliri!m, encephalopa$h% and)ordemen$ia, mood, an/ie$% and p"%cho$ic "%mp$om" &. >o.e,er,a,era+e alcoholic ma% pre"en$ .i$h a rela$i,el% normal appearance.

D. 1a&ora$or%Te"$":20

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No A- "peci#ic $e"$. 1a& $e"$in+ iden$i#ie" ac!$e and)or hea,% drin?in+ (J5drin?")da%). 'loodAlcohol 1e,el" ('A1): Doe"no$ de$ec$ hea,% drin?in+ &!$ iden$i#ie" ac!$e in$a?e (K 42947 ho!r") Poorpro+no"i" .hen A- occ!r" .i$h in$o/ica$in+ 'A1 (0.0790.40 +)dl) 2amma9+l!$am%l$ran"#era"e(22TP): Alcoholen:%ma$ic ind!c$ion 22TP

Normali:a$iona#$er 29* .ee?" o# a&"$inence ;en"i$i,i$%:609@05, "peci#ici$%: 705 i# ,al!e J*5 IU)1 Car&oh%dra$eDe#icien$ Tran"#errin (CDT):24 >ea,%drin?in+ ind!ce" de+l%co"%la$ion o# $ran"#errin+ Normali:e"in 492 .ee?" ;en"i$i,i$%: @09705, "peci#ici$%:709E05 i# ,al!e J20 IU)1 CDT < 22TP &e"$ dia+no"$iccom&ina$ion 0r%$hroc%$emean corp!"c!lar ,ol!me ((CB): Alcohol)ace$aldeh%dein$er#ere .i$h n!clear ma$!ra$ion o# red &lood cell" macroc%$o"i" =olicacid or '42 de#icienc% al"o macroc%$o"i"((CB JE4.5 *) Up$o a $hird o# hea,% drin?er" ;en"i$i,i$%:*09605, "peci#ici$%: 705

;$andardi:ed0,al!a$ion: The Clinical In"$i$!$e-i$hdra.al A""e""men$, re,i"ed (CI-A9Ar CAppendi/ 4D). 22 Slide19

4. Balida$ed inde$o/i#ica$ion, p"%chia$ric and medical)"!r+ical !ni$" 2. ;e,eri$% "caleran+in+ #rom 0 $o A, i$em" incl!de: A+i$a$ion An/ie$%

A!di$or%di"$!r&ance" Clo!din+o# "en"ori!m >eadache Na!"ea),omi$in+ Paro/%"mal".ea$" Tac$iledi"$!r&ance" Tremor Bi"!al di"$!r&ance" *. Ini$ialCI-A9Ar "e,eri$% and need o# medica$ion: ;core7940 (mild), !"!all% "ome na!"ea,an/ie$% and headache no need #or pharmacolo+ical $rea$men$ ;core40945 (modera$e) mar?ed a!$onomic ac$i,i$% ;coreJ 45 ("e,ere) impendin+ deliri!m$remen" and !r+enc% o# pharmacolo+ical $rea$men$ 6. ;!&"e8!en$a""e""men$": 0,er%697 ho!r" $o a""e"" e##ec$i,ene"" o# $rea$men$ Un$il"core L 7940 #or 26 ho!r"

=. Na$!ral co!r"eo# A- "%mp$om":

Slide20

4. Pro+re""ioncan &e di,ided in 6 "$a+e" (no$ e,er%one ha" all #o!r): a.;$a+e 4 (26 F 67 ho!r"):

i. @97 ho!r": an/ie$%, $remor, na!"ea and,omi$in+, hear$ ra$e and &lood pre""!re ii. In"omnia,ill!"ion and hall!cina$ion" ii. Pea? "e,eri$% occ!r" a#$er *@ ho!r" iii. E05 o# A-"ei:!re" occ!r in $hi" "$a+e i,. (o"$ A- ca"e"are "el#9limi$ed $o $hi" "$a+e &. ;$a+e 2 (67 FA2 ho!r"): In$en"i#ied "$a+e 4 "%mp$om" ;e,ere $remor" P"%chomo$or a+i$a$ion >all!cina$ion" c. ;$a+e * (A2 F405 ho!r"): GDeliri!m Tremen":H i.Con#!"ion and di"orien$a$ion ii.P"%chomo$or a+i$a$ion iii.Bi"!al and a!di$or% hall!cina$ion" i,. ;e,ere a!$onomic h%perac$i,i$% Admi""ion $o an ICU ma% &e .arran$ed d. ;$a+e 6 ( J A da%"): No$ $%picall% reco+ni:ed a"a par$ o# $he A- na$!ral hi"$or%. Al"o ?no.n a" pro$rac$ed .i$hdra.al: i. 1a"$ 2 F 6<.ee?". ;ome "%mp$om" la"$ mon$h" ii. An/ie$%,chronic #a$i+!e, depre""ion, "leep di"$!r&ance" and headache iii. ;%mp$om"con$ri&!$e $o relap"e

B. TR0AT(0NT o# AA. Trea$men$ ;e$$in+: Am&!la$or% orInpa$ien$M 4. O!$pa$ien$(O)P) $rea$men$ o,er,ie.:2* a. 705 can &e$rea$ed &. A- "e,eri$%: i.CI-A L7 ii.;ome ca"e" .i$h CI-A 7 F45 iii.No h/. o# A- "ei:!re" or deliri!m i,.No "erio!" medical)"!r+ical pro&lem" ,.No "erio!" comor&id p"%chia$ric or dr!+ pro&lem" ,i.>a" "ocial "!ppor$ ,ii.;!per,i"ion and ho!"in+ a,aila&le Slide21

2. Inpa$ien$ (I)P) $rea$men$2E a. 40 9205 o#pa$ien$": 'a"eline CI-A J 45 CI-A 7 F45 pl!" o$her admi""ion cri$eria (!l$iple epi"ode" o# A- and de$o/i#ica$ion" >i+h A- "e,eri$% d!rin+ pre,io!" epi"ode" >i"$or% o# A- "ei:!re" and)or deliri!m $remen" (a or medical or "!r+ical pro&lem"

Slide22

(a or p"%chia$ric and)or dr!+ pro&lem" Poor #amil%)"ocial "!ppor$, homele""ne"" Pre+nanc%

'. 'en:odia:epine" and A-: *0

Slide23

4.'en:odia:epine": =ir"$ line o#$rea$men$. Pro,ide $he &e"$ com&ina$ion o# e##icac%, "a#e$% and co"$ 2. ;i/ pro"pec$i,e$rial" in,ol,in+ 5 di##eren$ a+en$" a.2A'AArecep$or #!nc$ion &.2rea$er e##icac% $han place&o i.;ei:!re: K E05 ii. Deliri!m: K A05 c.2rea$er e##icac% and "a#e$% $han o$her "eda$i,e9h%pno$ic"

*. Choice o# a&en:odia:epine: All&en:odia:epine" are e##ec$i,e

Slide24

1on+erhal#9li#e &en:odia:epine" (e.+., chlordia:epo/ide C1i&ri!mD, dia:epam CBali!mD) (ore e##ec$i,e $han "hor$er hal# li#e in "ei:!re": K 575 ;moo$her A;hor$erhal#9li#e a+en$" (e.+., lora:epam CA$i,anD, o/a:epam C;era/D)

1e"" o,er"eda$ion Indica$ed in $he elderl% and li,er impairmen$

6. =i/ed "ched!le$herap%: *0

Slide25

a. A $%pical &en:odia:epine re+imen con"i"$":On da% 4, one o# $he #ollo.in+ N @ h: i.Chlorodia:epo/ide, 50 F 400 m+ ii. Dia:epam, 40F 20 m+ iii. 1ora:epam, 2F 6 m+ i,. -hen "%mp$om"no$ con$rolled (or CI-A J 7 F40) pro,ide addi$ional do"e ,.Do"e 205 each da% 5. >o.e,er in#i/ed "$andardi:ed $herap% .i$h &en:odia:epine": a.Do"e $o con$rol A- "%mp$om" ,ar% +rea$l% &. =i/ed re+imen"#re8!en$l% do no$ properl% $rea$ A- (i.e., !ndermedica$e or o,ermedica$e) c.Trea$men$ "ho!ld allo. i.Indi,id!ali:a$ion ii.Rapid appropria$e do"in+

@.;%mp$om9$ri++ered $herap%: *0,*4

Slide26

a.Allo." o& ec$i,e $i$ra$ion $o indi,id!al need": i. CI-A9Ar a""e""men$and moni$orin+ ii. (edica$ionadmini"$ra$ion $ri++ered &% a "e,eri$% $hre"hold &.T.o con$rolled clinical $rial": i.Compara&le e##icac% $o #i/ed "ched!le $rea$men$ ii.1e"" medica$ion, le"" "ide e##ec$", and "hor$er $rea$men$ ii. No "ei:!re" epi"ode" c.One o# $he"e a+en$" e,er% ho!r .hen CI-A i" 7940: i. Chlorodia:epo/ide,509400 m+ ii. Dia:epam, 40 F20 m+ iii. 1ora:epam, 296 m+

C. An$icon,!l"an$"and A4. Car&ama:epine(C'O) and Balproa$e (BPA): 2A, 27, *0, * 2 27 a. C'O: @con$rolled $rial", BPA: 4 con$rolled $rial: i.'o$h &e$$er $han place&o in mild $o modera$e Aii. C'O "imilar$han o/a:epam and lora:epam &!$ +rea$er red!c$ion o# di"$re"" and #a"$er re$!rn$o .or? ii. C'O al"o pro$rac$ed A- "%mp$om" (i.e., in"omnia, an/ie$%, p"%cholo+ical di"$re"") ii. 'o$h, C'O andBPA pre,en$ A- "ei:!re" in animal", limi$ed h!man da$a Slide

iii.An$i9?indlin+ e##ec$ "o ma% #!$!re A- "e,eri$% i,.Do no$ po$en$ia$e alcohol CN; and re"pira$or% depre""ion ,.No impairmen$ o# p"%chomo$or a&ili$ie" or co+ni$ion ,i. No a&!"epo$en$ial ,ii.1imi$ed da$a on pre,en$ion)$rea$men$ o# deliri!m ,iii. Nohema$olo+ical or hepa$ic $o/ic e##ec$" .hen !"ed #or A da%" &.C'O and BPA limi$a$ion" i.In +eneral no$ &e$$er $han &en:odia:epine" ii.;ide e##ec$" and po$en$ial $o/ici$% iii.5 F 40 $ime" +rea$er co"$

D.O$her A+en$": *0 Slide28 4. An$ip"%cho$ic" a. Pheno$ia:ine" and&!$%rophenone" &. 1e"" e##ec$i,e $han&en:odia:epine" pre,en$in+ deliri!m ii. "ei:!reri"? iii. (a%help con$rollin+ a+i$a$ion 2. 9Adrener+ican$a+oni"$ (propanolol CInderalD) and P9adrener+ic a+oni"$ (clonidineCCa$apre"D) a. A!$onomic ac$i,i$% &. (a% hide impendin+ "ei:!re"

*. (a+ne"i!m a. 1e,el" d!rin+ A&. ;!pplemen$a$ion doe" no$ A-"e,eri$% 6. 0$h%l Alcohol a.No e,idence o# e##icac% &.To/ic, e/pen"i,e and ri"? o# $i""!e dama+e

*.Nonpharmacolo+ical $rea$men$: a.N!ie$ en,ironmen$ $o "en"or% "$im!la$ion &. N!$ri$ion andh%dra$ion

Slide29

i. Oral $hiamine(&e#ore +l!co"e admini"$ra$ion) and #olic acid. Pre,en$" -ernic?e9Ior"a?o##"%ndrome ii.Doe" no$ pre,en$ "ei:!re" or deliri!m iii. Oral #l!id"and elec$rol%$e" i# nece""ar% (ma+ne"i!m, calci!m and pho"pha$e") c. Orien$a$ion $oreali$% d. ;!ppor$i,e&rie# in$er,en$ion": (o$i,a$e $o chan+e e. Re#erral $o AAand relap"e pre,en$ion $rea$men$

=. Concl!"ion": 4. A- i" a common pro&lem inclinical "e$$in+"

Slide30

2. A- pa$hoph%"iolo+% charac$eri:ed&%: a. Im&alance o#ne!roadap$i,e mechani"m &. 0/ci$a$or%ne!ronal ac$i,i$% *. Clinician" m!"$ac$i,el% "creen #or AD and po$en$ial A6. I# !n$rea$ed can &e deadl% 5. 'en:odia:epine" are $he mo"$e##ec$i,e and "a#e"$ $rea$men$

Re#erence": 4. (oore RD, 'one 1R, 2eller 2, (amon QA, ;$o?e" 0Q, 1e,ineD(. Pre,alence, de$ec$ion, and $rea$men$ o# alcoholi"m in ho"pi$ali:edpa$ien$". QA(A. 2@4: 60*960A, 4E7E. 2. APA, N!ic?Re#erence $o $he Dia+no"$ic Cri$eria #or D;(9IB9TR., American P"%chia$ricA""ocia$ion: -a"hin+$on D.C., 2000 *. ;ch!c?i$ (A, Dan?o 2P, ;mi$h T1, >e""el&roc? B, Iramer Q,'!chol: I. A 59%ear pro"pec$i,e e,al!a$ion o# D;(9IB alcohol dependence .i$hand .i$ho!$ a ph%"iolo+ical componen$. AlcoholClin 0/p Re" 2A: 7479725, 200*. 6. ;ch!c?i$(A, Tipp Q0, Reich T, >e""el&roc? B(, '!chol: II The hi"$orie" o# .i$hdra.alcon,!l"ion" and deliri!m $remen" in 4@67 alcohol dependen$ "!& ec$". Addic$ion. E0: 4**594*6A, 4EE5 5. ;ch!c?i$ (A, An$henelli R(, '!chol: II, >e""el&roc? B(,Tipp Q. The $ime co!r"e o# de,elopmen$ o# alcohol9rela$ed pro&lem" in men and.omen. Q ;$!d Alcohol. 5@: 2479225, 4EE5 @. ;ai$: R,OR(alle% ;; Pharmaco$herapie"#or alcohol a&!"e. -i$hdra.al and $rea$men$. (ed Clin Nor$h Am. 74: 7749E0A, 4EEA A. De -i$$e P, Pin$o 0, An""ea! (, Ber&anc? P. Alcohol and.i$hdra.al: #rom animal re"earch $o clinical i""!e". Ne!ro"ci 'io&eha, Re, 2A:47E94EA, 200* 7. T"ai 2C, Co%le2T. The role o# +l!$ama$er+ic ne!ro$ran"mi""ion in $he pa$hoph%"iolo+% o#alcoholi"m. Ann! Re, (ed 6E: 4A*9476, 4EE7

E. Dahcho!r A. De-i$$e Ph. Amino acid $ran"mi$$er "%"$em" in "!&"$ance9rela$ed di"order". In:DShaenen >, den 'oer QA, -e"$en&er+ >, -ilner P, edi$or". Te/$&oo? o#&iolo+ical p"%chia$r%. Ne. 3or?: -ile%: 2002. p. 645 F626. 40 -ei"" =, Par"on" 1>, ;ch!l$ei" 2, >%%$ia P, 1oran+ (T,'loom =0, Ioo& 2=. 0$hanol "el#9admini"$ra$ion re"$ore" .i$hdra.al9a""ocia$edde#iciencie" in acc!m&al dopamine and 59h%dro/%$r%p$amine relea"e in dependen$ra$". Q Ne!ro"ci 4@: *6A69*675, 4EE@ 44. >a.le% RQ, Nemero## C', 'i""e$$e 2, 2!ido$$i A, Ra.lin+"R, 1innoila (. Ne!rochemical correla$e" o# "%mpa$he$ic ac$i,a$ion d!rin+ "e,erealcohol .i$hdra.al. Alcohol Clin 0/p Re". 47: 4*4294*4@,4EE6 42. (erlo Pich 0, 1oran+ (, 3e+aneh (, Rodri+!e: de =on"eca=, Ra&er Q, Ioo& 2=, -ei"" =. Increa"e o# e/$racell!lar cor$ico$ropin9relea"in+#ac$or9li?e imm!noreac$i,i$% le,el" in $he am%+dala o# a.a?e ra$" d!rin+re"$rain$ "$re"" and e$hanol .i$hdra.al a" mea"!red &% microdial%"i". Q Ne!ro"ci. 45: 56*E9566A, 4EE5 4*. Ra""nic? ;, >einrich" ;C, 'ri$$on IT, Ioo& 2=.(icroin ec$ion o# a cor$ico$ropin9 relea"in+ #ac$or an$a+oni"$ in$o $he cen$raln!cle!" o# $he am%+dala re,er"e" an/io+enic9 li?e e##ec$" o# e$hanol .i$hdra.al.'rain Re". @05: 259*2, 4EE* 46. ;chmid$ 12, ;ander T. 2ene$ic" o# alcohol .i$hdra.al. 0!r P"%chia$r% 45: 4*594*E, 2000 45, >r!&ec O, Omenn2;. 0,idence o# +ene$ic predi"po"i$ion $o alcoholic cirrho"i" and p"%cho"i":$.in concordance" #or alcoholi"m and i$" &iolo+ical end poin$" &% :%+o"i$%amon+ male ,e$eran". Alcohol Clin 0/pRe". 5: 20A9245, 4E74 4@. Reed T, Pa+e -=, Bi?en RQ, Chri"$ian QC. 2ene$icpredi"po"i$ion $o or+an9"peci#ic endpoin$" o# alcoholi"m. Alcohol Clin 0/p Re". 20: 4527945**, 4EE@ 4A. Io"o&!d A, Cra&&e QC.0$hanol .i$hdra.al in mice &red $o &e +ene$icall% prone or re"i"$an$ $oe$hanol .i$hdra.al "ei:!re". QPharmacol 0/p Ther. 2*7: 4A094AA, 4E7@ 47. ;chmid$ 12, >arm" >, I!hn ;, Rommel"pacher >, ;ander T.(odi#ica$ion o# alcohol .i$hdra.al &% $he AE allele o# $he dopamine $ran"por$er+ene. Am Q P"%chia$r%. 455: 6A69 6A7,4EE7 4E. 1aine TP, Ahonen A, Ra"anen P, Poh alainen T, TiihonenQ, >ie$ala Q. The A4 allele o# $he D2 dopamine recep$or +ene i" a""ocia$ed .i$hhi+h dopamine $ran"por$er den"i$% in de$o/i#ied alcoholic". Alcohol Alcohol *@: 2@292@5, 2004 20. Coni+ra,eI(, Da,ie" P, >a&er P, -hi$#ield Q'. Tradi$ional mar?er" o# e/ce""i,e alcohol !"e.Addic$ion E7 ;!ppl 2: *496*, 200*

24. 1i$$enRO, Allen QP, =er$i+ Q'. 2amma9+l!$am%l$ran"pep$ida"eand car&oh%dra$e de#icien$ $ran"#errin: al$erna$i,e mea"!re" o# e/ce""i,ealcohol con"!mp$ion. Alcohol Clin 0/p Re". 4E:45649456@, 4EE5 22. ;!lli,an QT, ;%?ora I, ;chneiderman Q, Naran o CA,;eller" 0(. A""e""men$ o# alcohol.i$hdra.al: $he re,i"ed clinical in"$i$!$e .i$hdra.al a""e""men$ #or alcohol"cale (CI-A9Ar). 'r Q Addic$ 76:4*5*94*5A, 4E7E 2*. Pra$er CD, (iller I0, O%l"$ra R2. O!$pa$ien$ de$o/i#ica$iono# $he addic$ed or alcoholic pa$ien$. Am=am Ph%"ician. @0: 44A59447*, 4EEE 26. (%ric? >, An$on R=. Clinical mana+emen$ o# alcohol.i$hdra.al. CN; ;pec$r!m". 5: 2292@, 2000 25. 'allen+er QC, Po"$ R(. Iindlin+ a" a model #or alcohol.i$hdra.al "%ndrome". 'r Q P"%chia$r%4**: 4946, 4EA7 2@. (alcolm R, Ro&er$" Q;, -an+ -, (%ric? >, An$on R=. (!l$iple pre,io!" de$o/i#ica$ion" area""ocia$ed .i$h le"" re"pon"i,e $rea$men$ and hea,ier drin?in+ d!rin+ an inde/o!$pa$ien$ de$o/i#ica$ion. Alcohol. 2000 No,T22(*):45E9@6 2A. (alcolm R, (%ric? >, Ro&er$" Q, -an+ -, An$on R=,'allen+er QC. The e##ec$" o#car&ama:epine and lora:epam on "in+le ,er"!" m!l$iple pre,io!" alcohol.i$hdra.al" in an o!$pa$ien$ randomi:ed $rial. Q 2en In$ern 4A: *6E9*55,2002 27. (alcolm R, (%ric? >, Ro&er$" Q, -an+ -, An$on R=. Thedi##eren$ial e##ec$" o# medica$ion on mood, "leep di"$!r&ance, and .or? a&ili$%in o!$pa$ien$ alcohol de$o/i#ica$ion. AmQ Addic$ 44: 4649450, 2002 2E. -hi$#ield C1, Thomp"on 2, 1am& A, ;pencer B, P#ei#er (,'ro.nin+9=errando (. De$o/i#ica$ion o# 4,026 alcoholic pa$ien$" .i$ho!$p"%choac$i,e dr!+". QA(A. 2*E:460E9 4640, 4EA7 *0. (a%o9;mi$h (=. Pharmacolo+icalmana+emen$ o# alcohol .i$hdra.al. A me$a9 anal%"i" and e,idence9&a"ed prac$ice+!ideline. American ;ocie$% o# Addic$ion (edicine -or?in+ 2ro!p onPharmacolo+ical (ana+emen$ o# Alcohol -i$hdra.al. QA(A 2A7:4669454, 4EEA *4. Daeppen Q', 2ache P, 1andr% U, ;e?era 0, ;ch.ei:er B,2loor ;, 3er"in '. ;%mp$om9$ri++ered ,"#i/ed9"ched!le do"e" o# &en:odia:epine #or alcohol .i$hdra.al: a randomi:ed$rea$men$ $rial. Arch In$ern (ed 4@2: 444A94424, 2002 *2. (%ric? >, 'rad% IT, (alcolm R.Di,alproe/ in $he $rea$men$ o# alcohol .i$hdra.al. Am Q Dr!+ Alcohol A&!"e 2@: 45594@0,2000 Appendi/ 4. Addic$ion Re"earch =o!nda$ion Clinical In"$i$!$e-i$hdra.al A""e""men$

Appendi/ 4

CIWA-Ar
Pa#!en#:-------------------------- Da#e: ---------------- T!$e: ---------------.(26 ho!r cloc?, midni+h$ U 00:00) P*lse or (ear# ra#e, #a.en %or one $!n*#e:------------------------- /lood "ress*re:-----NA)SEA AND 0OMITING 99 A"? VDo %o! #eel "ic? $o %o!r "$omachM >a,e %o! ,omi$edMV O&"er,a$ion. 0 no na!"ea and no ,omi$in+ 4 mild na!"ea .i$h no ,omi$in+ 2 * 6 in$ermi$$en$ na!"ea .i$h dr% hea,e" 5 @ A con"$an$ na!"ea, #re8!en$ dr% hea,e" and ,omi$in+ TREMOR 99 Arm" e/$ended and #in+er" "pread apar$. O&"er,a$ion. 0 no $remor 4 no$ ,i"i&le, &!$ can &e #el$ #in+er$ip $o #in+er$ip 2 * 6 modera$e, .i$h pa$ien$R" arm" e/$ended 5 @ A "e,ere, e,en .i$h arm" no$ e/$ended TACTILE DIST)R/ANCES 99 A"? V>a,e %o! an% i$chin+, pin" and needle" "en"a$ion", an% &!rnin+, an% n!m&ne"", or do %o! #eel &!+" cra.lin+ on or !nder %o!r "?inMV O&"er,a$ion. 0 none 4 ,er% mild i$chin+, pin" and needle", &!rnin+ or n!m&ne"" 2 mild i$chin+, pin" and needle", &!rnin+ or n!m&ne"" * modera$e i$chin+, pin" and needle", &!rnin+ or n!m&ne"" 6 modera$el% "e,ere hall!cina$ion" 5 "e,ere hall!cina$ion" @ e/$remel% "e,ere hall!cina$ion" A con$in!o!" hall!cina$ion" A)DITORY DIST)R/ANCES 99 A"? VAre %o! more a.are o# "o!nd" aro!nd %o!M Are $he% har"hM Do $he% #ri+h$en %o!M Are %o! hearin+ an%$hin+ $ha$ i" di"$!r&in+ $o %o!M Are %o! hearin+ $hin+" %o! ?no. are no$ $hereMV O&"er,a$ion. 0 no$ pre"en$ 4 ,er% mild har"hne"" or a&ili$% $o #ri+h$en 2 mild har"hne"" or a&ili$% $o #ri+h$en * modera$e har"hne"" or a&ili$% $o #ri+h$en 6 modera$el% "e,ere hall!cina$ion" 5 "e,ere hall!cina$ion" @ e/$remel% "e,ere hall!cina$ion" A con$in!o!" hall!cina$ion" 0IS)AL DIST)R/ANCES 99 A"? VDoe" $he li+h$ appear $o &e $oo &ri+h$M I" i$" color di##eren$M Doe" i$ h!r$ %o!r e%e"M Are %o! "eein+ an%$hin+ $ha$ i" di"$!r&in+ $o %o!M Are %o! "eein+ $hin+" %o! ?no. are no$ $hereMV O&"er,a$ion. 0 no$ pre"en$ 4 ,er% mild "en"i$i,i$% 2 mild "en"i$i,i$% * modera$e "en"i$i,i$% 6 modera$el% "e,ere hall!cina$ion" 5 "e,ere hall!cina$ion" @ e/$remel% "e,ere hall!cina$ion" A con$in!o!" hall!cina$ion"

PARO1YSMAL SWEATS 99 O&"er,a$ion. 0 no ".ea$ ,i"i&le 4 &arel% percep$i&le ".ea$in+, palm" moi"$ 2 * 6 &ead" o# ".ea$ o&,io!" on #orehead 5 @ A drenchin+ ".ea$"

AN1IETY 99 A"? VDo %o! #eel ner,o!"MV O&"er,a$ion. 0 no an/ie$%, a$ ea"e 4 mild an/io!" 2 * 6 modera$el% an/io!", or +!arded, "o an/ie$% i" in#erred 5 @ A e8!i,alen$ $o ac!$e panic "$a$e" a" "een in "e,ere deliri!m or ac!$e "chi:ophrenic reac$ion" AGITATION 99 O&"er,a$ion. 0 normal ac$i,i$% 4 "ome.ha$ more $han normal ac$i,i$% 2 * 6 modera$el% #id+e$% and re"$le"" 5 @ A pace" &ac? and #or$h d!rin+ mo"$ o# $he in$er,ie., or con"$an$l% $hra"he" a&o!$

HEADACHE, 2)LLNESS IN HEAD 99 A"? VDoe" %o!r head #eel di##eren$M Doe" i$ #eel li?e $here i" a &and aro!nd %o!r headMV Do no$ ra$e #or di::ine"" or li+h$headedne"". O$her.i"e, ra$e "e,eri$%. 0 no$ pre"en$ 4 ,er% mild 2 mild * modera$e 6 modera$el% "e,ere 5 "e,ere @ ,er% "e,ere A e/$remel% "e,ere ORIENTATION AND CLO)DING O2 SENSORI)M 99 A"? V-ha$ da% i" $hi"M -here are %o!M -ho am IMV 0 orien$ed and can do "erial addi$ion" 4 canno$ do "erial addi$ion" or i" !ncer$ain a&o!$ da$e 2 di"orien$ed #or da$e &% no more $han 2 calendar da%" * di"orien$ed #or da$e &% more $han 2 calendar da%" 6 di"orien$ed #or place)or per"on

To$al CIWA-Ar ;core -----Ra$erR" Ini$ial" -----(a/im!m Po""i&le ;core @A