TITLZ OF PRoj=Tt Addiction Liabilitica of SYnthutic Sub3titutes for Codeine, Objectivp.%: To find a an-algaslc and antltvzsivs drug vhti.-.h wuld be as safe from Lli4 point of vlew or "xicity 2 and addictla,.% Ilability as Is codeine, ABST;LkCr (OR =,',,%!A.RY) OF RR.SULTS a. Since start of projcctt Lca'or the summary of reSU!t$, .@COV9@-3t This por.1 he 2 perlcd.fr"., L July 1951 to _13 October 1957& The proj-,-ct Was undertaken because no tynthetlc drug ua3 available s4Lch 6ns as saf a wit-ii respect to toxicity aid adell&ctic,-l I labil Ity as ua 3 Inc codzineo S14 a 27p' per cerit of t'he country's r.Ztd3 for n.,-.rcotte drugs are for code4.nop rut.%er t4%an ror potcnt a.-raloc3ics of the -=rph!ne type,, the t;nltcd States =zt continu3 to stockpi.le oplur.4 vntil adequatz 3ynthetl2c subs-tltutz3 ror codcl-iiz are 4evel" rol- of t:qe IILI@ri Addictio-.% Re3zarch C=tcr I edt Th,, this Investigation# Wiicli W!as b*oun at the req-aest of the Co=ltl,,ee2 on Dm,:; A.,.,flictlon a.-N.4 1,:@rcottci o: t.lie Yzal,.Loial Rescarch C@3uncilp consl-.t3 oA,.', ti%e d4ter-,al.-=-tion of ad,-.-tic*,.Ivc a. new dru@.: prop2ertIC3 Or.th S. cllnt.cal evaluation of +ha ard a.-.t!ttzssivc potm-nl-.y of the new dr-,-Cz r...,Liizt n-.cessarily be ::;zda elsaiwltere. f,,,r 0 n-e r. -n.- Is I c s 1a vb-c i dc r I d I ,-i d a t a I 1 1 @-i t:,. 0, c t d-zscrlr,tions I n n r e. v. -*4 -.,us reports a.-id -hllll rot bc,. berc, Dur n a period of I July 1951 to 31 E-ee 46 ncv dru:,I!s or mlxt,.,ires of dr-u(,%s have bean tested for addictive ";stanczz potentialitiea* Detailed LrXerratlon@concerning ttesz su. can be round.- in the a..nnual repog--tz for 1,92@4 throu@,,i 1956* Two substanc4s w',Ixic.1% were o4atstanding as poszlbls substitutc:s for codel.-.e for au;prestion of COU'.'h Veri@ fo%Lnd, These weret (1) d"3-mat!%.oxy-,@@metiiyl2r-,*rphlnan (dextroi-aetl,,orpb.,,,,.n)$, and (2) narcotlnee FurLi@.-.r clinital,reports@continue to Indicate that dextro:,.@,.thorphan is equivalent to codoi:rc In antltu4,,,sLve potencyo It# therefores see= a very satisfactory codetn2e substltuto for rall2f o&l cou,-,Ito lt 13 already:a,.rallabla ard on sale In th@.- United State3, FArcotine 13 now on cals and rcports of cll-.ilcal trlals of thl3 dru3 are Indicating tnat 114. ray also be a u5-3ful 2 for codcl,-i.0 Si@-@'Ca two ,.,,or of cou:;h hav-. been devzl-on-,,,d attention I-aa b-aen turncd to fin-,'A I.-. a co,=o-and whic@@% would ba as ef.,Icctlvo sjvd u3 s,,,Lre as codcl-.ia In rei'l2evi.-. -11@d e- d-5 O'@ pain,. S@;V*n potzntial Substitulas fcr code!-n.3 for paln r c It "14!ft w-aoe d l,"i t.@i a r c,:@ o r t f c r 1 914-1 .@as -ivzn to tne 2 IL SU-1.)Stituties for codeiae In relter of pei4i* C@@.-2ple *.a da ta on. toxil-ity cllnt.cal c-.ndltior.,s aral howzver, rot yzt available, oi','-.13,dfug 13 no*.r bain,, =--ar-Itated I1n t.%a U,-iitcd 'Otalt-.es by f-@'li LI'L I ly c.ad r#ing the curre@nt re.,ortin.1- I:uring the current reportlng period the addictive potentialities of five druos iiere@ evaluated wholly or In part* The results are prezented below-,-tuid@-r lrdivldual headinss: 2 Work on this cozvound w-as completod and the results,reported to the Drug Addiction Co=lttee In January 191,@6* The results continue to support those previously described* -In former add@icts the drug 44.oc:s rat'l.,id-uce a f,.-Il 2 or t.hose it docs su-pprezz abstir.=e fre.,n mrp.%Ina partially, Lut not c@oiipletelyo W.%crL It Is a"- niz- tercd c4ironiczlly to noiitoll;-Iecnt volunteers som.-, deGreq or tolerance2 to ti%c uadatlve errzc"A".s Is obterved,,- FollowLn-3 wlt'.,.Ldra-m@al af *.cr c.1t.rop.Ic intox.Icc-tic.-i. abstineice are milder 1,-,, deor--e th-an t..%oro after wl*-I2zdraw-31 or codolne. It was co-ncllad4.,d tl-,at d. ilmd defl.,ilte addiction prop- *@-ar Ic!sra th;@tt of cod@-inc, The C@%",-Mittec his t@.,erefori rccc.=zr*di@.d th- Uhis partlctt*,@r n,-,t bia by tlie U. .5. rarce,, -ic-. laws. lqoram hl'ne* Studlc@.%@,f this agent wcre Urder. taken for tuo reasonst first# it.lz -,-,r so ror the prcc. rorp.litne. a.-itaoonists which !,.ave Itiza addiction IkaLLlity '.-.aan does- sc@-..ondlys It Is a, n-wrfml retabotic product of -d by 14-de.-..ct,%ylation of morphin-.* As V4iic% 13 form, toleear.@:a to rorphine is acquired,. In =Is rat3 t'.he ability of t'2.he liver to d=ethylate corphlne Is red%,.cad* Studies of Its addlctlon liabillty,# therefore seem to be irportant thooreti. C-.Ily a3,woll a3 practically* In sInGle doses# norr-orpiiina is -a In Inducing sedati.-,nt In r,pcated f.2.r less patert than =rphi" do3c, 1,.o%yevzr, It Is =re potert -thrn -.,-orphine. On chronic administratio,-.p taie do&* of nor=rp.hine carnot be raised as r-apidly or to as high a level as can do3z or Tolcrance to t,%e sed--ative effect3 devclc"s r4re slo@.,Iy than does tolerance to tlic ucdative eff,;@c,*.z o4-" morphinoo tration or to persons cl-,,ror.@.Ic-"lly lntoxi,,-,.ted with priecipitatcs nlld sy!-?to@-.z o;r abztin2t.-.ce.0 "kllen rorr;n.,A"phino Iz withdraun after a p-eried of c.L%,-onic lataxicatlo.-4 sr.!.-,ptc4--3 of abs4iin.-.--nce are .-,Ildzr tl,t.an ttote saen aft;-,r witldtaw,-l of rior@r4hi@,lc* t!,.,;y ar@-as, In t.'-iose seen after withdr.-A-,eal.of cod!31:,."o cr t.%is tt,,e dr-u-g z,-,.pprc-.aes -tor!-z -r- inhz 3 It Is conclue,->d trzt -o 3q7 addlct@ivi.!, liabillty utict4 Is ?rvbtbly- less t.%an that of codlirew@ 'The charac%4.crls*%.Ics of are sucli that#: If It 13 an analo%-.3te I.,t ran#. It s,%culd be an excsllcnt druC-:'In c2op.,-4itlons associated vtl,'.h chronic palne (3) 14orcodainee Studies of norcodaine were under-m talcon because of the low addictiven*33 or tho parent cor,.pcundt r.ormorphin,e, T4hcse stu2dies a.-* still inco::--pleite* Prell-"rary studies indicate that-norcodaine probably,have Lhe Zama relationship to codclnz as n@@r=rphln.2 has to morpl@.Inco In repeated dose rtor--ad,::4n:-. Is r;.or2e po46@,-nt In lnduj,.-Ing azdatlon t!r,n is@ c--4.7"4t6ni,, I-o tr'?Iia of. n@)rr:cr.-)',, Is extr=cly mild hlollowlig wit'41,,draii-al or after chh-onlc Intoxication* 7-2p,.z drun Is effective orally# so ii'O Is a s-%Ibatltute for codainz,* unfort=atclyg howzvcro It Is rot a 3ynt.%atice (4) Thls corzpou.nd Is the a.-mlogle of nori-.orp4%lne in t.2%a =rphinan zeries, 0;,Aly prlr.@- I I..Inary ini'orratl%-In is as yc?4. available, Si,@-.glc do.;,,a3 ra.,,.(,, n 5 t4,p to 7,-Z =go do r.1-ot any or. nor--.cr2-hln-1. In r-,Ica'%.zd L--re c-,, ts e -:v r d t @-7 46 P- 2 i&,@.-n @DI-4zn In 50 pzr ctnt !gr,,atcr dose t,%z addictln- d@-lza of r.=klz.;;it t',1,40 dzi*.a are rxt to @e-1ve T..-% t-Si-a r--I.,.-tivc addlet.tol. of n r Iet4 Wo prgvicusly repvrted that t.'113 co4vound ;artially zul-;-pr-zs3ed rbstinanca from r,.orp.hine, Ti%is result was entiriily une,-..o.-..ctcd 2 since a c;ongencro d-3-hydroxy-N-,n.!-.,enct.%ylmorphinap i.-as lnactivi.* In t.%Is resp.-cto Since this rezult could possibly liav4 been due to cont=lnation with the potent 1-fom. of ti%e drugs e3p,@.-cially purtried $a=--ple3 ol,&* this co=po=d u-.ra obtained and te3tedo Th%-@ p@Llritlc-d drl-g also -;artl.y isu,?presued &-!>st-Inerco fro,.-. u:hen EIVZAI Is-. six ti4-. 3 the acca3tc.,T@cd dose of =rpil-I.Ince This cor-fir@-@A,-o tha prevlous rcs-%,dlt a,,iid cxcludgis the to of ti, rcs%;It :.ia L. ltvo-malsomcr* TIie addictica lidbility of tlia d,6-ug Is judgttd to 2 P L A 1: 5 Fu r%; d i a t fl uuring t-ho ccik-Lin3 et&Z-6@,%t zroAt*,,.3 we lnt-z.,,id to As soon as pomplet@z stu-@l&lzs on :acrcodcinz anA on nzrex 2 !,r@ o r cod@.- possible ttudlts on ina of nordro:@oran.* will -be ln'tiated a4 cd wi 'I@61.1 t.h a rsI t s W -itand to e Also 1. t@ia addictivznass uf 1-"ttar Ls :@elaz C,:).-@1t of ard also to 3 1 c ard c- sor,.z of t@.,coo dru@,s in Long RanC;e: U?c Intend to@ co-.Ttlr=a t.14 asaurch for su!@stitutes ror c'odialne until drucs ara fourd ut I cli ar;-,,p In the apinio,-i of the Co.-mittai an :-:ruZ Addictlo,.i aid I!arcotic3 of-the N*atlonal Res2earch Council# co=pl-ate'ly satistactory substitutas for codel-ito RE?OR@TS A-?',", cu,.-rent r-,,,-jort 2criod)o 10 Frazc&,# H* Fe# and Isbel@lbs 4n*; Furth,--r studi-us on (d-Propox@,p@licn2a)o Addcnd= @lzlne 10th Pi-eetin-* Comma, on J".'@rug Addictloa aid Larcoticza ?Iational Reseam"i Courclls Indianapolis$ -nuary Irdo 21-2,3 Ja 2i Fra3cr# 14-o Pop and lsbellp Y;Oi Addiction Liabilit0y of NCW A=IVZSIC31 T i.,- -@f I lo 1-4-carb, %oxv. t,.2c- o:4. rru<,i Addictio-.i aid -Frascr,, H.& Fo# 1:@bel It. n a-nd Van rn, Go Da: Lrfec-ts of @"iorplilne as Co:rpar-od wi,th..a l@'slxture oa- plu:2 Dtz-nlno-7hanyl-Miatolt (raptazola). 3 531 F-arris Itball, L@;lrector