THE ADD iCT ION IA ITY OF SYNRHET IC SLJBST ITURES FOR CODE l@X Pro jec t - Descr lpt Ion), kequest to the Office of Naval Research for Renewal of Contract MR 113-149 serial 18249 Naour 181-53 2 1. Stickgroure-J Information Since-July 1951, a project designed to develop-a synthetic drug which woutd be as safe as codeine with respect to foxielty, antifussive activ-lfyj, and addiction flabil.tty has been carried on vlfhln the National lnsfifu.',c;,of kte.,ifat P-calfh Add I c f.? q ii Research Centert PHS Hosl@ital, Lexington, Kentucky. This project has been financed In farge part by funds from the af Ice of Nava I @,-Ic'search and this c!c3cr '*Pt 1,-)n con2:sf ltufes a reqvest for rinewat of the project for fhe period I July 1956 to 30 June 1957. A :vnthetic substitute for codeine Is E>,idly needed stpice opium or -mrphtn,-, Jertved from opium c%-,os&'Zfut-e oniy source of codeine. Unless a synihe2@ic sul.-sti'tute for codeirc I"s p -jue to stockp;fe optur4i -ius tco r.- t 1. deveto ed the Unlted States- in orL4zr to o vlde adequarz svp, ro 1 ollas of -cd-Inz for bo@h !'-c civttien and rillitary populst I o n's i i, th cevent of war. T!ic facilities of the Ni,@,H Addiction Researc.@'Cen@er are -,ok sufficient to carry on f.%Is work In adc,?Itton- required for the f.ust too of 611 trcw analgesics" unless addtflonal funds supplied by the Department of Defeate. 2. Tort Accomplished to Date Previous work has been summarized to the aanual progress reports sent to Capt. F. H. Quimby, Head of the Physiology Branch, Office of Navat Rese2arch. Two drugs have been devefoped which are promi3tng peforiftal substitutes for codeine for relief- of cough. These d-rugs are ft-I dextrome'Lhorphan, and 12) carcotine. Neither drug possesses arty addiction liibility and both have relati2vely tow toxicity. They current ty are u:zder- fnteni'ive clinical study, fo-r- tussive effect. Although two very-promlalng,.&..Dttfus,3ive substitutes fot-. codeine have b"a found, no compouo-.d is yet available-,which Is as 2effective as codeine for the relief of mild gradcs of pata and which Is az safe as codeine wlth rcspect to both toxicity and addiction ftablil,&Y. t,.,Ore then O@S cot@ipounds Save been studlecf to rl:ato.,. Cf f@,?St- as Su 2 utst4ading bstitutes for codeine-for analgcslc use. The o -ompoo.-ids are alpha-di- and. al- 3'he de--froroiaiory iso;@-,cr accounts for all the anal_oeslc potency of these pariicitar 9 corrpounds. The drugs are nonioxic, arz better s-edab'tvos fliaa ra -norphine only slightly., is codetnes, suppr abstlncnce fro a tkd have been rep ed-fo be effecttve In f-he re I 1'ef' of 4. cc clinteat pain., although studles of 4he analsestc eff t2 are still Tnadequ4tg. 3. Need for Continuation of the ?raject_ Althovgh two drugs have been discovered that'have promise as potetittat aottfussive substitute& for codeine and several. drugs have been discovered which night serve as possible substitutes for codeine 2for anal@gesle, It Is still unknown .whe.'her any oft;, Sesc drugs vill be cc:rptefely sattz'Tactory -tor either purpose to@ clinical use Ft ii, therlt'Tde',i, essenf ial to continue The szarch since the targzr fhe nu.--ib--r of com-.-@ounds developect.-$;reafer Is the C'-hance of ftnding a coimplefely adequate substitute. 4. Terk Prooo3ed Durtng .the period t July 1956 4'o ')O Ivne 1957 we propose to cor,,otzte the silu,-41es on fhe verv Tpl,,-.,^-rtant c-or,i,c>ouad3 r-4ationed aoovlzo. This idroa Is so promisi.,Jg thas, e Su-b sl'u-lles dtrecf ac!dtct'ton liability studies ar rcqu2tred. cry fir,-.c c-->nsuming and ulil require six to ntn-, moni'Ns a re-v for completion. In addition.. we I.-is'-end to study the addletlo.-I ltabiliiy CT, N'-allyidit%ydrohydroxycodeinone to evaluate fhz addiction liability of tbz dthydrocodetne aitd @to s .tudv such 'be sugges'ed by the Commit-fcc on other substances as may Drug Addiction ofid i4arcofics, National Research Council. o S 2 The methods to be used are the standard addlettoia liability testing methods of the Nll,,H Addiction Research Center. These have been described In previous project descriptions aAd should be consulted for details# 6. Evaluation of 'Da t a The evaluation of data opfq-tn'cd t'a fhz ad,-4.ictton bi I Iy program has also bczn d'iscussed In previous proiccf descrtp.'Ions. 7. LOCC-41on of Prolect V@ork will be carried out at' the Ntt-H A-,Idl@ct-loa R,-search Center, PHS Pfospital, Lexlngi'on, Kentucky. T@.ts instifullton provtdes the two necessary facilities for'ihe type olt' work to be und,?rta',.en.- C!l a -,cot pa@ten-'s who vi'll volunicer experlncni-s wi8th drugs, and (2) sirict enyllrorir.,enfat conil"ol wv% lch prev,,z.-,iis ih,- -introdi-ic@ Ion. of. c-tru.@,,.s o.'i-,hcr fliai Sauey lnfo e e xoe r n i!i S "i 8. ExperTmenfat Personnel York witt-be carrlec3 out under the dlrecf !on- --if @.-*7 r3 ?.@',.D. Direc@or, Nili7i Add lcf ton Rc3carch Cent'er. This. tnvestfgii'or has had twclv@ 2years of cxp--rieucc In research In narcotic.drug addtcilon and has publlshzd razy paners tri f@.e fteld. I-,-f will be asslsfcd by two other experienced physiclans., Dr. I-',. F . F.raset- and Dr. Abraham '7ikler, both of who2m have had ex@en3ive ex.0c.-lence In research In addiction, ttith irany publtcatlons. In addition to these nzdtcal personnel the par&'-flmc servtces of a -blocher-Tist and research psychologist will b--.r-ade available. A spe2cial ward for the conduct of ihe.-e- SfUAleS 13 currently 'iff operat lo,.t. 9. Estir.:@fcd Co:f T,%z on-,our-i oT' mone y r-equzsfe-d has bc4@',-n 1,-icreased. This Is necessary in order 2to proviujc fun--Is for 'he 1;-.crease In CIVTI Service- pay vh-tch went fni'o effect In- @iiarch 1955. I Personnel 6 ?s chiatrtc Al-cs GS-5 ('w4210. p.a.) I -?bystcal Science Aide GS2,.@-5 2. R-.ser-vc frr p re r--, i un @ay T T r d I 'tal, P.-O I I dal ,Dezrf Im.0 Travzl 4. ?."II $cc I I alea .,s I_xpe.-Ise (Drugs , c',icr,-.Tca I 5, C, pho c.,7. r c p"# i cu-pp I IC 3C.c) @!arris r r,