il-IE AI)DICTIC;N LI.ABILITIRS OT SYNrr[ETIC SLT-3STI@iUT'-zS FOR COD,'x-INE Harris Isbell NI.I-IH Addiction Research Center, Lexington, Ky. H. F. Fraser and A. Wlkler lOr-149 2 NAonr-ll,,-60 To develop adequate synthetic substitutes for codeine, the oplat'.e which Is most widely used in medical practice-, and for iihich there Is no domestic natural source-of supply. The niost satisfactory analgesic substitutes for code',,,-ie so far aeveloped are d2-propoxyphene (Darvan, Lilly) and ethchepta,-.Ine (Zactir-fn2 Wyeth). They are substantially less addicting than codeine and neither Is subject to narcotic control but 'they are not as effective as codeine in relief of pain. Two effective cough suppressants have been discovered and'are on the market. The2y are dextro- methordhans Romilar, a synthetic, and narcotine a by- product of opium processing. A @otent synthetic anti- diarrheal or constipating agent R-1132) has-also been discovered which Is effective In doses of 5-10 Tg three times daily. It has definite addiction liability but most probably It would be 2 less subject to abuse than codeine. During the current year advances were rtade in the methodology for measuring abuse-liability of ne%i drucs. By employing a spec;-ally devised "attitude" questionnaire., It was found that there is considerable variation among narcotic drugs Insofar as they are identified as "dope" (2opiates), and addicts express definite oreferences. As an adjunct to objective measurements such an "attitude" questionnaire should be useful and si.-,iple procedure for evaluating the rela*,ive abuse liability of.new synthetics. Formerly in man, the -riethod for evaluating drugs by direct addiction (a procedure which simula2tes tha-"6 e,,rployed by the addict in his abuse of drugs) required from 'Lwo to six months to complete. P-xperiments during the current year demonstrated that In the cases of -.,ornhine, codeine and he-oin, a relatively hi-h ngree oL' to-crance and physical dencndence develope wtien these dr8i-,gs are chronically adminl-i*tle.-ed foe only 13-20 da@s. Th'Ls shortcnc-", "-.busell proccdure has made It possib'le to czr.,oare t'lie ad,-,Iiction liabilities of severn-I new syt-, 4Lhetic op'6ate-1114,e drugs with that of morphine In the same Individuals. Addiction studies were completed on 9 new compounds. Evaluation of 04.wo of these has been tubmitted to the Commil'.+-,z on Drug Addiction and 'f@larcotics, in'ational Research Council (phenazoclne and levophenacylmorphan). Both of these drugs were more'potent t2han morphine in Inducing motphine-like iteuphoria" and behavi,or and both completely substituted for morphine in addicted persons. Although definite physicol-. dependence developed following chronic administratici@ of both of these compounds, the degree of physical dependence was less than that observed in the case of morphine. Their effectiveness by the ora2l route has been inadequately explored. A conpound related to nalorphine structurallv (1-3- hydroxy-N-gar,L-i,a gari,@-,ia-dimethylallylmorphinan) was te7sted for addiction liability. In postadaicts, its effec-L,.s resemble those of morphine, rather than nalorphine and therefore It has no advantages at a substitute for c2odeine. A new very potcnt compound, 1-(Beta-diethylaminoethyl)- 2-(p-ethoxy-benzyl)..!.5-nitrobenzimidazole methane sulfonate, has been developed-by Ciba. In maa-s the eu hariant dose, on oral administration, was about 0.25 mg (EO-120 times as potent as oral morphine). It was 60 times as effective orally 2as-morphine is subcutaneously in suppressing abstinence from moi@'phine. During chronic administration,, postaddicts were much ir,.pressed by its overall sedative effects, although they recognized.it as opiate-like. Since the compound Induces definite tolerance and physical dependence its addiction liability would approximate that of -.iorphine. 2 P=4S FOR FUTURE Studies an several compounds have been completed and these will be prepared for publication. New drugs to be studied are (a) a butyl ester of R-11'2 (the antidiarrheal agent), (b) the methyl analogue of phenazocine (the counter- part of codeine in this series) and (c). 1-3-hydroxy-N- propargy2l-morphinan hydrobromide, an anatgesic which Is a morphine antagonist, and hence probably of low addiction liability. From the long-range point of view It is intended to continue the search for substitutes for codeine until drugs are found Vnich are.,-Ln the opinion of--the Com.--,iittee on Drug Addiction and Narcotics, completely satisfactory substitut2es for codeine. CURRENT REPORTS AND PLMLICATIC",IIS (a) H. F. Fraser and Harris Isbell (1959), "Addiction liabilities of (a) dl-2t-Hydroxy-5,9-dimethyl-2 (phanethyl)- 6,7-benzmorphan HBr7@IIH-7519), and (b) 1-3-Hydroxy-,14- phenacylmorphinan methane sulfon'ate (Nllf--7525)." Addendum 3, Min. 20th Meet.9 Corrmittee on Drug Addiction and I.Tarcotics., Nat. Res. Council. Washington.,-D.C. Nfatl. Acad. Sci. LIA31LI@s'Y CtF (Pro.,'-ect 0,-,scrlptlon) Rdquust to t'4ic (),,"fire ef Ilaval 1.@esearcl,. fo.- -Rencwal of Task I-,io. 101-14@"F Co2itract .Iince li':-)l tl,.e Iistl4f,.u,ta Oi'. %-'gntal licalILli .1 f.ction ri.escarcii U. '-j"i Pu,.bl-lc lilicalth "-:orvfce Lexingtonv bas been carry!,-.g on a k-4&-oject 2@L4csiored tu duveloo as,,@rthatic substitute for co-.Iclnz wiN.Ich would be as safe as codeine and as effective with respect to toxicity, antitussllhv@.- activitys constipative actlvlty, and addicti,-n Til@-c pro ject bas be-,n financcd In 1:ar-e part by funds ri-cm the c)fllb@"Occ of D;aval T.'i.,zearct, and thts descripli,.Ion c..-onstitulk.es a request for renewal of talic prolact to.- the period I July t@)60 to 10 June 1961. i'2r.e project w,--s 1,.iltlaA,6ed because syn*.heoic substitutes for codeine were badly'nue;ded sinca oplu-,n or imrplilne derive-u@ from opiu.,,,%. constitutz the only sources of c@Ducine, Codeine Is tahe m.,.-st wl,!ely ut--d narcotic d,.-ug In both civilian arid iiiaL'Ical -,)t,actice. T.,i-a 'Jnitad c.tates co,-isu,--cs 16 to 20 tons or thlz d,-ug y-arly so ti",at, unless adequa"e synthat'Ac substitu4@ are found,, @6?ie nation ru!st con@@"Inue to st1ocl,.pile oplura or In or-..Itsr to provida a",ZqUatg SUpplit3 for botli the civilian and iii I 1,tbary population In t.'-.a event of @;ar. T".a facilltics of the Addiction r%zse-;arch Center are not sufficii;nt to carry out thls.work.in ad%AAI%6.ioi to the evalua*%,Ion of potent r.(4w a.-,algcsLca sub-..Itted bv 4%.bc on Crug Addlcticn and Nzrcotic3 '-'Iattonal Council$ unless adi@@litional fur,-, are s,4-plied ttirouglt Depirt27,,.ent of Dufcr,.se. 2. 'ti act-ry arialical- 'substl",;tes fo.- co,;aire m-3sL satlzyf so far deval,,^.ped a.-c e t'.'L,,*iDheptazlnz (A@'dctirlrs '@@'yeth). 7ibe,v ar%-@ su','.,stantl:zlly less a@.Idiatin!3 t'49,z,-i codaiiie ;a4-4d raltlier is su-blcct ti narcfitlc cont&-ol I&@,put they ar-- not as efrectiva as c.-i-"Ialne In rellef- 2 of pain. T@.lo affi@ctive co--tgh supprassants tiave been d!3- covere,@-.' and arc o n Lli c ria r) t is t't@T, c- y a r a ,i a x t r o Tr. a t h oa:%. Ro=ilaro a synttcctlc, and narc:@itinet a by-product of oplu-- processing. A pot2gnt syntli,4etlc or conatipa4t,.ing agenl*. (n -I 1',.Z) ha3 also. been ditcovqrad Is el6orective In dose s c"4@' 5-10 mg ihrec tlr.-zs dai-ly. defirite ad--4'ictir,n liability but ri,@3st probably it 2wculd be less subject to abuze tl.,,an co%-.1idine. During the current year adva-r-4ces -.aaz In tj-@e @n,act'll'todoloCy for -wasuring o.-14" n;;.w UrtGs. By a spqclally 'la-utitude" It was fr,,u,.i:i t. at thcre Is constdorable variation a=-ong narcotic druss lr-sof(-Ar as Vii;y arc as "cope (opiates), and addicts ;;xpress dc&' lnio6.c pre4e-@ren%-.za. As an adjunct to ob'cctive rcasurc,-ients !st,,ch an "a*.titu.@Le" qrastlornalre zi-,.--uld bv us,--ful unu' sir-ple procadure,f-.r evaluati,--!j th,,-- v,,, liabillfty of new t;ynt6--@c*.Ics. For7,erly In ti,io riet,.,od 4'..2:)r evalua@,,.Irg dra.!.Os Ly dirE,,,--t (;a procciure v.,A, lch slv-*ula'kc3 -t#"at 1)y t" c a-@@:I.ct In of Vol c frog,. to six -durin,_l thz current year cic,-..tonstrated ttiat In the c-ases of :,-sorphln--62 co,-"Iulne-and hcrain, a relatively hioh degree o4'6 trilcrance a.,n-.1 ph,,sic:al @iepzn-%.4,-.nce whzn these dri-igs are for only days. This sliortened "ab-4,se" procedure @,.as t-,,.ade It possible to co,-,pare the addiction Ilabilitics cf s@-.vcral nzw sy.-.thetic opiate- lixe d.-U@;s witr, tliai*. of marpbine In tlia lndivil,'4ual3. Addict!.,;n studlzs t.-tere completci-i on 9 rc,,w co@,,,:pot,.nds. Evaluaticn of tw-.3 of t.iese has besn to t@@,Ac Co=lttee an Drug Addiction an-a 1414arcotica., liational I'Nescarch Co-artcll (phenazocine and levcphenacyl,.ncrnhan)* of t.'&-Sese dr-4Cs 6 werc riorc potc,-,t t,b-ien m-)rp@i!ne In lrducing au,'@horia" and behavi@;r and bol%,.Ii cor-,pletqly wlb3tltuted for @.n4rphin4 In a@@4Azilct--d persons. AlthouCh deflnille physical follo,@ilng chronic auninistrat!on of botl, of tiiese co.-n.pounds, the dc@rue of ph.-,sical depen,-I-t-,.nce 4 waa less tl@;,an ',,,'.iat observ2d in 4,hia caue or Tjl,.-.Ir offectl&,qcnezz by t,%e oral route has b,---cn lnac--3quatel,, related to nalorpiine str-,act,.irall,7 w-,s taster@l for 1119-"bilfty. In Its V-fA,;3c2*63 rest:.,.ribl-2 tih,,>se 04* a,-id th--rzf--rp- L@. lias no a;ivaj-itages as a subs'6ituti-. for codalne. A new ver, c,,-,mpound, ",;as L-c,-,n -eveloped-by t,-iba. In t4.ie c an oral was about r;,@.1 tlrnes ats potcnt as oral -iorp.%Lne). Lt was i.0 as el&lfec'Live orally as rorp.!iine Is e-ubcutanqojsly in suppressino frov. 2 !:iurl,-io cbronic a,-'.-ninist ral.lon, postual,@,A.",.Cts v-ere ttul.-h Imprested by 1%*s overall szdative effectsg altliour,#!A J. tl--.ey rec-Snized It a,, Liplate-l'i-.c 2 Slncc tl,4e co;.-;pound defl.-.Itc t-.Icra:ice and physica.1 d-.pendcncc Its ad.-4iction liability would approxl:@,.ate t'lliat of Nee@I for C,,nt i -@n of t@-c ?r: ct. t',Ie chief lustl,flcalllon fo7r conti.,%-,iatio,-i of pro I.-ct Is t;lie urcent nccd for a subntit-,.-t,-, for of c-a-scs or pal:i. Az p^tiitod out above# propoxyphene no Icii'-i-izr t,-,@ be. as pro.-ii3in- as t.-t-a3 origlnally 1,.opcd. P..t t,',.c $no completely satisfaciarj s-.*bstltuto for coecin:3 for pal,-i rellef has been -found. for tL,13 reason It Is cssential to [;'url.nft the pzriod-fror!i Julv I'@60 to 30 Juna 1961 'L-le Pr-lposz to test trie cltnical ad-l"lictiv,- propzs-t2l&cs OL, a bu*.yl eater c I'll-Il'@2- all;dl;)cu- qf. phanazocine t'4'i o c.,) Lintc:@,rpart cf c!odelne 1%.ydrobro-ii.le, an aralgesic ulh*gch Is a a.nd 44.hercfore probcibly2 -;f 1,.,w sokli ction liability. In additlon, studies oj-'% other su.@.stn-.ices rcl,,ar%--Icd as potenti-,il 'Ina substli*.Utias by the Cor..nittce on Or-ag Addiction -.bid code t.',arcotics ulil be carrlcd Qulk., as advised by tl,.at bz)oy. 'L"he melhods %i3ed aro the star"ard ,.ddictl,,,Wn llablllty testi:io of t4liz Addiction Research Conter. '7'.hes-a tests are ac"ptcd as 1.-,, .7al standards the I.-cm7,itt,.,c on l@rii,3 Addiction and t4arcotic-. ard hava been described In previous project dcscrlp*%.ioist which sliculd be consulted for datalls. lz-vnlurti,)n cc Data, -valuati@,n of data has in prz;viouz projec' des-.ript-ior.s. t-t I-- nf the pro.!@ict. -.iil*l carriz:a out -in tli,,e Centat.2-, P--IS @!,.ispital, Lext-i!otor,', vy. T'.',,Is lns*,Itu*.Lon prov!,-,@-s the t-.;-, nucessary r t';Iie of to b,, lcn t:i will v,,,Il un@l.@-.rta,-,en2,. (1) pooll.c;f pat. f-r with cru,,ra, whie-*h prevents lntro-.-Iuct,un o. dmgz oti.1,4r tl,;ap. ti'ioe,-e stu;iy lintc,: ?.I tuat !,.;;n. c.,.rrict@ ->u-*. u.-,icier ti-,c dla-Lc46i.,jn of F---orris L'jLrector, A-,j@ciicti,.-n rcnter. "or Iias '--a@; f If teen years t,.f cn;@erienca In researci on narcotlc di-ag addict@,,n z-nd lluz an c--xtcnsive the field. Fi; wl-11 bv- at:sistad by twr,- ot@ier expzrie'nced pbysiclar.is, 'L@ir. He P. -frase.- anzl Dr. oj' wt,.om have 'pad extens lv,-- research In t;'li5 type 2ok' wor'l@, and many publicatl,-:)nz. of an.@i researcl,. psychol::@gist ar@@ al-.o avallablc. A spi4clail. w;ard far 1',hs crn@iuc'?, of- tiese stuaics -ias been rzadc available by tha5 hospik6al and 13 currently in )pcration. 19. costs are shown attachcu sbac Itly 111-1 'r ,r,u-nt or raqu-es&ce, is Or,!Y sliol triat Zl,-anted flscal 1-crao,@ nt:s 6 of tliz sar.-4 Acti4-.1- Cl Premlo'u.-. F-,,y (nilh4k. difftrentlal,,, hoiiday pay2 etc.) estimate and I' 13 Ur ttaca Tr a-,tI l@liscallareoua (s-appl9iess equipments atcol ,total c- Thts figure does not lnclr.-d:a cost of beco-ne c-..Cfective 19"09 cis-ic7 cost, not prcsc,.-ttl,,r -2 THIS DOCUMENT IS BEING WITHHELD IN ITS ENTMETY.