Doc 0000151766

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THE ADDICTION LIABILITIES OF SYNTIIETIC SUBSTITUT3S FOR CODEINE Harris Isbell Addiction Research Center, Lexington, Ky. NI}~ H. F. Fraser and A. Wlkler NAonr-14-60 To develop adequate synthetic substitutes codeine, f~r the opiate which is most w!de.ly used in medical practice·, and for which there is no domestic natural source·of supply. most satisfactory analgesic substitutes for codeine Th~ so far developed are ~-propoxyphene (Darvon, Lilly) and ethoheptazine (Zactlrin, Wyeth). They are substantially less addicting than codeine and neither ls subject to narcotic control but they are not as effective as codeine I in relief of pain. Two effective couf;h have suppr~ssants been discovered and· are on the l'l".arket. They are dextro methorphan, Romilar, a synthetic, and narcotine. a by- . product of opium processing. A potent synthetic anti diarrheal or constipating agent (R-1132) has also been di~covered which is effective in doses of S-10 mg three times daily. It has definite addiction liability but most probably it would be less subject to abuse than codeine. During the current year advances were made in the methodology for measuring abuse-liability of ne\v drugs. By employing a specially devised 11attitude11 questionnaire, it was found that there ls considerable variation among narcotic drugs insofar they are identified "dope" a~ a~ (opiates), and addicts express definite preferences. As an adJunct to objective measurements such an "attitude" questionnaire should be useful and simple procedure for evalunting the relative abuse liability of_new synthetics. Formerly in man, the method for evaluating drugs by direct addiction (a procedure which simulates that employed by the addict in his abuse of drugs) required from two to six months to complete. Experiments during the current year demonstrated that in the cases of morphine, codeine and heroin, a relatively high degree of tolerance and physical dependence develope these drugs arc w~en chronic~lly ad.mini!'.;tered fot only 113-20 days. Thls shortened "abusett procedure has milde it possible to cctr.pa.re the nddicticn liabilities of sevcrn.l new synthetic drugs opi:1te-lil~e ·I __ , with that of morphine in the same individuals. Addiction studies were completed on 9 new compounds. Evaluation of two of these has been submitted to the Commit~ on Drug Addiction and Narcotics, National Research Council (phenazocine and levophenacylmorphan). Both of these drugs were more ·potent than morphine in inducing morphine-like "euphoria" and behav~or and both completely substituted for morphine in addicted persons. Although definite physic~ dependence developed following chronic administratlori of both of The page is a scanned document, likely a research paper or report, with primarily typewritten text. There are two handwritten annotations: a circled number "167" in the top right quadrant and a date-like notation "B-294" in the bottom right. The text discusses synthetic substitutes for codeine, addiction, and research methodology. There are no photographs, stamps, forms, diagrams, tables, redactions, or visual evidence of experimental procedures or facilities. submitted to the Commit~ on Drug Addiction and Narcotics, National Research Council (phenazocine and levophenacylmorphan). Both of these drugs were more ·potent than morphine in inducing morphine-like "euphoria" and behav~or and both completely substituted for morphine in addicted persons. Although definite physic~ dependence developed following chronic administratlori of both of these compounds, the degree of physical dependenci was less than that observed in the case _of morphine. Their effectiveness by the oral route has been inadequately explor~ A compound related to nalorphine structurally (l-3- hydroxy-N-gamma garr.". ila-dimethylallylmorphinan) was tested for addiction liability. In postaddicts, its effects resemble those of morphine, rather than nalorphine and therefore it has no advantages a3 a substitute for codeine. A new very pot~nt compound, 1-(Beta-d!ethylamlnoethyl)~ 2-( p-ethoxy-ben zyl) "'!-.5-nl t robenzimi4azole me thane sulfonate, has been developed Clba. In the euphoriant dose, ~y man~ on oral administration, was about 0.25 mg (d0-120 times as potent as oral morphine). It was 60 times as effective orally as ~orphine is subcutaneously in suppressing abstinence !rom morphine •. During chronic administration, postaddicts were much impressed by its overall sedative effects, although they recognized.it as opiate-like. Since the compound Induces definite tolerance and physical dependence its addiction liabili~y would approximate that of morphine. PLM{S FOR FUTURE Studies on several compounds have been completed and these will be prepared for publication. New drugs to be studied are (a) a butyl ester of R-1132 (the antidiarrheal asent), {b) the methyl analogue of phenazocine (the counter part of codeine in this series) and (c). l-3-hydroxy-N propargyl-morph!nan hydrobromide, an. anaTgesic which is a morphine antagonist, and hence probably of lo'J addiction llab!llty. From the long-range point of view it is intended to continue the search for substitutes for codeine until drugs are found which are, -in the opinion of.·the CoiTL11ittee on Drug Addiction and Narcotics, completely satisfactory substitutes for codeine. CURRENT REPORTS AND PUBLICATIONS (a) H. F. Fraser and Harris Isbell (1959), "Addiction liabilities of (a) dl-2'-Hydroxy-5,9-dimethyl-2 (phenethyl)- 6,7-benzmorphan HBr\NIH-7.519), and (b) 1-3-Hydroxy-N phena.cylmorphinan methane sulfonate (NIH-:7525)." Addendum J, Min. 20th Meet., Corr.mittee on Drug Addiction and Narcotics, Nat. Res. Council. Washington, .. D.C. Natl. Acad. Sci • A.) W"' (Pro~~ct D~ncrlptlon) No. NR 101-14? Tas~ Co:\t.ract. NAonr-lb-60 ..." ~ Sine~ 1751 the !h1.t!onal ln$tltut.~ of r,.!~ntal Health. J A:J.,Hcti on H~s'Zarch C~p-t.cr, U. S~ Publ:lc H.:al th Se rv! Ci.! Hcspi tal, . . ' t.exlnnton, Ry., ha~ ' teen earry!ng on The page is entirely text-based, resembling a typed report. There are no photographs, diagrams, or forms. There are no official stamps or markings visible. However, there is handwritten marginalia in the lower right corner, appearing to be a page number or document identifier: "B-293". The content discusses scientific research on morphine and other compounds, which might indicate the nature of the experiments or subjects without explicit visual evidence. D.C. Natl. Acad. Sci • A.) W"' (Pro~~ct D~ncrlptlon) No. NR 101-14? Tas~ Co:\t.ract. NAonr-lb-60 ..." ~ Sine~ 1751 the !h1.t!onal ln$tltut.~ of r,.!~ntal Health. J A:J.,Hcti on H~s'Zarch C~p-t.cr, U. S~ Publ:lc H.:al th Se rv! Ci.! Hcspi tal, . . ' t.exlnnton, Ry., ha~ ' teen earry!ng on a proJ~ct dcs1gnod t.o · develop a~1nthut!c ~ubst!tute fer coclc!n~ which would be us safe as eode!na and ns ~fiective \-Ji th 4esp~ct to tox1c1 t.y, nntltussiv~ cetivity, ccristlpat!ve act1vlty, and addiction 11~1::111 ty. 11Hz project hn~ been financed in larGe p<i.rt by funds from the 0!!1cc ot Naval RGt;earcn, and t.h1s d~!Jcrtptlnn ecnstitu~es n request !or rene~al of the proj~ct !~r the par1od 1 July t960 to 30 June 1961. The project \-res 1nit.lated because ~ynth3tic suhst.ltut.es for codeine were tau_ly· r.~<;Jed nlnc~ oplum or tnorphlna ~er!v~d. from O?lum constttut~ the only sources of ~odc!ne. Cod~lne is tha nm~t vt de ly ut;cd narcotJ c drug ln both c1v111an an<! mil 1 t:1ry sn~dical !)f'~cttce. Th.a Unitt}d Stst11n consurcc:S 16 to 20 tons ~r t.h1s drug y~arly ao that., unlt1S$ adequate synth~t.lc subst.itut~s ar~ foundi the nation mu$t. c-ont.!n_?e t.o stoeY.pllo opium or mot"phin0 ·'- ln to supplies for both the civil1an orJ~r pra~idd a~equate or and 1:11lit.. Clry population ln tha avent. \lal'". 1!16 rn.cillti~s ot the Nlr-11 Adulctton f\asearch Canter e.r~;: not. sufflciit!nt lo carry out thls.work_ in addition to the o! potent n<.!w ~valuation nnalg~s1cs subml tt~Zd by the C~r:~ml tt.ce on Crug Addicttcn anu l~'-rcot.i cs._, !'lat!on:ll P.esell:"Ch Council, unless u-idl tlanal ft.lnd.s a-rc su?pll~d through \.he D;;pa'rtm~nt. o! Du!enst:. . :t J\-c .. -t""' 2 • !..,:~.:,... ,r•h:. J'\t,. ..., . o : .. t-!· n11. v ,. 1 ~ .. - . " ~ - - .. · .. ., r ... · I .. t . - . " • '- _ .. . _ . •: . . The r.l·:lSt satls-factcry anal_gealc ·stlbstituter; fer c:od.~lne so far devcl;:p~d are ,!!-propo:cyphene (narvon, J..ill)r) and ethotcptn4:ln~ ( Za#ct.l r! n, h.'yeth). ~ey ar.: substantl o.lly lass addlctina codeine nnd nalther is subJect to narcotic ~mn control but they are as as ln nc~ ~r!cct1v~ ccde!n~ r~l!cf Rt:r.nilar, a :ynt~•etlc, and narcotine, a by-product. o! oplu:n .:a prcc~ssl ng. A pot~nt synthe tlc anti arr!1ca1 ot" constlpatin-J agent (R-11;2) has also which is effective be~n dl~covGrsd . ' 1n cos~s ar S-lo mg t.hra~ narcotic ~mn control but they are as as ln nc~ ~r!cct1v~ ccde!n~ r~l!cf Rt:r.nilar, a :ynt~•etlc, and narcotine, a by-product. o! oplu:n .:a prcc~ssl ng. A pot~nt synthe tlc anti arr!1ca1 ot" constlpatin-J agent (R-11;2) has also which is effective be~n dl~covGrsd . ' 1n cos~s ar S-lo mg t.hra~ t1r.:as dally. l t ::as cle!ln! t~ aa~1ct1nn 11a~1l1ty but r.~st probably it would be less $Ubject to than ccdelne. abu~a During the curr~nt ,year auvnnccs ucrc ::-:ada 1n the mr:thodol ogy for :ncasuring abuae-liabil i ty of n<::'t/ t.l.rugs. By /J-2V - ~·-· . -\ -~ -·-· !ountl tL:a.t. t.hcrt: ls cons1darilble varlat.lon a:::)ng narcotic ~an drug$ 1n~of3r as U1~y arc ldcntltlad a$ "dopa" (opiat.as), anu addicts Gxprcss As un ndjunct to dc!tnlt~ preferenc~s. . such an obj~ctlve n~asurements "attttu~e" quusttonnalr~ snculcl be useful nnd sicple proccuure tcr cvaluatlr.~ th~ r~latlv~ a~sc l!a!Jility of n-ew nynt!"~ctics. For.:1{:rly in ~.an, tha r.~ethou !or evaluat_ . l ng dru~!S by direct nL!;;!lctio~ (a procc .. !ur~ . . during tr.c: curr~nt year de~nstrn.ted that ln the caces of / morpbin;, Ct)Culntz·and. heroin, a ralativ~ly high degree o1~ tolerance physical dcpendenco when nn~ ccvclo~ th~se d~~gs are cl~ronically acn~nistarcc !or only lt-20 uays. This shortened "abusen proccdur~ ha!l mad~ 1 t po~s!ble to co~pa.re:· the llabtl!tlcs cf szvcral synthetic op1ats- ~duiction n~~ 1U•e drugs with that. or tt..:>rphin2 In· tha s·a-ne Individuals. completcu on 9 compounds. Adu1c~n studl~s ~~re n~w Evnluaticn of o! ttssu submitted to the t~ ha~ b~an Coomltt~e .. on Orng Addiction and. llarcot!es. National Hesr.:arch Coanc! 1 were mon:: potent Uu~n morph!ne in Inducing !!:.!).t"?~line-11!-t~ ~~uphoria" nnd behavior ~~d both cornplet~ly ~~stituteu • for ln addicted Although deflnita physical morphln~ p~r$ons. depen~cn~e d~veloped follo~Jng chronic a~mtnlstrat!on of both of thase co~pounds, lho dogrue of physical dependence wa~ leeS! than t!1at. obscrvad in th~ ca:;a o! morphine. A cor~poun;J related t.o nalorphin>l strt.lclurally {l-3- 'I for u-.rJict!m1 l!~bllt,ty. ln p~st.aJ.J.lcts, !ts effects r~st=.;:ible th,.>se oi mo.rph!na) ra.t.h>:~ ·than ~!!lor;?t·:in~ a ..n u A new ver.J potent compounJ,. 1-(Beta-r!lcthylnr.tinoetb:;l}- 2-(p-othnxy-benzyl)-5-n!tra.benziml::iazole methan~ sulf';)nat.e, mv on oral acminlstratlon. was about 0.25 (G0-120 tlm~s as pot;nt ns oral morphine). tt was to tl~~s as ~ffectlve orally as morp.h!ne 1 s $ubcutani.lou3ly ln SU?prczssin!J ab3tlnencc from morp~11ne. "During chronic a~~11nlstrat1on, postacdicts th~y reccgn!z~d lt as oplate-liiic~ Sine~ the compound lnduc~s definite tclcrancc and phys!cn~ eependencc !ts addicti·:m linbll i ty ~~ould npproxt:-;;ate that ot The document is a typewritten page with handwritten annotations. At the top, "6)(3)" is written in parentheses and appears to be a marker or identifier. Below the main text, a handwritten notation "B-292" is visible in the bottom right corner. There are no photographs, diagrams, forms, tables, or visual evidence of experimental procedures. The text itself discusses the addiction liability of synthetic substitutes for codeine and a project renewal request. The document page displays typed text with the heading "Page 2". There are no photographs, forms, diagrams, tables, or visual evidence of experimental procedures. However, there are several handwritten annotations. In the top right corner, there are two sets of curved black marks, possibly from a staple remover. A handwritten annotation "B-29/" is present in the bottom right corner. There are also several small, scattered black dots, likely ink or toner marks, throughout the page. The text itself appears to discuss the development of new drugs and their properties. tlm~s as pot;nt ns oral morphine). tt was to tl~~s as ~ffectlve orally as morp.h!ne 1 s $ubcutani.lou3ly ln SU?prczssin!J ab3tlnencc from morp~11ne. "During chronic a~~11nlstrat1on, postacdicts th~y reccgn!z~d lt as oplate-liiic~ Sine~ the compound lnduc~s definite tclcrancc and phys!cn~ eependencc !ts addicti·:m linbll i ty ~~ould npproxt:-;;ate that ot ~·:~rph1na ,... ,. Need for of the c~~t!nuation ?r~1cct. At prc~ent, u~e chi~! Justification tor continuation oi' t.~.G or pro J:;ct J n t.hcJ urg6nt. need !or u suboti tu ta !or rc ll~Zf -:::! 1 d of pain. A!; pollitQu out shove, no lonnl.!r g:-a~~s propoxyphen~ s~\!r~ to be· a:: pror.11s1na as \.ta3 ori gin:1ll:l hopad. At the r.;orl'.::nt no completely satis!actorJ sub~tttat~ fer coGeino for pain relief has besn ~found. for t.t!l' re:1son lt. 1=- essential tc Durino the p\!rio-d .from t~ July 1~(;0 to 30 Juncr 19f-l ~.. .. 1:1e: prcp~sz t.o test tt;:z clinical pf-.ar:-,..'lc~t(~!r.>' and ad..llcttvc ( propart!cs of oil butyl/ e!$t~r cf R--11;~ l-(3-cilpi~en:;l•J• car~cn! tl"i l-propyl) -4-ph~nyl•lJ,..-<:llrbethOX".Jpiperl d.i n~}; lhe / tr.ethy! analogu-e q! phenazocine ( t~;.: cnuntr~rpsrt c! c~.Jetne - In this series), and 1-3-hydroxy-!1-prcpargyl-nv"rph!n::tn and thcrui'or~ probably of low sf.ldlctlon l!nl::Lllly. In au~it!cn, studl~s or other r.ubst~~ces regar~c~ ns potential codelns substltut~s by the Comnlttce on D~~G AJdlction fuid t1arcot!cs \Jill b~ carrlcd out., tlS actv!seu by that buay. The rr:e L~od.a used aro th~ standard adci ctl. ~·n 1 i eb!l! ty Addiction and Narcotics and ~avo been d~scrihed ln prcvlou~ project. tl~!lcr!ptions, which should be: consult~d to:- details. or data has covered in ~valuatl~n be~n przv!ou~ proJ~ct dascript.ions. - 7• L~cat!~n ~r the ProJnct. C~nt.er-, PHS Hnspltal_. Le~!n~ton·, f.y. Th!s institution provi~~s . . ox~criQ~nts with c~ugs, m!c (2) str1~~ environ~cntal c~ntrol, 'dhich pr2vents lntro:iuctl.:.m J.n:s;s those unoer (}f oth~r t~:an ;' study into t~~i! ~x.~ri::1~ntal $1 tua.t!~n. ":::~nr~ wl t 1 b~ c_arric0. out uncler tbc dlr~ctLJn o! Harrl s lsbcll. H.D., D1r(:ctor, tn;:,a Ado.ict.l~.m fZellearch Center • . on narcotic dr".IO aualctbn and ha:l an c::xtcnslve bibliography 1r. th~ f1eld. H~ ~111 b~ a~slgtad by two other experi~nced pharoocologist, and research at's o.lso avallnblc. psychol~gist A sp>i:cial wnrd !or the c:-nu.uct o!· th~s~ studies has been mad•z __ available by th~ hospital nnd Is curr~ntly in op~rat!on. n·~c cst.1cated costs aril shown en. t.ll\: attache.! sheet.. 'I'll~ acount o! non_ey requ!!st.~d. is cr.ly sli9htly higher than ~ that.. gr~u~ted f~r ftscn.l ye~r l~j(;J, the di!fer\.-nc:c: ra~r~s~ntlng 1-\b This declassified CIA document page contains printed text and handwritten annotations. The text discusses variations in narcotic drug identification and addict preferences, and the process of evaluating the abuse liability of new synthetic drugs. There are no photographs, diagrams, tables, or forms visible on this page. The only handwritten markings are the page number "3" at the top right and a notation "B-290" at the bottom right. There are no official stamps or redactions present. wnrd !or the c:-nu.uct o!· th~s~ studies has been mad•z __ available by th~ hospital nnd Is curr~ntly in op~rat!on. n·~c cst.1cated costs aril shown en. t.ll\: attache.! sheet.. 'I'll~ acount o! non_ey requ!!st.~d. is cr.ly sli9htly higher than ~ that.. gr~u~ted f~r ftscn.l ye~r l~j(;J, the di!fer\.-nc:c: ra~r~s~ntlng 1-\b r al-. am ~ . .. ~ i h 1 ~ r , H • !J • ActinG vi r·~ctor 12 Nov.z:nb<?r fJ-~ .. '· ! C!tlr"k-stcnocl'"n?1ler (QS .. 4) tAR~ . ~... .-. ~ -~ Prem!uQ Pay {ntght different!a1, -/ holiday pay etc.) est.imnta 1 I ..... Rstiretnent·a.nd lusurtU\c~· Travel 3· Mls<:allaneous. (supplies:t cquip:ne..-.t.$ et.c.·} Tot.:1l ~. or G This figure does not 1neludz cost H\!sl th Lnsur~'"lca, to heco.ne effective 1 .1tl!y 1960 !:lnee cost not presently 51 kn-o~~l. ·• - ·.·'. \ . / -~ ~I'~ THIS DOCUMENT !S BEING WITHHELD !N ITS ENTlR ET Y. :J •. --.. -7-.~---11:':: --.:-;··· -=:_· ... ''." ........... ~ -~-·. . :. .: : .i -·. . .~-~-~(~;~~-.• "-· __ - .. • .. ;':,. -~ ~;! .:_,:·· ::·~: . ' '·.<· -·, ..· _.:-.· .·,_·;:.··.··_:·_-.·., ·. . : _··.:.~.--·-.~~:· . · ·. ~ . · .- . -- :-_.··.~-~~--.-~.-~~ . -- . _ :-.·~.·.-·.=.-_··_.·.-·.~.-.·.:'.·.·.·.~_· :·.·.-.~---,·-~.~_-~-" ~.-,;.~.~:~'-.·.•.--:-~e:·;"·~.;...~..:; .:-._··._:~·~.·-·:"':·:_·_~-.--.·~--~·.·_-:_.~__ ·.~.--.··.·,.~:.~,··.·:····: ·:.... : ~ .- - ;::.-: . . . ~ , i i ~ : ' ) : - < ~·. · ·. . ~ ...... -:-.. . -· . - :~-~~ - -· . ; .. . . - , ..... { : · ~ . ~ , --.- - ~ - : ~. ~ : ~ ~ ·. :. : : . .: : ~ . ·- _ .: . . ; .· : 1 · 0· " - - '· · ·.· •. _' =·_ . :~ . _ - . . : ~ _ ~ ._ .: ___ . _-; . _ . - . . . - . ~ . i . .~ :.·_--~.; - .~ - -'! - 0~ - ----~-=-.,··.·,;~ - ~---·.·_: · '_ · :_ · ·. . - : ·· · · ~ . . " ~ !: ~ :- f .: · ·. · ~. . -! :. : - .... ~ . ; · .;_ : ; · .-: .:.j: . .•J _, __ ~, ~ ·.. ·-.-.... - ~ ... --.. _.__ : The page is a typed document with some handwritten additions. "Page 4" is printed at the top right. Towards the bottom, the text notes "3. Need for Continuation of the Project." Below this, a handwritten annotation "B-289" is visible in the bottom right corner. There are no photographs, diagrams, forms, stamps, or redacted content present on this page. The document appears to be a research paper or report discussing drug effects and potential applications. ~ . . " ~ !: ~ :- f .: · ·. · ~. . -! :. : - .... ~ . ; · .;_ : ; · .-: .:.j: . .•J _, __ ~, ~ ·.. ·-.-.... - ~ ... --.. _.__ : This image appears to be a scanned document page, featuring typed text. There are no photographs, diagrams, stamps, forms, or redacted content visible. The only non-typed visual elements are handwritten annotations: a page number in the top right corner "Page 5", and a code "B-288" in the bottom right corner. The text appears to be a research proposal or report section, detailing proposed work and methods related to drug testing and addiction liability. The document is a typed page with handwritten annotations, including a page number "6" and a handwritten identifier "B-287" in the bottom right corner. The text discusses the evaluation of data, location of a project at PHS Hospital in Lexington, KY, and the experimental personnel involved. There are no photographs, diagrams, forms, tables, or obvious redactions visible on this page. The overall appearance is that of a standard research report or project description. This document page contains typed text with some handwritten annotations and stamps. A page number "Page 7" is visible at the top right. Below that, a heading "Estimated Cost" is present. The main body of the text discusses cost estimations and fiscal year figures. Handwritten annotations include "Attachment", a date "12 November 1959", and a signature "Abraham Wikler, M.D. Acting Director". At the bottom right, there is a handwritten mark and a stamped or handwritten identifier "B-286". There are no images, diagrams, organizational charts, forms with filled-in fields, or visual evidence of experimental procedures. The document is a typed list of expenses, likely part of a budget. It includes items such as "Personal Services" with categories like "Medical Aldes," "Psychologist," and "Clerk-stenographer," followed by numerical figures and cost estimates represented by horizontal lines. There are also lines for "Travel," "Miscellaneous," and "Total." A handwritten annotation in the bottom right corner reads "B-285." A note at the bottom clarifies that the figure does not include the cost of Health Insurance. The document is dated "10 November 1959." The page is mostly blank, with a single line of text stating "THIS DOCUMENT IS BEING WITHHELD IN ITS ENTIRETY." To the left of this text, there is a handwritten annotation that appears to be "# 168". There are also three circular ink marks in the upper left corner of the page. The rest of the page is clean, with no other visible markings, photographs, stamps, forms, diagrams, or evidence of experimental procedures.