A l@'-I\ T UL P F, O,TREQ@S REPO.RT Plepo7.tPrepared'my: A:orahamWikler, 1 Llllay 1960 For th-a Period: I November 19'08 to 1 Ma-y 19'00 1,TR: 101:149 COITTi-@ACT: NAo'nr-14-60 2 AM@'JAL RATE: CONTI.:@.ACTOR: -U. S. Public Health Service Nation-al L-isti@aite of @flental Health Bethesda 14, '.-.1,Al-@.ryland (Inquiries concerm'ng finances and contra.&, should be sent to this add.-e2ss. Inquiries about technical ivo.-k should be sent to address below). Director, NMfZd Addiction IZP-sea@rch Center USPHS Hospital Le@dnc.ton, Kentuclcy PP.INCIPAL IiNVES.LIGATO'2-R: Harris Isbell, M. D. A-sist@.nts: H. F. Fraser -.0 M. D. Abraliain Wilcler, M. D. C. R. Logan G. D. Van Horn 0. A. Kelly 0 W. -v"elch M. L. Glass C. R. Bro-vin R. Mosc- R. Co@-@ J. S I Pace TITLE OF PROTECT: Addiction Liabilities of Synthetic Substitutes for Codeine. Objectives: To find a synthetic analgesic and anutussive drug which would be as safe as codeine with regard to tomcity and addiction liability. ABSTRACT (OR SULU,,,@.Y) OF RESULTS: 2 a. Since start of Droject: Sd@a annual re-corts for 1952 through 1958. b. Durincr the curre,.it re-oortincr- Period: Continued from the period covered by Annual P.-ogress Report for I November 1957,-l November 1958, were the following investiga-tions: 1. d Methadone. The results of studies on this drug indicate that alt2hough it possesses low abuse lia:oility, it can produce toxic effects on chronic administration in high doses. At non-toxic dose levels it may be useful as a su@z)stitute for codeine as an antidiarrheal agent. I's analgesic potency kopears to be very low, wb-Ue its antitussive activity has no%-, been investigated adequately. 2. 1-(3-Di-ohenyl-3-carbo0nitril-pro-o771)-4 -Dhenvl-4 carbethox7- T)I-peridine (R-1132, Dioheno.@-,Vlate). Further studies revealed that while subcutaneous doses of 10-50 mg did not produce significant effects in postaddicts, intravenous doses in this range did produce definite morphine- like changes in behavior. These observations, as well as the results of "direct addiction" studies confirm the o-Dinion previously ex-oressed, that this compound does possess addictive properties, but the order of it,- abuse liability Is somewhat less than that of codeine. It is anticipated that R-1132 will be marketed in the near future as an araddiarrheal agent. 3. Metabolism of i,Tor--rnor2t)h.i.n.--n. Furthe.- studies were made to determine the nature o@ the conj-Lg,,,.ted form of urinarj normorp-bine. Ff-n-sults thus far i.?i-dicat,"@,,@hat this form is not a gli-leuronide nor a..'l ethereal sulfate. Studies on postaddicts were completed on nine ne,2-,z compounds. Of these, seven were found to rossess abuse liability comparable to that of morphine, and therefore to be unsuitable as substitutes for codeine. 1. 3-Hydrox7,-;-N-phenac,7@lmorDb-in-,,.-i met.',,@ne sulfo.,i-ate (1,4-IH-75IL5, LevoT)henacylmorphan)2. The eu-,o.',-iorogenic and morphine aostinence- suppressing potency of this compound is about ten times that of morphine, though the intensiiy @of the abstinence syndrome in "direct addiction" studies was somewhat less. -31 2. !@L-2'-Hydrox7-5,gdimethyl-2(2--ohenethyl)-8,7benzmorphan EBr (iNM-7Zl9, Phenazociiie). Euphoria, equivalent to 20-30 mg of morphine (subcut'aneously) is produced by 3-4 mg of this dx-@g by t.@ie same route. With respect to supt)ression of morpliine-a7z>slinence phenomena, 1 mg of this compound is equivalent to 8. 1 mg of morphine (in strikirg contrast to r-asultz@ obtained by others in the monkey, which indicated thp-t it was only one-sixth as potent as morphine in this regard), though the intensity of the abstinence syndrome in "dire.--t addiction" studiesvras s,omewhat less than tliat of morphine.2 3- Et-1171 4-,.ohen, ,11-1 E3(-pheTi7lamino)-Dro-,ovlal-4--oineridine carb la@,e ethane @-z@onate (NIH-75--'O). In doses of 15-9-0 mg this drug produces euphoria equivalent to 20-30 mg of morphine, and is about twice as potent as morphine in sup ressincr morp2hine-absU.-.ence phenomena. p 4. 1-(Beta-diethyl,,-w-inoethvl)-2-foenzyl-4-c.@iloro)-5-nit--?-obenzimi- dazole (ITI-H-7586). In oral doses of 100 rn-a this drug produces euph-ori.-o. and 2.62 mg are equivalent to I mg of morphine in suppressing mor7phine- abstine,,ice phenomena. 5. 1-(B(ita-dietb-vl-cl-minoethyl)-2-(-;D-ethoxvbenzvl)-5-nitrobenzimi.@ dazole methane sulfonati-, (ZTIH-7607). On oral administration this compound is 80-120 times as potert as morphine in eup.qorogenic potency, and about 60 times as effective as morphine in suppressing2 morphine- abstinence pher-c@'mena. After "direct addiction" to this drug, the inte.,isity of the abstinence syndron;,-5 is comparable to that, of morphine. 6. 1--3-F,.vdrox-7-@@T (-313-dimeth-,71?.Ilvl): mo,-.Ohinan HBr The potency of this drug) with respect both to its euphoroge2nic and morphine abstinence-suppressing activity, is comparable to that of morpi@ir,,,,. 7. N-(2-E(Meth7l)-phenet@h7la-mino,3--oro-o7l)--oL-o-oioanUide (LNM. 1- 7 ri @O 3 Diam-oromid . TIL-LougIf'its duration of action is much @hort--r (two to thrae hours), this compound 5produces euphoria in doses of 75 mg subcutaneously equivalent to Lliat of 20 mg of morphine, @nd at daily dose levels of 625 or 750 mg (in four divided doses per day),, it substitutes adequately for morphine in suppressing morphina.-a@bstinence phenomena, for the relatively short period of Its action. Two other new compounds proved to have considerably less abuse- liability than morphine: 1. D-3-@i,)Ietho@w-N--ohenethylmorph,:nan (=-7296A). This compound was inveq-tigated for theoretical reasons. In singld doses on oral administration, up to 1, 000 n:@q did not produce eu-Dhoria consistently, though 3 of 4 subjects rerorted mo=hine-like effects while receiving 500 mcj four times daily. It app,-z'ars to be aboli@6 1/25th as potent as morphine in sup.Dre---sing morphine-absunence phenomena, and in "direct addiction" studies at daily dose levels equivalent to-48 n-ig of morphine, no abstinence phenomena were obse2rved. T@owever,, there is no evidence at pre-sent that this compound will be useful clinically. 2. N-(l-Methvl-2--oi-o--ridinoethyl)-pro-oloanilide . Ecl (iN=-7602. Phenam-oromid). In single doses subcutaneously, this compound produces definite morphine-lil-ce effects, and at daily dose levels of 1135 r,-)g (in three 2 equally divided doses per day), it suppresses morphino-abst,.nence phenomena partially. However, at such levels, disturbing side-effects occurred which were compared by the subjects to those of d-lysergic acid diethylamide (LSD-25), cocaine or marihuana. For this reason, and also because it does possess definite abuse liability, it is not I i kely th,,-,t 5 this compound will prove to be an adequ%te substitute for codeine. -r-aga 7 Currently under ini7estigation are three other nev-i compounds differin- basically in chemical structure from both the opiate derivatives and synthetic analgesics studied heretofore. 1-tp-Chlor-phenethyl)-2-m--t2hyl- 6, 7-dimetb-oxy-l, 2,3, 4-tetrahydro-isoquiroUne Hcl (.L\TM-7672A) has been found in preliminary clinical trials elsewhere to exm-rt analuesic effects in MaLl compar,;-,bl-- to thoseol cod@,-iiib, and in mon?,.-ys it does not suppresz-) morphine-a:.os,6in2ence phenomena. 2-(Beta-hydroxy-_ohenethyla=iino)-pyridl:--ie Hel (Phenyrarnidol) a-:id N-Isopropy-1-2-meL'iyl-2-propyl-1, 3-propanediol dicarbamate (@arisoprodol) are currently martc--t,--d as "rauscle rela.-,-antslt (ascrib,-od to internuncial blo%--tdng a2&,ivity) and are said to reliev,-n certain types of pain. At present the data obt-ained in addictive studies on pos-L- addicts are insufficient to warrari,4, rt-ateme-.,its a:oout their ecouse li;a:buities. In addition, studies of a basic m(athodolocn-cal nature were made during the period of 2the present report to improve staridards of comr)arison of abus,-, liability of new compounds primarily L-i,@.ended for oral admL-li---t.-at,.on with that of morphine. The results indicate respect to suppr.-ssion of morphine abstinence phenomena, 1 mg of morphine qubcutaneously is equivale,.7it to 2.86 mg of morphine orally, 14. 7 mg of codeine orally, and 35 mg of d-propoxyohene orally. PLAI,r@;) FOR',.@7JTU.1@E Iiiamediate: Studies on the addiction liabilities of IM,1-7672A., phenyramidol a.,,id. carisoprodol will be completed. In addition,, similar studies will be made on a butyl ester of R-1132, the methyl analogue of ph--nazo2cine (tl@.e-@count--rpart of codeine in this series), and on 1-3-Hyd.,-o.-.7. N-proparcTIl-morpbinan l@@drobromide (1@.M--6045), an anal-aesic which is. a mor-ohine-anl,.agorist, and h,--,nce probably of low addiction liability. Long Range: rphe search will be continu2ed for synt,.@.,c-tic compounds with t'-,iera-olm . -utic proper-Li es similar to tho of codeine v-;hich, in t-lie opinion of the Committee on Drug Addiction and Narcotics, are com-olel'.--ly satisfactory subedtutes' for codeine. R.VPCRTS Ai%D PUBLICA-TIONTS (during the c2urre,-.t r,-mport period). 1. Fraser, E. F. and Isbell,, H.: Addietion Liabilities of (a) dl -21 - Hydrox-y-5, 9-dimethyl-2(2-phenethyl) -6, 7-benzmorphan HBr and (b).1-3-Hydro.V-T-\T-phenacylmor-o-hu= methane Sul-.-'onate ('iTEd-752-0). Adder0ldiiTr 3, 1,,-Tin, 20th Meet., Comm. on Drug Addiction a.-,id ',',Tarcotics, Natl. P,,es. Council, WashL-i,,rton, D. C. Natl. Acad. Sci. (Ian.) 1959. Page 0 2. Fras.er, H. F., Isbell, H. and Van Horn, G. D.: F-=an Pharma- cology and Addiction Liability of Noreodeine. -T. Pha=acol. & Exper. Therap. (in --Dress).' 3. Fraser, H. F. and Isbell, H. .- Pha '=acology and Addiction Liability of dl- and d-propomjphene.2 Bull. on rlarcotics, 12: (1) in press. 4. Fraser, H. F. and Isbell H. : H-aman Phar,-nacology and Addic- tiveness of Ethyl 1-(3-Cyu-=' -3,3-phenylpropyl)-4-phenyl-4-pioericU-ne carbo-.,cylate hydrochloride (R-113"4", -Diphenox7lat.-I). Bull. on 'i\Tarcotics (in press2). 5. Fraser, H. F. , L-be.U., H. and Wolbach, A. B. : Addicuveness of New Synthetic Analgestcs. I. Benzimidazole DeriVpt4VeS: (,a) 1-(Beta- diethylaminoet-hyl)-2-fo--n,-,yl-4-chloro)-5-nit.-obenzimidazole (NIH-7586, ARC-II-G-1), (b) 1-(Beta-diethylamin,)ethy2l)-2-(p-ethoxybenzyl)-5-nitro- benzimidazole methane sulfonate (NEH-7607, ARC I-G-2). II. I-)-3-Hydro7.-y- N-(3,3-diraethylallyl)-morphinan hydrobromid.- (NM-7446, ARC I-B-19), IIL N-(l-iVethyl-2-piperidiroetiyl)-propicanilide hydrochloride (Ph,-:n,"lm- 2 promid, hTIH-7602, tLRC I-1-1 and, N-E2-(E.LMethyl3-phenetliiyl,.lmino)-propyll -propioa-.iUid-- sulfate (Diampromid, NIH-7603, ARC-I-J'-I,I. Addendum,, 21st.LVieet. , Cornrn. on Drtig Addiction and T.\Tarcoties, N,,-4tl. R.-s. Council, 0 WashLngto.-,i, D. C. ITatl. Acad. Sci. (!an.) 1960. age 10 6i Fraser, H. F. and Isbell, H.: Human Pharmacology and Addiction Liabilities of '-Dhenazocine (dl -21-Hydroxy-5, 9-dimethyl-2-(2- phenethyl)-6,7-be=morphan HBr, l@M-7519) and Levophenacylmorph-%,-l (1-3-Hydroxy-N-phena2cylmorphinan methane sulfonate, NIE-7525). Bull., ress. on ITarcotics, 12: (2) in P' 7. Fras.-Ir, H. F., Van Horn, C- D. Martin, W. a and Isbell, H.: New Methods.Lor Evaluating Addicl-6io ,i Liability of Morphine-Like Drugs. I. Attitude 6f Opiate Addicts Towards Drugs. II. Short-Term Dir,-oct 2 Addiction Procedure. 1,,Ton-quotable Section, IEln. 21st Meet., Comm. on Drug Addiction and Narcotics, Natl-. Res. Council, Washington, D. C. ITatl. Acad. Sci. (.Tan.) 1960. Abraham Wikler, M.D. Acting Director (Vice Harris Is7oell, M.D.) 7 2,