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TITLE CF PRCjECT: AAdletlon LiabilItles of Syathetlc Substltutes fur Coleine..

Colective. To find & cyathetic analcesic snd antituzsive drug whlch sculd ta as sofe fron the polnt of view of tcxlclty and addtctloa llabllity as ls codelne.

SUAARY GF PESULTS

I. Since Start cf Prolect. This portlon of the suemary covers the perlod froa 1:July 175l to 31 December 195o. As stated above, the cbjectlve of ths prujeet ls tu find e synthetlc drug whlch eculd be as efiective and as saia fron tha polnt of vicw cf hucan icslclty end addlctlvs pr\~pertics as is codaine. Althoüch adequate syathatis susstltuies fur morphlne ars avellabie, such a cctelae substliutc is ncadad basauie no slagle drug whlch wculd comoletely roplaca codalne ts kreva. Savanty-flve per cent of tha ccuntry's neads are fsr drugs of the ccdeine type taibar thn for drvgs af the moroblne tyae. Thls means that the Ualted States must contlnus to stcckplle colum yntll adequota substltuies for codelne have beea devetczed. Tha Fela ef tha Niiti Addieitet Pesserch Senrer Ia thls lavetilcatios ccnslsts of thz dctepmiaatien oi the acdiciive srocertlas sf nes drurs. The cvaloation of tha aaalcesle end ontlfusslve sfieets ss welt as af cllnical t xlolty must necessarlly be made clsewharec.

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Tha actheds usad fcr stuéyins the eldlatlea liebilltles af. aex oaalceclci have been deserlted la detail ls tha roject dascriufions and la prevleus arorress repurts. and ellt net ba repaated.

Durino the oarled 1 july 1o51 to 31 Decaabar 195S. 05 drugs or mixtures oi drucs hova beas feated. Fer detalled Infcraatlcn cunceruing these substances see Annual Repcrts icr 1954 and 1955. Amcag thsse drvgt, tuo substances ehlch appeer to.ba cutsiandlng 4s posslble scbstitutes fcr codelae for auppressica of ccugh vere fcundt

111 D-3=ethexyvhetbvlaorphlsan. (deztrcmathorphos1.
(2) tarectine.

Clinlcel reoorts ccstlave ts fadicate. that cczirenethorpen is an aatiivssive sccnt ci sce velie. Since lt is laus tohio than cudelne end cossesses no dddicilao Hlebitlty it soams a very aaiisiscfury ecdelne substltute fcr antlfuaslve auracsgs. It Is alreedy evallabie and os calc to the Umlted Slstea. Nercctteg. ahich is not a synthetle drug, would gxtead tho nerpatig sunnly tineg it hs berrtefoee heen e rasis eduet 5 cptun.. Rgnurts of cllsical trials vlth narcotias are net as yat 8v311.b14.

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tn the last report we pointat cut that, although the procrcm had develobed tao drugs which aopeared ta. be potentlally useful codelae substitutes for suppresslen of cough, ao compouad was avallable icr relief of alld grades of paln whlch was as safe as codelne, aad seven drugs vith svma passlbility as potentlal cudelne substltutes sere llsted. Report for 1955 elso ccnteined laicrmattoa concernlng elohar dl-2-Pr9plonuxye4=dlmethylamlno-1,2-dloheny1-3-mcthvlbutane Ipropoxyphensl. Frellalnery clinlcsl trtals contlaus to Indicate that both the racenets and the dextrcrotatory iscmer of thls compound are es cffective as codelae ln rulleving mlld grades of paln. The addietive prcperties of these subatonces are qulte lqui Addicts could act inject thea readlly becauss cf the lorce dose requlred and beccuse they have scvere irrltant propertles.  Ehen taken craliyy they do no? Induce a full spectrua of morphine-llke subjcetlve effects. While In a vary high dcse they guzpress abstineace fram morohine ollghtly, they do aot craata a slcnlficant degree of addictien mhea adintstered to.oeracns not physicaily devenzent ca morphiag. They, thereiore, are very proaisiag subsfltutes for codzins ir relie? ci vain, but further data ca efflcecy sod tuxialty cust be cbtalned frun clinicil trlels bei.re a decislon is made that thay weuld be ccapietely satisfactury Codsinc substitutac.

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2. Results Durlno. the Current Reoortiac Perlud. Durlag the current raporting perlod ll Janvory to 3i December l95ol the addictlvo properties cf il new syothetle drues ware evalueted whcliy or In part. The results are presented belou under Individuel beadings.

0. dl-alpha-l,3-0lmethyl-4-phenyl-4-proptonoxyplperldlne laiphaorodine, NlH-34(21. Thts coapcund In doses of 50 to l00 mg. subcufanecusly Induces deflnite but short-Ilved subjective effects resembling those-caused by meperidlne.
150 mg: of the drug every Fcur hevrs partlally suopressea abstinence fron morphine ln strungly addicted patieats. The drug, therefcre, has eddictlca llablllty apprcaching that of : meperldine end Is not rcgardad as e promlsing codeins substltuic.

b. d-bete-f,3.Dtnethyl--pheayl-4-propioauxy-alngridine Ibeteprodiae, thH-34031. Tuenty-flvs to 30 Bg. of thls subatance subcutanecusly Induces marked morahiae-like subjectlve affects In former addiets. In doees of only 50 mg. every four hours. it svpareatad almoat ccaletely stças ci akstlaenca irem merahlnz ia atroagiv edllcted paileefs.lts. addictica liablllty 1s t.o bigh for 1t te.bu recarded es 0 orumlsiag codeine subatltute.

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∴ e.dt-beta-l-cthyl-3-sthyl.4-phenyl-A=proatotozyplperIdine INiti-7315). in doses of 20 to 30 mge, this comoouad Inducss marled norphlae-like cupharla In foroer morphine addlcts. Fifty pa. of the drug every fcur hours suopresses tymptcms uf abstinonce frua marphine coapletely. lts addletlcn llabtllty ls, thercicre, equal to that of morphing and It ls not a prualsiag codalne aubstitute.

d. d-4,4-Dlpheryl--plperldine-3-heptanons (d-ptoerldylmethadun, NIH-73431. 1n dosaa of 100 to 150 mg. subcutaneously thla drug lnduced 4 partlal pattern of moruhlng-like efieets conslsflng easqatlally of tethargy and drceilnass, l00 to l25 mg. of thls caaauund subcutanacusly every fcur to slx hours ceused partlal, but definlte, suopressico of abstinence lu 5 strcngly addicted patlente. Thls ls 5 very lateresiing rasult slace dextrorotstcry Iscmers ln tha mothadons series cenerally are Inectlve. Slacs the posslbllity sslsta that the drug kas been contealnatad with small emounts of a vary potent leverafatcry a iscaer, It mlll ba celavestigated uslngispeclally purificd tot of cstertat.

e. 112\~vorphotiaogthytl\~4-Phcayi=4-carbcthexy-aloerldine inilm\~72301. NiH-7289 In dosss of 50 fo 100 mg. subeutonscualy tadveai a definite frala vf murphiaeallke subjcctlve efferts in nontoleraat fufmer scrphlae addiets. l00 ng. of the drug every fcur hours sunafgssed abstleence frua morphine elaust cct pletely. lis addictlcn lleblllty 1s tco hish fcr 4t tu be regeried as à prenislng cedaine substiiufe.

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1. 1-3. hoxy-N-phengthyl-mopohInan (NlH-73021.

This drug ls a clne analogue of 1-3-Hydroxy-N-phenethylmurphinon ohich was descrlbed la the arevious aagual raoort as being cad of the moot potent morphlnc-llke coopcunis ever dlacovered. ln doses of as llttle as 5 mg. lt induces infense, lcac-lastlng mcrphlaa-like euchorla ln fcrasr morphine aicicts. Flve to l0 og, of ths coroound elther subcutaneously cr crolly suppressed abstinancs ircm aorphine almcst completsiy vhen. givea every slx to elght hours to strengiy oddicted palisnts. The comocund, therefere, has very merked addicttve prozerties and cannot be regardad as e ccdeine substltutg.

C• d-3-Methczy-N-pbenethyt-mcrohlaun (lüih-729d41. This coapound was teo lnsolubke te be Inlected subeutsnscusiy. in cral dosca af leo to 3o0 ag. no defiaiia evidance oi moruhine-likn effoets wos chservat, ofaer thesn dlzziness. hen 333 to 400 mc, were adminlstered cralty every fcer hours to struagly eddicte? raflents, abstineacs fron acrohias was partlatly but deflnitely suporsssed. The ancunt cf material avelicble eas sufflelont for ccnductlnn tasts la caiy S pafients. Sirre ccatemlnatlen elth caly 1s of the very potent l-lscaar would aeccunt f.e this unex seled rrtoit. tha corocoad cost be reiavesiigoted ualag s.eciolly puriied wcteriai.

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h. d-3-rzyphenethyl-morahlaan (NH-7295A1.

Like tte orecedlap cumpcusd, thle drug ls foo lnscluble and tco Irrltating to bo lnjected. in doses ranglag up tu 250 mg. orally It dld not Induce any deflalte subjective effeets of morphlne-llke nature. Deses of 333 mg. orally evary siz hours had ao effect cn the Intenilty of abstinence fros morphine In strengly oddicied patlenis. Thess findings lndicate a ioe. degree of oddicticn Ilabtllty. lf the ccapound Is elther on effectlve antitussive cr an effective onalgosic, it euuld be a potential codeine substitute.

1. d-2,2-01phany|-3-methy1-4uaorphol1oc-butyrtpyrrulldine INlr274v21. Coses cf 5 ts 10 mg. sf thls substance 公 subcutenecusly Induced jntense sublectlvs efiects ohlch vere descrlbed by foraer morphine addiets as resembling thuse ceused by a mlsture of heruln end cucaine. fiftcen to 20 mg. of the drug subcutanecusly every isur bours cumpieisiy supprcssed abstiacace fren morphins. The cwpcund, therefore, hos vefy high addletlen liabllliy which is ot least eqvat to fhat cf morphine, end ls not e potential ecdains svbstitute. it is. however, theoretlcelly interestiac siace it ls the first duztre rutetcry drug knoen to have such hich potency.

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1. 1-1b:ydrcxy-beta-cheayl-ethy1 1-4-heny1-4- carbethcxy plperlane INlH-729zl. Thls compound Is very Insoluble and coused Intense irritatlon when a solutlon made In aronolyns glyeol vas Injected subcutandcusly. No morphlsellke effacts verg seen with dusas ranging betpaen 5 to l50 mg. subcutanecusiy In I5 patieats. No suppresslcn of abstinence pas. observed shen 200 mg. were glven subcutanecusly et thg twentleth hcor cf abstinence irom morshine to 9 strcegly addicted petlents. Addletlon llablllty of thls compound Is, therefore, qulte.les. In all prcbabillty, It Is a completely lnert drug.

k.. d-aipba-4-01methylaaiac=1,2-dishcavt-3-msthy1-2 praplonoxy butane Iduarypoxyphensl. This ls the most aetive of the isoners cf prwpozyphene, and was sentiontd above. lt Is fairty Inscluble, sulte lrritatinc, onl csanut be lajected. in doses oi as,much as 400 mg. orally It does not Inducs a typlcal trala of morphine-liks sublectlve cficcts. Deses of 4CO mg. tbree times dally suppressed stlghtly, but deflnitelv, symotcas ef ebstlncnee frua ccrphins. Adelatatrattos of ss much es 400 ng. of the ccapound three tlaes dally fcr 30 days did nct lnduce a sicaiflzant decree of ohyslcal deceadenee in noatolgrant fcruer eddiat voiunieers. a ihis basia, It was revurted to the Drug Acdicticn Commlttes of tha Natlcaal Rasearch

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Councll that the coapcund had vary lcs addletlon lioblllty. Stnce prellminary cllateal Feports tndicote that It is as effective ss ccdelne es on enaigesic, further studles vers requettcd by 'tha Drug Addictlon Commlttec ln crder to deteraine more exoctly the addictlon-sustslalag actency of the ccnocuad. Thls ls belng accoaplished, using s "dcuble bltad" crcsscver deslgn in whlch furmer addiet vulunteers are addicted to morohine. after whlch they ore glven elther cudelne or doprcpoxyphene In ccded copsules so thet the Identity of the drugs is unknown to the obscrvers. After ten days of substltution aed althout the knouledgo of the ctseryers Identlcol placebo copsules ars subptlfutcd. Failents eill be althdrawn once frua codelce and oace froa propozyphene.: Pcsults of thls experlment shauld be availobie vithin fhe noxt slzty days.

PLAG FGR DHE FUTURE

Imiedlate laos. During the coatag slx montht we baoe to complate studies on taH-7225A dad NIH-7275A. The axperlaent wlth d-orcpexvehene otll ba saaolaied aad, unlras additicnal drugs are furzarded by the Orug Aidiatluo Cuaaittes ci the Natlenal Rsscarch Couacll, er lataad to tatura to direct testino of addlettye ltablllties ei scna of the marohint antancalsts particuierly. tiallylaorherola and Neorvayl-dihydrencraorohina.

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. Fe latend to cuntinus the search Fer tcaq Paang r an adequate syntheic substitute fcr cudelne untll a drug or drugs are fcund whlch are judçed by the Cosittee on Druc Addictlca and Nercotics. Natlcnal Razearch Councll. to fulfill all necessary requlremeats.

REPCRTS AND PUBLICATICNS InurIAg current report perled).

I. Isbell, H.: Medical Aspects of Cplate Addletlen. Bull. New York Acad. Med., 31: (121 886-901 (Dec.1 1955.

2. Fraser, H. F., Van Horn, G. D., end Ishell, H.: Studles en N-allylnoraerphine In Mant Antegunisa to Micrphine and Hercla and Effects of Mlxtures of N-allyincraurobine end Marphine. Am.
1. Mad, 5e, 231 111 1-8, 1955. ," 公

3. Fraser, H. F. and Isbell, He! Addictive Pofentietitles of Hexamethyleneiataes.. Federatlen Proc., 15: 11) 423 Carch) 1056.

4. Isbell, H.: Attempted Addlctlon to lalorphine. Federatlen Proc., 15: 111 442 lsarch1 1736.

5. Isbell, H.: Ths Seerch for a Hicaaddictiag Anetceslc. J.A..A., 1C1: 1131 1254 Uuly 231 1956.

6. lsbell, H.: Trends in Ressarch en Colate Addictlon. Tr, & Stud. Coil. ci chyslciaas, rhtiadelphla, : li) l-lo (lune) 1250.

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7. Fraser, H. E. and lsbell, H,t Addendua to the Minutes of the I7th Meetlegs Committee cn Drug Aldictioa and Narccties, Nhtlcnal Fesearch Csuncll, Vashingtua, D. C., 30-3t January 195s.  Reports cn Addlctlon Llablllty Tasts of Ncg Substances. pp 1-17.

Hl:le:tkh

Harrls Isbell, M.o.