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ABSTRACT OF RESULTS

a. Since Stort of Prolect: Thls portlon of the summary covers the perlod from 1 July 1951 to 31 Decznber 1954. As stated above, the objectlve of the projcct Is to flad a synthetlc drug whlch would be as effectlve aad as safe from the polnts of viey of human toxlelty and addictlon llablllty as ls codelne. Although adequate synthetle aubstltutes for morphine are avallable, such e substance is needed because no such drug of the codeine-type is knoun. Seventy-five per cent of the needs for narcoties are for codeine rather than morphine. Thle means that the Unlted States must continue to láport and stockplle oplum untll an adequate syathetic substltute for codelne has beea developed. The role of the NiiH Addictlon Reseerch Center in this Investlgation conslsts of thz determtnatlon of thc addletlve propertles of new drugs. The evaluatlon or the analgesic and antttussive effects must neccssarlly be made elsewhcre.

The methods used for studying the addietlon llablllties of new anatgcslcs have been descrlbed In detall in thz project deseriptions and in prevlous progress reporis. Drucs to be studied as synthetic substliutes for codelne ore reccmmeuded as promlslng by the Cormitiee on Drug nddlctlon and llarcotics of the Nlatlonal Reseerch Couacll. Then such drugs are recelved at the Nila Addlctlon Research Center the human phernacology of the compounds Is studled by determining effects of varlous doses on blood pressure,

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respiratory minute volume, body temperature, puplllory
sizz, eic. Folloeing completlon of the basie pharmaco
logleel vork, effects of the drugs on the behavlor of
former morphlne addicts are evaluated by administerlng
1n
them In doses based on the results obtalned/the pharmacological experlments. If the drug Induces behavloral effecte resembling those seen after administratlon of morphine or codelne, It is very likely to possesseddictlon llabtllty. The abllity of the drug to relleve or to prevent the
appearance of symptoms of abstinence from morphine is next studled la patlents strongly addicted to morphlne. If the crug under test relieves or suppresses abstinences It is 二
judged to have addictlon llabtilty. In such experiments, the dose of the drug.-under test which Is requlred to relleve or suppress the symptons of ebstinence and the degree of rellef or-suppresslon of abstInence are Indices for comparisop vlth the standard drug, codeine.

When an cspeclaily promising drug becomes avallable, lt Is siudled by the dlrect addietlon technic. Thls lnvolves the acntntsiratlon of ascending doses to former addict volunieers over perlods of tlne ranglng between 30 to l00 days.Durln: the addictlon oerlod, sultable measurements are carried out to detect and evaluate ths development of tolerance. Flnaliy, drugs srs wifhdrawn abruptly; and observetlons for the develooment of abstlnence symptons made.

The drugs studled during the perlod l July l95l to 31 December 1954 arc tabulated below:

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b. Resultsfuarlng Current Rcoortlan Perlod: The addletive properf s of elght drugs "lor classes of drugs) were evaluated wiflly or in part durlng fho current reportlng perlod. Results are shown below under the individual headings.

Investlgatlon of these two compounds was partially completed durIng the preceding reporting perlod 1See Numbers 13 and 14 In Table abovel. The results prevlously obtalned were conflrmed. The dextro form of the compound was completely Inert, devold of addictlon llablllty, and probably devold of eny Important therapeutic propertles. For this latter reason, It Is not promtsing as a synihetlc substitute for codelne. The levorotatory form of the drug, on the other hand, partlally suppressed abstlncnce' in patlents who were strongly eddicted to morphine. Sixty milllgrams.of the levo Isomer every four hours were sufflelent for thls purpose. The levo lsomer, therefore, bas hlgher addictlon.llablllty then that of codeine, but less than thaf of morphine. Although this drug is not too promlsiag, if might be of value ln fhe event a safer egent is not developed.

2. 4-4-Diphenyl-6-dimethylamlao-hexanone-3 1See Mbo. 16 in Table abovel. In doses of 60 to 75 mg. every four hours, thls compound suppressed almost cumpletely symptons out of abstinence from morphine In 5 patlents who were strongly addlcted to that drug. lts addletion llebility, therefore, ls judged to exczed that of codeine, but is somewhst less than

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that of norphlae. This compound Fepreseats another posslble substitute for codeine since It Is ln active use In Germany as a cough suppressant. Furthermore, it should be a mlld enalgeslc ond Is easlly synthesized.

3. Benzylmorphlne Myristyl Ester. This drug, whlch was developed In France, is insoluble in water and can be Injected only as oral suspenslon. For this reason, A all work carrled out wlth the drug has been by the oral route. Doses ranging up to 600 mg. orally did not Induce any definite morphlne-like effects ln nontolerant addtcts. Translent skin eruptlons consistIng of blotchy erythema and urticarlal whegls were observed In both of the patlents who received the lergest doses. The drug was completely ineffectIve in supprasslng abstinence from morphine. The drug Is nof regarded as a promialng spbstltute slnce lt is not a true synthetic, has too high toxlelty, and Is probably therapeutlcally inert.

4. Bets-dl-llethadol. in doses renglng between 30 to l00 mg. orally or subcutanzously, beta-dl-methadol did not Induce evidence ofmorphlnc-like actlon la lO nontolerant addicta. It was totally lneffective mn suppressmg symptoms of abstlnence from morphlac In strongly addicted patients. It Is, therefore, judged to have no addtetlon liablllty. Sinee there Is no clinical data avallable on the possible value of beta-dlmethadol as an aniitussive or andigesic agent, lis possibllltles as a synthetle substitute for codcine csnnot bo eveluated at

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the present -tle Thls drug Is, however, easlly chemlcally convertible to a-dl-acetyimethadol, a drug with very hlgh adclctlon llabillty. For this reason, It Is uallkely thof It would be regerded as belng a safe substltute for codeine. 5. Addlction Ilablllty of NalorphIne-iorphiae 5. Addlction llablllty of Nalorphlne-Morphlae

Il-lO) Mixture. In prevlous reports It was shown that mixtures of Nalorphine and morphlne were not llkely to be abused by drug addicts since morphine-lnduced euphorla Is effectively blocked for 3 hours by the Nalorphine and since Injectlon of such a mlxture-would preciplfate abstinence in addlcted Indlvlduals. Previous direct addictlon experIments with thls mixture lavolved adminlstration of very hlgh doses I"addlcting dose schedule"l. Nb Informaflon wos avallable on edminlatration of "therapeutle doses" chronlcolly. For this resgon,  patlents wers gtven l0 mg. morphlne plus I mg. Nalorphlne every four hours for 3O days, efter which the drug was. wlthdrawn. The unpleesent slde effccis noted with "addicting" schedules did not eppear wlth thls "therapsutlc" dose schedule. Definlte, alld abstinence, however, eppeered following wlihdrasal of the mixture, whlch was Just as intense as symptoms of abstinence following wlthdrawal of morphine after edmlalstratlon of lO mg. every four hours for 30 days to the same O patlents. Therefors, In one sense, the addiction llabillty of fhe mlxture ls os great as that of morphine. For thls reason, and beceuse the Nalorphine-rorphine mixture is rather Ineffective orelly, it

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Is not regarded a promising substitute for codelne.
Furthermore, It not true synthetic.

6. Morphine Antogonlsts Cther than Nalorphine.

Work Is. belno undertaken ln the hope of developlng e morphtne
antagontst which Is orally effectlve. The combinatlon of
such an antagonlst wlth e synthetic such as methadone, or
Racemorphan, might decrease addiction Ilabillty and, therefore,
be regarded.as a possible substitute for codelne. Work wlth
four synthetie antagonlsts hes been partly completed. 六 lal Levallorphan. This Is the levorotatory

Morphinan analogue of Nalorphinc. The drug has been shown to be an effective antagonlst to marphlne and Racemorphan, both subcutaneously and oralry. Ths antagonistlc effects perslst longer than do, those of Nalorphine. Serious toxic reactlons may occur with subcutaneous doses grcater fhan 5 mg. Thesestoxlc effects consist of nauseo: vomlting and preclpitous drops In blood pressure. Toxlc effects of the compound in doses whlch night be used In mixtures are not of any serlous consequence. Slnce the drug ls effective orally it offers deflnite possiblilties for the devolopment of a, mixture of the kind desired.

Ibl Dextronalorphan. This drug ls the dextrorotatory isomer of Levallorphan. Az expected, lt is qulie lnert and, therefore, ls not a promlsing constltuent of an anfagoalst-analgeslc mixturc.

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Icl Levallomcthorphan. Thls. compnuad Is the 3-methyl ether of Levailorphan and was found to be effectlve, elther oralry or subcutaneously, In ontagoalzing the effects of morphine or Racemorphan. Untoward slde effects appeared wlth doses greater than 5 ag. Whtle a deflnlte posslbllity as a constltuent of an anfegonlst-analgeslc mixfure, If possesses no advantages over the parent compound, Levallorphan.

[d)·3-Hydroxy-N-Propargyl-MorphInaa.Th1s

compound Is of especlat Interest since It produces analgesic effects In mice which are equal to those induced by meperidine. Despite thls, the drug is an effective untagonlst when admlaistered sibcutancously. but is far less effective when adminlstered orclly. :it bas been shown to precipltete symptoms of abstinence from morphine tn addlcted pallents and, therefore, It Is not likely to be abused by such paflents. It offers some promise as being e possible substitute for codeine for the rellef. of mild pain.

le) I-3-Acetoxy-N-allylaormorphinan. This

compound is also an cffectlve antagonist when injected subcutancousiy. it is far leus effeclive urally Gad, lhersfore, Is not as promlsing a constlfuent fcr en antagonlst-eneigeile alxture as Is Levallorphan.

7. Narcotine. This compound, though not chenically related to morphine, Is derlved from oplum, and in the past was regarded as a troublesoms wasfe produst of oalun processing. Evidence has nov become avallable that the drug is an cffective

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antitusslve In h.man and animals. If thls Is conflrmed, the drug might a possible substltute for codelnc as an antitusslve and would, therefore, have the effect of extending the supply.of codelne derlved fram oplum. In doses-ranging up to l00 mg., elfher orally or subcutaneously, the compaund does not Induce morphine-llke effects In nontolerant former morphine addicts. Nb untoward toxic effects were observed. If appears to be totalty devold of any ablllty to suppress symptoms of abstinence from morphlne. This compound ls, therefore, regarded as belng very promlsing.

8. Dihydrohydrohydroxymorphine. Fhls compouat Is the morphine analogue of eukodal (dthydrohydroxycodeinonel. 二一 In doses of 2 to 3 mgi subcutaneously,.It Induces marked morphine-llke effects, includlng euphorla. It relieves end suppresses abstinence from morphlne completely. lis addletlon Itablllty and toxtcity are far greater than those of codelnone. The drug is, therefore, not a sultable codelne substitute.

9. Propoxyphanonc (4-dimethylamlno-l, 2, diphenyi-2-oroplonoxy-3-methylbutane). Thls compound was Feccntly submitted by the Committee on Drug Addletica and Harcotlcs. The animal pharnacolocy aad preliminary clinleal experinents lndlcate that thls drur coy have analgeslc propertles gooroximately equlvalent to thoss of codohne. tt ts, therefore, a yery important drug stnce to date the potenttob subsiltutes

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for codelne have been satitusslves rather than analgesics. So far, only preliminary toxicologlcal Iaformatlon. ia avallable. In doses ranglng up to 250 mg. orally nc evidence of morphino-llke effects or morphine-like euphorla have been observed In nontolerant former morphine addicts. kb. serlous toxie effects have been observed.

SUMMARY. Of the compounds studled so far, two are regarded as extremely promising as antitussive agents. These compounds are Dextromethorphan and Narcotine. Cilnlcsl evaluatlon of the antitussive properties of both ere currently underway and It seems probable that both compounds wlll soon come tnto the market es constuents of antitussive mixtures. These drugs, =
however, constltute an answer to only half the problem. ln addition to lts use as an antltussive agent, codeine ls
extensively used for the rellef of nilder Srades of paln. As yet no drug Is avallable uhlch Is known.to be as effective as codelne for thls purpose aad which has as low addletlon liability ond os low toxlclty.
PLANS FCR FUTURE:

Immedlafe Plans: During the coming six months wz hope to partly conolcte studies of five compounds which havc been subnifted by fhe Committee oa Drug Addietloa and Parcotles. These compounds are Propoxyphenone ISee par. ? sbovel, thrce membcrs of the Azacyeloheptane serles, ond Elporydlmethodone.

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TheAzacycloheptanes are of great Intorest slnce no evidence of addiction Ilablllty.to one of these compounds was detected in an experlment uslng monkeys at the Ualverslty of Michigan. Preliminary.cllnical Informatloa has already Indleated that fhese drugs may be effective analgesles. If thls Is true, and If their addiction llabillty tslow, as lndicated by the experiments at Michigan, they might be effectlvely substltuted for codelne la rellevlng pala. The drug Plperydlmethadone. Is also olready in.cllnical use ln Great Britaln and, therefore, Is of some Interest. We also hope to proceed further wlth the development of antagonist-analgesic alxtures, with chlef emphasis on Levallorphan. Further studies of 3-fiydroxy-N-Prooargyl-Morphinan Idirect"addietlon) are also ladlcsted.

Lono-range Plans: We lntend to contloue the search for an adcquate synthettc substltute for codcins until a drug:, or drugs, 1s found whlch are ludsed by the Commlttee on Drug Addictlon and Narcotics of the Naflonal Rcsearch Councll futflll all the necessary requirements. Only suspenslon of the orolcct duc to leck of funds would cause work to ceasa prlor to the atfalnment of thts Soal.

1. Isbell, H.. and Fraser, H.F.: Addietlve Propertles of Methadone Derlvotlves labstrectl. Federation Proc., 13:(1) 369 (1:ar.) 1954.

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REPORTS AND PUBLICATICNS: ICORTID)

2. Fraser, H.F.,. Nash, T.L., Van Horn, G.D., and Isbell, H.: Use of Mlotlc Effects In EvaluafIng Apalgesic Drugs In Man. Arch. lnternat.de pharmacodyn. et de therap., 93: (4) 443-45 (Aug.1 1954.

3. Reports to Comalttee, on Drug Addlctlon and Narcuttcs, Nattonal Research Councll:

lal Work of NlkH Addletlon Research Center, Annual Report, 22-23 January 1954. Contains report on the addictlon Itabllltles of Nalllne-morphine gmixtures; 1 and d 2-N-Dlmcthyl-3-HydroxymorphInan; di, 1 and d 2:2-Diphenyl-4-DImethylaminoethyl valerafes; d! Ethyi 2,2-Diphenyl-4-Dimethylamlnobutyrafc; 4-4-Diphenyl-6-Dinethylanlno-Hexanone-3: dI 1-Methyi-4-Carbethoxy-Azacycloheptane: NPropargyl-Dihydro-normorphine; 1\_ond d Nallylnormorphine; and N-Allyldiacetylnormorphine. Ib) Addiçtion Liabillty of Narcotlae, 2 October 1954. tcl Addletlon Llebllity of Numorphan IDlhydrohy2roxy-Korphlnone), 2 Cctober 1954.

Harris isbell, M. D. Director of Reszerch

Attachments.