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TiTLE OF PROJECT: Addiction Llabilities of Synthetic Substitutes for Codeine.

Objectivest To find a synthetic analgesic and antitussive drug which would be as safe from the point of view of toxicity and addiction llability as is codslne.

ABSTRACT (OR SUBGARY) OF RESULTS

a. Since atart of projectt

This portion of tha summary of results covers the peried.from i July 1951 to 30 October 1957. The project was undertaken bacause no synthatic-drug was available which was as safe with respect to toxicity and aduiction liability as was codeine. Sinca 75 per cent of the country's needs for narcotic drugs are for codeins, rather than for potent analgesics of the morohtne typs. ths United States must continua to stockpile opiua until adequats synthetic substitutes Lor codelnc are deveioped. The role of the NIei Addiction Research Center in this investiçation, which was begun at the request of the Cemmittes on Drug Addiction and Narcotics of the National Rescarch Couneil, consists of,the determination of addictive properties of the new drugs. Tho clinical evaluation of the analgesic.and antitussive potency of the new drugs must necossarily be made elsewhere.

The nethods usod for studying the addietlon liabilitios of new analgosics have desn deseribeu in datall in the projuct descriptions in previous rsports and wili not ba repsated here.

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Durinn the period of 1 July 1951 to 31 Lecember 1930, h6 new drugs or mixtures of drugs have been tested for addictive potentialities. Detailed infcrmation concerning these substancsz can bo found in the annual reports for 192 through 1956. Two substances which were outstanding as possible substitutes for codelne for suppression of cough were found. These weret (1) d-3-methoxy-N-nethylaorphinan (dextromethorphan), and (2) narcotine. Further elinical regorts continue to indicate that dextroaethorphan is equivalent to codsine in antitussive potency. It, therefore, seems a very satisfactory codeins substitute for reilef of couch. It is alreadyavsilabla end on sale in ths : United States. Narcotine. is now on sale and reports of clinical trials of this drug are indicating that it may also be a useful antitussivs substitute for codeine.

Since two pronising substitutes for cocsine for the rellaf of cough have been developed attention has baen turned to finding a corpound which would ba as effectivo snd as safe as codeina in ralieving aild grades of pain, Seven potential substitutes for codeins for pain reltef wora listed in the report for 1955. In 1955 and 1956 considerabic attontlon was given to the compounds known ss di-srcsoxvohene eni d-prepoxyohirs. Continuiag cllntcal reports indicata that these druga ars roassnably afrective substitutes for codeine in relief of pain. Complete data on toxicity under clinical conditions are, howover, cot yet avsilablo. This drug is now baing marketed in tha Uaitcd States by Eli Lilly and Cospany.

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b. During the current resorting perlodt

During the current reporting period the eddictive potentlalitles of five drugs wero cvaluated wholly or in part. The results are presented belou under individual headings:

(1) d-1,2-Dipheny1-4-dimethylamino-3-methy1-2- propionoxybutane (d-procoxyohene). Work on this compound was completed and the results reported to tha Drug Addiction Committee in January 1956. The results continue to sapport those previously described. In former addicts the drug does not Induce a full spectrea of subjective effects roscmbling those induced by mciphins. It does suppress abstinence froa Eorphine partially, but not coaplctely. when it is administered chronically to nontolerent volunteers some degree of tolerance to the sedative effects is observed. Following withdrawal after chronic intoxicetion, syeptoms ef abstinence are milder in dogree than those after withdrawal of codoine. It was concluded that d-propoxyphene had definite addictlon llability viich, however, vae far less. than that of codeine. The Drug Addiction Coanittae hás therefors recomended that this particuiar agent not bo controlied by the U. S. narcotic laws.

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(2) Norrorphine. Studics of this agent wers undertaken for two reasonst first, it. io,thc precursor of tha Forphine antagonists which have Iess acdiction liability than does: morphinei secondly, it is a norral metabolic product of morphine Which is formed by N-demethylatlon of morphine. As tolerance to morphine is acquired in male rats the ability of the liver to demethylate sorphine is reduced. Studles of its addiction liabiilty, therefore, seem to be irportant theoretically as well as practically. In single doses, normorphins is far less potent than morphiae in inducing sedation. In repeated dose, hovever. It is rore potent than porphine. On chronic adainistration, the dose of norrorphine cannot he raised as rapidly or to as high a level as can the dose of morphine. Tolerance to the sedative effocts develops mcre alowly than does tolerance to the sedativo effects of norphina. The adainistration of n-allylnernorphine to persons chronically intoxicated with norsorphine precipitates aild symptoas of abstinence. When norporphine is witharawn after a period of chronic intoxicatlon, symptons of abstinonce are mlider than thosa seen aftar withdrawal of morphine; they ars, in fact, zilder than thoss seen efter withdrawal or eithar codsine or mothadone. Desplte this the drug suppresses abstinencs froa morphine conpistely. It. is therefore concluded that norsorphine has derinits

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addictive liabllity which is probebly.less than that of codzine. The charactoristics of nornorphine are such that, if it is an enalgesic in man, It shouid be an excallent drug in conditlons essociated with chronic pain.

(3) Norcodeine. Studias of norcodeine were undertaken because of tha low addictiveness of the parent compound, normorphine. These studies are stiil incomplete. Preliminary studies indicate that norcodeine will probabiy have the sans relationship to codeine es normorphins has to porphine. In repeated dose, norcodeins is core potent in inducing. sedation than Is codeine. As is- trua.of. normorphino, abstlaence is extramely nild following withdraval of norcodeine after chronic intoxicatlon. the drug is effective orally, so it is a promising substitute for codeine; unfortunately, however, it ls not a syathetic.

(4) L-3-liydroxymorphinan (Norlevorphaa). This compcund is ihe analogue or normorphine in the morphinaa series. Only prelininary inforsation is as yet availabla. Singis dosas ranging up to 70 mg. total do not lnduce any behavioral changes rascabling thoss seen after zorphine or. nornorphine, In repeatau doss, evldonce of nild aorphine-like effccts vore oboerved after edniniatretien o2 3o ra. fote tiuos Cally for one dsy. lt doas suppress abstinuncu froa corphins completely when given in 50 psr cant greater dosa than ths addicting dose of morphine, At the momant ths data are not sufficisnt to give an estimsto of tha reletive addiction.liabllity of this cospcund.

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(5) D-2-nethoxy-N-chenathylsorphiman (NIH-7296A).

We previcusly rsported that this compound partially suppreszed ebstinancs froa morphine. This result was entirely unexpected since a congener, d-3-hydroxy-N-phenethyimorphine, was inactive in this respect. Since this resuit could possibly have been due to contanination with the potent l-fora of the drugs especially purlfied sarples of this corpound were obtained and tested. The purified drug also partly suppressed sbstinence fron nicrphins vhen Civan in six timss the aceustomed dose of norphine. This confirns the previous result and excludes the posslbility of tha result being due to contamination with the levo-lsomer. The addlctlon liabiiity of tha drug is judged to be low, ani Is probasly lezs then thit of codcine.

Imediate: During the coming eight sonths we intend to complete studias on norcodeine and on nordronoran. As soon as possible studies on l-3-mcthoxy-rorphinan, the codcins analogus of nordromoran, will be Initiatad and coapared with the results obtstned with codtine and corccdsine. We also Intand to restudy the addictiveness of. d-nethadone. The latter projeet is being undertakon at the raquest of the Seoratary ef tha Drug Aediction Cornlttee. Because of the promising resuits with nor-coroounds of corphins and nordronoran ve also latend to undertakd basic vork on tha metabolisx, exeretien, distributlon, and fate of sone of these drugs in ran.

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Long Rangei Wa Intend to continue the ssarch for substitutes for codeine until drugs ara. found shich are, in the opinlon of the Camaittae on Crug Addiction and Narcotics of the Nationel Research Council, conpietely satisfactory substitutes for codcine.

REPORTS AID PUBLICATIONS (dorisg current raport perIod).

I. Fraser, H. F., and lsbell, H.: Further studies on d-1,2-Diphenyl-L-Dinethylamino-3-Hethyt-2-Propienoxybutens (d-Propoxyphene). Addendum Hin. 1Gth Meeting, Cone, on Drug Addiction and Narcotics, National Researeh Council, Indianapolis, Ind. 21-23 January 1957.

2: Fraser, H. P., and lsbell, E.1 Addiction Liability of New Analgesicst

1. 1-(2-morpholinethyl)-4-phenyl-4-carbethoxypiperidias (Sl-γeC9).

11. 1-(2-hydroxy-2-phenethy1)-4-pheny1-4-carbethoxypiperidine (NI8-7292).

111. 1-3-4athoxy-N-phanethylnorphinan (NIH-7362).

1V. d-2,2-Diphenyl-3-Nethyl-h-Horpholino-butyr1-. pyrol1dine(1-7422).

Addendus Min. 1êth MeetIngs. Coana. on Erug Addictioa and Narcetics, Kational Rcssarch Council, indianapolis, Ind. 21-23 January 1957.

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3.. Fraser, H. F.. Isbell, H., and Van Horn, G. D.:. Ffrects of Morphine as Coapared with a Hixture of Forphine plus Dianinc-Phanyl-Thiarole (Beptazola). Anesthesiology, 12: 531 (July-ug.) 1957.

Harris Isbell, M.D. Director

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