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Request' to the Offlce of Naval Research for Renewal of Contract NR 113-149 Serlal 18249 83 Naonr 18i-53

I. Backaround Informatlon

Since July l95l a project deslgned to develop a syathetle drug which would be as safe as codelne wlth respect to toxlclty, antitusslve actlvity, and addictlon flablllty has been carrled on withln the Nattonal lnstitute of Mental Heolth Addieilon Reseerch Center, PhiS Hospltal, lexington, Kentueky. Thls prolect has been flnanced ln large part by funds from the Office of Naval Reseerch and this descrlption constitutes a request for rentwel of the project for the perlod I july l957 to 30 June 1958.

A syathetlc substltute for codelne is badly needed slnce oplum or morphine derivod fron oplum constltute the only source of codelne. Ualess a syathetic substltute for codelne Is found the Ualted States must contlaue to steckplle oolun in order to provide adequate suoplles of codelne for botà the clvitlan and mllitary populattons ln the event oi var. The facillties of the NiMH Addlction Research Ceater are not sufflclent to carry out this work, in addltion to drug fesfing

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THE ADDICTION LIASILITY OF SYNTHETIC SUBSTITUTES FOR CODE INE

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required for the eyaluation of ali nzw analgeslea, unless eddfrional furds. are suppiled by the Department of Defense.

2. Work Accomollshed to Date

Prevlous work has been summarlzed In the annual progress reporti sent to Capt. F. H. Qulmby and Capt. T. K. Ruebush of the Physlology Branch, Offlce of Neval Research.

Two drugs have been developed whlch are promising pofentlal substitutes for codelne for rellef of cough. These drugs are (l] dextromethorphan, and (2) narcotine. Nelther drug possesses any addictlon llablllty and both have relatively lov toxiclty. The studles reported at the meeting of Commlttee on Drug Addictlon and Narcotics of the National Rezearch Counell, ln January l957, continue to Indlcate that the drugs are as effectlve as codelne for relief of cough. It seems almost certain, therefore, that the antlfussive phast of fhe problem has, In a sense, been tolved.

Although the antltussive problem Is no longer as presslng 84 It was, fhere are still no compounds avallable which are knoun to be as effective aad safe as codelne for rellef of mild grades of pala. More than 35 materlals bavd now been screened for this purpose. The outstanding substances whlch has been developed Is d-alpha-4-dlmzthylamlno-l,2-dlphenyl-3-methyl-4-proploaoxybutane, or d-Propoxyphene. Prellmlnary

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but unconflrmed work Indlcates that thls compound ts as effective as codsine as an analgesic In clinical praetIce. Extenslve work has shoua that, although the compound possesses addletIve potentlalitles, the overall addlction Ilobtllty fs conslderably less than thot of codelae. Thls drug,, therefore, 1t qutte promising, but final eveluatlon must wslt completlon of extensive clinlcal trlal for rellef of paln.

3. Need For Conttnuatton of the Prolect

The.chlef need for contlnuatlon of the project ls related to uncertaiaty concerniag the anatgeslc potency of d-Propoxyphene. if clinical trlals show thst thls drug Is as effecttve as codelne then all aspects of our original problem wouid be completely solved. Slnce, however, we cannot be certala et this time fhat d-Propoxyphene will replace codeine in clinical use, It ls stlll essentlal that the search for syathetic substltutes must be cont inued slnce the larger the number of compounds tested the sreater the chance of finding completely adequote substitutes.

4. Wort Prooosed

During tha perlod from 1 July 1957 to 30 June 1958 we propose to fest the addictlve properties of D-3-methoxy-Nphenethyl morphinan, D-3-hydroxy-N-phenethyl morphiaen, Narmorphine, Norcodelne, and N-allyidihydrohydroxy codeinone.

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In additlon, studles of other substances referred by the Committee on Drug Addlctlon and Narcotics of the Natlonal Research Counell wlll be carrled on.

5. Methods

The methods to be used are the standard addictlon Ilobllity testing methods of the Nlhti Addictloa Research Ceater. These methods are accepted as standard by the Commlttee on Drug Addletlon and Narcotics and heve been desertbed In previous project descrlptlons, whlch should be consulted for detalls.

6. Evaluatlon of Data

The evaluatlon of data ottained In the addletion itabtlity program has also been discussed In previcus project deserlptions.

7 Location of Project

Work will be carrled out at the NIMt Addlctlon Research Center, PHS Hospitel, Lexlngton, Kentucky. Thts Instltutlon proyides the two necessary factlltles for the type of work to be undertaken: lil a pool of petlente sho willl volunteer for experlments with drugs, and (2) strlct environmental control which.prevents the lniroductlon of drugs other than those under study lnto the experimenral sltuatlon.

8. Experimental Personnel

Work wlll be carrled out under the direction of Harris Isbell,

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M.D., Director, NIi Addictlon Research Center. This Investlgator has bad thtrteen years of experlence In research In narcotlc drug addiction and has publlshed many papers In the fleld. He wtll be assisted by two other experteaced physictans, Dr. H. F. Fraser and Dr. Abraham Wikler, both of whom have had extensive experience in research tn addlction, wlth many publlcations. In addltion to these medical personnel the part-time services of a blochemist and resaarch psychologist wiil be made avellable. A speclal ward for the conduct of these studles Is currently Ia operetlon.

9. Estimated Cost

to The amount of money requested has been held/the same figure es vos evallable in fiscal yeer l957.

l. Personnel

6 Psychlatrlc Aldes GS-5 (54345. p.a.] I Physlcal Sclence Aide GS-5

2..Reservz. for Fremiun Pay (Night differentlal, Holidey, Overtime)

3. Travel

4. Miscellaneous .Expense IDrugs, chenlcals, glasswares photographle supplies, etel

Herris tsbe!l, M. D. Director

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18 Februery 1957