[PAGE 1]
l. Background Informatlon

Slace July l95l, a project designed to develop a \$yathetlc drug which vould be as safe as codelne with respect to toxicity, antitusslve activity, and addlctlon Ilabllliy bas been carrled on wlthin the Natlonal lastItute-of Meafal Health Addictlon Research Center, PHS Hospltal, Lexiagton, Kentucky. Thls project has been ftnanced ln large part by funds from the Office of Naval Research and this descrlptlon constltutes a request for renewal of the project for the period I luly 1956 to 30 June 1957.

A syathetic substltute for ccdelne is badly needed slnce oplum or morphine derlved froo oplum constltute the oniy source of codelne. Ualess a synthetic substliute for codelne Is developed the Unlted States must continue to stockplle oplum In order to provlde adequatz supplies of codelne for both the civillas and mllitary populatlons In the event of war. The facllltles of the NIMH Addictlon Research Center are pol sufflcient to carry on thls work in addttlom to drug tostlng

Contract NR 113-149 Serlal 18249 Naonr 181-53

[PAGE 2]
2. Tort Accomollshed to Cate

Previous work has been summarlzed Ip the annual progress reports sent to Capt. F. H. Qulaby, Head of the Physlology Braach, Offlce of Naval Research.

Two drugs have been developed whlch are promislng poteatial substitutes for codelne for rellef of cougb. These drugs are (t) dexiromethorphan, and 12) narcotIne. Nelther drug possesses any addlctlon llibllity and both have relativety low toxiclty. They currently are uader intensive clinical study for antitusslve effect.

Although two very promlslng antttusslve substitutes for codeiae have beea found, no compound is yet avallable which ls as effectiye as codelne for the rellef of mlld grades of pala and whlch is as safe as codelae with respect to both toxlcity and addictlon Ilablllty. More thea 25 compounds bave been studled to date. Seven of these conpounds hove sone promise as substltutes for codeine for analgesic use. The outstandlng compouads are alpha-dl- and alpha-d-l,2-Diphenyl-2-propionoxydimetbylamlao-3-methyibutane.The dezirorotatory Isomer accounts for all the analgeslc potency of these particuler compouads. The drugs are nontoxic, are better sedatives than

required for the gluatlon of all new anaigeslcs, unless addttlonal funds ate supplled by the Department of Defense.

A-229

[PAGE 3]
Is codelne, suppri abstinence fron morpblne oaly sllghtlys and hove been repried-to be effectlve ln the relief of ellnlcal pain, although studies of the analgestc effect are stlll Inadequate.

3. Need for Contlnuatlon of the Prolect

Although two drugs hove been discovered that have promise
as potentlal antItussive substitutes for codelne and several.
drugs have been discovered which mlght serve as possible
substltutes for codelne for analgesla, It Is stlit unknoun
shether any of these drugs wlll be completely satlsfactory
to clinlcal use for elther purpose. tt is, therefore,
essentlat to contiaue the search slace the lerger the number
of compouads developed greater Is the chance of Flndlag a
completely adequate substltute. 1

4. Work Proposed

During the perlod 1 luly 1956 to 30 lune 1957 se propose to complete fhe studles on the very Important metbylbutsae compouads mentloned above. This drug Is so promlslag that direcf addictlon liability studles are requlred. Such siudies are very time consuming sad slll require slx to nine moaths for completion. In addltton, we Intend to study the addletlon Ilablllty of N-allyidlhydrchydroxycodeinone to eveluste the

4-228

[PAGE 4]
addicflon tiablllty of the dibydrocodelne and to study such otber substances as may'be suggested by the Committee oo Drug Addictloa end Narcoties, Natlonal Resesrch Councll.

5. Methods

The methods to be used are the staadard addictloa llabillty
testIng methods of the NihH Addietlon Research Center. These
have been described in prevlous project descriptlons aad
should be consulted for detalis. :

6. Evaluatlon of Data

The evaluatlon of deta obfalned fn fhe addictlop llabllity program has also been. discussed In previous prciect descrlptlons.

7. Locctlon of Proiect

1 Cork wlll be carrled out at the NikH Addlctioa Research Center, PHS Hospital, Lexlngton, Kentucky. Thls Institution provides the two necessary facllitles for he type of zork to be undertaken: (ll a pool cf petlents who siil voluateer for experlments with drugs, end (2) strict cavironmentat conirol whlch prevents the iatroducflon of drugs other than those under study Into the experimental slivetica.

A-227

[PAGE 5]
8.Experimental Personnel

Cork will -be carrled out yader the directlor of Horrls Isball, M.D.. Director, NiMH Addictton Research Cenier. This InvestIgotor has had twcive years of experleuce In research In narcotic drug addictlon and has pubilshed maay popers in the field. He will be assisted by two other experlenced physiclans, Dr. H. F. Fraser and Dr. Abraham Fikler, both of whom have had extensive experlence in reseorch in addiction, elth many publlcotlons. In addition to\_these medical personnel the port-time services of a blochemist and reszarch psychologist will be made avallable. A speclal ward for the conduct of ihese studies is currently 'in oparatlon.

9. Estlrated Cost

The amount of noney requested has been Increosed. Thls Is gecessary in order fo provide fuuds for the increase in Civft Service pay which weat lato effect ln March l955.

I. Personnel

6 Psvchlatric Aides GS-5 (\$4210. P.a.) I Physlcal Sclcnce Aide GS-5

2. Reserve for Premiva Pay INight differentlal, Holldey, Overtimel

3. Trovel

4 Miscellanecus Expease (Druas, chemicals, C!assvare, photographic supplies,, ctcl

Hi:ra

23 lanvary 1656

Herris Isbell, M.D. Director