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BACKGRCUNO INFCRMATION

Since july l95l, a prolect designed to determlne the eddletlon lleblllty of synthetic analgesics which might serve es substitutes fór codelne has been carrled on wlthin the National institute of Mentel Health, Addictlon Research Center, at the Pubiic Health Servlce Hospital, texington, Kentucky. During the perlod from july 195l to. July-l952 the project was flnenced by d grent of \$30,000. which was tronsferred to the Public Health Service by the Cffice of Naval Reseerch. From luly l, 1952 untll january 1953, the project was financed by en addltlonal grent of \$ló,l42.CO also from thz offtce of Naval Research. From Januery 1953 until June 30, 1953, the project has been flnanced dy.the Natlonal. Institute. of Miental Health. At that time the National institute of Mentel Health will no longer be able to supoort the aroject.

The redsons for corrying on research for synthetic substitutes for codeine lwhich was recommended by the Drug Addictlon Comalttee, National Research Counctl) are as follows:

The Addictlon ilabillty of Analceslcs Thtch Micht Serva as Substltutes for Codelne

Request for Renewat on NR 113-149 Ser. 31540

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Due to the disturbed Internatlonal situetlon, It Is possIble tha? the Uaited States might be cut off from ell Its usuel sources of oplum. The single source of codeine is from oplum or by synthesla from morphine derlved from opium. At the time the prolects were begun, thers was no synthetie compound avalieble which was as safe for generai vie as was codelne and, elthough synthetic analgesics were avatiable whtch would be entlrely adequete for the replacement of morphine, no synthetic was avellable whlch was as safe es codelne. Moreover, more than 60 per cent of the Armed forcest regutremsats for narcoties were for codeine rather then for morphlae. The Importance of the project is therefore obvlous, but unfortunately the facllltles of the Addiction Research Center were not sufficlent to carry out the work unless addliional funds could be obtalned and, of course, the work cannot be contlnued after Juiy l, l953 unless eddltional funds are made avallabic..

I1.SORK ACCCMPLISHED TO DATE

Part of the work accomplished to date war embodled in the smmi-aanual progress repert seat. to Dr. F H. Cutmby, Hcad of the Physlotogy Branch, Offlce of Navel Research In January 1953. lt may be brlefly summarized as follows:

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t. The racemle J-methyl ether of Nmethylmorphlnan peisessed too high addicflon llablllty for It to be regarded as a safe substttute for codelne.

2. All of the addictlon liabllity of racemic 3-methyt ether of N-methylmorphinen was found to be due to the leverotatory lsomer

3. The. dextrorotatory 3-methyl ether of N-methylmorph-Iaan is deyold of addlctlon Ilabillty.

Since thls compound had been raported to have powerful entttuislve effects in anlmals, extensive clinical testing in humans ls being carried out cisewhere. ?reliminary reports of results were made et the meeting of the Drug Addiction Comalttee, Natlonal Research Counetl, in January l953. Unfortunately, the reports of the clinical eificacy of the drug were conflicting and the matter ls not as yet settied.

4.3-cthylmethytamlns-l-l-2tdlthienyl-but-i-ene. Thls drug vas found to possess too high addictlon llabillty to be regarded as a sefe synthetle sutstitute for codelne. Moreover, It is rather ineffective shen given orally and produczs maay undesirable side effects. furtaer. investigatlon of this compovad ls not sarranted.

5. di, d, and t-2-2-dlphenylamino-ethyl valerates. Tork wlth these compounds hai almost been completed. ln doses

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of 75 mge, all pruce weat morphlne-like effects in former morphlne addicts. They are also reiativeiy laeifective in suppressing absttnence from morphlae. The low. patency and low.addletlon llabilittes of these compounds suggest that pre-Iimlhery clinical trlais of antttussive effect and side reactlons are warranted.

6.di-2-2-diphenyl-4-dtmethylamino-butyrate. Thts compound hes prosertles slmllar to those of the. valerotes and, therefore, deserves a preliminary cilnlcal trlal. 11I. NEED FOR CCNT INUATICN CF THE PROJECT

Although'the wort to date has uncovered five drugs i whtch may haye posslbllitles as synthetic substitutes for codeinz. we belleve the project shoutd:be contlnued. The most pronistng of the drucs studled ls the d-3-methyl ether of N-methylmorphlsan. This drug is completzly devoid of addictios liablllty and has lov toxicity. Unfortunately the reports concerning Its cllalcal efflcacy are confllctlng and, at the moment, It ls not certeln that it wlll serve as an odequate substitute for codeins. The other four. drucs have not been teated- clinlcaihy- tt 1s believed thet they are mnore tozls thas codeine end that untovard side reacttons may da produced. for this reason, we cannot be certain that an adequate synthetlc substitute for codelne is yet on hand.

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We propose  continue. testing additlonal drugs for e perlod of one year. The drugs to bestested Include: Il Normorphlnan; 2r 1 end d 3-hydroxy-2-n-dimethylmorphlnan; 3) I and d 3-propyl ethers of 3-hydroxymorphlnan; 4) other &gsnts as mey be suggested after coasultatlon wlth the Drug Addlctlon Committee of the Natlonal Researbh Sounctl.

v. METHOOS TO BE USED

These methods are the same as those described in prevlous project deserlptlons and in the semi-annual report to the Cffice of Navai Reizarch, They Includet

I. Determination of Human Pharmacolocy and Toxiclty. Thls lnvolves adalnistratlon of progresstyely Inereasing doses of the drug under study to human volunteers, chiefly former morphine sddicts. Cbservations on respiratory minute volume, puplllary sizé, blood pressure, pulse rete, etc., are made follouing administration of the drug.

2. Administration of Sincle Doses for the Detectlon of Eushorls. These exoerlments are conducted In exactiy the same way as those en human pharmacology, exceat detalled obiervaflcrs on the onyssoloricaf effects of-thz drug are not cade, because the taking of ohyslolegical observatlons tends to negete the plcasurable effects of the drugt. New methods are used in gauging the "euphorla" produced by the drug.

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These are: Il.unotrusive cllnicel observatiog for the appearence of overt behavlor resembling that sees afier administratlon of morphlne,'and 2l edministretton of projective and other psychological tests.

In both of the above types of testlag, drugs are given In a randomized belance ordar and by code. The order of edalnistratlon ls unknown to both the subjects and the observers. Bath poaltive and negatlve control druçs (morphine, codeins, and placebol are used.

3.Adminlstratlon of Single Doses of the Drug to Patlents Showing Slcas of Abstinence From Norohtne. This fvpe of experlmant is carrled out by obtaining patlents who have been takIng large amouats of oplates dally, After stabillzatlon on the least amount of morphine which would Just prevent the appearance of slgns of abstinencs, morphine is abruptly wtthdrawa for e perlod of 30 hours. At fhis tlme, a single large dost of the drug under study is adainistered and observatlons for Intensity of abstincnce are continued, Controls Include fhe edministratlon of morphine and of coceine to the tane patlenfs-duria this- we. arz locklng for drugs which have litile or no eficcts on abstinence from morphine.

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4. Suporesslon of Absflhince frcm Morohlre. This

tecante represents the more seasltive reflnement of the cae designed above. Patlents elth strong desendence on morphine are selected. After e aultable stabilization perlod,\_the morphine Is abrustly dlscontinued and the admtnlstratlon of the test drug ls begun before signs of abstinence eppear. if abstiaence Is suppressed completely or partialiy, administratlon of the new drug is contlaued for a perlod of l0 to i4 days, effer which lt Is abruptly wlthdrewn and observatlons for slgns of abstinence are made.

S. Direct Addietion. Thls technic Involves the admlalstratlon of suffictentiylarge amovnts of the drug under test to former morphine addict volunteers who have been ebstlnent for a perled oi at least three months before the experiment ls begun.. Sultable. observations for the detectlon of tolerance ere carrled out during the perlod of edministratlon. After 30 days or more of chronie Intoxlcatlon, the test druga are abruptly wlthdrsen.

VI.EVALUATION OF DATA

The drug we are seeking should have the following characteristics: Tl lt should probabiy be a weak enalgesic, as Judged by anlmal experimentatlon; 21 the. ratto of toxiclty to theropeutic effects should be favorable In anlmals and in manj 3l it should heve antltussive- effecis tn- onimal oharmacological experlments; 4) it should be a goed entitussive agent

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fa mani 5i It shoutd relleve or suppress absfinence from morphlne oniy partlally, end preferably not at all; ól It should lnducz oaiy a mlid grade of physleal depeadanca undar. condltions of hlgh dosage:

laformetlon submitted by pharmaceutical firma and universities concerning drugs whlch should be tested wtll. be sufficlent fo evaluate the actlons of the drug In animals. Studles on Its addictlon llebillfy wlll yield Informatlon on the pharmacolosy, toxicology and euphorle potency af the drug and on its ablllty to producz and support physical dependence on marphine. from these data d satisfectory evaluation of the addicilon llabtllty of the compound can be made. The determinatlon of antItussiye effcct must be done elzewherc. VII. LOCATION CF THE PROJECT ..

The experiments described above wtll be carrled out In the Natlonal lastitute of Mental Health, Addictlon Rescarch Center, Publie Health Service Hospltal, Lexlagton, Kentucky. This hospital is devoted entireiy to the treatmest and study of drug addictlon and, at the currénf fime, Is the only place In the world where these studies- cen be satisfactorliv careled out. The Instltution provides the two aecessary facllities for this type of work: ll a pool of patlents who will volunteer for experimeats of the type described above; 2) strlct envlronmental control, shlch pravenis tfe Infroduetion of

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of drugs other than those uacer study lato the exaerlaentol situation.

VIII. EXPERIMENTAL-PERSCNEL

Tort wilt be carrled out under the directlon of Harris lsbeli, M.C., Director of.the Addtction Research Center. This investiçator has had nine years of experlence in research In narcotic drug addictlon and has published moay papers tn this fleld. He wlll be essisted by tro other experlenced physlclans, Dr. H. F. Fraser and Dr, Abraham Elkier, both of whom have had extenslye experlence In research In addietion, and have many publicatlons in thls fleld. In addltlon to the medical personnel, the part-time services cf a blochemlst and a profcisional pzychologist will be made avallable. A peclal werd for conducting these studles has already been set up and is in operatlon at the time thls project descrlptlon 1s being written (Aprll 30, 19531.

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ESTIMATED COST

l.Personnel:

5 Psychlatric Aldzs GS-5
I Physlcal Sclence Aide GS=4
I Securlty Alde C?e-5
I 2sychologlst CS-5
Biological Aide G5-4

Reserve for Night Differentlal, Overtiae pay, Within-Crade ralses, etc

3.Mtscellaneous Expenses

Item 3, "Liiscellaneous Expenses" Includes money for the purchase of drugs, chemlcals, glassware, eiectroencephalocraphic and photogrephlc paper, needles, syrlnges, ete.

Hapris isbell, M.D. Director of' Rssearch

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