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THE ADDICTION LIASLLITY OF SYNTHETIC SUBETITUTES FOR CODEINE (Project Descriptlon)

Request to the Ofllce of Naval Fesearch for ths Renewal of Contract MAonr-25-59, NR 101-149

1. Eacaground Information

Since 1961 the Netional Institute of Mental. Eealth Addiction Research Conter has been carrying on a project cith the object of discovering syethetic substitutes for codeine which would be as safe as that drug with respect to toxicity aad addiction llability, and which would also be as effective as codeine as an antitussive, antidiarrheal, and analgesic agent. The project has been firanced partly dy funds fron ths Cäice of Navel Research. This descriçtion constitutes a request for renewal of the project for the perlod 1 July 1981 to 30 June 1962.

Initially the project was undertaken because codeire was the most widely used narcotle drug in beth civilian and military medical practice. Circe codeine is derived from opium, or mada from morphine derived from opium, this situstion made it necessary for the United Etates to stockplle opiun in event of war. The fecllities of the NMH Ardlction Research Center were not

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sufftcient to carry out tho work, in addition to evalnation of potent new analgesics submiited by the Committee on Drug Addiction and Narcoties of the National Fesearch Councll, unleas edditional hunds were suppliod through the Departxsnt of Deiense.

2. Wors Accomplished to Cate

More than 80 compounds have been examinsd in the nine years the project has been opersting. Two nonaddlctive, antitussive dregs (destrorzethorphan and nareotine) were found. Ethoheptarine (Zactirin) and d-propoxyphene (Earvon, Lilly) were found to be less addictive than codeins and both are analgesics clinically, but. anfortunately they are lecs potent and more torc than codeine. Diphenoxylate (8-l132) is a potent diarrheal agent which is less addictive than codeine.

During the current year we have examined nine new druzs. Two of these, phenyramidol and carisoprodol, are reputed to be Interaneial blockers that are effective in relisving pain due to muscular spasm. Nolthar drug possesses morphine-llre addietivensss, and therefora both have potontially reduced tha need for codeize as an anolgasic.

Cne new drug, 1-(p-Chlor-phenethyl)-2-methyì-3,7-dixethozy-1, 2,3, 4- tetrahydroicoquinoline (NIH-7972A or ARC I-K-1) is of great interest. CHnleally I-K-1 is mora cicsely related to papaverise than to morphine. In smal

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animals it induces a rather typical spectrum of morphine-lize effects and Its analgesic potency in anímals is almost equal to that of codeine. In forrzer morphine addicts only mlnor subjective and objective effects cccurred
tollowing oral ádministrstion of as much as 600 mg orally or 180 mg intra-3
vencusly. The drag wac only 1/Tth as potent as codeine intramuscularly In suppressing aoctizence from morphire. Following abrupt withirawal of I-f-1 efter oral administration of doses runníng up to as much as 1co0 mg daily for two months, so symptoms of abstinence were reported. Cbvioualy I-X-1 is much less addictive than is codeine. Despite this, prelimiaary elinical sors indicates that the compound may be as effectivo as codoine in relieving pain.  this Is true, thes I-K-1 roprecents ths greatest degree of disscclation botween analgesie poteny and addictiveness yet achieved.
Unfortunataly I-X-l is soluble only in highly acid solution and therafore is very irritating on injection.

Biochemical studies on the rate of excretion, metabolism, and fata of codelne were udertaken during the year. Codeine and lts metabollc products were isolated âuring administration and following discontinuation of codeine to former morphine addicts, using paper chromatography. The project is 二. not complete sincs final quantitation is to be carried cut, using a gas chromatograph which has not yet been obtatned. Among the objects of the project are to detormine vhat proportlon ef the cojsine is excreted as zorphine end what proçortion as norcodeine. This portion of tho project is to be extended to ro ao of the prooislrg codeine substitites. B-344 B-70,

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3. Noed for Cestlmuatlon of the Crofect

Although a qreat deal of progress bas been made and substltutos are now available for all purposes for which codeine is used, we still have no single drug which is as effective and nontoxtc as codeine. The analgesics, j Darvon and ethohsptasine, are nct nearly as effective as is codeine; clinical investigationdi I-K-1 is not comiplete and furtherzore that drug carnot to given by injectlon. No single synthetic yet discovered incorporates all tha properties of codoine. Further more data ls needed on the excretlon, álstribution, metabolisra and fate of those various synthetie substitutes.

4. York Froposed

Between 1 July 1951 and 1 July 1932 we propose to test the clinical pharmacology and addictivenoss of 4-3-Dimethylamino-l-dlphenylbutyl ethyl sulfone; 1, 2-Dimethyl-S-phemyl-3 pyrollidinol propionate ester; 1-Dimethylarino-3-phenylindane, 1-8'-hydroxy-2,6,9-trimethyt-8,7-benzmorphan; 1-2'Mathoxy-5,9-dlmsthyi-2phenethyi-8, 7-benamorphen; and alpha-dl-3- Acetoay-8-metiylamino-4; 4-diphenylheptare. All of these compcunds have been recommended for study by the Committes cn Crug Addiction and Narootles, National Research Councll,

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In adáition the project on the exeretion of codaine and its metabolites wil be corelsted as soon as a gas chromatograpà is obtained and placed in eperetton. Following this, studies on the mstabolism and fate of I-K-1, R-1132, end proçoxphene will be initiated.

5. Zethods

The rethods used are the standard addiction liasility testing methods of tha MpíH Aédictios Reséarch Center. These tasts ara accepted as lecal standards by the Committee on Drug Addiction and Narcotics, and have deen described in previous project descriptions which should be consulted for detatls.

The biochemical methods ueed are also standard and involve separation of the drugs and their metabolites by extraction with differential solvents az varlous pé, separation from ipurities by paper ehromatography, and Identification by a variety of end reactions including gas chromatography, ultraviolet spoctrophotometry and fluoreseonce measurements.

6. Evaluction of Eata

Evaluation of the data has been covered in previcus project dascriptlons.

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7. Location ef tho Prolect

The work will be carried out at the MTil Addictica Rssearch Center, FES Hospital, Lexington, Ky. This Institution provides tha two necessary facilities for the type of wors to be undertaken: 1) a pool of paticnts who wil volunteer for exorlmsnts with dugs, and S) strict environnenal control, which prevents introduction ál drugs cther than those undar study into the exerimental situation.

Compiete siochenical facilities are also avallable.

8. Experimental Fersomel

The wort will be carried cut under the directlos of Harris Isbell, M. D. , Director, NE Addiction Beceareh Certer. Thia investigator has bad 16 years experisnce in research on narcoue drug addiction and has an extensiva bihliography in the field. Ee will be assisted by two cther experienced physicians, Drs. A.F. Fraser and Abrahamn Wikler, both of whor have done extensive research in addiction and have many pabllcations. The part-tune services of a biochemist, neuropharmacologist, and research psyehoiogist are also available. A special ward for the conduct of these studles has been msia avallable by the hospital and has been operating for more thas eiçht years.

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9. Estimated Cost

The estlmated costs ere shown on the attached shest. The amount of money requested is the sare as that requested for fiscal year 1961.

Jarris Isbell, M. D. Director

Etzh

Attachment

12-28-60

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