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THE ADDICTION LIABILITY OF SYNTHETIC SUBSTITUTES FOR CODEINE (Project Description) Request to the Cffice of Naval Research for Renewal or Contract NR 101-149 (NAonr-17-58).

1.Backaround Information.

Since 195l the Kational Institute of Mental Health Addiction Research Center, U. S. Public Health Service Hospital, Lexington, Ky., has been carrying an a project designed to develop a synthetic substitute for codeine which would be as safc as codeine and as effective with respect to toxicity, antitussiva activity, constipative activity, and addiction liabillty. The project has been financed in large part by funds from the Offics of Naval Research, and this description constitutes a request fer renewal of the project for the period 1 July 1959 to 30 June 1960.

The project was initiated because synthetic substitutes for codeine wers badly needad since opium or morphine derived from opiua constitute the only sources of codeine. Codeine is the most widely used narcotic drug in both civilian and military modical practice. Ths United States consumes 16 to 20 tons of this drug yearly so that, unless adequate synthetic substitutes ara found, the nation must continuc to stockplle oplum or morphins

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in order to provide adequate supplios for both the civilian and military population in the event of war. The facilities of the NIlH Addiction Rescarch Center are not sufficlent to carry out this work in addition to the evaluation of potent new analgesics submitted by the Connittee on Drug Addiction and Narcoties, Natlonal Research Council, unless additional funds are supplled through the Departaent of Defense.

2. Work Accomplished to Tate.

Previous work has been sumrized in annual progress reports foruarded to Capt. F. H. Quimby and Capt. T. K. Ruebush, Head, Physiology Branch, Offico of Naval Research. Hore than SI drugs have been screened as potential substitutes for codeinc. Nwo very promising substitutes for suppression of cough, dextromethorphan and narcotine, have beon discovered and both are on the market. Nelther drug is addictive and both are effective and safe cough suppressants. Narcotine, unfortunately, is not a synthetic drug but a by-product of opiua processing. However, continuing reports to the Committee on Drug Addiction and Narcotics, NRC, and clinical reports In the medical literaturs indicats that both druga are effective cough suppressants. The antitussive phase of the problem is therefore, in a sense, no longer so urgent.

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There are however no conpounds available wiich are lotm to ba as effoctive and ss safe as codeine for the relief of mild grades of pain. The outstanding substances so far uncovcred In ths program are di- and d-Alpha-4-dimethylamino-1,2-diphenyl-3-mathyl-4-propionoxybutane (dl- or d-propoxyphene,"Darvon"). Addictiveness of these drugs is so low that the Comittee on Drug Addiction and Narcotics has ruled that they need not be subjected to the controls Imposed by the Harrison Narcotic Act. Preliainary ciinical data indicated that these drugs were nearly as effective as codeine in relieving pain. Unfortunately more recent information is not nearly so favorable, and we are now uncertain as to whother propoxyphene will bo an adequate substitute for codcine for pain relief. Sufficient clinical data are still not available. to assess toxicity of the compounds in ordinary clinical practicc.

During the past year 3-Methyl-N-desmethyimorphine (norcodeine) and. d-methadone were shown to be lesa addictive than codeine. Clinical trial of both substancas has been recommended.1-(3-Diphenyl-3-carbonitr11-propy1)-4-phenyl-h4- carbethoxypipsridine (R-ll32), which has besn shown to be extreneiy effectivs as a constipative agont and which may be capabie of replacing codaine or morphine for this purpose, was studied during the ycar. This compound, though addictive is

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less so than codeine. Two pronising potent analgesics, 3-Hydroxy-N-phenethyi benzmorphan (NIH-7519), and 3-Hydroxy-Nphenacylrorphinan (Nli-7525), were partly Investigated. Aithough both drugs are many tines as potent as morphine, abstinence was quite mild after withdrawal following direct addiction experiments. A study of the 3-methyl analogues of these drugs would be of considerable interest.

3. Need for Continuation of the Project.

At present, the chief justification for continuatlon of the project is the urgent need for a substitute for relicf of mlld grades of pain. As pointed out above, propoxyphene no longer seens to be ss promising as was originally hoped. At the moment no completely satisfactory substitute for codeine for pain relief has been found. For this reason it is essential to continue the szsrch.

During ths period from 1 July 1959 to 1 July l960 we propose to test the clinical pharmacology and addictive propertias of 3-Methoxy-N-phenethyl-benzmorphan (the methyl analogue of NIN-7519), and of 3-Methoxy-N-phenacylmorphinan (the mcthyl analoguc of NIH-7525). We also will undertake studies of 1-3-Hydroxy-N-gemma garma-dimethylallylmorphinan, a weak morphine antagonist that posscsses analgasic properties, and

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of the butyl ester analogue of R-ll32. Wa also hope to initiate studies on a new group of synthetic analgesics - the bensimidazoles. In addition, studiss of other substances regarded as potential codeine substitutes by the Committee on Drug Addiction and Narcotics vlll be carrled out, as advised by that body.

5. Methods.

The methods used are the atandard addiction liability testing methods of the NINH Addictlon Research Center. These tests are accepted as legal standards by the Committee on Drug Addiction and Narcotica and have been described in previous project descriptions, which should be consulted for details. 6. Evaluation of Cata.

Evaluation of data has been covered in previous project deseriptions.

7. Location of. the Prolect.

work wili be .carried out in the NIMH Addiction Research Center, PHS Hospital, Lexington, Ky. This institution provices the two necessary facllities for the type of work to be undertakon: (l) pool of patients who will volunteer for experiments with drugs, and (2) strict environmental control, which preyents introduction of drugs other than those under study into the experimental situation.

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8. Expsrimontal Personnel.

Work will be carried out under the direction of Harris Isbell, M.D., Director, NMiiH Addiction Research Centcr. This investigator has had fifteen years of expsrisnee In rescarch on narcotic drug eddiction and has an extensive bibiiograp::y in the field. Ne will be assisted by .two other expurisnced physlcians, Dr. H. F. Fraser and Dr. Abrahan Wikler, both of whoa have had extensive research in this type of work, and many publications. The part-time services of a biocheiaist, neuropharmcologist, and research psychologist are aiso available. A special ward for the cpnduct of these studies hes besn made avallabie by the hospitai and is currently in operation.

9. Estirated Cost.

The estimated costs are showm on the attached shoet. The amount of. money requested is identical to that requestod for the last year (fiscal 1959) and amounts to Se The personal services budget reflects some changes that have becn made among the personnel working on ths project.

31 January 1959

Pacu é

Harrts Isbell, Hi.D. Director

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1.Personal Services

4 Psychiatric Aldes (0S-6,

3 Psychologist (GS-5)

1 Animal Caretaker (GS-3)

1 Clerk-Stenographer (GS-4)

Prenium Pay (night. differential, holiday pay, etc.

Civil Service Retirement Total Personal Services

2.Travel

3. Miscallaneous (supplies, equipnent, ete.) TOTAL