TIM ADDIC'.'104'i LIABILITY OF SVIrrF.BTIC ',.eUBSTITUTES FOR CODBIT-ra, (Project Description) Request to the Office of liaval Research for Renewal of Contract II.R 101-149 HAonr-11-57 (0','IR : 441 e t) 2 11 Background Inforrmtion. Since July 1951 a project designed to develop a synthetic drug which would be as safe as codeine with respect to toxicity, antitussive activityp and addiction liability has been carried on within the llational Instittte of I!ental Health Addiction Research Centers U. S. Public Health Service liospital., Lexingto2n, Yi,entucky. This project has been financed In large part by funds from the Office of Naval Research# and this description consti- tutes request for renewal of the project-for the period 1 July 1958 to 30 June 1959. A synthetic substitute for codeine Is badly needed since opium, or morphine dtrived from opium$ constitute the only sources of codeln--. Un2less a synthetic substitute for code,-'&ne Is found the United States nmst continue to stocltpile opium in order to provide adequate supplies of codeine for both the civilian and n-ilitary population In theevent of war. Facillti-.3 of the Addiction Research Center are not sufficient to carry out this idorlts in addi*%,I-on to routine0 drug testing requi.-e,-! ?age 2 for the evaluation of all new analg>2pes>2pics>2po unless additional f>2pu>2pnds are suppliedthrough the Department of Defense, 2>1p. >2pT>2p,>2p%>2pIork Acco>2pmpl>2pished to Date. Prev>2pious work has been su>2pm>2p=>2p.>2p-r>2piz>2ped In the annual progress report sent to Captain F>2po >2p1>2p1>1p, Quimby and Captain T. >2pH>1p.>1p-Roebush>2p, 2 Read of the Phys>2piology Branch$ Office of >2pI>2ptaval Research.' T>2p%>2p->2pio drugs have been developed which are prom>2pis>2ping substi. tutes for codeine for relief of cough. T>2pA>2p%ese drugs are: d>2pextro>2p-methorphan>2pt and 2>1p) >1pnarcot>2pine>1p. Neither drug pose>2p.esses any s>2pign>2pif>2picant addiction liability and both have relatively low toxicity. Continuing reports to the Co>2pmm>2pitt>2pee on Drug Addiction 2 and Narcotics, ?.rational Research Council,, and clinical reports appearing In the literature Indicate that these drugs are effective cough suppres3ant3>1p. The antltuss>2pive phase of the .problem has$ therefore, In a sense been solved. Although the a>2pnt>2pituss>2pive problem Is no longer as pressing there are still no compounds available >2pi>2p&ich are known to be as effective and as safe as codeine for the relief of mild 2 grades of pain. over 46 new drugs or >1pm>1pi>1px>1pt>1pu>1pr>1pe>2ps of drugs have been screened for this purpose. The >1po>1pu>1pt>1p3>1pt>1pa>1pn>1pd>1pi>1pn>1pg substances so far developed are dl>2p- and d>2pwa>1plpha->2p4-d>2pimet>1phylam>2pino-1>2p.2>1p-d>2piph>2penyl>2p-3- met>2phyl>2p->2p4>1p-prop>2plonoxybutanes or dl>2p- and d>1p-propoxyphene>1p. The add>2pict>2pive>1pness of these compounds Is >1p3>1po low t>2pi>2p%at the Co0mmittee on Dr>2p4>2p,>2p->2plg Addiction and >2pI>2p%>2pTarc>1potlcs has ruled that they need not be Page .subjected to the controls imposed by the Harrison Act* Prelim-. inary clinical data Indicated that they were nearly as effective as codeine for the relief of pain. Complete data on toxicity and clinical use are still not available$ and morerecent reports Indicate that their analgesic potentialities =y not be as great as was originally claimed. 2 During the past IS months inportant leads have been. developed concerning the demethylated derivatives of morphine an,d morphinan, liormorphine has been shown to be an active agent for inducing sedation in man. It suppresses abstinence from morphine completely, buts unlike morphine, abstinence following withdrawal after direct addiction is quite mild. These studies are now being extended to Inc2lude nor'codeines 1-3-hydroxy- morphinan (.1-nordromoran) and l-,3-methoxy-morphinan, Evidence of some activity in d-isomer3 in the methadone series has also been obtained. We'hope to develop and complete studies on these compounds within the next 18 months. Need for Continuation of the Pro,ject. the chief need for continuation of the p9roject Is related to conflicting reports concerning the analgesic potency of dl- and d-propoxyphene. Original clinical trials for relief of chronic pain were promising. VLore recent trials against post- part= pain and chronic pain due to cancer have not been >1p?ase 6>2p0 Evaluation of ]Data. Evaluation of data obtained In the>2p.addiction>1p-l>2piab>2pil>2pi>2pl>2ply progra>2pm >1ph>1pa>2ps >1pa>1pl>2ps>1po >2pb>2p4>2pi>1pe>1pn >1pd>1pi>1ps>1pc>1pu>1ps>2ps>1pe>1pd in previous project descriptions. 7>1p. Location of Project. The work will be carried out-in the Nl>2pf>2p->2pt>2pi Addiction >1pR>1pe>1p3>1pe>2pi>1pr>1pc>1ph C2>2penter>2ps PHS Hospitals Lex>2pington>2po >2pKentucky>1p. This Institution provides the two >1pn>1pe>1pc>1pe>1ps>2ps>1pa>1pr>1py facilities for the typ>1p'e of work to be underta>2pl>2pi>2pten>2pt >1p1>1p) a pool of patients who will volunteer for experiments with drugsp and 2>1p) strict environmental control which prevents the Introduction of drugs other than those under study In an experimental situation. Ex>2pveri>2pmental Personnel. 2Work will be carried out under the direction of Harris- >1p1>1p3>1pb>1pe>1pl>1pl>2ps >2pI>2pA>1p.D>1p.>2p# Directors NI>2pK>2p">2pI Addiction Research Center, This Investigator has had 1>1p4 years of experience In research on narcotic drug addiction and has pub>1pl>2pi>2ps>2phed many papers>1p.>2pin the field, He will be ass>2p.isted by two other experienced physicians, Dr. R. F. Fraser and >2p6r>1p. Abraham >1pWil>2ptler>2ps both of whom have had 9 extensive experience in research on drug addictions with many publications. The part-time >1ps>1pe>1pr>1pv>1pi>1pc>1pe>2ps of a biochemist, neuro>1p- phar>2pr>2pacologist>1p, and research psychologist are also available. A special ward for the conduct of these studies Is currently in operation. toe >1p9>1p. Est>2pl>2pi>2pn>1p-at>2p@>2p-d Cost. The est>2pi>2pr>2paated costs are shown on the attached sheet. It will be noted that the >2p=ount of money requested Is higher than >2pIn past years. The Increase is d>2pi>2pi>2pe to increased costs in the perso>2pnnel>2p,serv>2pices account* to within-grade promotions for persons who have been with the project s2ince Its Inception in 1951>2p,>2p- need to provide money for Civil Service ret>2pirement >1p(>2pw>2ph>2pi>2pc>2ph was formerly not paid from operating funds); and to provide for 'Civil Service pay raise anticipated during the current fiscal year >1p(1958>1p)>2p. -If the Civ>2pil >2pServ>2plce pay raise does not eventuates this Item could be eliminated from the budget. On the other hand, If the ra>2pis>2pe Is greater than that provided for In the 3 budget>2p(6>2p.>2p.>2p0>2p4>2p) the figure will need to be Increased accordingly. >2pF>1p-arr>2pis Isbell$ M>1p,D>1p, Director Attachment 27 January 1958