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THE ADDICTICN LIABILITIES OF SYNTHETIC SUBSTITUTES FOR CODEINE

Harris Isbell NIMH Addiction Research Center, Lexington, Ky.

H. F. Fraser and A. Wikler

101-149

NAonr-14-60

To develop adequate synthetic substitutes fer codeine,
the opiate which is most widely used in medical practice,
and for which there is no domestic natural source'of supply. ¿

The most satisfactory analgesic substitutes for codeine so far developed are d-propoxyphene (Darvon, Lilly) and ethoheptazine (Zactirin, Wyeth). They are substantlally less addicting than codeine and neither Is subject to narcotic control but they are not as effective as codelne in relief of pain. Two effective cough suppressants have been discovered and'are on the market. They are dextromethorphan. Romilar, a synthetic, and narcotine a byproduct of opium processing. A potent synthetic antidiarrheal or constipating agent (R-1132) has also been discovered which is effective in doses of 5-10 mg three times daily. It has definite addiction liability but most probably lt would be less subject to abuse than codeine.

During the current year advances were made in the methodology for measuring abuse-liability of new drugs. By employing a specially devised "attitude" questicnnaire, it was found that there is considerable variation among narcotic drugs insofar as they are identifled as "dope" (opiates), and addicts express definite preferences. As an adjunct to objective measurements such an "attitude" questionnaire should be useful and simple procedure for evaluating the relative abuse liability of new synthetics. Formerly in man, the method for evaluating drugs by direct addiction (a procedure which simulates that empioyed by the addict in his abuse of drugs) required from two to six months to complete. Experiments during the current year demonstrated that in the cases of morphine, codeine and heroin, a relatively high degree of tolarance and physical dependence develope when these drugs are chronically administered for only 18-20 days. This shortcned "abuse" procedure has made It possibis to conpare the addiction liabillities of several new synthetic opiate-like drugs

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with that of morphine in the same individuais. with that of morpnine in tne same luuiviuuais.

Addiction studies were completed on 9 new compounds. Evaluation of two of these has been submitted to the Committez on Drug Addiction and Narcotics, National Research Council (phenazocine and levophenacyimorphan). Both of these drugs were more potent than morphine in Inducing morphine-like "euphoria""and behavior and both completeiy substituted
for morphine in addicted persons. Although definite physical dependence developed following chronic administration of both of these compounds, the degree of physical dependence was less than that observed in the case of morphine. Their
effectiveness by the oral route has been inadequately explored. atatnn?11i-2-

A compound related to nalorphine structuraily \i-shydroxy-N-gamma gamma-dimethylallyimorphinan) was tested for addiction liability. in postaddicts, its erfects resemble those of morphine, rather than nalorphine and therefore it has no advantages as a substitute for codeine.

A new very potent compound, 1-(Beta-diethylaminoethyl)- 2-(p-ethoxy-benzyl)-5-nitrobenzimidazole methane sulfonate, has been developed by Ciba. In man, the euphoriant dose, on oral administration, was about 0.25 mg (d0-120 times as potent as oral morphine). It was 60 times as effective orally as morphine is subcutaneously in suppressing abstinence from morphine, .During chronic administration, postaddicts were much impressed by its overall sedative effects, although they recognized.it as opiate-like. Since the compound induces definite tolerance and physical dependence its addiction liability would approximate that of morphine.

PLANS FOR FUTURE

Studies on several compounds have been completed and these will be prepared for publication. New drugs to be studied are (a) abutyl ester of R-ll32 (the antidiarrheal agent), (b) the methyi analogue of phenazocine (the counterpart of codeine in this series) and(c) l-3-hydroxy-Npropargyl-morphinan hydrobromide, an anaTgesic which is a morphine antagonist, and hence probably of low addiction liability. From the long-range point of view it is intended to continue the search for substitutes for codeine until drugs are found which are, -in the opinion of-the Committee on Drug Addiction and Narcotics, completely satisfactory substitutes for codeine.

CURRENT REPORTS AND PUELICATIONS

(a) H. F. Fraser and Harris Isbell (1959), "Addiction 1iabil1ties of (a) d1-2-Hydroxy-5,9-dimethyl-2 (phenethy1)- 6,7-benzmorphan HBr (NIH-7519), and (b) 1-3-Hydroxy-Nphenacylmorphinan methane sulfonate (NIH-7525)." Addendum 3, Min. 20th Meet., Committee on Drug Addiction and Narcotics, Nat. Res. Council. Washington, D.C. Natl. Acad. Sci.

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THE ADDICTION LIASILITY OF SYNTHIETIC SUDSTITUTES FOR CODEINE (Project Deseription) Request to the Office of Naval Research for Renewal of Task No. NR 101-149 Contract NAonr-ll-60

1. Background Inforration.

Since 1951 the Natlonal Instituts of Mental Hcalth Addietion Hesearch Centar, U. S. Publle Mealth Service Hospital, Lexington, Ky., has been carrying on a project designed to doveiop a -synthetic substitute for codeine which would be as safe as codeine and as sffective with respect to toxicity, antitussive cctivity, constipative activity, and addiction liabillty. Ths project has been financed in large part by funds from the Office of Naval Research, and this description constitutes a request for renewal of the project for the period 1 July r960 to 30 June 1961.

The project was initiated because synthetic substitutes
for codeine were badly needed sincs opium or morphine derived
fros opium constitute the only sources of codeine. Codeine is
the most widely used narcotlc drug in both civilian and military
medlcal practice. Tha United States consumes 16 to 20 tons of :
this drug yearly so that, uniess adequate synthetic substitutes
are found; the nation must continue to stockplle opium or morphine

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in order to provide ausquats supplies for both the civilian and uilitary population in the svent of var. Ths facilities of the NiiH Addietlon Sesearch Center ere not sufficlent to carry out this work in eddition to the evaluation of potent new analgesics submitted by the Cosaittes on Crug Adáictien and Narcotics, National Research Council, unless additional funds are supplled through the Department of Defense.

2. Wark Accompllshed to Date.

The most satisfactory analgeale substitutes Tcr codaine so far developed are d-propoxyphene (Darvon, Lilly) and ethoheptaalne (7actirin, Wyeth). They are substantially less addicting than codeine and nelther is subject to narcotic control but they are not as effective as codeine In rellef of pain. Two affective cough suppressants have been discovered and are on the market. Thsy are dextromethorphan, Roailar, a synthetic, and narcotine, a by-product of oplum processing. A potent synthetic antidlarrheal or conatipating agent (R-ll2) has also been discovered which is efrective in doses of 5-l0 mg three timas dally. lt has definite addiction llability but most probably it vould be less subject to abuse than codeine.

During the current year advances wore cade in the methodology for measuring abuse-liability of new drugs. By employlng a specially devised "attitude" questionnairs, it

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was found that there ls constderable variation among narcotic drugs Insofar as they are Identifled as "copa" (opiates), and addicts express dcfinite preferences, As an adjunct to objoctive meesurements such an "attitude" questionnaire should be useful and simple procedure for evaluating the relative abuse liability of new synthetics. Forneriy in man, the methot for evaluating drugs by dlrect aciiction (a proccdure which slaulates thst énployed by the addict in his abuso of drugs) required froa tuo to six months to conplete. Experiments during tho current year demonstrated that in the cases of morphins, coduine-and heroin, a relatively high dagree of tolerance and physical dependence develope when these drugs are chronically adainistered for only lü-20 days. This shortened "abuse" procedure has made it possible to compare the addiction llabilitics of savoral new synthetic opiatslike drugs with that of morphins In ths sams individuals. Adcicton studles were completeu on 9 new compounds. Evaluatien of two of these has besn submitted to the Committee on Drug Addiction and liarcotics, National Rescarch Council (phenazoclne and levophenacylmorphan). Both of these drugs were more potent then morphine in Inducing morphine-like "euohoria" and behavior and both completely substituted for morphine in acsieted persons. Although definite physical

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depencence developed following chronie auministratlon of both of these coapounds, the degrse of physical dependence was leas than that observed in the casa of morphine. Their effectivensss by the oral route has been Inadaquately explored.

A compounú related to nalorphine structurally (1-3- hydroxy-N-gamna gamma-dimethyiallyiaorphinan) was testad for audietion llabilfty. In postadalcts, Its effects resesble thoss of morphine, rather than nalorphine and therafore it has no auvantages as a substitute for codelne. A new very potent compound, l-(Bsta-slethylanincethyl)- 2-(p-ethoxy-benzyl)-5-nitrobenzimisazole methane suifonate, has been developed-by Cita. in man, the euphariant dose, on oral administration, was about 0.25 mg (8o-120 times as potent as oral morphine). It was éo times as effective orally as morphine Is subcutaneously in supprassing abatinence from morphine. During chronic adninistration, postaddicts wero nuch inpressed by its overall sedative effects, although they recogniasd it as oplate-like. Since the compound induces definite tolerance and physical dependence Its addiction liabiiity would approximate that or morphine

3. Neeu for Continuatien of the Pre lect.

At present, the chief Justification for continuatlon of tho projact ls the urgent need for a substituts for relief of ailld

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grades of pain. As pointed out above, propoxyphane no longer scens to be as proaising as was originally hopad. At the morent no completely satisfactory substitute for codeins for pain relief has besn found. For this reason it is essential to continus the search.

4. Work Proposed.

During the period-fron 1 July 1960 to 30 Junc 1961 ws proposs to test the clinical pharzacology and adlictivo properties of a buty1 ester of R-1132 (1-(3-diphenyl-3- carbonitril-propyl)-h-phenyl-h-carbethoxypipericine); the methyl analogus of phenazocine (the counterpart ef coueine In this serles), and 1-3-hydroxy-N-propargyl-morphinan hydrobromide, an analgesic which is a morphine-antaganiot, and therofore probably of low suaictlon liability- In adgition, studies of other substances regarded as potential codélns substitutes by the Coaaittse on Drug Addiction and Narcotics will'be carrled out, as advised by that body.

5. Methods.

Ths methods used are the standard addictlon liability testing Esthods of the NIlai Addiction Research Contar. Thess teats are accepted as lecal standarcs by the Committeo on Grug Addiction and Narcotics and hava been deseribed in previous project descriptlons, which should be consultau for details.

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6. Evaluatlon cr Data.

Evaluatlon of data has been covered in prevlous project descriptions.

7. Locatisn of the Proloct.

Work wili be carried out In the NlliH Asdiction Rosearch Center, PHS Haspltal, Lexington, Ky. This institution provides the tws necessary facillties for the type of worh to ba undertakent (1) poord patients who will volunteer for experinents with crugs, anc (2) strict environmental control, . whieh prevents introduction af drugs other than those under study into the experimental situation.

8.Experinantal Personnel.

Wark will bs carricd out under the direction of Harris Isbcli, M.D., Director, Nis Addiction Research Center. This Invsstigator has had fifteen years of experienco in research on narcotic árug addicuon and has an extensive bibllography in the field. He will bo asslsted by two other experienced physicians, Dr. H. F. fraser and Dr. Abrahaa Wirler, both of whoa have had extensivs research in this typa of work, and many publications. The part-time services of a biochesist, nauropharmacologist, and research psychologist ars also available. A spsciai ward for the coouuct of these studles has been made avallable by tha hosoital and Is currently in operatlon.

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9. Estinated Cost.

The estirated costs are shown on the attached sheet. The acount of money requested Is enly slightly higher than that granted for fiscal year lyéo, the differencs reprasenting $i { \stackrel { . . } { \cdot } } i { \stackrel { . } { \in } } i .$ the salary Incranents of within-grade promotions of the sare nuaber of personnel.

Abradan Wikler, M.D. Acting Director

, Attachsent

12 Novamber 1359

F=20 7

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1.Porsonal Services:

edtcal Aldes (5-6,)

1 Paychologist (0s-5)

1 Clerk-stenographer (GS-h)

1 Animal Carctaker (GS-3)

Premiua Pay (night differential, holiday pay, etc.) estinate Retirenent and Inaurancs

2. Travel

3. Miscallaneous (supplies, equipaent, etc.) Total

This figure does not ineluda cost of Heaith Insurance, to becose efiective 1 July 19éo, sinee cost not presently known.

Attacicant

10 Novembar 1959

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