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ABSTRACT lOP SUmmaRYY OF RESULTS

8. Slnce Start of Prolect'. This portlon of. the summery covers e pzrlod from July I, 195l to. January I, 1053. As stoted above; the objective of the project Is to find a synthetlc drug whlch Is as effective and as safe from the polnt of vlew of human toxicity and addictlon Ilabllity as Is codelne. The drug Is nceded because, although adequate synthetic substitutes for morphine are avallable, no such drug of the codeine type Is.avallable. Since 75 per cent of the needs for narcotics are for codeine rather then for morphine, thls meons that we must continue to import and stockpile opium until an adequate substitute for codelne has becn developed. The role of the NliH Addtctlon Research Center in thrs research is related to studying the addiction llabilitles of new drugs. The evaluatlon of analgesic end anti tussive effects necessarlly must be mode elsewhere.

Miethods used In studying addictlon Ilabilities of the new analgesics have been descrlbed in detail In the project descriptlons and in prevlous progress reports. Drugs to be studied are racommended ss promlalng by lhe Commiiiee on Drug Addiction and Narcotlcs ot the Natlonal Research Councll. When such drugs are recelved, the humen pharmacolggy of the compound, whlch Includes determinatlon of its effects on blood pressure, respiratory minute volume, temperature, puplllary size, etc., is carrled out. After this Is completed, . the effects of the drug on the behavior of fcrmer morphine addicts

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are evaluated by admlnisterlng the drug in amounts based on the results obtained In the pharmacological experiments. If the drug Induces behavior resembling that seen after morphine or codeine, it is likely to have addictlon liability. The abllity of the drug to relleve and to prevent the appzarance of syaptoms of abstinence from morphine Is next studied In patlents strongly addicted. to morphine. If the drug relieves or suppresses abstinence, It is judged to have addiction liabllity. In such experiments, the :
dose requlred to relieve or suppress abstinence, and the degrce of relief or suppresslon, are Indices for comparison fth the standard drug, codelne.

When en especially promising drug Is available, tt ts studlcd by the direct eddlction technlc. This Involves the administratlon of ascending doses to former addict voluntzers,over perlods of time ronging betueen 30 to l80 days.  During the addiction perlod, sultable measurements are carrled out to detect end evaluaiz the development of tolerancc. Finally, drugs are withdrawn abruptly and observotlons for deveiopment of abstinence symptoms made.

The drugs studled between 1 July 1951 and 1 January 1953 Included.d and L Dromoran, d and I 3-methyl ether of Dromoran, di, d and 1 2,2-diethylemlnocthyl valerate, di 2,2-diphenyl-4- dimethylamino butyrate, 3-ethylamino 1:l-(2 dithlenyl)-but-l-ene hydrochloride, and 3-diethylemino l:l (2' dithienyl)-but-l-ene hydrechloride.

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The follouing drugs are found to heve either tco high toxleliy or too great addieilon Ilablllty to be considered-os possIble substttutes for codeine: L Dromoran, I 3-mzthyl ether of Dromoran, 3-ethylmethylamino-l:l-(2'dithienyl)-but-l-ene, and 3-diethylamino-1:1 (2idithlenylbbut-l-ene. The following drugs have sufficicntly low toxlclty and sufficlently low addictlon liabilities to be regerded as potentlal codelne substltutes: d Dromoran, d 3-methyI ether of Dromoran, dl, d and 1 2:2-dlphenyl-aminoethyl vülerets, di2:2-diphanyl-4-dimethylamino butyrate. Of these drugs, the d 3-methyl cther of Dromoran appears to be the most promising and Is under clinical test for entitusslve veiue. This compound Is, 二一 however, known to be Ineffeciive as an analgesic. D Dromoran has been discarded, since It is not aneffeetivd antitusslve. It has been recommended that prellainery clinical testing be begun wlth d and 1 2,2-diphenyl-4-dimethylamlno valerate and wlth di cthyl-2.2-dlphenyl-4-dimethylamino butyrate.

b. Results Durino Current Reoorting Perlod. During the first six months of the reporting perlod the project was financed by funds from the Naiional lastltute of Mental Heelth. Since I July l953, It has been financed by the Ofilce of Naval Research. The report includes results obtalned during both periods of time.

The methods used were Identlcal with those described above.

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The followlng drugs-have been tested:

(l1 dl. d and I 2,2-dlphenyl-4-dimethylsmino velerate. Work with these compounds was completed during the flrst six months of the year. The results were Identicel with the tentatlve results reported In the last progress report. All of these compounds. in doses ai óo to 75 mg., Induce slight puplllary constrictlon, slight respiratory depresslon, and behavior resembling that seen after the administratlon of smoll amounts of morphine. No untoward slde effeets were observed mlth the doses used. All of the compounds \_were relatlvely Ineffective In suppressing abstinence from morphine and arg Judged to have low addictton Ilablllty. The dextrorojatory compound appears to. be the most efiective, Preiiminary cilnical testing of the dextraand levorotatory Isomers Is belng recommended to the Drug Addiction Committee.

121 d1 2,2-diphenyl-4-dimcthylamino butyrste. Thls compound has propertles resemblling those descrlbed under (l) sbove. but is even iess potent. Preilminary clinicsl trlal may be warranted.

(3) 3-ethyImethylamlao-1:1-12\*dIthleny1)-but-1-ene. Thls drug is the prototype of a completely new class of synthetic analgeslcs which was dlscovered In Great Brltdin. In doses of 30 to cO mg., It causes pupillary constrlction, depression of

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resplratory rate and minutc volume, and Induces behavlor strongly resembllng that scen after odminlstratlon of 15 to 30 mg. of morohlne sulfatc. The drug Is Irrltating to the skln and Is broken down In the body to unknown sulphur-contalning compsunds whlch cause\_marked discoloratlon of the urine. In some patlents, pecullar mental. reactlons conslsting elther of hypnogoglc delusions or true hallucinations but vitr maintenance of laslght were observed. The drug Is very effectlve In suppressing abstinence from morphine. Durlng a perlod of 30 days experimental addletlon, partial toleranccawss developed. Abstinence was preclpitated ty N-etlylnormorphine ond, or abrupt wlthdrasal, a defintte abstinence syadrome was observed which resembled abstlnence from morphine, ex=ept for time courta. This drug was judged to be too toxlc and to have toohigh addictlon lliabllity to be considered a good subsiltute for codelnez furthermore, It was retatively ineffective when glven orally.

(4) 3-dlethyiamino1:1-(2idithienyl1-but-l-ene.

Thls comoound ciosely rescmbles compound (3) above. iis properiies are almost identiesl slth those of compound l3l and it Is not regarded-as a promislne substitute for codelne.

(5t Aloha-l-methadol. This member of the methadone serles is a very potent drug. In doses of 30 to cO mg. It induces pupillary constriction, resplratory depression, etc. These effects sppear quite slowly.and ure still evident 72 hours followlng admin-Istratlon of thc druc eliher subcytaneously or orally. It is

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exiremely effectivuain suppresslng abstinence from morphine. The drug Is ludged to be too toxle and to hove too high addicflon Ilabillty to be regarded as a promising substItute for codeine.

(ó) Beta-d-acetyimethadol. This compound is simllar to (5l.  Its properties are such that lt is not regarded as a promisIng substitute for codeine.

17) Dextro- and levororatory 2,N-dimethyl-3-hydroxymorphlnan. The dextrcrotatory form of thls compound is qulte Inert In man. If does not produce morphine-like eifects and is completely ineffective In relieving and suppressing abstinence from morphlne. fo untoward toxic effects were observed with 二=
doses renging es high es 75 mg. subcutanecusly or orally. The levorotatory form of the drug hasmorphine-like effects whan given In doses of 30 to 60 mg. eliher hypodermically or orelly. It is folrly-effective in suppressing ebstinence from morphine. The levorotatory form Is judged to have greater addlction Ilabllity than that of codelne. However, in the eyent that d methyl Dromoren is not found to be an effective antItusslve egent, rocommendatlon for clinical trial of thls agent would be varranted, since, as judged'by animal tesfing, it is a very effective antitusslve drus.

(8) Mixiures ofN-Aliylnormorphine and iiorphine.

Mixtures of these drugs have been studled at the Facomoendatlon of the Drug Addletion Committee es the beglaning of a prosrem deslgned to detsrmine whether or not the addictlon liability of

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the more powerful synthetics can be attenuated by the additlon of Na!line or other morphine entsgonists without serlously Impairing therapeutic effects. The foliowlng mixtures have been studled: 1 to 10 (l mg. Nalllne to cach 10 mg. morphine), 1 to 5 (l mg. Nslline to cach 5 mg. of morphine), and I to 3 (l mg. Nalllne to each 3 mg, of morphlne). When administered subcutaneously, development of morphins-like euphorla In former morphine eddicts Is blocked wlth all these mixtures for periods ranging betwesn 2 to 3 hours. The higher the proportion of Nalline In the mixture the more effectiye Is the blocking and the longer It persists. Miosis Induced by morphine. is partlly antagonized by these mixtures. 二二 Depression of resplraiory minute volume, hoveyer, Is not antagonized when the drugs are administered simultaneously. These mixtures preclpitate abstinence or maks abstinence more Iniensc, rather than. relleve It. During direct addictlon experlments, patlents on all three mixtures complalned bitterly that the drug dld not have the desired effects, that it had no "kick" and that It did not makc them "high." Despite thls, evidence of morphine-like Intoxicatlon was observed, including pupllloey coastrlcttons excesslve somnolence, ete.  After a few days of chronic adminis tratlon of the mixture, profuse sueating would occur after each Injectlon. This would perslst for about 20 minutes, only to reappear following the next injection. Patlents also complolned of welrd dreams. On abrupt wlthdrawal of the mixture, some patlenis

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experlenced weird ams and hallucinatlons during the first 24 hours of abstlnence; thereefter, mlld morphine-llke abstinence was observed.. The intensity of abstInence after wlihdrawal of the mixtures was less than following wlthdrawel of morphinz.

Experiments wlih these mixtures have been encouraging. They appear to be relatively safe and they could not be abused by drug addicts, so thelr addiction llebility Is Judged fo be low or non-exlstent. However, certain drawbacks are apparent: both morphine and Nalline cre relatively Ineffective when adminlstered orally. It is also unknown whether the unpleosent effeets observed 三 during chronic adminlstrat-lon of, large "addictlng" doses would occur if thz doses were held in the usual therepeutic range. lf this occurs, the mixiures could not be used clinlcally.

(9) A-4-Diphenyl-ó-Dimethylamino-riexanone-3. Thls member of the methadone serles Induces mild morphine-like effecis. when adminlstered in doses of cO mg. eifher hypodermically or orally. No serlous toxlc effects have been observed wlth these large doses. Only translent, sllsht rellef of ebstlnence was sbserved following sdministration of éo to 75 mg. hypodermlcally to patients vith severe symptoms of withdrevel from morphine. Evaluation of thls drug is incomplete, but af the momont it ls regardad es possibly very promising from the polnt of view of low addlction Ilsblllty.

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(10) di, 1-methyl-4-phenyl-4-carbothoxy-azocycloheptene. This compound is & member of the demerol serles. Doses ranging up to I50 mg. subcutaneous!y induced neither subjectlve nor detect able objective effects in nontolerant former morphine addicts. However, when 2 patlents who were strongly addieted to morphine received 150 mg. of the drug ln a suppressive experlment, serious toxic reectlons menifssted.by dizziness, blurring of vision, anxiety, elevated blood pressure and, In one patient, signs of pulmonary edema ensued. Work with the compound has been suspended pending further animal toxicology at the University of Michigan. PLANS FOR FUTURE:

Immedlete. During the coming slx months we hope to complats work on the drugs Ilsted under Items (7):throvgh (lo) above. In addltion, we plan to Investtgate -the propertles of the folloving morphlne antogorists: (1) N-Allyinordiacetylmorphine, (2) N-Propyidihydronormorphine, (3) dextrerotatory N-Allylnordromoran, (4) levorotatory N-Allylnordromoran,, (5) levorotatory 3-methylether of N-Allylnordromoran. It Is hoped that some of these antagonists elll be effecilve orally. In the event that such an antagonist Is found, the effects oi oral administration of the antaçonist when combined wlth methadone, Dromoren end I 3-nethyl ether of . Dromoran will be studied in the hope of developing en craliy effectivs mlxture of an antagonist lpreferably syntheticl, together with a potent synthetic and orally effectlve analgeslc drug. Such mixtures should, like mlxtures of morphine end Nalllne, hovs

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reduced addictlon liabllity. Ge also plon to open a nem spprooch to the problem and to inyesiigate tlis possIblllty of combining codeine wlth a metabolic biocking agent, betu-dlethylaminoethylpropylacstete. This compound is reported to Increase the Intenslty of sffect and the length of actlon of a number of analgeslc drugs. Combining It vith codelne would represent one way of increasing the supply of codzine.

Long-renge Plans. We Intend to continue the seorch for an adequate substltute for codeine until a drug Is found which is Judged by the Drug Addictloa Commiitee oi the Natlonal Research Councli to fulfifl ell the nscessary requlrsments. Only suspensloa i of the prclect due.to lack of funds would cause work to cease prlor to the attalnment of this coa!.

RErORTS AND PUBLICATIONS IDurIng CurrenT reportIng perlodi

i. Isbell, H., Fraser, H.F., end Wikler, A.: Addiction Liablllry of Dithienylbutylemines. Federailon Proc., 12: 333 (Mar.) 1953.

2. Isbell, H., ond Fraser, H.F.: Astions and Addletlon Lisbllitizs of Dronoran Derlvatives In Men. J. Pharmacol. & Exper. Therep.. 107: 524-530 1Apr.1 1953.

3. Isbell, H., ond Fraser, H. F.: Actlcns and Addiction Llabliity of the Dithlenylbutenylanines In Man. J. Phermacol. & Exper. Therep., 102: 437-421 (0ec.1 1953.

4. Fraser, H. F., Isbeli, H., Vanhorn, G. D., and Nesh, T. L.: Use of Measurements oi Miotic Effccts In Evaluatlng Analezslc Crugs In Men lAistroci). J. Pharmesol. a Exper. Therep. (ln press).

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