Eddy, Nathan B.

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The History of the Development of Narcotics

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THE HISTORY OF THE DEVELOPMENT OFNARCOTICSNATHAN B. EDDY*Man and animals generally seek escape from discomfort. Man today seemsmore prone to do so than ever before and, as will be seen, has acquired a consider-able variety of means to that end. No one knows when man learned that therewere natural agents available, the poppy among them, to ease his pains; but he didacquire that knowledge, and there the history of narcotics begins. Legally andotherwise, narcotic has a broader connotation than opiate. Practically, however,the major part of the narcotics problem centers around the opiates and their syntheticsubstitutes, and this account of historical development will deal with these only.Chopra suggests that the food value of the seeds of the opium poppy was recog-nized much earlier than the somniferous property of the capsule or poppy head,"but the capsules were used in the preparation of soporific drugs and soothing bever-ages from time immemorial. Poppies were grown for the capsules in Asia Minormany centuries ago, and the Arabs carried the dried poppy heads to eastern countriesat a very early date. Eventually, someone discovered that at one stage in the develop-ment of the poppy plant, Nature seemed to concentrate its soporific properties-thatis, the ingredients responsible for them-in the plant juice which would exude fromthe lanced ripe poppy head. This juice, collected and dried, is crude opium.Opium became a household remedy and the mainstay of the physician in itscrude form, in pills, and in various liquid preparations-laudanum, paregoric, etc.-whatever the symptomatic need. It also became a medium of social exchange andself indulgence as a confection and, in modified form, for smoking. Even into thelatter half of the nineteenth century, there was little recognition of and less attentionpaid to overindulgence in or abuse of opium. It was the panacea for all ills. Whena person became tolerant to its action and dependent upon it so that abstinencesymptoms developed if a dose or two were missed, more was taken for the achesand pains and other discomforts of abstinence, just as it was taken for similarsymptoms from any other cause.In the first decade of the last century, just about 15o years ago, the curiosity ofSertiirner, a German pharmacist, brought about the separation and recognition of*M.D. 1911, Cornell University. Chief, Section on Analgesics, Laboratory of Chemistry, NationalInstitute of Arthritis and Metabolic Diseases, U. S. Department of Health, Education and Welfare; Secre-tary, Committee on Drug Addiction and Narcotics of the National Research Council; Member, Expert Panelon Drugs Liable to Produce Addiction, World Health Organization; Consultant, World Health Organiza-tion. Research Professor of Pharmacology, University of Michigan, 1930-39. Author of many papers onthe relation of chemical structure and action of narcotics and synthetic analgesics.' Chopra, Quasi-medical Use of Opium in India and Its Effects, 7 BULL. NARCOTICS, I (956).4 LAW AND CONTEMPORARY PROBLEMSthe main ingredient of opium Sertiirner called the agent morphine; but, althoughit was admittedly the most important active constituent of opium, physicians wereslow to use it in preference to the crude drug, and there were many assertions of thesuperiority of the latter, even after the discovery of the hypodermic syringe towardsthe middle of the century.Codeine, another of the natural alkaloids of opium, was isolated only a few yearsafter the discovery of morphine. It was tried almost immediately in clinical medi-cine3 but gained little popularity for about another fifty years. The first artificiallyproduced derivative of morphine appears to have been apomorphine; 4 ethylmorphine(dionin) was reported in i88;' and in 189o, Dott and Stockman described a seriesof morphine derivatives and discussed at length the modifications of action pro-duced by changes in chemical structure.'Up to this time, the principal objective of work in this field was elucidation ofthe structure of morphine. Attention, however, began to be focused on improve-ment in therapeutic effectiveness when diacetylmorphine (heroin) was introducedin I898.7 The frequent abuse of morphine and the phenomena of addiction hadbegun to be recognized, and heroin was hailed as a drug of increased effectivenesswith decreased addiction liability. This was the first of a series of such claims fornew agents arising from overenthusiastic misinterpretation of inadequate data,usually advanced in spite of warnings of danger. Even the early literature onheroin contains such warnings. Strube, for example, noted that his patients liked thenew drug and continued to take the heroin pills after he ceased to prescribe them;he admitted the possibility of addiction.' Nevertheless, heroin gained rapidly inpopularity, became eventually the drug of choice in the illicit drug traffic, and, insome quarters, still is considered indispensable.The next thirty years saw much work on the morphine structure, intensive in-vestigation of the details of morphine action in the body, but introduction of com-paratively few new morphine derivatives. Worth mentioning, however, are di-hydrocodeine, dihydromorphine, dihydrocodeinone (dicodid, Hycodan), dihydro-morphinone (Dilaudid), and dihydrohydroxycodeinone (eukodal), all of whichwere tried in Germany during this period. Dilaudid was introduced in this country2See Sertfiner, De la morphine et de l'acide m~conique, considerls comme parties essentielles del'opium, 5 ANN. D. CHIM. ET PHYS. 21 (1817).'See Barbier, Observations stir la codeine consideris comme agent therapeutique, 6 BULL. oEN. TINERAP.141 (1834).' See Matthiesen and Wright, Apomorphia, a New Base Derived from Morphine, ix PmtRm. J. & Tn.23, 40 (1869).See Grimaux, Sur la transformation de la morphine en codeine et en bases homologues, 92 CoMPr.REN. AcA. sc. 1140 (88s).'Dott and Stockman, Pharmacology of Morphine and Its Derivatives, 17 P oc. Roy. Soc'y EDIN. 321(1890)."See Dreser, Pharmakologisches fiber einige Morphinderivative, 24 DEUT. NiED. WNSMCR. 85(x898); Strube, Mittheilung fiber therapeutische Versuche mit Heroin, 35 BERL. MIN. WNSCUU. 903(z898).' Strube, supra note 7.HISTORYin 1932; the use of dicodid for cough began some years later; and interest in dihydro-codeine is currently being revived.Beginning in 1929 and continuing for about eleven years, the Drug AddictionCommittee of the National Research Council directed a comprehensive programof chemical, pharmacological, and clinical investigations, which included the pro-duction and testing of about 150 morphine derivatives and twice that number ofcompounds synthesized from simpler chemical structures. The program had twomajor accomplishments to its credit: the proof, by accumulation of systematic data,that chemical modification of morphine is not always followed by uniform modifica-tion of all of its many effects on the animal body; and the demonstration of sig-nificant analgesic (pain-relieving) action with simpler chemical substances notclosely related to the structure of morphine. Two of the new morphine derivativesassumed practical importance and were introduced to physicians generally. One ofthese, metopon, had increased analgesic power, especially when taken by mouth, withless of the dulling effect which morphine has on the senses generally. The other,desomorphine, had greatly increased analgesic power of short duration, with littleor no tendency to produce nausea or vomiting so commonly seen when morphineis used. None of the many synthetic substances investigated merited extensiveclinical trial, and no morphine-like analgesic without addiction liability was found.In the late x93o's, German chemists were looking for a synthetic substitute foratropine. One product of this research was shown to have significant analgesiceffect and, subsequently, other morphine-like properties; this was meperidine (pethi-dine, Demoral, Dolantin, etc.)Y Thus, a by-product of one investigation becamethe first wholly synthetic pain-relieving drug with an activity comparable practicallyto that of morphine. At first sight, meperidine appeared to bear no relation to thechemical structure of morphine, in spite of similarities of action. After the fact-i.e.,after the demonstration of its analgesic effect-however, Schaumann quite ingeni-ously showed that there were, indeed, chemical features common to the structures ofboth compounds.Recognition of the morphine-like characteristics of meperidine, caused it to bebrought almost immediately under narcotics control in Germany. At that time, inthis country, however, there were no means for bringing about such control of asubstance not derived from the natural sources specifically named in the narcoticslaw, and this lack was corrected only by the enactment of a special statute on July i,t944.10 Meanwhile, although tests at the Public Health Service Addiction ResearchCenter had demonstrated its addiction potentiality,1 ' the impression was fosteredthat meperidine was relatively safe in this respect. Unfortunately, this false im-pression persists, and persons have become addicted to meperidine who might haveescaped if there had been an understanding of the risk involved. Rasor and Crecrafto See Eisleb and Schaunann, Dolantin, cn neuantlge Spasmolytikum and Analgetikum (chemischesund pharmakologisehes), 65 Daur. ME1. ,VNscrm. 967 (1939).10 58 STAT. 721 (1944), 21 U. S. C. § 171(a) (1952)." See Himrnmelsbach, Studies of the Addiction Liability of "Demero" (D-r4o), 75 J. PHARMACOL.64 (r942); Further Studies of the Addiction Liability of Demerol, 79 id. at 5 (1943).6 LAW AND CoNTEMPoAY PROBLEMSreported the admission to the Public Health Service Hospital at Lexington of 457meperidine addicts in a thirty-eight-month period to September 1, 1954.12 Nearlyhalf of them were members of the medical or ancillary professions, who, for the mostpart, admitted that they turned to this drug because they thought it less likely toproduce addiction. Confirmed addicts, too, turn to meperidine when it is available;thirty-seven per cent of Rasor's cases had been addicted to other narcotics first.Meperidine is not readily available through illegal sources, but physicians seem lessloathe to prescribe it than other narcotics-most probably owing to the impressionof relative safety already commented on. The majority of meperidine addicts ad-mitted to Lexington stated that physicians were their source of supply.Meperidine production in this country was 123,362 ounces in 1946, 251,oo9 ouncesin 1952, and 394,048 ounces in 1955. Of the last amount, 329,348 ounces were fordomestic use, 20,108 ounces for export. Morphine production was about ioooooounces in 1946 and was 49,062 ounces in 1955. Again, these figures seem to reflectthe greater readiness of physicians to prescribe meperidine, because if one were toassume that all of the decrease in morphine production was replaced by meperidine,the amount required for such replacement should be only about 250,000 ounces, thedose ratio between the two drugs being of the order of 1:5"The discovery of meperidine had a greater effect on the over-all narcotic picturethan its replacement or potential replacement of morphine. As a replacement, itstill has the disadvantages of the latter, but the degree of success as a morphinesubstitute which it represented had a tremendously stimulating effect on the workof organic chemists in this field. The original German investigators and othersthere, in England, and in America made many meperidine derivatives, striving, ashad been done in the program of the Drug Addiction Committee, to dissociate bychemical modification the features responsible for pain relief from those whichproduced undesirable side-effects and addiction. A few of these modifications cameto clinical trial and some to considerable medical use. Alphaprodine, for example,is reported to be a very useful adjunct to nitrous oxide anesthesia. Ketobemidoneis a very powerful pain-relieving drug but develops an intense physical dependence(addiction) with great rapidity; its addiction liability has deterred manufacturersfrom developing it in this country and has led to a recommendation that its medicaluse be abolished entirely.German chemists again achieved an outstanding success in the 194o's by thesynthesis of methadone, qualitatively morphine-like in nearly all respects in animalsand man and quantitatively equivalent to morphine as a pain-relieving drug, milligramfor milligram.'3 Again, methadone seemed very unlike morphine (or meperidine) in12 Rasor and Crecraft, Addiction to Meperidine Hydrochloride (Demerol Hydrochloride), 157A. M. A. J. 654 (1955)."See Scott and Chen, The Action of s, z-diphenyl-z-(dimnethylanzinoisopropyl)-butanone-2, a PotentAnalgesic Agent, 87 J. PHARMACOL. 63 (946); Isbell, et al., Tolerance and Addiction L'abll'ty ol6-Dimethylamino-4, 4 -diphenyl-heptanone-3 (Methadon), 135 A. M. A. J. 888 (947); Denton andBeecher, New Analgesics. 11. A Clinical Appraisal of the Narcotic Power of Methadone and Its Isoners,r41 id. at 1146 (1949).HISTORYstructure; but again, close scrutiny revealed that there were structural characteristicscommon to all three. Methadone very easily substituted for morphine in an estab-lished addiction, readily produced tolerance and addiction when administered alone,but differed significantly from morphine in the abstinence syndrome which followedabrupt withdrawal of the drug. The methadone abstinence syndrome was slower inonset (two to three days as compared with about twelve hours after morphine), lessintense, and much more prolonged.Methadone is so morphine-like in all of its pharmacological characteristics thatit could undoubtedly be used in place of morphine in general medical practice. Theonly advantage of such use, however, would seem to be the relatively mild, prolongedabstinence syndrome, making withdrawal of the drug easier should addiction develop.A recent report compared more than 200 methadone derivatives with respectto the effect of chemical modifications on analgesic effectiveness.' 4 Only a few ofthese have been tried in man, and none has yet come into general use. Work onthis group of compounds continues, however, and currently two members of theseries give some promise of clinical usefulness.Through the years, chemists came to a very complete understanding of thechemical constitution of morphine but attained its total synthesis only quite recently.' 5This is an outstanding scientific achievement, but for the greatest analgesiceffectiveness, complete synthesis is not necessary. In 1947, Grewe had alreadysynthesized N-methylmorphinan, representing the basic ring structure of morphine,but without all of its peripheral groups;' 6 and in 1949, Schnider and Griissner moveda step closer to morphine by the preparation of 3-hydroxy-N-methylmorphiman(racemorphan, Dromoran).17 They also made the methyl ether-that is, the codeineanalog (racemethorphan)-in this new series. Racemorphan is a more powerfulanalgesic than morphine, with at least as long a duration of action. Like morphine,it is addicting; and like morphine, it is prone to produce the same side-effects, butperhaps somewhat less frequently. Racemorphan and racemethorphan are mixturesof optical isomers, and it has been proven that analgesic action and addiction areproduced by one of these isomers only. Most interestingly, the nonaddicting isomer(dextromethorphan) of the codeine analog has been shown to be an effective agentfor the relief of cough and is marketed for that purpose.The chemists have not nearly exhausted the possibilities in any one of thegroups of analgesic compounds which have been mentioned-modifications of mor-phine, meperidine, methadone, or morphinan structures. They have, nevertheless,branched out in other directions and synthesized entirely new structures which haveproved to be as potent as morphine in pain-relieving power, at least experimentally-"' Braenden, Eddy, and Halbach, Synthetic Substances with Morphine-like Effect. Relationship be-tween Chemical Structure and Analgesic Action, 13 BuLL. WORLD HEALTH ORG'N, 937 (1955).";See Gates and Tschudi, The Synthesis of Morphine, 74 J. Am. CHEm. Soc'y, 11o9 (1952); 78 id.at 138o (1956)."8 See Grewe, Synthetic Drugs with Morphine Action, A 59 ANr. CHM. 194 (1947)."'See Schnider and Griissner, Synthese von Oxy-Morphinanen, 32 HELVET. cmm. AarA 821 (1949)-LAW AND CONTEMPORARY PROBLEMSdithienylbutenylamines, hexamethyleneimines, and phenylcyclohexanes, for example,to name only three new types. Unfortunately, when significant analgesic actionappears, the ability to produce addiction is also demonstrable. There is one importantexception which may, however, be the clue to a solution of the problem, analgesicaction without addiction liability, which is the basis for all of the work on newanalgesic agents.A feature of the morphine structure is the occurrence in the molecule of anheterocyclic nitrogen carrying a methyl group, long believed to be optimal foranalgesic action. Forty years ago, Pohl substituted allyl for this methyl group incodeine and reported that the resulting compound was to some extent antagonistic tomorphine.' In i942, Weijlard and Erickson succeeded in making a similar sub-stitution in morphine. 9 This is the compound now known as nalorphine (Nalline).It is strongly antagonistic to many of the effects of morphine in suitable concentra-tion; it will not satisfy a morphine addiction nor produce physical dependence whenrepeatedly administered. Its antagonistic effect is demonstrated strikingly by theremoval of the respiratory depression produced by overdoses of morphine and mor-phine-like substances and by the precipitation of a typical abstinence syndrome if itis given to a morphine addict.In the laboratory, nalorphine exhibits little analgesic action. It can be given toman in combination with morphine, at least in certain dose ratios, without inter-fering materially with morphine's analgesic effect. Most recently, it has been reportedthat nalorphine given alone to patients in pain is as effective as morphine in re-lieving that pain2 Here, then, is one instance in which analgesia equivalent tothat of morphine can be produced by a compound which is not addicting. Nal-orphine is not a practical analgesic or a practical solution of the addiction problembecause of the occurrence of quite remarkable side-effects, worse if the individual hasreceived recently a dose of morphine. Perhaps, however, it is not too much to expectthat a nalorphine-like compound will be found without its disagreeable side-effects,a useful nonaddicting analgesic.In conclusion, we can agree with opinion expressed by the Drug Addiction Com-mittee of the National Research Council that "all needs for morphine and relatedsubstances for symptomatic relief can be met by synthetics now known."'" Thisdoes not say that synthetics are superior to the natural alkaloids, though some maybe. We have reached the point where we could make out with the synthetics inclinical practice if the need arose, and we may be on the brink of a practicalanalgesic without addiction liability.18 See Pohl, Olber das N-Allylnorcodein, einen Antagonisten des Morphins, 17 ZTseCtR. EXPER. PATH.THERP. 370 (1914)." See Weijlard and Erickson, N-Allylnormorphine, 64 J. AM. CHEM. So'&Y, 869 (1942)."0 See Lasagna and Beecher, The Analgesic Effectiveness of Nalorphine and Nalorphine-InorphineCombinations in Man, 112 J. PHARMACOL. 356 (1954); Keats and Telford, Nalorphine, a PotentAnalgesic in Man, x7 id. at i9o (1956).COMMIrrr-EE ON DRuG ADDICTION AND NARcoTncs, Minutes of Tenth Meeting, June 1952, in BULL.DRUG ADDICTION AND NARCOTICS 343 (1952).

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The History of the Development of Narcotics

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