Tuesday, 27.10.2020

Peter R. Martin: Historical Vocabulary of Addiction

Opium

 

       The noun opium is directly borrowed from classical Latin with related forms in French (opium in 13th century in Old French; opion in 15th century in Middle French), Italian (oppio also opio in 14th century) and Spanish (opio, 1555), according to the the current electronic edition of the Oxford English Dictionary (OED), the primary definition is: “A reddish-brown strongly scented addictive drug prepared from the thickened dried latex of the unripe capsules of the opium poppy, Papaver somniferum, used illicitly as a narcotic, and occasionally medicinally as a sedative and analgesic.” As the opium poppy extracts began to be formulated into medicinal preparations, a related term, the noun/adjective opiate, began to be used.  The original OED definition was: “any medicinal preparation containing opium, used chiefly to induce sleep or relieve pain.”  This definition was later modified: “specifically any drug derived from opium, especially morphine and codeine; any of a group of narcotic drugs structurally related to morphine or having physiological effects similar to those of morphine.”  Finally, the noun/adjective opioid came into use as pharmacognosy progressed and allowed the synthesis of molecules with similar actions to those extracted from the poppy, defined in the OED as: “any synthetic narcotic drug derived from or having properties similar to those of morphine.” Eventually, a clear distinction between the terms opioid and opiate was often not made. 

       Ancient Greek writings from the 9th century BCE mention what might well be opium in Homer’s Odyssey (Brownstein 1993): “Presently she [Helen] cast a drug into the wine of which they drank to lull all pain and anger and bring forgetfulness of every sorrow.”  The first documented use of the word opium according to OED was in about 1398 by the Cornish scholar John Trevisian who translated the Bartholomaeus Anglicus (Bartholomew the Englishman) compilation of the encyclopedia De proprietatibus rerum (“On the properties of things)”: the most widely circulated medieval encyclopedia, “Popy hatte papauer…Ther of comeþ Ius þat phisicians clepeþ opium oþer opion.” The OED notes that the first use of the term opiate dates from 1425 in Guy de Chauliac's Grande Chirurgie:  “Solaced or conforted with croco or mirra storacus, as castorio, as in philoneo & in opiatez [L. filonio et opiatis] & suppositoriez.”  The first use of the term opioid according to OED was in The Pharmaceutical Journal in 1957: “Acheson has suggested that the morphinans and other synthetic morphine substitutes should be called opioids.”

       The earliest of these quotes suggested the significant role of extracts from the opium poppy in the physician’s armamentarium.  Numerous subsequent mentions in OED refer to the uses of opium and opiates for analgesia in surgery (e.g., translation by H. von Brunschwig of Noble Experyence Vertuous Handy Warke of Surgeri.sig. Fiiij a/2, 1525: “Whan the payne is grete, then it is nedefull to put therto a lytell Opium.”) and for various medical complaints (e.g., Grete Herball 1525: xxix. sig. Bviv/1: “Agaynst payne of the heed called mygreyne or cephale gyve some hote opiate.”).  Laudatory quotations by eminent physicians have continued through history, including that of the so-called English Hippocrates, Sir Thomas Sydenham (1680): “Among the remedies which it has pleased almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium.”  Sir William Osler, the esteemed Canadian physician of the Victorian, era analogously proclaimed that opium was, “God's own medicine.” (Reference??)

       While the role of opium in medicine was being explored, it soon became apparent that problems were associated with repeated use of poppy extracts and not all about opiates was positive, especially recognition of potential toxicity and addiction (Martin 2016).  For example, the writer and traveler George Sandys (1615) alluded to out-of-control use of opium: “The Turkes are also incredible takers of Opium”;  the English satirist Edward Ward (1699) referred to a potential for loss of temper and possibility of violence related to taking opium: “Offer violence to your most pretious Lives, by taking…Opium”; and the disturbing consequences of discontinuing chronic opioid use were commented upon by the author, politician and arts patron Horace Walpole (1846):  “Lady Stafford used to say to her sister, ‘Well, child, I have come without my wit to-day;’ that is, she had not taken her opium.”  The physician Robert Godfrey (1674) wrote in his treatise Various Injuries and abuses in chymical and galenical Physick committed by Physicians and Apothecaries: “Instances… of such who with Opiates slept to Death.”  This quotation presaged by three centuries the current notion that physician prescribing was the basis for overdose deaths in the “opioid epidemic” of our day (Baumblatt, Wiedeman, Dunn et al. 2014).  Horatio Curtis Wood, the American physician, succinctly wrote (1875): “Death occurs from opium, in the great majority of cases, by failure of the respiration.” Wood’s observation resonates with present-day reports of declining life expectancy fueled by opioid overdose deaths (Hedegaard, Miniño A Warner 2018); such an unexpected decline has not been documented in the U.S. in the past century, since a four-year period which simultaneously included World War I and a flu pandemic.

       Opium has been used by mankind for thousands of years (Rudgley 1999).  Its use in prehistoric times preceded even that of alcohol with which it was subsequently combined, predominantly to relieve pain, as well as to enhance religious rituals and spiritual enlightenment by altered sensory experiences. The opioid poppy had been domesticated by farmers in the northeastern part of the Mediterranean since 6000 BCE.  Cultivation of the poppy spread westward during the Neolithic period with records of the seed found in Switzerland, Germany, extending northward to the British Isles and Poland.  Sumerians, in what today is Iraq, started using opium extracts derived from the seed capsules of the poppy at the end of the 3rd century BCE.  Arab traders brought opium to India and China between the 10th and 13th centuries and, subsequently, opium made its way from Asia Minor to all parts of Europe. 

       Friedrich Sertürner, a German apothecary, is credited with isolating the active ingredient from opium extracts at the beginning of the 19th century (Sertürner 1806).  Sertürner called the isolate morphium after Morpheus, the Greek god of dreams, as in his experimentation the compound highly effectively induced sleep.  The French chemist J.L. Gay-Lussac is known for popularizing Sertürner’s discovery and eventually changing the name to morphine (Brook, Bennett and Desai 2017).  Morphine was first listed in the London Pharmacopeia in 1836, but it was the creation of the hypodermic needle (Rynd 1845) which fueled the meteoric rise in use of morphine (Brook, Bennett and Desai 2017). The combination of high potency and the ability to inject the solution directly into the bloodstream to provide rapid pain relief on the battlefield led to morphine supplanting opium except in patent medicines.  Toxicity, especially addiction to opiates, became more apparent as potency rose.  Consequently, a great deal of energy was spent trying to develop a safer, more efficacious opiate that did not cause addiction.  Diacetylmorphine, or morphine diacetate, was first synthesized in 1874 by C. R. Alder Wright, an English chemist, but became popular only after it was independently re-synthesized 23 years later by another chemist, Felix Hoffmann, working at Bayer Pharmaceutical.  Bayer’s management reputedly coined the drug’s name “heroin” based on the German heroisch which means “heroic, strong” and pronounced the drug to be more potent than morphine and free from abuse liability. This was the first of several such claims for novel opiates throughout the 20th century that continue to the present (Van Zee 2009).  Another strategy to contain opiate addiction has been legislation to diminish supply, e.g. the International Opium Convention signed in 1912 by the United States and many other countries.  The Harrison Narcotics Tax Act became United States federal law on December 17, 1914, for regulation and taxation of the production, importation and distribution of opiates and coca products; this law is considered an important first step in the eventual criminalization of opioid users (Anon. 1915).

       The British organic chemist Sir Robert Robinson discovered the molecular structure of morphine (Gulland and Robinson 1923) for which he was awarded the 1947 Nobel Prize in Chemistry (Bentley 1987).  In 1939 meperidine, the first drug with a structure altogether different from that of morphine but with very similar pharmacological properties, was discovered by serendipity.  Meperidine has found use predominantly as an analgesic.  In 1946, methadone, another structurally unrelated compound with similar pharmacological profile to morphine was synthesized.  Methadone is widely used in the treatment of opioid use disorder due to its pharmacokinetic characteristic of a very slow elimination from the body and reduction of both craving (“narcotic hunger”) and the withdrawal syndrome from opioids with higher abuse liability like morphine or heroin (Dole and Nyswander 1965).  Both of these compounds are considered opioids, a point succinctly made by Martin (1967):  “We have adopted the term opioid, which was proposed by Professor George H. Acheson, to designate those analgesics whose pattern of pharmacological and agonistic effects is similar to that of morphine and… have called this pattern of effects the opioid syndrome.”  The synthesis of opioids with incrementally greater potencies has continued (Janssen, Niemegeers and Dony  1963).

       The final chapter in unravelling the compelling history of the opium poppy and man is the discovery of the stereospecific binding sites for the opioid molecule throughout the nervous system that account for its pharmacological actions (Pert and Snyder 1973) and understanding that these receptors bind endogenously produced molecules which have important physiological functions (Goldstein, Lowney and Pal 1971; Hughes, Smith, Kosterlitz et al. 1975).  This work would not have been possible without the synthesis by Weijlard and Erikson (1942) of nalorphine (N-allylnormorphine), the first opiate antagonist (Unna 1943), which could reverse many actions of opioids, including the respiratory depression produced by morphine or methadone (Fraser, Wikler, Eisenman and Isbell 1952).  Interestingly, nalorphine had analgesic properties but also caused anxiety and dysphoria because it was actually a mixed agonist-antagonist.  Nevertheless, nalorphine led to the first discovered pure antagonist devoid of agonistic activity and that was a competitive antagonist at several opioid receptors (Martin 1967).

       It should not escape the reader, that the word opium has extended meanings beyond physiology and medicine.  These definitions of the word have significant social and historical implications as defined in OED is:  “Something which soothes or dulls the senses; a stupefying agent; or something regarded as inducing a false sense of contentment amongst the general populace, especially whilst diverting attention from more important matters or pursuits (originally and especially with reference to religion).”  This meaning appeared in English quickly after the original use (e.g., Bishop Thomas Morton (1608) wrote: “Stupified with that Opium of implicit faith and blinde deuotion.”) and has played a special role in 20th century political philosophy (e.g., H.J. Stenning’s translation of Karl Marx (1926): “Religion is the moan of the oppressed creature, the sentiment of a heartless world, as it is the spirit of spiritless conditions. It is the opium of the people.”).

       The influential role in geopolitics of opium per se and subsequently, synthetic opioids, should not be forgotten.  The Western world literally destroyed China’s sovereignty, society and  economy in the mid-19th century via the opium trade (Bradley 2015).  As William Atherton DuPuy wrote (1916): “The smuggling of opium and of Chinamen was known to go hand in hand.”  Prior to the Opioid Wars China had ranked first in the world for many centuries in gross domestic product (GDP) before it tumbled precipitously during the 20th century (Maddison 2013).  China now seems to be returning the favor as the United States is struggling with its own Opioid Crisis fueled by illegally imported synthetic opioids related to fentanyl (Wee and Hernández 2018).

 

References:

Anonymous. Mental sequelae of the Harrison Law. N Y Med J 1915;102:1014.

Baumblatt JAG, Wiedeman C, Dunn JR, Schaffner W, Paulozzi LJ, Jones TF: High-risk use by patients prescribed opioids for pain and its role in overdose deaths. JAMA Intern Med. 2014 May;174(5):796-801.

Bentley KW: Sir Robert Robinson – his contribution to alkaloid chemistry. Nat Prod Rep 1987;4:13–23.

Bradley J: The China Mirage: The Hidden History of American Disaster in Asia. Little, Brown and Company, 2015.

Brook K, Bennett J, Desai SP: The Chemical History of Morphine: An 8000-year Journey, from Resin to de-novo Synthesis. J Anesth Hist 2017;3:50–55.

Brownstein MJ: A brief history of opiates, opioid peptides, and opioid receptors. Proc Natl Acad Sci U S A 1993;90:5391–5393.

Dole VP, Nyswander M: A medical treatment for diacetylmorphine (heroin) addiction: A clinical trial with methadone hydrochloride. JAMA 1965;193:646–650.

DuPuy WA: Uncle Sam, detective. New York, McKinlay Stone & Mackenzie, 1916.

Fraser HF, Wikler A, Eisenman AJ, Isbell H: Use of N-allyllnormorphine in treatment of methadone poisoning in man: report of two cases. JAMA 1952;148:1205–1207.

Godfrey R: Various injuries and abuses in chymical and galenical physick committed both by Physicians and Apothecaries, detected, etc. London, 1674.

Goldstein A, Lowney LI, Pal BK: Stereospecific and nonspecific interactions of the morphine congener levorphanol in subcellular fractions of mouse brain. Proc Natl Acad Sci USA 1971;68:1742–1747.

Gulland JM, Robinson R: The Morphine Group. Part I. A Discussion of the Constitutional Problem. J Chem Soc  1923;123:980–998.

Hedegaard H, Miniño A, Warner M: Drug Overdose Deaths in the United States, 1999–2017. Hyattsville, MD, National Center for Health Statistics, 2018.

Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morris HR: Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 1975;258:577–579.

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Wood HC: A treatise on therapeutics: comprising materia medica and toxicology, with especial reference to the application of the physiological action of drugs to clinical medicine. Philadelphia, J.B. Lippincott & Co., 1875.

 

July 4, 2019