Editing Morphine (section)

== History ==
[[File:Friedrich Wilhelm Adam Sertuerner.jpg|thumb|[[Friedrich Sertürner]]]]

The earliest known reference to morphine can be traced back to Theophrastus in the 3rd century BC, however, possible references to morphine may go as far back as 2100 BC as Sumerian clay tablets which records lists of medical prescriptions including opium-based cures.<ref>{{cite journal | vauthors = Norn S, Kruse PR, Kruse E | title = [History of opium poppy and morphine] | journal = Dansk Medicinhistorisk Arbog | volume = 33 | pages = 171–184 | date = 2005 | pmid = 17152761 | url = https://pubmed.ncbi.nlm.nih.gov/17152761 }}</ref>

An opium-based elixir has been ascribed to [[Alchemy|alchemists]] of [[Byzantine Empire|Byzantine]] times, but the specific formula was lost during the Ottoman conquest of [[Constantinople]] ([[Istanbul]]).<ref>{{cite journal |vauthors = Ramoutsaki IA, Askitopoulou H, Konsolaki E |title = Pain relief and sedation in Roman Byzantine texts: ''Mandragoras officinarum'', ''Hyoscyamos niger'' and ''Atropa belladonna'' |journal = International Congress Series |date = December 2002 |volume = 1242 |pages = 43–50 |doi = 10.1016/S0531-5131(02)00699-4 }}</ref> Around 1522, [[Paracelsus]] made reference to an opium-based elixir that he called ''laudanum'' from the Latin word ''laudāre'', meaning "to praise". He described it as a potent painkiller but recommended that it be used sparingly. The recipe given differs substantially from that of modern-day laudanum.<ref name="Sigerist">{{cite journal | vauthors = Sigerist HE |title=Laudanum in the Works of Paracelsus |journal=Bull. Hist. Med. |date=1941 |volume=9 |pages=530–544 |url=http://www.samorini.it/doc1/alt_aut/sz/sigerist-laudanum-in-the-work-of-paracelsus.pdf |access-date=5 September 2018}}</ref>

Morphine was discovered as the first active alkaloid extracted from the [[opium poppy]] plant in December 1804 in [[Paderborn, Germany|Paderborn]] by German pharmacist [[Friedrich Sertürner]].<ref name="pmid18443637"/><ref name=Luch2009 /><ref>{{cite journal | title = Friedrich Sertürner (Untitled letter to the editor) | date = 1805 | url = https://books.google.com/books?id=8A09AAAAcAAJ&pg=PA229 | archive-url = https://web.archive.org/web/20160817101928/https://books.google.com/books?id=8A09AAAAcAAJ&pg=PA229 | archive-date=17 August 2016 | journal = Journal der Pharmacie für Aerzte, Apotheker und Chemisten | trans-title = Journal of Pharmacy for Physicians, Apothecaries, and Chemists | language = de | volume = 13 | pages = 229–243; see especially "III. Säure im Opium" (acid in opium), pp. 234–235, and "I. Nachtrag zur Charakteristik der Säure im Opium" (Addendum on the characteristics of the acid in opium), pp. 236–241 }}</ref> In 1817, Sertürner reported experiments in which he administered morphine to himself, three young boys, three dogs, and a mouse; all four people almost died.<ref name=Dahan2010>{{cite journal | vauthors = Dahan A, Aarts L, Smith TW | title = Incidence, Reversal, and Prevention of Opioid-induced Respiratory Depression | journal = Anesthesiology | volume = 112 | issue = 1 | pages = 226–38 | date = January 2010 | pmid = 20010421 | doi = 10.1097/ALN.0b013e3181c38c25 | doi-access = free }}</ref> Sertürner originally named the substance ''morphium'' after the Greek god of dreams, [[Morpheus (mythology)|Morpheus]], as it has a tendency to cause sleep.<ref name=Clay2013/><ref>Sertürner coined the term ''morphium'' in: Sertuerner (1817) [https://babel.hathitrust.org/cgi/pt?id=uc1.b4433519;view=1up;seq=74 "Ueber das Morphium, eine neue salzfähige Grundlage, und die Mekonsäure, als Hauptbestandtheile des Opiums"] (On morphine, a new salifiable [i.e., precipitable], fundamental substance, and meconic acid, as principal components of opium), ''Annalen der Physik'', '''55''' : 56–89. It was [[Joseph Louis Gay-Lussac|Gay-Lussac]], a French chemist and editor of ''Annales de Chimie et de Physique'', who coined the word ''morphine'' in a French translation of Sertuener's original German article: Sertuener (1817) [https://babel.hathitrust.org/cgi/pt?id=nyp.33433062742444;view=1up;seq=29 "Analyse de l'opium: De la morphine et de l'acide méconique, considérés comme parties essentielles de l'opium"] (Analysis of opium: On morphine and on meconic acid, considered as essential constituents of opium), ''Annales de Chimie et de Physique'', 2nd series, '''5''' : 21–42. From p. 22: ''" ... car il a pris pour cette substance, que j'appelle ''morphine'' (''morphium''), ce qui n'en était qu'une combinaison avec ''l'acide de l'opium''."'' ( ... for he [i.e., French chemist and pharmacist Charles Derosne (1780–1846)] took as that substance [i.e., the active ingredient in opium], which I call "morphine" (or ''morphium''), what was only a compound of it with ''acid of opium''.)</ref> Sertürner's morphium was six times stronger than opium. He hypothesized that, because lower doses of the drug were needed, it would be less addictive. However, Sertürner became addicted to the drug, warning that "I consider it my duty to attract attention to the terrible effects of this new substance I called morphium in order that calamity may be averted."<ref>{{cite journal | vauthors = Offit P |title=God's Own Medicine |journal=[[Skeptical Inquirer]] |date=March–April 2017 |volume=41 |issue=2 |page=44}}</ref>

The drug was first marketed to the general public by Sertürner and Company in 1817 as a [[analgesic|pain medication]], and also as a treatment for opium and alcohol addiction. It was first used as a poison in 1822 when [[Edme Castaing]] of France was convicted of murdering a patient.<ref>{{cite book |title = Annual Register |date = 1824 |publisher = J. Dodsley |page = [https://archive.org/details/annualregister03dodsgoog/page/n2 1] |url = https://archive.org/details/annualregister03dodsgoog |quote = Edme. |access-date = 1 September 2015 }}</ref> Commercial production began in Darmstadt, Germany, in 1827 by the pharmacy that became the pharmaceutical company Merck, with morphine sales being a large part of their early growth.<ref>{{cite book | vauthors = Kirsch DR |url=https://www.worldcat.org/oclc/966360188 |title=Drug Hunters. |date=2016 |publisher=Arcade Publishing |isbn=978-1-62872-719-7 |oclc=966360188}}</ref><ref>{{cite book |url=https://www.worldcat.org/oclc/1162209949 |title=Cocaine global histories |date=1999 |publisher=Routledge | vauthors = Gootenberg P |isbn=92-9078-018-5 |location=London |pages=90 |oclc=1162209949}}</ref> In the 1850s, [[Alexander Wood (physician)|Alexander Wood]] reported that he had injected morphine into his wife Rebecca as an experiment; the myth goes that this killed her because of respiratory depression,<ref name=Dahan2010/> but she outlived her husband by ten years.<ref>{{cite book | title= The Pursuit of Oblivion: A Global History of Narcotics| vauthors = Davenport-Hines R | page=68| publisher=W.W. Norton | year=2003 | isbn=978-0-393-32545-4}}</ref>

Later it was found that morphine was more addictive than either alcohol or opium, and its extensive use during the [[American Civil War]] allegedly resulted in over 400,000<ref>{{cite journal | vauthors = Vassallo SA |title = Lewis H. Wright Memorial Lecture |journal = ASA Newsletter |date = July 2004 |volume = 68 |issue = 7 |pages = 9–10 |url = http://www.asahq.org/For-Members/Publications-and-Research/Periodicals/ASA-Newsletter/July-2004-ASA-Newsletter.aspx |url-status = dead |archive-url = https://web.archive.org/web/20140202213600/http://www.asahq.org/For-Members/Publications-and-Research/Periodicals/ASA-Newsletter/July-2004-ASA-Newsletter.aspx |archive-date = 2 February 2014 }}</ref> people with the "soldier's disease" of morphine addiction.<ref>{{cite web |url = http://www.druglibrary.org/schaffer/library/studies/ledain/nonmed4.htm |title = Opiate Narcotics |website = The Report of the Canadian Government Commission of Inquiry into the Non-Medical Use of Drugs |publisher = Canadian Government Commission |url-status = live |archive-url = https://web.archive.org/web/20070404004733/http://druglibrary.org/schaffer/Library/studies/ledain/nonmed4.htm |archive-date = 4 April 2007 }}</ref> This idea has been a subject of controversy, as there have been suggestions that such a disease was in fact a fabrication; the first documented use of the phrase "soldier's disease" was in 1915.<ref>{{cite web |url = http://www.druglibrary.org/schaffer/history/soldis.htm |title = Mythical Roots of US Drug Policy – Soldier's Disease and Addicts in the Civil War | vauthors = Mandel J |url-status = live |archive-url = https://web.archive.org/web/20070405235357/http://druglibrary.org/schaffer/history/soldis.htm |archive-date = 5 April 2007 }}</ref><ref>{{cite web |url = http://www.amusingfacts.com/facts/Detail/soldiers-disease-morphine.html |title = Soldiers Disease A Historical Hoax? |year = 2006 |publisher = iPromote Media Inc |url-status = dead |archive-url = https://web.archive.org/web/20070927041927/http://www.amusingfacts.com/facts/Detail/soldiers-disease-morphine.html |archive-date = 27 September 2007 }}</ref>

Diacetylmorphine (better known as [[heroin]]) was synthesized from morphine in 1874 and brought to market by [[Bayer]] in 1898. Heroin is approximately 1.5 to 2 times more potent than morphine weight for weight. Due to the [[lipophilicity|lipid solubility]] of diacetylmorphine, it can cross the [[blood–brain barrier]] faster than morphine, subsequently increasing the reinforcing component of addiction.<ref name="pmid11961074">{{cite journal | vauthors = Winger G, Hursh SR, Casey KL, Woods JH | title = Relative reinforcing strength of three N-methyl-D-aspartate antagonists with different onsets of action | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 301 | issue = 2 | pages = 690–7 | date = May 2002 | pmid = 11961074 | doi = 10.1124/jpet.301.2.690 | s2cid = 17860947 }}</ref> Using a variety of subjective and objective measures, one study estimated the relative potency of heroin to morphine administered intravenously to post-addicts to be 1.80–2.66&nbsp;mg of morphine sulfate to 1&nbsp;mg of diamorphine hydrochloride (heroin).<ref name="martin and fraser">{{cite journal | vauthors = Martin WR, Fraser HF | title = A comparative study of physiological and subjective effects of heroin and morphine administered intravenously in postaddicts | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 133 | pages = 388–99 | date = September 1961 | issue = 3 | doi = 10.1016/S0022-3565(25)26119-5 | pmid = 13767429 }}</ref>

[[File:MorphineAdvertisement1900 - no watermark.JPG|thumb|Advertisement for curing morphine addiction, c. 1900<ref>{{cite journal |year = 1900 |title = Morphine Easy Home Cure |journal = Overland Monthly |volume = 35 |issue = 205 |pages = 14 |url = http://quod.lib.umich.edu/m/moajrnl/ahj1472.2-35.205/22:6?page=root;rgn=full+text;size=100;view=image |url-status = live |archive-url = https://web.archive.org/web/20140201235613/http://quod.lib.umich.edu/m/moajrnl/ahj1472.2-35.205/22%3A6?page=root%3Brgn%3Dfull+text%3Bsize%3D100%3Bview%3Dimage |archive-date = 1 February 2014 }}</ref>]]
[[File:Morphine Monojet.jpg|thumb|left|An ampoule of morphine with integral needle for immediate use. Also known as a "[[syrette]]". From WWII. On display at the [[Army Medical Services Museum]].]]
Morphine became a controlled substance in the US under the [[Harrison Narcotics Tax Act]] of 1914, and possession without a prescription in the US is a criminal offense.
Morphine was the most commonly abused narcotic analgesic in the world until heroin was synthesized and came into use. In general, until the synthesis of [[dihydromorphine]] ({{circa|1900}}), the dihydromorphinone class of opioids (1920s), and [[oxycodone]] (1916) and similar drugs, there were no other drugs in the same efficacy range as opium, morphine, and heroin, with synthetics still several years away ([[pethidine]] was invented in Germany in 1937) and opioid agonists among the semi-synthetics were analogues and derivatives of codeine such as [[dihydrocodeine]] (Paracodin), [[ethylmorphine]] (Dionine), and [[benzylmorphine]] (Peronine). Even today, morphine is the most sought-after prescription narcotic by heroin addicts when heroin is scarce, all other things being equal; local conditions and user preference may cause [[hydromorphone]], [[oxymorphone]], high-dose oxycodone, or [[methadone]] as well as [[dextromoramide]] in specific instances such as 1970s Australia, to top that particular list. The stop-gap drugs used by the largest absolute number of heroin addicts is probably codeine, with significant use also of [[dihydrocodeine]], poppy straw derivatives like poppy pod and poppy seed tea, [[propoxyphene]], and [[tramadol]].

The structural formula of morphine was determined by 1925 by [[Robert Robinson (organic chemist)|Robert Robinson]].<ref>{{cite journal | vauthors = Gulland JM, Robinson R |title=Constitution of codeine and thebaine |journal=Memoirs and Proceedings of the Literary and Philosophical Society of Manchester |date=1925 |volume=69 |pages=79–86}}</ref> At least three methods of total synthesis of morphine from starting materials such as coal tar and petroleum distillates have been patented, the first of which was announced in 1952, by [[Marshall D. Gates, Jr.]] at the [[University of Rochester]].<ref>{{cite web |url = http://www.rochester.edu/news/show.php?id=20 | vauthors = Dickman S |title = Marshall D. Gates, Chemist to First Synthesize Morphine, Dies |date = 3 October 2003 |website = Press Release |publisher = University of Rochester |url-status = live |archive-url = https://web.archive.org/web/20101201103129/http://www.rochester.edu/news/show.php?id=20 |archive-date = 1 December 2010 }}</ref> Still, the vast majority of morphine is derived from the opium poppy by either the traditional method of gathering latex from the scored, unripe pods of the poppy, or processes using poppy straw, the dried pods and stems of the plant, the most widespread of which was invented in Hungary in 1925 and announced in 1930 by Hungarian pharmacologist [[János Kabay]].<ref>{{cite journal | vauthors = Bayer I | title = [János Kabay and the poppy straw process. Commemoration on the 50th anniversary of his death] | journal = Acta Pharmaceutica Hungarica | volume = 57 | issue = 3–4 | pages = 105–10 | date = July 1987 | pmid = 3314338 }}</ref>

In 2003, there was a discovery of endogenous morphine occurring naturally in the human body. Thirty years of speculation were made on this subject because there was a receptor that, it appeared, reacted only to morphine: the [[μ-opioid receptor|μ<sub>3</sub>-opioid receptor]] in human tissue.<ref>{{cite journal | vauthors = Zhu W, Cadet P, Baggerman G, Mantione KJ, Stefano GB | title = Human white blood cells synthesize morphine: CYP2D6 modulation | journal = Journal of Immunology | volume = 175 | issue = 11 | pages = 7357–62 | date = December 2005 | pmid = 16301642 | doi = 10.4049/jimmunol.175.11.7357 | doi-access = free }}</ref> Human cells that form in reaction to cancerous [[neuroblastoma]] cells have been found to contain trace amounts of endogenous morphine.<ref name="Poeaknapo_2004" />