Morphine

 ( World Health Organization Essential Medicines ) 

Urinary concentrations of endogenous codeine and morphine have been found to significantly increase in individuals taking L-DOPA for the treatment of Parkinson's disease.

Morphine and most of its derivatives do not exhibit optical isomerism, although some more distant relatives like the morphinan series (levorphanol, dextrorphan, and the racemic parent chemical racemorphan) do, and as noted above stereoselectivity in vivo is an important issue.

• Halogenating or making other modifications at positions 1 or 2 on the morphine carbon skeleton.
• The methyl group that makes morphine into codeine can be removed or added back, or replaced with another functional group like ethyl and others to make codeine analogues of morphine-derived drugs and vice versa. codeine analogues of morphine-based drugs often serve as prodrugs of the stronger drug, as in codeine and morphine, hydrocodone and hydromorphone, oxycodone and oxymorphone, nicocodeine and nicomorphine, dihydrocodeine and dihydromorphine, etc.
• Saturating, opening, or other changes to the bond between positions 7 and 8, as well as adding, removing, or modifying functional groups to these positions; saturating, reducing, eliminating, or otherwise modifying the 7–8 bond and attaching a functional group at 14 yields hydromorphinol; the oxidation of the hydroxyl group to a carbonyl and changing the 7–8 bond to single from double changes codeine into oxycodone.
• Attachment, removal, or modification of functional groups to positions 3 or 6 (dihydrocodeine and related, hydrocodone, nicomorphine); in the case of moving the methyl functional group from position 3 to 6, codeine becomes heterocodeine, which is 72 times stronger, and therefore six times stronger than morphine
• Attachment of functional groups or other modification at position 14 (oxymorphone, oxycodone, naloxone)
• Modifications at positions 2, 4, 5, or 17, usually along with other changes to the molecule elsewhere on the morphine skeleton. Often this is done with drugs produced by catalytic reduction, hydrogenation, oxidation, or the like, producing strong derivatives of morphine and codeine.

Many morphine derivatives can also be manufactured using thebaine or codeine as a starting material. Replacement of the N-methyl group of morphine with an N-phenylethyl group results in a product that is 18 times more powerful than morphine in its opiate agonist potency. Combining this modification with the replacement of the 6-hydroxyl with a 6-methylene group produces a compound some 1,443 times more potent than morphine, stronger than the Bentley compounds such as etorphine (M99, the Immobilon tranquilliser dart) by some measures. Closely related to morphine are the opioids morphine- N-oxide (genomorphine), which is a pharmaceutical that is no longer in common use; and pseudomorphine, an alkaloid that exists in opium, form as degradation products of morphine.

As a result of the extensive study and use of this molecule, more than 250 morphine derivatives (also counting codeine and related drugs) have been developed since the last quarter of the 19th century. These drugs range from 25% the analgesic strength of codeine (or slightly more than 2% of the strength of morphine) to several thousand times the strength of morphine, to powerful opioid antagonists, including naloxone (Narcan), naltrexone (Trexan), diprenorphine (M5050, the reversing agent for the Immobilon dart) and nalorphine (Nalline). Some opioid agonist-antagonists, partial agonists, and inverse agonists are also derived from morphine. The receptor-activation profile of the semi-synthetic morphine derivatives varies widely and some, like apomorphine are devoid of narcotic effects.

Many salts of morphine are used, with the most common in current clinical use being the hydrochloride, sulfate, tartrate, and citrate; less commonly methobromide, hydrobromide, hydroiodide, lactate, chloride, and bitartrate and the others listed below. Morphine diacetate (heroin) is not a salt, but rather a further derivative, see above.Heroin (morphine diacetate) is a Schedule I controlled substance, so it is not used clinically in the United States; it is a sanctioned medication in the United Kingdom and in Canada and some countries in Continental Europe, its use being particularly common (nearly to the degree of the hydrochloride salt) in the United Kingdom.

Morphine meconate is a major form of the alkaloid in the poppy, as is morphine pectinate, nitrate, sulfate, and some others. Like codeine, dihydrocodeine and other (especially older) opiates, morphine has been used as the salicylate salt by some suppliers and can be easily compounded, imparting the therapeutic advantage of both the opioid and the NSAID; multiple barbiturate salts of morphine were also used in the past, as was/is morphine valerate, the salt of the acid being the active principle of valerian. Calcium morphenate is the intermediate in various latex and poppy-straw methods of morphine production, more rarely sodium morphenate takes its place. Morphine ascorbate and other salts such as the tannate, citrate, and acetate, phosphate, valerate and others may be present in poppy tea depending on the method of preparation.Morphine valerate was one ingredient of a medication available for both oral and parenteral administration popular a number of years ago in Europe and elsewhere called Trivalin—not to be confused with the current, unrelated herbal preparation of the same name—which also included the valerates of caffeine and cocaine. A version containing codeine valerate as a fourth ingredient is distributed under the name Tetravalin.

The salts listed by the United States Drug Enforcement Administration for reporting purposes, in addition to a few others, are as follows:

The poppy straw methods predominate in Continental Europe and the British Commonwealth, with the latex method in most common use in India. The latex method can involve either vertical or horizontal slicing of the unripe pods with a two-to five-bladed knife with a guard developed specifically for this purpose to the depth of a fraction of a millimetre and scoring of the pods can be done up to five times. An alternative latex method sometimes used in China in the past is to cut off the poppy heads, run a large needle through them, and collect the dried latex 24 to 48 hours later.

In India, opium harvested by licensed poppy farmers is dehydrated to uniform levels of hydration at government processing centers and then sold to pharmaceutical companies that extract morphine from the opium. However, in Turkey and Tasmania, morphine is obtained by harvesting and processing the fully mature dry seed pods with attached stalks, called poppy straw. In Turkey, a water extraction process is used, while in Tasmania, a solvent extraction process is used.

Opium poppy contains at least 50 different alkaloids, but most of them are of low concentration. Morphine is the principal alkaloid in raw opium and constitutes roughly 8–19% of opium by dry weight (depending on growing conditions). Some purpose-developed strains of poppy now produce opium that is up to 26% morphine by weight. A rough rule of thumb to determine the morphine content of pulverised dried poppy straw is to divide the percentage expected for the strain or crop via the latex method by eight or an empirically determined factor, which is often in the range of 5 to 15. The Norman strain of P. somniferum, also developed in Tasmania, produces down to 0.04% morphine but with much higher amounts of thebaine and oripavine, which can be used to synthesise semi-synthetic opioids as well as other drugs like stimulants, emetics, opioid antagonists, anticholinergics, and smooth-muscle agents.

In the 1950s and 1960s, Hungary supplied nearly 60% of Europe's total medication-purpose morphine production. To this day, poppy farming is legal in Hungary, but poppy farms are limited by law to . It is also legal to sell dried poppies in flower shops for use in floral arrangements.

It was announced in 1973 that a team at the National Institutes of Health in the United States had developed a method for total synthesis of morphine, codeine, and thebaine using coal tar as a starting material. A shortage in codeine-hydrocodone class cough suppressants (all of which can be made from morphine in one or more steps, as well as from codeine or thebaine) was the initial reason for the research.

Most morphine produced for pharmaceutical use around the world is converted into codeine as the concentration of the latter in both raw opium and poppy straw is much lower than that of morphine; in most countries, the usage of codeine (both as end-product and precursor) is at least equal or greater than that of morphine on a weight basis.

An opium-based elixir has been ascribed to Alchemy of Byzantine Empire times, but the specific formula was lost during the Ottoman conquest of Constantinople (Istanbul). 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.

Morphine was discovered as the first active alkaloid extracted from the opium poppy plant in December 1804 in Paderborn by German pharmacist Friedrich Sertürner. 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. Sertürner originally named the substance morphium after the Greek god of dreams, Morpheus, as it has a tendency to cause sleep.Sertürner coined the term morphium in: Sertuerner (1817) "Ueber das Morphium, eine neue salzfähige Grundlage, und die Mekonsäure, als Hauptbestandtheile des Opiums" (On morphine, a new salifiable i.e.,, fundamental substance, and meconic acid, as principal components of opium), Annalen der Physik, 55 : 56–89. It was 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) "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., took as that substance i.e.,, which I call "morphine" (or morphium), what was only a compound of it with acid of opium.) 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."

The drug was first marketed to the general public by Sertürner and Company in 1817 as a 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. 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.

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 people with the "soldier's disease" of morphine addiction. 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.

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 of diacetylmorphine, it can cross the blood–brain barrier faster than morphine, subsequently increasing the reinforcing component of addiction. 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 mg of morphine sulfate to 1 mg of diamorphine hydrochloride (heroin).

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 (), 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. 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. 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.

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 μ₃-opioid receptor in human tissue. Human cells that form in reaction to cancerous neuroblastoma cells have been found to contain trace amounts of endogenous morphine.

• In Australia, morphine is classified as a Schedule 8 drug under the variously titled State and Territory Poisons Acts.
• In Canada, morphine is classified as a Schedule I drug under the Controlled Drugs and Substances Act.
• In France, morphine is in the strictest schedule of controlled substances, based upon the December 1970 French controlled substances law.
• In Germany, morphine is a verkehrsfähiges und verschreibungsfähiges Betäubungsmittel listed under Anlage III (the equivalent of CSA Schedule II) of the Betäubungsmittelgesetz.
• In Switzerland, morphine is scheduled similarly to Germany's legal classification of the drug.
• In Japan, morphine is classified as a narcotic under the Narcotics and Psychotropics Control Act (麻薬及び向精神薬取締法, mayaku oyobi kōseishinyaku torishimarihō).
• In the Netherlands, morphine is classified as a List 1 drug under the Opium Law.
• In New Zealand, morphine is classified as a Class B drug under the Misuse of Drugs Act 1975.
• In the United Kingdom, morphine is listed as a Class A drug under the Misuse of Drugs Act 1971 and a Schedule 2 Controlled Drug under the Misuse of Drugs Regulations 2001.
• In the United States, morphine is classified as a Schedule II controlled substance under the Controlled Substances Act under main Administrative Controlled Substances Code Number 9300. Morphine pharmaceuticals are subject to annual manufacturing quotas; in 2017 these quotas were 35.0 tonnes of production for sale, and 27.3 tonnes of production as an intermediate, or chemical precursor, for conversion into other drugs. Morphine produced for use in extremely dilute formulations is excluded from the manufacturing quota.
• United Nations (UN), morphine is a Schedule I drug under the Single Convention on Narcotic Drugs.

Animal and human studies and clinical experience back up the contention that morphine is one of the most euphoric drugs known, and via all but the IV route heroin and morphine cannot be distinguished according to studies because heroin is a prodrug for the delivery of systemic morphine. Chemical changes to the morphine molecule yield other euphorigenics such as dihydromorphine, hydromorphone (Dilaudid, Hydal), and oxymorphone (Numorphan, Opana), as well as the latter three's methylated equivalents dihydrocodeine, hydrocodone, and oxycodone, respectively; in addition to heroin, there are dipropanoylmorphine, diacetyldihydromorphine, and other members of the 3,6 morphine diester category like nicomorphine and other similar semi-synthetic opiates like desomorphine, hydromorphinol, etc. used clinically in a number of countries of the world but also produced illicitly in rare instances.

In general, non-medical use of morphine entails taking more than prescribed or outside of medical supervision, injecting oral formulations, mixing it with unapproved potentiators such as alcohol, cocaine, and the like, or defeating the extended-release mechanism by chewing the tablets or turning into a powder for snorting or preparing injectables. The latter method can be as time-consuming and involved as traditional methods of smoking opium. This and the fact that the liver destroys a large percentage of the drug on the first pass impacts the demand side of the equation for clandestine re-sellers, as some customers are not needle users and may have been disappointed with ingesting the drug orally. As morphine is generally as hard or harder to divert than oxycodone in a lot of cases, morphine in any form is uncommon on the street, although ampoules and phials of morphine injection, pure pharmaceutical morphine powder, and soluble multi-purpose tablets are popular where available.

Morphine is also available in a paste that is used in the production of heroin, which can be smoked by itself or turned into a soluble salt and injected; the same goes for the penultimate products of the Kompot (Polish Heroin) and black tar processes. Poppy straw as well as opium can yield morphine of purity levels ranging from poppy tea to near-pharmaceutical-grade morphine by itself or with all of the more than 50 other alkaloids. It also is the active narcotic ingredient in opium and all of its forms, derivatives, and analogues as well as forming from the breakdown of heroin and otherwise present in multiple batches of illicit heroin as the result of incomplete acetylation.

Informal names for morphine include: Cube Juice, Dope, Dreamer, Emsel, First Line, God's Drug, Hard Stuff, Hocus, Hows, Lydia, Lydic, M, Miss Emma, Mister Blue, Monkey, Morf, Morph, Morphide, Morphie, Morpho, Mother, MS, Ms. Emma, Mud, New Jack Swing (if mixed with heroin), Sister, Tab, Unkie, Unkie White, and Stuff.