For other meanings of opium, see Opium (disambiguation). For opium-derived and opium-like substances, see Opiates and Opioids.


Opium poppy fruit exuding latex from a cut.


Source plant(s)
Papaver somniferum

Part(s) of plant

Geographic origin
Indochina Region

Active ingredients
Morphine, Codeine

Main producers
Afghanistan (primary), Pakistan,Northern India, Thailand, Laos,Myanmar, Mexico, Colombia, Hungary

Main consumers
worldwide (#1: U.S.)

Wholesale price
$3,000 per kilogram

Retail price
$16,000 per kilogram

Opium (poppy tears, lachryma papaveris) is the dried latex obtained from opium poppies (Papaver somniferum). Opium contains up to 12% morphine, an opiate alkaloid, which is most frequently processed chemically to produce heroin for the illegal drug trade. The latex also includes codeine and non-narcotic alkaloids, such as papaverine, thebaine and noscapine. The latex is obtained by lacerating (or "scoring") the immature seed pods (fruits); the latex leaks out and dries to a sticky brown residue. This is scraped off the fruit. Meconium historically referred to related, weaker preparations made from other parts of the poppy or different species of poppies. Modern opium production is the culmination of millennia of production, in which the morphine content of the plants, methods of extraction and processing, and methods of consumption have become increasingly potent.

Cultivation of opium poppies for food, anesthesia, and ritual purposes dates back to at least the Neolithic Age. The Sumerian, Assyrian, Egyptian, Minoan, Greek, Roman, Persian and Arab Empires each made widespread use of opium, which was the most potent form of pain relief then available, allowing ancient surgeons to perform prolonged surgical procedures. Opium is mentioned in the most importantmedical texts of the ancient world, including the Ebers Papyrus and the writings of Dioscorides, Galen, and Avicenna. Widespread medical use of unprocessed opium continued through the American Civil War before giving way to morphine and its successors, which could be injected at a precisely controlled dosage.

In China recreational use of the drug began in the fifteenth century but was limited by its rarity and expense. Opium trade became more regular by the seventeenth century, when it was mixed with tobacco for smoking, and addiction was first recognized.[citation needed] Opium prohibition in China began in 1729 yet was followed by nearly two centuries of increasing opium use. China had a positive balance sheet in trading with the British, which led to a decrease of the British silver stocks. Therefore, the British tried to encourage Chinese opium use to enhance their balance, and they delivered it from Indian provinces under British control. A massive confiscation of opium by the Chinese emperor, who tried to stop the opium deliveries, led to two Opium Wars in 1839 and 1858, in which Britain suppressed China and traded opium all over the country. After 1860, opium use continued to increase with widespread domestic production in China, until more than a quarter of the male population were regular consumers by 1905. Recreational or addictive opium use in other nations remained rare into the late nineteenth century, recorded by an ambivalent literature that sometimes praised the drug.

Global regulation of opium began with the stigmatization of Chinese immigrants and opium dens in San Francisco, California, leading rapidly from town ordinances in the 1870s to the formation of theInternational Opium Commission in 1909. During this period, the portrayal of opium in literature became squalid and violent, British opium trade was largely supplanted by domestic Chinese production, purified morphine and heroin became widely available for injection, and patent medicines containing opiates reached a peak of popularity. Opium was prohibited in many countries during the early twentieth century, leading to the modern pattern of opium production as a precursor for illegal recreational drugs or tightly regulated legal prescription drugs. Illicit opium production, now dominated by Afghanistan, was decimated in 2000 when production was banned by the Taliban, but has increased steadily since the fall of the Taliban in 2001 and over the course of the War in Afghanistan.[1][2] Worldwide production in 2006 was 6610 metric tonnes[3]—nearly one-fifth the level of production in 1906. Opium for illegal use is often converted into heroin, which is less bulky, thereby making it easier to smuggle, and which multiplies its potency to approximately twice that of morphine. Heroin can also be taken by intravenous injection, intranasally, or vaporized.


Ancient use (4200 BCE – 800 CE)

Poppy crop from the Malwa India(probably Papaver somniferum var. album.[4])

At least seventeen finds of Papaver somniferum from Neolithic settlements have been reported throughout Switzerland, Germany, and Spain, including the placement of large numbers of poppy seed capsules at a burial site (the Cueva de los Murciélagos, or "Bat cave," in Spain), which have been carbon-14 dated to 4200 BCE[citation needed] Numerous finds of Papaver somniferum or Papaver setigerum from Bronze Age andIron Age settlements have also been reported.[5] The first known cultivation of opium poppies was in Mesopotamia, approximately 3400 BCE, by Sumerians who called the plant Hul Gil, the "joy plant."[6][7] Tablets found at Nippur, a Sumerian spiritual center south of Baghdad, described the collection of poppy juice in the morning and its use in production of opium.[4] Cultivation continued in the Middle East by the Assyrians, who also collected poppy juice in the morning after scoring the pods with an iron scoop; they called the juice aratpa-pal, possibly the root of Papaver. Opium production continued under the Babylonians andEgyptians.

Opium was used with poison hemlock to put people quickly and painlessly to death, but it was also used in medicine. The Ebers Papyrus, ca. 1500 BCE, describes a way to "stop a crying child" using grains of the poppy-plant strained to a pulp. Spongia somnifera, sponges soaked in opium, were used during surgery.[6] The Egyptians cultivated opium thebaicum in famous poppy fields around 1300 BCE. Opium was traded from Egypt by the Phoenicians and Minoans to destinations around the Mediterranean Sea, including Greece, Carthage, and Europe. By 1100 BCE, opium was cultivated on the Mediterranean island ofCyprus, where surgical-quality knives were used to score the poppy pods, and opium was cultivated, traded, and smoked.[8] Opium was also mentioned after the Persian conquest of Assyria and Babylonia in the sixth century BCE[4]

From the earliest finds, opium has appeared to have ritual significance, and anthropologists have speculated that ancient priests may have used the drug as a proof of healing power.[6] In Egypt, the use of opium was generally restricted to priests, magicians, and warriors, its invention credited to Thoth, and it was said to have been given by Isis to Ra as treatment for a headache.[4] A figure of the Minoan "goddess of the narcotics," wearing a crown of three opium poppies, ca. 1300 BCE, was recovered from the Sanctuary of Gazi, Crete, together with a simple smoking apparatus.[8][9] The Greek gods Hypnos (Sleep), Nyx (Night), and Thanatos (Death) were depicted wreathed in poppies or holding poppies. Poppies also frequently adorned statues of Apollo, Asklepios, Pluto, Demeter, Aphrodite, Kybele and Isis, symbolizing nocturnal oblivion.[4]

Islamic Societies (500-1500 CE)

As the power of the Roman Empire declined, the lands to the south, and east of the Mediterranean sea became incorporated into the Islamic Empire, which assembled the finest libraries and the most skilled physicians of the era. Many Muslims believe that the hadith of al-Bukhari prohibits every intoxicating substance as haraam, but the use of intoxicants in medicine has been widely permitted by Scholars, even though it is prohibited under Islamic Law.[10] Dioscorides’ five-volume De Materia Medica, the precursor of pharmacopoeias, remained in use (with some improvements in Arabic versions[11]) from the 1st to 16th centuries and described opium and the wide range of uses prevalent in the ancient world.[12] Somewhere between 400 and 1200 CE, Arab traders introduced opium to China.[4][7][13] The Persian physician Abu Bakr Muhammad ibn Zakariya al-Razi Rhazes (845-930 CE) maintained a laboratory and school in Baghdad, and was a student and critic of Galen, made use of opium in anesthesia and recommended its use for the treatment of melancholy in Fi ma-yahdara al-tabib (In the Absence of a Physician), a home medical manual directed toward ordinary citizens for self-treatment if a doctor was not available.[14][15] The renowned Andalusianophthalmologic surgeon Abu al-Qasim Ammar (936-1013 CE) relied on opium and mandrake as surgical anaesthetics and wrote a treatise, al-Tasrif, that influenced medical thought well into the sixteenth century.[16] The Persian physician Abū ‘Alī al-Husayn ibn Sina (Avicenna) described opium as the most powerful of the stupefacients, by comparison with mandrake and other highly effective herbs, in The Canon of Medicine. This classic text was translated into Latin in 1175 and later into many other languages and remained authoritative into the seventeenth century.[17] Şerafeddin Sabuncuoğlu used opium in the fourteenth century Ottoman Empire to treat migraine headaches, sciatica, and other painful ailments.[18]

Reintroduction to Western medicine

Latin translation of Avicenna‘s Canon of Medicine, 1483

Opium became stigmatized in Europe during the Inquisition as a Middle Eastern influence and became a taboo subject in Europe from approximately 1300 to 1500 CE.[citation needed] Manuscripts of Pseudo-Apuleius‘s fifth-century work from the tenth and eleventh centuries refer to the use of wild poppy Papaver agreste or Papaver rhoeas (identified as Papaver silvaticum) instead of Papaver somniferum for inducing sleep and relieving pain.[19]

The use of Paracelsuslaudanum was introduced to Western medicine in 1527, when Philip Aureolus Theophrastus Bombast von Hohenheim, better known by the name Paracelsus, returned from his wanderings in Arabia with a famous sword, within the pommel of which he kept "Stones of Immortality" compounded from opium thebaicum, citrus juice, and "quintessence of gold."[7][20][21] The name "Paracelsus" was a pseudonym signifying him the equal or better of Aulus Cornelius Celsus, whose text, which described the use of opium or a similar preparation, had recently been translated and reintroduced to medieval Europe.[22] The Canon of Medicine, the standard medical textbook that Paracelsus burned in a public bonfire three weeks after being appointed professor at the University of Basel, also described the use of opium, though many Latin translations were of poor quality.[20] Laudanum was originally the sixteenth-century term for a medicine associated with a particular physician that was widely well-regarded, but became standardized as "tincture of opium," a solution of opium in ethyl alcohol, which Paracelsus has been credited with developing. During his lifetime, Paracelsus was viewed as an adventurer who challenged the theories and mercenary motives of contemporary medicine with dangerous chemical therapies, but his therapies marked a turning point in Western medicine. In the seventeenth century laudanum was recommended for pain, sleeplessness, and diarrhea by Thomas Sydenham,[23] the renowned "father of English medicine" or "English Hippocrates," to whom is attributed the quote, "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."[24] Use of opium as a cure-all was reflected in the formulation of mithridatium described in the 1728 Chambers Cyclopedia, which included true opium in the mixture. Subsequently, laudanum became the basis of many popular patent medicines of the nineteenth century.

The standard medical use of opium persisted well into the nineteenth century. U.S. president William Henry Harrison was treated with opium in 1841, and in the American Civil War, the Union Army used 2.8 million ounces of opium tincture and powder and about 500,000 opium pills.[4] During this time of popularity, users called opium "God’s Own Medicine."[25]

The most important reason for the increase in opiate consumption in the United States during the 19th century was the prescribing and dispensing of legal opiates by physicians and pharmacist to women with ”female problems” (mostly to relieve painful menstruation. Between 150,000 and 200,000 opiate addicts lived in the United States in the late 19th century and between two-thirds and three-quarters of these addicts were women.[26]

[edit]Recreational use in Islamic societies

An imaginary view of an Ottoman opium seller

In Islamic societies, opium is said to have been used for recreational purposes from the 14th century onwards. Testimonies of historians, diplomats, religious scholars, intellectuals and travellers, Ottoman and European, confirm that, from the 16th to the 19th century, Anatolian opium was eaten in Constantinople as much as it was exported to Europe. From eating it, dervishes drew ecstasy, soldiers courage, dignitaries and people bliss and voluptuousness. It is not only to the pleasures of coffee and tulips that the Ottomans initiated Europe. It was also Turkey which, long before China, supplied the West with opium.[27] In hisConfessions of an English Opium-Eater (1821, p. 188), it is still about Ottoman, not Chinese, addicts that Thomas de Quincey writes: "I question whether any Turk, of all that ever entered the paradise of opium-eaters, can have had half the pleasure I had". Extensive textual and pictural sources also show that poppy cultivation and opium consumption were widespread in Safavid Iran [28] and Moghol India.[29] Modern day Iran has the largest number of opium smokers in the world.[30]

[edit]Recreational use in China

An opium den in 18th-century Chinathrough the eyes of a Western artist.

A Chinese opium house, photograph, circa 1900.

Main article: Opium den

The earliest clear description of the use of opium as a recreational drug in China came from Xu Boling, who wrote in 1483 that opium was "mainly used to aid masculinity, strengthen sperm and regain vigor," and that it "enhances the art of alchemists, sex and court ladies." He described an expedition sent by the Chenghua Emperor in 1483 to procure opium for a price "equal to that of gold" in Hainan, Fujian, Zhejiang,Sichuan and Shaanxi where it is close to Xiyu. A century later, Li Shizhen listed standard medical uses of opium in his renowned Compendium of Materia Medica (1578), but also wrote that "lay people use it for the art of sex," in particular the ability to "arrest seminal emission." This association of opium with sex continued in China until the twentieth century. Opium smoking began as a privilege of the elite and remained a great luxury into the early nineteenth century, but by 1861, Wang Tao wrote that opium was used even by rich peasants, and even a small village without a rice store would have a shop where opium was sold.[31]

Smoking of opium came on the heels of tobacco smoking and may have been encouraged by a brief ban on the smoking of tobacco by the Ming emperor, ending in 1644 with the Qing dynasty, which had encouraged smokers to mix in increasing amounts of opium.[4] In 1705, Wang Shizhen wrote that "nowadays, from nobility and gentlemen down to slaves and women, all are addicted to tobacco." Tobacco in that time was frequently mixed with other herbs (this continues with clove cigarettes to the modern day), and opium was one component in the mixture. Tobacco mixed with opium was called madak (or madat) and became popular throughout China and its seafaring trade partners (such as Taiwan, Java and the Philippines) in the seventeenth century.[31] In 1712, Engelbert Kaempfer described addiction to madak: "No commodity throughout the Indies is retailed with greater profit by the Batavians than opium, which [its] users cannot do without, nor can they come by it except it be brought by the ships of the Batavians fromBengal and Coromandel."[13]

Fueled in part by the 1729 ban on madak, which at first effectively exempted pure opium as a potentially medicinal product, the smoking of pure opium became more popular in the eighteenth century. In 1736, the smoking of pure opium was described by Huang Shujing, involving a pipe made from bamboo rimmed with silver, stuffed with palm slices and hair, fed by a clay bowl in which a globule of molten opium was held over the flame of an oil lamp. This elaborate procedure, requiring the maintenance of pots of opium at just the right temperature for a globule to be scooped up with a needle-like skewer for smoking, formed the basis of a craft of "paste-scooping" by which servant girls could become prostitutes as the opportunity arose.[31]

[edit]Chinese diaspora

Beginning in 19th-century China, famine and political upheaval, as well as rumors of wealth to be had in nearby Southeast Asia, led to the Chinese Diaspora. Chinese emigrants to cities such as San Francisco, London, and New York brought with them the Chinese manner of opium smoking and the social traditions of the opium den.[32][33] The Indian Diaspora distributed opium-eaters in the same way, and both social groups survived as "lascars" (seamen) and "coolies" (manual laborers). French sailors provided another major group of opium smokers, having contracted the habit in French Indochina, where the drug was promoted by the colonial government as a monopoly and source of revenue.[34][35] Among white Europeans, opium was more frequently consumed as laudanum or in patent medicines. Britain’s All-India Opium Act of 1878 formalized social distinctions, limiting recreational opium sales to registered Indian opium-eaters and Chinese opium-smokers and prohibiting its sale to workers from Burma.[36] Likewise, American law sought to contain addiction to immigrants by prohibiting Chinese from smoking opium in the presence of a white man.[32]

Because of the low social status of immigrant workers, contemporary writers and media had little trouble portraying opium dens as seats of vice, white slavery, gambling, knife and revolver fights, a source for drugs causing deadly overdoses, with the potential to addict and corrupt the white population. By 1919, anti-Chinese riots attacked Limehouse, the Chinatown of London. Chinese men were deported for playing puck-apu, a popular gambling game, and sentenced to hard labor for opium possession. Both the immigrant population and the social use of opium fell into decline.[37][38] Yet despite lurid literary accounts to the contrary, nineteenth-century London was not a hotbed of opium smoking. The total lack of photographic evidence of opium smoking in Britain, as opposed to the relative abundance of historical photos depicting opium smoking in North America and France, indicates that the infamous Limehouse opium smoking scene was little more than fantasy on the part of British writers of the day who were intent on scandalizing their readers while drumming up the threat of the "yellow peril."[39][40]

[edit]Prohibition and conflict in China

Main articles: Prohibition (drugs) and Opium Wars

Destruction of opium in China

Opium prohibition began in 1729, when Emperor Yongzheng of the Qing Dynasty, disturbed by madak smoking at court and carrying out the government’s role of upholding Confucian virtue, officially prohibited the sale of opium, except for a small amount for medicinal purposes. The ban punished sellers and opium den keepers, but not users of the drug.[13] Opium was banned completely in 1799 and this prohibition continued until 1860.[41]

English opium ships

Under the Qing Dynasty, China opened itself to foreign trade under the Canton System through the port of Guangzhou (Canton), and traders from the British East India Company began visiting the port by the 1690s. Due to the growing British demand for Indian tea and the Chinese lack of interest in British commodities other than silver, the British became interested in opium as a high-value commodity for which China was not self-sufficient. The British traders had been purchasing small amounts of opium from India for trade since Ralph Fitch first visited in the mid-sixteenth century.[13] Trade in opium was standardized, with production of balls of raw opium, 1.1 to 1.6 kilograms, 30% water content, wrapped in poppy leaves and petals, and shipped in chests of 60-65 kilograms (one picul).[13] Chests of opium were sold in auctions inCalcutta with the understanding that the independent purchasers would then smuggle it into China (see Opium Wars).

After the 1757 Battle of Plassey and 1764 Battle of Buxar, the British East India Company gained the power to act as diwan of Bengal, Bihar, and Orissa (See company rule in India). This allowed the company to pursue a monopoly on opium production and export in India, to encourage ryots to cultivate the cash crops of indigo and opium with cash advances, and to prohibit the "hoarding" of rice. This strategy led to the increase of the land tax to 50% of the value of crops, the starvation of ten million people in the Bengal famine of 1770, and the doubling of East India Company profits by 1777. Beginning in 1773, the British government began enacting oversight of the company’s operations, culminating in the establishment of British India in response to the Indian Rebellion of 1857. Bengal opium was highly prized, commanding twice the price of the domestic Chinese product, which was regarded as inferior in quality.[42] The Sassoon family was heavily involved in the opium trade in both China and India.

India is also an opium producing nation. In India, Nimach, Mandsour (Madhya Pradesh), and Chittorgarh (Rajasthan) are major centers for opium production because these areas are suitable for the opium crop i.e. climate, soil. It is the major crop of this region. Nimach has a opium & alkaloid factory which is the organisation of Govt. of India producing alkaloids from opium for pharmaceutical medicine.

Some competition came from the newly independent United States, which began to compete in Guangzhou (Canton) selling Turkish opium in the 1820s. Portuguese traders also brought opium from the independent Malwa states of western India, although by 1820, the British were able to restrict this trade by charging "pass duty" on the opium when it was forced to pass through Bombay to reach an entrepot.[13] Despite drastic penalties and continued prohibition of opium until 1860, opium importation rose steadily from 200 chests per year under Yongzheng to 1,000 under Qianlong, 4,000 under Jiaqing, and 30,000 under Daoguang.[43] The illegal sale of opium became one of the world’s most valuable single commodity trades and has been called "the most long continued and systematic international crime of modern times."[44]

In response to the ever-growing number of Chinese people becoming addicted to opium, Daoguang of the Qing Dynasty took strong action to halt the import of opium, including the seizure of cargo. In 1838, the Chinese Commissioner Lin Zexu destroyed 20,000 chests of opium in Guangzhou (Canton).[13] Given that a chest of opium was worth nearly $1,000 in 1800, this was a substantial economic loss. The British, not willing to replace the cheap opium with costly silver, began the First Opium War in 1840, winning Hong Kong and trade concessions in the first of a series of Unequal Treaties.

Map showing the amount of Opium produced in China in 1908

Following China’s defeat in the Second Opium War in 1858, China was forced to legalize opium and began massive domestic production. Importation of opium peaked in 1879 at 6,700 tons, and by 1906, China was producing 85% of the world’s opium, some 35,000 tons, and 27% of its adult male population regularly used opium —13.5 million people consuming 39,000 tons of opium yearly.[45] From 1880 to the beginning of the Communist era, the British attempted to discourage the use of opium in China, but this effectively promoted the use of morphine, heroin, and cocaine, further exacerbating the problem of addiction.[46]

Scientific evidence of the pernicious nature of opium use was largely undocumented in the 1890s when Protestant missionaries in China decided to strengthen their opposition to the trade by compiling data which would demonstrate the harm the drug did. Faced with the problem that many Chinese associated Christianity with opium, partly due to the arrival of early Protestant missionaries on opium clippers, at the 1890 Shanghai Missionary Conference, they agreed to establish the Permanent Committee for the Promotion of Anti-Opium Societies in an attempt to overcome this problem and to arouse public opinion against the opium trade. The members of the committee were John Glasgow Kerr, MD, American Presbyterian Mission in Canton; B.C. Atterbury, MD, American Presbyterian Mission in Peking; Archdeacon Arthur E. Moule, Church Missionary Society in Shanghai; Henry Whitney, MD, American Board of Commissioners for foreign Missions in Foochow; the Rev. Samuel Clarke, China Inland Mission in Kweiyang; the Rev. Arthur Gostick Shorrock, English Baptist Mission in Taiyuan; and the Rev. Griffith John, London Mission Society in Hankow.[47] These missionaries were generally outraged over the British government’s Royal Commission on Opium visiting India but not China. Accordingly, the missionaries first organized the Anti-Opium League in China among their colleagues in every mission station in China. American missionaryHampden Coit DuBose acted as first president. This organization, which had elected national officers and held an annual national meeting, was instrumental in gathering data from every Western-trained medical doctor in China, which was then published as William Hector Park compiled Opinions of Over 100 Physicians on the Use of Opium in China (Shanghai: American Presbyterian Mission Press, 1899). The vast majority of these medical doctors were missionaries; the survey also included doctors who were in private practices, particularly in Shanghai and Hong Kong, as well as Chinese who had been trained in medical schools in Western countries. In England, the home director of the China Inland Mission, Benjamin Broomhall, was an active opponent of the Opium trade, writing two books to promote the banning of opium smoking: The Truth about Opium Smoking and The Chinese Opium Smoker. In 1888, Broomhall formed and became secretary of the Christian Union for the Severance of the British Empire with the Opium Traffic and editor of its periodical, National Righteousness. He lobbied the British Parliament to stop the opium trade. He and James Laidlaw Maxwell appealed to the London Missionary Conference of 1888 and the Edinburgh Missionary Conference of 1910 to condemn the continuation of the trade. When Broomhall was dying, his son Marshall read to him from The Times the welcome news that an agreement had been signed ensuring the end of the opium trade within two years.

Official Chinese resistance to opium was renewed on September 20, 1906, with an anti-opium initiative intended to eliminate the drug problem within ten years. The program relied on the turning of public sentiment against opium, with mass meetings at which opium paraphernalia was publicly burned, as well as coercive legal action and the granting of police powers to organizations such as the Fujian Anti-Opium Society. Smokers were required to register for licenses for gradually reducing rations of the drug. Addicts sometimes turned to missionaries for treatment for their addiction, though many associated these foreigners with the drug trade. The program was counted as a substantial success, with a cessation of direct British opium exports to China (but not Hong Kong[48]) and most provinces declared free of opium production. Nonetheless, the success of the program was only temporary, with opium use rapidly increasing during the disorder following the death of Yuan Shikai in 1916.[49]

Beginning in 1915, Chinese nationalist groups came to describe the period of military losses and Unequal Treaties as the "Century of National Humiliation," later defined to end with the conclusion of the Chinese Civil War in 1949.[50] The Mao Zedonggovernment is generally credited with eradicating both consumption and production of opium during the 1950s using unrestrained repression and social reform. Ten million addicts were forced into compulsory treatment, dealers were executed, and opium-producing regions were planted with new crops. Remaining opium production shifted south of the Chinese border into the Golden Triangle region, at times with the involvement of Western intelligence agencies.[42] The remnant opium trade primarily served Southeast Asia, but spread to American soldiers during the Vietnam War, with 20% of soldiers regarding themselves as addicted during the peak of the epidemic in 1971. In 2003, China was estimated to have four million regular drug users and one million registered drug addicts.[51]

See also: Japanese opium policy in Taiwan (1895-1945)

[edit]Prohibition outside China

There were no legal restrictions on the importation or use of opium in the United States until the San Francisco, California, Opium Den Ordinance, which banned dens for public smoking of opium in 1875, a measure fueled by anti-Chinese sentiment and the perception that whites were starting to frequent the dens. This was followed by an 1891 California law requiring that narcotics carry warning labels and that their sales be recorded in a registry, amendments to the California Pharmacy and Poison Act in 1907 making it a crime to sell opiates without a prescription, and bans on possession of opium or opium pipes in 1909.[52]

At the US federal level, the legal actions taken reflected constitutional restrictions under the Enumerated powers doctrine prior to reinterpretation of the Commerce clause, which did not allow the federal government to enact arbitrary prohibitions but did permit arbitrary taxation.[53] Beginning in 1883, opium importation was taxed at $6 to $300 per pound, until the Opium Exclusion Act of 1909 prohibited the importation of opium altogether. In a similar manner the Harrison Narcotics Tax Act of 1914, passed in fulfillment of the International Opium Convention of 1912, nominally placed a tax on the distribution of opiates, but served as a de facto prohibition of the drugs. Today, opium is regulated by the Drug Enforcement Administration under the Controlled Substances Act.

Following passage of a regional law in 1895, Australia’s Aboriginal Protection and restriction of the sale of opium act 1897 addressed opium addiction among Aborigines, though it soon became a general vehicle for depriving them of basic rights by administrative regulation. Opium sale was prohibited to the general population in 1905, and smoking and possession was prohibited in 1908.[54]

Hardening of Canadian attitudes toward Chinese opium users and fear of a spread of the drug into the white population led to the effective criminalization of opium for non-medical use in Canada between 1908 and the mid-1920s.[55]

In 1909, the International Opium Commission was founded, and by 1914, thirty-four nations had agreed that the production and importation of opium should be diminished. In 1924, sixty-two nations participated in a meeting of the Commission. Subsequently, this role passed to the League of Nations, and all signatory nations agreed to prohibit the import, sale, distribution, export, and use of all narcotic drugs, except for medical and scientific purposes. This role was later taken up by theInternational Narcotics Control Board of the United Nations under Article 23 of the Single Convention on Narcotic Drugs, and subsequently under the Convention on Psychotropic Substances. Opium-producing nations are required to designate a government agency to take physical possession of licit opium crops as soon as possible after harvest and conduct all wholesaling and exporting through that agency.[4]


Bayer heroin bottle

Opium use still continues in various countries throughout southeast Asia, such as Laos, Burma and Cambodia. Modern day Iran has the highest amount of opium smokers in the world.[30] Globally, however, opium has gradually been superseded by a variety of purified, semi-synthetic, and synthetic opioids with progressively stronger effects, and by other general anesthetics. This process began in 1804, whenFriedrich Wilhelm Adam Sertürner first isolated morphine from the opium poppy.[56][57] The process continued until 1817, when Sertürner published the isolation of pure morphine from opium after at least thirteen years of research and a nearly disastrous trial on himself and three boys.[58] The great advantage of purified morphine was that a patient could be treated with a known dose—whereas with raw plant material, asGabriel Fallopius once lamented, "if soporifics are weak they do not help; if they are strong they are exceedingly dangerous." Morphine was the first pharmaceutical isolated from a natural product, and this success encouraged the isolation of other alkaloids: by 1820, isolations of narcotine, strychnine, veratrine, colchicine, caffeine, and quinine were reported. Morphine sales began in 1827, by Heinrich Emanuel Merck of Darmstadt, and helped him expand his family pharmacy into the Merck KGaA pharmaceutical company.

Codeine was isolated in 1832 by Pierre Jean Robiquet.

The use of diethyl ether and chloroform for general anesthesia began in 1846-1847, and rapidly displaced the use of opiates and tropane alkaloids from Solanaceae due to their relative safety.[59]

Heroin, the first semi-synthetic opiate, was first synthesized in 1874, but was not pursued until its rediscovery in 1897 by Felix Hoffmann at the Bayer pharmaceutical company in Elberfeld, Germany. From 1898 to 1910 heroin was marketed as a non-addictive morphine substitute and cough medicine for children. By 1902, sales made up 5% of the company’s profits, and "heroinism" had attracted media attention.[60]Oxycodone, a thebaine derivative similar to codeine, was introduced by Bayer in 1916 and promoted as a less-addictive analgesic. Preparations of the drug such as Percocet and OxyContin remain popular to this day.

A range of synthetic opioids such as methadone (1937), pethidine (1939), fentanyl (late 1950s), and derivatives thereof have been introduced, and each is preferred for certain specialized applications. Nonetheless, morphine remains the drug of choice for American combat medics, who carry packs of syrettes containing 16 milligrams each for use on severely wounded soldiers.[61] No drug has yet been found that can match the painkilling effect of opioids without also duplicating much of its addictive potential.

[edit]Modern production and usage

[edit]Papaver somniferum

Raw opium

Main article: Opium poppy

In South American countries, opium poppies (Papaver somniferum) are technically illegal, but nonetheless appear in some nurseries as ornamentals. They are popular and attractive garden plants, whose flowers vary greatly in color, size and form. A modest amount of domestic cultivation in private gardens is not usually subject to legal controls. In part, this tolerance reflects variation in addictive potency: a cultivar for opium production, Papaver somniferum L. elite, contains 92% morphine, codeine, and thebaine in its latex alkaloids, whereas the condiment cultivar "Marianne" has only one-fifth this total, with the remaining alkaloids made up mostly of narcotoline and noscapine.[62]

Seed capsules can be dried and used for decorations, but they also contain morphine, codeine, and other alkaloids. These pods can be boiled in water to produce a bitter tea that induces a long-lasting intoxication (See Poppy tea). If allowed to mature, poppy pods (poppy straw) can be crushed and used to produce lower quantities of morphinans. In poppies subjected to mutagenesis and selection on a mass scale, researchers have been able to use poppy straw to obtain large quantities of oripavine, a precursor to opioids and antagonists such as naltrexone.[63]

Poppy seeds are a common and flavorsome topping for breads and cakes. One gram of poppy seeds contains up to 33 micrograms of morphine and 14 micrograms of codeine, and the Substance Abuse and Mental Health Services Administration formerly mandated that all drug screening laboratories use a standard cutoff of 300 nanograms per milliliter in urine samples. A single poppy seed roll (0.76 grams of seeds) usually did not produce a positive drug test, but a positive result was observed from eating two rolls. A slice of poppy seed cake containing nearly five grams of seeds per slice produced positive results for 24 hours. Such results are viewed as false positive indications of drug abuse and were the basis of a legal defense.[64][65] On November 30, 1998, the standard cutoff was increased to 2000 nanograms (two micrograms) per milliliter.[66] During the Communist era in Eastern Europe, poppy stalks sold in bundles by farmers were processed by users with household chemicals to make kompot ("Polish heroin"), and poppy seeds were used to produce koknar, an opiate.[67]

[edit]Harvesting and processing

Harvesting opium

When grown for opium production, the skin of the ripening pods of these poppies is scored by a sharp blade at a time carefully chosen so that neither rain, wind, nor dew can spoil the exudation of white, milkylatex, usually in the afternoon. Incisions are made while the pods are still raw, with no more than a slight yellow tint, and must be shallow to avoid penetrating hollow inner chambers or loculi while cutting into the lactiferous vessels. In Indian Subcontinent, Afghanistan, Central Asia and Iran, the special tool used to make the incisions is called a nushtar or "nishtar" (from Persian, meaning a lancet) and carries three or four blades three millimeters apart, which are scored upward along the pod. Incisions are made three or four times at intervals of two to three days, and each time the "poppy tears," which dry to a sticky brown resin, are collected the following morning. One acre harvested in this way can produce three to five kilograms of raw opium.[68] In the Soviet Union, pods were typically scored horizontally, and opium was collected three times, or else one or two collections were followed by isolation of opiates from the ripe capsules. Oil poppies, an alternative strain of P. somniferum, were also used for production of opiates from their capsules and stems.[69]

Black tar opium seized in Afghanistan, spring 2005

Raw opium may be sold to a merchant or broker on the black market, but it usually does not travel far from the field before it is refined into morphine base, because pungent, jelly-like raw opium is bulkier and harder to smuggle. Crude laboratories in the field are capable of refining opium into morphine base by a simple acid-base extraction. A sticky, brown paste, morphine base is pressed into bricks and sun-dried, and can either be smoked, prepared into other forms or processed into heroin.[7]

The production of wheat in Deh Dehi has decreased dramatically since farmers had invested into the opium trade. Over some years, the opium trade has become the key economic activity in the village. A farmer reported that he can earn between 1000-2000 lakhs annual profit from poppy cultivation instead of the 20 he would make cultivating wheat. Now, all the irrigated land is given over to the poppy cultivation, and most of the men and women who worked in the livestock trade are either involved in the opium trade or work overseas.[70]

Other methods of preparation (besides smoking), include processing into regular opium tincture (tinctura opii), laudanum, paregoric (tinctura opii camphorata), herbal wine (e.g. vinum opii), opium powder (pulvis opii), opium sirup (sirupus opii) and opium extract (extractum opii).[71] Vinum opii is made by combining sugar, white wine, cinnamon, and cloves. Opium syrup is made by combining 997.5 part sugar syrup with 2.5 parts opium extract. Opium extract (extractum opii) finally can be made by macerating raw opium with water. To make opium extract, 20 parts water are combined with 1 part raw opium which has been boiled for 5 minutes (the latter to ease mixing).[71]

Heroin is widely preferred because of increased potency. One study in postaddicts found heroin to be approximately 2.2 times more potent than morphine by weight with a similar duration; at these relative quantities, they could distinguish the drugs subjectively but had no preference.[72] Heroin was also found to be twice as potent as morphine in surgical anesthesia.[73] Morphine is converted into heroin by a simple chemical reaction with acetic anhydride, followed by a varying degree of purification.[74][75] Especially in Mexican production, opium may be converted directly to "black tar heroin" in a simplified procedure. This form predominates in the U.S. west of the Mississippi. Relative to other preparations of heroin, it has been associated with a dramatically decreased rate of HIV transmission among intravenous drug users (4% in Los Angeles vs. 40% in New York) due to technical requirements of injection, although it is also associated with greater risk of venous sclerosis and necrotizing fasciitis.[76]

[edit]Illegal production

International drug routes

See also: Opium production in Afghanistan and Illegal drug trade

Opium production has fallen greatly since 1906, when 41,000 tons were produced, but because 39,000 tons of that year’s opium were consumed in China, overall usage in the rest of the world was much lower.[77] These figures from 1906 have been criticized as over-estimates.[78] In 1980, 2,000 tons of opium supplied all legal and illegal uses.[13] Recently, opium production has increased considerably, surpassing 5,000 tons in 2002. However, the World Health Organization has estimated that current production of opium would need to increase fivefold to account for total global medical need.[78]

In 2002, the price for one kilogram of opium was $300 for the farmer, $800 for purchasers in Afghanistan, and $16,000 on the streets of Europe before conversion into heroin.[79]

Following documented trends of increasing availability mirroring increased American military and geo-political regional involvement, Afghanistan is currently the primary producer of the drug. After regularly producing 70% of the world’s opium, Afghanistan decreased production to 74 tons per year under a ban by the Taliban in 2000, a move which cut production by 94 per cent. A year later, after American and British troops invaded Afghanistan, removed the Taliban and installed the interim government, the land under cultivation leapt back to 285 square miles, with Afghanistan supplanting Burma to become the world’s largest opium producer once more. Opium production in that country has increased rapidly since, reaching an all-time high in 2006. According to DEA statistics, Afghanistan’s production of oven-dried opium increased to 1,278 tons in 2002, more than doubled by 2003, and nearly doubled again during 2004. In late 2004, the U.S. government estimated that 206,000 hectares were under poppy cultivation, 4.5% of the country’s total cropland, and produced 4,200 metric tons of opium, 76% of the world’s supply, yielding 60% of Afghanistan’s gross domestic product.[80] In 2006, the UN Office on Drugs and Crime estimated production to have risen 59% to 407,000 acres (1,650 km2) in cultivation, yielding 6,100 tons of opium, 82% of the world’s supply.[81] The value of the resulting heroin was estimated at $3.5 billion, of which Afghan farmers were estimated to have received $700 million in revenue. For farmers, the crop can be up to ten times more profitable than wheat. The price of opium is around $138 per kilo. However, opium production has led to rising tensions in Afghan villages. Though direct conflict has yet to occur, the opinions of the new class of young, rich men involved in the opium trade are at odds with those of the traditional village leaders.[82]

An increasingly large fraction of opium is processed into morphine base and heroin in drug labs in Afghanistan. Despite an international set of chemical controls designed to restrict availability of acetic anhydride, it enters the country, perhaps through its Central Asian neighbors which do not participate. A counternarcotics law passed in December 2005 requires Afghanistan to develop registries or regulations for tracking, storing, and owning acetic anhydride.[83]

Besides Afghanistan, smaller quantities of opium are produced in Pakistan, the Golden Triangle region of Southeast Asia (particularly Myanmar), Colombia and Mexico.

200 g Spanish opium ball

Chinese production mainly trades and profits off of North America. In 2002, they were seeking to expand through eastern United States. Due to post 9/11 era, trading between borders became difficult and because new international laws were set into place, opium trade became more diffused. Power shifted from remote to high-end smugglers and opium traders. Outsourcing became a huge factor for survival for many smugglers and opium farmers.[84]

[edit]Legal production

Main article: Opium licensing

Legal opium production is allowed under the United Nations Single Convention on Narcotic Drugs and other international drug treaties, subject to strict supervision by the law enforcement agencies of individual countries. The leading legal production method is the Gregory process, whereby the entire poppy, excluding roots and leaves, is mashed and stewed in dilute acid solutions. The alkaloids are then recovered viaacid-base extraction and purified. This process was developed in the UK during World War II, when wartime shortages of many essential drugs encouraged innovation in pharmaceutical processing.

Legal opium production in India is much more traditional. As of 2008, opium was collected by farmers who were licensed to grow 0.1 hectare of opium poppies (0.24 acre), who to maintain their licenses needed to sell 56 kilograms of unadulterated raw opium paste. The price of opium paste is fixed by the government according to the quality and quantity tendered. The average is around 1500 rupees ($29 US) per kilogram.[85] Some additional money is made by drying the poppy heads and collecting poppy seeds, and a small fraction of opium beyond the quota may be consumed locally or diverted to the black market. The opium paste is dried and processed in two government opium and alkaloid factories before it is packed into cases of 60 kilograms for export. Purification of chemical constituents is done in India for domestic production, but typically done abroad by foreign importers.[86]

Legal opium importation from India and Turkey is conducted by Mallinckrodt, Noramco, Abbott Laboratories, and Purdue Pharma in the United States, and legal opium production is conducted by GlaxoSmithKline, Johnson and Johnson, Johnson Matthey, and Mayne in Tasmania, Australia; Sanofi Aventis in France; Shionogi Pharmaceutical in Japan; and Macfarlan Smith in the United Kingdom.[87] The UN treaty requires that every country submit annual reports to the International Narcotics Control Board, stating that year’s actual consumption of many classes of controlled drugs as well as opioids and projecting required quantities for the next year. This is to allow trends in consumption to be monitored and production quotas allotted.

A recent proposal from the European Senlis Council hopes to solve the problems caused by the massive quantity of opium produced illegally in Afghanistan, most of which is converted to heroin and smuggled for sale in Europe and the USA. This proposal is to license Afghan farmers to produce opium for the world pharmaceutical market, and thereby solve another problem, that of chronic underuse of potent analgesics where required within developing nations. Part of the proposal is to overcome the "80-20 rule" that requires the U.S. to purchase 80% of its legal opium from India and Turkey to include Afghanistan, by establishing a second-tier system of supply control that complements the current INCB regulated supply and demand system by providing poppy-based medicines to countries who cannot meet their demand under the current regulations. Senlis arranged a conference in Kabul that brought drug policy experts from around the world to meet with Afghan government officials to discuss internal security, corruption issues, and legal issues within Afghanistan.[88] In June 2007, the Council launched a "Poppy for Medicines" project that provides a technical blueprint for the implementation of an integrated control system within Afghan village-based poppy for medicine projects: the idea promotes the economic diversification by redirecting proceeds from the legal cultivation of poppy and production of poppy-based medicines (See Senlis Council).[89] However, there has been criticism of the Senlis report findings by Macfarlan Smith, who argue that though they produce morphine in Europe, they were never asked to contribute to the report.[90]

[edit]Cultivation in the UK

In late 2006, the British government permitted the pharmaceutical company Macfarlan Smith (a Johnson Matthey company) to cultivate opium poppies in England for medicinal reasons, after Macfarlan Smith’s primary source, India, decided to increase the price of export opium latex. This move is well received by British farmers, with a major opium poppy field based in Didcot, England. The British government has contradicted the Home Office’s suggestion that opium cultivation can be legalized in Afghanistanfor exports to the United Kingdom, helping lower poverty and internal fighting whilst helping NHS to meet the high demand for morphine and heroin. Opium poppy cultivation in the United Kingdom does not need a licence; however, a licence is required for those wishing to extract opium for medicinal products.[91]


An Akha man smokes a pipe containing opium mixed with tobacco.

In the industrialized world, the USA is the world’s biggest consumer of prescription opioids, with Italy one of the lowest because of tighter regulations on prescribing narcotics for pain relief.[92] Most opium imported into the United States is broken down into its alkaloid constituents, and whether legal or illegal, most current drug use occurs with processed derivatives such as heroin rather than with pure and untouched opium.

Intravenous injection of opiates is most used: by comparison with injection, "dragon chasing" (heating of heroin with barbital on a piece of foil), and madak and "ack ack" (smoking of cigarettes containing tobaccomixed with heroin powder) are only 40% and 20% efficient, respectively.[93] One study of British heroin addicts found a 12-fold excess mortality ratio (1.8% of the group dying per year).[94] Most heroin deaths result not from overdose per se, but combination with other depressant drugs such as alcohol or benzodiazepines.[95]

The smoking of opium does not involve the burning of the material as might be imagined. Rather, the prepared opium is indirectly heated to temperatures at which the active alkaloids, chiefly morphine, are vaporized. In the past, smokers would utilize a specially designed opium pipe which had a removable knob-like pipe-bowl of fired earthenware attached by a metal fitting to a long, cylindrical stem.[96] A small "pill" of opium about the size of a pea would be placed on the pipe-bowl, which was then heated by holding it over an opium lamp, a special oil lamp with a distinct funnel-like chimney to channel heat into a small area. The smoker would lie on his or her side in order to guide the pipe-bowl and the tiny pill of opium over the stream of heat rising from the chimney of the oil lamp and inhale the vaporized opium fumes as needed. Several pills of opium were smoked at a single session depending on the smoker’s tolerance to the drug. The effects could last up to twelve hours. Opium in its rawest form contains half the potency of synthetically compared drugs; such as oxycodone, morphine patches or trentanol.[citation needed]

In Eastern culture, opium is more commonly used in the form of paregoric to treat diarrhea. This is a weaker solution than laudanum, an alcoholic tincture which was prevalently used as a pain medication and sleeping aid. Tincture of opium has been prescribed for, among other things, severe diarrhea.[97] Taken thirty minutes prior to meals, it significantly slows intestinal motility, giving the intestines greater time to absorb fluid in the stool.

[edit]Chemical and physiological properties

Morphine is the primary biologically active chemical constituent of opium.

Codeine is another biologically active chemical constituent of opium.

See also: Opioid, Opiate, and Morphinan

Opium contains two main groups of alkaloids. Phenanthrenes include morphine, codeine, and thebaine are the main narcotic constituents. Isoquinolines such as papaverine and noscapine have no significant central nervous system effects, and are not regulated under the Controlled Substances Act. Morphine is the most prevalent and important alkaloid in opium, consisting of 10%-16% of the total, and is responsible for most of its harmful effects such as lung edema, respiratory difficulties, coma, or cardiac or respiratory collapse, with a normal lethal dose of 120 to 250 milligrams[98]—the amount found in approximately two grams of opium.[68] Morphine binds to and activates mu opioid receptor in the brain, spinal cord, stomach and intestine. Regular use can lead to drug tolerance or physical dependence. Chronic opium addicts in 1906 China[77] or modern-day Iran[99] consume an average of eight grams of opium daily.

Both analgesia and drug addiction are functions of the mu opioid receptor, the class of opioid receptor first identified as responsive to morphine. Tolerance is associated with the superactivation of the receptor, which may be affected by the degree of endocytosis caused by the opioid administered, and leads to a superactivation of cyclic AMP signaling.[100] Long-term use of morphine in palliative care and management of chronic pain cannot be managed without the possible development of drug tolerance or physical dependence. Many techniques of drug treatment exist, including pharmacologically based treatments with naltrexone, methadone, or ibogaine.[101]

[edit]Slang terms

Some slang terms for opium include "tar", "dope", and "Big O". ("Tar" and "dope" can also refer to heroin.)[102]

[edit]Cultural references

There is a longstanding literary history by and about opium users. Thomas de Quincey‘s 1822 Confessions of an English Opium-Eater is one of the first and most famous literary accounts of opium addiction written from the point of view of an addict and details both the pleasures and the dangers of the drug. De Quincey writes about the great English Romantic poet Samuel Taylor Coleridge (1772–1834), whose poem "Kubla Khan" is also widely considered to be a poem of the opium experience. Coleridge began using opium in 1791 after developing jaundice and rheumatic fever and became a full addict after a severe attack of the disease in 1801, requiring 80-100 drops of laudanum daily.[103] George Crabbe is another early writer who wrote about opium. "The Lotos-Eaters", an 1832 poem by Alfred Lord Tennyson, reflects the generally favorable British attitude toward the drug. In The Count of Monte Cristo(1844) by Alexandre Dumas, père, the Count is assuaged by an edible form of opium, and his experience with it is depicted vividly.

Edgar Allan Poe presents opium in a more disturbing context in his 1838 short story "Ligeia", in which the narrator, deeply distraught for the loss of his beloved, takes solace in opium until he "had become a bounden slave in the trammels of opium," unable to distinguish fantasy from reality after taking immoderate doses of opium. In music, Hector Berlioz‘ 1830 Symphony Fantastique tells the tale of an artist who has poisoned himself with opium while in the depths of despair for a hopeless love. Each of thesymphony‘s five movements takes place at a different setting and with increasingly audible effects from the drug. For example, in the fourth movement, "Marche au Supplice," the artist dreams that he is walking to his own execution. In the fifth movement, "Songe d’une Nuit du Sabbat," he dreams that he is at a witch’s orgy, where he witnesses his beloved dancing wildly along to the demented Dies Irae.

Towards the end of the nineteenth century, references to opium and opium addiction in the context of crime and the foreign underclass abound within English literature, such as in Wilkie CollinsThe Moonstone (1868), where it is used to attempt to uncover the jewel thief. Opium features in the opening paragraphs of Charles Dickens‘s 1870 serial The Mystery of Edwin Drood and in Arthur Conan Doyle‘s 1891 Sherlock Holmes short story "The Man with the Twisted Lip". In Oscar Wilde‘s 1890 The Picture of Dorian Gray, the protagonist visits an opium den "for forgetfulness," unable to bear the guilt and shame of committing murder. Opium likewise underwent a transformation in Chinese literature, becoming associated with indolence and vice by the early twentieth century.[49] Perhaps the best-known literary reference to opium is Karl Marx‘s metaphor in his "Contribution to the Critique of Hegel’s ‘Philosophy of Right’," where he refers to religion as "the opium of the people." (This phrase is more commonly quoted as "the opiate of the masses.")

In the twentieth century, as the use of opium was eclipsed by morphine and heroin, its role in literature became more limited, and often focused on issues related to its prohibition. In The Good Earth by Pearl S. Buck, Wang Lung, the protagonist, gets his troublesome uncle and aunt addicted to opium in order to keep them out of his hair. William S. Burroughs autobiographically describes the use of opium beside that of its derivatives. His associate Jack Black’s memoir You Can’t Win chronicles one man’s experience both as an onlooker in the opium dens of San Francisco, and later as a "hop fiend" himself. The book and subsequent movie The Wonderful Wizard of Oz may allude to opium at one point in the story, when Dorothy and her friends are drawn into a field of poppies, in which they fall asleep. Opium is also repeatedly mentioned in the novel, The House of the Scorpion, by Nancy Farmer. The plot revolves partly around the poppy flower and opium drug.

[edit]See also

Medicine portal

Pharmacy and Pharmacology portal


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[edit]Further reading

[edit]External links



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From Wikipedia, the free encyclopedia

For other uses, see Heroin (disambiguation).

This article has multiple issues. Please help improve it or discuss these issues on the talk page.

This article is semi-protected.


Systematic (IUPAC) name

(5α,6α)-7,8-didehydro- 4,5-epoxy- 17-methylmorphinan- 3,6-diol diacetate


CAS number

ATC code

CID 5462328



Chemical data


Mol. mass
369.41 g/mol

Diamorphine, Diacetylmorphine, Acetomorphine, (Dual) Acetylated morphine, Morphine diacetate

Pharmacokinetic data

<35% (oral), 44–61% (inhaled)[1]

Protein binding
0% (morphinemetabolite 35%)


<10 minutes [1]

90% renal asglucuronides, restbiliary

Therapeutic considerations

Pregnancy cat.
Category X

Legal status
Prohibited (S9) (AU)Schedule I (CA) ? (UK)Schedule I (US)

Dependence Liability
Extremely High

Inhalation, Transmucosal, Intravenous, Oral, Intranasal, Rectal, Intramuscular

Yes(what is this?) (verify)

Heroin, or diacetylmorphine (INN), also known as diamorphine (BAN), is a semi-synthetic opioid drug synthesized from morphine, a derivative of the opium poppy. It is the 3,6-diacetyl ester of morphine (di(two)-acetylmorphine). The white crystalline form is commonly the hydrochloride salt diacetylmorphine hydrochloride, though often adulterated thus dulling the sheen and consistency from that to a matte white powder, which heroin freebase typically is.[2] 90% of Heroin is said to be produced in Afghanistan.[3]

As with other opioids, heroin is used as both an analgesic and a recreational drug, and has a high potential for abuse. Frequent and regular administration is associated with tolerance and physical dependence, which may develop into addiction.

Internationally, heroin is controlled under Schedules I and IV of the Single Convention on Narcotic Drugs.[4] It is illegal to manufacture, possess, or sell diacetylmorphine without a license in Belgium, Denmark,Germany, Iran, India, the Netherlands, the United States, Australia, Canada, Ireland, Pakistan, the United Kingdom and Swaziland.

Under the name diamorphine, it is a legally prescribed controlled drug in the United Kingdom. It is available for prescription to long-term users in the Netherlands, United Kingdom, Switzerland, Germany andDenmark alongside psycho-social care,[5][6] and a similar program is being campaigned for by liberal political parties in Norway.




The German drug company Bayer named its new over the counter drug "Heroin" in 1895.[7] The name was derived from the German word "heroisch" (heroic) due to its perceived "heroic" effects upon a user.[7] It was chiefly developed as a morphine substitute for cough suppressants that did not have morphine’s addictive side-effects. Morphine at the time was a popular recreational drug, and Bayer wished to find a similar but non-addictive substitute to market.[8] However, contrary to Bayer’s advertising as a "non-addictive morphine substitute," heroin would soon have one of the highest rates of dependence amongst its users.[9]


Old advertisement for Bayer Heroin.

Bayer Heroin bottle.

The opium poppy was cultivated in lower Mesopotamia as long ago as 3400 BCE.[10] The chemical analysis of opium in the 19th century revealed that most of its activity could be ascribed to two alkaloids, codeine and morphine.

Diacetylmorphine was first synthesized in 1874 by C. R. Alder Wright, an English chemist working at St. Mary’s Hospital Medical School in London. He had been experimenting with combining morphine with various acids. He boiled anhydrous morphine alkaloid with acetic anhydride for several hours and produced a more potent,acetylated form of morphine, now called diacetylmorphine. The compound was sent to F. M. Pierce of Owens College in Manchester for analysis. Pierce told Wright:

Doses … were subcutaneously injected into young dogs and rabbits … with the following general results … great prostration, fear, and sleepiness speedily following the administration, the eyes being sensitive, and pupils constrict, considerable salivation being produced in dogs, and slight tendency to vomiting in some cases, but no actual emesis. Respiration was at first quickened, but subsequently reduced, and the heart’s action was diminished, and rendered irregular. Marked want of coordinating power over the muscular movements, and loss of power in the pelvis and hind limbs, together with a diminution of temperature in the rectum of about 4°.[11]

Wright’s invention did not lead to any further developments, and diacetylmorphine only became popular after it was independently re-synthesized 23 years later by another chemist, Felix Hoffmann. Hoffmann, working at the Aktiengesellschaft Farbenfabriken (today the Bayer pharmaceutical company) in Elberfeld, Germany, was instructed by his supervisor Heinrich Dreser to acetylate morphine with the objective of producing codeine, a constituent of the opium poppy, pharmacologically similar to morphine but less potent and less addictive. Instead the experiment produced an acetylated form of morphine one and a half to two times more potent than morphine itself.

From 1898 through to 1910 diacetylmorphine was marketed under the trade name Heroin as a non-addictive morphine substitute and cough suppressant. Bayer marketed the drug as a cure for morphine addiction before it was discovered that it rapidly metabolizes into morphine. As such, heroin is essentially a quicker acting form of morphine. The company was embarrassed by the new finding, which became a historic blunder for Bayer.[12]

In the U.S.A. the Harrison Narcotics Tax Act was passed in 1914 to control the sale and distribution of "heroin" and other opioids, which allowed the drug to be prescribed and sold for medical purposes. In 1924 the United States Congress banned its sale, importation or manufacture. It is now a Schedule I substance, which makes it illegal for non-medical use in signatory nations of the Single Convention on Narcotic Drugs treaty, including the United States.

Later, as with Aspirin, Bayer lost some of its trademark rights to "heroin" under the 1919 Treaty of Versailles following the German defeat in World War I.[13]


When taken orally, diacetylmorphine undergoes extensive first-pass metabolism via deacetylation, making it a prodrug for the systemic delivery of morphine.[14] When the drug is injected, however, it avoids this first-pass effect, very rapidly crossing the blood-brain barrier due to the presence of the acetyl groups, which render it much more lipid-soluble than morphine itself.[15] Once in the brain, it then is deacetylated into 6-monoacetylmorphine (6-MAM) and morphine which bind to μ-opioid receptors, resulting in the drug’s euphoric, analgesic (pain relief), and anxiolytic (anti-anxiety) effects; diacetylmorphine itself exhibits relatively low affinity for the μ receptor.[16] Unlike hydromorphone and oxymorphone, however, administered intravenously, diacetylmorphine creates a larger histamine release, similar to morphine, resulting in the feeling of a greater subjective "body high" to some, but also instances of pruritus (itching) when they first start using.[17]

Both morphine and 6-MAM are μ-opioid agonists which bind to receptors present throughout the brain, spinal cord and gut of all mammals. The μ-opioid receptor also binds endogenous opioid peptides such as β-endorphin, Leu-enkephalin, and Met-enkephalin. Repeated use of diacetylmorphine results in a number of physiological changes, including decreases in the number of μ-opioid receptors. [citation needed] These physiological alterations lead to tolerance and dependence, so that cessation of diacetylmorphine use results in a set of extremely uncomfortable symptoms including pain, anxiety, muscle spasms, and insomnia called the opioid withdrawal syndrome. Depending on usage it has an onset 4 to 24 hours after the last dose of diacetylmorphine. Morphine also binds to δ– and κ-opioid receptors.

There is also evidence that 6-MAM binds to a subtype of μ-opioid receptors which are also activated by the morphine metabolite morphine-6β-glucuronide but not morphine itself.[18] The contribution of these receptors to the overall pharmacology of heroin remains unknown.

A subclass of morphine derivatives, namely the 3,6 esters of morphine, with similar effects and uses includes the clinically-used strong analgesics nicomorphine (Vilan), and dipropanoylmorphine; there is also the latter’s dihydromorphine analogue,diacetyldihydromorphine (Paralaudin).

Usage and effects

Worldwide, the UN estimates there are more than 50 million regular users of heroin, cocaine and synthetic drugs.[19] Global users of heroin are estimated at between 15.16 million and 21.13 million people aged 15–64.[20]

Medical use

Under the name diamorphine, heroin is prescribed as a strong analgesic in the United Kingdom, where it is given via subcutaneous, intramuscular, intrathecal or intravenous route. Its use includes treatment for acute pain, such as in severe physical trauma,myocardial infarction, post-surgical pain, and chronic pain, including end-stage cancer and other terminal illnesses. In other countries it is more common to use morphine or other strong opioids in these situations.

In 2005, there was a shortage of diamorphine in the UK, due to a problem at the main UK manufacturers.[21] Due to this, many hospitals changed to using morphine instead of diamorphine. Although there is no longer a problem with the manufacturing of heroin in the UK, many hospitals there have continued to use morphine.

Diamorphine continues to be widely used in palliative care in the United Kingdom, where it is commonly given by the subcutaneous route, often via a syringe driver, if patients could not easily swallow oral morphine solution. The advantage of diamorphine over morphine is that diamorphine is more soluble and smaller volumes of diamorphine are needed for the same analgesic effect. Both of these factors are advantageous if giving high doses of opioids via the subcutaneous route, which is often necessary inpalliative care.

The medical use of diamorphine (in common with other strong opioids such as morphine, fentanyl and oxycodone) is controlled in the United Kingdom by the Misuse of Drugs Act 1971. In the UK, it is a class A controlled drug. Registers of its use are required to be kept in hospitals.

Heroin is also used as a maintenance drug in the treatment of heroin addicts. Though this is somewhat controversial among proponents of a zero tolerance drug policy it has proven superior to methadone in improving the social and health situation of addicts.[22] See: Heroin prescription for addicts

Recreational use

One stamp of heroin

Diacetylmorphine is used as a recreational drug for the transcendent relaxation and intense euphoria it induces. Anthropologist Michael Agar once described heroin as "the perfect whatever drug."[23] Tolerancequickly develops, and users need more of the drug to achieve the same effects. Its popularity with recreational drug users, compared to morphine, reportedly stems from its perceived different effects.[24] In particular, users report an intense rush that occurs while the diacetylmorphine is being metabolized into 6-monoacetylmorphine (6-MAM) and morphine in the brain. Diacetylmorphine produces more euphoria than other opioids upon injection. One possible explanation is the presence of 6-monoacetylmorphine, a metabolite unique to diacetylmorphine. While other opioids of recreational use, such as codeine, produce only morphine, heroin also leaves 6-MAM, also a psycho-active metabolite. However, this perception is not supported by the results of clinical studies comparing the physiological and subjective effects of injected diacetylmorphine and morphine in individuals formerly addicted to opioids; these subjects showed no preference for one drug over the other. Equipotent injected doses had comparable action courses, with no difference in subjects’ self-rated feelings of euphoria, ambition, nervousness, relaxation, drowsiness, or sleepiness.[25]

Chunky "No.3" heroin

Short-term addiction studies by the same researchers demonstrated that tolerance developed at a similar rate to both diacetylmorphine and morphine. When compared to the opioids hydromorphone, fentanyl, oxycodone, and pethidine/meperidine, former addicts showed a strong preference for diacetylmorphine and morphine, suggesting that diacetylmorphine and morphine are particularly susceptible to abuse and addiction. Morphine and diacetylmorphine were also much more likely to produce euphoria and other positive subjective effects when compared to these other opioids.[25]

Data from The Lancet shows illicit heroin to be the most addictive and most harmful of 20 drugs.[26]

One of the most common methods of illicit heroin use is via intravenous injection (colloquially termed "slamming" or "shooting up"). Heroin base (commonly found in Europe), when prepared for injection will only dissolve in water when mixed with an acid (most commonly citric acid powder or lemon juice) and heated. Heroin in the US is most commonly found in the hydrochloride salt form, requiring just water to dissolve. Users tend to initially inject in the easily accessible arm veins, but as these veins collapse over time, through damage caused by the acid, the user will often resort to injecting in other veins.

Recreational users may also administer the drug through snorting, or smoking by inhaling its vapors when heated; either with tobacco in a rolled cigarette or by heating the drug on aluminium foil from underneath.[27] When heated the heroin powder changes to a thick liquid, similar in consistency to molten wax, and it will run across the foil giving off smoke which the user inhales through a tube, usually made from foil also so that any heroin that collects on the inside of the tube can be smoked afterward. This method of administration is known as chasing the dragon (whereas smoking methamphetamine is known as "chasing the white dragon").

The diacetylmorphine dose used for recreational purposes is dependant on the frequency and level of use. A first-time user may ingest between 5 and 20 mg of diacetylmorphine, while an addict may require several hundred mg per day.[28]


The onset of diacetylmorphine’s effects depends upon the route of administration. Studies have shown that the subjective pleasure of drug use (the reinforcing component of addiction) is proportional to the rate at which the blood level of the drug increases.[29] Intravenous injection provides the fastest and most intense rush[30] within 7 to 8 seconds. Intra-muscular injection produces a relatively slow onset of 5 to 8 minutes. Snorting or smoking reaches peak effects within 10 to 15 minutes.[31] If taken orally, the effects take approximately half an hour to set in, with an absence of a rush.

Possible long-term effects of intravenous usage of illicit heroin.[32]

Main short-term effects of heroin usage.[32]

Large doses of heroin can cause fatal respiratory depression, and the drug has been used for suicide or as a murder weapon. The serial killer Dr Harold Shipman used it on his victims, as did Dr John Bodkin Adams (see his victim: Edith Alice Morrell).

Because significant tolerance to respiratory depression develops quickly with continued use and is lost just as quickly during withdrawal, it is often difficult to determine whether a heroin death was an accident, suicide or murder. Examples include the overdose deaths of Sid Vicious, Janis Joplin, Tim Buckley, Layne Staley, Bradley Nowell, Ted Binion, and River Phoenix.[33]

Recreational uses:

Medicinal uses:


Central nervous system:



Cardiovascular & Respiratory:




  • Itching
  • Flushing/Rash


Diamorphine ampoules for medicinal use

Detection in biological fluids

The major metabolites of heroin, 6-MAM, morphine, morphine-3-glucuronide and morphine-6-glucuronide, may be quantitated in blood, plasma or urine to monitor for abuse, confirm a diagnosis of poisoning or assist in a medicolegal death investigation. Most commercial opiate screening tests cross-react appreciably with these metabolites, as well as with other biotransformation products likely to be present following usage of street-grade heroin such as 6-acetylcodeine and codeine. However, chromatographic techniques can easily distinguish and measure each of these substances. When interpreting the results of a test, it is important to consider the heroin usage history of the individual, since a chronic user can develop tolerance to doses that would incapacitate an opiate-naive individual, and the chronic user often has high baseline values of these metabolites in his system. Furthermore, some testing procedures employ a hydrolysis step prior to quantitation that converts many of the metabolic products to morphine, yielding a result that may be many times larger than with a method that examines each product individually.[34]


This section does not cite any references or sources.
Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (August 2008)

In the Netherlands, diamorphine (heroin) is a List I drug of the Opium Law. It is available for prescription under tight regulation to long-term heroin addicts for whom methadone maintenance treatment has failed. Heroin is exclusively available for prescription to long-term heroin addicts, and cannot be used to treat severe pain or other illnesses.

In the United States, heroin is a schedule I drug according to the Controlled Substances Act of 1970, making it illegal to possess without a DEA license. Possession of more than 100 grams of heroin or a mixture containing heroin is punishable with a minimum mandatory sentence of 5 years of imprisonment in a federal prison.

In Canada, heroin is a controlled substance under Schedule I of the Controlled Drugs and Substances Act (CDSA). Any person who seeks or obtains heroin without disclosing authorization 30 days prior to obtaining another prescription from a practitioner is guilty of an indictable offense and subject to imprisonment for a term not exceeding seven years. Possession of heroin for the purpose of trafficking is guilty of an indictable offense and subject to imprisonment for life.

In Hong Kong, heroin is regulated under Schedule 1 of Hong Kong’s Chapter 134 Dangerous Drugs Ordinance. It is available by prescription. Anyone who supplies heroin without a valid prescription can be fined $10,000 (HKD). The penalty for trafficking or manufacturing heroin is a $5,000,000 (HKD) fine and life imprisonment. Possession of heroin without a license from the Department of Health is illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time.

In the United Kingdom, heroin is available by prescription, though it is a restricted Class A drug. According to the 50th edition of the British National Formulary (BNF), diamorphine hydrochloride may be used in the treatment of acute pain, myocardial infarction, acute pulmonary oedema, and chronic pain. The treatment of chronic non-malignant pain must be supervised by a specialist. The BNF notes that all opioid analgesics cause dependence and tolerance but that this is "no deterrent in the control of pain in terminal illness". When used in the palliative care of cancer patients, heroin is often injected using a syringe driver.


The European Monitoring Centre for Drugs and Drug Addiction reports that the retail price of brown heroin varies from 14.5 per gram in Turkey to €110 per gram in Sweden, with most European countries reporting typical prices of €35-40 per gram. The price of white heroin is reported only by a few European countries and ranged between €27 and €110 per gram.[35]

The United Nations Office on Drugs and Crime claims in its 2008 World Drug Report that typical US retail prices are US$172 per gram.[36]

Production and trafficking: The Golden Triangle

Primary worldwide producers of heroin.


Heroin, also known as diacetyl morphine is produced from acetylation of morphine derived from natural opium sources. Numerous mechanical and chemical means are used to purify the final product. The final products have different appearance depending on purity and have different names.[37]

History of heroin traffic

This section may contain original research. Please improve it by verifying the claims made and addingreferences. Statements consisting only of original research may be removed. More details may be available on thetalk page. (September 2007)

The origins of the present international illegal heroin trade can be traced back to laws passed in many countries in the early 1900s that closely regulated the production and sale of opium and its derivatives including heroin. At first, heroin flowed from countries where it was still legal into countries where it was no longer legal. By the mid-1920s, heroin production had been made illegal in many parts of the world. An illegal trade developed at that time between heroin labs in China (mostly in Shanghai and Tianjin) and other nations. The weakness of government in China and conditions of civil war enabled heroin production to take root there. Chinese triad gangs eventually came to play a major role in the heroin trade. The French Connection route started in the 1930s.

Heroin trafficking was virtually eliminated in the U.S. during World War II due to temporary trade disruptions caused by the war. Japan’s war with China had cut the normal distribution routes for heroin and the war had generally disrupted the movement of opium.

After World War II, the Mafia took advantage of the weakness of the postwar Italian government and set up heroin labs in Sicily. The Mafia took advantage of Sicily’s location along the historic route opium took westward into Europe and the United States.[38]

Large scale international heroin production effectively ended in China with the victory of the communists in the civil war in the late 1940s.[citation needed] The elimination of Chinese production happened at the same time that Sicily’s role in the trade developed.

Although it remained legal in some countries until after World War II, health risks, addiction, and widespread recreational use led most western countries to declare heroin a controlled substance by the latter half of the 20th century.

In late 1960s and early 70s, the CIA supported anti-Communist Chinese Nationalists settled near SinoBurmese border and Hmong tribesmen in Laos. This helped the development of the Golden Triangleopium production region, which supplied about one-third of heroin consumed in US after 1973 American withdrawal from Vietnam. As of 1999, Myanmar (formerly Burma), the heartland of the Golden Triangle remained the second largest producer of heroin, after Afghanistan.[39]

Soviet-Afghan war led to increased production in the Pakistani-Afghani border regions, as U.S.-backed mujaheddin militants raised money for arms from selling opium, contributing heavily to the modernGolden Crescent creation. By 1980, 60% of heroin sold in the U.S. originated in Afghanistan.[39] It increased international production of heroin at lower prices in the 1980s. The trade shifted away from Sicily in the late 1970s as various criminal organizations violently fought with each other over the trade. The fighting also led to a stepped up government law enforcement presence in Sicily.


International drug routes

See also: Opium#Modern production and usage

Traffic is heavy worldwide, with the biggest producer being Afghanistan.[40] According to U.N. sponsored survey,[41] as of 2004, Afghanistan accounted for production of 87 percent of the world’s heroin.[42]Afghan opium kills 100,000 people every year worldwide.[43]

The cultivation of opium in Afghanistan reached its peak in 1999, when 350 square miles (910 km2) of poppies were sown. The following year the Taliban banned poppy cultivation, a move which cut production by 94 percent. By 2001 only 30 square miles (78 km2) of land were in use for growing opium poppies. A year later, after American and British troops had removed the Taliban and installed the interim government, the land under cultivation leapt back to 285 square miles (740 km2), with Afghanistan supplanting Burma to become the world’s largest opium producer once more.[44] Opium production in that country has increased rapidly since, reaching an all-time high in 2006. War in Afghanistan once again appeared as a facilitator of the trade.[45] Some 3.3 million Afghans are involved in producing opium.[46]

At present, opium poppies are mostly grown in Afghanistan, and in Southeast Asia, especially in the region known as the Golden Triangle straddling Myanmar, Thailand, Vietnam, Laos and Yunnan province in the People’s Republic of China. There is also cultivation of opium poppies in the Sinaloa region of Mexico and in Colombia. The majority of the heroin consumed in the United States comes from Mexico andColombia. Up until 2004, Pakistan was considered one of the biggest opium-growing countries.

Conviction for trafficking in heroin carries the death penalty in most Southeast Asian, some East Asian and Middle Eastern countries (see Use of death penalty worldwide for details), among which Malaysia,Singapore and Thailand are the most strict. The penalty applies even to citizens of countries where the penalty is not in place, sometimes causing controversy when foreign visitors are arrested for trafficking, for example the arrest of nine Australians in Bali, the death sentence given to Nola Blake in Thailand in 1987, or the hanging of an Australian citizen Van Tuong Nguyen in Singapore.

Risks of use

Prepping Heroin

  • For intravenous users of heroin (and any other substance), the use of non-sterile needles and syringes and other related equipment leads to several serious risks:
  • Poisoning from contaminants added to "cut" or dilute heroin
  • Chronic constipation
  • Addiction and increasing tolerance
  • Physical dependence can result from prolonged use of all opioids, resulting in withdrawal symptoms on cessation of use
  • Decreased kidney function (although it is not currently known if this is due to adulterants or infectious diseases)[47]

Many countries and local governments have begun funding programs that supply sterile needles to people who inject illegal drugs in an attempt to reduce these contingent risks and especially the contraction and spread of blood-borne diseases. The Drug Policy Alliance reports that up to 75% of new AIDS cases among women and children are directly or indirectly a consequence of drug use by injection. The United States federal government does not operate needle exchanges, although some state and local governments do support needle exchange programs.

Anthropologists Philippe Bourgois and Jeff Schonberg, who did a decade of field work among homeless heroin and crack addicts in San Francisco, reported that the African-American addicts they observed were more inclined to "direct deposit" heroin into a vein, rather than "skin-popping" their injections. (Skin-popping was a far more widespread practice among the white addicts: "By the midpoint of our fieldwork, most of the whites had given up searching for operable veins and skin-popped. They sank their needles perfunctorily, often through their clothing, into their fatty tissue.") Bourgois and Schonberg describes how the cultural difference between the African-Americans and the whites leads to this contrasting behavior, and also points out that the two different ways to inject heroin comes with different health risks. Skin-popping more often results in abscesses, and direct injection more often leads to fatal overdose and also to hepatitis C and HIV infection.[48]

A heroin overdose is usually treated with an opioid antagonist, such as naloxone (Narcan), or naltrexone, which has high affinity for opioid receptors but does not activate them. This reverses the effects of heroin and other opioid agonists and causes an immediate return of consciousness but may precipitate withdrawal symptoms. The half-life of naloxone is much shorter than that of most opioid agonists, so that antagonist typically has to be administered multiple times until the opioid has been metabolized by the body.

Depending on drug interactions and numerous other factors, death from overdose can take anywhere from several minutes to several hours due to anoxia because the breathing reflex is suppressed by µ-opioids. An overdose is immediately reversible with an opioid antagonist injection. Heroin overdoses can occur due to an unexpected increase in the dose or purity or due to diminished opioid tolerance. However, many fatalities reported as overdoses are probably caused by interactions with other depressantdrugs like alcohol or benzodiazepines.[49] It should also be noted that since heroin can cause nausea and vomiting, a significant number of deaths attributed to heroin overdose are caused by aspiration of vomit by an unconscious victim. Some sources quote the median lethal dose (for an average 75 kg opiate-naive individual) as being between 75 and 375 mg.[50] Street heroin is of widely varying and unpredictable purity. This means that the user may prepare what they consider to be a moderate dose while actually taking far more than intended. Also, tolerance typically decreases after a period of abstinence. If this occurs and the user takes a dose comparable to their previous use, the user may experience drug effects that are much greater than expected, potentially resulting in a dangerous overdose.

It has been speculated that an unknown portion of heroin related deaths are the result of an overdose or allergic reaction to quinine, which may sometimes be used as a cutting agent.[51]

A final factor contributing to overdoses is place conditioning. Heroin use is a highly ritualized behavior. While the mechanism has yet to be clearly elucidated, longtime heroin users display increased tolerance to the drug in locations where they have repeatedly administered heroin. When the user injects in a different location, this environment-conditioned tolerance does not occur, resulting in a greater drug effect. The user’s typical dose of the drug, in the face of decreased tolerance, becomes far too high and can be toxic, leading to overdose.[52]

A small percentage of heroin smokers and occasionally IV users may develop symptoms of toxic leukoencephalopathy. The cause has yet to be identified, but one speculation is that the disorder is caused by an uncommon adulterant that is only active when heated.[53][54][55] Symptoms include slurred speech and difficulty walking.

Cocaine is sometimes used in combination with heroin, and is referred to as a speedball when injected or moonrocks when smoked together. Cocaine acts as a stimulant, whereas heroin acts as a depressant. Coadministration provides an intense rush ofeuphoria with a high that combines both effects of the drugs, while excluding the negative effects, such as anxiety and sedation. The effects of cocaine wear off far more quickly than heroin, thus if an overdose of heroin was used to compensate for cocaine, the end result is fatal respiratory depression.[citation needed]

Harm reduction

Modified Syringe for Rectal Administration

Main articles: Harm reduction, Safe injection sites, and Needle exchange programs

Harm reduction is a public health philosophy that seeks to reduce the harms associated with the use of heroin. One aspect of harm reduction initiatives focuses on the behaviour of individual users. This includes promoting safer means of taking the drug, such as smoking, nasal use, oral or rectal insertion. This attempts to avoid the higher risks of overdose, infections and blood-borne viruses associated with injecting the drug. Other measures include using a small amount of the drug first to gauge the strength, and minimize the risks of overdose. For the same reason, poly drug use (the use of two or more drugs at the same time) is discouraged. Users are also encouraged to not use heroin on their own, as others can assist in the event of an overdose. Injecting heroin users are encouraged to use new needles, syringes, spoons/steri-cups and filters every time they inject and not share these with other users.

Governments that support a harm reduction approach usually fund Needle & Syringe exchange programs, which supply new needles and syringes on a confidential basis, as well as education on proper filtering prior to injection, safer injection techniques, safe disposal of used injecting gear and other equipment used when preparing heroin for injection may also be supplied including citric acid sachets/vitamin C sachets, steri-cups, filters, alcohol pre-injection swabs, sterile water ampules and tourniquets (to stop use of shoe laces or belts).

Another harm reduction measure employed for example in Europe, Canada and Australia are safe injection sites where users can inject heroin and cocaine under the supervision of medically trained staff. Safe injection sites are low threshold and allow social services to approach problem users that would otherwise be hard to reach.[56]


Main article: Heroin withdrawal

Black tar heroin

The withdrawal syndrome from heroin (the so-called cold turkey) may begin within 6 to 24 hours of discontinuation of the drug; however, this time frame can fluctuate with the degree of tolerance as well as the amount of the last consumed dose. Symptoms may include: sweating, malaise, anxiety, depression, priapism, extra sensitivity of the genitals in females, general feeling of heaviness, cramp-like pains in the limbs, excessive yawning or sneezing, tears, rhinorrhea, sleep difficulties (insomnia), cold sweats, chills, severe muscle and bone aches; nausea and vomiting, diarrhea, cramps, and fever.[57]

Heroin prescription for addicts

Main article: Heroin assisted treatment

The UK Department of Health’s Rolleston Committee report in 1926 established the British approach to heroin prescription to users, which was maintained for the next 40 years: dealers were prosecuted, but doctors could prescribe heroin to users when withdrawing from it would cause harm or severe distress to the patient. This "policing and prescribing" policy effectively controlled the perceived heroin problem in the UK until 1959 when the number of heroin addicts doubled every 16th month during a period of ten years, 1959–1968.[58] The failure changed the attitudes; in 1964 only specialized clinics and selected approved doctors were allowed to prescribe heroin to users. The law was made more restrictive in 1968. Beginning in the 1970s, the emphasis shifted to abstinence and the use of methadone, until now only a small number of users in the UK are prescribed heroin.[59]

In 1994 Switzerland began a trial heroin maintenance program for users that had failed multiple withdrawal programs. The aim of this program is to maintain the health of the user to avoid medical problems stemming from use of illicit street heroin. Reducingdrug-related crime and preventing overdoses were two other goals. The first trial in 1994 involved 340 users, although enrollment was later expanded to 1000 based on the apparent success of the program. Participants are allowed to inject heroin in specially designed pharmacies for 15 Swiss francs per day.[60] A national referendum in November 2008 showed 68% of voters supported the plan,[61] introducing heroin prescription into federal law. The trials before were based on time-limited executive ordinances.

The success of the Swiss trials led German, Dutch,[62] and Canadian[63] cities to try out their own heroin prescription programs.[64] Some Australian cities (such as Sydney) have instituted legal heroin supervised injecting centers, in line with other widerharm minimization programs.

Since January 2009 Denmark has prescribed heroin to a few addicts that have tried methadone and subutex without success.[65] Beginning in February 2010, addicts in Copenhagen and Odense will be eligible to receive free heroin. Later in 2010 other cities including Århus and Esbjerg will join the scheme. In total, around 230 addicts will be able to receive free heroin.[66] However, Danish addicts will only be able to inject heroin according to the policy set by Danish National Board of Health.[67] Of the estimated 1500 drugs users who does not benefit from the current oral substitution treatment, approximately 900 will not be in the target group for treatment with injectable heroin, either because of "massive multiple drug abuse of non-opioids" or "not wanting treatment with injectable heroin".[68]

In July 2009, the German Bundestag passed a law allowing heroin prescription as a standard treatment for addicts; while heroin prescription was started in 2002, it was only authorized as a large-scale trial.[69]

Popular culture

This "In popular culture" section may contain minor or trivial references. Please reorganize this content to explain the subject’s impact on popular culture rather than simply listing appearances, and remove trivial references. (January 2010)

  • In the 1926 novel, The Murder of Roger Ackroyd, there is a discussion between the book’s protagonist, Hercule Poirot, and the book’s narrator, Dr. James Sheppard, regarding a discovery the former made in a summer house on the estate where the novel’s titular character was murdered. In Chapter 13, “The Goose Quill,” Poirot discovers a goose quill used by addicts to carry “snow,” as the powdered form of heroin was then known. This clue is considered integral to solving the murder.

“Yes, heroin ‘snow.’ Drug-takers carry it like this, and sniff it up the nose.”

“Diamorphine hydrochloride,” I murmured mechanically.

“This method of taking the drug is very common on the other side. Another proof, if we wanted one, that the man come from Canada or the States.”[70]

  • The Basketball Diaries is a 1978 book written by American author and musician Jim Carroll. It is an edited collection of the diaries he kept between the ages of twelve and sixteen. Set in New York City, they detail his daily life, sexual experiences, high school basketball career, Cold War paranoia, the counterculture movement, and, especially, his addiction to heroin, which began when he was 13. The book was made into a film under the same name in 1995 starring Leonardo DiCaprio.
  • Irvine Welsh‘s 1993 novel Trainspotting which was later made into a feature film under the same name explores the turbulent lives of an eccentric group of heroin users.
  • Allen Hoey‘s 2006 novel, Chasing the Dragon, examines the use of heroin among jazz musicians in the 1950s.
  • A 2007 book entitled The Heroin Diaries by author and musician Nikki Sixx from Mötley Crüe and Sixx:A.M. chronicles his heroin addiction in his diary between the years 1986–1987, as well as his chronic extreme hedonism, attitudes, drug use and his inevitable route to dying and coming back to life.
  • A 2008 book entitled, The Death Proclamation of Generation X: A Self-Fulfilling Prophesy of Goth, Grunge and Heroin, by researcher Maxim W. Furek, investigates the prominence of heroin in music, motion pictures, and Generation X culture. Published by i-Universe. (ISBN 978-0-595-46319-0)
Musicians who have used heroin, or written about heroin use

Question book-new.svg

This section needs additional citations for verification.
Please help improve this article by adding reliable references. Unsourced material may be challenged and removed. (December 2009)

  • Kurt Cobain (front man of the grunge band Nirvana) was addicted to heroin for a stomach problem: he said he could not get any relief from any other substance. He allegedly committed suicide after taking heroin.
  • Jim Morrison reportedly died of an overdose of heroin in a bathtub in Paris.
  • The Velvet Underground song "Heroin" (from their first album The Velvet Underground and Nico) describes the use and effects of the drug, with Lou Reed singing from the perspective of a heroin addict, describing his thoughts and feelings while under the effects of the drug, while the music (led by a dissonant viola and guitar strums) is played to resemble the effects of heroin use (with rushed and calm parts interchanging). The song was ranked #448 on Rolling Stone Magazine‘s list of the 500 Greatest Songs of All Time. Another famous song from the album, "I’m Waiting for the Man", tells the story of a New Yorker waiting for his drug dealer, describing the city environment, and then buying and using the heroin, only to conclude singing "until tomorrow, but it’s just another time".
  • Led Zeppelin guitar player Jimmy Page struggled with heroin from 1975 to the early 1980s. The heroin had very serious effects on him, including hampering his guitar playing skills, and making him ultra-thin in the early 80’s.
  • David Bowie‘s first single "Space Oddity", was seemingly about his experience with heroin, as his 1980 single "Ashes to Ashes" included the lines that refer to Major Tom as "… a junkie/strung out on heaven’s high/hitting an all-time low."[71]
  • Sid Vicious from the Sex Pistols died of a heroin overdose, and allegedly stabbed his girlfriend to death while both were strung out on heroin.[73]
  • Dee Dee Ramone of punk rock band The Ramones was addicted to heroin throughout most of his career. After leaving the band in 1992, he seemed to give up the substance. However, he was found dead from a heroin overdose in 2002.
  • Brad Nowell died of a heroin overdose shortly before Sublime‘s first major label album came out.
  • B.G. (rapper from New Orleans) raps about his previous addiction to heroin (via injection) in numerous songs.
  • Etta James stated in her autobiography that she had many troubles with heroin addiction in the 1970s and 80s, admitting she was often in rehabilitation centers.
  • Jerry Garcia (guitarist for the Grateful Dead) was a user of heroin for many years. He died in a rehabilitation facility, undergoing treatment for his heroin addiction.
  • Phil Anselmo of Pantera was reported to have been addicted to Heroin up until the early 2000s.
  • GG Allin, cult punk rock singer, was addicted to heroin and died of an accidental overdose in 1993, only six days after leaving prison and three days after attending the premier of the film, Hated.
  • NOFX drummer, Erik Sandin was a heroin addict from the 80’s to the early 90’s. The band told him if he didn’t quit doing heroin, they wouldn’t allow him to play on their new album. He quit taking heroin and since then has been completely sober and has been NOFX’s drummer since that period.
  • Comedian Mitch Hedberg was arrested for heroin possession in 2003 and died of an accidental ‘speedball’ overdose in 2005. [74]
Film and TV
  • Quentin Tarantino’s 1994 film Pulp Fiction fully depicts the steps of heroin injection by Vincent Vega (John Travolta), and subsequent near-fatal overdose by Mia Wallace (Uma Thurman) via snorting.
  • Darren Aronosfky’s 2000 film Requiem for a Dream, based on the book of the same name, depicts the lives of a group of heroin addicts and the devastating results of their addiction.
  • The film Trainspotting, based on the book of the same name, revolves around a group of heroin users and the attempts of one of the group to quit.
  • The film Rent (2005), based on the musical by Jonathan Larson, includes a character, Mimi who struggles with a heroin addiction and has contracted AIDS from her usage.
  • The film Candy starring Heath Ledger focused on a couple very much in love and destroyed by heroin addiction.
  • Party Monster, a movie based on James St. James’ true tales of New York City club kids in the late 1980s, shows an extreme use of heroin and other drugs such as ketamine (Special K) and cocaine.
  • The Film Gia based on a true story of model Gia Carangi is about her addiction and use of heroin and how it affected her.[75]
  • The film Christiane F. portrays the troubles of young heroin users in Berlin.
  • 1971’s The panic in needle park starring Al Pacino revolves around Pacino’s character and his girlfriend’s addictions to heroin and the repercussions of it. The film features graphic scenes of users injecting the drug.
  • Season 3 of the TV series 24 depicts Kiefer Sutherland starring as Jack Bauer struggling with a heroin addiction.

See also

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Medicine portal



Recreational drug use


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External links

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From Wikipedia, the free encyclopedia

"Phy" redirects here. For the abbreviation for the physical layer of the OSI Model, see PHY.

Not to be confused with Methedrine, Methedrone, Mephedrone, or Methylone.


Systematic (IUPAC) name



CAS number

ATC code
N02AC52 N07BC02,R05DA06

CID 4095

IUPHAR ligand ID



Chemical data


Mol. mass
309.445 g/mol

eMolecules & PubChem

Pharmacokinetic data

40-90% (oral)


24-36 h

Urine, Test by specific gravity and bilirubin

Therapeutic considerations

Pregnancy cat.
Reduction of oxygen to unborn child due to depression of breathing

Legal status
Schedule II (US) Class A(UK)

Dependence Liability
Very High

oral, intravenous, insufflation, sublingual, rectal

Yes(what is this?) (verify)

Methadone (also known as Symoron, Dolophine, Amidone, Methadose, Physeptone, Heptadon, Phy and many other names) is a synthetic opioid, used medically as an analgesic, antitussive and a maintenance anti-addictive for use in patients on opioids. It was developed in Germany in 1937. Although chemically unlike morphine or heroin, methadone also acts on the opioid receptors and thus produces many of the same effects. Methadone is also used in managing chronic pain owing to its long duration of action and very low cost.

Methadone is useful in the treatment of opioid dependence. It has cross-tolerance with other opioids including heroin and morphine and a long duration of effect. Oral doses of methadone can stabilise patients by mitigating opioid withdrawal syndrome. Higher doses of methadone can block the euphoric effects of heroin, morphine, and similar drugs. As a result, properly dosed methadone patients can reduce or stop altogether their use of these substances.

Methadone is approved for different indications in different countries. Common is approval as an analgesic and approval for the treatment of opioid dependence. It is not intended to reduce the use of non-narcotic drugs such as cocaine, methamphetamine, or alcohol.

Today, a number of pharmaceutical companies produce and distribute methadone. The racemic hydrochloride is the only form available in most countries, such as the Netherlands, Belgium, France and in the United States, as of March 2008. The tartrate and other salts of the laevorotary form (levomethadone, with trade names including Polamidone and Heptadon) are available in Europe and elsewhere. These are possibly more potent and lack the cardiac effects such as lengthened QT interval caused by the dextrorotary form. The major producer remains Mallinckrodt, who sells bulk methadone to most of the producers of generic preparations and also distributes its own brand name product in the form of tablets, dispersible tablets and oral concentrate under the name Methadose in the United States.[1]




40mg of Methadone

Methadone was developed in 1939 Germany by scientists working for I.G. Farbenkonzern at the Farbwerke Hoechst (it is synthesised from 1,1-diphenylbutane-2-sulfonic acid and dimethylamino-2-chloropropane) who were looking for an synthetic opioid that could be created with readily available precursors, to solve Germany’s opium shortage problem.[2]

On September 11, 1941 Bockmühl and Ehrhart filed an application for a patent for a synthetic substance they called Hoechst 10820 or polamidon (a name still in regular use in Germany) and whose structure had no relation to morphine or the opiate alkaloids (Bockmühl and Ehrhart, 1949).

After the war, all German patents, trade names and research records were requisitioned and expropriated by the Allies. The records on the research work of the I.G. Farbenkonzern at the Farbwerke Hoechst were confiscated by the U.S. Department of Commerce Intelligence, investigated by a Technical Industrial Committee of the U.S. Department of State and then brought to the US.

The drug was given the trade name Dolophine from the Latin dolor meaning pain (Cf. Dipidolor for piritramide, Dolantin for pethidine, and the "-phine" ending common in many trade and chemical names for analgesics of all types in German, English, French, and other languages) and was not named either in honour of or personally by Adolf Hitler as explored in greater detail below.

It was only in 1947 that the drug was given the generic name “methadone” by the Council on Pharmacy and Chemistry of the American Medical Association (COUNCIL…1947). Since the patent rights of the I.G. Farbenkonzern and Farbwerke Hoechst were no longer protected each pharmaceutical company interested in the formula could buy the rights for commercial production of methadone for just one dollar (MOLL 1990). Commercial production was first introduced in 1947 by the U.S. company Eli-Lilly. Only then was methadone given the trade name Dolophine, derived from the Latin dolor (pain).

Methadone was introduced into the United States in 1947 by Eli Lilly and Company as an analgesic (they gave it the trade name Dolophine, which is now registered to Roxane Laboratories). Since then, it has been best known for its use in treating narcotic addiction. A great deal of anecdotal evidence was available "on the street" that methadone might prove effective in treating heroin withdrawal and it had even been used in some hospitals. It was not until studies performed at the Rockefeller University in New York City by Professor Vincent Dole, along with Marie Nyswander and Mary Jeanne Kreek, that methadone was systematically studied as a potential substitution therapy. Their studies introduced a sweeping change in the notion that drug addiction was not necessarily a simple character flaw, but rather a disorder to be treated in the same way as other diseases. To date, methadone maintenance therapy has been the most systematically studied and most successful, and most politically polarizing, of any pharmacotherapy for the treatment of drug addiction patients.

Methadone (as Dolophine) was first manufactured in the USA by Eli Lilly and Company Pharmacueticals, who first obtained FDA approval on August 14, 1947, for their Dolophine 5 mg and 10 mg Tablets. Mallinckrodt Pharmacueticals did not receive approval until December 15, 1947 to manufacture their bulk compounding powder. Mallinckrodt received approval for their branded generic, Methadose, on April 15, 1993 for their 5 mg and 10 mg Methadose Tablets. Mallinckrodt who also makes 5 mg, 10 mg and 40 mg generic tablets in addition to their branded generic Methadose received approval for their plain generic tablets on April 27, 2004.[3]

The results of the early major studies showed methadone could effectively interrupt illicit opioid use and reduce the associated costs to society, findings which have been consistent with later research and backed up by modern knowledge of the psychological, social and pharmacological mechanisms of illicit opioid addiction.

[edit]Origin of Dolophine name

A persistent but untrue urban legend claims that the trade name "Dolophine" was coined in tribute to Adolf Hitler by its German creators, and it is sometimes even claimed that the drug was originally named "adolphine" or "adolophine" or "Dolphamine". Typically, the claim is still presented as fact by Church of Scientology literature[4] and was repeated by actor and vocal Scientologist Tom Cruise in a 2005 Entertainment Weekly interview.[5] However, as the magazine pointed out, this is not true: the name "Dolophine" was in fact created after the war by the American branch of Eli Lilly,[6] and the pejorative term "adolphine" (never an actual name of the drug) appeared in the United States in the early 1970s.[7]


Methadone acts by binding to the µ-opioid receptor, but also has some affinity for the NMDA ionotropic glutamate receptor. It is metabolized by the enzymes CYP3A4, CYP2B6 and CYP2D6, with great variability between individuals. Its main route of administration is oral. Adverse effects include hypoventilation, constipation and miosis, in addition to tolerance, dependence and withdrawal difficulties. The withdrawal period can be much more prolonged than with other opiates, spanning anywhere from two weeks to six months.

[edit]Mechanism of action

Methadone is a full µ-opioid agonist. Methadone also binds to the glutamatergic NMDA (N-methyl-D-aspartate) receptor, and thus acts as a receptor antagonist against glutamate. Glutamate is the primary excitatory neurotransmitter in the CNS. NMDA receptors have a very important role in modulating long term excitation and memory formation. NMDA antagonists such as dextromethorphan (DXM), ketamine (a dissociative anaesthetic, also M.O.A+.), tiletamine (a veterinary anaesthetic) and ibogaine(from the African tree Tabernanthe iboga, also M.O.A+.) are being studied for their role in decreasing the development of tolerance to opioids and as possible for eliminating addiction/tolerance/withdrawal, possibly by disrupting memory circuitry. Acting as an NMDA antagonist may be one mechanism by which methadone decreases craving for opioids and tolerance, and has been proposed as a possible mechanism for its distinguished efficacy regarding the treatment of neuropathic pain. Methadone also acted as a potent, noncompetitive α3β4 neuronal nicotinic acetylcholine receptor antagonist in rat receptors, expressed in human embryonic kidney cell lines.[8]


Methadone has a slow metabolism and very high fat solubility, making it longer lasting than morphine-based drugs. Methadone has a typical elimination half-life of 15 to 60 hours with a mean of around 22. However, metabolism rates vary greatly between individuals, up to a factor of 100,[9][10] ranging from as few as 4 hours to as many as 130 hours,[11] or even 190 hours.[12] This variability is apparently due to genetic variability in the production of the associated enzymes CYP3A4, CYP2B6 and CYP2D6. Many substances can also induce, inhibit or compete with these enzymes further affecting (sometimes dangerously) methadone half-life. A longer half life frequently allows for administration only once a day in Opioid detoxification and maintenance programs. Patients who metabolize methadone rapidly, on the other hand, may require twice daily dosing to obtain sufficient symptom alleviation while avoiding excessive peaks and troughs in their blood concentrations and associated effects.[11] This can also allow lower total doses in some such patients. The analgesic activity is shorter than the pharmacological half-life; dosing for pain control usually requires multiple doses per day.[citation needed]

The toxic effects of an overdose can be treated with naloxone.[13] Naloxone is preferred to the newer, longer acting antagonist naltrexone. Despite Methadone’s much longer duration of action compared to either heroin and other shorter-acting agonists, and the need for repeat doses of the antagonist naloxone, it is still used for overdose therapy. As naltrexone has a longer half life, it is more difficult to titrate. If too large a dose of opioid antagonist is given to a dependent patient, it will result in withdrawal symptoms (possibly severe). When using naloxone, the naloxone will be quickly eliminated and the withdrawal will be short lived. Doses of naltrexone take longer to be eliminated from the patient’s system.

[edit]Route of administration

The most common route of administration at a methadone clinic is in a racemic oral solution, though in Germany, only the R enantiomer (the L optical isomer) has traditionally been used, as it is responsible for most of the desired opioid effects.[11] This is becoming less common due to the higher production costs.

Methadone is available in traditional pill, sublingual tablet, and two different formulations designed for the patient to drink. Drinkable forms include ready-to-dispense liquid, and "Disket" which is a tablet designed to disperse itself in water for oral administration, used in a similar fashion to Alka-Seltzer. The liquid form is the most common as it allows for smaller dose changes. Methadone is almost as effective when administered orally as by injection. In fact, injection of methadone may not result in a "rush" as with most stronger opioids, because its extraordinarily high volume of distribution causes it to diffuse into other tissues in the body, particularly fatty tissue; the peak concentration in the blood is achieved at roughly the same time, whether the drug is injected or ingested. When injecting Methadone, only pills have the least-dangerous cautions although it can easily cause collapsed veins, bruising, swelling and possibly other harmful effects. Methadone pills often contain talc[14][15] that, when injected, produces a swarm of tiny solid particles in the blood, causing numerous minor blood clots. These particles cannot be filtered out before injection, and will accumulate in the body over time, especially in the lungs and eyes, producing various complications such as pulmonary hypertension, an irreversible and progressive disease.[16][17][18] Methadose/Methadone should not be injected either.[19] While it has been done in extremely diluted concentrations, instances of cardiac arrest have been reported as well as damaged veins from sugar and other ingredients (Sugar-Free syrups also should not be injected). Oral medication offers safety, simplicity and represents a step away from injection-based drug abuse in those recovering from addiction. U.S. federal regulations require the oral form in addiction treatment programs.[20]

[edit]Adverse effects

Adverse effects of methadone include:[13][21][22][23][24]

[edit]Detection in biological fluids

Methadone and its major metabolite, EDDP, are often measured in urine as part of a drug abuse testing program, in plasma or serum to confirm a diagnosis of poisoning in hospitalized victims, or in whole blood to assist in a forensic investigation of a traffic or other criminal violation or a case of sudden death. Methadone usage history is considered in interpreting the results as a chronic user can develop tolerance to doses that would incapacitate an opioid-naive individual. Chronic users often have high methadone and EDDP baseline values.[25]


In the United States, deaths linked to methadone more than quadrupled in five years. According to the U.S. National Center for Health Statistics,[26] as well as a 2006 series in the Charleston (West Virginia) Gazette,[27] medical examiners listed methadone as contributing to 3,849 deaths in 2004. That number was up from 790 in 1999. Approximately 82 percent of those deaths were listed as accidental, and most deaths involved combinations of methadone with other drugs (especiallybenzodiazepines).

Although deaths from methadone are on the rise, methadone-associated deaths are not being caused primarily by methadone intended for methadone treatment programs, according to a panel of experts convened by the Substance Abuse and Mental Health Services Administration, which released a report titled "Methadone-Associated Mortality, Report of a National Assessment". The consensus report concludes that "although the data remain incomplete, National Assessment meeting participants concurred that methadone tablets and/or diskettes distributed through channels other than opioid treatment programs most likely are the central factor in methadone-associated mortality."[28]

In 2006, the U.S. Food and Drug Administration issued a caution about methadone, titled “Methadone Use for Pain Control May Result in Death.” The FDA also revised the drug’s package insert. The change deleted previous information about the usual adult dosage. The Charleston Gazette reported, "The old language about the ‘usual adult dose’ was potentially deadly, according to pain specialists." [29]


Methadone treatment may impair driving ability.[30] Drug abuse patients had significantly more involvement in serious crashes than non-abuse patients in a study by Queensland University. In the study of a group of 220 drug abuse patients, most of them poly-drug abusers, 17 were involved in crashes killing people, compared with a control group of other patients randomly selected having no involvement in fatal crashes.[31] However, there have been multiple studies verifying the ability of methadone maintenance patients to drive.[32]

[edit]Tolerance and dependence

As with other opioid medications, tolerance and dependence usually develop with repeated doses. Tolerance to the different physiological effects of methadone varies. Tolerance to analgesia usually occurs during the first few weeks of use; whereas with respiratory depression, sedation, and nausea it is seen within approximately 5–7 days.[citation needed] There is no tolerance formed to constipation produced by methadone or other opioids; however, effects may be less severe after time and can often be alleviated through increase intake of dietary fiber (fruits and vegetables, high-fiber cereals, etc.) or fiber supplements.[citation needed]

[edit]Withdrawal symptoms

Physical symptoms[citation needed]

Cognitive symptoms[citation needed]

Withdrawal symptoms have shown to be up to twice as severe than those of morphine or heroin at equivalent doses but are significantly more prolonged; methadone withdrawal symptoms can last for several weeks or more. A general guideline is a 1:1 ratio for trouble free detox. Being on a constant dose of say 100ml for one year, can take 18–24 months for safe detoxification. At high maintenance doses, sudden cessation of therapy can result in withdrawal symptoms described as "the worst withdrawal imaginable," lasting from weeks to months.[33]

There is a trend in the management of opiate addiction towards the reduction of a patient’s methadone dosage to a point where they can be switched to buprenorphine or another opiate with an easier withdrawal profile. Methadone’s long half-life and minimal side-effect profile makes it ideal for maintenance, but is not considered to be a desirable opiate to withdraw from when attempting to become completely opiate-free.[citation needed] However, when detoxing at a recommended rate (typically 1-2 mgs per week), withdrawal is either minimal or nonexistent, as the patient’s body has time to adjust to each reduction in dose.

[edit]Methadone maintenance treatment

MMT (Methadone Maintenance Treatment), a form of opiate replacement therapy, reduces and/or eliminates the use of illicit opiates, the criminality associated with opiate use, and allows patients to improve their health and social productivity.[34] In addition, enrollment in methadone maintenance has the potential to reduce the transmission of infectious diseases associated with opiate injection, such as hepatitis and HIV.[34] The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with opiates. Methadone maintenance has been found to be medically safe and non-sedating.[34] It is also indicated for pregnant women addicted to opiates.[34]

In Russia, methadone treatment is illegal. Health officials are not convinced of the treatment’s efficacy. Instead, doctors encourage immediate abstinence from drug use, rather than the gradual process that methadone substitution therapy entails. Patients are often given sedatives and painkillers to cope with withdrawal symptoms.[35]


Methadone maintenance treatment significantly decreases the rate of HIV infection for those patients participating in MMT programs (Firshein, 1998). At proper dosing, methadone usually reduces the appetite for and need to take opiates, and also block the euphoric effects of them, thus greatly reducing the motivation of patients to use.

Methadone offers patients the freedom from active addiction and use of mind-altering drug use and in turn allows them to seek psychological, psychiatric and self-help based therapies for both the disease of addiction and other concurrent illnesses, which would not be possible when experiencing severe ongoing withdrawal and/or cravings. In addition, and perhaps most importantly, methadone allows addicts to become productive members of society. Freed from the need to obtain money through often illicit means, opiate addicts can return to their normal lives, or develop skills, further their education, and (re)join the workforce.

A proper dose used in methadone maintenance therapy will block or greatly reduce cravings for illicit opioids, while not inducing any euphoric feelings or other subjective sense of being high, and if dose is high enough, will actively prevent the patient from experiencing any high if they do use other opioids. Methadone-based treatment is significantly more effective clinically and more cost effective than no-drug treatment modalities for opiate-dependent patients.[36]


A majority of patients require 80–120 mg/d of methadone, or more, to achieve these effects and require treatment for an indefinite period of time, since methadone maintenance is a corrective but not a curative treatment for opiate addiction.[34] Lower doses are sometimes not as effective, or do not provide an equivalent blockade effect as higher dosages can. Some patients will be prescribed as much as 500 mg of methadone a day; though a dose as low as 10 mg can prove fatal in an opiate naive individual.

In the United States clinics typically start patients at a low dose, generally only starting patients on methadone when they are in withdrawal and providing a small test dose, after which the patients are observed for possible adverse effects. Assuming there are no complications, the remaining portion of the first day’s dose is then given. After this the doses are titrated until they reach either a clinically sufficient level that prevents withdrawal, cravings and possible continued use of illicit opioids, or until they reach a maximum dose set by clinic policy. For example, a clinic may start patients at 30 mg and raise the dosage 5 mg a day until the patient feels at a comfortable level, or will stop at 80 mg and allowing the patient to move up by 5 mg or 10 mg every 2 or 3 days, free from withdrawal symptoms and intense cravings. Once stabilized patients may require periodic dose adjustments as their clinical or subjective tolerance changes.

The most common and traditional dosing regimens, however, tend to fall far short of providing optimum or even sufficient results for a number of patients. This is due to the ceilings many clinics place on dose levels.[37][38]

Until recently a 100-mg/d dose was regarded as a ‘glass ceiling,’ rarely to be penetrated. In practice much lower thresholds were maintained even though the optimal dose varies greatly between patients, often quite higher than this and with no inherent threshold in the possible dose, as the toxic dose for patients with very high tolerance can exceed this ten-fold or more. The blood concentrations of patients on an equivalent dose (when adjusted for body weight) can vary as much as 17-fold, or up to 41-fold when influenced by other medications, leading to a vast range of potentially required doses.[39][40]

In the United States, federal law was changed in 2001 to eliminate some restrictions imposed on patients dosed on more than 100 mg per day.


While there is much debate generally over treatment schedules and duration, patients can often obtain indefinite treatment at their methadone clinic—lasting as long as the patient requires it. Many factors determine the treatment schedule, including specific clinic policies which sometimes require patients to taper regardless of their desire to do so. In general, methadone maintenance is seen as ongoing symptom management rather than a curative treatment. This has buttressed the arguments of those who view methadone as just another prescription drug taken for a long-term, chronic condition.

[edit]Dosage reduction

A patient’s dose of methadone may be reduced by a slow taper with minimal discomfort. Patients undergoing MMT at a clinic where they are given a daily dose have the opportunity to attempt a dose reduction and return to the previous dose if they are feeling discomfort. Policies on dose reduction vary from clinic to clinic, from a focus on eventually tapering the patient off of methadone altogether to a focus on maintaining a high dose to prevent the use of illicit opiods. Many methadone clinics will adjust doses upon personal evaluation of the correct care for the individual patient. A higher methadone dose may be considered preferable by a clinic treating patients addicted to illicit opiods, in order to discourage the use of illegal opiods. This can be due to the large increase in tolerance, a chemical blocking effect caused by methadone above certain doses, or by filling a psychological or physical need that illicit opiods were previously being used for.

To minimize or prevent patient discomfort, the methadone dose must be decreased slowly. Typical reduction rates vary and should be adjusted based on patient response.

Frequently this adjustment is monitored on a daily basis. Most of the literature focuses on methadone maintenance patients visiting clinics daily, focused on heroin substitution. Chronic pain patients wishing to decrease their methadone dose must follow similar titration regimens. However their doctor may substitute alternative opiods during this period, altering what rate is compatible with patient comfort when compared with complete detoxification.

The Centre for Addiction and Mental Health, Ontario, Canada has this recommendation: [41]

Methadone tapering works best when done as a slow and gradual reduction in dose, dropping 5 mg every three to 14 days. At this rate there should be very few, if any, physical symptoms during the taper. Once the dose is lowered to around 20 mg, the tapering may be slowed down to an even more gradual reduction, to reduce or eliminate any symptoms. Nowadays, most methadone providers will allow you to choose the rate at which your dose is reduced.

Aegis Medical Systems Tapering Off of Methadone Maintenance: Evidence-Based Guidelines [42]

recommends regular evaluation of the patient’s withdrawal symptoms, counseling where needed, and a generally slow rate, noting:

Dr. J. Thomas Payte, a highly experienced clinician and researcher, has suggested that a 7-10 day period between dose decreases should be adequate time to adjust before the next drop.

Clinical experience reminds us of an important rule in tapering, “THE SLOWER, THE BETTER,”

The College of Pharmacists of British Columbia discusses more specific rates on page 19 of a slide presentation:[43]

Stopping Methadone

  • Greater detox. completion rates with greater time spent in MMT & slower taper.
  • Taper rate
    • < 10 mg or 10% per week.
    • Slower taper below 20-30 mg.

Mallinckrodt, the primary manufacturer of methadone in the US, has guidelines [44] that include

For Medically Supervised Withdrawal After a Period of Maintenance Treatment There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. It is generally suggested that dose reductions should be less than 10% of the established tolerance or maintenance dose, and that 10 to 14-day intervals should elapse between dose reductions. Patients should be apprised of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.

Other documents discussing the recommended rate of dose reduction can be found from Health Canada[45] and the Canadian Department Of Health And Human Services [46]

[edit]Visits to clinics

Methadone has traditionally been provided to people who are opiate dependent in a highly regulated methadone clinic, generally associated with an outpatient department of a hospital, though this varies country by country. For example in Australia, Methadone maintenance treatment (MMT) is delivered by private pharmacies for a nominal fee to the client (regardless of the fact it is free as it is subsidised by the Federal government). This nominal fee covers the costs of providing the service, such as purchase and maintenance of supplies and equipment like dosing cups and precision measuring devices, supply costs involved in transporting a highly regulated drug from supplier to the pharmacy, extensive record-keeping as per government requirements, and compensation to the pharmacy staff for the time involved in preparing for and dosing a client (none of which are funded by the Federal government).

In many Western countries, new patients are required to visit the clinic daily so that they may be observed taking their dose by the dispensing nurse, but may be allowed to leave the clinic with increasing supplies of "take home doses" or "carries" after several months of adherence to the clinic’s regulations, including consistent negative drug-screen results. The way that MMT is delivered in some countries create barriers to scaling up access to the treatment. For example, in Australia, people who are on MMT are dosed in a designated area in front of other pharmacy customers.[citation needed] This can inhibit people’s willingness to access treatment due to a lack of confidentiality and anonymity. In most well-designed pharmacies in Australia, however, dosing occurs in a discreet location away from other customers, and may even take place in a room specially designed for this purpose. In some countries or regions, law stipulates that clinics may provide at most one week’s worth of methadone (up to 30 days in the USA but states may allow as few as three), except for patients unable to visit the clinic without undue hardship due to a medical disability or infrequent exceptions made for necessary travel to areas without clinics, and this level is only reached after a few years of proper results.

In the U.S., MMT patients generally receive psycho-social support (i.e. "counseling"), which is provided on site. Although laws vary, this is required in many states and countries regardless of whether a person needs or wants to engage in that kind of intervention (for example, recent changes in Taiwan). Patients are often forced to attend 10 hours or more of therapy per week, having their daily dose withheld (thereby inducing withdrawal) for failure to comply. Methadone maintenance is rarely covered by private insurance and patients are encouraged to enroll in public welfare programs or face upwards of $500USD per month. Since a supervised dose costs more than a take-home dose, and the risk of diversion, clinics are reluctant to provide take-home privileges.


Methadone clinics in the Netherlands are free for Dutch patients as methadone treatment (as well as most other common methods of addiction treatment) is fully covered under the basic health insurance clause, and since every person over the age of 18 is obliged to have health insurance in the Netherlands, everyone is insured against any such costs. For opioid dependent homeless people, all treatment costs are covered by the government subsidization in the Netherlands.

In Germany, MMT is also fully covered for by all public and private insurances. The annual costs per patient are less than 3000 euros, while Heroin assisted treatment costs up to 10.000 euros per year.

Methadone clinics in the U.S. charge anywhere from $50–300 per week, which may be covered by private insurance or Medicaid. However, the many "cash-only" clinics do not accept insurance, forcing patients to pay up front and then seek reimbursement from their carrier.

Those patients who lack insurance often struggle to pay the fees. Individuals who fall behind usually face an administrative discharge dubbed the "fee-tox" (a rapid decrease in dose lasting a week or two), or even refusal to dose (which is medically unapproved). Re-admission to programs is usually contingent upon paying all back balances plus an intake fee (which can be up to $1000 in the US, but is generally much less).

Cost analyses of methadone clinics often compare the cost of clinic visits versus the overall societal costs of illicit opiod use.[47][48]


In recent years, methadone has gained popularity among physicians for the treatment of other medical problems, such as an analgesic in chronic pain. The increased usage comes as doctors search for an opioid drug that can be dosed less frequently than short-acting drugs like morphine or hydrocodone. Another factor in the increased usage is the low cost of methadone. [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65]

While the cost for pain patients varies based on many factors, leading to few specifics in the literature, one source[66] states:

Prices vary; however, in some cases monthly costs to patients for oral methadone can be more than 30-fold less than equianalgesic doses of other generic or brand-name opioid analgesics.

A week’s supply will typically have a retail cost of $50–$70 in the United States, compared to hundreds of dollars for alternative opioids. Methadone, with its long half-life (and thus long duration of effect) and good oral bioavailability, is a common second-choice drug for pain that does not respond to weaker agonists. A major drawback is that unlike OxyContin (oxycodone continuous release), methadone is not technologically engineered for sustained release of the drug so blood concentrations will fluctuate greatly between dosing. This problem is overcome to a great extent by the practice of dosing methadone two or three times a day in pain patients. Some physicians also choose methadone for treating chronic pain in patients who are thought to have a propensity for addiction, because it causes less of an intoxicated or euphoric "high". The effect is of morphine-equivalent origin.

On November 29, 2006, the U.S. Food and Drug Administration issued a Public Health Advisory about methadone titled "Methadone Use for Pain Control May Result in Death and Life-Threatening Changes in Breathing and Heart Beat." The advisory went on to say that "the FDA has received reports of death and life-threatening side effects in patients taking methadone. These deaths and life-threatening side effects have occurred in patients newly starting methadone for pain control and in patients who have switched to methadone after being treated for pain with other strong narcotic pain relievers. Methadone can cause slow or shallow breathing and dangerous changes in heart beat that may not be felt by the patient." The advisory urged that physicians use caution when prescribing methadone to patients who are not used to the drug, and that patients take the drug exactly as directed.[67] As with any strong medication that can be fatal in large doses, methadone must be taken properly and with due care. Otherwise, the accumulation of methadone could potentially reach a level of toxicity if the dose is too high or if the user’s metabolism of the drug is slow. In such a situation, a patient who fared fine after the first few doses could reach high levels of the drug in his body without ever taking more than was prescribed. For this reason, it is reasonable to make sure that patients who do not have a tolerance to opiates be prescribed methadone in initially small doses, and that when sent home, patients and their families are made very aware of the symptoms characteristic of opiate overdose. Also, there is some evidence that methadone and other opioids may cause cardiac conduction problems (prolonged QTc interval[68]) although there are few documented cases of fatalities resulting from this side effect with methadone.

In an effort to turn the tide on reported increases in methadone-related adverse events, the DEA announced in a recent advisory that manufacturers of methadone hydrochloride 40-mg tablets have agreed to restrict their distribution of that particular formulation of the drug.

As of 1. January 2008, manufacturers will ship the methadone hydrochloride 40-mg formulation only to hospitals and facilities that have been authorized for detoxification and maintenance treatment of patients with opioid addiction. In addition, manufacturers of the drug will instruct their wholesale distributors to stop supplying the formulation to any facility that doesn’t meet the criteria.

The DEA advisory stresses that the 40-mg formulation of methadone hydrochloride is indicated only for the detoxification and maintenance treatment of opioid-addicted patients and is not FDA-approved for use in pain management.

Federal law does not restrict the prescribing, dispensing or administration of methadone for the treatment of pain, and the 5-mg and 10-mg methadone formulations will continue to be available as a tool that family physicians can use to treat patients for pain. Despite the FDA directive, many doctors continue to prescribe Methadone as a pain killer, but only to patients which have shown to be responsible in their use of previous pain killers. One reason for use of Methadone is its advantages for opioid rotation.

Patients with long-term pain will sometimes have to perform so-called opioid rotation.[69] By this is meant switching from one opioid to another, usually at intervals of between a few weeks and, more commonly, several months. Opioid rotation is good because switching to another opioid gives lower dose, and because of this less side effects, to achieve the desired effect. Then, with the new opioid, tolerance grows, higher doses are needed, and toxicity in relation to analgesic effects increase. So then it is time rotate again to another opioid. Such opioid rotation is standard practice for managing patients with tolerance development problems. Usually, when doing opioid rotation, one cannot go down to a completely naive dose, because there is cross-tolerance, so some of the high tolerance is brought over to the new opioid. However, Methadone has much lower cross-tolerance, when switching to it from other opioids, than other opioids.[70] This means that Methadone can start at a low dose, and the time for the next switch will be longer.

All opioids have as a major side effect tiredness, which can go to an almost half-awake stage (=sedation, in medical terms). Many patients report that Methadone’s sedation effect is often less pronounced than with other opioids and cite this as a major argument for preferring Methadone as an analgesic.[71]


Methadone linctus, which is about one-third the concentration of the liquid methadone used for opioid maintenance, is used where available and approved for such use as a cough syrup for violent coughing. Narcotic cough suppressants are very useful against dry, unproductive coughing, especially that which persists after an illness has otherwise resolved and/or is a manifestation of recurring bronchitis, causes pain in the chest, and/or prevents the patient from sleeping. These drugs work directly on the coughing centre in the brain, and several branches of the opioid family contain effective cough suppressants.

Natural and semi-synthetic opiates with antitussive effects include codeine, ethylmorphine (also known as dionine or codethyline), dihydrocodeine, benzylmorphine, laudanum, dihydroisocodeine, nicocodeine, nicodicodeine, hydrocodone, hydromorphone,acetyldihydrocodeine, thebacon, diamorphine (heroin), acetylmorphone, noscapine and pholcodine and others. Amongst other synthetics are dimemorfan and dextromethorphan in the morphinan group, tipepidine of the thiambutenes, and other drugs of the open-chain (methadone) type with antitussive efficacy include levomethadone, normethadone and levopropoxyphene. There is also the newer synthetic Zipeprol, classified as ‘Other'(not available in the U.S. or CA).

[edit]Methadone as treatment for leukemia

Researchers in Germany have discovered that methadone has surprising killing power against leukemia cells, including treatment-resistant forms of the cancer. Their laboratory study, published in the 1 August 2008 issue of Cancer Research, a journal of the American Association for Cancer Research, suggests that methadone holds promise as a new therapy for leukemia, especially in patients whose cancer no longer responds to chemotherapy and radiation.[72]

Similar drugs

See also: Heroin-assisted Treatment and Buprenorphine

There are two methadone isomers. The racemic mixture is more common as it is cheaper to produce. The laevorotary isomer, which is isolated by several recrystalisations from racemic methadone, is more expensive to produce. It is stronger than the racemic mixture and is marketed especially in continental Europe as an analgesic under the trade names Levo-Polamidone, Polamidone, Heptanone, Heptadone, Heptadon and others. It is used as the hydrochloride salt almost exclusively with some uncommon pharmaceuticals and research subjects consisting of the tartrate.

The closest chemical relative of methadone in clinical use is levo-α-acetylmethadol or LAAM. It has a longer duration of action (from 48 to 72 hours), permitting a reduction in frequency of use. In 1994, it was approved as a narcotic addiction treatment. In the Netherlands, like methadone and all other strong opioids, LAAM is a List I drug of the Opium Law, and in Schedule II of the United States Controlled Substances Act. LAAM has since been removed from the US and European markets due to reports of rare cardiac side effects.

Other drugs which are not structurally related to methadone are also used in maintenance treatment, particularly Subutex (buprenorphine) and Suboxone (buprenorphine combined with naloxone). In the NL, Switzerland, the UK and a few other European countries, however, not only buprenorphine and oral methadone but also injectable methadone and pharmaceutical diamorphine (heroin) or other opioids may be used for outpatient maintenance treatment of opiate addiction, and treatment is generally provided in much less heavily regulated environments than in the United States. In the United Kingdom, diamorhpine is used extremely selectively and is not available on prescription to addicts; except in specialist trils which involved no more than 300 participants. A study from Austria indicated that oral morphine (in the form of MS-Contin) provides better results than oral methadone, and studies of heroin maintenance have indicated that a low background dose of methadone combined with heroin maintenance may significantly improve outcomes for less-responsive patients.[73] Other opiates such as dihydrocodeine in both extended-release and immediate-release form are also sometimes used for maintenance treatment as an alternative to methadone or buprenorphine in some European countries.[74]

Another close relative of methadone is dextropropoxyphene, first marketed in 1957 under the trade name of Darvon. Oral analgesic potency is one-half to one-third that of codeine, with 65 mg approximately equivalent to about 600 mg of aspirin. Dextropropoxyphene is prescribed for relief of mild to moderate pain. Bulk dextropropoxyphene is in Schedule II of the United States Controlled Substances Act, while preparations containing it are in Schedule IV. More than 100 tons of dextropropoxyphene are produced in the United States annually, and more than 25 million prescriptions are written for the products. Since dextropropoxyphene produces relatively modest pain relief compared to other opioids but still produces severe respiratory depression at high doses, it is particularly dangerous when abused, as drug users may take dangerously high doses in an attempt to achieve narcotic effects. This narcotic is among the top 10 drugs reported by medical examiners in recreational drug use deaths. However, dextropropoxyphene is still prescribed for the short term relief of opiate withdrawal symptoms, particularly when the aim of treatment is to smooth detoxification to a drug free state rather than a switch to maintenance treatment.

Other analogues of methadone which are still in clinical use are dipipanone (Diconal) and dextromoramide (Palfium) which are shorter-lasting but considerably more effective as analgesics. In the 1980s and beginning of the 1990s, before pharmaceutical grade IV heroin treatment became available to heroin addicts, as either single drug replacement for street heroin, or to be used alongside prescribed methadone, oral dextromoramide was prescribed to heroin addicts instead, because even when taken orally it still produces a strong, so called "rush", without the need of IV administration and any of the risks involved with it. These drugs have a high potential for abuse and dependence and were notorious for being widely abused and sought after by drug addicts in the 1970s. They are still rarely used for the relief of severe pain in the treatment of terminal cancer or other serious medical conditions.


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External links

Opioids (N02A)

Opium and
Poppy straw

Crude opiate extracts/
whole opium products

Compote/Kompot/Polish heroin · Diascordium · B & O Supprettes · Dover’s powder · Laudanum · Mithridate · Opium · Paregoric · Poppy straw concentrate · Poppy tea · Smoking opium · Theriac

Natural Opiates

Opium Alkaloids
see also: Components of Opium

Codeine · Morphine · Oripavine · Pseudomorphine · Thebaine

Alkaloid Salts Mixtures

Pantopon · Papaveretum (Omnopon) · Tetrapon


Morphine Family

14-Hydroxymorphine · 14β-Hydroxymorphine · 14β-Hydroxymorphone · 2,4-Dinitrophenylmorphine · 6-Methyldihydromorphine · 6-Methylenedihydrodesoxymorphine ·6-Acetyldihydromorphine/6-Monoacetyldihydromorphine · Acetyldihydromorphine · Azidomorphine · Chlornaltrexamine · Chloromorphide · Dihydrodesoxymorphine (Desomorphine) ·Dihydromorphine · Ethyldihydromorphine · Hydromorphinol · Methyldesorphine · N-Phenethylnormorphine · Pseudomorphine · RAM-378

3,6 Diesters of Morphine

Acetylpropionylmorphine · Acetylbutyrylmorphine · Diacetyldihydromorphine (Dihydroheroin) · Diacetyldibenzoylmorphine · Dibutyrylcodeine · Dibutyrylmorphine · Dibenzoylmorphine ·Diformylmorphine · Dipropanoylmorphine · Heroin (Diacetylmorphine) · Nicomorphine · Tetrabenzoylmorphine · Tetrabutyrylmorphine

Codeine-Dionine Family

14-Hydroxydihydrocodeine · Acetylcodeine · Benzylmorphine · Codeine methylbromide · Desocodeine · Dimethylmorphine (Methocodeine) · Methyldihydromorphine (Dihydroheterocodeine) ·Ethylmorphine (Dionine) · Heterocodeine · Isocodeine · Morpholinylethylmorphine (Pholcodine) · Myrophine · Nalodeine · Transisocodeine


14-Ethoxymetopon · 14-Methoxymetopon · 14β-Hydroxymorphone · 14-O-Methyloxymorphone · 14-Phenylpropoxymetopon · 7-Spiroindanyloxymorphone · 8,14-Dihydroxydihydromorphinone ·Acetylmorphone · Ethyldihydromorphinone · Hydromorphinone · Hydromorphone · Hydroxycodeine · Methyldihydromorphinone · Metopon · Morphinol · Morphinone ·N-Phenethyl-14-ethoxymetopon · Oxymorphol · Oxymorphone · Pentamorphone · Semorphone


14-Cinnamoyloxycodeinone · Thebacon (Acetyldihydrocodeinone / Dihydrocodeinone enol acetate) · Codeinone · Codorphone · Codoxime · Hydrocodone · Oxycodone

Dihydrocodeine Series

14-hydroxydihydrocodeine · Acetyldihydrocodeine · Dihydrocodeine · Dihydrodesoxycodeine/Desocodeine · Dihydroisocodeine · Nicocodeine · Nicodicodeine

Nitrogen Morphine Derivatives

Codeine-N-Oxide · Heroin-N-Oxide · Hydromorphone-N-Oxide · Morphine-N-Oxide


Hydromorphazone · Morphazone · Oxymorphazone


α-chlorocodide · Pholcodine

Active Opiate

Codeine-N-Oxide (Genocodeine) · Dihydromorphine-6-glucuronide · Hydromorphone-N-Oxide · Heroin-7,8-Oxide · Morphine-6-glucuronide · 6-Acetylmorphine · Morphine-N-Oxide (Genomorphine) · Naltrexol · Norcodeine ·Normorphine


Morphinan Series

4-chlorophenylpyridomorphinan · Cyclorphan · Dextrallorphan · Dimemorfan · Levargorphan · Levallorphan · Levorphanol · Levorphan · Levophenacylmorphan · Levomethorphan · Norlevorphanol · N-Methylmorphinan · Oxilorphan ·Phenomorphan · Methorphan / Racemethorphan · Morphanol / Racemorphanol · Ro4-1539 · Stephodeline · Xorphanol


1-Nitroaknadinine · 14-episinomenine · 5,6-Dihydronorsalutaridine · 6-Ketonalbuphine · Aknadinine · Butorphanol · Cephakicine · Cephasamine · Cyprodime · Drotebanol · Fenfangjine G · Nalbuphine · Sinococuline · Sinomenine (Cocculine) ·Tannagine


5,9-DEHB · Alazocine · Anazocine · Bremazocine · Cogazocine · Cyclazocine · Dezocine · Eptazocine · Etazocine · Ethylketocyclazocine · Fluorophen · Ketazocine · Metazocine · Pentazocine · Phenazocine · Quadazocine · Thiazocine · Tonazocine · Volazocine ·Zenazocine



4-Fluoromeperidine · Allylnorpethidine · Anileridine · Benzethidine · Carperidine · Difenoxin · Diphenoxylate · Etoxeridine (Carbetidine) · Furethidine · Hydroxypethidine (Bemidone) · Hydroxymethoxypethidine · Morpheridine ·Oxpheneridine (Carbamethidine) · Meperidine-N-Oxide · Pethidine (Meperidine) · Pethidine Intermediate A · Pethidine Intermediate B (Norpethidine) · Pethidine Intermediate C (Pethidinic Acid) · Pheneridine · Phenoperidine · Piminodine ·Properidine (Ipropethidine) · Sameridine


Allylprodine · Isopromedol · Meprodine (α-meprodine / β-meprodine) · MPPP (Desmethylprodine) · PEPAP · Prodine (α-prodine / β-prodine) · Prosidol · Trimeperidine (Promedol)


Acetoxyketobemidone · Droxypropine · Ketobemidone · Methylketobemidone · Propylketobemidone


Alvimopan · Loperamide · Picenadol

Open Chain


Dextromethadone · Dextroisomethadone · Dipipanone · Hexalgon (Norpipanone) · Isomethadone · Levoisomethadone · Levomethadone · Methadone · Methadone intermediate · Normethadone · Norpipanone · Phenadoxone (Heptazone) ·Pipidone


Dimepheptanol (Racemethadol) · Levacetylmethadol · Noracetylmethadol


Dextromoramide · Levomoramide · Moramide intermediate · Racemoramide


Diethylthiambutene · Dimethylthiambutene · Ethylmethylthiambutene · Piperidylthiambutene · Pyrrolidinylthiambutene · Thiambutene · Tipepidine


Dextropropoxyphene (Propoxyphene) · Dimenoxadol · Dioxaphetyl Butyrate · Levopropoxyphene · Norpropoxyphene


Diampromide · Phenampromide · Propiram


IC-26 · Isoaminile · Lefetamine · R-4066


3-Allylfentanyl · 3-Methylfentanyl · 3-Methylthiofentanyl · 4-Phenylfentanyl · Alfentanil · α-methylacetylfentanyl · α-methylfentanyl · α-methylthiofentanyl · Benzylfentanyl · β-hydroxyfentanyl · β-hydroxythiofentanyl · β-methylfentanyl · Brifentanil · Carfentanil ·Fentanyl · Lofentanil · Mirfentanil · Ocfentanil · Ohmefentanyl · Parafluorofentanyl · Phenaridine · Remifentanil · Sufentanil · Thenylfentanyl · Thiofentanyl · Trefentanil


6,14-Endoethenotetrahydrooripavine · 7-PET · Acetorphine · Alletorphine · BU-48 · Buprenorphine · Butorphine · Cyprenorphine · Dihydroetorphine · Diprenorphine (M5050) · Etorphine · 18,19-Dehydrobuprenorphine (HS-599) · N-cyclopropylmethyl-noretorphine ·Nepenthone · Norbuprenorphine · Thevinone · Thienorphine


Ethoheptazine · Meptazinol · Metheptazine · Metethoheptazine · Proheptazine


Bezitramide · Piritramide


Clonitazene · Etonitazene · Nitazene


18-MC · 7-Acetoxymitragynine · 7-Hydroxymitragynine · Akuammidine · Akuammine · Eseroline · Hodgkinsine · Ibogaine · Mitragynine · Noribogaine · Pericine · ψ-Akuammigine


BW373U86 · DPI-221 · DPI-287 · DPI-3290 · SNC-80

Opioid peptides
see also: The Opioid Peptides

Casomorphin · DADLE · DALDA · DAMGO · Dermenkephalin · Dermorphin · Deltorphin · DPDPE · Dynorphin · Endomorphin · Endorphin · Enkephalin · Gliadorphin · Morphiceptin · Nociceptin · Octreotide · Opiorphin · Rubiscolin · TRIMU 5


3-(3-Methoxyphenyl)-3-ethoxycarbonyltropane · AH-7921Azaprocin · BDPC · Bisnortilidine · BRL-52537 · BromadolineC-8813 · Ciramadol · DoxpicomineEnadoline · Faxeladol · GR-89696 · Herkinorin · ICI-199,441 · ICI-204,448 · J-113,397 · JTC-801 · LPK-26 ·Methopholine · N-Desmethylclozapine · NNC 63-0532 · Nortilidine · O-Desmethyltramadol · Phenadone · Prodilidine · Profadol · Ro64-6198 · Salvinorin A · SB-612,111 · SC-17599 · RWJ-394,674 · TAN-67 · Tapentadol · Tecodine · Tifluadom · Tilidine · Tramadol ·Trimebutine · U-50,488 · U-69,593 · Viminol · W-18 ·

Opioid Antagonists

5′-Guanidinonaltrindole · β-Funaltrexamine · 6β-Naltrexol · Alvimopan · Amiphenazole · Binaltorphimine · Chlornaltrexamine · Clocinnamox · Cyclazocine · Cyprodime · Diprenorphine (M5050) · Fedotozine · JDTic · Levallorphan · Methocinnamox · Methylnaltrexone ·Nalfurafine · Nalmefene · Nalmexone · Naloxazone · Naloxonazine · Naloxone · Naloxone benzoylhydrazone · Nalorphine · Naltrexone · Naltriben · Naltrindole · Norbinaltorphimine · Oxilorphan · S-allyl-3-hydroxy-17-thioniamorphinan (SAHTM)



From Wikipedia, the free encyclopedia

  (Redirected from Subutex)


Systematic (IUPAC) name



CAS number

ATC code
N02AE01 N07BC01

CID 644073



Chemical data


Mol. mass
467.64 g/mol

eMolecules & PubChem

Pharmacokinetic data

70-90% (sublingual, fromethanolic solution)
~50-60% (sublingual, high-dose tablet)
~50% (transdermal)

Protein binding


20-70, mean 37 hours

biliary and renal

Therapeutic considerations

Pregnancy cat.

Legal status
Schedule III (V some states)[1](USA)
Schedule 8 (Aust)
Class C(UK)
Cat. ASingapore}
Schedule III Germany}

sublingual, IM, IV, transdermal,intranasal

Yes(what is this?) (verify)

Suboxone 8 mg tablet

Buprenorphine (Subutex, Temgesic, Buprenex, or Suboxone [buprenorphine:naloxone 4:1 preparation]) is a semi-synthetic opioid that is used to treat opioid addiction in higher dosages (>2mg) and to control moderate pain in non-opioid tolerant individuals in lower dosages (~200µg).

Buprenorphine is an Bentley-derivative opioid of the phenanthrene class with extremely high binding affinity at the µ-opioid receptor. It has partial agonist activity at the µ-opioid receptor, partial or full agonistactivity at the ORL1/nociceptin receptor, and competitive antagonist activity at the kappa, and antagonist activity at the delta opioid receptors. Buprenorphine hydrochloride was first marketed in the 1980s by Reckitt & Colman (now Reckitt Benckiser) as an analgesic, available generally as Temgesic 0.2 mg sublingual tablets, and as Buprenex in a 0.3 mg/ml injectable formulation. In October 2002, the Food and Drug Administration (FDA) of the United States of America additionally approved Suboxone and Subutex, buprenorphine’s high-dose sublingual pill preparations indicated for detoxification and long-term replacement therapy in opioid dependency, and the drug is now used predominantly for this purpose. In the European Union, Suboxone and Subutex, buprenorphine’s high-dose sublingual pill preparations were approved foropioid addiction treatment in September 2006. In the Netherlands, Buprenorphine is a List II drug of the Opium Law, though special rules and guidelines apply to its prescription and dispensation. In the USA, it has been a Schedule III drug under the United NationsConvention on Psychotropic Substances since it was rescheduled from Schedule V just before FDA approval of Suboxone and Subutex.[2] In recent years, buprenorphine has been introduced in most European countries as a transdermal formulation for the treatment of chronic pain.



[edit]Commercial preparations

British firm Reckitt & Colman (now Reckitt Benckiser) first marketed buprenorphine under the trade names Temgesic (sublingual/parenteral preparations, no active additives) and Buprenex (parenteral, no activeadditives). Two more recent formulations[disambiguation needed] from Reckitt Benckiser have been approved for opioid addiction treatment throughout most of the world, instead of Methadone. Subutex (white color, oval shape, bitter, no active additives) and Suboxone (orange color, hexagonal shaped tablet, orange flavored, one part naloxone for every four parts buprenorphine). Subutex and Suboxone are available in 2 mg and 8 mg sublingual dosages. On October 8, 2009 Roxane Laboratories of Columbus, Ohio, United States of America won FDA approval for a generic preparation of Subutex and as of October 23, 2009 announced that it is ready for distribution nation wide in 2 mg and 8 mg sublingual dosages. The demand for this generic is so high that Roxane did not produce enough to meet market demand, resulting in pharmacies running out and being unable to order more; this is being rectified by Roxane. no Teva Pharmaceutical Laboratories of Tel Aviv, Israel has also received approval, as of 1 April 2010 for a generic formulation of Subutex sublingual tablets in 2mg and 8mg dosages which are currently available in limited distribution in America as of 20 June 2010.

In India: Tidigesic-0.2 mg (slow release)or 0.3 mg/mL injectable by Sun Pharmaceuticals;Bupregesic (0.3 mg/mL) by Neon Laboratories; Morgesic (0.3 mg/mL) by Samarth Pharma; Norphin (0.3 mg/mL) Unichem Laboratories.

Suboxone contains buprenorphine as well as the opioid antagonist naloxone to deter the abuse of tablets by intravenous injection. Controlled trials in human subjects suggest that buprenorphine and naloxone at a 4:1 ratio will produce unpleasant withdrawal symptoms if taken intravenously by patients who are addicted to opioids,[3][4][5][6][7] but has no such effect when taken sublingually. However, the Suboxone formulation still has potential to produce an opioid agonist "high" if injected by non-dependent persons which may provide some explanation to street reports indicating that the naloxone is an insufficient deterrent to injection of suboxone.[8][9][citation needed]

A solution for injection (usually by the intramuscular route) is marketed for the British veterinary market by Alstoe Animal Health as Vetergesic, licensed for analgesia and sedation in dogs.

Since 2001 buprenorphine is also available transdermally as 35, 52.5 and 70 mcg per hour transdermal patches that deliver the dose over ninety-six hours. This application form is marketed as Transtec in most European countries by Grunenthal[10] (Napp Pharmaceuticals in the UK[11], Norpharma in Denmark) for the treatment of moderate to severe cancer pain and severe non-cancer pain not responding to non-opioids. Moreover, a new 5, 10 and 20 mcg per hour patch is marketed as Butrans or Norspan, a once-weekly patch for moderate chronic pain not responding to non-opioids, marketed by Napp Pharmaceuticals Ltd., and Mundipharma and Grunenthal respectively.

A novel implantable formulation of buprenorphine (Probuphine), using a polymer matrix sustained-release technology, has been developed to offer treatment for opioid dependence while minimizing risks of patient noncompliance and illicit diversion.

In addition a new formulation of Buprenorphine is being developed using Biodelivery Sciences FDA Approved BEMA (BioErodible MucoAdhesive)technology and will be developed both for acute pain conditions such as postoperative pain and chronic pain conditions such as low back, osteoarthritis, and neuropathic pain as well as opioid dependence..

[edit]Pharmacology and pharmacokinetics

Buprenorphine is a thebaine derivative with powerful analgesia approximately twenty-five to forty times as potent as morphine,[12] and its analgesic effect is due to partial agonist activity at μ-opioid receptors, i.e., when the molecule binds to a receptor, it is less likely to transduce a response in contrast to a full agonist such as morphine. Buprenorphine also has very high binding affinity for the μ receptor such that opioid receptor antagonists (e.g. naloxone) only partially reverse its effects. These two properties must be carefully considered by the practitioner, as an overdose cannot be easily reversed. Overdose is unlikely in addicted patients or people with tolerance to opioids who use the drug sublingually as meant in the case of Subutex/Suboxone, especially if there is no alcohol involved. Concomitant use of alcohol with any opioid increases the risk of overdose. One French study showed a higher incidence of fatal overdose in patients who injected both buprenorphine and benzodiazepines, specifically, temazepam, together. [citation needed] Buprenorphine can be safely taken with prescribed benzodiazepines at normal dosage, as long as the patient is tolerant to either opioids or benzodiazepines, and the drugs are taken in the dosages prescribed and by the route of administration prescribed, and not injected. Use in personsphysically dependent on full-agonist opioids while not already in withdrawal will trigger an extremely intense form of opioid withdrawal, – called "precipitated withdrawal" or "precipitated withdrawal syndrome" – that cannot be reversed by high doses of any other opioid, and will be increased in intensity if increased doses of buprenorphine are administered. This form of intense withdrawal may last anywhere from two to approximately thirty-six hours.

Buprenorphine has been shown to act as an epsilon-opiod antagonist. Several selective agonists and antagonists are now available for the putative epsilon receptor,[13][14] Buprenorphine is also a κ-opioid receptor antagonist, and partial/full agonist at the recombinant human ORL1 nociceptin receptor.[15]

Buprenorphine hydrochloride is administered by intramuscular injection, intravenous infusion, via a transdermal patch, as a sublingual tablet or an ethanolic liquid oral solution. It is not administered orally, due to very high first-pass metabolism.

Buprenorphine is metabolised by the liver, via CYP3A4 (also CYP2C8 seems to be involved) isozymes of the cytochrome P450 enzyme system, into norbuprenorphine (by N-dealkylation). The glucuronidation of buprenorphine is primarily carried out byUGT1A1 and UGT2B7, and that of norbuprenorphine by UGT1A1 and UGT1A3. These glucuronides are then eliminated mainly through excretion into the bile. The elimination half-life of buprenorphine is 20-73 hours (mean 37). Due to the mainly hepatic elimination, there is no risk of accumulation in patients with renal impairment.[16]

Buprenorphine’s main active metabolite, norbuprenorphine, is a μ-opioid, δ-opioid, and nociceptin receptor full agonist, as well as a κ-opioid receptor partial agonist.[17][18] Buprenorphine antagonizes its effects.

Plasma concentrations after application of transdermal buprenorphine increase steadily and the minimum effective therapeutic dose (100 pg/ml) is reached at eleven hours and twenty-one hours for a single 35 and 70 μg/h patch, respectively. Peak plasma concentration (Cmax) is reached in about sixty hours (305 and 624 pg/ml for the 35 and 70 μg/h strength patch, respectively), and is markedly longer than with 0.3 mg intravenous buprenorphine (0.41 hours). Transdermal buprenorphine has a half-life of approximately thirty hours, and a bioavailability of approximately 50%, which is comparable to sublingual buprenorphine.

[edit]Clinical use

[edit]Pain indications

Depending on the application form, buprenorphine is indicated for the treatment of moderate to severe chronic pain (pain that has outlived its use to prevent injury and after three months) or for peri-operative analgesia. For the treatment of chronic pain, the transdermal formulations (not currently available in the U.S.A and Canada as of January 2010) are preferred, which can be used both for chronic cancer pain as well as chronic non-malignant pain, such as musculosceletal and neuropathic pain. The intravenous formulation is mainly used in postoperative pain (for example, as patient controlled analgesia (PCA)) and the sublingual formulation is, for example, used as breakthrough medication for patients with basic transdermal treatment. Advantages of buprenorphine in the treatment of chronic pain are, from a clinical perspective, its relatively long half-life, the option of sublingual and transdermal application and the excellent safety profile (ceiling effect for respiratory depression, lack of immunosuppressive effect, low pharmacokinetic interaction potential, no accumulation in renal impairment). Although not enough western literature is available, use of inj. buprenorphine in ‘spinal’ anaesthesia is rising in countries like India. Up to 150 micrograms of the drug (0.5 ml) of the preservative free solution is added to the local anaesthetic bupivacaine, and a smoother analgesia is obtained with the benefit of the patient remaining pain-free until up to eight to ten hours of the spinal being given.

[edit]Blockade Effect

Buprenorphine (Subutex) itself binds more strongly to receptors in the brain than do other opioids, making it more difficult for opioids to react when buprenorphine is in the system

[edit]Antidepressant potential

A clinical trial conducted at Harvard Medical School in the mid-1990s demonstrated that a majority of unipolar non-psychotic patients with major depression refractory to conventional thymoleptic antidepressants could be successfully treated with buprenorphine.[19] See opioids for other (predominantly favorable) experiments with buprenorphine and other opioids for psychological relief. However, psychological distress, such as clinical depression, is currently not an approved indication for the use of any opioid, and legally it falls in to a "grey zone".[20][21] Some doctors nevertheless are realising its potential as an antidepressant in cases where the patient cannot tolerate or is resistant to conventional thymoleptic antidepressants. Both mental and physical pain are regulated by the same chemical networks in the brain. Depression is commonly accompanied by co-morbid pain symptoms. Endogenous opiates, such as endorphins and enkephalins, mediate pain perception in the body. In the brain, they are significantly involved in regulating mood and behavior, and decreasing the perception of pain and depression.


Like full agonist opiates, buprenorphine can cause drowsiness, vomiting and respiratory depression. Taking buprenorphine in conjunction with central nervous system (CNS) depressants in people who are not tolerant to either agent can cause fatal respiratory depression. Sedatives, hypnotics, and tranquilizers – which are all benzodiazepines – can be dangerous if ingested with buprenorphine by a person who is tolerant to neither opioids or benzodiazepines. Co-intoxication with ethanol carries the greatest risk for lethal overdose.[22]

[edit]Adverse effects

Common adverse drug reactions associated with the use of buprenorphine are similar to those of other opioids and include: nausea and vomiting, drowsiness, dizziness, headache, itch, dry mouth, miosis, orthostatic hypotension, male ejaculatory difficulty, decreased libido, and urinary retention. Constipation and CNS effects are seen less frequently than with morphine.[23] Hepatic necrosis and hepatitis with jaundice have been reported with the use of buprenorphine, especially after intravenous injection of crushed tablets.

The most severe and serious adverse reaction associated with opioid use in general is respiratory depression, the mechanism behind fatal overdose. Buprenorphine behaves differently than other opioids in this respect, as it shows a ceiling effect for respiratory depression.[23] Moreover, former doubts on the antagonisation of the respiratory effects by naloxone have been disproved: Buprenorphine effects can be antagonised with a continuous infusion of naloxone.[24] Concurrent use of buprenorphine and CNS depressants (such as alcohol or benzodiazepines) is contraindicated as it may lead to fatal respiratory depression. Benzodiazepines, in prescribed doses, are not contraindicated in individuals who are tolerant to either opioids or benzodiazepines.

People on medium- to long-term maintenance with Suboxone or Subutex do not have a risk of overdose from buprenorphine alone, no matter what dosage is taken or route of administration it is taken by, due to the "ceiling effect" on respiratory depression. Overdoses occurring in maintenance patients are cases of multiple-drug intoxication, usually buprenorphine taken with excessive amounts of ethanol and/or benzodiazepine drugs. It is safe for a patient to take a prescribed dose of benzodiazepines with buprenorphine as long as the patient has a tolerance to either opioids or benzodiazepines. As a matter of course, all patients on buprenorphine maintenance are tolerant to opioids, and maintenance doses are always higher than the dose at which the "ceiling effect" on respiratory depression is reached (~3±1 milligrammes, depending on method of analysis).[citation needed]

People switching from other opiates should wait until mild to moderate withdrawal symptoms are encountered. Failure to do so can lead to the rapid onset of intense withdrawal symptoms, known as precipitated withdrawal.[25] For short acting opioids such as codeine, hydrocodone, oxycodone (and OxyContin), hydromorphone, pethidine, heroin, and morphine, 12-24 hours from the last dose is generally sufficient. For longer acting opioids such as fentanyl and methadone, 2-3 days from the last dose is needed to prevent precipitated withdrawal.

Conversely, switching from buprenorphine to other opioids is generally safe and can occur immediately. For users of Suboxone, it is advised to wait a few hours from the last dose before switching to other opioids to allow the naloxone in Suboxone to be eliminated from the body (it has a short half-life). Generally the new opioid will not be as strong or effective for several days until the remaining buprenorphine has been eliminated from the body. This is due to the blockade effect, where the buprenorphine is strongly bound to the opiate receptors in the brain and not allowing the new (full agonist) opioid to completely bind to and activate the receptors. This explains the phenomenon where Suboxone users trying to get high off of say oxycodone cannot until several days have passed since the last Suboxone dose; of course this also explains why Suboxone is an effective maintenance/opioid addiction therapy medication because users cannot decide on a whim to quickly stop their maintenance dosing to get high.

[edit]Detection in biological fluids

Buprenorphine and norbuprenorphine, its major active metabolite, may be quantitated in blood or urine to monitor use or abuse, confirm a diagnosis of poisoning or assist in a medicolegal death investigation. There is a significant overlap of drug concentrations in body fluids within the possible spectrum of physiological reactions ranging from asymptomatic to comatose, and therefore it is important to have knowledge of the route of administration of the drug and the individual’s tolerance to opioids when interpreting analytical results.[26]

[edit]Recreational use

Buprenorphine is also used recreationally, typically by opioid (opioid naive) users, often by insufflation. Recreational users of Suboxone who crush the tablet and inhale it through their nose report intense feelings of euphoria similar to that of cocaine and Ecstasy. Opioid tolerant users and those already using buprenorphine/Suboxone for opioid addiction therapy find that insufflation is no different than taking the pill sublingually, and obtaining euphoria virtually impossible. Many recreational users also report withdrawal symptoms. Due to the high potency of tablet forms of buprenorphine, only a small amount of the drug need be ingested to achieve the desired effects.

Buprenorphine abuse is very common in Scandinavia, especially in Finland and Sweden. In 2007, the authorities in Uppsala county in Sweden confiscated more buprenorphine than cocaine, ecstasy and GHB.[27] In Finland recreational use of buprenorphine is on the rise; in 2005, Finland’s incidence of Subutex abuse (most often injected intravenously) surpassed the incidence of recreational usage of amphetamines. Intravenous administration of dissolved Subutex pills and insufflation of pulverized pills are the most common ways of recreational buprenorphine use.[28]

[edit]Dependence treatment

Buprenorphine sublingual preparations are often used in the management of opioid dependence (that is, dependence on heroin, oxycodone, hydrocodone, morphine, oxymorphone, fentanyl or other opioids). The Suboxone and Subutex preparations were approved for this indication by the United States FDA in October 2002. This was only possible due to the Drug Addiction Treatment Act of 2000 which overturned a series of 1914–1920 Supreme Court rulings that had found that maintenance and detox treatments were not a form of medical treatment.[citation needed] Although the rulings had the power of legal precedent prior to 2000, it is likely that they were not the intended interpretation of the laws passed originally by congress.[citation needed]

The Drug Addiction Treatment Act allowed medical professionals to prescribe and administer opioids to manage addiction ("maintenance") as well to perform short-term detox. Such use of opioids was previously allowed only in specially registered drug treatment centers. These restrictions were removed only for Schedule III through V drugs. As such they do not include methadone and stronger opioids, but do allow for the medical use of buprenorphine.

The first buprenorphine treatment program for opiate addiction in the United States was founded by Dr. David McDowell at Columbia University[29] and reported an 88% success rate with its patients.[30]

The use by medical professionals of medication-assisted treatment in the management of opioid dependence is still regulated, owing in part to the controversy of this form of harm reduction treatment. In the United States a special federal waiver (which can be granted after the completion of an eight-hour course) is required in order to treat outpatients for opioid addiction with Subutex and Suboxone. In addition, each approved prescriber is only allowed to treat thirty patients with buprenorphine for opioid addiction in an outpatient setting.[31]

On of December 12, 2006 the U.S. Congress passed additional legislation which relaxed the latter restriction for doctors who specialize in treating addiction through group therapy.[citation needed]. It allows physicians with at least one year of clinical experience with Buprenorphine to request an additional exemption within DATA 2000, which increases the limit to hundred outpatients, effective as of 12/29/2006 (public law 109-469).[citation needed]

Similar restrictions are placed on prescribers in many other jurisdictions. For example, Buprenorphine is regulated in the same way as methadone in Australia, and while the number of patients per doctor isn’t capped, the patient is required to visit a pharmacy daily in order to receive a supervised dose of their medication.[citation needed]

On September 21, 2006, actor and comedian Artie Lange revealed on The Howard Stern Show that he had overcome heroin addiction the previous year. He said buprenorphine was essential to countering the effects of opioid withdrawal and described it as a ‘miracle pill’. The withdrawal from buprenorphine after short-term use is generally far milder than other potent opioids, but can have a longer duration than short-acting opioids of abuse.

[edit]Buprenorphine versus methadone

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Buprenorphine and methadone are medications used for detoxification, short- and long-term maintenance treatment. Each agent has its relative advantages and disadvantages.

In terms of efficacy (i.e. treatment retention, mostly negative urine samples), high-dose buprenorphine (such as that commonly found with Subutex/Suboxone treatment; 8–16 mg typically) has been found to be superior to 20–40 mg of methadone per day (low dose) and equatable anywhere between 50–70 mg (moderate dose)[32], to up to 100 mg (high dose)[33] of methadone a day. In all cases, high-dose buprenorphine has been found to be far superior to placebo and an effective treatment for opioid addiction, with retention rates of 50% as a minimum.[32][33][34][35] It is also worth noting that while methadone’s effectiveness is generally thought to increase with dose, buprenorphine has a ceiling effect at 32 mg[36] That is, while a methadone dose of 80 mg will likely be more effective than a methadone dose of 60 mg, (see Methadone dosage) a buprenorphine dose of 40 mg will not be more effective than a buprenorphine dose of 32 mg.

Buprenorphine sublingual tablets (Suboxone and Subutex for opioid addiction) have a long duration of action which may allow for dosing every two or three days, as tolerated by the patient, compared with the daily dosing (some patients receive twice daily dosing) required to prevent withdrawals with methadone. Once one has been taking a maintenance dose of methadone for some time, withdrawal effects do not begin in earnest until 48–72 hours and in some cases 96 hours or more after the last dose taking. In the United States, following initial management, a patient is typically prescribed up to a one month supply for self-administration. It is often misunderstood that the patient has to receive other therapy in this situation, but the law simply states that the prescribing physician needs to be capable of referring the patient to other addiction treatment, such as psychotherapy or support groups.

Buprenorphine may be more convenient for some users because patients can be given a thirty day take home dose relatively soon after starting treatment, hence making treatment more convenient relative to those who need to visit a methadone dispensing facility daily. The facilities, which are regulated at the state and federal level in the US, initially are only permitted to allow patients to receive take home doses (to be self-administered at the appropriate time) on a day when the clinic is regularly closed or on a pre-scheduled holiday. It is only after a minimum of several months of compliance (i.e., proven sobriety, demonstration of being able to safely store the medication) that patients of methadone clinics in most countries are permitted regularly scheduled take home doses aside from the possible exceptions for weekends and holidays. Ultimately, American patients on methadone maintenance therapy are permitted a maximum of a one month supply of take home medication, and this is only permitted after a minimum of two years compliance. In the US state of Florida, patients cannot receive a month supply until five years of compliance. Most buprenorphine patients are not prescribed more than one month’s worth of buprenorphine at a time. However, buprenorphine patients, as a rule, are able to get their one month supply much earlier in their use of the drug than methadone patients.

Buprenorphine as a maintenance treatment thereby offers an advantage of convenience over methadone. Buprenorphine patients are also generally not required to make daily office visits and are often very quickly permitted to obtain a one month prescription for the medication. Methadone patients in the United States who are not subject to additional strictures beyond the federal law regarding a patient’s take-home supply also benefit in convenience. States with excessive regulation on methadone dispensation see professionals advocating for office-based methadone treatment, similar to the standard of office-based buprenorphine treatment. Such treatment with full opiate agonists is already available on a limited basis in the UK, and has been ever since heroin was made illegal, with an interruption of a few decades which occurred, likely under pressure from the United States,[citation needed] during the worldwide escalation of the War on Drugs which occurred during the 1960s and 1970s. In fact, in the UK a doctor may prescribe any opiate to a person, regardless of their complaint (excluding diamorphine and dipipanone for addiction, where they require a special licence from the Home Office). In practice, methadone is most often used, although morphine and heroin are also less frequently prescribed on a maintenance basis. The UK has a smaller number of opiate users, per capita, than the United States,[citation needed] which many attribute to the availability of full opiate agonist prescriptions to users, which reduces the amount of opiates sold illicitly and, in turn, the number of users of other drugs who encounter and begin using the opiates. Therefore, it could be argued that buprenorphine may not be as attractive a treatment option in the UK due to full opiate agonists such as heroin maintenance being an option for a small amount of addicts seeking treatment. (see Heroin prescription)

Buprenorphine may and is generally viewed to have a lower dependence-liability than methadone. In other words, withdrawal from buprenorphine is less difficult. Like methadone treatment, buprenorphine treatment can last anywhere from several days (for detoxification purposes) to an indefinite period of time (life-long maintenance) if patient and doctor both feel that is the best course of action. Additionally, the opinion of those in the medication assisted treatment field is generally shifting to longer-term treatment periods, which may last indefinitely, due to the anti-depressant effects opioids seem to have on some patients, as well as the high relapse potential among those patients discontinuing maintenance therapy. The choice of buprenorphine versus methadone in the mentioned situation (by the patient) is usually due to the benefits of the less-restrictive outpatient treatment; prescriptions for take-home doses for up to a month early versus the possibility of heavy restrictions in some states and frequent visits to the clinic and the possibility of the "stigma" of going to a methadone clinic as compared to making trips to a doctor’s office. Buprenorphine is also significantly more expensive than methadone and this seems to add to its better reputation. Also, in some states, there is a long waiting list for admission to a methadone maintenance program versus those with the money to afford seeing an addiction specialist each month in addition to the cost of medication. In studies done methadone is considered more addicting physically and mentally.[citation needed] The sometimes less-severe withdrawal effects may make it easier for some patients to discontinue use as compared with methadone, which is generally thought to be associated with a more severe and prolonged withdrawal. However, no evidence thus far exists that sustaining abstinence post-buprenorphine maintenance is any more likely than post-methadone maintenance.

Another issue of concern for patients considering beginning any maintenance therapy or switching from one maintenance therapy to another is the transition associated with this switch. Due to buprenorphine’s high-affinity to opioid receptors in the brain, care needs to be taken when a patient is transitioning from one drug (i.e., heroin) or medication (i.e., methadone) to buprenorphine. Essentially, if an opioid-dependent patient is not in sufficient withdrawal, introduction of buprenorphine may precipitate withdrawal. In layman’s terms, in a sufficient dose, buprenorphine "pushes" any other opioids off of the receptors, but is itself not always "strong enough" to counteract the withdrawal symptoms this causes.[37] Thus, opioid-dependent patients, particularly those on methadone or another long-acting medication or drug should be thoroughly honest with their prescribing doctor about their drug use, particularly in the days immediately preceding their induction onto buprenorphine, whether for detoxification or maintenance. In contrast, the transition from buprenorphine or other opioids to methadone is generally easier, and any discomfort or side effects are more likely to be easily remedied with dose adjustments.

Buprenorphine, as a partial μ-opioid receptor agonist, has been claimed and is generally viewed to have a less euphoric effect compared to the full agonist methadone, and was therefore predicted less likely to be diverted to the black market (as reflected by its C–III status versus methadone’s more restrictive C–II status in the USA), as well as that buprenorphine is generally accepted as having less potential for abuse than methadone. It is also worth noting that neither methadone nor buprenorphine are to cause euphoria when taken long-term at the appropriate dose. However, in at least one study in which opiate users who were currently not using were given buprenorphine, several other opioids, and placebo intramuscularly, subjects identified the drug they were injected with as heroin when it was actually buprenorphine.[38] This evidence tends to support the contentions of those who reject the notion that buprenorphine, when injected, is only marginally euphoric, or significantly less euphoric than other opiates.

It should be noted that, in an effort to prevent injection of the drug, the Suboxone formulation includes naloxone in addition to the buprenorphine. When naloxone is injected, it is supposed to precipitate opiate withdrawal and blocks the effects of any opiate. The naloxone does not precipitate withdrawal or block the effect of the buprenorphine when taken sublingually. The Subutex formulation does not include naloxone, and therefore has a higher potential for injection abuse. However, Subutex is prescribed significantly less than Suboxone for just this reason. Methadone, on the other hand, is typically given to patients at clinics in a liquid solution, to which water is generally added. This makes injection difficult without evaporating the liquid and taking other measures. Therefore, injection of buprenorphine as found in the preparations provided to opiate users is simpler than injection of methadone, although data on the relative incidence is not currently available. Although methadone is generally not a drug of choice for opioid addicts due to its long-acting nature and relatively little euphoria associated with its use, especially when compared to other drugs of abuse such as heroin and Oxycodone, it is used by addicts to relieve withdrawal symptoms when their opiate of choice cannot be obtained. Most methadone bought from the black market is thought to be bought by already opioid-dependent persons attempting to circumvent the substance abuse treatment system and detoxify themselves with the methadone or simply by people who wish to use the drug recreationally, just as other opiates are used. In the US, buprenorphine is found far less often on the black market as compared to methadone. The vast majority of the methadone diverted to the black market is not diverted from methadone clinics for opioid dependent persons, but rather it is diverted by a minority of the people who receive prescription for methadone for pain.

[edit]Blockade effect

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The Suboxone preparation contains the μ-opioid receptor antagonist naloxone. Buprenorphine itself is mixed agonist/antagonist, and, as such, buprenorphine blocks the activity of other opiates and induces withdrawal in opiate dependent individuals who are currently physically dependent on another opiate. This is why users must wait until they are in withdrawal before beginning treatment with buprenorphine.

Buprenorphine itself binds more strongly to receptors in the brain than do other opioids, making it more difficult to become intoxicated via other opioids when buprenorphine is in the system, regardless of the presence of the naloxone. If enough buprenorphine is in the system, however, it has the same type of effect as naloxone, i.e. it completely or nearly completely blocks or reverses opiate effects from other opioids. 0.3 mg of buprenorphine parenterally is equivalent in antagonistic effect to between 0.4 and 2.0 mg of naloxone parenterally, but with a much longer half-life. Methadone also blocks the effects of other opioids at higher doses, however under ~40 mg, the block in effects is barely present. At commonly used methadone maintenance doses, the degree of blockade is similar to that produced by equivalent buprenorphine doses. Unlike buprenorphine, however, this is not due to opiate antagonist-like action of methadone. Instead, daily use of methadone, like daily use of any of the opiate agonists, results in tolerance to all opiates, called "cross-tolerance". However, it is still possible to use other opioids on either treatment regime, although many people find "getting high" to be difficult or unattainable.

Switching to buprenorphine from methadone is often difficult and withdrawals lasting several days or more are often encountered mostly when the methadone dose is any higher than 30 mg/day (the suggested and usual dose for switching to buprenorphine). A 30 mg dose of methadone is relatively low, and some patients have difficulty reaching that dose, for a variety of reasons, usually the emergence of withdrawal symptoms.[39] Healthy users of methadone who commit to a slow taper, however, frequently find success in tapering to 30 mg in order to switch to buprenorphine, as well as in tapering off of methadone completely without the use of buprenorphine. Switching to buprenorphine at higher doses of methadone may be uncomfortable for the user. One reason is that users must be in withdrawal before switching to buprenorphine, and users of opiates with long half-lives, like methadone, may need to wait several days after their last dose of methadone before they are fully in withdrawal and ready to begin buprenorphine. Users of heroin, hydrocodone, oxycodone, and morphine, as well as most other common opiates, only need to wait a maximum of twenty-four hours before they are fully in withdrawal and ready to begin buprenorphine. For this reason, some doctors switch methadone users to a shorter acting opiate, such as morphine, for a few days before allowing withdrawal to occur and beginning buprenorphine. Unfortunately, due to the unique qualities of both methadone and buprenorphine, switching to and using buprenorphine during pregnancy instead of methadone is unlikely to be helpful, since the strain of withdrawal on the body is far more dangerous for a fetus than the use of an opiate such as methadone—about which the data suggests that after the first few weeks of life, no developmental differences are found between children born to mothers who were stable on an opiate during pregnancy versus those who were not taking any opiates during pregnancy. This stands in stark contrast to the results of using the otherwise socially acceptable drug alcohol during pregnancy. Also, data regarding buprenorphine’s safety during pregnancy is less available than data on methadone during pregnancy—data which has established the safety of methadone during pregnancy and the lack of lasting effects on children of mothers on methadone during pregnancy. On the other hand, switching from buprenorphine to methadone is relatively easy as methadone is a full opiate agonist which does not have a ceiling, and can stop the withdrawal symptoms of users at any dosage of other opiates, including buprenorphine.

[edit]Inpatient rehabilitation

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The practice of using buprenorphine (Subutex or Suboxone) in an inpatient rehabilitation setting is increasing rapidly,[citation needed] whereas methadone-based detox is the standard. It is also being used in social model treatment settings. These rehabilitation programs consist of "detox" and "treatment" phases. The detoxification ("detox") phase consists of medically-supervised withdrawal from the drug of dependency on to buprenorphine, sometimes aided by the use of medications such asbenzodiazepines like oxazepam or diazepam (modern milder tranquilizers that assist with anxiety, sleep, and muscle relaxation), clonidine (a blood-pressure medication that may reduce some opioid withdrawal symptoms), and anti-inflammatory/pain reliefdrugs such as ibuprofen. Switching to buprenorphine from a short-acting drug including heroin, morphine, fentanyl, hydromorphone (Dilaudid) and hydrocodone (Vicodin), or oxycodone (Oxycontin, Percocet) is not too difficult for most people, and as long as the patient waited until they were in full withdrawals or longer before starting the buprenorphine medication, little further acute symptoms are an issue; The patient needs to be stabilized on a proper dose and monitored regardless. Switching from methadone is much more difficult, and with all cases if the patient takes buprenorphine prematurely (before full withdrawal symptoms) it can precipitate worse withdrawals than would have been had if the person had waited properly, and they can be long-lasting.

The treatment phase begins once the patient is stabilized and receives medical clearance. This portion of treatment comprises multiple therapy sessions, which include both group and individual counseling with various chemical dependency counselors, psychologists, psychiatrists, social workers, and other professionals. Additionally, many treatment centers utilize 12-step facilitation techniques, embracing the 12-step programs practiced by such organizations as Alcoholics Anonymous and Narcotics Anonymous. Some on maintenance therapies have veered away from such organizations as Narcotics Anonymous, instead opting to create their own 12-step fellowships (such as Methadone Anonymous[40]) or depart entirely from the 12-step model of recovery (using a program such as SMART Recovery.[41])

Patients who enter rehabilitation voluntarily (as opposed to those who are court-ordered) can often choose a facility with the option of only staying for detox. Alternatively they can enter treatment facilities that provide the option to complete both detox and longer-term treatment. Completing both increases the probability of success.[citation needed] Abstinence alone has a very low efficacy in rehabilitating patients. In contrast, buprenorphine maintenance has a high efficacy.[32][33] Most rehabilitation programs do not have or do not allow scientific studies to be conducted to contrast to abstinence alone and buprenorphine or methadone maintenance, including Narcotics Anonymous. NA’s twelve traditions and overriding principle of anonymity would make such research potentially contentious and internally problematic.[citation needed] While the maintenance / abstinence debate is a hot topic and strong arguments in support of both Narcotics Anonymous and buprenorphine maintenance have been made, individuals tend to gravitate the alternative that works best for them. Furthermore, the two approaches need not necessarily be mutually exclusive. Rehabilitation programs typically average about thirty days for primary care, but some may extend anywhere from ninety days to six months in an extended care unit. It is considered essential by the programs that administer them that patients in abstinence-based treatment form networks with other addiction survivors and engage in mutual-help groups, aftercare and other related activities after treatment in order to improve their chances of achieving long-term abstinence from opioids. Statistically, long-term abstinence is not widely prevalent.

Buprenorphine is sometimes used only during the detox protocol with the purpose of reducing the patient’s use of mood-altering substances. It considerably reduces acute opioid withdrawal symptoms that are normally experienced by opioid-dependent patients on cessation of those opioids, including diarrhea, vomiting, fever, chills, cold sweats, muscle and bone aches, muscle cramps and spasms, restless legs, agitation, gooseflesh, insomnia, nausea, watery eyes, runny nose and post-nasal drip, nightmares, etc. The buprenorphine detox protocol usually lasts about seven to ten days, provided that the patient does not need to be detoxed from any additional addictive substances, as previously mentioned.

During this time, Suboxone or Subutex will be administered or the patient will be monitored taking the medication. Generally, the patient takes a single dose each day (a single dose may keep the patient comfortable for up to forty-eight to seventy-two hours, but medical professionals in many treatment facilities prescribe one or more than one dose every twenty-four hours to ensure that a consistent, active level of the medication remains in the patient’s central nervous system, a key element of maintenance; also the level of dosage is usually around the previously described plateau, after which there is no noticeable increase in the effects of the drug. Typically, the first day dosage is no more than 8 mg or it may precipitate withdrawals as antagonistic effects overwhelm agonistic effects, after which initial daily dose totals around 8–16 mg of either Suboxone or Subutex. The dosage is slowly tapered each day and the medication is usually stopped thirty-six to forty-eight hours prior to the end of the detox program, with the patient’s vitals monitored up until discharge from the detox program.

During the detox period of any situation, because of risk of naloxone related side-effects, Subutex is urged over Suboxone by the manufacturer.

[edit]Indications under investigation

Buprenorphine has been used in the treatment of the neonatal abstinence syndrome, a condition in which newborns exposed to opioids during pregnancy demonstrate signs of withdrawal.[42] Use currently is limited to infants enrolled in a clinical trial conducted under an FDA approved investigational new drug (IND) application.[43]


  1. ^ http://codes.ohio.gov/orc/3719.41
  2. ^ List of psychotropic Substances under international control
  3. ^ Mendelson J, Jones RT, Fernandez I, Welm S, Melby AK, Baggott MJ. Buprenorphine and naloxone interactions in opiate-dependent volunteers. Clin Pharmacol Ther. 1996 Jul;60(1):105-14.
  4. ^ Fudala PJ, Yu E, Macfadden W, Boardman C, Chiang CN. Effects of buprenorphine and naloxone in morphine-stabilized opioid addicts. Drug Alcohol Depend. 1998 Mar 1;50(1):1-8.
  5. ^ Stoller KB, Bigelow GE, Walsh SL, Strain EC. Abstract Effects of buprenorphine/naloxone in opioid-dependent humans. Psychopharmacology (Berl). 2001 Mar;154(3):230-42.
  6. ^ Strain EC, Preston KL, Liebson IA, Bigelow GE. Abstract Acute effects of buprenorphine, hydromorphone and naloxone in methadone-maintained volunteers. J Pharmacol Exp Ther. 1992 Jun;261(3):985-93.
  7. ^ Harris DS, Jones RT, Welm S, Upton RA, Lin E, Mendelson J. Buprenorphine and naloxone co-administration in opiate-dependent patients stabilized on sublingual buprenorphine. Drug Alcohol Depend. 2000 Dec 22;61(1):85-94.
  8. ^ Strain EC, Stoller K, Walsh SL, Bigelow GE. Effects of buprenorphine versus buprenorphine/naloxone tablets in non-dependent opioid abusers. Psychopharmacology (Berl). 2000 Mar;148(4):374-83.
  9. ^ Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) 40. Laura McNicholas. US Department of Health and Human Services.
  10. ^ Transtec Summary of Product Characteristics
  11. ^ Napp Pharmaceuticals
  12. ^ http://coretext.org/show_detail.asp?recno=6481 Reckitt Benckiser Buprenorphine Bibliography
  13. ^ Fujii H, Narita M, Mizoguchi H, Murachi M, Tanaka T, Kawai K, Tseng LF, Nagase H (August 2004). "Drug design and synthesis of epsilon opioid receptor agonist: 17-(cyclopropylmethyl)-4,5alpha-epoxy-3,6beta-dihydroxy-6,14-endoethenomorphinan-7alpha-(N-methyl-N-phenethyl)carboxamide (TAN-821) inducing antinociception mediated by putative epsilon opioid receptor". Bioorg. Med. Chem. 12 (15): 4133–45. doi:10.1016/j.bmc.2004.05.024. PMID 15246090.
  14. ^ Fujii H, Nagase H (2006). "Rational drug design of selective epsilon opioid receptor agonist TAN-821 and antagonist TAN-1014". Curr. Med. Chem. 13 (10): 1109–18. doi:10.2174/092986706776360851. PMID 16719773.
  15. ^ Huang P. et al. (2001): "Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist", J. Pharmacol. Exp. Ther. 297(2):688-95. PMID 11303059
  16. ^ http://dmd.aspetjournals.org/content/early/2009/09/22/dmd.109.028605.full.pdf
  17. ^ Yassen A, Kan J, Olofsen E, Suidgeest E, Dahan A, Danhof M (May 2007). "Pharmacokinetic-pharmacodynamic modeling of the respiratory depressant effect of norbuprenorphine in rats". The Journal of Pharmacology and Experimental Therapeutics 321 (2): 598–607. doi:10.1124/jpet.106.115972. PMID 17283225.
  18. ^ Huang P, Kehner GB, Cowan A, Liu-Chen LY (May 2001). "Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist". The Journal of Pharmacology and Experimental Therapeutics 297 (2): 688–95. PMID 11303059.
  19. ^ Bodkin JA. et al. (1995): "Buprenorphine treatment of refractory depression", Journal of Clinical Psychopharmacology 15:49-57. PMID 7714228
  20. ^ Drug War Ensnares Doctors, Not Dealers – Oct 2, 2003
  21. ^ The War on Drugs Is a War on Doctors by Rep. Ron Paul
  22. ^ Suboxone FAQ
  23. ^ a b Budd K, Raffa RB. (edts.) Buprenorphine – The unique opioid analgesic. Thieme 2005 (ISBN 3-13-134211-0)
  24. ^ Van Dorp E. et al. (2006) Naloxone reversal of buprenorphine- induced respiratory depression. Anesthesiology 105 (1): 51-57
  25. ^ http://www.naabt.org/documents/naabt_precipwd.pdf
  26. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 190-192.
  27. ^ "Subutex Abuse on the Rise (Swedish)", Upsala Nya Tidning, 2007-05-06. Retrieved on 2008-08-27.
  28. ^ Hermansson, Gunnar "Subutex Instead of Heroin (Swedish)". Retrieved on 2008-08-27.
  29. ^ Buprenorphine: New Medication to Treat Substance Abuse, Matthew Dougherty.
  30. ^ New Ways to Loosen Addiction’s Grip, Anahahd O’Connor, The New York Times, August 3, 2004
  31. ^ naabt.org
  32. ^ a b c R. S. Schottenfeld et al. (1997) Department of Psychiatry, Yale University School of Medicine
  33. ^ a b c Rolley Johnson et al., NEJM, 343(18):1290–1297, 2000
  34. ^ Strain et al. (1998)
  35. ^ Ling et al. (1998).
  36. ^ Buprenorphine
  37. ^ Suboxone.com – Frequently Asked Questions
  38. ^ Buprenorphine and reward
  39. ^ AJ Giannini. Drugs of Abuse–Second Edition. Los Angeles, Practice Management Information Corporation, 1997.
  40. ^ Methadone Anonymous
  41. ^ Smart Recovery’s organization website
  42. ^ Kraft WK, et. al., Sublingual Buprenorphine for Treatment of the Neonatal Abstinence Syndrome: A Randomized Trial. Pediatrics. 2008; 122:e601-7 PMID 18694901 [1]
  43. ^ Clinicaltrials.gov NCT00521248

[edit]External links


From Wikipedia, the free encyclopedia

This article is about the drug. For other meanings, see Morphine (disambiguation).

"Morphia" redirects here. For other uses, see Morphia (disambiguation).

Not to be confused with Morphea or morpholine.

Please help improve this article by expanding it. Further information might be found on the talk page. (January 2009)


Systematic (IUPAC) name



CAS number
64-31-3 (neutral sulfate),
52-26-6 (hydrochloride)

ATC code

CID 5288826



Chemical data


Mol. mass

Pharmacokinetic data

~25% (oral); 100% (IV);

Protein binding

Hepatic 90%

2–3 h

Renal 90%, biliary 10%

Therapeutic considerations

Pregnancy cat.

Legal status
Controlled (S8) (AU)Schedule I (CA) ? (UK)Schedule II (US)

Dependence Liability
Extremely high

Inhalation (smoking),insufflation (snorting),oral, rectal,subcutaneous (S.C),intramuscular (I.M), andintravenous (I.V)

Yes(what is this?) (verify)


Recreational uses:


Side effects:


Ear, nose, throat, andskin:









Morphine (INN) (pronounced /ˈmɔrfiːn/) (MS Contin, MSIR, Avinza, Kadian, Oramorph, Roxanol, Kapanol) is a potent opiate analgesic psychoactive drug and is considered to be the prototypical opioid. In clinical medicine, morphine is regarded as the gold standard, or benchmark, of analgesics used to relieve severe or agonizing pain and suffering. Like other opioids, e.g. oxycodone (OxyContin, Percocet, Percodan), hydromorphone (Dilaudid, Palladone), and diacetylmorphine (heroin), morphine acts directly on the central nervous system (CNS) to relieve pain. Morphine has a high potential for addiction; toleranceand psychological dependence develop rapidly, although physical addiction may take several months to develop.



[edit]Trade names

Morphine is marketed under many different brand names in various parts of the world:

[show]Morphine brand names


An opium-based elixir has been ascribed to alchemists of Byzantine times, but the specific formula was supposedly lost during the Ottoman conquest of Constantinople.[1] Around 1522, Paracelsus made reference to an opium-based elixir which he called, laudanum from the Latin word laudare meaning "to praise." He described it as a potent pain killer, but recommended that it be used sparingly. In the late eighteenth century, when the East India Company gained a direct interest in the opium trade through India, another opiate recipe called ‘laudanum’ became very popular among physicians and their patients.

Morphine was discovered as the first active alkaloid extracted from the opium poppy plant in December 1804 in Paderborn, Germany by Friedrich Sertürner.[2] The drug was first marketed to the general public by Sertürner and Company in 1817 as an analgesic, and also as a treatment for opium and alcohol addiction. 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[3] sufferers from the "soldier’s disease" of morphine addiction.[4][5] 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.[6][7]

Diacetylmorphine (better known as heroin) was synthesized from morphine in 1874 and brought to market by Bayer in 1898. Heroin is approximately 1.5–2 times more potent than morphine on a milligram-for-milligram basis. 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).[8]

Advertisement for curing morphine addiction, ca. 1900[9]

An ampoule of morphine with integral needle for immediate use. 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. Until the synthesis of dihydromorphine (ca. 1900), the dihydromorphinone class of opioids (1920s), and oxycodone (1916) and similar drugs, there generally 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 amongst 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, ormethadone 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. 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 Dr. Marshall D. Gates, Jr. at the University of Rochester.[10] 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 the chemist János Kábay.

In 2003, there was 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 apparently only reacted to morphine: the mu3 opiate receptor in human tissue.[11] Human cells that form in reaction to cancerous neuroblastoma cells have been found to contain trace amounts of endogenous morphine.[12]


Morphine can be used as an analgesic to relieve:

Morphine can also be used:

  • as an adjunct to general anesthesia
  • in epidural anesthesia or intrathecal analgesia
  • for palliative care (i.e., to alleviate pain without curing the underlying reason for it, usually because the latter is found impossible)
  • as an antitussive for severe cough
  • in nebulized form, for treatment of dyspnea, although the evidence for efficacy is slim.[14] Evidence is better for other routes.[15]
  • as an antidiarrheal in chronic conditions (e.g., for diarrhea associated with AIDS, although loperamide (a non-absorbed opioid acting only on the gut) is the most commonly used opioid for diarrhea).
  • for remarkable relief of acute pulmonary edema through an unknown mechanism
  • To lower and stabilise blood glucose in diabetics and combat other diabetic effects including diabetic neuropathy — morphine and whole opium preparations were used for this purpose well into the 1960s in North America and Europe and in much curtailed fashion now and in other countries. Morphine will also impact hypertension, levels of lipids like cholesterol in blood, and improve laboratory indices in certain types of anaemia, although whole opium preparations are preferred for these purposes if allowed. Most often, chronic pain patients with one or more of the four above conditions are treated with morphine rather than synthetics like pethidine.
  • Experimentally for refractory depression. Morphine, hydromorphone, opium products and the like were used on-label for depression from antiquity or prehistoric time up into the middle 1950s.

[edit]Side effects


Like loperamide and other opioids, morphine acts on the myenteric plexus in the intestinal tract, reducing gut motility, causing constipation. The gastrointestinal effects of morphine are mediated primarily by μ-opioid receptors in the bowel. By inhibiting gastric emptying and reducing propulsive peristalsis of the intestine, morphine decreases the rate of intestinal transit. Reduction in gut secretion and increases in intestinal fluid absorption also contribute to the constipating effect. Opioids also may act on the gut indirectly through tonic gut spasms after inhibition of nitric oxide generation.[16] This effect was shown in animals when a nitric oxide precursor, L-Arginine, reversed morphine-induced changes in gut motility.[17]


In controlled studies comparing the physiological and subjective effects of injected heroin and morphine in individuals formerly addicted to opiates, subjects showed no preference for one drug over the other. Equipotent, injected doses had comparable action courses, with no difference in subjects’ self-rated feelings of euphoria, ambition, nervousness, relaxation, drowsiness, or sleepiness.[8] Short-term addiction studies by the same researchers demonstrated that tolerance developed at a similar rate to both heroin and morphine. When compared to the opioids hydromorphone, fentanyl, oxycodone, and pethidine/meperidine, former addicts showed a strong preference for heroin and morphine, suggesting that heroin and morphine are particularly susceptible to abuse and addiction. Morphine and heroin were also much more likely to produce euphoria and other positive subjective effects when compared to these other opioids.[8]

Other studies, such as the Rat Park experiments, suggest that morphine is less physically addictive than others suggest, and most studies on morphine addiction merely show that "severely distressed animals, like severely distressed people, will relieve their distress pharmacologically if they can."[18] In these studies, rats with a morphine "addiction" overcome their addiction themselves when placed in decent living environments with enough space, good food, companionship, areas for exercise, and areas for privacy. More recent research has shown that an enriched environment may decrease morphine addiction in mice.[19]

Morphine is a potentially highly addictive substance. It can cause psychological dependence and physical dependence as well as tolerance, with an addiction potential identical to that of heroin. When used illicitly, a very serious narcotic habit can develop in a matter of weeks, whereas iatrogenic morphine addiction rates have, according to a number of studies, remained nearly constant at one case in 150 to 200 for at least two centuries.[citation needed] In the presence of pain and the other disorders for which morphine is indicated, a combination of psychological and physiological factors tend to prevent true addiction from developing, although physical dependence and tolerance will develop with protracted opioid therapy. These two factors do not add up to addiction without psychological dependence which manifests primarily as a morbid seek orientation for the drug.[citation needed]


Tolerance to the analgesic effects of morphine is fairly rapid. There are several hypotheses about how tolerance develops, including opioid receptor phosphorylation (which would change the receptor conformation), functional decoupling of receptors from G-proteins (leading to receptor desensitization),[20] mu-opioid receptor internalization and/or receptor down-regulation (reducing the number of available receptors for morphine to act on), and upregulation of the cAMP pathway (a counterregulatory mechanism to opioid effects) (For a review of these processes, see Koch and Hollt.[21]) CCK might mediate some counter-regulatory pathways responsible for opioid tolerance. CCK-antagonist drugs, specifically proglumide, have been shown to slow the development of tolerance to morphine.


Cessation of dosing with morphine creates the prototypical opioid withdrawal syndrome, which unlike that of barbiturates, benzodiazepines, alcohol, sedative-hypnotics &c. is not fatal by itself in neurologically healthy patients without heart or lung problems; it is in theory self-limiting in length and overall impact in that a rapid increase in metabolism and other bodily processes takes place, including shedding and replacement of the cells of many organs.

None the less, suicide, heart attacks, strokes, seizures proceeding to status epilepticus, and effects of extreme dehydration do lead to fatal outcomes in a small fraction of cases.

Acute morphine and other opioid withdrawal proceeds through a number of stages. Other opioids differ in the intensity and length of each, and weak opioids and mixed agonist-antagonists may have acute withdrawal syndromes which do not reach the highest level. As commonly cited, they are:

  • Stage I: Six to fourteen hours after last dose: Drug craving, anxiety
  • Stage II: Fourteen to eighteen hours after last dose: Yawning, perspiration, lacrimation, crying, running nose, dysphoria, "yen sleep"
  • Stage III: Sixteen to twenty-four hours after last dose: Nose running like faucet and increase in other of the above, dilated pupils, piloerection (gooseflesh), muscle twitches, hot flashes, cold flashes, aching bones & muscles, anorexia (loss appetite for food) and the beginning of intestinal cramping.
  • Stage IV: Twenty-four to thirty-six hours after last dose: Increase in all of the above including severe cramping and involuntary leg movements ("kicking the habit"), loose stool, insomnia, elevation of blood pressure, moderate elevation in body temperature, increase in frequency of breathing and tidal volume, increased pulse, restlessness, nausea
  • Stage V: Thirty-six to seventy-two hours after last dose: Increase in the above, fetal position, vomiting, free and frequent liquid diarrhoea which sometimes can accelerate the time of passage of food from mouth to out of system to an hour or less, involuntary urination and ejaculation which is often painful, saturation of bedding materials with bodily fluids, weight loss of two to five kilos per 24 hours, increased WBC and other blood changes.
  • Stage VI: After completion of above: Recovery of appetite ("the chucks"), and normal bowel function, beginning of transition to post-acute and chronic symptoms which are mainly psychological but which may also include increased sensitivity to pain, hypertension, colitis or other gastrointestinal afflictions related to motility, and problems with weight control in either direction.

Some authorities give the above as grades zero to four, and others add chronic withdrawal as a seventh stage. Some separate post-acute and chronic withdrawal, others do not. For an example of the use of the above system, methadone clinics require, in the absence of a direct and documented referral from a doctor, Stage II withdrawal symptoms and/or recent needle marks and/or surrender of injecting equipment and/or unused drug at the intake appointment to begin the methadone maintenance or withdrawal process; two urine tests positive for opioids must then be collected shortly thereafter.

The withdrawal symptoms associated with morphine addiction are usually experienced shortly before the time of the next scheduled dose, sometimes within as early as a few hours (usually between 6–12 hours) after the last administration. Early symptoms include watery eyes, insomnia, diarrhea, runny nose, yawning, dysphoria, sweating and in some cases a strong drug craving. Severe headache, restlessness, irritability, loss of appetite, body aches, severe abdominal pain, nausea and vomiting, tremors, and even stronger and more intense drug craving appear as the syndrome progresses. Severe depression and vomiting are very common. During the acute withdrawal period systolic and diastolic blood pressure increase, usually beyond pre-morphine levels, and heart rate increases,[22] which could potentially cause a heart attack, blood clot, or stroke.

Chills or cold flashes with goose bumps ("cold turkey") alternating with flushing (hot flashes), kicking movements of the legs ("kicking the habit"[23]) and excessive sweating are also characteristic symptoms.[24] Severe pains in the bones and muscles of the back and extremities occur, as do muscle spasms. At any point during this process, a suitable narcotic can be administered that will dramatically reverse the withdrawal symptoms. Major withdrawal symptoms peak between 48 and 96 hours after the last dose and subside after about 8 to 12 days. Sudden withdrawal by heavily dependent users who are in poor health is very rarely fatal. Morphine withdrawal is considered less dangerous than alcohol, barbiturate, or benzodiazepine withdrawal.[25]

The psychological dependence associated with morphine addiction is complex and protracted. Long after the physical need for morphine has passed, the addict will usually continue to think and talk about the use of morphine (or other drugs) and feel strange or overwhelmed coping with daily activities without being under the influence of morphine. Psychological withdrawal from morphine is a very long and painful process.[26] Addicts often suffer severe depression, anxiety, insomnia, mood swings, amnesia (forgetfulness), low self-esteem, confusion, paranoia, and other psychological disorders. The psychological dependence on morphine can, and usually does, last a lifetime.[27] There is a high probability that relapse will occur after morphine withdrawal when neither the physical environment nor the behavioral motivators that contributed to the abuse have been altered. Testimony to morphine’s addictive and reinforcing nature is its relapse rate. Abusers of morphine (and heroin) have one of the highest relapse rates among all drug users.

[edit]Hepatitis C

Researchers at the University of Pennsylvania have demonstrated that morphine withdrawal complicates hepatitis C by suppressing IFN-alpha-mediated immunity and enhancing virus replication. Hepatitis C virus (HCV) is common among intravenous drug users. This high association has piqued interest in determining the effects of drug abuse, specifically morphine and heroin, on progression of the disease. The discovery of such an association would impact treatment of both HCV infection and drug abuse.[28]


A morphine overdose occurs by intentionally or accidentally taking too much of it. A large overdose can cause asphyxia and death by respiratory depression if the person does not get medical attention or an antidote (Naloxone) immediately.[29]

Treatments include administration of activated charcoal, intravenous fluids, laxatives and naloxone. The latter is an antidote to reverse the effect of the poison. Multiple doses of it may be needed.[29]

The minimum lethal dose is 200 mg but in case of hypersensitivity 60 mg can bring sudden death. In case of drug addiction, 2-3 g/day can be tolerated. See L. Macchiarelli P. Arbarello G. Cave Bondi N.M. Di Luca T.Feola Medicina Legale (compendio) II edition ; Minerva Medica Publications, Italy, Turin 2002

[edit]Effects On Other Systems and Processes

It has been said by various sources for at least 200 years that under ideal circumstances, use of opium and its derivatives and synthetic analogues may promote longevity and slow or switch off the aging process. In practise, any such effect would have to compete with whatever comorbid conditions the medical patient has and the health problems the unsupervised user may have as the result of the illegality, cutting agents, purity, and other properties of the drugs he or she actually ingest and otherwise. However, the fact that opioids slow metabolism, lower blood pressure, moderate blood sugar levels, and have the above-listed acute and chronic effects on the endocrine system, blood, heart, and lungs (all other things being equal) may be a reason for this supposition, as examples of opioid-use careers from 50 to 100 years in length are uncommon but certainly in existence, even in the 19th Century, when the life expectancy was lower. Some users of opioids both under medical care and unsupervised may look younger after several years of use on account of hormonal effects and skin changes related to opioid effects.

In the late 1990s, research into the neurological and other systemic effects of what was initially presumed to be somewhat average lower blood oxygen concentrations in chronic users of opioids which create respiratory depression led to inconclusive results.

The theory that high dose protracted opioid use may, by itself, harm the liver or kidneys does not appear to have a basis in empirically determined medical fact, however, the fluid-balance problems attendant to opioid withdrawal could eventually lead to a higher incidence of kidney stones if not treated properly, and the paracetamol content of many proprietary medications containing weak and mid-range opioids like hydrocodone can certainly be injurious to some bodily systems, as can massive and/or chronic overdoses of aspirin, salicylates, ibuprofen, and other NSAIDs.


The following conditions are relative contraindications for morphine:

Although it has previously been thought that morphine was contraindicated in acute pancreatitis, a review of the literature shows no evidence for this.[31]


Main article: Opioid receptor

Endogenous opioids include endorphins, enkephalins, dynorphins, and even morphine itself. Morphine appears to mimic endorphins. Endogenous endorphins are responsible for analgesia (reducing pain), causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or excitement.

Morphine is the prototype narcotic drug and is the standard against which all other opioids are tested. It interacts predominantly with the μ-opioid receptor. These μ-binding sites are discretely distributed in the human brain, with high densities in the posterior amygdala, hypothalamus, thalamus, nucleus caudatus, putamen, and certain cortical areas. They are also found on the terminal axons of primary afferents within laminae I and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of the trigeminal nerve.[32]

Morphine is a phenanthrene opioid receptor agonist – its main effect is binding to and activating the μ-opioid receptors in the central nervous system. In clinical settings, morphine exerts its principal pharmacological effect on the central nervous system andgastrointestinal tract. Its primary actions of therapeutic value are analgesia and sedation. Activation of the μ-opioid receptors is associated with analgesia, sedation, euphoria, physical dependence, and respiratory depression. Morphine is a rapid-acting narcotic, and it is known to bind very strongly to the μ-opioid receptors, and for this reason, it often has a higher incidence of euphoria/dysphoria, respiratory depression, sedation, pruritus, tolerance, and physical and psychological dependence when compared to other opioids at equianalgesic doses. Morphine is also a κ-opioid and δ-opioid receptor agonist, κ-opioid’s action is associated with spinal analgesia, miosis (pinpoint pupils) and psychotomimetic effects. δ-opioid is thought to play a role in analgesia.[32] Although morphine does not bind to the σ-receptor, it has been shown that sigma agonists, such as (+)pentazocine, antagonize morphine analgesia, and sigma antagonists enhance morphine analgesia,[33] suggesting some interaction between morphine and the σ-opioid receptor.

The effects of morphine can be countered with opioid antagonists such as naloxone and naltrexone; the development of tolerance to morphine may be inhibited by NMDA antagonists such as ketamine or dextromethorphan.[34] The rotation of morphine with chemically dissimilar opioids in the long-term treatment of pain will slow down the growth of tolerance in the longer run, particularly agents known to have significantly incomplete cross-tolerance with morphine such as levorphanol, ketobemidone,piritramide, and methadone and its derivatives; all of these drugs also have NMDA antagonist properties. It is believed that the strong opioid with the most incomplete cross-tolerance with morphine is either methadone or dextromoramide.

[edit]Gene expression

Studies have shown that morphine can alter the expression of a number of genes. A single injection of morphine has been shown to alter the expression of two major groups of genes, for proteins involved in mitochondrial respiration and for cytoskeleton-related proteins.[35]

[edit]Effects on the immune system

Morphine has long been known to act on receptors expressed on cells of the central nervous system resulting in pain relief and analgesia. In the 1970s and ’80s, evidence suggesting that opiate drug addicts show increased risk of infection (such as increased pneumonia, tuberculosis, and HIV) led scientists to believe that morphine may also affect the immune system. This possibility increased interest in the effect of chronic morphine use on the immune system.

The first step of determining that morphine may affect the immune system was to establish that the opiate receptors known to be expressed on cells of the central nervous system are also expressed on cells of the immune system. One study successfully showed that dendritic cells, part of the innate immune system, display opiate receptors. Dendritic cells are responsible for producing cytokines, which are the tools for communication in the immune system. This same study showed that dendritic cells chronically treated with morphine during their differentiation produce more interleukin-12 (IL-12), a cytokine responsible for promoting the proliferation, growth, and differentiation of T-cells (another cell of the adaptive immune system) and less interleukin-10(IL-10), a cytokine responsible for promoting a B-cell immune response (B cells produce antibodies to fight off infection).[36]

This regulation of cytokines appear to occur via the p38 MAPKs (mitogen activated protein kinase) dependent pathway. Usually, the p38 within the dendritic cell expresses TLR 4 (toll-like receptor 4), which is activated through the ligand LPS (lipopolysaccharide). This causes the p38 MAPK to be phosphorylated. This phosphorylation activates the p38 MAPK to begin producing IL-10 and IL-12. When the dendritic cell is chronically exposed to morphine during their differentiation process then treated with LPS, the production of cytokines is different. Once treated with morphine, the p38 MAPK does not produce IL-10, instead favoring production of IL-12. The exact mechanism through which the production of one cytokine is increased in favor over another is not known. Most likely, the morphine causes increased phosphorylation of the p38 MAPK. Transcriptional level interactions between IL-10 and IL-12 may further increase the production of IL-12 once IL-10 is not being produced. Future research may target the exact mechanism that increases the production of IL-12 in morphine treated dendritic cells. This increased production of IL-12 causes increased T-cell immune response. This response is due to the ability of IL-12 to cause T helper cells to differentiate into the Th1 cell, causing a T cell immune response.[citation needed]

Further studies on the effects of morphine on the immune system have shown that morphine influences the production of neutrophils and other cytokines. Since cytokines are produced as part of the immediate immunological response (inflammation), it has been suggested that they may also influence pain. In this way, cytokines may be a logical target for analgesic development. Recently, one study has used an animal model (hind-paw incision) to observe the effects of morphine administration on the acute immunological response. Following hind-paw incision, pain thresholds and cytokine production were measured. Normally, cytokine production in and around the wounded area increases in order to fight infection and control healing (and, possibly, to control pain), but pre-incisional morphine administration (0.1-10.0 mg/kg) reduced the number of cytokines found around the wound in a dose-dependent manner. The authors suggest that morphine administration in the acute post-injury period may reduce resistance to infection and may impair the healing of the wound.[37]


[edit]Absorption and metabolism

Morphine can be taken orally, rectally, subcutaneously, intravenously, intrathecally or epidurally. On the streets, it is becoming more common to inhale (“chasing the dragon”), but for medicinal purposes, intravenous (IV) injection is the most common method of administration. Morphine is subject to extensive first-pass metabolism (a large proportion is broken down in the liver), so if taken orally, only 40–50% of the dose reaches the central nervous system. Resultant plasma levels after subcutaneous (SC), intramuscular (IM), and IV injection are all comparable. After IM or SC injections, morphine plasma levels peak in approximately 20 minutes, and after oral administration levels peak in approximately 30 minutes.[38] Morphine is metabolised primarily in the liver and approximately 87% of a dose of morphine is excreted in the urine within 72 hours of administration. Morphine is primarily metabolized into morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G)[39] via glucuronidation by phase II metabolism enzyme UDP-glucuronosyl transferase-2B7 (UGT2B7). About 60% of morphine is converted to M3G, and 6–10% is converted to M6G.[40] The cytochrome P450 (CYP) family of enzymes involved in phase I metabolism plays a lesser role.[citation needed] Not only does the metabolism occur in the liver but it may also take place in the brain and the kidneys. M3G does not undergo opioid receptor binding and has no analgesic effect. M6G binds to mu-receptors and is a more potent analgesic than morphine.[40] Morphine may also be metabolized into small amounts of normorphine, codeine, and hydromorphone. Metabolism rate is determined by gender, age, diet, genetic makeup, disease state (if any) and use of other medications. The elimination half-life of morphine is approximately 120 minutes, though there may be slight differences between men and women. Morphine can be stored in fat, and thus can be detectable even after death. Morphine is able to cross the blood-brain barrier but because of poor lipid solubility, protein binding, rapid conjugation with glucuronic acid and ionization, it does not cross easily. Diacetylmorphine, which is derived from morphine, crosses the blood-brain barrier more easily, making it more potent.[41]

[edit]Detection in biological fluids

Morphine and its major metabolites, morphine-3-glucuronide and morphine-6-glucuronide, may be quantitated in blood, plasma or urine to monitor for abuse, confirm a diagnosis of poisoning or assist in a medicolegal death investigation. Most commercial opiate screening tests based on immunoassays cross-react appreciably with these metabolites. However, chromatographic techniques can easily distinguish and measure each of these substances. When interpreting the results of a test, it is important to consider the morphine usage history of the individual, since a chronic user can develop tolerance to doses that would incapacitate an opiate-naive individual, and the chronic user often has high baseline values of these metabolites in his system. Furthermore, some testing procedures employ a hydrolysis step prior to quantitation that converts the metabolic products to morphine, yielding a result that may be many times larger than with a method that examines each product individually. Interpretation can be confounded by usage of codeine or ingestion of poppy seed foods, either of which leads to the presence of morphine and its conjugated metabolites in a person’s biofluids.[42]

[edit]Effects on human performance

Most reviews conclude that opioids produce minimal impairment of human performance on tests of sensory, motor, or attentional abilities. However, recent studies have been able to show some impairments caused by morphine, which is not surprising given that morphine is a central nervous system depressant. Morphine has resulted in impaired functioning on critical flicker frequency (a measure of overall CNS arousal) and impaired performance on the Maddox Wing test (a measure of deviation of the visual axes of the eyes). Few studies have investigated the effects of morphine on motor abilities; a high dose of morphine can impair finger tapping and the ability to maintain a low constant level of isometric force (i.e. fine motor control is impaired)[43], though no studies have shown a correlation between morphine and gross motor abilities.

In terms of cognitive abilities, one study has shown that morphine may have a negative impact on anterograde and retrograde memory[44], but these effects are minimal and are transient. Overall, it seems that acute doses of opioids in non-tolerant subjects produce minor effects in some sensory and motor abilities, and perhaps also in attention and cognition. It is likely that the effects of morphine will be more pronounced in opioid-naive subjects than chronic opioid users.

In chronic opioid users, such as those on Chronic Opioid Analgesic Therapy (COAT) for managing severe, chronic pain, behavioural testing has shown normal functioning on perception, cognition, coordination and behaviour in most cases. One recent study[45] analysed COAT patients in order to determine whether they were able to safely operate a motor vehicle. The findings from this study suggest that stable opioid use does not significantly impair abilities inherent in driving (this includes physical, cognitive and perceptual skills). COAT patients showed rapid completion of tasks which require speed of responding for successful performance (e.g. Rey Complex Figure Test) but made more errors than controls. COAT patients showed no deficits in visual-spatial perception and organization (as shown in the WAIS-R Block Design Test) but did show impaired immediate and short-term visual memory (as shown on the Rey Complex Figure Test – Recall). These patients showed no impairments in higher order cognitive abilities (i.e. Planning). COAT patients appeared to have difficulty following instructions and showed a propensity towards impulsive behaviour, yet this did not reach statistical significance. Importantly, this study reveals that COAT patients have no domain-specific deficits, which supports the notion that chronic opioid use has minor effects on psychomotor, cognitive, or neuropsychological functioning.

It is difficult to study the performance effects of morphine without considering why a person is taking morphine. Opioid-naive subjects are volunteers in a pain-free state. However, most chronic-users of morphine use it to manage pain. Pain is a stressor and so it can confound performance results, especially on tests that require a large degree of concentration. Pain is also variable, and will vary over time and from person to person. It is unclear to what extent the stress of pain may cause impairments, and it is also unclear whether morphine is potentiating or attenuating these impairments.


3D chemical structure of morphine. Thebenzylisoquinoline backbone is shown in blue.

Morphine is a benzylisoquinoline alkaloid with two additional ring closures.

Most of the licit morphine produced is used to make codeine by methylation. It is also a precursor for many drugs including heroin (diacetylmorphine), hydromorphone, and oxymorphone. 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 produces a compound some 1,443 times more potent than morphine, stronger than the Bentley compounds such as etorphine.

The structure-activity relationship of morphine has been extensively studied. The structural formula of morphine was determined in 1925 and confirmed in 1952 when two methods of total synthesis were also published. As a result of the extensive study and use of this molecule, more than 200 morphine derivatives (also counting codeine and related drugs) have been developed since the last quarter of the 19th Century. These drugs range from 25 per cent the strength of codeine or a little over 2 per cent of the strength of morphine, to several hundred times the strength of morphine to several powerful opioid antagoinsts including naloxone (Narcan), naltrexone (Trexan), and nalorphine (Nalline) for human use and also the amongst strongest antagonists known, such as diprenorphine (M5050), the reversing agent in the Immobilon large animal tranquilliser dart kit; the tranquilliser is another ultra-potent morphine derivative/structural analogue, viz., etorphine (M99). Morphine-derived agonist-antagonist drugs have also been developed. Elements of the morphine structure have been used to create completely synthetic drugs such as the morphinan family (levorphanol, dextromethorphan and others) and other groups which have many members with morphine-like qualities. The modification of morphine and the aforementioned synthetics has also given rise to non-narcotic drugs with other uses such as emetics, stimulants, antitussives, anticholinergics, muscle relaxants, local anaesthetics, general anaesthetics, and others.

Most semi-synthetic opioids, both of the morphine and codeine subgroups, are created by modifying one or more of the following:

  • Halogenating or making other modifications at positions 1 and/or 2 on the morphine carbon skeleton.
  • The methyl group which 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 and/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.

Both morphine and its hydrated form, C17H19NO3H2O, are sparingly soluble in water. In five liters of water, only one gram of the hydrate will dissolve. For this reason, pharmaceutical companies produce sulfate and hydrochloride salts of the drug, both of which are over 300 times more water-soluble than their parent molecule. Whereas the pH of a saturated morphine hydrate solution is 8.5, the salts are acidic. Since they derive from a strong acid but weak base, they are both at about pH = 5; as a consequence, the morphine salts are mixed with small amounts of NaOH to make them suitable for injection.[46]

A number of salts of morphine are used, with the most common in current clinical use being the hydrochloride, sulphate, tartrate, acetate, citrate; less commonly methobromide, hydrobromide, hydroiodide, lactate, chloride, and bitartrate and the others listed below. Morphine meconate is a major form of the alkaloid in the poppy, as is morphine pectinate, nitrate 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 ofvalerian. Calcium morphenate is the intermediate in various latex and poppy-straw methods of morphine production. 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 produced industrially was one ingredient of a medication available for both oral and parenteral administration popular many years ago in Europe and elsewhere called Trivalin (not to be confused with the curremt, unrelated herbal preparation of the same name) which also included the valerates of caffeine and cocaine, with a version containing codeine valerate as a fourth ingredient being distributed under the name Tetravalin.

Closely related to morphine are the opioids morphine-N-oxide (genomorphine) which is a pharmaceutical which is no longer in common use; and pseudomorphine, an alkaloid which exists in opium, form as degradation products of morphine.

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

[show]Forms of morphine, salts & chemical form to freebase conversion ratios


A Hungarian chemist, János Kabay, found and internationally patented a method to extract morphine from poppy straw. In the opium poppy the alkaloids are bound to meconic acid. The method is to extract from the crushed plant with diluted sulfuric acid, which is a stronger acid than meconic acid, but not so strong to react with alkaloid molecules. The extraction is performed in many steps (one amount of crushed plant is at least six to ten times extracted, so practically every alkaloid goes into the solution). From the solution obtained at the last extraction step, the alkaloids are precipitated by either ammonium hydroxide or sodium carbonate. The last step is purifying and separating morphine from other opium alkaloids. Opium poppy contains at least 40 different alkaloids, but most of them are of very low concentration. Morphine is the principal alkaloid in raw opium and constitutes ~8-19% of opium by dry weight (depending on growing conditions) [41]. 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 2 acres (8,100 m2). It is also legal to sell dried poppy 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.

The UN Office On Drugs & Crime Bulletin On Narcotics, issue II of 1952, describes the process which led to the final determination of the structural formula of morphine in 1925 and the invention of two methods of total synthesis of morphine.

Most morphine produced for pharmaceutical use around the world is actually 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 an order of magnitude greater than that of morphine on a weight basis and codeine is by far the most commonly-used opioid in the world. Whilst strains of poppies have been engineered to produce much higher yields of the other useful opioid pharmaceutical precursors thebaine and oripavine, no known strain of P. somniferum will produce more codeine than morphine under most or all possible conditions.

[edit]Extraction and detection

Morphine can be isolated from whole blood samples by solid phase extraction (SPE) and detected using liquid chromatography-mass spectrometry (LC-MS).

[edit]Illicit use

Example of different morphine tablets

The euphoria, comprehensive alleviation of distress and therefore all aspects of suffering, promotion of sociability and empathy, "body high", and anxiolysis provided by narcotic drugs including the opioids can cause the use of high doses in the absence of pain for a protracted period, which can impart a morbid craving for the drug in the user. Being the prototype of the entire opioid class of drugs means that morphine has properties that may lend it to misuse. Morphine addiction is the model upon which the current perception of addiction is based.

Animal and human studies and clinical experience back up the contention that morphine is one of the most euphoric of drugs, and via all but the IV route heroin and morphine cannot be distinguished according to studies. Chemical changes to the morphine molecule yield other powerful 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 &c. used clinically in many countries of the world but in many cases also produced illicitly in rare instances.

Misuse of morphine generally 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, and/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 every bit 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 many 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 very popular where available.

Morphine is also available in a paste which is used in the production of heroin which can be smoked by itself or turned to 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 breakdown of heroin and otherwise being present in many batches of illicit heroin as the result of incomplete acetylation.

[edit]Precursor to other opioids, in a pharmaceutical manufacturing setting

Morphine is a precursor in the manufacture in a large number of opioids such as dihydromorphine, hydromorphone, nicomorphine, and heroin as well as codeine, which itself has a large family of semi-synthetic derivatives. Morphine is commonly treated with acetic anhydride and ignited to yield heroin.[47] The pharmacology of heroin and morphine is identical except the two acetyl groups increase the lipid solubility of the heroin molecule, causing it to cross the blood-brain barrier and enter the brain more rapidly. Once in the brain, these acetyl groups are removed to yield morphine, which causes the subjective effects of heroin. Thus, heroin may be thought of as a more rapidly acting form of morphine.[48].

[edit]Precursor to other opioids, in an underground and illicit setting

Illicit morphine is rarely produced from codeine found in over the counter cough and pain medicines. This demethylation reaction is often performed using pyridine and hydrochloric acid.[49]

Another source of illicit morphine comes from the extraction of morphine from extended release morphine products, such as MS-Contin. Morphine can be extracted from these products with simple extraction techniques to yield a morphine solution that can be injected.[50] Alternatively, the tablets can be crushed and snorted, injected or swallowed, although this provides much less euphoria although retaining some of the extended-release effect and the extended-release property is why MS-Contin is used in some countries alongside methadone, dihydrocodeine, buprenorphine, dihydroetorphine, piritramide, levo-alpha-acetylmethadol(LAAM) and special 24-hour formulations of hydromorphone for maintenance and detoxification of those physically dependent on opioids.

Another means of using or misusing morphine is to use chemical reactions to turn it into heroin or another stronger opioid. Morphine can, using a technique reported in New Zealand (where the initial precursor is codeine) and elsewhere known as home-bake, be turned into what is usually a mixture of morphine, heroin, 3-monoacetylmorphine, 6-monoacetylmorphine, and codeine derivatives like acetylcodeine if the process is using morphine made from demethylating codeine by mixing acetic anhydride or acetyl chloride with the morphine and cooking it in an oven between 80 and 85°C for several hours.

Since heroin is one of a series of 3,6 diesters of morphine, it is possible to convert morphine to nicomorphine (Vilan) using nicotinic anhydride, dipropanoylmorphine with propionic anhydride, dibutanoylmorphine and disalicyloylmorphine with the respective acid anhydrides. Glacial Acetic acid can be used to obtain a mixture high in 6-monoacetylmorphine, nicotinic acid (vitamin B3) in some form would be precursor to 6-nicotinylmorphine, salicylic acid may yield the salicyoyl analogue of 6-MAM, and so on.

Homebake or other clandestinely-produced heroin produced from extended-release morphine tablets may be known as Blue Heroin because of the blue colour of some of these tablets, even though the coloured coating of the tablet is usually removed before processing, many strengths of the tablets are not blue, bluish or a related colour like purple, and the final product tends not to be blue. A writer of a 2006 description of producing heroin from 100 mg as well as some 30 and 15 mg MS-Contin type tablets coined the term Blue Heroin to distinguish his, her or their product from New Zealand-style homebake as the process was shorter and began with uncoated tablets which in the case of the 100 mg tablet was at or above 35 per cent morphine sulphate by weight, resulting in a final liquid injectable which was brown-purple and quite potent. The drugs present in the final product are limited to heroin, 6-monoacetylmorphine, 3-monoacetylmorphine, and morphine, with the 6-MAM being just as or more sought than the heroin for reasons elucidated in the Wikipedia heroin article.

The clandestine conversion of morphine to ketones of the hydromorphone class or other derivatives like dihydromorphine (Paramorfan), desomorphine (Permonid), metopon &c. and codeine to hydrocodone (Dicodid), dihydrocodeine (Paracodin) &c. is more involved, time consuming, requires lab equipment of various types, and usually requires expensive catalysts and large amounts of morphine at the outset and is less common but still has been discovered by authorities in various ways during the last 20 years or so. Dihydromorphine can be acetylated into another 3,6 morphine diester, namely diacetyldihydromorphine (Paralaudin), and hydrocodone into thebacon.

[edit]Legal classification

[edit]Access to morphine in poor countries

Although morphine is cheap, people in poorer countries often do not have access to it. According to a 2005 estimate by the International Narcotics Control Board, six countries (Australia, Britain, Canada, France, Germany, and the United States) consume 79 percent of the world’s morphine. The less affluent countries, accounting for 80 percent of the world’s population, consumed only about 6 percent of the global morphine supply. Some countries import virtually no morphine, and in others the drug is rarely available even for relieving severe pain while dying.

Experts in pain management attribute the under-distribution of morphine to an unwarranted fear of the drug’s potential for addiction and abuse. While morphine is clearly addictive, Western doctors believe it is worthwhile to use the drug and then wean the patient off when the treatment is over.[52]

[edit]See also

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The Poor Man’s Guide to OTC Codeine Extraction
Variations of this particular method have been posted in the past. This method has been refined to ensure the most effective extraction with the least amount of loss. It has also been confirmed by chemical analysis at a University lab.
This method is for ingestion only. If one were to inject the resulting brew into their bloodstream, they would likely suffer some rather unpleasant effects such as fluid buildup in their lungs and possibly death. You have been warned.
This method has been simplified for the layperson, and does not go into complex explanations of the chemical interactions and solubility factors involved in this process. Information on the scientific principals behind this process are beyond the scope of this document. For more detailed information regarding these issues, refer to the "further reading" section at the end of this guide.
The Theory:
Acetaminophen and codeine are both fairly soluble in water. Codeine will dissolve in both hot and cold water. Acetaminophen (and aspirin too) on the other hand, will not.
The minimum temperature for acetaminophen to dissolve in water is a good 5-10 degrees higher than codeine. Therefore, if one were to lower the temperature of the water to below the minimum solubility temperature of the acetaminophen, then one would be left with a codeine/water mixture, with the acetominophen falling to the bottom.
One could conclude that by dissolving acetaminophen/codeine pills in hot water, and then cooling the solution, one could separate the two compounds, and filter the resulting liquid to entirely remove the acetaminophen.
The Methodology:
Step one: Grab some Tylenol #1 or AC&C caplets from your local pharmacy. These are available in most countries with the exception of the United States. Some American states do sell 8mg codeine/300mg tylenol tablets, but require that release forms be signed to track your usage and "protect" you.
Step two: Crush a respectable amount of the pills into a fine powder. Each pill only has 8mg of codeine, so base your dosage on your tolerance for this type of chemical. Beginners could probably get a good rally from around 12-20 tablets.
Step three: Place the resulting pill-powder into a glass of fairly hot, but not boiling, water. Hot tap water should do the trick. Stir. Make sure most of the powder dissolves. Any powder that does not dissolve after vigorous mixing will most likely be acetaminophen. So not to worry.
Step four: Allow the mixture to cool to room-temperature. Bringing the temperature down too fast will reduce the effectiveness of the process. That’s why we let the mixture cool to room temperature first before proceeding to…
Step five: Place the mixture in the freezer and allow it to cool to the point where it is just above freezing. Anywhere from five to ten celsius is good. In an average freezer, this could take up to half an hour. No need to accurately measure the temperature, as long as it "feels cold" then it should be OK.
Step six: Take the cooled liquid out, and slowly filter it into another container. If you don’t have any good chemical filters, a coffee filter will do nicely. For best results, use Melita natural brown coffee filters. They aren’t bleached, and will allow for a more pure end-result. Once the filtration process is complete, take a look at the filter. The resulting powder left on the filter is the acetaminophen.
Step seven: Take the resulting brew and drink it down. It will taste very bitter. You can try throwing some kool-aid mix in with it, or even mix it with some strong chocolate milk to cut the flavour. Alternatively, you can drink it straight and "chase" it with some cola, much like any other foul tasting substance.
The Test:
The liquid solution produced by the extraction process was shown to have almost no traces of acetaminophen whatsoever (less than ~1% of the original content). The analisys indicated that the mixture consisted of codeine, water, caffeine, and cornstartch. Cornstartch is apparently used as a binding agent in the pills themselves, and as such made its way into the final product.
Unfortunately this method does not also filter out the caffeine. So, when filtering large quantities of Over the Counter codeine pills, don’t forget that you’ll also be getting large amounts of caffeine in the end result. Be aware.
Further Reading:
The Codeine Faq — Includes the process from which the above was based upon.


"Can I extract freebase codeine from AC&C tablets"

     Yes you can. but it may be illegal to do so in your area.

     This is a mixture of Aspirin with both caffeine and codeine. These
     are easily available in Canada and the UK. If it has acetaminophen
     in it it will not work.

     Last year someone posted the poor mans guide to Codeine
     extraction. While this helped save the liver of many users, the
     problem was the caffeine remained, and the end product not
     smokable. This guide will show people with some chemistry
     experience how to make smokeable freebase codeine.

     Items needed:
     Aspirin with Codeine tablets. 1000 tabs minimum
     Funnels and filter paper (preferably a Buchner funnel for fast
     Seperatory funnel.
     Beakers, Evaporating dishes ETC

     Chemicals needed.
     5 % phosphoric acid solution.
     Sodium Hydroxide.

     Put tablets in a very large glass bowl and add the hot 5%
     Phosphoric acid solution. The pills will start to disintegrate
     immediately. The reason we are using a 5% phosphoric acid instead
     of just water is so the phosphoric acid will supplement the
     Phosphate in the Codeine phosphate, and to help to increase
     extraction. The reason we are using hot water is to get the most
     codeine into the water quickly. Most of the aspirin will
     precipitate as soon as the mixture is cooled.

     When all the pills have dissolved, stir well, cool your mixture to
     just above freezing. Filter the mixture. When the water has
     drained, take the solids and put it back in the glass bowl. Filter
     the solids three times to ensure that all codeine had been removed
     from the mixture. Discard the remaining paste, as this is mostly
     aspirin, and the codeine is in the water. Note that this step can
     be done in an hour or two with a Buchner or vacuum filter. It can
     take days with gravity filtration.

     You now probably have a large volume of dirty looking water that
     you must evaporate down to a manageable volume of say 100 to 150
     millilitres. Remember that codeine is sensitive to light and heat.
     Codeine sublimates (turns into a gas) at moderate temperature and
     light is known to break it down. This means that care is needed
     when evaporating the water down.

     What you have now is a mixture of codeine, caffeine, some residual
     aspirin and phosphoric acid in about 100-150 ml solution Now comes
     the fun part.

     The next step is to get rid of the caffeine. 1 gram of caffeine
     will dissolve in 5.5 ml of chloroform, but it takes 4.5 Litres of
     chloroform to dissolve 1 gram of codeine phosphate.

     Extraction #1 (caffeine)
     Put your mixture in a seperatory funnel. Wash three times with 20
     ml chloroform. Making sure to shake and vent thoroughly between
     each wash. Remember that chloroform is heavier than water and it
     will be the bottom layer. After the three
     washes you should be left with 60 ml chloroform that has all the
     caffeine from you mixture. This chloroform can be discarded or
     kept if you can recover the chloroform.

     You now have to make the remaining solution in the seperatory
     funnel basic with the addition of NaOH. Bringing it up to 11
     should do the trick. As you add the NaOH you will quickly start to
     see pure codeine freebase start to precipitate out of the solution
     as white crystals.

     Do this right in the seperatory funnel, and please remember to
     shake and vent the funnel thoroughly as many times as it takes
     till there is no more reaction. Don't be too alarmed if the funnel
     get extremely hot due to the chemical reaction, but it may be wise
     to slow the rate at which you are adding the NaOH in this case.

     Remember how above I told you that it took four and a half Litres
     to dissolve 1 gram of codeine phosphate? Now you have pure codeine
     freebase floating around the solution in the seperatory funnel ,
     and 1 gram of codeine freebase dissolves in 0.5 ml chloroform.
     This is 9000 times more soluble than before we added the NaOH.
     With the adjusted PH any residual aspirin is not soluble in

     Extraction # 2 (codeine)
     Do three 10 to 20 Ml washes with chloroform (remember chloroform
     is the bottom layer)
     And evaporate in an evaporation dish. The chloroform will quickly
     evaporate and you are left with codeine freebase the bottom of the

     Yield: Approx 7 grams codeine freebase per 1000 pills (with 8mg
     C/P per pill)


     1. This is not cost effective for anything less than 1000 pills,
     3000 -5000 preferred.

     2. Several washes of the paste will increase yield. You can tell
     by the colour of the water when you have all the goodies.

     3. Remember that chloroform is a proven carcinogen; so be thorough
     in your work. Make sure evaporation is complete.

     4. DCM can likely be used as a chloroform replacement.

     5. Remember that this process will not work with acetaminophen,
     Tylenol 1,2,3,4 ETC.
     It will only work with AC&C. (Aspirin, caffeine and codeine)

     6. Wear gloves and glasses when dealing with chemicals. Lab safety
     procedures do apply to you.

     7. Sodium hydroxide can burn your dick off.

     8. Smoking codeine freebase can be extremely addictive.



Extractions and reactions

The material herein is presented strictly for research purposes only

Warning signCodeine Information does not condone any illegal behaviour. Actual performance of the below described extractions and chemical reactions without an appropriate authorisation may be illegal in your country. If you wish to read the articles on this page, you agree that you will not use the information from this site for purposes other than research (academic or personal), and you will not attempt any of the chemical reactions presented on this site if you don’t have an appropriate authorisation or licence.

If you intend to use the information on this site for any illegal purposes (according to your local law) you must leave now.

The methods described on this page apply to codeine, dihydrocodeine, hydrocodone and oxycodone. Remember that ingestion of any reaction products on this page can be fatal.

Related information: Opiates facts

Cold water extraction

The purpose of this experiment is to extract an opiate/opioid substance from combination tablets.

The cold water method presented below relies on fact that opiates are generally very soluble in cold water, while paracetamol, aspirin, and ibuprofen are only very slightly soluble.

Note: Pseudoephedrine and caffeine are relatively soluble in water, and will be present in the final product.

Don’t use dispersible tablets because it’s very hard to extract secondary substances from them.

Coffee filtersEquipment needed:

  • Minimum two glasses or cups
  • Paper filters (unbleached coffee filters will do)
  • Measure glass

The term secondary substance refers to paracetamol, aspirin or ibuprofen.


  1. Crush thoroughly the tablets and carefully dissolve in cold (ca 20° C) water. Use approximately 2ml of water per 1 tablet, eg 100ml of water for 50 tablets. You may add more water if you can’t dissolve the tablets easily. If you want to evaporate the liquid, it’s better to use distilled water instead of tap water.

    Warning: Boiling and hot water may destroy codeine.

  2. Cool the solution down to approximately 5° C (41° F) stirring occasionally. Very low temperatures make the secondary substances even less soluble.
  3. Leave the solution in a cool place for about 20 minutes to let the secondary substances settle on the bottom of the container.
  4. Wet the filter(s) with very cold water to prevent it from absorbing the solution and put it in the glass. Stick an elastic/rubber band around the container to keep the filter in place.
  5. Coffee filterPour the solution through the filter to filter out the secondary substance from codeine.
  6. Discard used filters with secondary substance solids left.

Note: Even if you think you have eliminated the secondary substances from the liquid, don’t attempt to ingest the product (it is illegal to do so if you don’t have appropriate doctor’s prescription).

If you want to minimise the amount of secondary substance, you can attempt to evaporate some liquid and repeat the filtering.


Some of the chemical reactions and/or substances mentioned below are very dangerous. In order to minimise the risk of skin/eye burns, please employ at least basic precautions:

  • Wear protective glasses at all times
  • When handling chemicals that can produce toxic fumes (eg some non-polar solvents) wear a certified organic vapour mask (not a particle masks from hardware stores). Work in well ventilated environment and use fume cabinet when necessary. Fumes of some solvents may quickly produce permanent brain damage.
  • Sodium hydroxide (caustic soda) is a highly corrosive substance. Always wear safety glasses and hand gloves.Wear protective gloves and laboratory coat when handling corrosive chemicals (eg strong bases such as sodium hydroxide)
  • Make sure you use reagent grade chemicals. They’re much more expensive than industrial grade chemicals (eg from hardware stores) but they guarantee ~99.99% purity. Some industrial grade chemicals may include secondary substances, such as toxic heavy metals, etc. If in doubt, consult the material safety data sheet (hazard sheet) of a given chemical or contact manufacturer’s representative.
  • Always double-check and verify the reactions you perform.

Following the above instructions may save your health and time spent in hospital or prison.

Improved codeine extraction
From: OI812
Newsgroups: alt.drugs.hard
Subject: Improved codeine Extraction
Date: Mon, 28 Jun 1999 04:25:07 -0600

Before I get flamed for not posting this to ADC (I will), I am posting in ADH since so many of you have asked about extracting codeine from APAP in this group. Having tried the cold water method and finding the yield intolerable, I set out to find a better way of extracting codeine from your basic T3’s. I think I’ve hit on a better method with a lot better yield (>90%)

To do this, you will need some chloroform or other solvent in which codeine base will dissolve, APAP won’t. Merck says that chloroform works best, although I suspect that methylene chloride will work just as well. Ether will work, but it’s just too dangerous for my taste. You will also need some dry sodium carbonate. (bicarb might work here, although I haven’t tried it.) DO NOT USE SODIUM HYDROXIDE, IT REACTS WITH THE APAP TO FORM SOME SORT OF EVIL LOOKING BLUE GOOP. Na(CO3)2 WILL RAISE THE pH JUST FINE. Lastly, you will need a large pyrex lasagna pan in which to evaporate your product to dryness.

First, place uncrushed T3’s or other APAP/codeine product in a small glass or beaker and cover with enough distilled water so that the pills will break down into a thin paste. For 30 T3’s, I use about 30-35 ml of H20. Let the pills soak until completely broken down into paste. Next add about 5-8 grams of dry sodium carbonate to reduce the codeine phosphate to codeine base. The paste will thicken somewhat and bubbles of CO2 will form in the paste as the codeine phosphate is reduced. Add enough distilled water so that the mixture is about the consistency of thin pancake batter and stir the mixture thoroughly with a wooden or glass rod. The pH of the mixture should be about 11 or greater. If it isn’t, add more Na(CO3)2 until it is.

Next, pour the mixture into the pyrex pan and rinse the beaker with a few ml of distilled water and add the rinse water to the mix in the pan. Use the stir rod to spread the grayish mixture around the pan so that the layer is as thin as possible. Let the mix dry overnight. You can pop the pan into an oven set to warm, (no hotter), if you want to speed things up.

After the mixture has completely dried, use a single-edge razor blade to scrape the mixture from the pan. It should just flake off in slabs. Now, wrap the dried material in a coffee filter and crush it so that the pieces are about the size of grains of rice. It isn’t necessary to grind the stuff any finer, since it would probably clog the filter in the last step anyhow. Pour the dry crushed mixture into a glass bottle with a screw-on top and pour in enough chloroform to completely cover the "gravel" in the bottle. Seal the bottle and shake for a few minutes. Let the contents settle for a minute or two while you set up a gravity filtering apparatus. This can be a coffee filter in a metal strainer, or if you have it, a piece of filter paper in a glass filter funnel. You can’t use plastic because thechloroform will attack it and ruin your product. Clean and dry the pyrex pan and set it under the filter to catch the filtered chloroform. Shake the chloroform/"gravel" mixture and pour it into the filter, letting the chloroform/codeine mixture run into the glass pan. Let the chloroform evaporate while you put the wet gravel back into the bottle and shake with a fresh portion of chloroform. It isn’t necessary to use as much as you did the first time. Again pour the chloroform/gravel mix into the filter paper.

After the second portion of chloroform has run through the filter, you can drip a few ml of clean chloroform onto the filter paper and wet gravel to get the last bit of codeine from the APAP and chalk. You should set the glass pan with the chloroform outside to evaporate to dryness. Do not place it into an oven to force dry it. While chloroform is not very flamable, I found out the hard way thatchloroform vapor is broken down on contact with the heating elements of the stove to form deadly phosgene gas.

Be patient, soon enough you will have nearly pure codeine base in the bottom of the glass pan. After the codeine has evaporated, you might notice that the codeine is sticky. This is because evaporating chloroform gets very cold and room humidity will condense into the mixture. If this happens, you can oven warm the codeine, but only after you can no longer smell the chloroform in it. You can now use the razor blade to scrape up the crude product. The codeine base will not weigh as much as an equivalent amount of codeine phosphate, because you have stripped the phosphateions and left behind the pure alkaloid. Fear not, it is still potent orally, just remember to adjust your dose downward. codeine base weighs only 75.3% as much as an equimolar amount of codeine phosphate. If you want to re-salt it, you can use the following proces:

Into 20 ml of acetone add 2 ml of phosphoric acid and set this mixture aside. Dissolve your crude codeine base into enough acetone so that it just dissolves. You might have to warm up the acetoneto get it to dissolve completely. If you want to clean up any insoluble contaminants at this point, take a pasteur pipet and pack a small wad of cotton into the point where the pipet narrows. Using another pipet, drip the codeine/acetone mixture through the cotton. Follow this with a ml or two of clean acetone to get all the codeine from the pipet filter. Next, mix the acetone/phosphoric acidsolution into the acetone/codeine base solution in a 50/50 ratio. As you stir the resultant misture, you will see the codeine phosphate quickly precipitate from the acetone as a sticky gummy mass. As you stir the solution, the final product should form a bolus on the stirring rod and look like a wad of chewing gum. Rinse the bolus in a small amount of fresh acetone and then smear it on a glass plate to dry. As the acetone evaporates, the codeine phosphate (CP) will appear to melt. This is because the CP is highly hygroscopic and is absorbing water from the air. Gently warm the CP in an oven to drive off the last of the acetone and then use a pipet or syringe to first drip water onto the CP, and then suck up the CP solution. You may now drink your product, or you can again reduce it to codeine base and extract it with chloroform if you prefer a much purer, powdered product.

Even after two acid-base extractions, I have gotten up to 93% of the available codeine from T3’s with absolutely zero APAP in the finished product. If you choose codeine base as your final product, you can now easily turn it into even yummier alkaloids, but that is for another posting.

Sorry about the long cross-posting, but I believe in sharing information which will result in a purer (read: safer) final product.

B.B. Welch

The above descriptions were included in this document without permissions of their authors. The articles can be freely accessed at many places including Google Discussion Groups.

Other methods

Chromic’s Coldwater Codeine Extraction – simple procedure for eliminating caffeine

Masking the bitter taste

Codeine and other opiates have a very bitter taste. Try adding some icing sugar or cordial to make the opiate a bit more edible.

Testing for paracetamol

The amount of paracetamol, aspirin or ibuprofen you get in the finished product depends on many factors including temperature and amount of water used to dissolve tablets, and quality of the filters used. Just make sure you use reasonable amount of water per tablet (I recommend max. 3ml/1 tablet) and very fine paper filters.

Sodium Hydroxide method

An excerpt from Dextromethorphan FAQ written by William E. White briefly explains how to test for presence of paracetamol:

"Acetaminophen (paracetamol) turns a purplish-brown color on reaction with sodium hydroxide (NaOH). This is a fairly rapid reaction, which you can try out yourself by dissolving an acetaminophentablet in water and adding some of this solution to a sodium hydroxide solution. It does not appear that ammonia (NH4OH solution – Bongoman) will work instead of sodium hydroxide. However, since you aren’t going to be ingesting the final product, feel free to use lye instead of reagent grade sodium hydroxide. So let’s say you have a solution which you think may contain acetaminophen. Call it Solution A. Prepare a concentrated sodium hydroxide solution (Solution B) by dissolving as much sodium hydroxide as you can in a small amount (say, 50mL) of water. Be careful and wear your safety glasses! Now, take a dropper, and add a little bit of Solution A into Solution B. If you see a purple or brown color form, you can bet that there’s acetaminophen in your Solution A. The problem is, if you don’t see any color, that doesn’t necessarily mean the acetaminophen (or some byproduct of it from the extraction) isn’t there. Now, it may be that this is an effective test for detecting the presence and absence of acetaminophen, but I’m not sure yet. So consider this a point for further research, and nothing more."

Sodium Hydroxide (NaOH) can be purchased OTC in most chemical supply stores.

Simple method

Put 3-4 tablets of paracetamol tablets in the same amount of water as you’ve used to extract the codeine, and compare the clarity of the two solutions. If the liquid with paracetamol only is more ‘cloudy’ than liquid with codeine, it means you have less paracetamol in the codeine liquid than in the tablets you’ve just dissolved. Remember that codeine solution also includes binders, fillers and other substances used in manufacture of the tablets thus the codeine liquid will always be more ‘cloudy’.

Opiate powder

Codeine freebase :)To obtain codeine in powder, you need to evaporate the water. At home, you can use at least three different methods:

  • You can simply leave the prepared filtered solution in an opened container (eg petri dish) in a cool, dry and dark place for a couple of days.
  • Blow on the liquid with a hair dryer.
  • Put the liquid in a kitchen oven set to a low temperature.

Note: Codeine is very sensitive to heat; it may lose its potency or decompose when heated. Avoid exposing codeine to temperatures greater than 60°C.

Once the liquid evaporates you can scrap the codeine off. If there was any fillers or binders left with codeine, the powder can stick to the container.


There is no point repeating information already available on the web. Check out the following sites for information on freebasing opiates:


The Illicit Preparation of Morphine and Heroin from Pharmaceutical Products Containing Codeine:

‘Homebake’ Laboratories in New Zealand

K.R. Bedford, S.L. Nolan, R. Onrust and J.D. Siegers

Forensic Science International 34(3), 197-204 (1987)

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Since 1983 a large number of small-scale illicit laboratories producing morphine and heroin from commercially available, codeine-based pharmaceutical products have been encountered in New Zealand. The codeine demethylation procedure is based on the use of pyridine hydrochloride Very simple laboratory equipment and reagents are required and these can be utilised by people with little or no chemical background, following a recipe-like procedure. The process yields a characteristic product known as ‘homebake’. This process is fully described.


Fig. 1.

Illicit heroin cases submitted to Chemistry Division.

The patterns of drug abuse found in New Zealand (NZ) are influenced by the fact that it is a geographically isolated country with a small population (3.3 million). One recent feature has been the emergence of small-scale illicit laboratories producing morphine and heroin from codeine derived from commercially available codeine-based pharmaceutical products. This paper describes the background to this development, the methods used in such laboratories, and the approach taken by the forensic scientist in examining them.

In the late 1970s high quality South-East Asian heroin became widely available in NZ for the first time. Subsequent police operations in NZ, Australia and Britain led in 1980 to the collapse of the so-called ‘Mr Asia’ drug syndicate, responsible for much of this activity. Following this, and other successful NZ police and customs investigations, the amount of heroin available in NZ declined dramatically. This is illustrated in Fig. 1 which shows the number of illicit heroin cases submitted each year to the Chemistry Division of the NZ Department of Scientific and Industrial Research (DSIR).

Chemistry Division of the DSIR provides scientific support services to the police and customs in NZ. The resulting shortage, coupled with the established market for heroin, led to the development of a simple method for the production of morphine and heroin from codeine. Codeine, in certain compound products is not controlled under the NZ Misuse of Drugs Act (1975) and is available without prescription from retail pharmacies. The first laboratory using the process was seized in Auckland in January 1983. In the three years which followed to January 1986, Auckland police alone seized over 50 such laboratories, either fully functional or as disassembled ‘kits’, and over 90 were seized in NZ as a whole. Laboratories have been encountered in kitchens and bathrooms in most parts of the country. The home-made product of this simple recipe-like procedure has become known as ‘homebake’. The equipment required for these laboratories is very simple and the product is normally made in small batches for the addict’s own use, although there has been a trend towards the sale of samples of the end product.

Fig. 2.

The O-demethylation of codeine to yield morphine.

Sources of codeine

The codeine used in the homebake process may be derived from one of a number of possible sources. In a few cases codeine phosphate has been obtained from pharmacy burglaries. In most instances, however, it is derived from pharmaceutical products which may he purchased without a doctor’s prescription. Those available in NZ containing the highest proportions of codeine are: ‘Codral Forte’ — 225 mg aspirin, 150 mg paracetamol, 30 mg codeine phosphate; ‘Pirophen’ — 325 mg aspirin, 325 mg paracetamol, 10 mg codeine phosphate. Awareness among pharmacists of the way in which these particular products are being misused has resulted in greater vigilance and has led to a wide variety of other preparations containing lesser amounts of codeine also being utilised.

The conversion of codeine to morphine

Fig. 3.

The relationship between heroin, morphine,

and the two monoacetylmorphines.

The O-demethylation of codeine to yield morphine (Fig. 2) has been reported using a variety of reagents including sodium propylmercaptide in dimethylformamide1 and boron tribromide in chloroform2. These methods require a considerable measure of chemical expertise and suitable laboratory equipment. The homebake laboratories have employed a very simple method based on the use of pyridine hydrochloride. This reagent was introduced to opiate chemistry by Rapoport and Bonner3 and applied to the conversion of codeine to morphine by Rapoport et al.4. Rapoport and Bonner carried out the reaction under nitrogen at a temperature of 220°C. Morphine is prone to decomposition or oxidation reactions at elevated temperatures and the nitrogen atmosphere prevents or reduces these. It also limits the access of moisture which reduces the yield.

The acetylation of

morphine to form heroin

In the acetylation of morphine to yield heroin (diacetylmorphine) the phenolic OH group on the 3-carbon is the first to react to give, as an intermediate, 3-O-monoacetylmorphine, which is further acetylated to heroin. Similarly, when heroin is deacetylated, either by hydrolysis or enzymatically, the more reactive 3-acetyl group tends to be removed first to yield 6-O-monoacetylmorphine as the predominant intermediate, although low levels of 3-O-monoacetylmorphine may also be formed under these conditions (Fig. 3)5.

Experimental Details

In this section the procedure followed in homebake laboratories is fully described. Additional comments on the method, based on studies carried out in this laboratory on the reactions involved, are included in the discussion section.

1. Extraction of codeine

Several packets of tablets, sufficient to yield about 2 g of codeine, are crushed and mixed with water. The mixture is filtered using a filter pump, Buchner funnel and side-arm flask, to remove tablet binding agents, diluents and other excipients. The aqueous filtrate is poured into a separating funnel and sodium hydroxide solution added to make the solution strongly alkaline. This is then extracted with chloroform (about 50 ml). The chloroform layer is drained off and evaporated to dryness using gentle heating (often on a domestic stove). The aqueous layer containing aspirin and paracetamol is discarded. The codeine base is recovered as a white crystalline solid for use in Step 3.

2. Preparation of pyridine hydrochloride

In a beaker pyridine (20 ml) and concentrated hydrochloric acid (25 ml) are strongly heated (to about 190°C) to drive off water. The product is cooled rapidly to form a waxy white solid which is stored in a sealed container in a freezer to minimise exposure to moisture and avoid decomposition.

3. Reaction of codeine and pyridine hydrochloride

The reaction is carried out using a boiling tube which is flame-dried before use. Pyridine hydrochloride (3.5 g) as prepared in Step 2 is then heated in the tube until it melts and any residual moisture is driven off. Any resulting condensation on the inside walls of the tube is wiped off. Codeine base (1.5 g) is added to the tube which is then stoppered with a rubber bung covered with filter paper and heated until the mixture starts to fume. Heating is continued until a reddish-orange colour develops in the reaction melt, which becomes noticeably more viscous (6-12 min). The contents of the boiling tube are then poured into a 500 ml separating funnel and the volume made up to 100 ml with water. Sodium hydroxide solution (10%) is added until the contents of the separating funnel are strongly basic. As the sodium hydroxide is added the contents turn milky-brown before becoming clear brown again. Chloroform (20 ml) is added. After extraction the greyish-brown chloroform layer is either discarded or put aside for later recovery of the codeine contained in it. The aqueous layer is poured into a 400 ml beaker and the pH is carefully adjusted to pH 9 using hydrochloric acid and narrow-range indicator paper. The solution is rapidly filtered under suction, using a Buchner funnel and 2 filter papers, to remove a fine, dark brown residue containing unwanted by-products. The filtered solution is then poured into a clean beaker and precipitation is induced by vigorously rubbing the side of the beaker with a ‘seeding stick’ as the pH is carefully lowered to 8.5 with additional hydrochloric acid. (In homebake laboratories a split wooden clothes peg is often used as the ‘seeding stick’.) The product is allowed to settle for at least 5 min before being filtered off under vacuum. The morphine product is recovered as a powder, ranging in colour from beige to dark brown.

4. Conversion of morphine to heroin

Morphine powder as prepared in Step 3 is placed in a spoon. A small amount of acetic anhydride is added and the mixture ignited. Addition of acetic anhydride may be repeated. A brown or black tar-like residue remains.

Results and Discussion

1. Procedural details

The procedure outlined in the experimental section has been followed many times in this laboratory. The glassware and other equipment required for the reaction are remarkably simple and readily available from scientific supply companies. The main items include several beakers, a separating funnel, a filter pump and tap attachments, a Buchner flask and funnel, a boiling tube with a rubber bung or cork and an evaporating basin. The chemicals necessary include hydrochloric acid, pyridine, chloroform and sodium hydroxide. Acetic anhydride is also necessary if the final step to heroin is intended. Hydrochloric acid and sodium hydroxide are widely available. Chloroform, pyridine and acetic anhydride are available from chemical supply companies. Recent awareness among supply companies of the significance of a request for small amounts of these chemicals has led to stricter monitoring of orders. In a number of laboratories pyridine has been replaced by a crude mixture of picolines (methylpyridine isomers) and other substituted pyridines. In at least two cases the mixture also contained an intense purple dye indicating that it had been obtained from a chemical distributor where the mixture of pyridines and dye is added to ethanol in the course of preparing ‘methylated spirits’ (denatured alcohol).

The most common source of heat found in these laboratories has been small methylated spirits burners. These give a cooler flame than do laboratory bunsen burners and enable better control of the reaction between codeine and pyridine hydrochloride. In a few laboratories investigated, heating had been carried out using cooking oil on a domestic stove element. Under laboratory conditions the reaction has been carried out using a heated sand bath.

The use of a rubber hung in the boiling tube to produce a sealed reaction vessel is a simple solution to the problems of morphine oxidation and decomposition on heating and the need to minimise access of moisture to the reaction mixture.

2. Product yields

Homebake laboratory operators have claimed yields of morphine equivalent to 50% conversion from codeine but the reaction also forms a complex mixture of by-products, whose structures are now being studied by us. In our laboratory using these procedures nett yields have not exceeded 30%. Indeed, in the light of Rapoport and Bonner’s work this appears to be the maximum that could be expected3. Morphine having a purity of 92% calculated as the anhydrous free base and determined by HPLC has been prepared, although purities in the 80% region are more typical. Negligible codeine is present with the morphine, indicating that the chloroform extraction step is efficient in removing this. This high purity, with little or no codeine contamination, is characteristic of ‘homebake’ morphine.

The crude method used to acetylate the resultant morphine can result in up to 60% conversion to heroin. The brown or black tar-like residue is used either by heating it strongly on a piece of aluminium foil and inhaling the fumes or by injection. If the injection route is used, water is added to the spoon, a small amount of acid may be added to assist dissolution, and the mixture warmed. The syringe is filled using a cigarette filter to remove insoluble by-products of the reaction. A distinctive feature of the product is that it contains unusually high levels of 3-O-monoacetylmorphine, clearly present because of incomplete acetylation of morphine (Fig. 3). ln complete contrast to the usual situation with illicit heroin, the 3-O-monoacetylmorphine level exceeds that of 6-O-monoacetylmorphine6. Recent studies have elucidated the requirements for the formation of 3-O-monoacetylmorphine and also its decomposition, since it is readily hydrolysed5,7-9. In homebake heroin the initial high 3-O-monoacetylmorphine level is rapidly reduced by this hydrolysis, particularly as the product is frequently dissolved in a small amount of water containing acid, in preparation for injection.

One completed synthesis, based on an initial quantity of approx. 2 g of codeine, yields an acetylated product which is dissolved in 4-5 ml of water. The concentration of heroin in this solution is typically between 10 and 40 mg/ml, depending on the skill of the operator. Obviously the solution also contains morphine and 3-O-monoacetylmorphine. This should provide enough for several ‘fixes’ or allow for a small surplus to be sold, depending on the level of addiction of the user.


Countering these homebake laboratories has proved to be a frustrating exercise for police and for forensic scientists called on to provide scientific support. The entire procedure from extraction of the codeine tablets through to the preparation of usable heroin solution can be completed by a practised operator in a few hours. The simplicity of the laboratory equipment allows easy portability. It has been known for operators to arrive at an address one afternoon and leave the next morning after having completed one or more syntheses. To support a charge of manufacturing morphine and/or heroin in court., the forensic scientist is asked by the prosecution to show that the required equipment and chemicals are present and, at least for key steps in the procedure, that they have been used. This frequently requires the determination of only trace amounts of products and by-products on the equipment seized. Laboratory operators have become aware of this and carefully clean and destroy vital evidence as they proceed. In some cases the equipment for the laboratory has been divided and kept in two places to prevent an operator being caught in possession of the full set.

On the other hand the problem is to some extent self-limiting. The laboratories are on a small scale, producing only enough product to satisfy the ‘habit’ of an individual addict and perhaps a few friends or clients. There are indications that the method does not lend itself to a large scale operation and the percentage yield drops significantly if attempts are made to increase the quantities involved. Although the original laboratory operators had chemical knowledge. subsequent operators have had to be taught the method. The percentage yield in the codeine to morphine conversion step is unpredictable and small variations in the experimental conditions at several crucial stages can make the difference between success. partial success and total failure. Experience is a big factor in judging the point of maximum yield in the reaction of codeine and pyridine hydrochloride and also in manipulation of the pH to obtain maximum recovery of the morphine product. Although heroin may be produced by this method more cheaply than it can be bought on the street in NZ. it is doubtful that the procedure would be persevered with if good quality imported heroin were readily available. A small number of similar laboratories have been encountered in Australia (Government Analytical Laboratories, pers. comm.) but because of the factors already discussed, it seems unlikely that the method described in this paper will become popular elsewhere.

In only one of the laboratories so far seized in Auckland has there been any indication of thinking beyond the pyridine hydrochloride based process. In that laboratory an unopened supply of boron tribromide was discovered. There via, no evidence of any attempt to use this reagent. Boron tribromide leads to a far more efficient conversion of codeine to morphine2, but it is felt that the expertise and laboratory equipment required are likely to continue to make it an unattractive alternative to the remarkably simple and readily available chemicals and equipment used in the homebake process.


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