1

OPIATES MASTER COURSE

The Master Opiate Course: An Introduction Chapter 1

9 CEU (CALIFORNIA ACUPUNCTURE BOARD)

9 PDA (NCCAOM ELIGIBLE)

By Dustin Siena, L.Ac., Dipl.Ac., Dipl.C.H.
CHAPTER 1

INTRODUCTION

The class commonly referred to as “OPIATES” were coined that name because one of the derivative alkaloids / constituent found in the plant, “OPIUM”, comes from the latex sap of the Opium Poppy Flower.

HISTORY

Cultivation of opium poppies for food, anaesthesia, and ritual purposes dates back to at least the Neolithic Age (new stone age). The Sumerian, Assyrian, Egyptian, Indian, Minoan, Greek, Roman, Persian and Arab Empires all 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 important medical 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 this 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. 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. In India, its cultivation, as well as the
manufacture and traffic to China, were subject to the East India Company, as a strict monopoly of the British government.[2] For supervising and managing the business, there was an extensive and complicated system of government agencies. 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 the International 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.[3][4] Worldwide production in 2006 was 6610 metric tons[5]—nearly one-fifth the level of production in 1906.

ANCIENT HISTORY
Opium has been actively collected since prehistoric times, and may be the soma plant ubiquitously mentioned in the Rig Veda. Though western scholars typically date the text at 1500 BCE, Indian scholars maintain that the verses and the history contained in them have been orally transmitted thousands of years before. “Soma” is Vedic Sanskrit for moon, describing both the shape of the bulb and its nocturnal juice emission, which in ancient times would have been visible by moonlight only.[7] A common name for males in Afghanistan is “Redey,” which in Pashto means “poppy.”[8] This term may be derived from the Sanskrit words “rddhi” and “hrdya,” which mean “magical,” “a type of medicinal plant”, and “heart-pleasing”. The upper South Asian belt of Afghanistan, Pakistan, northern India, and Burma still account for the world’s largest supply of opium.

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. Numerous finds of Papaver somniferum or Papaver setigerum from Bronze Age and Iron Age settlements have also been reported.[9] The first known cultivation of opium poppies was in Mesopotamia, approximately 3400 BCE, by Sumerians who called the plant Hul Gil, the “joy plant.”[10][11] 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.[6] 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 and Egyptians.

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.[10] 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 Cyprus, where surgical-quality knives were used to score the poppy pods, and opium was cultivated, traded, and smoked.[12] Opium was also mentioned after the Persian conquest of Assyria and Babylonian lands in the sixth century BCE.[6]

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.[10] 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.[6] 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.[12][13] 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.[6]

Islamic societies (500–1500 CE)

Opium users in Java during the Dutch colonial period, ca. 1870

As the power of the Roman Empire declined, the lands to the south, and east of the Mediterranean sea became incorporated into the Islamic Empires. Some Muslims believe that hadiths such as in Sahih Bukhari prohibits every intoxicating substance, though the use of intoxicants in medicine has been widely permitted by scholars.[14] Dioscorides’ five-volume De Materia Medica, the precursor of pharmacopoeias, remained in use (with some improvements in Arabic versions[15]) from the 1st to 16th centuries and described opium and the wide range of uses prevalent in the ancient world.[16]

Somewhere between 400 and 1200 CE, Arab traders introduced opium to
China.[6][11][17] The Persian physician 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-la-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.[18][19]

The renowned Andalusian ophthalmologic surgeon Abu al-Qasim al-Zahrawi (“Abulcasis”, 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.[20]

The Persian physician Ab_ ʻAl_ 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.[21] _erafeddin Sabuncuo_lu used opium in the fourteenth century Ottoman Empire to treat migraine headaches, sciatica, and other painful ailments.[22]

Reintroduction to Western medicine

Latin translation of Avicenna’s Canon of Medicine, 1483

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.[23]

The use of Paracelsus’ laudanum was introduced to Western medicine in 1527, when Philippus Aureolus Theophrastus Bombastus 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.”[11][24][25] 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.[26] 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.[24] 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 ethanol, 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,[27] 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.”[28] 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.

During the 18th century, opium was found to be a good remedy for nervous disorders. Due to its sedative and tranquilizing properties, it was used to quiet the minds of those with psychosis, help with people that were considered insane, and also to help treat patients with insomnia.[29] However, despite its medicinal values in these cases, it was noted that in cases of psychosis it could cause anger or depression and due to the drugs euphoric effects, it could cause depressed patients to become more depressed after the effects wore off because they would get used to being high.[29]

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.[6] During this time of popularity, users called opium “God’s Own Medicine.”[30]

Recreational use outside China (15th to 19th century)

An artist’s view of an Ottoman opium seller

Opium is said to have been used for recreational purposes from the 14th century onwards in Muslim societies. 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. In 1573, for instance, a Venetian visitor to the Ottoman Empire observed that many of the Turkish natives of Constantinople regularly drink a “certain black water made with opium” that makes them feel good, but to which they become so addicted
that if they try to go without they will “quickly die.”[31] From eating it, dervishes were said to draw ecstasy, soldiers courage, and others 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.[32] In his Confessions 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 pictorial sources also show that poppy cultivation and opium consumption were widespread in Safavid Iran[33] and Moghol India.[34]

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 pharmacists to women with ”female problems” (mostly to relieve menstrual pain). 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.[35]

RECREATIONAL USE IN CHINA (15th to 19th Century)_

An opium den in 18th-century China through the eyes of a Western artist

A Chinese opium house, photograph 1902

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.[36]

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.[6] 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.[36] 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 from Bengal and Coromandel.”[17]

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.[36]

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.[37][38] 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.[39][40] 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.[41] Likewise, American law sought to contain addiction to immigrants by prohibiting Chinese from smoking opium in the presence of a white man.[37]

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 keno and sentenced to hard labor for opium possession. Both the immigrant population and the social use of opium fell into decline.[42][43] 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.”[44][45]

PROHIBITION IN CHINA

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.[17] Opium was banned completely in 1799 and this prohibition continued until 1860.[46]

British 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 Emperor’s prohibition of British commodities other than silver, British traders resorted to trade 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.[17] 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).[17] Chests of opium were sold in auctions in Calcutta with the understanding that the independent purchasers would then smuggle it into China.

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 exercise a monopoly over 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 and to the doubling of East India Company profits by 1777. It is also claimed to have contributed to the starvation of ten million people in the Bengal famine of 1770. Beginning in 1773, the British government began enacting oversight of the company’s operations, and in response to the Indian Rebellion of 1857 this policy culminated in the establishment of direct rule over the Presidencies and provinces of British India. Bengal opium was highly prized, commanding twice the price of the domestic Chinese product, which was regarded as inferior in quality.[47]

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.[17] 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.[48] 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.”[49]

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).[17] 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, the British 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. The quote “We English, by the policy we have pursued, are morally responsible for every acre of land in China which is withdrawn from the cultivation of grain and devoted to that of the poppy; so that the fact of the frowth of the drug in China ought only to increase our sense of responsibility.” is by Lord Justice Fry.

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.[47] From 1880 to the beginning of the

Communist era, Britain 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.[50]

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.[51] 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 missionary Hampden 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 were 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[52]) 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.[53]

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.[54]

In the northern provinces of Ningxia and Suiyuan in China, Chinese Muslim General Ma Fuxiang both prohibited and engaged in the opium trade. It was hoped that Ma Fuxiang would have improved the situation, since Chinese Muslims were well known for opposition to smoking opium[55] Ma Fuxiang officially prohibited opium and made it illegal in Ningxia, but the Guominjun reversed his policy; by 1933, people from every level of society were abusing the drug, and Ningxia was left in destitution.[56] In 1923,
an officer of the Bank of China from Baotou found out that Ma Fuxiang was assisting the
drug trade in opium which helped finance his military expenses. He earned $2 million from taxing those sales in 1923. General Ma had been using the bank, a branch of the Government of China’s exchequer, to arrange for silver currency to be transported to Baotou to use it to sponsor the trade.[57]

Mitsubishi and Mitsui were involved in the opium trade during the Japanese occupation of China.[58]

The Mao Zedong government 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.[47] 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.[59]

PROHIBITION OUTSIDE OF CHINA

There were no legal restrictions on the importation or use of opium in the United States until the San Francisco 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.[60]

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.[61] 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.[62]

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.[63]

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 the International 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.[6]

REGULATION IN BRITAIN & UNITED STATES

Before the 1920s regulation in Britain was controlled by the pharmacists. Pharmacists that were found to have prescribed opium for illegitimate causes and anyone found to have sold opium without a proper qualifications would be prosecuted.[64] Due to the passing of the Rolleston Act in Britain in 1926, doctors could prescribe opiates such as morphine and heroin on their own accord based on if they felt that their patients needed

it. This Act came about due to the fact that Britain didnʼt see peopleʼs addiction as an indulgence, but rather as a medical problem that needed weaning off the drug rather than cutting the patient off altogether.[65] The passing of this act put the control of opium use in the hands of medical doctors instead of pharmacists. However, as the
20th century continued, the addiction to opiates, especially heroin in young people, continued to rise and so the sale and prescription of opiates was limited to doctors in treatment centers and if these doctors were found to be prescribing opiates without just cause, then they could lose their license to practice or prescribe drugs.[65] The abuse
of opium in the United States began in the late 19th century and was largely stigmatized with Chinese immigrants. During this time the use of opium had little negative connotation and was used freely until 1882 when a law was passed to confine opium smoking to specific dens.[65] Until the full ban on opium based products came into
effect just after the turn of the century, physicians in the US considered opium a miracle drug that could help with many ailments. Therefore, the ban on said products was more a result of negative connotations towards its use and distribution by Chinese immigrants who were heavily persecuted during this particular period in history.[65] As the 19th century progressed however, there was a doctor by the name of Hamilton Wright that worked to decrease the use of opium in the US by submitting the Harrison Act to congress. This act put taxes and restrictions on the sale and prescription of opium, as well as trying to stigmatize the opium poppy and its derivatives as “demon drugs,” to try and scare people away from them.[65] This act and the stigma of a demon drug on opium, led to the criminalization of people that used opium-based products.

OBSOLESCENCE

Bayer heroin bottle

Globally, 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, when Friedrich Wilhelm Adam Sertürner first isolated morphine from the opium poppy.[66][67] 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.[68] The great advantage of purified morphine was that a patient could be treated with a known dose—whereas with raw plant material, as Gabriel 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.[69]

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.[70] 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.[71] No drug has been found that can match the painkilling effect of opioids without also duplicating much of its addictive potential.

HISTORY OF ALKALOIDS & EXTRACTS FROM OPIUM: MORPHINE

An opium-based elixir has been ascribed to alchemists of Byzantine times, but the specific formula was lost during the Ottoman conquest of Constantinople (Istanbul).[67] Around 1522, Paracelsus made reference to an opium-based elixir that he called laudanum from the Latin word laudare, meaning “to praise” He described it as a potent painkiller, 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.

Friedrich Sertürner
Morphine was discovered as the first active alkaloid extracted from the opium poppy plant in December 1804 in Paderborn, Germany, by Friedrich Sertürner.[68] 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. Commercial production began in Darmstadt, Germany in 1827 by the pharmacy that became the pharmaceutical company Merck, with morphine sales being a large part of their early growth.[64]

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[69] sufferers from the “soldier’s disease” of morphine addiction.[70][71] 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.[72][73]

Advertisement for curing morphine addiction, ca. 1900[75]

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. In general, until the synthesis of dihydromorphine (ca. 1900), the dihydromorphinone class of opioids (1920s), and oxycodone (1916) and similar drugs, there were no other drugs in the same efficacy range as opium, morphine, and heroin, with synthetics still several years away (pethidine was invented in Germany in 1937) and opioid agonists among the semi-synthetics were analogues and
derivatives of codeine such as dihydrocodeine (Paracodin), ethylmorphine (Dionine), and benzylmorphine (Peronine). Even today, morphine is the most sought after prescription narcotic by heroin addicts when heroin is scarce, all other things being equal; local conditions and user preference may cause hydromorphone, oxymorphone, high-dose oxycodone, or methadone as well as dextromoramide in specific instances such as 1970s Australia, to top that particular list. The stop-gap drugs used by the largest absolute number of heroin addicts is probably codeine, with significant use also of dihydrocodeine, poppy straw derivatives like poppy pod and poppy seed tea, propoxyphene, and tramadol.

The structural formula of morphine was determined by 1925 by Robert Robinson. 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.[76] 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, it appeared, reacted only to morphine: the mu3 opiate receptor in human tissue.[77] Human cells that form in reaction to cancerous neuroblastoma cells have been found to contain trace amounts of endogenous morphine.[78]

HISTORY OF HEROIN

Diacetylmorphine (better known as heroin) was synthesized from morphine in 1874 and brought to market by Bayer in 1898. The name was derived from the Greek word “Heros” because of its perceived “heroic” effects upon a user.[51] It was developed chiefly 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.[52] However, contrary to Bayer’s advertising as a “non-addictive morphine substitute,” heroin would soon have one of the highest rates of dependence among its users.[53]

Heroin is approximately 1.5 to 2 times more potent than morphine weight for weight. Due to the lipid solubility of diacetylmorphine, it is able to cross the blood–brain barrier faster than morphine, subsequently increasing the reinforcing component of addiction.[74] 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).[15]

Synthesis of heroin from opium

Bayer Heroin bottle

The opium poppy was cultivated in lower Mesopotamia as long ago as 3400 BCE.[54] 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 or morphine diacetate. 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°.[55]

Advertisement for Bayer Heroin

Wright’s invention did not lead to any further developments, and diacetylmorphine became popular only 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 trademark 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, diacetylmorphine is in essence a quicker-acting form of morphine. The company was embarrassed by the new finding, which became a historic blunder for Bayer.[56]

In the U.S.A., the Harrison Narcotics Tax Act was passed in 1914 to control the sale and distribution of diacetylmorphine 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.

The Health Committee of the League of Nations banned diacetylmorphine in 1925, although it took more than three years for this to be implemented. In the meantime, the first designer drugs, viz. 3,6 diesters and 6 monoesters of morphine and acetylated analogues of closely related drugs like hydromorphone and dihydromorphine were produced in massive quantities to fill the worldwide demand for diacetylmorphine—this continued until 1930 when the Committee banned diacetylmorphine analogues with no therapeutic advantage over drugs already in use, the first major legislation of this type.[57]

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.[58]

THE CURE HAS BECOME THE PROBLEM: METHADONE, SUBUTEX, SUBOXONE

Also there is a new class of medications that are used by expensive drug addiction and drug detoxification facilities which are used to help get people off of the full opiate agonists such as vicodine, oxycontin, oxycodone, norco.

Currently, there are 3 drugs that are most commonly used for this purpose: Methadone
(Adolphine), Suboxone (Burpenorphine / Naloxone), and Subutex (Buprenorphine).

Currently, Suboxone is the the medication used most often for the purpose of Opiate
Detoxification.

As Methadone is progressively being replaced with Buprenorphine, we shall discuss
Buprenorphine in depth in the Buprenorphine Chapter.

POPULATION GROWTH IS AGING

The problem that is facing America is that the baby-boomer population represents the largest potential segment of the population.

Originally 76 Baby Boomers were estimated to be born. Currently in 2012, it is estimated that 28% of the American population are boomers. About 85% of Baby Boomers expect to continue to work after retirement. About 15% of Baby Boomers plan never to retire.

By Age 65, around two-thirds of seniors have at least one chronic disease and see seven (7) Physicians. Twenty Percent (20%) of those older than 65 have five (5) or

more chronic diseases, see fourteen (14) Physicians and average forty (40) DOCTOR VISITS PER YEAR.

This means that as people live longer, degenerative and age related disorders such as sciatica, arthritis, and other degenerative diseases that compromise the skeletal structure of the body will produce pain for millions of people, necessitating Pain medication prescriptions by Physicians.

We must understand this class of drugs and every single issue related to their usage, since in excess of 76 Million Baby Boomers represent approximately 1/3 of the population of the United States.

NATURALLY OCCURRING ACTIVE CONSTITUENTS MORPHINE, CODEINE, THEBAINE
Some of the other major “OPIATES” that are also biologically ACTIVE CONSITUENTS found in the latex sap of the Opium Poppy Flower are MORPHINE, CODEINE, and THEBAINE. These are naturally occurring derivatives found in a PLANT. These are NON-SYNTHETIC or NATURALLY OCCURRING.

32 TOTAL NATURALLY OCCURRING ACTIVES IN OPIUM LATEX SAP
2 EXAMPLES ARE PAPAVERINE & NOSCAPINE

It is estimated that the Opium Poppy Flower has approximately 32 naturally occurring ALKALOIDS present. PAPAVERINE and NOSCAPINE are two examples of some of the other less-known Alkaloids that are also present in Opium (from the Latex sap). PAPAVERINE and NOSCAPINE are not as widely known because Western Medicine has made their own determination that these 2 substances, along with 24 other ALKALOIDS have little or no effect on the human Central Nervous system (CNS). Because of this reason these 2 substances, along with another 24 Alkaloids present in Opium are not considered “True Opiates”.

TERMINOLGY & NOMENCLATURE: OPIATES, OPIODS, NON

An “OPIATE” generally refers to only the Alkaloids in the latex sap of the Opium Poppy Flower, AND the “Natural” and “Semi-Synthetic” derivatives of Opium. This is confusing to many, and this term “Opiate” is often used incorrectly used to refer to all drugs with opium-like or morphine-like pharmacological actions. The correct term for this phenomena would the broader term “OPIOD.”

This is simply the current and accepted nomenclature that differentiates Opiates from
Opiods, and either Opiates/Opiods from Non-Opiates or Non-Opiods.

ACTIVE ALKALOIDS
As Health Care providers, I suggest that we consider any ACTIVE ALKALOID in the PLANT OPIUM, an “OPIATE.” However, my opinion is simply an opinion, and for the purpose of this course, when referring to Naturally Occurring Alkaloids in the Opium Poppy Flower, we will simply be very specific as to what we are referring to.

CLASSIFICATION SYSTEM: IS IT NATURAL OR SYNTHETIC A simply way is to classify OPIATES as NATURAL, SYNTHETIC, or SEMI- SYNTHETIC.

NATURAL OPIATES
NATURAL OPIATES would be Morphine, Codeine, and Thebaine. These are the names of the Alkaloids, and often drugs have brand names.While Morphine and Codeine are well-known, Thebaine is not one of the Alkaloids that most Health Care Providers are as familiar with, but is becoming a huge issue in the addiction world in the form of Buprenorphine (Brand Names: Subutex, Suboxone).

SYNTHETIC OPIATES

SYNTHETIC OPIATES do not naturally occur as one of the 32 Alkaloids in the latex sap of the Opium Poppy Flower, but do exist in the Pharmaceutical world.

SEMI-SYNTHETIC OPIATES
In terms of SEMI-SYNTHETICS, a few of the more widely-known Pharmaceutical Opiates fall into this class. Hydrocodone, Hydromorphone and Oxymorphone are all SEMI-SYTHETIC OPIATES.

HEROIN is not pharmacologically active and must be first metabolized.The active metabolites of heroin are morphine, 6-monoacetylmorphine and 3-monoacetylmorphine.

The classification is an important note if we wish to truly understand much of the reasons behind addiction, dependency, and even pharmacology. The behavior and biological activity of a “Natural” occurring Alkaloid vs. a Synthetic occurring Alkaloid vs. a Semi-Synthetic occurring Alkaloid, often can be quite dramatic.

THE PLANT PHARMACOLOGICAL MATRIX
Whenever one ingredient, alkaloid, or constituent is plucked out of a plant, it becomes unstable and has specific and unique properties which often are not predicable long- term. This is because a plant contains a “MATRIX” of multiple Alkaloids, Constituents, and Active Biologically Significant Ingredients that all work synergistically as part of the entire Plant. This is why Traditional Medicine such as Traditional Oriental Medicine, Ayurvedic Medicine, Native-American Herbal Medicine, South-American Medicine, and virtually every single ancient civilization utilizes the “Plant Matrix.” This simply means
that when they consume a plant, they do not “isolate” or “pluck” one ingredient out of the
plant, they brew, decoct, smoke, or consume the entire part of the plant they are using.

In the case of Opium, currently, Pharmacological Science estimates approximately 32
Alkaloids that occur naturally in the latex sap of the Opium Flower. This means that in the future, even though this plant has been studied quite extensively, there may be new alkaloids discovered and named, making that list of 32 Alkaloids grow.

Also, Opium Poppy Flower is a plant, with many different varieties, This means each variety of Opium Poppy Flower may have higher amounts and varying proportions of Active Constituents that are unique to that specific variety. And even specific to that area where it is grown, the mineral and nutrient profile of the soil, the climate of the region where it is grown, the altitude, and the age of the plant. All these are factors that differentiate the pharmacological activity of one variety from another, such as the hundreds of varieties of Opium Poppy Flower.

EXAMPLE OF OPIUM PRIOR TO THE PHARMACOLOGICAL INDUSTRIAL COMPLEX

For millennia, many Middle-Eastern individuals smoke “Opium.” In this case we are using the word “Opium” to refer to the Latex sap of the Flower, which contains at least
32 Alkaloids that have been identified and named.

Smoking Opium seems to have a very powerful analgesic effect, and there are many individuals that become addicted to smoking Opium.

We are mentioning this example not to encourage individuals to smoke Opium, but to convey how powerful “Plant Medicines” is. Plant Medicine is a system which utilizes the

raw material such as a twig, root, stem, leaf, flower, vine of plant as the source material, and then consumes the material through various methodologies such as brewing, decocting as a tea, smoking, or eating. This is the original and traditional form of medicine, prior to isolating one alkaloid from a plant.

PLANTS ARE THE INSPIRATION FOR MOST PHARMACEUTICALS Many individuals believe that the large Pharmaceutical Industry creates most of the current Pain Medications available through scientific discovery that is completely original. This is simply not accurate. In fact, today in medicine in 2012, the “OPIATE CLASS” of Medications are still the most commonly prescribed class of medications for Pain prescribed by Physicians. This includes all forms: Natural, Synthetic, and Semi- Synthetic.

The Natural occurring alkaloids: Morphine, Codeine, and Thebaine are prescribed on a daily basis throughout the world to million of humans, and animals as well.

The Semi-Synthetics: Hydrocodone, Hydromorphone and Oxymorphone are also prescribed to million of individuals, and do not occur naturally in nature. However, these are considered Opiates, and exist from Pharmacologists studying many of the NATURAL ALKALOIDS in OPIUM such as Morphine, Codeine, and Thebaine, and slightly modifying the original molecule to make a “SYNTHETIC” version of the “NATURAL” version.

This is a shining example of how Plants are usually the inspiration for many Pharmaceutical substances that gross sales in excess of billion of dollars, and are used by billions of people (and many animals).

Opiates belong a large group called BENZYLISOQUINOLINE alkaloids.

ESTERS OF MORPHINE
Semi-natural opiates that are either morphine prodrugs or are so similar to morphine that they are not semi-synthetic, but are more natural in nature due to the fact that they are morphine salts. Examples of such drugs include diacetylmorphine (morphine diacetate; heroin) (morphine prodrug), the metabolite 6-MAM (morphine prodrug), nicomorphine (morphine dinicotinate), dipropanoylmorphine (morphine dipropionate), desomorphine (di-hydro-desoxy-morphine), methyldesorphine, acetylpropionylmorphine, dibenzoylmorphine, diacetyldihydromorphine, and several others.[8]

MOST OPIATES STILL EXTRACTED FROM PLANT MATERIAL TODAY
The full synthesis of opiates from naphthoquinone (Gates synthesis) or from other
simple organic starting materials is quite tedious and not economical. Therefore, most of the opiate-type of analgesics in use today are STILL extracted from Papaver
Somniferum or semi-synthesized from Thebaine.

WITHDRAWAL EFFECTS

Opiate withdrawal syndrome effects are associated with cessation of prolonged opiate usage.

In facilities the logical threat of relapse is possible when Post-acute-withdrawal syndrome is under-emphasized to patients in transitional phases, especially with short-term suboxone, methadone or health facilities.

OPIATE EPIDEMIC
Pain medication has become a near epidemic in the United States, transcending age, social status, and income levels. While the reasons for starting opiates varies within each sector and age group, the end result is dependency and long-term health side- effects that are induced from taking opiate agonists, partial opiate agonists, and other medications that affect Mu Receptors.

OPIATE COMPARISON CHART

Opioids elicit analgesic (pain killing) effects in humans and animals by binding to the _-opioid receptor within the central nervous system. The following table lists commonly used opioid drugs and their relative potencies. Values for the potencies of opioids listed on this table are given as taken orally unless another route of administration is provided. As such, their bioavailabilities differ, and they may be more potent when taken intravenously.

Analgesic/opi oid Strength[1]
(morphine) Equivalent dose (10 mg morphine) Bioavailability Half-life of active metabolites (hours)
Aspirin (non- 1/360 no equivalent total 3.1–9
opioid) dose
Diflunisal 1/160 1600 mg 80–90% 8–12
(NSAID, non-
opioid)
Propoxyphene[ 1/13 to 1/20 130-200 mg
2]
Codeine 1/10 100 mg ≈90% 2.5–3 (C6G 1.94;[3]
morphine 2–3)
Tramadol 1/10 100 mg 68–72% 5.5–7 (≈9)[clarification needed]
Anileridine[4] 1/4 40 mg
Pethidine 0.36 28 mg 50–60% 3–5
Hydrocodone 0.6 17 mg ≥80% 3.8–6
Morphine (oral) -1 (10 mg) ≈25% 2–3
Oxycodone 1.5–2.0 5.0–6.7 mg ≤87% 3–4.5
Methadone 3-4 2.5-3.33 mg 40–90% 15–60
(acute) [5] [6]
Morphine 4 2.5 mg 100% 2–3
(IV/IM)
Diamorphine 1.9–4.3 2.3–5.2 mg 100% <0.6
(Heroin;
IV/IM)[7]
Hydromorphon 5 2 mg 30–35% 2–3
e[8]
Oxymorphone 7 1.4 mg 10% 7.25–9.43
Methadone 7.5 1.35 mg 40-90% 15-60
(chronic) [9]

Levorphanol[10 8 1.3 mg 70% 11–16
]

Buprenorphine[ 40 0.25 mg 35–40%

20–70, mean 37
11]

(sublingual)

Fentanyl 50–100 0.1–0.2 mg 33% (oral);
92% (transdermal)

0.04 (IV); 7 (transdermal)

Sufentanyl 500–1,000 10–20 _g 4.4

Etorphine[12] 1,000–3,00
0

3.3–10 _g

Carfentanil [10] 10,000–100 0.1–1.0 _g 7.7
,000

FENTANYL

Please note that Fentanyl yields a potency about 50-100x stronger than that of
Morphine, and is one of the most potent Opiates used today.

METHADONE

Methadone is different from most opioids considering its potency can vary depending on how long you take it. Acute use; 1-3 days, yields a potency about
4x stronger than that of Morphine and Chronic use (7 days+) yields a potency

about 7-8x that of morphine due to methadone being stored in fat tissue, thus giving higher serum levels with longer use.

BUPRENORPHINE (SUBUTEX & SUBOXONE)

(Note: This section on Buprenorphine shall be brief. For the complete information in this course on Buprenorphine, please refer to the Buprenorphine Section in Chapter. X)

SUBUTEX & SUBOXONE: THE NEW METHADONE

Buprenorphine is quickly replacing Methadone as the medication most individuals are put on to help them wean off opiates. The brand names for Buprenorphine are “Subutex” and “Suboxone.” Subutex is Burphenorphine, while Suboxone is a compound combining Buprenorphine and Naloxone.

BUPRENORPHINE – 40X STRONGER THAN MORPHINE

Buprenorphine is become an Epidemic. Please note, it yields a potency about
40x stronger than that of morphine.

BURPENORPHINE – LONG HALF-LIFE at 72 HOURS

Also itʼs half-life is the longest of any substance in this chart, ranging anywhere between 20-70 Hours, with a mean of 72 hours for half-life of active metabolites.

OPIOD TERMINOLOGY

An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract. The receptors in these organ systems mediate both the beneficial effects and the side effects of opioids.

Opioids are among the world’s oldest known drugs; the use of the opium poppy for its therapeutic benefits predates recorded history. The analgesic (painkiller) effects of opioids are due to decreased perception of pain, decreased reaction to

pain as well as increased pain tolerance. The side effects of opioids include sedation, respiratory depression, constipation, and a strong sense of euphoria. Opioids can cause cough suppression, which can be both an indication for opioid administration or an unintended side effect. Opioid dependence can develop with ongoing administration, leading to a withdrawal syndrome with abrupt discontinuation. Opioids are well known for their ability to produce a feeling of euphoria, motivating some to recreationally use opioids.

Although the term opiate is often used as a synonym for opioid, the term opiate is properly limited to the natural alkaloids found in the resin of the opium poppy (Papaver somniferum). In some definitions, the semi-synthetic substances that are directly derived from the opium poppy are considered to be opiates as well, while in other classification systems these substances are simply referred to as semi-synthetic opioids.

Medical uses

Pain

Opioids have long been used to treat acute pain (such as post-operative pain). They have also been found to be invaluable in palliative care to alleviate the severe, chronic, disabling pain of terminal conditions such as cancer, and degenerative conditions such as rheumatoid arthritis. However, opioids should be used cautiously in chronic non-cancer pain (see below). High doses are not necessarily required to control the pain of advanced or end-stage disease. Tolerance (a physical reaction which makes the body less responsive to
analgesic and other effects of opiates) may occur. Requirements can level off for many months at a time, depending on severity of pain, which varies. This is despite the fact that opioids have potential for tolerance, which essentially means in many cases opioids are a successful long-term care strategy for those in chronic cancer pain.

In recent years there has been an increased use of opioids in the management of non-malignant chronic pain. This practice has now led to a new and growing problem with addiction and misuse of opioids.[1]

ADVERSE EFFECTS

Common adverse reactions in patients taking opioids for pain relief include:
nausea and vomiting, drowsiness, itching, dry mouth, miosis, and constipation.[2]

Infrequent adverse reactions in patients taking opioids for pain relief include: dose-related respiratory depression (especially with more potent opioids), confusion, hallucinations, delirium, urticaria, hypothermia,

bradycardia/tachycardia, orthostatic hypotension, dizziness, headache, urinary retention, ureteric or biliary spasm, muscle rigidity, myoclonus (with high doses), and flushing (due to histamine release, except fentanyl and remifentanil).[2]

Opioid-induced hyperalgesia has been observed in some patients, whereby individuals using opioids to relieve pain may paradoxically experience more pain as a result of their medication. This phenomenon, although uncommon, is seen
in some palliative care patients, most often when dose is escalated rapidly.[3][4] If encountered, rotation between several different opioid analgesics may mitigate the development of hyperalgesia.[5][6]

Both therapeutic and chronic use of opioids can compromise the function of the immune system. Opioids decrease the proliferation of macrophage progenitor cells and lymphocytes, and affect cell differentiation (Roy & Loh, 1996). Opioids may also inhibit leukocyte migration. However the relevance of this in the context of pain relief is not known.

Men who are taking moderate to high doses of an opioid analgesic long-term are likely to have subnormal testosterone levels, which can lead to osteoporosis and decreased muscle strength if left untreated. Therefore, total and free testosterone levels should be monitored in these patients; if levels are suboptimal,
testosterone replacement therapy, preferably with patches or transdermal preparations, should be given. Also, prostate-specific antigen levels should be monitored.[7]

MANAGING ADVERSE EFFECTS

Nausea: tolerance occurs within 7–10 days, during which antiemetics (e.g. low dose haloperidol once at night) are very effective. Due to severe side effects such as tardive dyskinesia, haloperidol is currently rarely used. A related drug, Compazine (prochlorperazine) is more often used, although it has similar risks. Stronger antiemetics such as ondansetron or tropisetron may be indicated if nausea is severe or continues for an extended period, although these tend to be avoided due to their high cost unless nausea is really problematic. A cheaper alternative is dopamine antagonists, e.g. domperidone and metoclopramide. Domperidone does not cross the blood–brain barrier, so blocks opioid emetic action in the chemoreceptor trigger zone without adverse central anti-

dopaminergic effects (not available in the U.S.) Some antihistamines with anti- cholinergic properties (e.g. orphenadrine or diphenhydramine) may also be effective. The first-generation anti-histamine hydroxyzine is very commonly used, with the added advantages of not causing movement disorders, and also possessing analgesic-sparing properties.

_ 5-HT3 antagonists (e.g. ondansetron)
_ Dopamine antagonists (e.g. domperidone)
_ Anti-cholinergic antihistamines (e.g. diphenhydramine)

Vomiting: this is due to gastric stasis (large volume vomiting, brief nausea relieved by vomiting, oesophageal reflux, epigastric fullness, early satiation), besides direct action on the vomiting centre of the brain. Vomiting can thus be prevented by prokinetic agents (e.g. domperidone or metoclopramide 10 mg every eight hours). If vomiting has already started, these drugs need to be administered by a non-oral route (e.g. subcutaneous for metoclopramide, rectally for domperidone).

_ Prokinetic agents (e.g. domperidone)
_ Anti-cholinergic agents (e.g. orphenadrine)

Drowsiness: tolerance usually develops over 5–7 days, but if troublesome, switching to an alternative opioid often helps. Certain opioids such as fentanyl, morphine and diamorphine (heroin) tend to be particularly sedating, while others such as oxycodone, tilidine and meperidine (pethidine) tend to produce comparatively less sedation, but individual patients responses can vary markedly and some degree of trial and error may be needed to find the most suitable drug for a particular patient. Treatment is at any rate possible – CNS stimulants are generally effective.

_ Stimulants (e.g. caffeine, modafinil, amphetamine, nicotine)
Itching: tends not to be a severe problem when opioids are used for pain relief, but if required then antihistamines are useful for counteracting itching. Non- sedating antihistamines such as fexofenadine are preferable so as to avoid increasing opioid induced drowsiness, although some sedating antihistamines such as orphenadrine may be helpful as they produce a synergistic analgesic effect which allows smaller doses of opioids to be used while still producing effective analgesia. For this reason some opioid/antihistamine combination products have been marketed, such as Meprozine (meperidine/promethazine) and Diconal (dipipanone/cyclizine), which may also have the added advantage of reducing nausea as well.

_ Antihistamines (e.g. fexofenadine)

Constipation: develops in many people on opioids and since tolerance to this problem does not develop readily, most patients on long-term opioids will need a laxative. Over 30 years experience in palliative care has shown that most opioid constipation can be successfully prevented: “Constipation … is treated [with laxatives and stool-softeners]” (Burton 2004, 277). According to Abse, “It is very important to watch out for constipation, which can be severe” and “can be a very considerable complication” (Abse 1982, 129) if it is ignored. Peripherally acting opioid antagonists such as alvimopan (Entereg) and methylnaltrexone (Relistor) have been found to effectively relieve opioid induced constipation without triggering withdrawal symptoms, although alvimopan is contraindicated in
patients who have taken opioids for more than seven days, is only FDA-approved for 15 doses or less, and may increase risk of heart attack.[8][9] For mild cases, a lot of water (around 1.5 L/day) and fiber might suffice (in addition to the laxative and stool-softeners).

_ Stool-softening and peristalsis-promoting laxatives (e.g. docusate in combination with bisacodyl or senna).
_ Peripherally-acting opioid antagonists (e.g. methylnaltrexone) effectively prevent constipation while not affecting centrally mediated analgesia or provoking withdrawal syndrome, however these can still potentially reduce the efficacy of opioid analgesics in the treatment of conditions where much of the pain relief comes from action at peripherally situated opioid receptors, such as in inflammatory conditions like arthritis or post-surgical pain.
_ High water intake and dietary fiber

For more severe and/or chronic cases, the drugs that are used work by not increasing peristalsis, but by preventing water uptake in the intestine, leading to a softer stool with a larger component of water, and, additionally, by acidifying the environment inside the intestine, which both decreases water uptake and enhances peristalsis (e.g. lactulose, which is controversially noted as a possible probiotic). The following drugs are generally efficacious:

_ Polyethylene glycol 3350±10% dalton powder for solution (MiraLax, GlycoLax).
_ Lactulose syrup
One combination, oxycodone/naloxone, aims to reduce systemic side effects by combining oxycodone with an opioid suppressor, naloxone, in a form which does not pass through the blood–brain barrier. Thus, the constipation effect is suppressed, but not the pain reduction.

Respiratory depression: although this is the most serious adverse reaction associated with opioid use it usually is seen with the use of a single, intravenous dose in an opioid-naïve patient. In patients taking opioids regularly for pain relief, tolerance to respiratory depression occurs rapidly, so that it is not a clinical problem. Several drugs have been developed which can partially block
respiratory depression, although the only respiratory stimulant currently approved for this purpose is doxapram, which has only limited efficacy in this application.[10][11] Newer drugs such as BIMU-8 and CX-546 may however be much more effective.[12][13][14]

_ Respiratory stimulants: carotid chemoreceptor agonists (e.g. doxapram), 5- HT4 agonists (e.g. BIMU8), _-opioid agonists (e.g. BW373U86) and AMPAkines (e.g. CX717) can all reduce respiratory depression caused by opioids without affecting analgesia, but most of these drugs are only moderately effective or have side effects which preclude use in humans. 5- HT1A agonists such as 8-OH-DPAT and repinotan also counteract opioid- induced respiratory depression, but at the same time reduce analgesia, which limits their usefulness for this application.
_ Opioid antagonists (e.g. naloxone, nalmefene, diprenorphine) Hyperalgesia: side effects such as hyperalgesia and allodynia, sometimes accompanied by a worsening of neuropathic pain, may be consequences of long- term treatment with opioid analgesics, especially when increasing tolerance has resulted in loss of efficacy and consequent progressive dose escalation over
time. This appears to largely be a result of actions of opioid drugs at targets other
than the three classic opioid receptors, including the nociceptin receptor, sigma receptor and Toll-like receptor 4, and can be counteracted in animal models by antagonists at these targets such as J-113,397, BD-1047 or (+)-Naloxone respectively.[15][16][17][18] No drugs are currently approved specifically for counteracting opioid-induced hyperalgesia in humans and in severe cases the only solution may be to discontinue use of opioid analgesics and replace them with non-opioid analgesic drugs. However since individual sensitivity to the development of this side effect is highly dose dependent and may vary depending which opioid analgesic is used, many patients can avoid this side effect simply through dose reduction of the opioid drug (usually accompanied by addition of a supplemental non-opioid analgesic), rotating between different opioid drugs, or by switching to a milder opioid with mixed mode of action that also counteracts neuropathic pain, particularly tramadol or tapentadol.[19][20][21][22]

_ NMDA antagonists such as ketamine
_ SNRIs such as milnacipran
_ anticonvulsants such as gabapentin or pregabalin

Finally, opioid effects (adverse or otherwise) can be reversed with an opioid antagonist such as naloxone or naltrexone. These competitive antagonists bind to the opioid receptors with higher affinity than agonists but do not activate the receptors. This displaces the agonist, attenuating and/or reversing the agonist effects. However, the elimination half-life of naloxone can be shorter than that of the opioid itself, so repeat dosing or continuous infusion may be required, or a longer acting antagonist such as nalmefene may be used. In patients taking opioids regularly it is essential that the opioid is only partially reversed to avoid a severe and distressing reaction of waking in excruciating pain. This is achieved by not giving a full dose but giving this in small doses until the respiratory rate has improved. An infusion is then started to keep the reversal at that level, while maintaining pain relief. Opioid antagonists remain the standard treatment for respiratory depression following opioid overdose, with naloxone being by far the most commonly used, although the longer acting antagonist nalmefene may be used for treating overdoses of long-acting opioids such as methadone, and diprenorphine is used for reversing the effects of extremely potent opioids used in veterinary medicine such as etorphine and carfentanil. However since opioid antagonists also block the beneficial effects of opioid analgesics, they are generally useful only for treating overdose, with use of opioid antagonists
alongside opioid analgesics to reduce side effects, requiring careful dose titration and often being poorly effective at doses low enough to allow analgesia to be maintained.

SAFETY

Studies over the past 20 years have repeatedly shown opioids to be safe when they are used correctly. In the UK two studies have shown that double doses of bedtime morphine did not increase overnight deaths,[23] and that sedative dose increases were not associated with shortened survival (n=237).[24] Another UK study showed that the respiratory rate was not changed by morphine given for breathlessness to patients with poor respiratory function (n=15).[25] In Australia, no link was found between doses of opioids, benzodiazepines or haloperidol and survival.[26] In Taiwan, a study showed that giving morphine to treat breathlessness on admission and in the last 48 hours did not affect survival.[27] The survival of Japanese patients on high dose opioids and sedatives in the last
48 hours was the same as those not on such drugs.[28] In U.S. patients whose ventilators were being withdrawn, opioids did not speed death, while benzodiazepines resulted in longer survival (n=75).[29] Morphine given to elderly patients in Switzerland for breathlessness showed no effect on respiratory function (n=9, randomised controlled trial).[30] Injections of morphine given subcutaneously to Canadian patients with restrictive respiratory failure did not

change their respiratory rate, respiratory effort, arterial oxygen level, or end-tidal carbon dioxide levels.[31] Even when opioids are given intravenously, respiratory depression is not seen.[32]

Carefully titrating the dose of opioids can provide for effective pain relief while minimizing adverse effects. Morphine and diamorphine have been shown to have a wider therapeutic range or “safety margin” than some other opioids. It is impossible to tell which patients need low doses and which need high doses, so all have to be started on low doses, unless changing from another strong opioid.[33]

Opioid analgesics do not cause any specific organ toxicity, unlike many other drugs, such as aspirin and acetaminophen. They are not associated with upper gastrointestinal bleeding and renal toxicity.[7]

TOLERANCE

Tolerance is the process whereby neuroadaptation occurs (through receptor desensitization) resulting in reduced drug effects. Tolerance is more pronounced for some effects than for others; tolerance occurs quickly to the effects on mood, itching, urinary retention, and respiratory depression, but occurs more slowly to the analgesia and other physical side effects. However, tolerance does not develop to constipation or miosis (the constriction of the pupil of the eye to less than or equal to two millimeters). Tolerance to opioids is attenuated by a number of substances, including:

_ calcium channel blockers[34][35]
_ intrathecal magnesium[36] and zinc[37]
_ NMDA antagonists, such as dextromethorphan, ketamine,[38] and memantine.[39]
_ cholecystokinin antagonists, such as proglumide[40][41][42]
_ Newer agents such as the phosphodiesterase inhibitor ibudilast have also been researched for this application.[43]
Tolerance is a physiologic process where the body adjusts to a medication that is frequently present, usually requiring higher doses of the same medication over time to achieve the same effect. It is a common occurrence in individuals taking high doses of opioids for extended periods, but does not predict any relationship to misuse or addiction.

Dependence is characterised by unpleasant withdrawal symptoms that occur if opioid use is abruptly discontinued. The withdrawal symptoms for opiates include severe dysphoria, sweating, nausea, rhinorrea, depression, severe fatigue,

vomiting and pain. Slowly reducing the intake of opioids over days and weeks will reduce or eliminate the withdrawal symptoms.[33] The speed and severity of withdrawal depends on the half-life of the opioid; heroin and morphine withdrawal occur more quickly and are more severe than methadone withdrawal, but methadone withdrawal takes longer. The acute withdrawal phase is often
followed by a protracted phase of depression and insomnia that can last for months. The symptoms of opioid withdrawal can also be treated with other medications, such as clonidine, antidepressants and benzodiazepines, but with a low efficacy.[44] Physical dependence does not predict drug misuse or true addiction, and is closely related to the same mechanism as tolerance.

ADDICTION

Addiction is the process whereby physical and/or psychological dependence develops to a drug – including opioids. The withdrawal symptoms can reinforce the addiction, driving the user to continue taking the drug. Psychological
addiction is more common in people insufflating or injecting opioids recreationally rather than taking them orally for medical reasons.[33] In European nations such as Austria, Bulgaria, and Slovakia, slow release oral morphine formulations are used in opiate substitution therapy for patients who do not well tolerate the side effects of buprenorphine or methadone. In other European countries including
the UK, this is also legally used for OST although on a varying scale of acceptance.

RECREATIONAL USE

Drug misuse is the use of drugs for reasons other than what the drug was prescribed for. Opioids are primarily misused due to their ability to produce euphoria. Misuse can also include giving drugs to people for whom it was not prescribed or selling the medication, both of which are crimes punishable by jail time in some, if not most countries.

PHARMACOLOGY

Opioid comparison

Opioids bind to specific opioid receptors in the nervous system and other tissues. There are three principal classes of opioid receptors, _, _, _ (mu, kappa, and delta), although up to seventeen have been reported, and include the _, _, _, and
_ (Epsilon, Iota, Lambda and Zeta) receptors. Conversely, _ (Sigma) receptors are no longer considered to be opioid receptors because: their activation is not reversed by the opioid inverse-agonist naloxone, they do not exhibit high-affinity binding for classical opioids, and they are stereoselective for dextro-rotatory isomers while the other opioid receptors are stereo-selective for laevo-rotatory isomers. In addition, there are three subtypes of _-receptor: _1 and _2, and the newly discovered _3. Another receptor of clinical importance is the opioid- receptor-like receptor 1 (ORL1), which is involved in pain responses as well as having a major role in the development of tolerance to _-opioid agonists used as analgesics. These are all G-protein coupled receptors acting on GABAergic neurotransmission.

The numbered substitution positions of the morphine molecule
The pharmacodynamic response to an opioid depends upon the receptor to
which it binds, its affinity for that receptor, and whether the opioid is an agonist or an antagonist. For example, the supraspinal analgesic properties of the opioid agonist morphine are mediated by activation of the _1 receptor; respiratory depression and physical dependence by the _2 receptor; and sedation and spinal analgesia by the _ receptor. Each group of opioid receptors elicits a distinct set of neurological responses, with the receptor subtypes (such as _1 and _2 for example) providing even more [measurably] specific responses. Unique to each opioid is its distinct binding affinity to the various classes of opioid receptors (e.g. the _, _, and _ opioid receptors are activated at different magnitudes according to the specific receptor binding affinities of the opioid). For example, the opiate alkaloid morphine exhibits high-affinity binding to the _-opioid receptor, while ketazocine exhibits high affinity to _ receptors. It is this combinatorial mechanism that allows for such a wide class of opioids and molecular designs to exist, each with its own unique effect profile. Their individual molecular structure is also responsible for their different duration of action, whereby metabolic breakdown (such as N-dealkylation) is responsible for opioid metabolism.

TABLE OF MORPHINAN OPIODS

Morphine family

Morphine

2,4- Dinitrophenylmor

6-MDDM

Chlornaltrexamin

Desomorphine
e
phine

Dihydromorphine

Hydromorphinol

Methyldesorphin

N- Phenethylnormor

RAM-378
phine
e
3,6-diesters of morphine

Acetylpropionylm

Dihydroheroin

Dibenzoylmorphi

Dipropanoylmorp

Heroin
orphine hine
ne

Nicomorphine
Codeine-dionine family

Codeine

6-MAC

Benzylmorphine

Codeine methylbromide

Dihydroheterocodeine

Ethylmorphine

Heterocodeine

Pholcodine

Myrophine
Morphinones and morphols

14- Cinnamoyloxyco

14- Ethoxymetopon

14- Methoxymetopo

PPOM

7- Spiroindanyloxymorpho
deinone
n
ne

Acetylmorphone

Codeinone

Conorphone

Codoxime

Thebacon

Hydrocodone

Hydromorphone

Metopon

Morphinone

N-Phenethyl-14- Ethoxymetopon

Oxycodone

Oxymorphone

Pentamorphone

Semorphone
Various semi-synthetics

Chloromorphide

14- Hydroxydihydroc

Acetyldihydrocod

Dihydrocodeine

Nalbuphine
eine
odeine

Nicocodeine

Nicodicodeine

Oxymorphazone

1-Iodomorphine
Active opiate metabolites

M6G

6-MAM

Norcodeine

Normorphine

Morphine-N- oxide
Synthetic morphinans

Cyclorphan

DXA

Levorphanol

Levophenacylmo

Levomethorphan
rphan

Norlevorphanol

Oxilorphan

Phenomorphan

Furethylnorlevor

Xorphanol
phanol

Butorphanol

Cyprodime

Drotebanol
Orvinols & Oripavine derivatives

7-PET

Acetorphine

BU-48

Buprenorphine

Cyprenorphine

Dihydroetorphine

Etorphine

Norbuprenorphin
e
Opioid antagonists & inverse agonists

5′- Guanidinonaltrin

Diprenorphine

Levallorphan

MNTX

Nalfurafine
dole

Nalmefene

Naloxazone

Naloxone

Nalorphine

Naltrexone

Naltriben

Naltrindole

6_-Naltrexol-d4
Morphinan dimers

Pseudomorphine

Naloxonazine

Norbinaltorphimi
ne

HISTORY
Non-clinical use was criminalized in the U.S by the Harrison Narcotics Tax Act of
1914, and by other laws worldwide. Since then, nearly all non-clinical use of opioids has been rated zero on the scale of approval of nearly every social institution. However, in United Kingdom the 1926 report of the Departmental Committee on Morphine and Heroin Addiction under the Chairmanship of the President of the Royal College of Physicians reasserted medical control and established the “British system” of control—which lasted until the 1960s; in the U.S. the Controlled Substances Act of 1970 markedly relaxed the harshness of the Harrison Act.

Before the twentieth century, institutional approval was often higher, even in Europe and America. In some cultures, approval of opioids was significantly higher than approval of alcohol. Opiates were used for depression and anxiety up until the mid 1950s.[47]

SOCIETY & CULTURE

GLOBAL SHORTAGES

Morphine and other poppy-based medicines have been identified by the World Health Organization as essential in the treatment of severe pain. However, only six countries use 77% of the world’s morphine supplies, leaving many emerging countries lacking in pain relief medication.[48] The current system of supply of raw poppy materials to make poppy-based medicines is regulated by the International Narcotics Control Board under the provision of the 1961 Single Convention on Narcotic Drugs. The amount of raw poppy materials that each country can demand annually based on these provisions must correspond to an estimate of the country’s needs taken from the national consumption within the preceding two years. In many countries, underprescription of morphine is rampant because of the high prices and the lack of training in the prescription of

poppy-based drugs. The World Health Organization is now working with different countries’ national administrations to train healthworkers and to develop national regulations regarding drug prescription to facilitate a greater prescription of
poppy-based medicines.[49]

Another idea to increase morphine availability is proposed by the Senlis Council, who suggest, through their proposal for Afghan Morphine, that Afghanistan could provide cheap pain relief solutions to emerging countries as part of a second-tier system of supply that would complement the current INCB regulated system by maintaining the balance and closed system that it establishes while providing finished product morphine to those suffering from severe pain and unable to access poppy-based drugs under the current system.

UNITED STATES APPROVAL

The sole clinical indications for opioids in the United States, according to Drug
Facts and Comparisons, 2005, are:

_ Moderate to severe pain, i.e., to provide analgesia or, in surgery, to induce and maintain anesthesia, as well as allaying patient apprehension right before the procedure. Fentanyl, oxymorphone, hydromorphone, and morphine are most commonly used for this purpose, in conjunction with other drugs such as scopolamine, short and intermediate-acting barbiturates, and benzodiazepines, especially midazolam which has a rapid onset of action and shorter duration than diazepam (Valium) or
similar drugs. The enhancement of the effects of each drug by the others is
useful in troublesome procedures like endoscopies, complicated and difficult deliveries (pethidine and its relatives and piritramide where it is used are favoured by many practitioners with morphine and derivatives as the second line), incision & drainage of severe abscesses, intraspinal injections, and minor and moderate-impact surgical procedures in patients unable to have general anesthesia due to allergy to some of the drugs involved or other concerns.
_ Cough (codeine, dihydrocodeine, ethylmorphine (dionine), hydromorphone and hydrocodone, with morphine or methadone as a last resort.)
_ Diarrhea (generally loperamide, difenoxin or diphenoxylate; but paregoric, powdered opium or laudanum or morphine may be used in some cases of severe diarrheal diseases, e.g. cholera); also diarrhea secondary to Irritable Bowel Syndrome (Codeine, paregoric, diphenoxylate, difenoxin, loperamide, laudanum)
_ Anxiety due to shortness of breath (oxymorphone and dihydrocodeine only)

_ Opioid dependence (methadone and buprenorphine only)
Opioids are not typically used for psychological relief (with the narrow exception of anxiety due to shortness of breath).

Opioids are often used in combination with adjuvant analgesics (drugs which have an indirect effect on the pain). In palliative care, opioids are not recommended for sedation or anxiety because experience has found them to be ineffective agents in these roles. Some opioids are relatively contraindicated in renal failure because of the accumulation of the parent drug or their active metabolites (e.g. codeine and oxycodone). Age (young or old) is not a contraindication to strong opioids. Some synthetic opioids such as pethidine have metabolites which are actually neurotoxic and should therefore be used only in acute situations.

CLASSIFICATION

There are a number of broad classes of opioids:

_ Natural opiates: alkaloids contained in the resin of the opium poppy, primarily morphine, codeine, and thebaine, but not papaverine and noscapine which have a different mechanism of action; The following could be considered natural opiates: The leaves from Mitragyna speciosa (also known as kratom) contain a few naturally-occurring opioids, active via Mu- and Delta receptors. Salvinorin A, found naturally in the Salvia divinorum plant, is a kappa-opioid receptor agonist.
_ Esters of morphine opiates: slightly chemically altered but more natural in nature than the semi-synthetics as most are morphine prodrugs, diacetylmorphine (morphine diacetate; heroin), nicomorphine (morphine dinicotinate), dipropanoylmorphine (morphine dipropionate),
desomorphine, acetylpropionylmorphine, dibenzoylmorphine, diacetyldihydromorphine;[50]
_ Semi-synthetic opioids: created from either the natural opiates or morphine esters, such as hydromorphone, hydrocodone, oxycodone, oxymorphone, ethylmorphine and buprenorphine;
_ Fully synthetic opioids: such as fentanyl, pethidine, levorphanol, methadone, tramadol and dextropropoxyphene;
_ Endogenous opioid peptides, produced naturally in the body, such as endorphins, enkephalins, dynorphins, and endomorphins. Morphine, and some other opioids, which are produced in small amounts in the body, are included in this category.
_ There are also drugs such as tramadol and tapentadol that are chemically not of the opioid class, but do have agonist actions at the _-opioid

receptor. Although their exact mechanism of action is not fully understood, they both have a dual mode of action, the second mode of action appearing to be on the noradrenergic and serotonergic systems.[51] This second mechanism of action was discovered during testing in where the drugs showed signs of analgesia even when naloxone, an opioid antagonist, was administered.[52]

Some minor opium alkaloids and various substances with opioid action are also found elsewhere, including molecules present in kratom, Corydalis, and Salvia divinorum plants and some species of poppy aside from Papaver somniferum. There are also strains which produce copious amounts of thebaine, an important raw material for making many semi-synthetic and synthetic opioids. Of all of the more than 120 poppy species, only two produce morphine.

Amongst analgesics are a small number of agents which act on the central nervous system but not on the opioid receptor system and therefore have none
of the other (narcotic) qualities of opioids although they may produce euphoria by relieving pain—a euphoria that, because of the way it is produced, does not form the basis of habituation, physical dependence, or addiction. Foremost amongst these are nefopam, orphenadrine, and perhaps phenyltoloxamine and/or some other antihistamines. Tricyclic antidepressants have painkilling effect as well, but they’re thought to do so by indirectly activating the endogenous opioid system. Paracetamol is predominantly a centrally acting analgesic (non-narcotic) which mediates its effect by action on descending serotoninergic (5-hydroxy triptaminergic) pathways, to increase 5-HT release (which inhibits release of pain mediators). It also decreases cyclo-oxygenase activity. It has recently been discovered that most or all of the therapeutic efficacy of paracetamol is due to a metabolite ( AM404, making paracetamol a prodrug) which enhances the release of serotonin and also interacts as with the cannabinoid receptors by inhibiting the uptake of anandamide.

Other analgesics work peripherally (i.e., not on the brain or spinal cord). Research is starting to show that morphine and related drugs may indeed have peripheral effects as well, such as morphine gel working on burns. Recent investigations discovered opioid receptors on peripheral sensory neurons.[53] A significant fraction (up to 60 %) of opioid analgesia can be mediated by such peripheral opioid receptors, particularly in inflammatory conditions such as arthritis, traumatic or surgical pain.[54] Inflammatory pain is also blunted by endogenous opioid peptides activating peripheral opioid receptors.[55]

It has been discovered in 1953, that the human body, as well as those of some other animals, naturally produce minute amounts of morphine and codeine and possibly some of their simpler derivatives like heroin and dihydromorphine, in

addition to the well known endogenous opioid peptides. Some bacteria are capable of producing some semi-synthetic opioids such as hydromorphone and hydrocodone when living in a solution containing morphine or codeine respectively.

Many of the alkaloids and other derivatives of the opium poppy are not opioids or narcotics; the best example is the smooth-muscle relaxant papaverine. Noscapine is a marginal case as it does have CNS effects but not necessarily similar to morphine, and it is probably in a category all its own.

Dextromethorphan (the stereoisomer of levomethorphan, a semi-synthetic opioid agonist) and its metabolite dextrorphan have no opioid analgesic effect at all despite their structural similarity to other opioids; instead they are potent NMDA antagonists and sigma 1 and 2-receptor agonists and are used in many over-the- counter cough suppressants.

Salvinorin A is a unique selective, powerful _-opioid receptor agonist. It is not properly considered an opioid nevertheless, because 1) chemically, it is not an alkaloid; and 2) it has no typical opioid properties: absolutely no anxiolytic or cough-suppressant effects. It is instead a powerful hallucinogen.

ENDOGENOUS OPIATES

Opioid-peptides that are produced in the body include:

_ Endorphins
_ Enkephalins
_ Dynorphins
_ Endomorphins
_-endorphin is expressed in Pro-opiomelanocortin (POMC) cells in the arcuate nucleus, in the brainstem and in immune cells, and acts through _-opioid receptors. _-endorphin has many effects, including on sexual behavior and appetite. _-endorphin is also secreted into the circulation from pituitary corticotropes and melanotropes. _-neo-endorphin is also expressed in POMC cells in the arcuate nucleus.

met-enkephalin is widely distributed in the CNS and in immune cells; [met]- enkephalin is a product of the proenkephalin gene, and acts through _ and _- opioid receptors. leu-enkephalin, also a product of the proenkephalin gene, acts through _-opioid receptors.

Dynorphin acts through _-opioid receptors, and is widely distributed in the CNS, including in the spinal cord and hypothalamus, including in particular the arcuate nucleus and in both oxytocin and vasopressin neurons in the supraoptic nucleus.

Endomorphin acts through _-opioid receptors, and is more potent than other endogenous opioids at these receptors.

OPIUM ALKALOIDS

Phenanthrenes naturally occurring in (opium):

_ Codeine
_ Morphine
_ Thebaine
_ Oripavine[56]
Preparations of mixed opium alkaloids, including papaveretum, are still occasionally used.

ESTERS OF MORPHINE

_ Diacetylmorphine (morphine diacetate; heroin)
_ Nicomorphine (morphine dinicotinate)
_ Dipropanoylmorphine (morphine dipropionate)
_ Diacetyldihydromorphine
_ Acetylpropionylmorphine
_ Desomorphine
_ Methyldesorphine
_ Dibenzoylmorphine

_ Dihydrocodeine
_ Ethylmorphine
_ Heterocodeine

ETHERS OF MORPHINE

SEMI-SYNTHETIC ALKALOID DERIVATIVES

_ Buprenorphine
_ Etorphine
_ Hydrocodone
_ Hydromorphone
_ Oxycodone
_ Oxymorphone

_

Fentanyl ANILIDOPIPERIDINES
_
_
_ Alphamethylfentanyl
Alfentanil
Sufentanil
_
_
_ Remifentanil
Carfentanyl
Ohmefentanyl

PHENYLPIPERIDINES
_ Pethidine (meperidine)
_ Ketobemidone
_ MPPP
_ Allylprodine
_ Prodine
_ PEPAP
_
DIPHENYLPROPYLAMINE DERIVATIVES
_ Propoxyphene
_ Dextropropoxyphene
_ Dextromoramide
_ Bezitramide
_ Piritramide
_ Methadone
_ Dipipanone
_ Levomethadyl Acetate (LAAM)
_ Difenoxin
_ Diphenoxylate
_ Loperamide (used for diarrhoea, does not cross the blood–brain barrier)

BENZOMORPHAN DERIVATIVES
_ Dezocine – agonist/antagonist
_ Pentazocine – agonist/antagonist
_ Phenazocine

ORIPAVINE DERIVATIVES
_ Buprenorphine – partial agonist
_ Dihydroetorphine
_ Etorphine

MORPHINAN DERIVATIVES
_ Butorphanol – agonist/antagonist
_ Nalbuphine – agonist/antagonist
_ Levorphanol
_ Levomethorphan

_ Lefetamine
_ Meptazinol
_ Tilidine
_ Tramadol
_ Tapentadol

OTHERS

_ Nalmefene
_ Naloxone
_ Naltrexone

OPIOD ANTAGONISTS

QUIZ – CHAPTER 1. – OPIATE COURSE

PLEASE ANSWER TRUE OR FALSE TO THE BELOW STATEMENTS.

1. OPIATES ORIGINALLY CAME FROM THE OPIUM POPPY FLOWER.

2. OPIATES ARE CONSIDERED THE GOLD STANDARD IN PAIN CONTROL AND MANAGEMENT IN WESTERN MEDICINE.

3. OPIATES ARE ADDICTIVE.

4. BUPRENORPHINE IS A PARTIAL OPIATE AGIONIST.

5. NALOXONE IS AN OPIOD ANTAGONIST.

6. BUTORPHANOL IS A MORPHINAN DERIVATIVE.

7. HYDROCODONE, OXYMORPHONE, & OXYCODONE ARE ALL SEMI- SYNTHETIC ALKALOID DERIVATIVE OPIODS.

8. ENDORPHINS, DYMORPHINS, AND ENKEPHALINS ARE CONSIDERED ENDOGENOUS OPIATES.

9. FENTANYL IS CONSIDERED PHARMACOLOGICALLY 50-100X STRONGER THAN MORPHINE.

10. BUPRENORPHINE (SUBUTEX, SUBOXONE) IS CONSIDERED PHARMACOLOGICALLY 30X STRONGER THAN MORPHINE.

11. CARFENTANIL IS CURRENTLY CONSIDERED THE STRONGEST OPIOD KNOWN TO MAN, CONSIDERED PHARMACOLOGICALLY 10,000 –
100,000 X STRONGER THAN MORPHINE.

12. CURRENTLY, APPROX. 32 ALKALOID HAVE BEEN DISCOVERED IN THE LATEX SAP OF THE OPIUM POPPY FLOWER

Test Acu Post

The commercial harvesting of American ginseng began in Canada in 1716 after a Jesuit priest, working among the Iroquois, heard of the root so valued by the Chinese. Reasoning that the environment of French Canada closely resembled that of Manchuria, he began searching for examples of this wondrous herb growing in the Canadian hardwood forests and after three months of searching he discovered American ginseng growing near Montreal. Thus began a vigorous export of ginseng from Canada to China where American ginseng quickly became much in demand. Before long ginseng was discovered growing in the wild in New England, New York, Massachusetts and Vermont and many an American fortune was made on the ginseng trade.

By the end of the nineteenth century, however, the wild root was near extinction in North America due to over-harvesting and the destruction of its natural habitat. At this point, farmers began cultivating the sensitive plant and after numerous failed attempts the first harvests of cultivated ginseng reached the market. From 1880 to 1960 the ginseng trade experienced
many ups and downs for reasons as diverse as blight and world wars but since the 1960s the trade in American ginseng has grown steadily.

In the 1990s more North Americans than ever have been converted by the wonderful and various curative properties of ginseng and in addition to the trade still flourishing with China, there is a sizeable domestic market for the root.

9 Crazy-Cool Toys You Can Control With Your Smartphone

Who says that toys are made for children only? Although we may have outgrown the toys we grew up with, some of the toys you can find in the market these days can really make you want to let out your inner child. So, to heck with age recommendations, let’s check out some of the new, innovative toys that you can play with your iOS or Android device.

In this list, you will find 9 toys that you can maneuver with your smartphone or tablet. They include airplanes, tanks, robots and more. These toys can fly, drive, turn, flip and rotate, avoid obstacles and even take pictures and record videos. See if these toys can make you feel like you want to be a kid again.

Recommended Reading: High-Tech Toys & Gadgets Designed For Kids

1. Ollie

Ollie is a toy you can maneuver with your iOS or Android device. It can reach up to speeds of 14mph. It has a durable colored shell with built-in LEDs, and they can spin, flip and do plenty of tricks while you control them from your smartphone. Ollie is connected to your smartphone in a 30 meter range, via Bluetooth. Watch it in action here. [$99.99-149.99]

2. Smart Plane

Smart Plane is touted as the “R/V aircraft imagined” – a slow-flying durable plane that can withstand flying both indoors and outdoors. The app, available for iOS and Android, is built to simulate a fly-from-the-cockpit atmosphere complete with FlightAssist technology. The plane is powered by a 1g lithium-polymer battery which can last up to 30 mins of “airtime”. When you’re done, charge it up in 15 minutes and go again. [$67.99]

3. TankBot

Tankbot is a maze master – it navigates around obstacles with ease, and help from infrared sensors. You can also let it roam free, or control it from your smartphone. Just tap it with your iOS or Android device to connect, then race your Tankbot or battle against other Tankbots. It is available in seven colors and can be charged via USB. Its dimensions are 13.5 × 23.5 × 7.5 cm. [$24.95]

4. Wireless Spy Tank

Need to run a little espionage? This Wireless Spy Tank is the perfect tool for the job. Equipped with a camera to stream and record live videos and still images, the tank can travel up to 200 ft unobstructed, half of that distance around walls. The visual feed comes with night vision plus you can not only hear what it hears, but also “speak” on its behalf, using its speakers. Avaialble for iOS and Android devices. [$156]

5. Romo

Romo is a robot which can be controlled by an iOS device, and is primed to teach kids about robotics, mobile and game programming. It can detect faces, chase a moving target, and serve as a moving video chat platform. Users can give Romo missions to carry out and upgrade Romo to become more expressive along the way. Its company, Romotive hopes to be able to make Romo compatible with Android soon. [$129]

6. MOTO TC Rally

The MOTO TC Rally is rechargeable via USB and can be driven with your smartphone. Tilt your iOS device (iOS 6 and above) to steer your rally car or use the steering wheel on your touchscreen. The fun part about this is should you race your rally car with another, you can inflict virtual damage and change the way the car handles. The rally car comes with bonuses and attacks that you can earn as you drive. [$59.99]

7. Petcube

Hate leaving your pets at home when you go to work? With Petcube you can watch your pet, talk to it and even play with it remotely using your iOS or Android device. Petcube has a built-in camera, microphone and a laser pointer to help you do that. This interactive wireless camera lets you watch your pets pet even when you’re not home, and you can also get your friends to join in and play remotely. [$199]

8. Power 3.0 Paper Plane Conversion Kit

Always wanted your paper airplane to fly longer and go further? Maybe what you need is some help from Powerup 3.0, a conversion kit that turns a regular paper airplane into a flying drone! The kit comes with paper plane templates (they have 8) which is available on their site as well. Charge up the smart module, attach your folded plane design to the Powerup 3.0 and use your iOS or Android device to fly your plane into the horizon. [$49.99]

9. iPhone-Controlled Bug

Yes, this is a bug you can control with your iPhone. It is designed to look like an insect, although I’m not sure what kind. Anyways, it can work up to a distance of 6 meters, and it is powered with a USB-rechargeable battery. You can “steer” it with a transmitter that you can plug into your headphone jack. It moves pretty fast and can really creep your friends out; just make sure they don’t step on it! [$39.95]

20 Cute Tea Infusers That Will Make Coffee Lovers Jealous

Some of us like coffee, others are crazy about tea. We are fans of both, and more so of the wacky and cool designs tea infusers come in these days. The rectangular tea bag was invented in the 1940s and well, 70 years on we should be using tea infusers in whichever design we damn well please!

Here are 20 rather quirky and geeky designs of tea infusers you can find all over the Web. Fan of the Beatles? Try the yellow submarine tea infuser. Prefer Star Wars instead? Check out the Death Star tea infuser (it looks as cool as it sounds). If you have no special preferences, then just go with the cute animal designs instead – we won’t judge. Name your favorite in the comments or share with us any awesome-looking tea infuser you already have.

More on Hongkiat:

Arta Tea Leaf Infuser. This tea infuser takes up the whole mug, turning your cup into a plant pot. [$15.95]

Babushka Russian Nesting Doll. Two inches high, these Babushka dolls are a delight to have in your cup of tea.

Climber Tea Infuser. Made of stainless steel and full of adventure, this little guy is hanging tough from the edge of your cup. [$12]

Star Wars Death Star Tea Infuser. Apparently now the dark side serves tea. [$19.99]

Frog Tea Infuser. The froggy grin should be able to put a smile on your face. [$12]

SUCK UK Goldfish Tea Infuser. Now your pot is a fishbowl! [$9.97]

Kikkerland Robot Tea Infuser. If the frog or the climber doesn’t do it for you, maybe this robot here will. It also comes with a drip tray. [$9.21]

Fred and Friends MANATEA. The sea creature sailors allegedly mistake as mermaids (probably during a drunken state) is now in tea infuser mode. [$7.45]

Mr. Tea Infuser. A cup of tea to you is a jacuzzi pool for Mr Tea. [$9.99]

Grip-Easy Tea Infuser in Music Note Style. You can’t call yourself a fan of good music without this tea infuser. [$6.35]

Tea Duckie Tea Infuser. Rubber ducky has left the waters of your bath for the waters of your tea. [$9]

Shark Fin “Sharky” Tea Infuser. Can you hear the infamous two-tone music that signals the arrival of the great white? [$16.99]

DCI Tea at Sea Tea Infuser. Drop anchor! Available in red and blue. [$7.29]

Tea Strainer T-Man. As cute as this one is, the designer is still looking for a manufacturer for it, so if you are interested, drop him a line!

teaTanic. Don’t worry this ship isn’t going down. It’s clinging on the side of the cup for dear life. [€13]

Strawberry Design Tea Infuser. Perfect for a spot of strawberry tea! [$1.55]

Umbra Buddy Loose Leaf Tea Infuser. Look at him just hanging about, with no worry in the word – exactly how you should be taking your tea. [$14.99]

Water Lily Floating Tea Infuser. This one might be better for cups with larger rims. [CAD$10]

Tea Sub – Yellow Submarine. Bet you were looking for this since we mentioned it in the intro. Isn’t it adorable? [$6.39]

MMI25 – You Tea Infuser This heart-shaped tea infuser is the perfect gift alongside the heart-shaped “To Mug” right next to it. [$30]

Now Read:

40 Unusually Creative Mugs, Cups & Glasses

How to Test Web Navigation with Card Sorting and Tree Testing

Websites, apps, software, any product with a menu needs a way to get around. While your navigation can be fun, creative, or at times unorthodox, it always needs to be functional first. When discussing usability testing for information architecture, you’ll often hear about the two most effective tests: card sorting and tree testing.

IMAGE: NetFuel

Both tests are simple and easy to conduct, and both tests yield vital data to maximize the organization of your site. Card sorting comes before you create your structure, so you can understand how your users naturally organize your site. Tree testing comes after, as a way to validate your success or point out room for improvement.

More on Hongkiat:

Card Sorting

The beauty of card sorting is in its simplicity. All you do is write the different elements of your product on note cards or Post-It notes, then have your participants organize them in a way that makes the most sense to them.

If that’s even too much to handle, you you can also go with a usability testing tool like OptimalSort, which can analyze the data for you. Either way, the result gives you a solid understanding of how your target users would intuitively navigate your product.

IMAGE: Smashing Magazine

Card Sorting Variations

There are a few different strategies to card sorting, depending on your needs. Donna Spencer, card sorting expert and Founder of Maadmob, shares her personal experience in an article for Boxes and Arrows. For such a simple activity, there’s plenty of variation and controls that will affect the kind, and validity, of data you receive.

The initial distinction to make is open or closed, explained below:

Open Sorting – Users are provided only with the elements cards, and then are left to group them however they see fit. Once grouped, users are asked to give names to the groups themselves. This is recommended for generating new ideas since you can work backwards from the users’ natural thought processes.

Closed Sorting – As with open sorting, users are given the elements cards; however, they are asked to categorize them into predefined groups. This is recommended if you’re working within the restrictions of pre-existing categories, as with updating an already developed website structure. 

Open vs. closed is the primary decision, but there are other methods for varying your results:

Groups vs. Individuals – Groups allow users to work collaboratively, for better or worse, and can help you learn about multiple users at once; however, group dynamics might affect your results. 

Remote vs. On-location – Online software tools allow you to test more users in a faster time, yet you’re unable to directly observe their decision-making processes. On-location gives you a fuller understanding of how your users came to their decisions, but requires more planning and scheduling.

Card Sorting Guidelines

Of course there’s room for customizing your card sorting, but William Hudson, UX Strategist and Consultant, lists some general benchmarks that can apply to any method you choose. Most useful, he lists the approximate times you can expect people to sort a given number of elements:

  • ~20 minutes for 30 elements
  • ~30 minutes for 50 elements
  • ~60 minutes for 100 elements

Using this time structure, you can plan out in advance how long the tests will take to administer, once the cards are written or the software established. However, in our personal experience, these guidelines are a bit generous one of our closed card sorts involved 47 cards and four categories, but only required an average of three minutes to complete.

Another universal rule is to avoid complex language on the cards. Big words – at least words with many syllables – and technical jargon run the risk of confusing the test-takers, or them misinterpreting the meaning. While simple wording is good advice in general for the language usage of a product, it’s essential for card sorting since overly complex labeling will disrupt the natural thought processes.

A lot of experts agree on the merits of card sorting. Pierre Croft, IA and UX expert for Decibel Digital encourages card sorting because it can help deflect the bad ideas of HIPPOS (highest paid people in the room) who might not know how to build a good website. He also lists out some pointers to keep in mind when preparing your test:

(1) Don’t mix parent and child categories – In other words, use categories from the same level, or else you will confuse your participants.

(2) Have blank cards and pens handy – While this is standard procedure for open card sorting, it’s also quite useful for closed card sorting. After the formal testing is done, you can provide a couple blank cards for participants to write down additional categories. While the information might be “off-the-record,” it could bring to light some useful insights.

(3) Don’t intervene – Intervention will obscure the data, so avoid the temptation. Of course give the test-takers some guidance if they’re confused, but only for issues not related to the results.

(4) It’s OK if users don’t group everything – A lack of grouping can be just as telling as a fully complete one. If this happens, make sure you ask the user why. If you’re running a closed sort and not everything is sorted, you can also provide blank cards to see why the existing categories weren’t chosen.

(5) Set time limits beforehand – This makes scheduling easier in general, and gives the participants an idea of how much time to spend on their tasks.

(6) Limit your cards – If your website has hundreds or even thousands of pages, you can choose only first and second-level pages to keep things manageable. For example, “Contact Us,” “Terms of Agreement,” and other utility pages can be omitted since they can be found on almost all websites out there (so you wouldn’t really be testing anything unique to your site).

Tree Testing

On the opposite spectrum of card sorting, tree testing allows you to test the information architecture after its designed. Tree testing works by stripping out the visual elements of your navigation system to see how the basic structure fares on its own. With a tree test, you examine only the labelling and hierarchy of your content.

Martin Rosenmejer of Webcredible calls tree testing one of the most important steps early in the design process. In a nutshell, a tree test involves participants finding different information on a clickable sitemap (or “tree”).

Using a usability testing tool like Treejack, you then record task success (clicking to the correct destination) and task directness (certainty of users that they found what was needed). It’s a foolproof method for seeing how well your users can find their way around your product.

Description: tree5.png

As displayed above, when we redesigned Yelp’s website, we provided a tree representing the support site and then gave users 10 tasks (for example, finding information on what to do with bad reviews). Because the overall task success rate was 53% and directness was 46%, we knew that the IA needed changing – but we knew exactly where to make those changes.

Simply put, a site search bar (or a three-line hamburger menu) is just not enough if the navigation is poor because users won’t know what is available to search. The rule of thumb for web design is to make the user think as little as possible, because searching requires users to recall from memory, it negatively affects the UX.

If we’ve sold the idea of tree testing on you already, Jeff Sauro, Founding Principal of MeasuringU, goes into details about how to properly run them. He explains that tree testing is used primarily for two reasons:

(1) Determine a product’s searchability – How well can users navigate the site, and what areas cause the most problems with navigation?

(2) Validate a change – Did a recent update correctly fix the problem, or are further revisions necessary?

Tree testing is, at heart, a statistical test. As with other quantitative tests, the data will be more accurate with more participants. How accurate? Check out this chart to find the smallest margin of error within your means; we recommend aiming for 20% error or better.

Conclusion

We can’t stress enough the importance of information architecture – if the content isn’t structured logically with a simple flow, it might as well not exist. That’s why these early tests can help identify and solve the problems before they actually become problems.

The strength of tests like these is that the data is modeled after the users’ natural behavior, and when it comes to testing your IA, no tests do it better than these two.

Editor’s note: This is written for Hongkiat.com by Jerry Cao. Jerry is a content strategist at UXPin where he develops in-app and online content for the wireframing and prototyping platform. For advice and case studies on 30 different types of usability tests, check out The Guide to Usability Testing.

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7 Steps to Better Website Feedback

How to Enable Chrome DevTools App for Remote Debugging

The Chrome DevTools App is created by Kenneth Auchenberg in an attempt to take devtools out of the browser – in this case out of the Chrome browser. This application is built based on NW.js and can run on Mac OS X as well as on Linux and Windows.

There are many reasons that prompted the maker to create this but his vision consists of giving developers the convenience of remote debugging across multiple browsers, all from the same unified platform (app). The idea will take some time to catch on and materialize due to a variety of reasons (and resistance, which you can read up on at his blog).

We’ll take a brief look at the Chrome DevTools App and see what Google has to offer developers.

More on Hongkiat:

Installation

Download the Chrome-Devtools.app.zip and extract it. Double click to run. Start your Chrome Browser and enable remote debugging.

To do this on the Mac, open the terminal and run the command below:

sudo /Applications/Google Chrome.app/Contents/MacOS/Google Chrome –remote-debugging-port=9222

If you run windows, open the Command Prompt and use this command:

start chrome.exe –remote-debugging-port=9222

How to Use

When your Chrome is already open, with the remote debugging feature enabled, you can now browse to any site. For example we opened Hongkiat.com for this exercise. Next, we head over to the Chrome DevTools app window, and refresh this list (the button is at the bottom right side).

Now you will see the Hongkiat.com link listed (as shown below).

Now click the ‘Go’ button. You will be taken to a new window. That’s it. You have the Chrome DevTools app up and running already. What you’ll see here is the same as when you “inspect element”’ on t he Chrome browser.

And from here you can use the Chrome DevTools app just like using DevTools on Chrome natively: you can inspect the DOM element, debug JavaScript, work with Console and more.

What’s next?

This app is still very experimental. But for now, the idea of taking the DevTool out of Chrome allows developers to treat the app as a functional editor, and work with other runtimes like node.js and iOS. For more possibilities, you can check out Auchenberg’s train of thought here.

50 Clean And Minimalistic WordPress Themes

Complexity in design is not everyone’s cup of tea. Banners, sliders, and other design elements distract users from your work. Minimalistic, clean sites allow your content to shine without unnecessary details bogging it down. These kinds of themes are perfect for showcasing your work, without all that clutter.

And that’s why in this roundup, I’m showcasing 50 clean and minimalistic WordPress themes for use in blogging, as a portfolio, for a photography site, magazines, corporate sites and more, to fit any taste. Here you’ll find 30 free and 20 premium clean minimalistic themes. You can be sure that a site built using one of them will load fast and Google would love it!

More on Hongkiat:

So, scroll down and enjoy the showcase.

Free WordPress Minimalistic Themes

1.Globaly by TemplateMonster

Globaly is a free responsive WordPress theme with dark yet clean minimalistic design.

2. Ares by FreeWPThemes

Ares is a corporate theme with a beautiful full-width slider on the homepage, a light airy look, and of course responsive design.

3. StanleyWP by gentsthemes

Stanley is a Twitter Bootstrap WordPress theme best for showcasing work portfolios.

4. Daily by Robert Brodziak

Daily is a minimal blogging or portfolio theme, depending on your needs.

5. Expositio by Wpshower

Expositio is a responsive portfolio theme made for designers and photographers with big clean layout.

6. Dazzling by FreeWPThemes

This elegant, clean theme is the perfect choice for blogs and magazines. The slider in the header can be used for featured posts.

7. Pure WordPress Theme by Webdesigner Depot

Pure is a quite simple, creative and playful theme for all creative needs. It’s a great solution for online portfolio.

8. Pho WordPress Theme by Slobodan Manic

Pho is a gallery-style minimalistic theme suitable for designers and photographers.

9. Cudazi Mono by Curt Ziegler

Cudazi is a fashionable clean WordPress theme with custom post types, widget areas and drag and drop menus for more flexibility.

10. Fukasawa by Anders Norén

Fukasawa is a minimal blogging theme for photographers and other creatives.

11. Lawyeria Lite by codeinwp

Lawyeria Lite is a clean, responsive, multi purpose WordPress theme perfectly suitable for lawyers and other corporate purposes.

12. Bravo by wpmultiverse

This theme was created for business blogging. It has a light, clean design to make sure you look professional and elegant.

13. Swell Lite by David Morgan

Swell Lite was created for bloggers and it has an extremely minimalistic design. The theme features full width custom header photo, and an option to add your own logo on it.

14. PlumBelt Lite by codeinwp

This theme was made for plumbers, according to its name. In any case, it could be used for any other small business, craft, teaching, and others. It features a responsive layout, featured image and sticky posts.

15. Sydney by FreeWPThemes

Sydney is a great business theme which can be used by both businessmen and freelancers. It provides a lot of customization possibilities to add your personal touch.

16. Whimsy Framework by Natasha K. Cross

Whimsy Framework is a parent theme for WordPress that has everything a normal theme has to offer. It has custom widgets and responsive customizable design which work great for business needs.

17. Torch by MageeWP

Torch is a business theme with 100% responsive design. You can change the color scheme in just single click. Also, it’s SEO-friendly and well-coded.

18. Enlightenment by One Designs

Enlightenment is one more multi purpose theme in this collection. It features a huge number of features, such as custom logo, menu icons and descriptions, custom layouts, portfolio, image lightbox and infinite scroll.

19. IH Photographer by Rohit Tripathi

This theme was created with a purpose for portfolio in mind.

20. TA Portfolio by ThemeArt

TA portfolio is a one-page WordPress theme with minimalistic clean design. Perfect as portfolio sites for designers, freelancers and other small businesses.

21. Codium Now by henri

Codium Now is a WordPress theme featuring Pinterest-like design. You can easily add header to this theme, change the colors and background, add various widgets to enhance the features.

22. CORDILLERA by MageeWP

This minimalistic theme with flat design suits any kind of business purposes. It’s responsive and fully customizable.

23. Tesla by FreeWPThemes

Tesla is a simple yet elegant theme for bloggers with a portfolio section. It can be used for any creative purposes. It features a small slider in header, and nice thumbnails to showcase your work in portfolio section.

24. Zerif Lite by codeinwp

Zerif Lite is a responsive flat one page theme excellent or creative agencies, freelancers, and business portfolios. It’s a Retina-ready and SEO-friendly e-Commerce theme.

25. Asteria Lite by towfiqi

You may build any type of website on the base of this theme: business, blog, or portfolio. It has three page templates, responsive design, and many other useful features.

26. White Paper by JustPX

White Paper is a clean laconic theme for bloggers.

27. Sensible by FreeWPThemes

Sensible is a WordPress theme “for almost anything.” And that’s true. Its modern, clean look makes it suitable for any type of sensible business.

28. Keratin by themecot

Keratin is a masonry grid-based theme with clean light style. It’s suitable for blogs, magazines, and newspapers.

29. The Thinker Lite by Anariel Design

The Thinker Lite is a WordPress theme made for bloggers. It has a clean minimalistic design focusing on content.

30. Aileron by themecot

Alieron has clean design and modern look suitable for creative bloggers.

Premium Themes

31. DW Jason by Design Wall

DW Jason is an elegant WordPress theme which can be used to create your own portfolio or resume online. It’s fully responsive and retina ready to fit in any screen resolution. [$49]

32. Trail by Theme Trust

This is an awesome portfolio theme with a focus on huge images and typography. [$59]

33. Pure by Theme Trust

Pure theme is up to its name. It’s a super minimalistic and a clean theme for bloggers. [$59]

34. Milo by Minimal

This delightful, clean feature-rich theme is an excellent choice for portfolio of any type. Moreover, it’s WooCommerce ready and mobile-friendly. [$99]

35. 7th floor by Theme Fashion

7th Floor is a modern-looking nice WordPress theme for blogging. You can change fonts, sizes, and colors with ease. [$35]

36. Hero WordPress Theme by Theme Trust

Big slider and thumbnails showcasing images is all you’ll find in this theme. [$59]

#37 Flat WordPress Theme by themify.me.

Flat WP theme is all about… flat. This theme is minimalistic, despite the range of color it uses. See for yourself. [$49]

38. Chic & Modern by Theme Fashion

Chic & Modern is a luxury blogging theme for fashionistas. It’s fully customizable to fit in your needs. [$30]

39. Infinity by Theme Trust.

If you’re looking for really clean portfolio theme – you found it! Infinity features project filtering and infinite scrolling for blog posts. [$59]

40. Mex by cththemes

Mex is a simple and elegant WordPress theme for business with full-size image header. [$43]

41. Nudge by wearesupa

Nudge is a brand new theme created in 2015. It is fully responsive parallax scrolling theme for any business or creative purposes. Colors, fonts, images and any other website elements can be customized. [$58]

42. Gear by Theme Trust

Gear is a new sleek clean theme for online store. It can be used for a store of any kind starting with candies to clothing. [$59]

43. Bokeh by ImanGM

Boken is a fantastiс unusual theme for blogging and business. It has unique page navigation that will help your site stand out from the crowd. [$43]

44. Bloc by Alley-Cat

Bloc is a responsive, clean and minimal theme with multiple post types, beautiful icon sets and a page builder. The theme portfolio features make it possible to display any work of creative professionals. [$48]

45. Accessories by aztheme

The theme pack includes unlimited color skins, a revolution slider, mega menu, visual composer, contact forms support, multiple blog formats, 600+ Google Web fonts, and quick product view. [$58]

46. Superba by THBThemes

This theme was originally designed for photographers. This theme is WooCommerce compatible. Moreover, it has 2 blog layouts, 3 different portfolio layouts, a portfolio filter, unlimited sidebars and a child theme version. [$58]

47. Milk by Pryanikov

Milk is a clean Pinterest style theme which suits to photographers, designers, and any other creatives that need to showcase their projects online. You can play around with various hovers, color palettes, and fonts. [$43]

48. Peliegro by Peenapo

Peliegro is a modern, clean blogging theme that will help your content stand out! It can be used for personal blogs, newspapers, magazines, or even portfolios. [$43]

49. VAN – Minimalist Agency by Theme-Studio

This light, clean theme is the best for those who want to create a portfolio with WooCommerce options. Responsive design makes it looks beautiful on any screen resolution. [$58]

50. Expressivo by Knacc

This fully responsive clean theme for blogging will make your content shine. It features a clean style and tiny details, like blue icons and elegant logo that make all the difference. [$48]

Now Read:

20 WordPress Themes To Revamp Your Site For 2015

Fresh Resources for Web Developers – April 2015

How’s your (friendly reminder) April Fool’s Day this year? Well, for the rest of us who aren’t into pranks, here’s the latest instalment of fresh resources for web designers and developers.

For April we have a number of great apps to increase productivity, a library that improves user experience with large datalist, a Photoshop extension that gives you weather widgets, and a handy web tool that caches web font.

CSS Ruler

There are a number of unit measurements in CSS; a few are fixed while some others are relative such as em, rem and ch. CSS Ruler is a tool where you can visually compare the units scale with one another.

ResponsiveJP

ResponsiveJP features a number of responsive websites from Japan, mainly as a reference for web designers who are finding it hard to work out responsiveness when it comes to non-Latin typographical content. It helps you to stretch your perspective and get an inside look at eastern web design trends as well.

Google Fonts Alternate

Many Google services are blocked in China, Google Font included — it is almost certain that Google Font will not render properly in China. If you would like serve the Google Font collection in China mainland, point the font stylesheet to an alternate source from Useso, for example:

 // Google Font stylesheets. <link href='http://fonts.googleapis.com/css?family=Open+Sans' rel='stylesheet' type='text/css'> // Alternate link <link href='http://libs.useso.com/css?family=Open+Sans' rel='stylesheet' type='text/css'> 

Good luck and godspeed!

Muir Icons

Muir Icons is a collection of icons designed to match OS X Yosemite. Named after John Muir, a naturalist and activist who helped preserve the original Yosemite, yes, that national park in the U.S. At the time of this writing, there are already 3 volumes of these icon sets released. Each consist of popular app icons such as Adobe Creative Suites, Twitter, Sketch, Skype and SublimeText.

CouleursApp

CouleursApp is a small app that allows you to pick up colors anywhere on your screen. It improves the built-in Mac color picker app. It supports a number of color formats including Hex and the UIColor of Swift.

Compatibility: OS X 10.10 or above

Weather

Weather is a Photoshop extension that adds weather widgets onto your Photoshop workspace. It is a handy tool to help you decide whether it is time to leave your desk and go outside to enjoy nice weather.

Compatibility: Photoshop CC

Awesomplete

Awesomplate is a JavaScript library that mimics HTML5 <datalist> element. You can add a list of suggestions within an input element that will appear as your user types. It ia a practical approach to improving user experience, particularly when dealing with a large datalist.

Compatibility: IE9+, Chrome, Firefox, Safari 5+, Mobile Safari.

Noizio

Noizio is an app with a collection of natural noises: sounds of the wind, ocean and thunderstorms. It may help you better focus on your work by providing a calm environment which allows you to detach from the hustle and bustle of a pressurized working atmosphere. At least, it did for me.

Compatibility: OS X 10.8 or above

Hocus Focus

This is one for those who find it hard to focus. HocusFocus is an app that will cleverly hides windows and workspaces within your OS X desktop for a certain period of time, leavng only the window(s) you use most. It makes you more efficient, cleans the clutter from your desktop and helps you focus on your work.

Compatibility: OS X 10.10 or above

PixelCounter

PixelCounter counts the pixels in your images. Just drag and drop an image or a whole directory of your project into the app, and it will count and add up all the pixels in your JPEG, PNG, WebP, GIF, and even SVG images. Now, if we could only start a trend where we charge clients by the pixels… hmm.

Compatibility: OSX 10.8 or above, Windows 7 or above, and Linux (Coming Soon)

UI Blurbs

UIBlurbs generates a fictitious user profile and is the perfect web app to use in tandem with UIFaces and UINames for building a design prototype.

localFont

localFont is a webapp that improves web font performance. As you drag and drop a font (.woff, or .ttf), it will encode and embed the font in CSS. It also generates a few lines of JavaScript that will cache the font in the user’s localStorage (read our previous tutorial about using Cookie & HTML5 localStorage).

15 Useful Web Typography Tools, Libraries And Frameworks

Dealing with typography on the web has been real quirky. Each browser has their own algorithm to render fonts which could lead to unexpected discrepancies. There are only a few CSS properties you can use to have some control over fonts, such as font kerning, font smoothing, in creating DropCaps etc. On top of that, we have to deal with a lot of layout issues when it comes to fonts.

The good news is there are resources that you can use to take over the wheel when it comes to website typography. Here are 15 web tools, libraries and frameworks you can use to that end.

More on Hongkiat:

TypeRendering

In a nutshell, TypeRendering works similar to Modernizr, except it only identifies the browser engine for font rendering. This library adds custom classes based on its discoveries which can be used to apply specific styling rules for type rendering.

KerningJS

Kerning is not customizable for use on the web yet – font-kerning support is still poor at the moment – but a new standard property is coming our way. KerningJS is a Javascript library that gives you a few new properties for better kerning control, for example -letter-kern.

 #heading { -letter-kern: 1px 1px 0 0 0 1px 0 2px 0 0 0 0 0; } 

Keep in mind that the above example is non-standard and only applicable with KerningJS.

DropcapJS

Though creating a dropcap is doable with current CSS standards, the outcome is not perfect yet. Sometimes it is downright undesirable. DropcapJS, developed by Adobe Web Platform, is entrusted with the mission to allow web designer to apply a perfect dropcap easily.

LiningJS

LiningJS is a JavaScript library which adds the line class in each line of your paragraph. This allows you to style the line separately. It simulates the idea of ::nth-line(), ::nth-last-line() and ::last-line pseudo-classes which is not present in CSS still. Here is an example how we style the first line of a paragraph with LiningJS:

 p .line[first] { font-weight: 600; text-transform: uppercase; } 

In addition, LiningJS also supports Chinese paragraph flow.

UnderlineJS

UnderlineJS is a JavaScript library that makes the text underline better. Check out the demo to see what I mean, be sure to hover over the lines. Compare the demo with the underline output of current CSS text-decoration standard and you’d probably be a fan of underlineJS too.

FlowType

This plugin will dynamically adjust font size based on a specific wrapper width. FlowType helps you apply an ideal number of characters per line at any screen width. The library comes with options where one can set min/max screen width, min/max font size, and font ratio.

HatchShow

HatchShow expands the size of a font to fill the entire width of its container. The plugin works out of the box with the algorithm; in a nutshell, it measures the container width, and length of the font character and appends the proper size of the font.

GridLover

GridLover is a great tool to generate basic styles for typography arrangement (size, line height, and margin) with an easy slider UI. It generates the styles in SCSS, LESS, and Stylus so you can include it right away in your project regardless of which CSS-Preprocessor you use.

TypeScale

TypeScale is an online tool that will help you to easily determine the right font size for your website. The tool provides a simple intuitive GUI to insert base font size, scale, and font family you want to use. The results will be visualized for you so you can play around with the scale, to get just the right value. Just grab the CSS once you are done.

Modular Scale

Modular Scale is a tool to generate ideal font scaling for body and heading text. It outputs in Sass which should be used in conjunction with its Sass library. Alternately, you may use JavaScript .

Font-To-Width

Font-To-Width (FTW) is a Javascript library that makes a font fit to its width container. It will determine the font size along with the word spacing required for the font. Should you want to make a pretty headline, this is the library you may want to try.

FFFFallback

FFFFallback, a handy tool that allows you to find the best font stack that will degrade gracefully. The tool comes in a form of a bookmarklet, which will analyze the font family on your page and suggest a set of fonts to use as fallback.

Font Pair

Google Font is one of the most popular web font library used by millions, and host above 500 font families. Font Pair is a collection of paired Google Fonts, where you can find a various combination between font families and type faces easily. Font Pair makes choosing font pairing a little less overwhelming.

TypeSettings

TypeSettings is a collection of CSS rule set to define proper font scaling, vertical rhythm, and responsive ratio of typography. TypeSettings comes in Sass and Stylus which allows for flexibility to meet your project needs by adjusting the variables.

Typeplate

Typeplate is probably one of the most complete starter kit for setting up typography. Typeplate ships with a handful of basic typographic styles that address scaling, colors, small capital, dropcap, indenting, hyphenation, blockquote, code block and a lot more stuff.

Now Read:

Showcase of Web Designs with Beautiful Typography

5 Simple Ways to Boost Your Online Sales Revenue

Have you ever seen your analytics reports and noticed that your store isn’t making enough money? How did that feel? It must have felt pretty bad. In those moments of desperation, you’d probably do anything to increase your store’s revenue.

IMAGE: Olly

What happens next is pretty common: you start looking for different ideas on how to increase your revenue, but find nothing useful. The truth is: it’s pretty hard to find simple tactics to use for increasing your revenue. Sure, implementing a $100K PPC campaign might help, but it’s not simple nor realistic for your needs.

That’s why in this post I want to show you 5 simple ways you can start increasing your e-commerce store revenue today. These tips are so simple, you will have no excuse to not put them into action to improve your store.

More on Hongkiat:

1. Add Relevant Upsells

First of all, an upsell is a sales technique where you offer your customers the chance to purchase upgrades (better features, better specifications, more volume) or to get the more expensive versionof what they’re buying, so you can maximize the value of their purchase (higher price).

In order to add relevant upsells into your store, there are four main things you need to do:

  1. Make a list of all the products you sell.
  2. Separate those products into two lists: the regular ones and the expensive ones
  3. Tie the better products with the regular ones
  4. Talk to a developer to add a section in your product page, where you show your upsells

Depending on which e-Commerce platform you use, you can skip all those steps and add a plugin that automatically gets it done for you. For example: Product Upsell by Shopify, OpenCart’s Also Bought, and Magento’s offering, Automatic Cart Upsells & Cross-sells.

Upsell In Action

As always, the best way to see an upsell in action is to go to the king of e-Commerce sites: Amazon. Let’s say you want to buy a great DSLR camera. You select the Nikon D5500 as a great option to buy. This is what you’ll see at first.

So you’ve found what you’re looking for but wait, if you scroll down, you’ll see the following upsells:

And more:

In these two cases you’ll notice that not every product is more expensive. In some cases, they even add cross-sells (see next point). That’s fine. What this says is you don’t have to show your upsells and cross-sells separately; you can use them together to have a bigger impact in your sales. The key is that you must offer items that can add value or improve the user experience of your client.

Why This Is Simple

Because once you add your upsells to your website, it’s just a matter of waiting for them to take effect. Of course, you need to check daily or weekly how they’re performing. Also, the best thing you could do before launching your upsells is testing them first.

Create an A/B test, where in the A version your store is the same as usual, and where the B has the upsells. If you see a decrease in the average order value, or in conversion rates in the B version, then don’t make your upsells public. On the other hand, if in that same version you start to see bigger average order values and revenue, then publish it and start making more money.

Further Reading

2. Add Timely Cross-sells

If upsells represent upgrades and more expensive versions of a product a customer is buying, a cross-sell is giving options for add-ons.

In the previous example I showed you how Amazon tries to sell you other expensive items related to the one you wanted to buy at first. But as you saw, they don’t always show more expensive items next to your desired product. Sometimes they show other similar items – that’s cross-selling.

In the previous case, cross-sells for the Nikon D5500 are lenses, bags and flashes, among other accessories. Cross-selling works so good for Amazon that it’s said it’s responsible of 35% of their e-Commerce revenue back in 2006.

Adding cross-sells to a store is a more difficult process than adding upsells, because there are many ways to choose what products to cross-sell. For instance, an online store that sells sneakers has many cross-selling options to choose from, such as socks, laces, jeans, other sneakers from the same brand, similar sneakers from other brands.

However, just because it’s hard it does not mean you can’t do it. If you want to add cross-sells to your store, I’ll give you two recommendations:

  1. Take the time to adapt the upselling steps I previously mentioned to cross-selling (be patient)
  2. Depending on the e-Commerce platform of choice, buy and install a cross-selling plugin for instance:

Similarly to upselling, the key to effective cross-sells is providing value to the customer’s life – think about the customer first before suggesting a cross-sell.

Why This Is Simple

Because cross-selling has shown its effectiveness in many companies, including Amazon. Also, just as with Upselling, once you set up your cross-sells, there’s nothing much to do except to analyze its impact on your company’s revenue. If it goes up, it works. If it doesn’t, then there’s something wrong that needs to be fixed (probably something related to your site’s usability, a coincidence, or a bug).

Further Reading

3. Define Your Best-Selling Products

Do you really know which your best selling products are? You may think this is an obvious thing, but it’s usually not. Knowing your best sellers is key, because it helps you understand your customers better, and most importantly, it allows you to know what you should be selling more of.

To learn which are your best selling products, access your Google Analytics account, and go to Conversions > e-Commerce > Product Performance. In that report, you can choose to sort your products by units sold and revenue, among other metrics.

Once you know which your best selling products are, it’s just a matter of selling more of them, either by setting up paid ads, upsell and cross-selling them, among other strategies.

Why This Is Simple

Because knowing what is selling the most is the best way to know what you should keep selling. Also, it helps you understand your customers better.

Further Reading:

4. Test Your CTA

Testing is a great way to increase revenue because it takes a specific element of a page, and it shows if a change in that element can help you increase your conversion rates. If it does, you get an increase in your revenue. If you don’t, well, you don’t.

You can test many elements of a page, such as:

  • Your site structure
  • Your product page structure
  • Your checkout process
  • Your product’s copy

However, I say, to test specifically your call-to-actions (i.e. the buttons that your customers click when they want to buy your products) because it’s the simplest thing you can test that can help you increase your revenue. Also, testing your call-to-actions (aka. CTA’s) is a pretty straightforward process.

More on Hongkiat:

Testing Call-To-Actions

1. First and foremost, develop a hypothesis that you want to test, like “I think changing the CTA’s color to blue will increase its contrast, which will increase the CTR (click-through rate).”

2. Construct a plan of action to test those hypotheses, in which you define what tasks need to be done for your tests to take effect. For example:

3. Run the test.

4. Finally, analyze the results. If the newer version (the B version) increased your conversion rates, then keep it. If not, reject it.

(Even though testing is a complex topic, I don’t want to make things more complicated than they are. For your needs, this is pretty much you need to know.)

There are three things you should test in your CTA’s:

  • Your CTA’s copy (e.g. ìBuy Nowî versus ìAdd to Cartî)
  • Your CTA’s size
  • Your CTA’s positioning (at the right of the image, below the description, etc.)

To see the power of testing your CTA’s, and how you should do it, take a look at this post.

Read Also: Essential E-Commerce Tools To Understand Your Users Better

Why This Is Simple

Because testing is a simple process: come up with a few hypotheses every month, deploy the tests in your site with the help of Optimizely, wait a few weeks, and boom, you have increased your revenue. Of course, tests can fail, so if they do, don’t panic. In fact, I’d say most of them will, especially when you first start. Keep doing it until you find a winning formula.

After a while, you’ll develop a sixth sense about your customers, and you’ll start to know what things will probably increase your conversion rates.

Further Reading:

5. Add Better Product Images

What’s the one big advantage offline shopping has over its online counterpart? The product’s touch and feel .

If I had to choose one serious advantage of offline shopping it is that I can see, feel, touch, smell (yeah, it sounds weird, but hey, I don’t judge) and even try the products on. The closest thing to that experience online are the product’s pictures and things like:

  • Different angles
  • Zoom in
  • Product test, or in action
  • A video
  • A 360 degree view of the product

Of course, don’t forget to make the images look professional. Things like lighting, filters and custom touches make a huge difference when it comes to making a product look good. That’s why it’s important to always err on the side of choosing professional photographs instead of taking a DIY solution.

If you can’t afford a professional photographer, try what Richard Lazazzera did with his own store.

Why This Is Simple

Adding extra images (2 or 3) can give your customer the final push to buy a product. Every time you add or change something to your store, think about how this will affect your customer. Competing with offline stores is hard. Make your customer’s experience as flawless and simple as possible.

Further Reading

Have you ever tried any of these 5 ways I talked about in this post? If so, what was your experience? Please share your answers in the comments below.

Editor’s note: This is written for Hongkiat.com by Ivan Kreimer. Ivan is the Growth Marketer at Receiptful, an API that lets you send beautiful email receipts that help increase an e-Commerce store’s revenue with the usage of targeted, marketing messages and upsells.

Now Read:

10 Online Services To Sell Digital Products Effortlessly