Opioids: Origins, Naturally Occurring, and Semisynthetic PDF

## Chapter 11: Opioids - In this chapter, you will learn about a class of drugs referred to as opiates or opioids. - These terms are often used interchangeably to denote any drug, natural or synthetic in origin, with properties similar to opium or its principal active ingredient, morphine. - Tech...

## Chapter 11: Opioids - In this chapter, you will learn about a class of drugs referred to as opiates or opioids. - These terms are often used interchangeably to denote any drug, natural or synthetic in origin, with properties similar to opium or its principal active ingredient, morphine. - Technically *opiate* should be used only to refer to naturally occurring constituents of opium, while *opioid* is used in reference to all opiate-like drugs, including semisynthetic derivatives and fully synthetic substances that bind to opioid receptors. Often this distinction is not made, and this text will use the all-encompassing term opioid to refer to all drugs in this class. - The opioid family of drugs is also commonly referred to as narcotic analgesics or just narcotics. - This term derives from the Medieval Latin word *narcoticum* meaning to make stiff or numb. - Technically, a narcotic is a drug that causes sleep. - The narcotic analgesics produce analgesia (a loss of sensitivity to pain) and make a person sleepy. - This name distinguishes these drugs from non-narcotic analgesics such as acetylsalicylic acid (Aspirin) and acetaminophen (Tylenol), which also relieve pain but without causing sleepiness, and they are not opioids. - One difficulty with the word *narcotic* is that, over the years, it has acquired a new meaning and is now commonly used to refer to many drugs that are habit-forming. - It has also developed a distasteful connotation; thinking about narcotics conjures up images of depraved addicts who are slaves to the drug and its suppliers. - This misuse of the term has been given legal sanction, further increasing the confusion. - In the United States the *Harrison Narcotic Act of 1914* defined both marijuana and cocaine as narcotics, along with opioids. - In Canada the *Narcotic Control Act* passed in 1961 regulates the use of many habit-forming drugs, some of which, like marijuana, are not narcotics at all in the sleep-producing sense, but in a legal sense they have become "narcotics." - Because it has so many meanings and connotations, the term narcotic will be avoided. ### Origins and Sources of Opioids - **Naturally Occurring and Semisynthetic Opioids:** - A poppy named *Papaver somniferum* is the principal natural source of opium. - The plant manufactures opium for only 10 days in its life cycle, after the petals of its flower have fallen off, so the substance must be gathered during that brief time span. - Scratches made in the seedpod of the poppy exude a milky fluid called latex (this can be seen in Figure 11-1). - The seedpod is "scored" one day and the coagulated substance is scraped off the next, compressed into cakes and dried. - This is opium. - The opium poppy originated in Asia Minor but now is grown throughout the world in countries with similar climates. - India is the largest producer and only licit supplier of opium to the world’s markets, exporting between 300 and 600 tons annually over the past decade. - The largest importing country is the United States, which purchased roughly 60% of India’s exported opium in 2013, followed by Japan, which imported 36%. - The bulk of imported opium is used for the extraction of its active ingredients. - Afghanistan, Laos and Myanmar are the countries in which the vast majority of illicit poppy cultivation occurs. - Poppy straw, which consists of all parts of the Papaver somniferum plant except the seeds, is another raw source of active opioid ingredients. - Poppy straw cultivation and export has increased in recent years with Australia being the leading producer and the Czech Republic the main exporter. - Opium poppies (left) and poppy seedpods that have been scored right. The white substance seeping from the cuts in the seedpods latex, which contains opium. - **Of the several active constituents of opium and poppy straw, morphine is the most abundant.** - Morphine was first isolated from opium by the German chemist Frederick Sertürner. - He called it morphium after Morpheus, the Greek god of dreams, and published his findings in 1805. - Though the significance of his work was not immediately recognized, in 1831, Sertürner was awarded a prize by the Institute of France for his discovery. - Heinrich Emanuel Merck (founder of the German company Merck pharmaceuticals) began manufacturing and selling morphine commercially in 1827. - Today, morphine is widely used medically for pain management and is sold under its generic name morphine sulfate as well as a variety of trade names. - The various formulations of morphine (and other opioids) are listed in Table 11-1, along with common medical and recreational routes of administration. - The opium supplied by India contains morphine in concentrations of about 9.5-12%. - Analysis of opium cultivated throughout Afghanistan during the early- to mid-2000s found that its morphine content was approximately 14.4%, though some samples contained far less (5.1%) and some far more (24.8%). #### Table 11-1 Opioid Drug Formulations and Routes of Administration | Opioid Drug | Routes of Administration for Pharmaceutical Formulations | Common Recreational Routes of Administration | |---|---|---| | Morphine | Oral (tablet, capsule); Rectal (suppository); Parenteral (i.v., i.m., s.c. injectable solution)| Injected, swallowed, smoked | | Heroin | Parenteral (i.v.,i.m., s.c.)* | Injected, snorted, smoked| | Codeine | Oral (tablet, capsule, syrup); Parenteral (i.m., s.c. injectable solution)|Injected, swallowed (often mixed with soda or flavorings)| | Hydrocodone | Oral (tablet, capsule, syrup)|Injected, swallowed, snorted| | Oxymorphone | Oral (tablet); Rectal (suppository); Parenteral (i.v., i.m., s.c. injectable solution)|Injected, swallowed, snorted| | Oxycodone | Oral (tablet, capsule); Rectal (suppository) | Injected, swallowed, snorted| | Fentanyl | Oral (lozenge, sublingual tablet, buccal tablet, buccal film, sublingual spray); Intranasal (spray); Parenteral (i.v., i.m. injectable solution); Transdermal (patch) | Injected, snorted, smoked| | Methadone | Oral (tablet, solution); Parenteral (i.v., i.m., s.c. injectable solution) | Injected, swallowed | | Buprenorphine | Oral (tablet, sublingual tablet, buccal film); Parenteral (i.v., i.m.); Transdermal (patch) | Injected, snorted, sublingual | *Heroin is not used medically in the United States, but is prescribed (as diamorphine) as a second-line maintenance treatment for opioid addiction in other countries. - **Heroin (diacetylmorphine or diamorphine) is a semisynthetic derivative of morphine, synthesized by adding two acetyl groups to the morphine molecule.** - About 10 kg of dry opium would be required to produce 1 kg of pure heroin. - Heroin is about 10 times more lipid soluble than morphine and therefore reaches the brain more quickly and in higher concentrations to produce a greater analgesic effect. - Common forms of heroin include a white or brownish powder and a black sticky substance known as "black tar heroin." - In the United States heroin is a Schedule I drug that is illegal to manufacture, possess, or sell and cannot be prescribed for medical use. - In Canada and the United Kingdom, the possession and recreational use of heroin is illegal but, under restricted conditions for therapeutic purposes, it may be legally prescribed. - When used medically, it is usually referred to as *diacetylmorphine* or *diamorphine*, rather than heroin. - Other semisynthetic morphine derivatives include *hydromorphone* (e.g., Dilaudid), *benzylmorphine* (Peronine), and *ethylmorphine* (Dionina). - **In 1821, while experimenting with a new process for isolating morphine, French chemist Pierre J. Robiquet serendipitously isolated another of the poppy’s natural active ingredients-codeine.** - The codeine content of opium is less than morphine, averaging about 2.5% of Indian opium and 5.9% of Afghan opium content. - Most of the codeine currently being manufactured for medical use is derived from morphine through a semi-synthetic process rather than in its natural form from opium or poppy straw. - In the United States morphine and codeine are legally available only by prescription. - In Canada, the same is true for morphine, but codeine is available in small quantities without a prescription in some over-the-counter painkillers and cough medicines (antitussives). - This is also the case in other countries such as the United Kingdom, Australia, France, and Japan. - Mixing prescription-strength codeine cough syrup with soda or alcohol has become an increasingly popular recreational use of the drug by youth. - Street names for these concoctions include *syrup*, *sizzurp*, *purple drank*, and *lean*, referring to the typical slumped posture of intoxicated users. - Hydrocodone is a semisynthetic opioid derived from codeine and is the most frequently prescribed opioid in the United States. - Hydrocodone is equally if not more effective than codeine at suppressing cough and nearly equivalent to morphine in its ability to relieve pain. - Hydrocodone is marketed under several trade names, including *Vicodin* (when combined with acetaminophen), *Vicoprofen* (when combined with ibuprofen), and *Alor* (when combined with acetylsalicylic acid). - It is also widely used illegally as a recreational drug. - **Thebaine, also known as paramorphine, is a third active constituent of Papaver somniferum.** - Compared to morphine and codeine, it is present in much lower quantities, averaging 1.0-1.5% of Indian opium and 4.0% of Afghan opium content. - Since 1999, poppy straw has replaced opium as the major source of thebaine. - Unlike morphine and codeine, thebaine is not used therapeutically in its natural form as it may cause convulsions when taken in high doses. - It is, however, used to make various semisynthetic opioids such as *buprenorphine*, *etorphine*, *naloxone*, *naltrexone*, *oxymorphone*, and *oxycodone*, amongst others. - Of these, *oxymorphone* and *oxycodone* are likely the most familiar but also the oldest of the thebaine derivatives, having been first synthesized in 1914 and 1917, respectively. - Oxymorphone is marketed as *Opana*, which is available in both immediate- and extended-release tablets, and as *Numorphan* in suppository and injectable formulations. - Oxycodone is combined with non-opioid analgesics and sold under a variety of trade names, including *Percocet* and *Endocet* (when formulated with acetaminophen) or *Percodan* and *Endodan* (when formulated with acetylsalicylic acid). - In Germany and Europe, it is combined with the opioid-receptor competitive antagonist *naloxone* and marketed as *Targin*. - The addition of naloxone lessens the adverse gastrointestinal effects of oxycodone by blocking gut opioid receptors and also deters injected or intranasal use because of naloxone’s ability to precipitate acute withdrawal when sufficient amounts quickly enter the bloodstream. - Oxycodone is also sold in stand-alone formulations, the most notorious of which is *OxyContin*-a high-dose, controlled-release, long-acting, orally administered tablet. - First marketed in 1996, OxyContin was designed to provide extended relief for sufferers of moderate to moderately severe pain. - Opioid abusers soon discovered that crushing the tablet and swallowing, snorting, or dissolving and injecting it intravenously allowed for the entire dose of oxycodone to be experienced at once. - When used this way, oxycodone is highly addicting and very dangerous and misuse of OxyContin caused numerous accidental overdoses throughout the late-1990s and 2000s. - In 2010, a new tamper-resistant formulation of OxyContin was introduced and marketed under the trade names *OxyNEO* (in Canada) and *OxyContin OP* (in the United States). - The reformulated tablets are considered abuse-deterrent because they have a physiochemical barrier that prevents them from being broken or crushed into a fine powder (as was possible with original OxyContin), they resist dissolving in water, and form a gel-like substance when heated, all of which discourage snorting or injecting the drug. - Though some drug misusers found ways of defeating the physiochemical deterrents and continued to inhale or inject oxycodone, the U.S. Food and Drug Administration determined in 2013 that the tablet’s reformulation does indeed make certain forms of abuse more difficult and approved abuse-deterrent labeling for the product. - During and following the rapid phase-out period of original-formulation tablets, OxyContin abuse rates plummeted as many addicts shifted to using other oxycodone formulations, other prescription opioids, or heroin. - **A number of opioid drugs are neither found in nor derived from opium or poppy straw and bear little chemical resemblance to morphine.** - Yet, these laboratory-made compounds stimulate opioid receptors with varying degrees of receptor selectivity, binding affinity, and analgesic or antitussive effectiveness. - One well-known synthetic opioid is meperidine (Demerol), called pethidine in the United Kingdom, which is used to treat moderate to severe acute pain. - It has a slightly faster onset and a shorter duration of action compared to morphine. - Another synthetic opioid is fentanyl which was marketed in the 1960s as *Sublimaze* and used primarily as an intravenous anesthetic until the 1990s. - Since then, fentanyl-containing tablets, lozenges, sublingual spray, and controlled-release preparations (patches) have expanded the drug’s use as an analgesic for severe-pain sufferers, including many cancer patients. - In recent years, outbreaks of fentanyl overdose deaths in North America have pushed the drug into the spotlight. - Between 2005 and 2007, more than 1000 deaths, mostly in Chicago, Detroit, and Philadelphia, resulted from use of non-pharmaceutical, counterfeit fentanyl tablets synthesized in a single clandestine laboratory in Mexico. - The tablets were found to contain fentanyl mixed with heroin. - The most recent 2013-2014 outbreak in the United States covers a much broader area and involves both fentanyl and its analogs (structurally similar compounds, such as acetylfentanyl) being bought as heroin. - A spike in deaths also occurred in Canada between 2013 and 2015 from use of fentanyl tablets purportedly sold as *OxyContin*. - Like earlier deaths, these most recent U.S. and Canadian outbreaks are the result of clandestinely manufactured or illegally imported substances. - **Compared to heroin, fentanyl is 30-50 times more potent, meaning that a relatively small dose can be lethal, even in an opioid-tolerant individual.** - Licit users of fentanyl can overdose as a result of taking the drug in higher-than-prescribed doses or in combination with other drugs such as alcohol. - In April, 2016, the musician Prince died of accidental fentanyl overdose after having been prescribed the medication. - Additional deaths result from the illicit, non-prescribed use of fentanyl diverted via pharmacy theft, fraudulent prescriptions, and illegal distribution. - Still others die from taking fentanyl that they believe to be heroin, or from taking heroin tainted with fentanyl or one of its many analogs which are also highly potent. - Additional examples of synthetic opioids include *sufentanil* (Sufenta), *levorphanol* (Levo-Dromoran), *pentazocine* (Talwin), and *tramadol* (ConZip). - Recently, use of the synthetic opioid drugs *dextropropoxyphene* (Darvon) and *phenazocine* (Narphen) has been discontinued in many countries due to adverse side effects, a small therapeutic index, and the availability of safer effective alternatives. - Synthetic and semisynthetic opioids are used medically, not only for the treatment of pain and cough, but also as detoxification and maintenance therapies for opioid addiction. - Methadone was developed in Germany and originally used in the 1930s-1940s as an analgesic. - In 1960s United States, amidst the growing popularity of heroin, methadone (under the trade name *Dolophine*) was marketed as a legal, longer-lasting, and safer alternative to illegal heroin. - Methadone became recognized as a "treatment" for heroin addiction in 1970 and clinics began to distribute the drug to addicts as a maintenance therapy. - Compared to heroin and morphine, methadone is far more effective when administered orally and has a longer duration of action. - But, like heroin and morphine, it has abuse potential and has been linked to overdose deaths. - Another opioid maintenance therapy drug is *buprenorphine*, a semisynthetic derivative of thebaine. - Under the trade names *Subutex* and *Suboxone*, burprenorphine has been prescribed to treat opioid addiction since the early 2000s, though it is also a highly effective and long-lasting pain reliever (sold as *Buprenex*). - Unlike most opioid drugs, buprenorphine’s effects do not seem to tolerate substantially with chronic use. - The synthetic opioid *levomethadyl acetate* (LAAM) was once widely used as a second-line therapy for opioid addiction but was withdrawn from European and North American markets in the early 2000s because of adverse side effects, especially its ability to cause dangerous heart arrhythmia. - **In the privacy of their clandestine laboratories, aspiring chemists have over the years synthesized a mindboggling array of opioid-like designer drugs.** - These molecularly altered versions of controlled substances are designed to produce similar pharmacological and psychoactive effects of a known drug but, given that they are technically unscheduled, attempt to circumvent laws restricting the possession, use, and distribution. - They are also easier or cheaper to make or buy, and it is often the case that end-users don’t really know what they’re getting. - One notorious example of "bathtub chemistry" gone wrong relates to *desmethylprodine* (MPPP), an analog of meperidine developed in the 1940s by Hoffmann-La Roche pharmaceuticals but never marketed. - The effects of MPPP closely mimic those of heroin, but its synthesis is much simpler than that of fentanyl or meperidine. - **In 1977, a 23-year-old chemistry graduate student at the University of Maryland set up a laboratory in the basement of his parents’ home and, based on the 1947 publication of Hoffmann-La Roche’s work in the Journal of Organic Chemistry, began synthesizing MPPP for personal use.** - Unbeknownst to him, the drug he manufactured contained an impurity-a compound called *MPTP*. - When it enters the brain, MPTP is metabolized into a neurotoxin that destroys cells of the substantia nigra, part of the extrapyramidal motor system that provides dopamine stimulation to the basal ganglia. - After several months of synthesizing and injecting the drug, the young man developed severe stiffness and difficulty moving, which required him to be hospitalized. - He was diagnosed with juvenile Parkinson’s disease and prescribed L-DOPA, which improved his symptoms at first, but his condition later further deteriorated. - The young chemist committed suicide by cocaine overdose 2 years later. - In the early 1980s, more young people who had used MPPP clandestinely manufactured in a Texas laboratory suffered similar symptoms and received the same unusual diagnosis of juvenile Parkinson’s disease. - Neurologist J. William Langston investigated these cases and reported the likely connection between MPTP contamination and the development of Parkinsonian symptoms. - Langston coined the term *frozen addict* to refer to the state of these individuals. - Other designer drugs have been created based on the fentanyl molecule or its analogs, especially *a-methylfentanyl*. - These substances are collectively referred to as *white Persian* or *China white*, which was the 1970s-1980s street name for a-methylfentanyl and is currently a street name for fentanyl. - One surreptitious synthesis of China White involves extracting fentanyl from the *Duragesic patch* and combining it with acetaminophen and caffeine. - Recently, the synthetic opioid *W-18*, reported to be 100 times more potent than fentanyl, has been linked to numerous deaths in Canada. - **In 2011, the first U.S. report of adverse effects resulting from use of the street drug *krokodil* came out of Chicago.** - Since that time, the drug has shown up in other U.S. states. - Krokodil is believed to have originated in the Ukraine and Russia where it is also referred to as *Russian heroin*. - Its popularity in former Soviet countries grew beginning in 2003 as a result of the decreased availability and high cost of Afghan heroin. - In addition, Eastern Europe countries have implemented extremely harsh drug possession policies. - In 2011, an estimated 100,000 Russians and 20,000 Ukrainians used krokodil. - But it was the drug’s entry into other European and North American countries, and Internet portrayals of its devastating effects in some users, that caught the public’s attention. - The psychoactive ingredient in krokodil is desomorphine, an opioid similar in structure to morphine. - Desomorphine was first synthesized in 1932 in the United States and marketed in Switzerland by Hoffmann-La Roche in 1940 as Permonid, a post-operative analgesic, though its use is now prohibited internationally. - As the designer drug krokodil, desomorphine can be synthesized from codeine in a relatively simple process that requires little equipment and only low-cost, easily available chemicals. - First, a strong alkali-containing product (such as Drano, a drain and pipe cleaner) is added to crushed codeine-containing analgesic tablets that are, in many countries, sold over-the-counter. - Then, an organic solvent (usually gasoline, lighter fluid, or paint thinner) is used to extract the codeine. - Hydrochloric acid (obtained from batteries) is added to acidify the mixture and convert the codeine base into a water soluble salt. - The extracted codeine is subsequently mixed with iodine, water, and red phosphorus obtained from the striking pads of matchboxes. - The mixture is then heated to produce desomorphine. - The entire process can take less than an hour. - **The potency of desomorphine as an analgesic is estimated to be about ten times that of orally administered morphine.** - Though it is a powerful analgesic that, like other opioids, is capable of producing sedation, respiratory depression, and dependence, these effects are not what garnered attention for krokodil. - The designer drug earned the moniker krokodil (Russian for crocodile) either because the synthetic pathway that generates desomorphine from codeine tablets entails an intermediate opioid analog (a-chlorocodide) that sounds like the word crocodile, or (more likely) due to the rough, scaly, green skin that can result from repeated use. - Chronic krokodil users have developed gangrenous wounds and deep abscesses all over the body; rotting ears, nose, lips, and gums; osteonecrosis of the jaw; thrombophlebitis and deteriorating veins that require surgical removal of vessels and surrounding soft tissue and muscle; tissue infection and necrosis that leads to parts of limbs or large pieces of dead skin falling off in large chunks; and limbs that require amputation. - Such adverse effects are the result of the amateur chemistry used to make krokodil, which produces a drug suspension contaminated with toxic byproducts that users inject intravenously. - These contaminants cause the outwardly visible signs of krokodil abuse and are what garnered attention for the drug on the world wide web. - Organ systems are also adversely affected by krokodil use, with medical reports of liver and kidney inflammation, endocarditis, pneumonia, meningitis, hypothyroidism, multiple organ failure, and death. - Neurotoxic effects, such as loss of cognitive function, memory loss, speech difficulty, loss of motor skills, hallucination, and changes in personality have also been documented. - In an attempt to mitigate the rising use and health costs of krokodil, over-the-counter sales of codeine were banned in Russia in 2012, though the drug can now be bought on the black market. - The ready availability of high-purity, low-cost heroin in North America makes it unlikely that krokodil, with its serious adverse effects, will be widely used. ### History of Opium Use - There is evidence that the opium poppy was being cultivated in the western Mediterranean region in the sixth millennium BCE, and opium capsules found in grass bags in Neolithic burial sites in northern Spain date to about 4200 BCE. - Originally wild, the opium poppy was also cultivated in Assyria and Babylon by at least the second century BCE. - Opium is mentioned frequently in Assyrian medical tablets dated to the seventh century BCE that are likely copies of much earlier manuscripts. - The earliest known written reference to opium is Sumerian and dates to about 4000 BCE. - In it, the ideogram symbolizing the opium poppy is translated as "joy plant." - By the second century BCE, opium use had spread throughout the Middle East and North Africa. - It was, for example, mentioned in the Ebers Papyrus, early Egyptian medical scrolls that date to 1550 BCE. - In these early writings, the poppy is primarily considered a medicine, though the nonmedicinal properties of the plant were certainly appreciated. - The ancient Greeks knew of opium as well, with mentions of it as early as the eighth century BCE. - The Greek physician Hippocrates recommended the use of opium for a number of conditions, as did the Roman physicians Pliny and Galen. - The Arab physician Avicenna recommended it for diseases of the eye and to treat diarrhea. - The use of opium spread in every direction with the expansion of Middle Eastern culture. - It was carried east to India by Arab traders in the ninth century and then from India to China, where it was used primarily as a medicine and taken orally. - Later, when tobacco smoking was banned by a Chinese emperor in 1644, the Chinese turned to filling their pipes with opium. - Thus began the practice of opium smoking, a very efficient method of drug delivery that ensured the popularity of the drug in that country. - Arabs also traded opium, along with spices and other goods, with the merchants of Venice. - In the early part of the sixteenth century, Europeans became aware of opium primarily through the efforts of traveling physicians. - A Swiss doctor known as Paracelsus traveled throughout Europe and carried opium in the pommel of his saddle. - He called it "the stone of immortality." - Other physicians quickly adopted the drug and prescribed it in various forms to their patients, with great success. - Thomas Sydenham, an English physician, wrote in 1680, "Among the remedies it has pleased Almighty God to give to man to relieve his sufferings, none is so universal or so efficacious as opium." - The popular use of opioids increased steadily in Britain throughout the seventeenth and eighteenth centuries. - By the start of the nineteenth century, many British were addicted to opioids, though the situation was not yet deemed to be an important social or medical problem. - During the nineteenth century, British consumption of opioids increased drastically. - Opium was available in many formulations and easily accessible in food stores, pubs, and even from peddlers on the street. - The most popular formulation was tincture of opium, or laudanum, which contained 10% powdered opium dissolved in alcohol and could be purchased without prescription. - Its principal medical use was in treating pain and cough. - In 1825, the opium consumption rate in Britain was between 1 and 2 pounds per 1,000 population and rising, which began to generate some concern by the 1830s. - The Merck pharmaceutical family began manufacturing morphine in Germany in 1827, though its use in Europe became widespread only after the invention of the hypodermic glass syringe in the mid-1850s. - Unlike opium, morphine remained more under the control of the medical profession and was never widely sold in shops. - This restriction did not hinder its popularity; physicians generally prescribed it when requested. - Because the lower classes seldom saw a doctor, morphine use centered amongst the middle and upper classes. - It wasn’t until the late 1860s, when British opium consumption rates surpassed 10 pounds per 1,000 population, that legislative effort was made to control it. - The easy availability of the drug was recognized as the main factor contributing to its problematic use. - In 1868, the British Parliament passed the *Pharmacy Act*, which made pharmacist shops the only legal dispenser of opioids. - This was the first of several laws that slowly took the use of opioids out of the hands of the people and under the control of the medical profession. - This regulatory change was prompted more by the development of social, economic, and political interests than by scientific theory or medical research. - The passing of the Pharmacy Act marked the start of a new belief about addiction-that it was a medical, rather than a social, concern and should be handled by physicians. - Though Americans shared the Brits’ fondness of opioids, the story of opioid use in the United States is somewhat different. - In 1870, when British consumption of opium was more than 10 pounds per 1,000 population, American consumption rates were greater than 13 pounds per 1,000. - In part, opium was being consumed orally in the form of patent medicines, but a great deal of it was refined into morphine and injected by means of the recently developed hypodermic syringe. - This route of administration may have become popular because of the wide use of morphine injections to treat wounded soldiers during the Civil War. - In 1914, Congress passed the *Harrison Narcotic Act*, which, in effect, made it illegal to be an addict and illegal for physicians to prescribe opioids to addicts. ### Heroin - Heroin was invented in 1898 by Heinrich Dreser who worked as the head of drug safety and efficacy testing for Bayer Company of Germany. - Earlier that year, researchers at Bayer discovered that adding an acetyl group to salicylic acid (an effective pain and fever remedy that, unfortunately, is corrosive and produces terrible gastric effects) diminished its corrosive properties. - The result was acetylsalicylic acid (ASA, trademarked as Aspirin). - In search of a miraculous pain killer that would be his claim to fame, Dreser used the same tactic to alter the morphine molecule, creating diacetylmorphine (or diamorphine) which the Bayer company marketed as Heroin. - This trade name was derived from the German heroisch, meaning heroic, to imply the concentrated power of the drug. - Early tests of the compound revealed that heroin was much more effective than morphine as an analgesic but did not cause as much nausea and vomiting. - It was advertised in newspapers and magazines and, in 1899, Bayer Company produced more than a ton of heroin which it exported to more than 20 different countries. - Bayer also claimed that heroin was not addictive, which medical professionals believed for many years to be true. - It did not take long for morphine users to discover heroin, nor to realize that heroin did not require injection but could be sniffed into the nostrils. - This fact, and the relative lack of nausea, likely enhanced its appeal to casual users. - By the 1920s, newspapers in the United States associated heroin with crime, industrial unrest, and a series of Bolshevik bombings. - As such, in 1924 heroin use was banned by the U.S. Congress, even making it illegal for doctors to prescribe heroin for any reason. - This law, along with the Harrison Narcotic Act of 1914, are still in effect in the United States. - The synthesis of heroin was the first of countless attempts to find the "holy grail" of opioids-a drug that would provide equal or greater analgesia than morphine without the undesirable side effects of respiratory