Category:Opioids

Few medicines have a history as long, as consequential, or as troubled as the opioids. Their story runs from the ancient Near East to a present-day overdose crisis, and it has repeatedly followed a single pattern: a new and more potent preparation is introduced as a solution to the dangers of the one before it, and in time proves to carry dangers of its own.

The opium poppy (Papaver somniferum) is one of the oldest plants associated with human medicine. Archaeological finds of poppy capsules at Neolithic European sites date back more than six thousand years, and the plant was known across the ancient Mediterranean and Near East.^[1]

A widely repeated account holds that the Sumerians of lower Mesopotamia cultivated the poppy around 3400 BCE and called it a "joy plant" (hul gil). This claim appears throughout popular and even biomedical literature.^[2] Sumerian "joy plant" account▲0▼ However, some scholars regard it as a poorly supported "factoid", arguing the archaeological evidence does not establish recreational poppy use in Mesopotamia and that the plant was more likely first domesticated in Neolithic Europe for its seeds.^[1] Disputed as unsupported factoid▲0▼

What is better attested is the plant's place in the classical world. Greek and Roman physicians, including Hippocrates and later Galen, described preparations of poppy juice for pain, sleeplessness, and other complaints.^[2] The poppy was also bound up with the era's mythology of sleep and dreams: it was associated with Hypnos, the god of sleep, and with his counterpart Thanatos; at the healing temples of Asclepius, the sick were given poppy preparations partly in the hope of a revelatory dream. This same association of the poppy with sleep would later give morphine its name.

In sixteenth-century Europe, the physician Paracelsus described an opium preparation he called laudanum, from the Latin for "to praise"; alcoholic tinctures of opium under that name became a common remedy in European medicine over the following centuries.^[3]

By the early nineteenth century, laudanum was widely and legally available, and opium acquired a notable place in literary culture. In 1821 Thomas De Quincey published Confessions of an English Opium-Eater, an autobiographical account of his laudanum use widely regarded as the first literary memoir of addiction; it linked opium to the imaginative life of the Romantic era and influenced later writers.^[4]

Opium was also a major article of international trade. Most consequential was the nineteenth-century commerce between British India and China; Chinese attempts to halt the inflow of opium, and the British use of force in response, led to the conflicts known as the Opium Wars.^[2] The trade was not solely British, prominent American merchants, including John Jacob Astor and Boston trading firms, also participated in the nineteenth-century opium commerce with China.^[5]

A turning point came between 1803 and 1804, when the young German pharmacist Friedrich Wilhelm Sertürner isolated a crystalline substance from opium. He named it after Morpheus, the Greek god of dreams, morphium, later morphine.^[6] It is generally regarded as the first alkaloid isolated from a plant, and it allowed, for the first time, pain treatment with a defined compound in measured doses. The firm E. Merck began commercial production in 1827.

Morphine's use expanded enormously after the mid-nineteenth-century adoption of the hypodermic syringe, which allowed direct injection. Widespread medical and battlefield use, including during the American Civil War, was followed by recognition of how readily morphine produced dependence.^[3]

The pattern then repeated. In 1874 the English chemist C. R. Alder Wright first synthesized diacetylmorphine from morphine, though the compound attracted little attention at the time. In the 1890s chemists at the Bayer company in Germany developed it further, and Bayer brought it to market in 1898 under the trade name Heroin.^[3] It was promoted as a cough remedy and as a non-addictive substitute for morphine, a claim that proved badly wrong, as heroin is, if anything, more rapidly habit-forming. Heroin was withdrawn from ordinary medical use and made illegal in many countries in the early twentieth century.

Through the nineteenth century, opium and its derivatives were largely unregulated in the United States and were widely sold in patent medicines. A series of early-twentieth-century laws changed this. The Pure Food and Drug Act of 1906 required medicines to disclose ingredients such as opiates on their labels; this measure alone is reported to have reduced opiate sales substantially.^[7] The Smoking Opium Exclusion Act of 1909 banned the importation of opium prepared for smoking. The Harrison Narcotics Act of 1914 required those who produced, imported, or distributed opiates, including prescribing physicians, to register and pay a tax; it was subsequently interpreted by courts and enforcement officials to prohibit the prescribing of opioids to maintain people who were addicted, which moved much opioid use outside legal medicine.^[7]

The most recent chapter is the opioid overdose epidemic, most acute in North America, in which several hundred thousand deaths have been recorded since 1999.^[8] Public-health analyses commonly describe it in three waves.^[8]

The first wave began in the 1990s with a sharp rise in the prescribing of opioid medicines for chronic pain. OxyContin, an extended-release oxycodone product, was approved by the U.S. Food and Drug Administration on December 12, 1995, and marketed from 1996 by Purdue Pharma; the company was later found to have promoted the medicine with misleading claims that understated its addictive potential, and it and members of the Sackler family that owned it became the subject of extensive litigation.^[9][10]

The second wave, from around 2010, saw a rise in heroin overdose deaths, as some people dependent on prescription opioids moved to heroin, which had become cheaper and more available.^[8]

The third wave, from around 2013, has been driven by illicitly manufactured synthetic opioids, above all fentanyl, which is far more potent by weight than morphine and is frequently mixed into other illicit drugs, often without the user's knowledge.^[8] Some analysts describe a fourth wave marked by combined use of fentanyl with stimulants such as methamphetamine or cocaine.^[11]

The progression from opium to heroin to fentanyl, each successive material more potent by weight than the last, has been linked not only to medical and market factors but also to drug prohibition itself. The "iron law of prohibition", a term coined by Richard Cowan in 1986 and summarized as "the harder the enforcement, the harder the drugs", holds that when a substance is prohibited, the illicit market tends to favour more concentrated and potent forms, because these are more efficient to conceal, store, and transport for a given value.^[12] The economist Mark Thornton has published research describing this effect for illegal drugs, and an analogous shift is commonly noted during alcohol prohibition in the United States, when consumption moved from beer toward more concentrated spirits. Commentators have invoked the same reasoning to explain why, in the 2010s, heroin was increasingly displaced by fentanyl and other still more potent synthetic opioids. Those who emphasize this argument present it as a case against prohibition; it remains one explanation among several for the rising potency of the illicit opioid supply.^[12]

A range of harm-reduction measures has been adopted in response to the epidemic. Naloxone, a medicine that can reverse an opioid overdose, has been distributed widely to the public; other measures include fentanyl test strips, syringe services programs, and, in some jurisdictions, supervised consumption sites.^[13] A person who has stopped breathing during an opioid overdose may also be sustained by rescue breathing until emergency help or naloxone is available.

Opioids bind opioid receptors, especially the µ-opioid receptor, with additional activity at the κ and δ receptors, found in the nervous system and elsewhere in the body. Binding at the µ-opioid receptor is associated with the analgesic effects of opioids, with their euphoric effects, and with respiratory depression, the mechanism by which opioid overdose causes death.^[3] As with medicines generally, that opioids bind these receptors is well established; the fuller relationship between receptor binding and the range of clinical effects, including the development of tolerance and of dependence, is more complex and remains a subject of research, and should not be regarded as a closed question.

The opioids include compounds of natural origin such as morphine and codeine; semi-synthetic compounds such as heroin (diacetylmorphine), oxycodone, hydrocodone, and buprenorphine; and synthetic compounds such as fentanyl, methadone, and tramadol. Naloxone and naltrexone are opioid antagonists, they block opioid receptors rather than activating them. The list is not exhaustive.

The central acute danger of opioids is respiratory depression: at sufficient dose, opioids slow and can stop breathing, and this is the mechanism of fatal overdose. Risk is substantially increased when opioids are combined with other central nervous system depressants, including alcohol and benzodiazepines, and when potency is unknown, the particular hazard of illicitly manufactured fentanyl. Repeated use is associated with tolerance and with physical dependence, and a withdrawal syndrome on stopping. Figures for these risks in the literature are population estimates that vary between studies, and individual response varies considerably between people.