Morphine

• 1. Introduction

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  Morphine is, by many measures, the most addictive substance known to humanity. A study published in The Lancet ranked it first among all addictive substances, ahead of cocaine, nicotine, barbiturates, and ethanol. It is a pain medication derived from the opium poppy, listed on the World Health Organization's List of Essential Medicines, and yet six wealthy nations consume nearly 79% of the world's supply while the 80% of humanity living in less affluent countries share only about 6%. That gap sits at the center of morphine's story. It is a molecule that relieves suffering at one end of the world and remains out of reach at the other. It was named after Morpheus, the Greek god of dreams. It has been the benchmark against which every opioid developed since has been measured. And it begins with a German pharmacist in a town called Paderborn in December 1804, who nearly killed himself and three young boys finding out what it could do.

• 2. Friedrich Sertürner's Discovery

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  Friedrich Sertürner isolated morphine from the opium poppy in December 1804 in Paderborn, Germany. This was the first isolation of a medicinal alkaloid from any plant, and Sertürner noticed early on that the compound caused drowsiness in rats and stray dogs. He reported his findings in 1805. In 1817, he went further. He administered morphine to himself, three young boys, three dogs, and a mouse. All four people nearly died.

  Sertürner named the substance morphium after Morpheus, the Greek god of dreams, because of its sleep-inducing properties. He calculated that his morphium was six times stronger than raw opium and believed that, because smaller doses were needed, the drug would prove less addictive than the plant itself. He was wrong. He became addicted, and he said so plainly, writing that he considered it his duty to warn the world of the "terrible effects" of the substance he had named.

  The drug was first marketed to the public in 1817 by Sertürner and Company, sold both as a pain medication and, in a bitter irony, as a treatment for opium and alcohol addiction. Commercial production moved to Darmstadt, Germany, in 1827, when the pharmacy that later became the pharmaceutical company Merck began producing it, with morphine sales forming a large portion of their early growth. By 1853-1855, when the hypodermic syringe was invented, morphine's reach expanded dramatically.

• 3. The Civil War and the Soldier's Disease

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  The hypodermic needle made morphine faster and more potent. Its extensive use during the American Civil War allegedly resulted in over 400,000 people developing morphine addiction, a condition that came to be called the "soldier's disease." That figure and the name itself have been contested; the first documented use of the phrase "soldier's disease" did not appear until 1915, decades after the war ended.

  It was later established that morphine was more addictive than either alcohol or opium, the very substances it had been marketed to treat. Diacetylmorphine, better known as heroin, was synthesized from morphine in 1874 and brought to market by Bayer in 1898. Heroin is roughly 1.5 to 2 times more potent than morphine by weight. It crosses the blood-brain barrier faster because of its lipid solubility, which increases its addictive pull. In a controlled study comparing the two drugs in people formerly addicted to opiates, subjects showed no preference for one over the other. Equipotent injected doses had comparable effects, with heroin reaching the brain only slightly quicker. The reason for this near-equivalence is chemical: heroin is a prodrug for morphine. Once inside the body, heroin converts to morphine before binding to the opioid receptors in the brain and spinal cord where morphine produces its subjective effects.

  Morphine became a controlled substance in the United States under the Harrison Narcotics Tax Act of 1914. It had been the most commonly abused narcotic analgesic in the world until heroin displaced it.

• 4. How Morphine Works

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  Morphine is a phenanthrene opioid receptor agonist. Its primary action is binding to and activating the mu-opioid receptor, known as the MOR, in the central nervous system. The MOR is not evenly distributed in the brain; it appears in high densities in the posterior amygdala, hypothalamus, thalamus, nucleus caudatus, and putamen, as well as in certain cortical areas. Activation of the MOR produces analgesia, sedation, euphoria, physical dependence, and respiratory depression.

  Morphine creates pain relief through a specific cluster of neurons in the rostral ventromedial medulla, which researchers call the "morphine ensemble." These neurons project down to the spinal cord, connecting to inhibitory neurons called SCGal neurons, which release the neurotransmitter GABA and a neuropeptide called galanin. The inhibition of those SCGal neurons is what drives morphine's pain-relieving effect. The neurotrophic factor BDNF, produced within the morphine ensemble neurons, is required for this action to occur at all, and increasing BDNF levels can enhance morphine's analgesic effect even at lower doses.

  When taken by mouth, only 40% to 50% of a morphine dose reaches the central nervous system, because the liver breaks down a large portion of it before it enters general circulation. After intravenous administration, morphine reaches peak effect in about 20 minutes. The elimination half-life is approximately 120 minutes, and about 87% of a dose is excreted in the urine within 72 hours. Morphine is metabolized primarily into two compounds: morphine-3-glucuronide, which has no analgesic effect, and morphine-6-glucuronide, which binds to mu-receptors and is half as potent as morphine in humans.

• 5. Addiction and Withdrawal

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  Relapse rates for morphine users reach as high as 98%, by the estimate of some medical experts. That number captures something about the nature of morphine's hold on the brain. Addiction studies have shown that tolerance develops at similar rates for both morphine and heroin. When former addicts were offered a range of opioids including hydromorphone, fentanyl, oxycodone, and pethidine, they showed a strong preference for heroin and morphine over the others, specifically because of the higher rates of euphoria and other positive subjective effects those two drugs produced.

  Withdrawal from morphine unfolds in stages over days. The earliest signs begin 6 to 14 hours after the last dose: drug craving, anxiety, irritability, perspiration. By 14 to 18 hours, heavy sweating and yawning appear, along with a waking trance-like state researchers call "yen sleep." Stages III through V, spanning the first 36 to 72 hours, bring dilated pupils, muscle twitches, severe bone and muscle pain, vomiting, and weight loss of 2 to 5 kilograms per 24 hours. Major withdrawal symptoms peak between 48 and 96 hours after the last dose and subside after about 8 to 12 days. Unlike withdrawal from alcohol, barbiturates, or benzodiazepines, morphine withdrawal is not fatal in otherwise healthy people.

  The psychological dependence that follows the physical withdrawal is a different matter. Long after the body no longer needs morphine, people with addiction typically continue to think and talk about the drug, finding ordinary daily activities difficult to manage without it. Psychological withdrawal is described as usually a long and painful process, marked by severe depression, anxiety, insomnia, mood swings, paranoia, and confusion. The physical symptoms generally resolve within 7 to 10 days, but the psychological dependence overlaps and extends well beyond that.

• 6. Production and Global Supply

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  In 2013, approximately 523 tons of morphine were produced worldwide. Only about 45 tons of that total were used directly for pain relief, an increase of 400% over the previous two decades, with most of that use concentrated in developed nations. About 70% of morphine production goes into making other opioids: hydromorphone, oxymorphone, and heroin among them. Most licit morphine is converted into codeine, because the natural concentration of codeine in both raw opium and poppy straw is much lower than that of morphine.

  Morphine makes up roughly 8% to 19% of opium by dry weight, depending on growing conditions. Some purpose-developed strains now produce opium that reaches up to 26% morphine by weight. The Norman strain of Papaver somniferum, developed in Tasmania, goes in the opposite direction, producing down to 0.04% morphine but much higher amounts of thebaine and oripavine, which are used to synthesize semi-synthetic opioids.

  In the 1950s and 1960s, Hungary supplied nearly 60% of Europe's total medication-purpose morphine production. A poppy straw extraction method still widely used today was invented in Hungary in 1925 and announced in 1930 by Hungarian pharmacologist János Kabay. In India, licensed poppy farmers sell their opium to pharmaceutical companies after it is dehydrated at government processing centers. A 2005 estimate by the International Narcotics Control Board found that Australia, Canada, France, Germany, the United Kingdom, and the United States together consumed 79% of the global morphine supply. Some countries import virtually none at all, leaving patients without access to pain relief even at the end of life.

• 7. A Molecule That Grows Others

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  More than 250 morphine derivatives have been developed since the last quarter of the 19th century. The range is extraordinary: some compounds carry only about 25% of the analgesic strength of codeine, while others reach several thousand times the potency of morphine itself. Replacing the N-methyl group of morphine with an N-phenylethyl group produces a compound 18 times more powerful. Combining that change with another modification at the 6-hydroxyl position yields a compound some 1,443 times more potent than morphine, stronger by some measures than etorphine, the active ingredient in the Immobilon tranquilizer dart used in large-animal veterinary medicine.

  Naloxone, the overdose reversal drug sold under the name Narcan, is itself derived from morphine. So is naltrexone. Both are opioid antagonists that can completely reverse morphine's effects, though naloxone must often be given in multiple doses because its duration of action is shorter than morphine's.

  The first total chemical synthesis of morphine was devised by Marshall D. Gates, Jr. in 1952, using coal tar as a starting material. Multiple research groups followed with their own synthesis routes. Despite these achievements, Michael Freemantle has expressed the view that it is "highly unlikely" that chemical synthesis will ever be cost-competitive with simply extracting morphine from the opium poppy. Meanwhile, researchers have been attempting to produce morphine biosynthetically in genetically engineered yeast. As of June 2015, they could produce a key intermediate called S-reticuline from sugar, and convert R-reticuline into morphine, but the intermediate step between them remained unsolved. By August 2015, the first complete yeast synthesis of thebaine and hydrocodone was reported, though the process would need to be 100,000 times more productive to be commercially viable.

• 8. The Body's Own Morphine

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  In 2003, researchers confirmed something that had been speculated for three decades: morphine occurs naturally in the human body. The suspicion had grown from the existence of the mu-3-opioid receptor in human tissue, which appeared to react specifically to morphine. Human cells that form in response to cancerous neuroblastoma cells were found to contain trace amounts of endogenous morphine.

  The human body synthesizes morphine through a pathway that begins with the amino acid L-tyrosine. That pathway runs through dopamine, through a compound called norlaudanosoline, through reticuline, and eventually through codeine before arriving at morphine. The enzyme CYP2D6, a cytochrome P450 isoenzyme, is involved in two steps of this process, including the final conversion of codeine to morphine. People taking L-DOPA for Parkinson's disease show significantly increased urinary concentrations of both endogenous codeine and morphine, because L-DOPA feeds into the same pathway.

  The body also produces endorphins, which are chemically related to morphine and act on the same receptors, though they are distinct compounds. The discovery that morphine is not only a drug extracted from a plant but also a molecule the human body makes for itself reframes something fundamental about why morphine acts on us the way it does. The receptors it targets evolved in part around molecules the body already produced. That convergence between the chemistry of the poppy and the chemistry of the human brain is the deeper story beneath the drug's long and complicated history.