Legacy of the “Joy Plant”

There is a new, allegedly less addictive painkiller in the pharmaceutical pipeline, CR845, by Cara Therapeutics. Although CR845 is being touted as “non-addictive” (here and here); or a “non-absusable alternative to narcotic opioids” by Cara Therapeutics, that remains to be seen. CR845 is anticipated to be a Schedule 5 controlled substance. This is significantly less addictive than OxyContin and other opioid pain relievers, which are mostly Schedule 2. Even a less addictive pain medication would be great. But the history of opiates is full of similar promises.

The earliest reference to opium was in 3,400 BC where the Sumerians in lower Mesopotamia referred to it as Hul Gil, the “joy plant.” They, in turn, passed the knowledge of the opium poppy to the Assyrians, who gave it to the Babylonians, who passed it on to the Egyptians. The Egyptians were famous for their poppy fields and the opium trade flourished during the eighteenth dynasty (around 1500 to 1300 BC) under the reigns of Thutmose IV, Akhenaton and King Tutankhamen.  Roman gladiators used opium to enhance their fighting … and to die as painlessly as possible if mortally wounded.

Hippocrates, the father of medicine, saw opium as a helpful narcotic for treating disease. The great physician Galen, cautioned that opium should be used sparingly in 158 AD. He said it was better to endure pain than to be bound to the drug. It wasn’t until 400 AD that opium was introduced into China by Arab traders.

A History Channel documentary reported that Alexander the Great used opium to help his soldiers march farther because they couldn’t feel the pain in their feet; and they could sleep through the night because the wounded were sleeping peacefully under the influence of opium. He introduced opium to India, where it’s cultivation flourished. One of the goals of Columbus was to bring back opium from India, as its access had been cut off when the Arabs were expelled from Spain. He didn’t get to India, but he brought back tobacco from the New World and smoking tobacco became common throughout Europe.

Portuguese traders began smoking a tincture of opium with their tobacco around 1500. They also discovered the euphoric effect was instantaneous. In 1680, the English apothecary Thomas Sydenham introduced laudanum, a compound of opium, sherry wine and herbs. Dutch traders introduced the practice of smoking opium to the Chinese around 1700. The Chinese loved the habit and it led to cultural and political ruin. By 1800, 1/3 of the country was addicted to opium.

In 1803, a German chemist named Friedrich Sertuerner synthesized morphine from opium. Sertuerner’s wife overdosed on morphine and died. He then publically warned against its dangers. But morphine was also a great step forward in medicine. It allowed doctors to do true surgery for the first time. Morphine was heralded as “God’s own medicine” for its reliability and long-lasting effects. By 1827, the E. Merck & Company of Darmstadt Germany was commercially manufacturing morphine.

A new technique for administering morphine was developed by Dr. Alexander Wood of Edinburg when he invented the syringe in 1843. Wood believed that if morphine was injected instead of swallowed, “patients would not hunger for it.” He was wrong; and several of his patients became dependent. There is a mythical story that Wood’s wife was among the earliest of these addicts, and died of a morphine overdose. But according to Richard Davenport-Hines, she outlived her husband and survived until 1894.

Needles and morphine were quickly in demand. You could order morphine, opium and syringes through the mail … from Sears and Roebucks. They became a blessing during the Civil War on the battlefield. But their use created a generation of young ex-soldiers as morphine addicts. Morphine addiction became known as “the soldier’s disease” or “the army’s disease.”  This was the first drug epidemic in the United States. Nineteenth century America became “a dope fiend’s paradise.”

Morphine even became part of medical missionary efforts in China. They were selling opium pills and morphine powders, which became known as “Jesus opium.” The Chinese Recorder and Missionary Journal, Vol. 19, published in 1888, had a letter from a concerned person in Foochow: “Missionaries who dabble in this kind of business, probably most of them innocently, should know that their supposed help to suffering humanity is in the majority of the cases an injury to the patient and a positive evil in the church.”

Dr. John Witherspoon warned his fellow doctors in a June 23, 1900 article about their indiscriminant use of morphine. The morphine habit was growing at an alarming rate; and doctors were culpable for “too often giving this seductive siren until the will-power is gone.” Pointing to the Great First Physician, he said doctors should “save our people from the clutches of this hydra-headed monster” which wrecked lives and filled jails and lunatic asylums.

Looking for a non-addictive derivative of opium that could be used as a cough suppressant, the Bayer chemist Felix Hoffman successfully synthesized diacetylmorphine—heroin. When a Bayer executive introduced the drug to the Congress of German Naturalists and Physicians, he said it was 10 times more effective as a cough suppressant than codeine; it was more effective than morphine as a pain reliever and not habit-forming. Bayer began to sell it commercially in 1898 and by 1899 was producing about 1 ton of heroin yearly. The Boston Medical and Surgical Journal said heroin had many advantages over morphine, including: “It’s not hypnotic, and there’s no danger of acquiring a habit.”

Reports of “heroinism” had already surfaced, by 1900, but it took time for the sale and endorsements of heroin to stop. In 1906, the American Medical Association approved heroin for medical use, while cautioning that a “habit” was “readily formed.” In 1913, Bayer stopped making heroin. In 1919 it became illegal for doctors to prescribe heroin to addicts. In 1924, the US banned the use and manufacture of heroin altogether.


Evolution of Synthetic Painkillers

The documentary, “American Addict” (available on Netflix) reported that 106,000 Americans die from prescription drugs each year. In the first six months of 2008, 67% of the oxycodone that was prescribed throughout the U.S. came out of Broward County Florida. What was going on? Mid Eastern states had a prescription drug-monitoring program; Florida didn’t.  Drug seekers from those states went south for their drugs.

By the end of the 1800s, a wide variety of “patent medicines” had come onto the market. They were called “patent” medicines because their formula was a secret; so the ingredients weren’t listed. “Some of the patent medicines were up to 50% morphine by volume. And no matter what ails you, if you take something that is 50% morphine by volume, you’re going to feel better.” And some people began to use opiated “cure-alls” as intoxicants. These cure-alls were popular among women. “The typical opiate user in the nineteenth century was a middle class, middle–aged, white woman living in the middle of the country,” according to Pat Morgan of UCLA.

When Congress passed the Pure Food and Drug Act of 1906, it required the patent medicine industry to label its ingredients. “As a result of these regulations, most of the patent medicines went out of business immediately.” Addiction decreased dramatically; as a result of Americans becoming aware of what these drugs could do, according to historian Cliff Schaffer. But heroin addiction was just coming into its own (See another article, “Legacy of the ‘Joy Plant’”).

By 1913, heroin replaced morphine as the leading cause of hospital admissions for narcotics problems in the US. It was the leading drug of abuse in New York City. In 1914 the federal government passed the Harrison Tax Act. This legislation required an opiate prescriber to get a license and pay a tax; and an opiate user had to be a patient of a licensed prescriber. It created an estimated 100,000 to 200,000 criminals out of users and addicts. Heroin eventually became an illicit substance in 1924 with the Heroin Act, which made it illegal to manufacture, possess or distribute heroin—even for medical use. But the chemists of the world were already working to develop synthetic substitutes.

Oxycodone was first synthesized in 1916 at the University of Frankfurt. It was hoped that it could be a less addictive substitute for morphine and heroin. By the 1920s, there were reports of “euphoric highs” in patients using oxycodone. It was first introduced to the US in 1939. In the early 1960s, the US classified it as a Schedule II drug.  In 1950, Percodan (oxycodone and aspirin), was put on the market by Endo Pharmaceuticals. In 1971, Percocet (oxycodone and acetaminophen) was launched by Endo Phrmaceuticals. In 1996, OxyContin, a time-release form of oxycodone became available from Purdue Pharmaceuticals.

The time-release mechanism that was supposed to make OxyContin more difficult to abuse was quickly and easily neutralized by crushing the tablet before snorting the powder or mixing it with water to inject it. Users compare the high from oxycodone to heroin. In 2010, an abuse-deterrent formulation of OxyContin was introduced. The intent was to make it more difficult to crush. The New England Journal of Medicine published an article, “Effect of Abuse-Deterrent Formulation of OxyContin” in July of 2012 that indicated the new formula did indeed decrease it as a drug of abuse. But 24% of those who had abused OxyContin reported they found a way to defeat the tamper-resistant properties. Sixty-six percent reported switching to another opioid, with heroin being the most common choice. Heroin is easier to use, cheaper and easily available. The article concluded “Abuse-deterrent formulations may not be the “magic bullets” that many hoped they would be.”

Not to be deterred by these conclusions, Purdue Pharmaceuticals recently received approval for Terginiq ER, a combination of oxycodone and naloxone, a drug that is supposed to block the euphoric effects of oxycodone if it is crushed (so it can’t be snorted or dissolved and injected). But if you simply swallow Teriniq ER, the naloxone is not activated. “When the pills are swallowed they are as addictive as pure oxycodone.” Nevertheless, the FDA sees the approval of abuse-deterrent medications like Targiniq ER as a positive step in its fight address the public health crisis of prescription drug abuse in the U.S.

Hydrocodone was first synthesized in 1920, of course, by Germans. In 1924, it was first sold by Knoll Pharmaceuticals in Germany as Dicodid. Knoll was also responsible for the introduction and marketing of oxycodone as Dinarkon in 1917, and Dilaudid (hydromorphone), in 1926. Through a series of mergers, Knoll became a part of Abbott Laboratories in June of 2002.

In 1929, the U.S. Bureau of Social Hygiene gave the National Research Council several million dollars to study various new compounds like hydrocodone, to see if there was a less addictive opioid than morphine or heroin. Nathan Eddy tested the safety, efficacy and side effects of 350 drugs, including morphine, codeine, Dilaudid and hydrocodone. His results showed that hydrocodone was an effective painkiller, with predicable side effects. It also “induced euphoria, and therefore there was a danger of addiction.” Eddy said that tolerance developed more slowly than with morphine or Dilaudid and the occurrence of abstinence syndromes were less severe than with other drugs. This suggested an individual could become dependent on it without knowing it until they are really hooked.

With the Controlled Substances Act of 1971, pure hydrocodone was classified as a Schedule II controlled substance, as was opium and morphine. But in combination with other drugs, it could be regulated as a Schedule III drug. In 1978, Knoll Pharmaceuticals introduced Vicodin, five milligrams of hydrocodone with 500 milligrams of acetaminophen. Generic Vicodin became available in 1983.

Hydrocodone had become the most prescribed medication in the U.S. “Since 2007, more U.S. prescriptions were written for hydrocodone + acteminophen than any other drug.” In 2012 alone, there were over 135 million prescriptions written.

In 2002, emergency room reports involving hydrocodone had increased by 500% since 1990. That same year, the FDA recommended tighter warnings on drugs containing acetaminophen because of the concerns it can cause liver damage. In October of 2014, Vicodin was reclassified as a Schedule II drug. The purpose of the change was to minimize its use as a recreational drug, while ensuring that patients with severe pain still have reasonable access.

A new hydrocodone painkiller called Zohydro, with 5 to 10 times the power of Vicodin, was approved by the FDA in October of 2013. This approval ignored the 11 to 2 vote AGAINST APPROVAL by its own advisory panel. Zohydro is pure hydrocodone. Melanie Haiken, a contributor to Forbes, wondered if we need a new opiate painkiller, given that we don’t seem to be able to prevent the ones we already have from ending up in the wrong hands. She commented: “The U.S., with just 5 percent of the world’s population, now accounts for 84 percent of global oxycodone (OxyContin) consumption and more than 99 percent of hydrocodone (Vicodin, Lortab) consumption. That’s a lot of painkillers.”