1 The Opioid Crisis: A Brief History

Christopher Florido, Kyle Sonnabend and Charles E. Ray Jr.

1.1 History

The opium poppy (Papaver somniferum) is a domesticated annual plant and today it is found only in association with human activity, seen either in planted fields or incidentally in environments near these cultivated areas. ? [1] The exact origins of the plant have not been identified, and no wild progenitor is known. ? [1] Throughout history the opium poppy has been used for a variety of purposes including as food and for oil from its seeds, as well as animal fodder and heating fuel from its stalks. Most notoriously, it has been used for its analgesic and euphoric properties. The poppy capsule contains more than 50 alkaloids including morphine, codeine, thebaine, and papaverine, among others. ? [1] These compounds can be obtained by slicing the capsule and extracting the opium latex and, in more recent history, have been isolated and concentrated for both medicinal and recreational use.

It is difficult to pinpoint the first recorded cultivation and use of the opium poppy because descriptions of drugs and medications by ancient authors tend to be ambiguous. That said, many sources seem to agree that the Sumerians of ancient Mesopotamia (a region of Western Asia roughly corresponding to modern-day Iraq, Kuwait, Eastern Syria, and Southeastern Turkey) cultivated poppies and isolated opium from poppy seeds in the third millennium BC. ? [2] They referred to the poppy as "hul gil" or "the plant of joy." Early descriptions of opium poppy use suggest it was taken orally or inhaled from heated vessels as part of religious rituals. It would eventually become widely used for both medicinal and recreational purposes. Wherever it originated, opium cultivation spread to ancient Greek, Persian, and Egyptian societies.

Egyptians obtained knowledge of the opium poppy from the ancient Sumerians and began cultivation of opium around 1300 BC. ? [3] The opium trade flourished during the reign of Thutmose IV, Akhenaton, and King Tutankhamen. The trade route extended to the Phoenicians and Minoans who would move the opium poppy into Greece, Carthage, and Europe. ? [3]

There are many references to the opium poppy in the ancient Greek culture. The divinities Hypnos (Sleep), Nxy (Night), and Thanatos (Death) were portrayed wearing wreaths containing poppies or with poppies in their hands. ? [4] In The Odyssey, the Greek author Homer refers to a preparation given to Telemachus and his friends by Helen, the daughter of Zeus, to forget their grief over Odysseus' absence. Some modern pharmacologists believe that this preparation contained opium. ? [2] Hippocrates, the "father of modern medicine," mentions the inclusion of the opium poppy in medicinal preparations for use as a hypnotic, narcotic, and cathartic. ? [4]

Starting around the 8th century AD, Arab traders brought the opium poppy to India and China. Between the 10th and 13th centuries trade extended from Asia to all parts of Europe. ? [2] Manuscripts from the 16th century describe opioid abuse and tolerance in Turkey, Egypt, Germany, and England. The problem of addiction was perhaps most rampant in China where the practice of smoking opium became commonplace in the mid-17th century when tobacco smoking was banned. ? [2] Although suppression of the sale and use of opium in China was attempted, these efforts ultimately failed because the British and French forced the Chinese to permit opium trade through various means. ? [2]

German pharmacist Friedrich Wilhelm Adam Sertürner isolated the active ingredient in opium between 1803 and 1806. ? [2] He named this alkaloid "morphine" after Morpheus, the "god of dreams." ? [2] It was first marketed commercially by Merck pharmaceuticals in 1827. ? [5] Its use became more widespread after the invention of the hypodermic syringe and hollow needle in the 1850s. It was at this time that morphine began to be used for minor surgical procedures, postoperative pain, chronic pain, and as an adjunct to general anesthetics. ? [2] Although the problem of opium addiction was well known at this time both in the United States and abroad, it was assumed that because injected morphine could control pain at much lower doses, it would be less likely to cause addiction. ? [6] When heroin was first synthesized in 1898, it was similarly pronounced to be more potent and therefore have less potential for addiction. ? [2] These examples are the first instances when such unfounded (and ultimately untrue) claims have been made about an opioid drug, but not the last.

The discovery of morphine and heroin would lead to the first wave of opioid addiction in the United States. This first epidemic had diverse origins stemming from a poor understanding of the etiology of painful conditions to the lack of alternative therapies. These drugs saw uses including (but not limited to) treatment of the common cold, diarrhea, hangovers, and painful injuries. ? [7]

In the first half of the 20th century, the addictive potential of morphine and heroin became the subject of much political debate in the United States. Initially, individual states were allowed to regulate the manufacture and sale of these substances. Then, the "Harrison Act" was passed in 1914 which imposed taxes on all aspects of opioid import, production, and sale, and also (more or less) restricted the legal use of opioids to patients with a medical prescription. Interestingly, the Supreme Court's interpretation of the act ultimately decided that opioids could be prescribed for symptomatic treatment of pain but not for maintenance of addiction. ? [6] Following the "Harrison Act," increasingly severe laws regarding the sale and possession of opiates were passed at the federal level. This ultimately led toward mandatory minimum prison sentences of 10 years by 1956.

In addition to increasingly strict laws and policies, additional social strategies were employed in the first half of the 20th century. The primary tactics of these campaigns were silence and exaggeration. ? [6] Silence took the form of suppression of exposure to opioids, such as banning films that depicted narcotic use. Exaggeration took the form of a national campaign launched in 1924 which made false claims, for example, the claim that one ounce of heroin could addict 2000 people. ? [6] The goal of these strategies was to discourage experimentation and abuse, but ultimately these tactics led to widespread ignorance and ultimately a loss of credibility regarding government statements on narcotics. This paved the way for a renewed enthusiasm for narcotic use starting in the 1960s. For the remainder of the 20th century, opioid addiction epidemics in the United States primarily resulted from transient increases in illicit heroin use in urban areas. ? [7] Starting in the 1990s that would change.

The opioid crisis in the United States was declared a national public health emergency in 2017. ? [8] Although continued illicit production and sale of opioids are factors in this epidemic, sanctioned medical use also plays a significant role. In the 1990s, the American Pain Society pronounced pain as a "fifth vital sign" in an effort to improve patient care. The American Pain Society, in partnership with the American Academy of Pain Medicine, also released a consensus statement endorsing the use of opioids to treat chronic pain in noncancer patients. Concurrently, the pharmaceutical industry initiated aggressive marketing campaigns that advocated long-term use of opioids to treat chronic pain and simultaneously minimize the risks of addiction. In tandem with the efforts of the American Pain Society to improve patient care with regard to pain, state medical boards loosened restrictions on opioid prescription. As a result, retail sales of the drugs oxycodone and hydrocodone increased by 866 and 280%, respectively, from 1997 to 2007. ? [9] Aggressive marketing campaigns and concordant high-volume prescriptions are believed to be major contributors to increasing opioid abuse and opioid-related deaths. In fact, an estimated 80% of Americans who become addicted to heroin start with prescription opioids. ? [9]

The modern opioid epidemic is a challenging problem with a complex history. Chronic opioid addiction is a life-threatening disease, and efforts to combat the epidemic must contend with all facets of the problem, including illicit production, as well as medical use under prescriptive authority.

1.2 Epidemiology

The World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) track cases of illicit drug use, nonfatal overdose, and drug-related deaths. According to the WHO, an estimated 275 million people (worldwide) used an illicit drug at least once in 2016. ? [10] Out of those, an estimated 34 million people used opioids and an estimated 27 million people suffered from opioid use disorders. ? [10] The majority of people with opioid dependence are reported to use illicit...