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Oxycodone: The Narcotic Pain Reliever

Oxycodone [Figure 1] is currently marketed under brand names, Oxycontin and Roxicodone, where oxycodone is the only active ingredient present. Additionally, it is marketed in combination treatments with aspirin (called Percodan) and acetaminophen (named Roxicet). Oxycodone is used medically to treat moderate to severe pain (acute and chronic pain) and is widely associated with substance abuse. It was the 54th most commonly prescribed medication in the United States in 2020, with more than 12 million prescriptions documented (Warner et al., 2011). The drug is known to have common side effects such as euphoria, loss of appetite, drowsiness, dizziness, itching, dry mouth, nausea, vomiting, sweating, and addiction or otherwise described as substance dependence.

Figure 1: The chemical structure of oxycodone (Wikipedia, 2008).
The Chemistry and Mechanism of Action

The chemical structure of oxycodone is similar to that of codeine, differing in a few areas as highlighted in Figure 2. Codeine is an opioid drug closely related to morphine and, like morphine, is derived from opium poppies. Oxycodone has a hydroxyl group at carbon 14 whereas codeine only has a hydrogen bond. Oxycodone, in addition, has a carbonyl group (as in ketone), whereas codeine has a hydroxyl group and an additional double bond in the same position. The structure of oxycodone is similarly related to hydrocodone, differing only in the hydroxy group that is seen in oxycodone. The chemical synthesis of oxycodone is derived from thebaine, which is the main alkaloid extracted from Papaver bracteatum (Iranian opium or Persian poppy, Figure 3). Thebaine is industrially converted from a variety of different compounds such as oxycodone, hydrocodone, hydropmorphone, naltrexone, naloxone, and many other structurally similar opioids (Sadiq et al., 2022).

Figure 2: The synthetic route of thebaine to oxycodone (Galetti, 2023).

Oxicodone's mechanism of action is activated by the m-opioid receptor. These receptors are located at the ends of the nerves and like most receptors bind chemical messengers (otherwise known as neurotransmitters), the nerve cells are activated upon binding which triggers electric pulses carrying the message forward. Oxycodone's action works by stimulating the opioid receptors found in the central nervous system: this activates several responses ranging from analgesia (pain relief) to respiratory depression to euphoria. People who take the drug repeatedly can develop a tolerance or resistance to the drug's effects, and oral admission of oxycodone has roughly 1.5 times the effect of an equivalent dose of morphine (Gallego et al., 2007).

History of Oxycodone

In 1916 German scientists Martin Freund and Edmund Speyer synthesized oxycodone from thebaine and it was clinically evaluated in humans the same year [Figure 3]. Thebaine is a naturally occurring alkaloid derived from opium. In 1919 oxycodone was marketed as Eukadol by the global pharmaceutical company E. Merck. Clinical evaluation in both animals and humans found oxycodone to be slightly more analgesic than morphine, with prolonged action and fewer side effects. The pharmaceutical giant E. Merck continued their efforts to obtain an effective pain sedative and made extensive advances in the field of analgesia and sedative medications. In 1928 after conducting clinical trials they released a combination treatment known as SEE [Figure 4] containing three drugs, namely: scopolamine, ephedrine (Epheronin), and oxycodone (Eukadol) (Defalque & Wright, 2003). Each compound in the combination treatment was proved to contribute a specific function; ephedrine was a known central nervous system stimulant used to lower blood pressure during anesthesia; scopolamine was a known anticholinergic drug mainly used to treat motion sickness, nausea, and vomiting; and oxycodone was used as the sedative and analgesic. The combination treatment proved effective in prolonged analgesia, sedation, euphoria, and amnesia without significant respiratory or circulatory depression. In 1942 the name was changed to Scophedal. Scophedal became popular in Germany and Central Europe in the 1930s and was extensively used during World War II for mass casualties. After 1945 the drug lost its popularity and production ceased in 1987. The concept of mixing a sympathomimetic drug with a sedative or analgesic compound to prevent respiratory or circulatory depression was new in 1928. In the US, laboratory work and small clinical trials were conducted with similar mixtures from 1942 through 1962, but they were all experimental (Weber, 2005). The combination therapy SEE came in two strengths;

  • SEE I, a 1ml ampule containing 0.5mg scopolamine, 10mg eukodal, and 25mg ephetonin and

  • SEE II, a 1ml ampule containing 1mg scopolamine, 20mg eukodal, and 50mg ephetonin.

Figure 3: German scientists Martin Freund and Edmund Speyer (Wikipedia & Geni, n.d.).

In 1970 President Richard Nixon passed the Controlled Substance Act (CSA) in the United States resulting in all products that contained oxycodone being classified as Schedule II controlled substances. Almost two decades later Purdue Pharma, a privately owned pharmaceutical company based in Stamford, Connecticut, developed Oxycontin (Ogle et al., 2012). Oxycontin is an extended-release oral formulation of oxycodone hydrochloride indicated for the management of moderate to severe pain. It was approved for use in 1995 by the FDA, however, no long-term studies were conducted relating to its addictive nature. Due to the delayed absorption and slow-release formulation of oxycontin, the drug was then thought to be less addictive than immediate-release oxycodone. Oxycontin was available in various doses ranging from 10 mg to 80 mg; by comparison, Percocet and Tylox (immediate-acting oxycodone products) only contain 5 mg of oxycodone. It quickly became one of the top-selling painkillers on the market and was considered a medical breakthrough by many medical specialists. Sales increased from $48 million in 1996 to $1.1 billion in 2000. The strength, duration, and known dosage of Oxycontin are the primary reasons why the drug is attractive to both abusers and legitimate users. However, by November 2000 there were reports concerning the abuse and addictive nature of oxycontin. Purdue Pharma at the request of the FDA, added a “Black Box Warning” sign to the drug label, alerting patients of the potential dangers and addictive nature of Oxycontin. It was the first ever commonly used medication at the time to indicate a warning label regarding its addictive nature. Nevertheless, Purdue Pharma continued marketing Oxycontin aggressively, for example by providing practitioners with free coupons. They also released advertisements wrongly claiming that less than 1% of patients taking Oxycontin develop an addiction to the opioid. This led the FDA to issue warning letters to Purdue Pharma and other opioid manufacturers cautioning against promoting misleading information (Comer et al., 2010). David Kessler, who was the FDA commissioner at the time of Oxycontin, later released a statement about the approval of Oxycontin, stating that “No doubt it was a mistake. It was certainly one of the worst medical mistakes, a major mistake.” (Mitchell, 2018). As of September 2013, the FDA issued new labeling guidelines for long-acting and extended-release opioids, requiring manufacturers to remove moderate pain as an indication for use, instead stating that the drug is prescribed for pain severe enough to require daily, around-the-clock, long-term opioid treatment. As a result of the new labeling, physicians are still able to prescribe opioids moderately, as needed.

Figure 4: SEE; Scopolamine, Ephedrine and Eukodal (oxycodone) (Galetti, 2023).
Medical Uses

Oxycodone’s immediate-release formulation is FDA-approved for the management of moderate to severe pain, as well as acute or chronic pain relief. The use of oxycodone medication has been deemed appropriate in scenarios in which other pain management strategies are insufficient [Figure 4]. Effective analgesic therapy such as oxycodone, when used appropriately, has been shown to improve patients' quality of life. Oxycodone is also available as an extended-release tablet, intended to be taken every twelve hours. An independent study conducted in July 1996 found that the extended-release formulation had a variable duration of action, ranging from 10 to 12 hours. A 2006 review, reported that the controlled-release oxycodone was found to be comparable to immediate-release oxycodone, morphine, and hydromorphone in treating moderate to severe pain in cancer patients. The reviewer concluded that the extended-release formulation of oxycodone was indeed a valid alternative to morphine and a first-line treatment option for cancer patients (Fortunato et al., 2023; Sunshine et al., 1996).

In the US, extended-release oxycodone is further approved for the treatment of children as young as 11 years old. The approved uses are for the relief of cancer pain, trauma pain, or pain due to major surgery, in children who have already been treated with other opioids, and who can tolerate at least 20mg of oxycodone per day. Duragesic (fentanyl), is the only other extended-release opioid analgesic approved for children, and oxycodone extended-release formulation has proven to be an effective alternative (Sunshine et al., 1996).

Figure 5: The Iranian opium poppy flower, Papaver bracteatum (The Flower Cartel, n.d.).
The Opioid Epidemic in the United States

The opioid epidemic in the United States is ongoing and is the result of extensive and ongoing overuse of opioid medications, both legally and illegally. If oxycodone is administered in high doses, or in people not tolerant to opioids, can cause major complications, including; thoracic breathing, bradycardia (slower than normal heart rate), cold or clammy skin, low blood pressure, absence of breathing, miosis, circulatory failure, and death. In 2011 the United States claimed that oxycodone overdose was the leading cause for drug-related deaths in the country. The following year heroin and fentanyl were reported as the leading cause of drug-related deaths. Oxycodone overdose has also been described as the main reason for spinal cord infractions and ischemic damage, caused by reduced blood flow to the brain due to prolonged or suppressed breathing (Comer et al., 2010).

The death rate from overdoses involving opioids, including prescription and illicit opioids, was raised up to nearly 645,000 people between 1999 and 2021, during which three distinct waves were seen. The first wave was attributed to prescription opioid overdose deaths (natural and semi-synthetic opioids as well as methadone) which started in the early 1990s to 1999, following the increased prescribing of opioids, specifically oxycodone. The second wave was seen in 2010, involving overdose deaths attributed to heroin, and the third wave in 2013 which was attributed to a significant increase in overdose deaths involving synthetic opioids, particularly due to illicitly manufactured fentanyl. The illicit fentanyl market continues to change, and it is often found mixed with heroin, counterfeit pills, and cocaine (Manchikanti et al., 2012; Wilkerson et al., 2016). The U.S. Department of Health and Human Services has estimated that about 11 million people in the U.S. consume oxycodone in a recreational way. It was reported that 42800 emergency room visits in 2007 occurred due to patients that had consumed oxycodone, and in 2008, 14800 deaths were related to recreational use of oxycodone and hydrocodone. The amount of opioid drug overdose deaths reported in 2007 was 49000 out of 72000 in the U.S. Since the reformulation of Oxycontin caused an increase in the price, recreational users have changed to heroin, which has become easier and cheaper to obtain.

The New Yorker published an article in October 2017 about the owners of Purdue Pharma, brothers Mortimer, Raymond, and Arthur Sackler [Figure 6], and their links to oxycodone production and their involvement in the manipulation of the market (Keefe, 2017). The article links Raymond and Arthur Sackler's business practices with the rise of direct pharmaceutical marketing and eventually to the rise of addiction to oxycodone in the United States. The article implies that the Sackler family members are allegedly responsible for a large part of the opioid epidemic in the U.S. Maura Healey, Massachusetts' attorney general, filed a lawsuit alleging that Purdue Pharma and the Sackler family knew that high doses of Oxycontin over long periods would lead to serious side effects, including addiction (Wilkerson et al., 2016). The family eventually agreed to pay $6 billion in settlement fees for their role in fuelling the opioid epidemic.

Figure 6: The Sackler family (Daily Mail, n.d.).

Oxycodone's history is a compelling narrative of both medical progress and societal struggle. As oxycodone has exemplified the complexity surrounding opioid medication since it was first developed to alleviate pain and reduce the risk of addiction, it has become synonymous with the complexities surrounding opiates as a whole. There is no doubt that oxycodone remains a valuable tool in the arsenal of pain management, however, its misuse and the devastating opioid epidemic that followed have left a lasting effect. Oxycodone's history suggests that prescriptions should be made responsibly, patients should be educated, and strict regulations should be enforced to prevent misuse.

We must continue to work together as healthcare providers, pharmaceutical companies, policymakers, and the general public to strike a balance between providing relief from pain and guarding against overdose and addiction risks. Oxycodone's story is a reminder of the need for a comprehensive and compassionate approach to pain management that takes into account both the benefits and the potential harms of opioid medications.

Bibliographical References

Comer, S., Sullivan, M., Vosburg, S., Kowalczyk, W., & Houser, J. (2010). Abuse liability of oxycodone as a function of pain and drug use history. Drug and alcohol dependence, 109(1-3), 130–138.

Defalque, R. J., & Wright, A. J. (2003). Scophedal (SEE) was it a fad or a miracle drug? Bulletin of Anesthesia History, 21(4), 12–14.

Fortunato, J., Kullgren, J., Houchard, G., Hirsch, J., Shirilla, N., Bumb, M., & Li, J. (2023). Oxycodone Extended-Release Capsule Utilization for Pain Management in a Cancer Palliative Care Clinic: A Retrospective Review. Journal of Pain & Palliative Care Pharmacotherapy, 1–12.

Keefe, P. R. (2017). The family that built an empire of pain. The New Yorker, 30.

Manchikanti, L., Fellows, S. H. B., Janata, J. W., Pampati, V., Grider, J. S., & Boswell, M. V. (2012). Opioid epidemic in the United States. Pain Physician, 15(3S), S9.

Mitchell, J. (2018). How the FDA Helped Pave the Way for an Opioid Epidemic. Mississippi Clarion Ledger.

Ogle, A., Moore, K., Barrett, B., Young, M. S., & Pearson, J. (2012). Clinical history and characteristics of persons with oxycodone-related deaths in Hillsborough County, Florida in 2009. Forensic Science International, 223(1-3), 47–52.

Ordonez Gallego, A., Gonzalez Baron, M., & Espinosa Arranz, E. (2007). Oxycodone: a pharmacological and clinical review. Clinical and Translational Oncology, 9, 298–307.

Sadiq, N. M., Dice, T. J., & Mead, T. (2022). Oxycodone. In StatPearls. StatPearls Publishing.

Sunshine, A., Olson, N. Z., Colon, A., Rivera, J., Kaiko, R. F., Fitzmartin, R. D., Reder, R. F., & Goldenheim, P. D. (1996, Jul). Analgesic efficacy of controlled-release oxycodone in postoperative pain. Journal of Clinical Pharmacology, 36(7), 595–603.

Warner, M., Chen, L. H., Makuc, D. M., Anderson, R. N., & Minino, A. M. (2011). Drug poisoning deaths in the United States, 1980–2008. NCHS data brief, 81(81), 1–8.

Weber, M. (2005). Oxycodon–A psychopharmacologic-historical note on an opium analgesic. Pharmacopsychiatry, 38(05), 243.

Wilkerson, R. G., Kim, H. K., Windsor, T. A., & Mareiniss, D. P. (2016). The opioid epidemic in the United States. Emergency Medicine Clinics, 34(2), 1–23.

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Nicole Galetti

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