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Pharmacology 101: Fentanyl and Naloxone Pharmacology for EMS, Part 1

Pharmacology 101 is an online column designed to keep EMS providers informed on formularies, dosages, effects, applications, and current research related to medications administered in the prehospital setting. If you have a medication-related question you’d like the author to address, contact editor@emsworld.com.

“Presently she cast a drug into the wine of which they drank to lull all pain and anger and bring forgetfulness of every sorrow.”

The Odyssey, Homer (ninth century B.C.)

“And now my beauties, something with poison in it I think, with poison in it, but attractive to the eye and soothing to the smell…poppies, poppies, poppies will put them to sleep.”

—The Wicked Witch of the West, The Wizard of Oz (1939)

Every EMS caregiver is likely familiar with the signs and symptoms of opioid overdose: respiratory depression, pinpoint pupils, and decreased responsiveness. And who doesn’t know its reversal agent, naloxone? So why do an article on an old topic? While recognizing and responding to opioid overdoses may be old hat to many, the spirit of this column is to educate caregivers to a higher level of knowledge in pharmacology topics. To that end, this article series will address several points:

  • What is the epidemiology of opioid overdose? How significant is it?
  • What is the history of opioids, and what are their origins? What were the origins of fentanyl?
  • What is the pharmacology of fentanyl?
  • What is naloxone, and is it truly “harmless”?
  • Which is better, intranasal or intramuscular naloxone administration?

Epidemiology of Opioid Overdoses in the U.S.

As the use of synthetic opioids has increased, so have the harms associated with them. From 1999–2017, opioids represented 56.8% of drug overdose deaths.1 And according to the Department of Health and Human Services and CDC, “Opioids were involved in approximately 70% (46,802) of drug overdose deaths during 2018.”2 These are not insubstantial numbers!

While some may believe opioids are a relatively new pharmacological development, opioid use was first recorded in approximately 1500 B.C. in the Ebers Papyrus, which described the extraction of opium from the poppy plant. It is generally agreed the Sumerians had cultivated poppies and isolated opium as early as the end of the third millennium B.C.3,4

Opium was brought to China and India by Arab traders as early as the eight century A.D., then progressed from Asia Minor to Europe between the 10th and 13th centuries. In the 16th century descriptions of addiction began to appear in Turkey, Egypt, Germany, and England.5

More recently opioids have been used in various formulations including laudanum, paregoric, Dover’s powder, and Godfrey’s Cordial. Morphine was isolated in 1804 and named after Morpheus, the Greek god of dreams.5 Seventy years later heroin was synthesized. In the 1890s heroin was actually marketed as an antitussive agent.4 As prominent researcher Michael Brownstein, MD, PhD, has dryly noted, “Heroin was synthesized and pronounced to be more potent than morphine and free from abuse liability. This was the first of several such claims for novel opiates. To date, none has proven valid.”5

In the 20th century the Harrison Narcotics Tax Act of 1914 made it illegal to use opioids for nonmedicinal purposes.4 Later synthetic opioids made in laboratories appeared, including methadone and fentanyl. While the term opiates and opioids are often used interchangeably, according to the CDC, “Opiates refer to natural opioids such as heroin, morphine, and codeine,” and “Opioids refer to all natural, semisynthetic, and synthetic opioids.”6

The History of Fentanyl

According to legendary anesthesiologist Ted Stanley, MD, it was in 1953 that Belgian physician Paul Janssen started to research how to create the most powerful narcotic analgesic possible, and his team began to manipulate the structure of the meperidine molecule. Dozens of new and more potent opioids were synthesized by Janssen and his colleagues in the coming years. Finally in 1960 their team developed fentanyl, which at its time was the most potent opioid in the world. Furthermore, it was also the fastest-acting and most lipid-soluble (lipid solubility promotes faster uptake into the brain). According to the reports, fentanyl had 100–300 times the potency of morphine!7,8 Furthermore, a slight molecular change to the fentanyl molecule produced carfentanil, an opioid with approximately 10,000 times the potency of morphine.7  

In 1972 fentanyl received FDA approval for use during anesthesia and the perioperative period, and shortly thereafter overdoses of fentanyl began to be reported. These had the classic opioid overdose toxidrome of severe respiratory depression, apnea, and death.8 The abuse of fentanyl and its analogs remains a substantial problem today.

From 2017 to 2018, overall deaths from all opioids, prescription opioids, and heroin decreased, but deaths from synthetic opioids increased by 10%. The increase is thought to be propelled by illicitly manufactured fentanyl and fentanyl analogs.2 An image provided by the National Institute on Drug Abuse (see Figure 1) shows the dramatic rise in deaths involving synthetic narcotics other than methadone (mainly fentanyl) in comparison to other substances.9  

EMS caregivers are frequently first responders to opioid overdoses, including fentanyl. In subsequent articles we’ll discuss the pharmacology of fentanyl and naloxone, with the goal of increasing EMS caregivers’ knowledge of both drugs through a more nuanced exploration of their pharmacological properties.

The views and opinions expressed in this article are those of the authors and do not necessarily reflect those of people, institutions, or organizations they have been, currently are, or will be affiliated with.

References

1. Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G. Drug and Opioid-Involved Overdose Deaths—United States, 2013–2017. MMWR, 2018; 67(5,152): 1,419–27.

2. Wilson N, Kariisa M, Seth P, Smith H, Davis NL. Drug and Opioid-Involved Overdose Deaths—United States, 2017–2018. MMWR, 2020; 69(11): 290–7.

3. Crocq MA. Historical and cultural aspects of man’s relationship with addictive drugs. Dialogues Clin Neurosci, 2007; 9(4): 355–61.

4. Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR. Goldfrank’s Toxicologic Emergencies, 10th ed. McGraw-Hill Education, 2014.

5. Brownstein MJ. A brief history of opiates, opioid peptides, and opioid receptors. Proc Natl Acad Sci USA, 1993; 90(12): 5,391–3.

6. Centers for Disease Control and Prevention. Opioid Overdose, www.cdc.gov/drugoverdose/index.html.

7. Stanley TH. The history and development of the fentanyl series. J Pain Symptom Manage, 1992; 7(3 SUPPL.): 3–7.

8. Stanley TH. The fentanyl story. J Pain, 2014; 15(12): 1,215–26.

9. National Institute on Drug Abuse. Overdose Death Rates, www.drugabuse.gov/drug-topics/trends-statistics/overdose-death-rates.

Daniel Hu, PharmD, BCCCP, has Doctor of Pharmacy degree and is a critical care and emergency medicine pharmacist. He is a frequent speaker at conferences and has many publications in peer-reviewed journals. 

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