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The History of Fentanyl

Fentanyl is a very potent synthetic opioid, first synthesized in 1960.

It is similar to morphine in its chemical structure, but it is many times more potent. Most sources report that fentanyl is between 50 and 100 times more potent than morphine.

Like the majority of other opioid drugs, it is used in the treatment of severe pain. Fentanyl’s specific medicinal uses include the treatment of postoperative pain and chronic pain for people who have significant tolerance to other opioids.

Prescription forms of fentanyl include Actiq, Duragesic, and Sublimaze. The drug can also be produced illicitly and may be marketed under numerous street names, such as Apache, China White,China Girl, Murder Eight, or Tango & Cash.

Fentanyl Abuse

Because of its high potency, fentanyl is a dangerous drug of abuse. According to data that the Substance Abuse and Mental Health Services Administration (SAMHSA) provides:

  • In 2016, about 1.8 million people reported using fentanyl at least once, and 228,000 of those individuals reported misusing the drug at least once.
  • In 2017, about 2 million people reported using fentanyl at least once, and 245,000 of those people reported misusing the drug at least once.

Fentanyl is probably best known as a significant drug of abuse and for its reported association with opioid overdose deaths.
Although prescriptions for powerful opioids have started to decline overall, opioid-related overdoses have increased. Synthetic opioids like fentanyl are increasingly responsible for these deaths in the United States. According to the National Institute of Drug Abuse, in 2010, opioid-related overdose deaths that involved fentanyl comprised 14.3 percent of deaths, whereas, in 2017, this rose to 59 percent.
The history of the development of fentanyl foreshadowed its potential dangers. 

The 1950s: New Synthetic Opioids

In the early 1950s, Janssen Pharmaceutica and other drug companies developed very rapid-acting analgesic medications to treat pain and be used as anesthetics. At the time, popular opioids for the treatment of postsurgical pain and chronic pain were morphine and Demerol (meperidine).
Dr. Paul Janssen, the founder of Janssen Pharmaceutica, began to develop new synthetic opioids using Demerol as their structural basis. The strategy was to find new molecules that were more powerful than morphine or Demerol that could result in analgesics with fewer side effects.
One of the challenges was to develop a molecule that would more easily penetrate the blood-brain barrier than the existing opioids could.

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Fentanyl Is Developed

From 1953 to 1957, Janssen Pharmaceutica created many potent fat-soluble pain relievers.
The major advancement of the research was the development of an opioid known as phenoperidine, a synthetic drug that was believed to be 25 times more potent than morphine and more than 50 times more potent than Demerol based on animal research studies. At the time, it was the most potent opioid available, but it could not be marketed in the United States because the Janssen Company did not have an organization in the country at that time.

The company continued to synthesize new molecules related to phenoperidine, and fentanyl was first synthesized in 1960. This drug was even more potent than phenoperidine (estimated to be 10 times more potent).
Fentanyl also had the fastest onset of action and was the most potent opioid drug in the world at the time. It was not practical for oral administration because the majority of the compound was destroyed when it was taken orally. Therefore, it was considered to only be useful via intravenous administration (by injection).

Not Initially Popular in the United States

Fentanyl was often used in European countries in combination with other intravenous medications. Only small amounts of fentanyl were needed in these combinations, and many different combinations were used.
A couple of technical terms that may be encountered when investigating the use of combinations of drugs include:

  • Neuroleptanalgesia, which is the technique of giving two drugs together as anesthetics
  • Neuroleptanesthesia, which is the term used when nitrous oxide is added to the mixture of the other drugs

An anesthesiologist in Belgium during the latter part of the 1960s and early 1970s (George de Castro) became interested in developing “stress-free analgesia.” This was the use of a drug combination that provided the analgesic effects with no significant alteration of heart functioning and would also block the production of stress-responding hormones. He found that fentanyl worked. His results were only published in a regional journal that was not widely known.
Fentanyl use was enjoying success in Europe at this time, but not in the United States. Janssen Pharmaceutica was having difficulty getting the drug approved by the U.S. Food and Drug Administration (FDA).

Medical Fentanyl Use

Opposition to the use of fentanyl in the United States included a very distinguished anesthesiologist of the time, Robert Dripps, MD. He believed that fentanyl was far too potent for medicinal use as an anesthesia medication and caused rigidity in patients who used it.

For these reasons, he believed that the use of the drug during surgery would require patients to be intubated, and the approval of the drug would lead to significant problems with its abuse later due to its potency.

Eventually, Dripps was convinced to alter his stance as a result of discussing the situation with Janssen. The drug was approved in 1968, but it was approved for use only when it was used in combination with the tranquilizer droperidol (brand name: Inapsine).  The ratio of droperidol to fentanyl was 50:1, and this combination became known by the brand name Innovar in America; it was known as Thalamonal elsewhere.

Accompanying Drugs

In the United States, neuroleptanalgesia or neuroleptanesthesia never achieved significant popularity with physicians due to numerous variations in techniques and the occurrence of dysphoria (negative mood states) in individuals following surgery.
In 1972, fentanyl became available alone for use in anesthesia, but it was only used in tiny amounts.

Medicinal Fentanyl Use Increases

In the late 1970s and early 1980s, fentanyl was found to be very useful as an anesthetic during cardiac and vascular surgery.

Because of this, there was a dramatic increase in use and sale of the drug. This led to generic forms of the drug becoming very popular when the drug’s patent expired.
At this time, it was only being used during the preoperative period by anesthesiologists, but the drug was inexpensive and easy to produce, so fentanyl began to find other uses. It became available for use in transdermal patches and lollipops for the treatment of acute pain after surgery and even for chronic pain for individuals who needed steady, sustained levels of a powerful opioid. 

Pills and a syringe on the floor

The Downside to the Approval of Fentanyl

The development of fentanyl and its medical use initially began with the need to find a more effective anesthetic, and later, it morphed to provide more effective pain relief to patients who needed it. However, some of the earlier concerns about the development of very potent and powerful opioids were realized.

  • Overdoses on fentanyl appeared only a few years after its approval in the United States.
  • Clinicians started to report cases of misuse and illicit use very soon after its approval.
  • As more variations in the method to administer the drug became available in the decades following its approval, overdose-related deaths also increased in the United States.
  • The increase of fentanyl-related overdose is a result of numerous factors, including inappropriate prescriptions made by physicians, accelerating misuse of the drug by patients with a prescription for it, and illicit use of the drug by opioid abusers.


Initially, the use of oral forms of fentanyl was approved only for hospital use. Even this approval was held up for some time because there was concern about unintentional overdoses on fentanyl occurring in hospital settings.
The U.S Food and Drug Administration (FDA) required a risk mitigation strategy for the use of most of the newer fentanyl products because it was believed these products would eventually be used by patients outside of a hospital setting. In 2011, the FDA developed a risk evaluation strategy for the entire class of rapid/immediate-release fentanyl products that attempted to:

  • Prescribe and dispense these medications only to appropriate patients
  • Decrease inappropriate use of these products
  • Prevent accidental exposure to people for whom the medication is not intended, such as children
  • Provide education for patients and prescribers on the potential misuse and abuse of these medications

However, the illicit laboratories that produce and sell fentanyl and analogs of the drug are not affected by these policies. Since the late 1970s, many illegal laboratories have produced these drugs, leading to an increase in fentanyl-related overdoses in the United States and the alarming practice of combining fentanyl with heroin.

Should Pharmaceutical Companies Be Held Accountable?

Many of the sanctions and controls on opioids have reduced prescription rates for these drugs. Now, there are attempts to hold pharmaceutical companies responsible for the rise in opioid-related overdoses in the United States in a similar manner to the numerous lawsuits aimed at tobacco companies.

Given some of the marketing practices by these companies, there is certainly some justification for these actions. However, opioid medications like fentanyl do have useful medical uses. 

While pharmaceutical companies should be held accountable for questionable marketing strategies, there is the argument that they do not force individuals to abuse these drugs. Many individuals abuse the drugs with the knowledge that it is a dangerous practice.

The best path forward is prevention and aiming to help as many people struggling with opioid abuse as possible.


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(February 2019). Fentanyl. National Institute on Drug Abuse. Retrieved March 2019 from

(2008). A Tribute to Dr. Paul AJ Janssen: Entrepreneur Extraordinaire, Innovative Scientist, and Significant Contributor to Anesthesiology. Anesthesia and Analgesia. Retrieved March 2019 from

(March 2019). Phenoperidine. National Center for Biotechnology Information. PubChem Compound Database. Retrieved March 2019 from

(2010). Anesthesia: A Comprehensive Review E-Book. Elsevier Health Sciences. from

(April 1992). The History and Development of the Fentanyl Series. Journal of Pain and Symptom Management. Retrieved March 2019 from

(2014). The Wondrous Story of Anesthesia. New York, Springer. from

(December 2014). The Fentanyl Story. The Journal of Pain. Retrieved March 2019 from

(December 2011). FDA Approves Shared System REMS for TIRF Products. Emerging Solutions in Pain. Retrieved March 2019 from

(August 2018). Abuse of fentanyl: An emerging problem to face. Forensic Science International. Retrieved March 2019 from

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