Biomedical Research

The Historical Development of Fentanyl

Fentanyl has become one of the most valuable drugs for pain treatment throughout the world. Since its creation, fentanyl has been administered in a number of ways, including patches and sprays. Learn more about the studies, uses, and developments of this drug!


Fentanyl has become one of the most valuable drugs for pain treatment throughout the world. Most commonly, it is used intravenously for intraoperative analgesia: drugs used during surgery.1 Additionally, fentanyl’s patch form is often prescribed for cancer patients who experience intense pain. Since its creation, fentanyl has been administered in a number of ways, including patches and sprays.1  


 Dr. Paul Janssen, founder of Janssen Pharmaceutica, was interested in creating a fast acting analgesic for treatment. While morphine and meperidine were both available during this time, they often performed poorly or were not fast-acting enough.2 With this research in mind, Janssen’s team desired to create new molecules that were more powerful than both of the former drugs. To begin their pursuits, Jassen’s team began by working with meperidine, which was easier to manipulate, as it is not as complex as morphine.3 The research team hypothesized that the piperidine ring, a cyclohexane in which one of the carbons is replaced by a nitrogen that is found in morphine and meperidine, was crucial in the production of analgesia.3,4 However, they discovered that the rate of production was not fast acting, as morphine and meperidine were unable to easily penetrate into the central nervous system.3 In order to create drugs that were capable of doing this, the team began removing a number of chemical structures like ethyl and methyl groups to create lipid-soluble drugs.3 In doing so, Janssen and his team were able to create dozens of far more potent and lipid-soluble drugs, including phenoperidine in 1957.2 


Phenoperidine was proven to be an incredibly potent drug; it is 25 times more potent than morphine and 50 times more potent than meperidine.3 Phenoperidine’s strength led the team to continue to synthesize molecules related to phenoperidine in hopes of creating even more effective drugs.3 Finally, in 1960, they created fentanyl.3 Fentanyl was more than 10 times more potent than phenoperidine, and 100 to 200 times more potent than morphine.3 Additionally, it had a much greater liquid solubility than the molecules that came before it: its octanol/water partition coefficient, a method of expressing the lipophilicity of a compound, was 813.3,5 Furthermore, it had the fastest onset action rate at the time of its creation.3 Fentanyl’s onset rate was 277 compared to 4.7, 71, and 39.1 for meperidine, morphine, and phenoperidine respectively.3

However, the Janssen Company experienced difficulty in getting the Food and Drug Administration’s (FDA) approval for use in the United States.3 In particular, Dr. Dripps, a professor of anesthesiology at the University of Pennsylvania, believed that fentanyl was far too strong of a drug to administer,  and it would consequently lead to abuse.3  To ease his concerns, Dr. Janssen met with Dr. Dripps, and they reached a compromise: fentanyl would only be administered in a 1: 50  ratio with droperidol.3 This ratio convinced Dr. Dripp that fentanyl would be safe to use, as both him and Dr. Janssen knew that droperidol did not have a pleasing effect if used recreationally.3 The 50:1 ratio of droperial to fentanyl,  Dr. Dripps believed,  would decrease the chances of fentanyl being abused.3 The FDA subsequently approved, and fentanyl began to be administered in the United States only in a 1-mL vial containing 50 µg.3

Soon, this was not the only way fentanyl began being administered in the United States. Fentanyl’s success as an analgesic prompted Alza Corporation to develop a fentanyl patch in the 1980s.3 This patch would later be known as Duragesic.3 


The next major development in fentanyl administration was not as intentional.3 Dr. Janssen suggested to Dr. Ted Stanley to study the effect of carfentanil, a cousin of fentanyl, on several animals including rats, dogs, and ferrets.3 Yet, it was not until Dr. Stanley observed the Rhesus monkeys, when the idea of a new fentanyl product was created.3 The monkeys did not respond well to the carfentanil delivery techniques implemented by the research team, but Dr. Stanley knew that monkeys were fond of sugar cubes and grew curious as to whether or not carfentanil could be injected into sugar cubes.3 This prompted researchers to deliver two sugar cubes that had been injected with different doses of carfentanil to two monkeys.3 Within minutes, the monkeys finished eating the sugar cubes.3 The monkey that had eaten the sugar cube with the larger dose became narcotized and the monkey who had the smaller dose became mildly sedated.3 

This experience caused Dr. Stanley to wonder if there was a similar technique to deliver fentanyl to children.3 Days later, fentanyl on a lozenge stick, essentially a lollipop, was being developed.3 In 1984, Oralet produced a product resembling a red lollipop that was marketed as a child friendly method of administering fentanyl.3 Their creation was fast-acting: the onset was approximately 5-15 minutes and the effect lasted between 1-2 hours, which was one of Dr. Janssen’s main goals in creating fentanyl.3 Thus, a new company, Anesta, was formed in order to get oral transumyatcocan fentanyl citrate, OTFC, approved by the FDA and then launched into the market.3 

While Oralet was available for clinical use, it was not until Dr. Perry Fine and Dr. Michael Ashburn, clinicians at University of Utah, grew curious as to whether or not OTFC could relieve severance to chronic pain in cancer patients that Oralet was prescribed more frequently.3 Dr. Fine and Dr. Ashburn determined that Oralets works as an effective analgesic for patients who experienced breakthrough pain, BTP, in ten to fifteen minutes.3 This was faster than any opioid available on the market at the time.3 Furthermore, they discovered that the unit was not necessary to relieve pain; this was another benefit of an OTFC Unit: clinicians now had the capability to titrate the correct dosage of fentanyl for their patients.3

Dr. Fine and Dr. Ashburn’s results prompted Anesta to develop a new OTFC unit: Actiq.3

Oralet was specially designed to look more like a lollipop and less like traditional medicine, as it was created for out of hospital use.3 Its counterpart, Actiq, maintained a more traditional medical design as it was approved to be used in hospitals only.3 By the end of 2000, Anesa was purchased by Cephalon, making Actiq experience commercial success.3


Actiq’s widespread use convinced many more companies to develop similar products.3 In 2006, Cephalon created Fentora, which is essentially the same product as Actiq, except it contains no sugar.3 Also, Fentora’s main achievement was starting the search for effective methods of administering fentanyl that were not OTFC, such as OraVescent.3 OraVescent drug delivery systems release carbon dioxide when a tablet containing fentanyl makes contact with saliva. This release alters the pH causing the tablet to dissolve at a faster rate.3 Finally, when the tablet is completely dissolved, the carbon dioxide is gone.3 OraVescent’s biggest value is that it produces faster blood levels of fentanyl when compared to Actiq.3 Finally, a more recent method of administering fentanyl has been by spray.3 The spray encapsulates Dr. Janssen’s primary goal of synthesizing fentanyl, creating an even more fast-acting and effective opioid.3 The fentanyl spray uses un-ionized fentanyl and has an onset time of five minutes or less.3 Furthermore, the nasal spray shows promise of widespread use as it appears to treat approximately 80% of BTP cases.3 While more research needs to be conducted, these early results are incredibly promising.3 

Afifa Zahid, Youth Medical Journal 2020


  1. Peng, P. W.; Sandler, A. N. A Review of the Use of Fentanyl Analgesia in the Management of Acute Pain in Adults. Anesthesiology [Online] 1999, 90 (2), 576–599.
  2. Stanley, T. H.; The History and Development of the Fentanyl Series. Journal of Pain Symptom Management [Online] 1992, 7 (3), 1-5.

Stanley, T. H.; The Fentanyl Story. The Journal of Pain [Online] 2014, 15 (12), 1215–1226


By Afifa Zahid

Hi my name is Afifa Zahid and I am a senior at Bard High School Early College Manhattan and I'm interested in neurology .

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