In 1953, Paul Janssen founded his company, Janssen Pharmaceutica, initially working out of the third floor of his father’s building. “We didn’t even have a calculator, let alone a computer for the simplest calculations,” Janssen wrote in 2000. “To reduce expenditure we economized by performing simple tests on pieces of gut from newly slaughtered rabbits, which I collected early in the morning from a butcher in Turnhout.”
Despite its modest beginnings, the company hit the ground running with its discovery of a drug called ambucetamide, used to alleviate menstrual pain. Janssen would also invent loperamide (Imodium), for diarrhea, as well as chemicals that became critical to the fields of psychiatry, mycology, and parasitology. To spur his company’s ascent, he recruited star Belgian scientists from the Belgian Congo, after the political upheaval there that would lead to the country’s independence and the end of colonial rule. He was soon managing a large staff—its members called him Dr. Paul—but still closely involved with creating new chemicals. He literally daydreamed about molecules. “I often watched him at meetings,” wrote Sir James Black, a physiology and medicine Nobel laureate of King’s College London, “when bored with the proceedings, finding solace inside his head as he doodled new chemical compounds!”
One of these new chemicals was fentanyl, which Janssen and his team first synthesized in 1959 by experimenting with the chemical structure of morphine.
Derived naturally from the resin of the opium poppy, morphine was chemically isolated at the dawn of the nineteenth century by German pharmacist Friedrich Sertürner, who named it for Morpheus, the Greek god of dreams. By Janssen’s time it was the reigning pain reliever. Janssen began subtly altering parts of its chemical structure to create new compounds. He tested the effectiveness of these creations, including fentanyl, on lab mice, placing the mice on hot plates and slowly turning up the heat to gauge their reactions.
He developed many morphine derivatives, but fentanyl was particularly profitable for Janssen Pharmaceutica. Doctors found it superior to morphine because of the way it acted. Like morphine, it bound with a receptor in the brain (which we now call the “mu” receptor) to cause pain relief. But fentanyl came on faster, was much more powerful, and wasn’t as likely to cause nausea. “Fentanyl,” Janssen later wrote, “made it possible for the first time to perform lengthy operations and, together with its successors, heralded a revolution in the operating theatre. Without this compound and its analogue, sufentanil, open-heart surgery [as performed today] would not be possible.”
The drug was a revelation, and it went on to become the world’s most widely used anesthetic. Janssen Pharmaceutica was purchased by American behemoth Johnson &. Johnson in 1961, and Paul Janssen continued working for the company, tasked with developing other types of fentanyl, referred to as analogues. But almost from the start, fentanyl’s potential addictive dangers were recognized, and it was placed under international control by a United Nations agreement in 1964. This led countries including the United States and the United Kingdom, in 1971, to schedule it—that is, to ban its recreational use. Indeed, its euphoric qualities would prove too much for many users to resist. “Fentanyl is a good medicine but a bad drug,” Justice Tettey, chief of the Laboratory and Scientific Section at the United Nations Office on Drugs and Crime, summed up later. “It has excellent pain relieving properties, but is liable to abuse and can rapidly lead to dependency.”
Despite fentanyl’s quick success as a painkiller in Europe, during the 1960s it was almost blocked for sale in the United States by the Food and Drug Administration. One vocal opponent to the drug’s approval was University of Pennsylvania anesthesiology professor Robert Dripps. A rare outlier who believed fentanyl’s high potency could lead to abuse, he eventually agreed to a compromise after being lobbied by Paul Janssen himself: fentanyl would be available, but only when diluted with another drug called droperidol, a sedative—also patented by Janssen—that was believed to mitigate fentanyl’s detrimental effects. A ratio of fifty parts droperidol to one part fentanyl produced a “bad high” when taken recreationally, Dripps and Janssen agreed, and thus was unlikely to be abused. The FDA approved this combination in 1968. Fentanyl’s success boosted Janssen’s bottom line, which drove Paul Janssen and his colleagues to develop many other fentanyl analogues. Some, like alpha-methylfentanyl, were never turned into medicines that were sold. Others, however, made it to market, including sufentanil, used in long-lasting surgeries, and carfentanil, a veterinary medicine that is the strongest fentanyl analogue ever made commercially.