Light before Dark: Fentanyl

Those who don’t like certain aspects of the 1960s – and there are many who don’t – might add another item to their list of complaints. They should add what the Centers for Disease Control and Prevention in Atlanta at the end of 2018 called the deadliest drug in the United States – a substance killing thousands in our country and thousands around the world; something few had heard of just five years ago but was killing more Americans under age 55 than guns, and more people than AIDS at the height of the crisis.

FENTANYL:  a child of the 1960s and a terrible problem fifty years later.

And the emphasis on later is important because at first it was a medical boon, the product of curiosity; an innovation in patient care, in surgery, and in the management of pain.

I’d like to look at the good side of fentanyl a bit with this column this month. Next time, we’ll turn a bit to the terrible problem that inadvertently developed later.

Albert Hoffman (1906-2008) is the big personality in most accounts of the era when it comes to drugs. After all, his lab in Switzerland, ergot, and the famous bike ride in 1943 produced LSD, the “fuel” of the counterculture of Haight-Asbury, Timothy Leary, and the even the psychedelic character of later Beatles tunes.

Still, it was another European chemist – Belgian this time – a structure activity pharmacologist and medical doctor named Paul Janssen (pictured, 1926-2003) who might be more important today. He was the creator in 1960 of fentanyl by experimenting with the structure of a widely-used opioid called meperidine (demerol), originally synthesized in the late 1930s by the German chemical company IG Farben.

Since 1953, Janssen had run his own shop, initially as part of his father’s medicine company, and through the 1950s had indulged his passion for tinkering with molecules.

Janssen and his colleagues would invent new compounds for the relief of diarrhea (immodium), and in the areas of psychiatry (Haldol), mycology, and parasitology. But it was in the areas of surgery and pain that he made his most notorious, and initially excellent, mark. With the goal to increase lipid solubility (absorption/bioavailability), Janssen Pharmaceutica researchers were able to change the basic molecular structure of meperidine to an opioid known as phenoperidine, 25 times more potent than morphine and 50 times that of meperidine-demerol. Further molecule tinkering and experiments in mice yielded a still faster acting, shorter duration, and a 10X more potent compound than phenoperidine. This was something called fentanyl.

Here was a kind of “super-synthetic” – not the simple modifications of morphine that came from opium poppies growing on hillsides in Burma and Afghanistan: “natural” compounds like codeine, hydrocodone, oxycodone, and hydromorphone.

No. Fentanyl didn’t come from poppies. It was “unnatural” – produced from a fully synthetic opioid root – meperidine – and this root was manipulated molecule by molecule by wizards like Paul Janssen into more and more artificial products, each stronger than the next – until he arrived at the most potent opioid drug then known. This was fentanyl, which became a platform in 1960 for even stronger “analogues” like alfentanil, sufentanil, and the monstrous carfentanil.


But wait . . .

As bad as these seem today, in our period, they were part of a revolution, a good one – in anesthesia.

First Edition was 1957

Janssen sent fentanyl to clinicians around Brussels who confirmed the usefulness of the new molecule when combined with one of a number of intravenous and inhaled substances (such as nitrous oxide and oxygen) to accomplish a technique with the complicated name “neurolept anesthesia.” The use of the “new kid” fentanyl became popular in this way across Western and Eastern Europe by the mid-1960s, but the United States stood outside this acceptance.

. . . until Johnson & Johnson bought Janssen Pharmaceutica and Janssen himself elicited the imprimatur for fentanyl from the influential experimental anesthesiologist, Robert Dripps (1911-1973), of the University of Pennsylvania.

The green light did not come immediately. Dripps found an opioid 100 times stronger than morphine unnecessary and likely problematic for the average clinician. Moreover, for its rapid onset of action, it might be used as a drug of abuse. Still, a compromise was reached by restricting fentanyl only in combination with a 50:1 dose of the tranquilizer droperidol, which prevented potential abusers from any kind of high, and on this basis was approved by the FDA with brand names like Innovar and Thalamonal in 1968.

Approval was not acceptance by medical practitioners, and it took two more pieces to complete the “puzzle” to fentanyl’s widespread medical use.

In the late 1960s, high-dose opioid anesthesia in the operating room became commonplace, consisting mainly of morphine and oxygen, and several published studies reported good results with patients requiring major surgery, specifically in the cardiovascular area (e.g., see E. Lowenstein et al, “Cardiovascular response to large doses of intravenous morphine in man,” N.Engl J.Med, 1969). The period 1960-75 was a breakthrough time for heart surgery with names like Shumway, Barnard, Cooley, DeBakey, Zuhdi, and Reitz (see “Surgery Timeline” under SCIENCES) and high-dose narcotic anesthesia helped these pursuits, blocking the production of stress-responding hormones, creating remarkable cardiovascular stability in patients.

Morphine as general anesthesia’s chief ingredient, while popular and effective, showed unwelcome side effects including severe hypertension, hypotension, post-operative amnesia, and bradycardia; and in the early 1970s doctors seeking alternatives turned to FDA-approved fentanyl.

By the mid-1970s fentanyl had replaced morphine almost completely in the operating theater as the key ingredient in anesthesia, without the side effects. The acceptance of fentanyl as a pure opioid anesthetic or as a supplement to other hypnotics or inhaled agents stimulated innovation in J&J’s Janssen unit to develop new powerful compounds such as alphamethlfentanyl, sufentenil, and carfentanil in the mid 1970s. These various agents, always built from the fentanyl base, came at the same time as the anti-rejection drug ciclosporan. Heart surgeons finally had the basic tools to extend life through extended and involved transplant operations.

Innovation continued into the 1980s with the fentanyl patch (Duragesic) for pain, nasal sprays, lozenges, and the fentanyl “lollipop” to head off breakthrough pain, and accompany servicemen on the field of battle.

* * * * *

Fentanyl and its analogues have benefited patients in operating rooms and in the management of pain. For decades they were the focus of the kind of innovation that makes America a leader in solving problems in a variety of areas – in this case, medical chemistry and surgery.

In the late 1970s, though, the fentanyl story turned dark, and a new, sinister type of innovation appears. These years are certainly outside our period. They serve to connect the 1960s to the present and explain why today looks the way it does which, after all, is the purpose of this column. We’ll make this important connection next time.

Janssen Pharma in Beerse, Belgium today

Until March,

February 7, 2021

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