Remembering the Classics-Honoring a Hero, Paul Janssen!
Alan Jay Schwartz, MD, MSEd and Myron Yaster, MD
When I started my career (early 1980s), newborn “anesthesia” was really newborn resuscitation in the OR. Monitoring was primitive (precordial stethoscope, finger on the pulse, manual blood pressure, and no pulse oximetry or capnography) and dialing in even a sub minimum alveolar concentration (MAC) dose of halothane often resulted in cardiovascular collapse. Interestingly, adults undergoing CABG surgery had similar problems until Dr Ted Stanley, https://medicine.utah.edu/anesthesiology/about/department-history/stanley one of the giants of anesthesia pioneered the use of fentanyl as the key component of balanced anesthesia for heart surgery. Using high dose fentanyl and muscle relaxants, Stanley was able to produce ideal operating conditions without the cardiovascular collapse.[1] Pediatric anesthesiologists Drs. Scott Robinson and George Gregory[2] picked up on this and changed the course of newborn anesthesia by substituting fentanyl for halothane in newborn anesthesia. Others followed and refined the dose and how to administer it during newborn anesthesia.[3-5]
Fentanyl became the mainstay opioid not only as a “single high dose” agent but as a component of virtually all modern anesthetics. And of course you know that illicit fentanyl is now the primary, lethal element driving opioid overdose deaths.[6]
But have you ever wondered who invented fentanyl and how such a potent opioid got FDA approval? This is a fascinating tale that we will review in today’s remembering the classics PAAD.[7] And as you will see, fentanyl was but one of the medical pharmaceutical triumphs of one person, Dr. Paul Janssen.[7] Myron Yaster MD
Original article
Stanley TH, Egan TD, Van Aken H. A tribute to Dr. Paul A. J. Janssen: entrepreneur extraordinaire, innovative scientist, and significant contributor to anesthesiology. Anesth Analg. 2008 Feb;106(2):451-62, table of contents. doi: 10.1213/ane.0b013e3181605add. PMID: 18227300.
The renowned cardiopulmonary physiologist, Julius Comroe, MD (1911-1984) recognized and taught us that advances in science are not the result of one individual’s giant leap to the top of the mountain but rather of deliberate and measured climb in small steps scaling to the heights. Such describes the life and accomplishments of Belgian physician, Paul Adriaan Jan Janssen (1926-2003). Today’s remembering the classics PAAD highlights the stirring tribute of Janssen crafted by Dr. Ted Stanley, a collaborator of Dr Janssen’s who championed the cardiac anesthesia use of the fentanyl family of opioids. Dr. Stanley is legendary as well and we will return to discuss his many contributions in a future PAAD. From the paper:
“Paul Janssen was the founder of Janssen Pharmaceutica (now a subsidiary of Johnson and Johnson) and the developer of over 80 pharmaceutical compounds that proved useful in human, botanical, and veterinary medicine. He and his coworkers synthesized the fentanyl family of drugs, many other potent analgesics, droperidol, etomidate, and numerous other important medicines, including Diphenoxylate (Lomotil), Haloperidol, and Risperidone (Risperdal)] that were extremely useful in psychiatry, parasitology, gastroenterology, cardiology, virology, and immunology. Anesthesiology and medicine as a whole have benefited a great deal from his resourcefulness, creativity, and entrepreneurial spirit.”[7]
Reading the tribute catalogues 50 names of collaborators, mentors, mentees, family members and others who corroborated Comroe’s appreciation of the “team” aspect of scientific advance climbing to the arcadia.
As recipients of anesthesiology education at The University of Pennsylvania (PENN), we were especially interested in the text recounting the approval of fentanyl when Janssen and Robert D Dripps, MD, PENN’s legendary anesthesiology Chair discussed considerations of its risk vs benefit at its U.S. FDA approval process. Dripps initially opposed approval of fentanyl because of its high potency. He also thought fentanyl’s tendency to produce rigidity could obligate endotracheal intubation of many patients. Dripps was ahead of his time and eerily right on target with his premonition that such a potent opioid would lead to many abuse problems. The compromise that ushered in fentanyl’s approval was the restriction of it use only when combined with droperidol. The fixed 50:1 droperidol:fentanyl ratio named Innovar was employed for a neurolept-analgesia technique, an anesthetic technique that is rarely used clinically in today’s modern anesthetic practice.
Stanley, Van Aken and Talmage’s tribute ended with a summary placing emphasis of Janssen’s legacy:
“…Paul Janssen was surely a scientist of great historical significance to clinical pharmacology and to anesthesiology in particular…he forged a path of innovative thinking and creativity [and collaborative mentorship] that has had a huge impact on the quality of human life and the practice of anesthesia…The specialty of anesthesia has been fortunate to have had such a talented and energetic man interested in our therapeutic area.”[7]
Stanley, Van Aken and Talmage’s tribute is a must read to appreciate the winding journey taken by those who have forged ahead with the development of effective and safe clinical anesthesia patient care.
If any of you reading today’s PAAD had personal experiences and memories of Dr. Janssen please share them with Myron (myasterster@gmail.com) and he will post in a Friday reader response.
References
1. Stanley TH, Webster LR: Anesthetic requirements and cardiovascular effects of fentanyl- oxygen and fentanyl-diazepam-oxygen anesthesia in man. AnesthAnalg 1978, 57(4):411–416.
2. Robinson S, Gregory GA: Fentanyl-air-oxygen anesthesia for ligation of patent ductus arteriosus in preterm infants. AnesthAnalg 1981, 60(5):331–334.
3. Yaster M: The dose response of fentanyl in neonatal anesthesia. Anesthesiology 1987, 66(3):433–435.
4. Anand KJ, Sippell WG, Aynsley-Green A: Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet (London, England) 1987, 1(8524):62–66.
5. Anand KJ, Hickey PR: Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery [see comments]. NEnglJMed 1992, 326(1):1–9.
6. Kharasch ED, Clark JD, Adams JM: Opioids and Public Health: The Prescription Opioid Ecosystem and Need for Improved Management. Anesthesiology 2022, 136(1):10–30.
7. Stanley TH, Egan TD, Van Aken H: A tribute to Dr. Paul A. J. Janssen: entrepreneur extraordinaire, innovative scientist, and significant contributor to anesthesiology. Anesthesia and analgesia 2008, 106(2):451–462, table of contents.