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Journal of Pain and Symptom Management S67

Proceedings of the Symposium Updates of the Clinical Pharmacology of Opioids with Special Attention to Long-Acting Drugs

Fentanyl
Theodore H. Stanley, MD
University of Utah Health Sciences Center, Salt Lake City, Utah, USA

Abstract Fentanyl, a potent lipid-soluble opioid which was first synthesized more than 40 years ago, is still the most popular opioid used in the perioperative period throughout the world. Fentanyls introduction, versatility, and popularity have resulted in its use in many acute and chronic pain conditions and a multitude of novel delivery systems in the last two decades. In spite of the development of more potent, safer, faster onset, and both shorter and longer lasting alternative opioids, fentanyl remains the mainstay of anesthesiologists and Certified Registered Nurse Anesthetists in the perioperative period, and for many pain physicians throughout the world. J Pain Symptom Manage 2005;29:S67S71. 2005 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Fentanyl, anesthesiology, pain, lipid soluble

Introduction
The story of fentanyl, one of the most popular opioid analgesics in modern anesthesia and pain therapy, begins in Belgium in the late 1950s. At this time, Dr. Paul Janssen, founder of Janssen Pharmaceutica, currently one of the most profitable divisions of Johnson & Johnson, became interested in strong analgesics to treat a potpourri of pain syndromes that were poorly or inadequately treated at the time. Janssen, a structure-activity pharmacologist and medical doctor as well, began looking at the structure of meperidine, an opioid which he considered simple enough to experiment with from a structure perspective, but inadequate as an analgesic molecule because of its lack of potency. Janssen reasoned that by changing the basic meperidine structure to increase its lipid solubility, he might increase potency and, perhaps,

Address reprint requests to: Theodore H. Stanley, MD, University of Utah Health Sciences Center, 30 North 1900 East, Salt Lake City, UT 84132, USA. Accepted for publication: January 5, 2005.
2005 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.

specificity. Over the course of 34 years, a number of new molecular entities with significant opioid analgesic activity were synthesized and tested in numerous animal models. The best of the molecules was a drug that was later called fentanyl. In those days, Janssen, after experimenting with a new molecule in the laboratory, often gave the compounds to clinician friends of his who would study the drugs in a clinical setting. George De Castro, an anesthesiologist in the Brussels area, was probably the first clinician to evaluate fentanyl. De Castro began experimenting with fentanyl as a component of narcotic/hypnotic/nitrous oxide/oxygen anesthesia. He also used the drug in combination with inhaled drugs, and some years later as a pure narcotic anesthetic in very large doses. De Castro was impressed with the potency, speed of onset, and relatively short duration of fentanyl. He reported back to Janssen that this would be a useful compound. The Janssen Company, on the basis of De Castros positive reports, began studies throughout Europe, which led to fentanyls approval in most of the Western European countries in the early to mid-1960s. At that time
0885-3924/05/$see front matter doi:10.1016/j.jpainsymman.2005.01.009

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fentanyl was usually used in small increments in combination with one of a number of intravenous hypnotics. The technique, called neurolept anesthesia, involved the combination of fentanyl and rather large doses of droperidol, with or without nitrous oxide and oxygen. This technique became reasonably popular, first in many Western and then later in most Eastern European countries. Janssen realized that fentanyl, as well as any of his drugs ultimate success, depended upon acceptance and use in the United States, and as a result, he sought the advice of an influential American anesthesiologist. In 1963 Janssen Pharmaceutica was purchased by Johnson & Johnson. At the time of the purchase, and for many years later, Dr. Paul Janssen was the single largest shareholder of the Johnson & Johnson Company. Through his contacts with many of the divisions of Johnson & Johnson, Dr. Janssen was introduced to Robert Dripps, Professor and Chairman of Anesthesiology at the University of Pennsylvania in Philadelphia. Janssen tried to convince Dripps to help him get fentanyl exposed to anesthesiologists in the United States so that eventually the drug could be studied and approved by the U.S. Food and Drug Administration (FDA). At first, Dripps was very much opposed to the thought of introducing this incredibly potent opioid into U.S. anesthetic practice. Dripps reasoned that a drug that was 100 times more potent than morphine was unnecessary and probably would create more problems than advantages for the average clinician. Dripps was also particularly concerned that fentanyl might be used as a drug of abuse due to its relatively rapid onset of action. After years of negotiations, Janssen finally convinced Dripps that fentanyl was useful, but the compromise was that the drug would only be introduced as a component of a mixture that also contained droperidol. The mixture was called Innovar and was finally approved in 1968 for use in clinical anesthesiology. The rationale of combining droperidol with fentanyl was based on the fact that droperidol produced such negative psychic effects that potential abusers would likely not take the combination in an attempt to elicit a high from fentanyl. Innovar was introduced with hopes that the neurolept anesthetic technique, as was becoming popular in Western Europe, would also

become popular in the United States. For a variety of reasons that are too complex to go into at this time, fentanyl in combination with droperidol never became widely accepted, but the drug was not often abused. Perhaps for that reason, approximately 4 years later, the Janssen Company was successful in getting fentanyl approved by the FDA as a sole agent. It is important to recognize that after fentanyl became available, it was rarely used in doses of more than 12.515 g. Indeed, its most popular application was as a component of nitrous oxide/opioid/oxygen anesthesia in which less than 50 g would be a dose that might be used for a 2- or 3-hour surgical procedure. Given that fentanyl was only available in a very small 50 g (1 ml) ampoule, was used in very modest doses of 1035 g for any single patient, generated sales less than US$ 50 million per year during the first 35 years of its availability in the United States, and was virtually unknown outside of the operating room in the United States, it is remarkable that 30 years later the drug has achieved such widespread popularity. The most important event that increased the popularity of fentanyl in the operating room was the concept of high-dose opioid anesthesia, which was first introduced into the United States by Lowenstein and colleagues in a report published in the New England Journal of Medicine in December 1969. This study led to many others in the next 34 years, evaluating highdose morphine/oxygen anesthesia as a technique for very sick patients undergoing open heart surgery and then later, major vascular surgery. The popularity of the technique stemmed from remarkable cardiovascular stability that occurred in this group of patients. Within a few years, virtually every anesthesiologist was using a variant of the high-dose morphine/oxygen technique to anesthetize patients for open-heart surgery. Morphines popularity lasted for only a short period of time. Within a few years, problems with incomplete amnesia, severe hypertension, hypotension, bradycardia, marked increase in volume requirements, and problems with prolonged postoperative respiratory depression resulted in much less enthusiasm with high-dose morphine/oxygen anesthesia. It was in this environment that Stanley and his co-workers began evaluating other potent opioids as alternatives to high dose

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morphine. For the first 34 years, studies were confined to animals. After these initial studies, tentative exploration with a high-dose fentanyl/oxygen technique was begun in patients with severe valvular disease and then later in patients with coronary artery disease. Highdose fentanyl/oxygen anesthesia proved superior to high-dose morphine, and within a few years, replaced morphine as the technique of choice for virtually every patient undergoing cardiac surgery. This stimulated the Janssen Laboratories in Beerse, Belgium, to evaluate potential alternatives to fentanyl as a pure opioid anesthetic or as supplements for use in combination with intravenous hypnotics or inhaled agents. As a result of these studies, alfentanil and sufentanil were developed and later studied and approved both in the Unites States and most of Western Europe. In the mid 1980s, the thought of putting fentanyl, a very lipid-soluble opioid, in a skin patch evolved at the Alza Corporation. After developing a prototype, studies were initiated with the fentanyl patch (later called Duragesic) for patients after surgery to help treat postoperative pain. The fentanyl patch delivered appropriate amounts of fentanyl through the skin and into the body, and many studies demonstrated that use of the patch reduced the need for other opioids in the postoperative period. However, approximately 1012% of patients experienced rather significant respiratory depression. As a result of these problems, the FDA indicated to Alza that the drug would not likely be approved in opioid-nave patients after surgery; therefore, the company sought an approval in opioid-tolerant patients. The studies supporting this indication were performed in slightly more than 350 patients, most of whom had cancer. The fentanyl patch (Duragesic) was approved for use as a treatment for chronic pain in this type of patient. Since its approval in 1990, Duragesic has experienced remarkable growth that has resulted in sales of $1.2 billion in 2002 and $1.7 billion in 2003. In addition to the fentanyl patch, other novel delivery systems incorporating fentanyl have been developed and used by numerous clinicians both in the United States and throughout Western Europe. Actiq, commonly known as the fentanyl lollipop, was also approved in the 1990s for opioid-tolerant patients. Actiqs principal indication is for patients experiencing

breakthrough pain. Actiq is also often used offlabel for all types of acute pain. An earlier form of Actiq, called Oralet, was approved for premedication before surgery and before painful procedures. Oralet did not prove to be a popular drug for premedication but had numerous advocates around the United States. Other companies have studied fentanyl incorporated into a lozenge, nasal spray, buccal patches, dissolvable oral tablets, and numerous transmucosal delivery systems. Aerosolized fentanyl has been studied for pulmonary tracheal and pharyngeal absorption. An injectable solid that slowly releases sufentanil is currently under clinical investigation. In addition, fentanyl is being evaluated in a number of iontophoretic delivery systems. Fentanyl is still one of the most popular drugs for use in the operating room, as a short intravenous infusion, as a premedicant before surgery, and as a postoperative analgesic delivered parenterally. It is amazing that fentanyl, which was developed over 40 years ago, is still the most popular opioid analgesic in the perioperative period and possibly in all of pain therapy as well.

Suggested Readings
1. Janssen PAJ. A review of the chemical features associated with strong morphine-like activity. Br J Anaesth 1962;34:260268. 2. Bennett GM, Stanley TH. Cardiovascular effects of fentanyl during enflurane anesthesia in man. Anesth Analg 1979;58:179182. 3. Stanley TH. Anesthesia with high doses of analgesics. Proceedings of the 1979 Boerhaave Course Analgesia in Anesthesia and Obstetrics. Martinus Nijnoff: Leiden, Holland, 1979:5362. 4. Grell FL, Koons DA, Danson JS. Fentanyl in anesthesia: a report of 500 cases. Anesth Analg 1970; 49:523532. 5. Goroszeniuk JC, Whitwam JC, Morgan M. Uses of methohexitone, fentanyl and nitrous oxide for short operative procedures. Anaesthesia 1977;32: 209211. 6. Holmes CM. Supplementation of general anaesthesia with narcotic analgesics. Br J Anaesth 1976; 48:907913. 7. De Castro J, Mundeleer R. Anesthesie sans barbituratiques: la neuroleptanalgesie. Anaesth Analg (Paris) 1959;16:10221056.

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8. Hecker BR, Lake CL, DeFasio CA, et al. The decrease of the minimum alveolar anesthetic concentration produced by sufentanil in rats. Anesth Analg 1983;62:987990. 9. Stanley TH, Berman L, Green O, Robertson DH. Plasma catecholamine and cortisol responses to fentanyl-oxygen anesthesia for coronary-artery operations. Anesthesiology 1980;53:250253. 10. Stanley TH. Hemodynamic effects of narcotics. Cleveland Clinic Quarterly 1981;48:2229. 11. de Lange S, Stanley TH, Boscow MJ. Alfentaniloxygen anesthesia for coronary artery surgery. Br J Anaesth 1981;53:1129111296. 12. Bailey PL, Andriano KP, Pace NL, et al. Small doses of fentanyl potentiate and prolong diazepam induced respiratory depression. Anesth Analg 1984; 63:183. 13. Corssen G, Domino EF, Sweet RB. Neuroleptanalgesia and anesthesia. Anesth Analg 1964;43:748 762. 14. Corssen G, Chodoff P, Domino EF, Khan DR. Neuroleptanalgesia and anesthesia for open heart surgery. J Thoracic Cardiovasc Surg 1965;49:901 920. 15. Fitch W, Barker J, Jennett WB, McDowall DG. The influence of neurolept-analgesic drugs on cerebrospinal fluid pressure. Br J Anaesth 1969;41: 800806. 16. Lowenstein E, Hallowell P, Levine FH, et al. Cardiovascular response to large doses of intravenous morphine in man. N Engl J Med 1969;281:1389 1393. 17. De Castro J. Analgesic anesthesia based on the use of fentanyl in high doses. Anesthesia vigile et subvigile 1977;1:87166. 18. Lowenstein E. Morphine anesthesiaa perspective. Anesthesiology 1971;35:563565. 19. Stoelting RK, Gibbs PS. Hemodynamic effects of morphine and morphine-nitrous oxide in valvular heart disease and coronary artery disease. Anesthesiology 1973;38:4552. 20. Stanley TH, Gray NH, Stanford W, Armstrong R. The effects of high-dose morphine on fluid and blood requirements in open-heart procedures. Anesthesiology 1973;38:536541. 21. Hasbrouk JD. Morphine anesthesia for openheart surgery. Ann Thorac Surg 1970;10:364369. 22. McDermott RW, Stanley TH. The cardiovascular effects of low concentrations of nitrous oxide during morphine anesthesia. Anesthesiology 1974;41:8991. 23. Arens JF, Benbow BP, Ochsner JL, Theard R. Morphine anesthesia for aorto-coronary bypass procedures. Anesth Analg 1972;51:901909. 24. Frey E. Cardiovascular effects of high dosages of fentanyl, meperidine and naloxone in dogs. Anesth Analg 1974;53:4047.

25. de Lange S, Boscoe M, Stanley TH, Pace NL. Comparison of sufentanil-O2 and fentanyl-O2 for coronary artery surgery. Anesthesiology 1982;56:112 118. 26. Stanley TH. Narcotic anesthesia: advantages and disadvantages. Res Staff Phys 1981;July:6772. 27. Nauta J, de Lange S, Koopman D, et al. Anesthetic induction with alfentanil: comparison with thiopental, midazolam and etomidate. Can Anaesth Soc J 1983;30:5360. 28. Nauta J, de Lange S, Koopman D, et al. Anesthetic induction with alfentanil: a new short-acting narcotic analgesic. Anesth Analg 1982;61:267272. 29. de Lange S, Boscoe MJ, Stanley TH, et al. Antidiuretic and growth hormone responses during coronary artery surgery with sufentanil-oxygen and alfentanil-oxygen anesthesia in man. Anesth Analg 1982;61:434438. 30. De Castro J, Van de Water A, Wouters , et al. comparative study of cardiovascular neurological and metabolic side effects of eight narcotics in dogs. Acta Anaesthesiol Belg 1979;30:599. 31. Strauer B. Contractile responses to morphine, piritramide, meperidine and fentanyl: a comparative study of effects on the isolated ventricular myocardium. Anesthesiology 1957;18:623633. 32. Eisele JH, Reitan JA, Torten M, Miller CH. Myocardial sparing effect of fentanyl during halothane anesthesia in dogs. Br J Anaesth 1975;47:937940. 33. Stanley TH, Webster LR. Anesthetic requirements and cardiovascular effects on fentanyl-oxygen and fentanyl-diazepam-oxygen anesthesia in man. Anesth Analg 1978;57:411416. 34. Lunn JK, Webster LR, Stanley TH, Woodward A. High dose fentanyl anesthesia for coronary artery surgery: plasma fentanyl concentration and influence of nitrous oxide on cardiovascular responses. Anesth Analg 1979;58:390395. 35. Lappas DG, Fahmy NR, Moss J, Slater EE. Effects of fentanyl-diazepam anesthesia on hemodynamics, plasma catecholamines and rennin activity in critically ill patients. Anesthesiology 1981;55:A250. 36. de Lange S, Stanley TH, Boscoe M, et al. Catecholamine and cortisol responses to sufentanil-O2 and alfentanil-O2 anaesthesia during coronary artery surgery. Can Anaesth Soc J 1983;30:248254. 37. Stanley TH. High-dose fentanyl. Mt Sinai J Med 1983;50:308311. 38. Stanley TH, Leysen JE, Niemegeers CJ, Pace NL. Narcotic dosage and central nervous system opiate receptor binding. Anesth Analg 1983;62:705709. 39. Stanley TH, de Lange S. The effect of population habits on side effects and narcotic requirements during high dose fentanyl anesthesia. Can Anaesth Soc J 1984;31(4):368376. 40. Stanley TH. Opioids and stress free anesthesia: fact or fiction. In: Scott DB, McClure J, Wildsmith

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JAW, eds. Regional anaesthesia 18841984 (Proceedings of the Centennial Meeting of European Society of Regional Anaesthesia). Sodertalje, Sweden: ICM AB, 1984:154158. 41. Strauer B. Contractile responses to morphine, piritramide, meperidine and fentanyl: a comparative study of effects on the isolated ventricular myocardium. Anesthesiology 1972;37:304310. 42. Eisele JH, Reitan JA, Torten , Miller CH. Myocardial sparing effect of fentanyl during halothane anesthesia in dogs. Br J Anaesth 1975;47:937940. 43. Stanley TH, Webster LR. Anesthetic requirements and cardiovascular effects of fentanyl-oxygen and fentanyl-diazepam-oxygen anesthesia in man. Anesth Analg 1978;57:411416. 44. Lunn JK, Webster LR, Stanley TH, Woodward A. High dose fentanyl anesthesia for coronary artery surgery: Plasma fentanyl concentrations and influence of nitrous oxide on cardiovascular responses. Anesth Analg 1979;58:390395. 45. Lappas DG, Fahmy NR, Moss J, Slater EE. Effects of fentanyl-diazepam anesthesia on hemodynamics, plasma catecholamines and rennin activity in critically ill patients. Anesthesiology 1981;55:A250. 46. Stanley TH. The pharmacology of intravenous narcotic anesthetics. In: Miller RD, ed. Anesthesia. New York: Churchill Livingstone, 1981:425449. 47. Bailey PL, Wilbrink J, Zwanikken P, et al. Anesthetic induction with fentanyl. Anesth Analg 1985; 64:4853. 48. Liu WS, Bidwai AV, Hodges MR, Stanley TH. Comparison of the cardiovascular effects of nitroglycerin before and during morphine-nitrous oxide anesthesia in the dog. Anaesthesiologica Sinica 1984; 22:185191. 49. Bailey PL, Port JD, Pace NL, Stanley TH. The ED50 of carfentanil for elk immobilization with and without the tranquilizer R51703. J Wild Management 1985;49:931934. 50. Stanley TH, Port JD. Fentanyl anesthesia in dogs [letter]. Anesthesiology 1985;62:837838. 51. Benthuysen JL, Stanley TH. Concerning the possible nature of reported fentanyl seizures [letter]. Anesthesiology 1985;62:205. 52. Stanley TH. The physiological background of stress-free anesthesia. Anesth Sinica 1984;22:321 323. 53. Stanley TH. Anesthetic management: Injectable agents of the future (and other techniques). In: Proceedings of the 2nd International Congress of Veterinary Anesthesia in Sacramento, CA October 710, 1985. Santa Barbara, CA: Veterinary Practice Pub. Co. for the American College of Veterinary Anesthesiologists, pp. 1820. 54. Stanley TH. Anesthesiology in the 21st Century: analgesia, sedative and anesthetic focusing. Int J Clin Monit and Comput 1986;3:2125.

55. Stanley TH. Future possibilities in pharmacologic pain control. Postgrad Med (Special Report Patient Controlled Analgesia) August 28, 1986, pp. 5155. 56. Clark NJ, Meuleman T, Liu WS, et al. Comparison of sufentanil-N2O and fentanyl-N2O in patients without cardiac disease undergoing general surgery. Anesthesiology 1987;66:130135. 57. Bailey PL, Port JD, McJames S, et al. Is fentanyl an anesthetic in the dog? Anesth Analg 1987;66: 542548. 58. Stanley TH. Species differences. Br J Anaesth 1988;60:116S118S. 59. Stanley TH, de Lange S. Comparison of sufentanil-oxygen and fentanyl-oxygen anesthesia for mitral and aortic valvular surgery. J Cardiothorac Anes 1988;2:611. 60. Stanley TH. New routes of administration and new delivery systems of anesthetics [editorial]. Anesthesiology 1988;68:665668. 61. Nelson PS, Streisand JB, Mulder SM, et al. Comparison of oral transmucosal fentanyl citrate and an oral solution of meperidine, diazepam and atropine for premedication in children. Anesthesiology 1989;70:616621. 62. Streisand JB, Stanley TH. Opioids: New techniques in routes of administration. Curr Opin Anesth 1989;2(4):456462. 63. Stanley TH, Hague B, Mock DL, et al. Oral transmucosal fentanyl citrate (lollipop) premedication in human volunteers. Anesth Analg 1989;69:2127. 64. Streisand JB, Stanley TH, Hague B, et al. Oral transmucosal fentanyl citrate premedication in children. Anesth Analg 1989;69:2834. 65. Stanley TH, Leiman BC, Rawal N, et al. The effects of oral transmucosal fentanyl citrate premedication on preoperative behavioral responses and gastric volume and acidity in children. Anesth Analg 1989;69:328335. 66. Ashburn MA, Fine PG, Stanley TH. Oral transmucosal fentanyl citrate for the treatment of breakthrough cancer pain: a case report. Anesthesiology 1989;71:615617. 67. Tarver SD, Stanley TH. Alternative routes of drug administration and new drug delivery systems. Adv Anesthesia 1989;7:337368. 68. Ashburn MA, Streisand JB, Tarver SD, et al. Oral transmucosal fentanyl citrate for premedication in paediatric outpatients. Can J Anaesth 1990;37:856 866. 69. Stanley TH, Bailey PL. Fentanyl and sufentanil anesthesia revisited: Establish an effective plasma concentration and achieve it at the right time. Anesthesiology 1991;74:388389. 70. Stanley TH. The history and development of the fentanyl series. J Pain Symptom Manage 1992;7: S3S7.