Vol. 29 No. 5S May 2005 Journal of Pain and Symptom Management S67

Proceedings of the Symposium “Updates of the Clinical Pharmacologyof Opioids with Special Attention to Long-Acting Drugs”

FentanylTheodore H. Stanley, MDUniversity of Utah Health Sciences Center, Salt Lake City, Utah, USA

AbstractFentanyl, 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.Fentanyl’s introduction, versatility, and popularity have resulted in its use in many acuteand chronic pain conditions and a multitude of novel delivery systems in the last twodecades. In spite of the development of more potent, safer, faster onset, and both shorterand longer lasting alternative opioids, fentanyl remains the mainstay of anesthesiologistsand Certified Registered Nurse Anesthetists in the perioperative period, and for many painphysicians throughout the world. J Pain Symptom Manage 2005;29:S67–S71. � 2005U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Key WordsFentanyl, anesthesiology, pain, lipid soluble

IntroductionThe story of fentanyl, one of the most popular

opioid analgesics in modern anesthesia andpain therapy, begins in Belgium in the late1950s. At this time, Dr. Paul Janssen, founderof Janssen Pharmaceutica, currently one of themost profitable divisions of Johnson & Johnson,became interested in strong analgesics to treata potpourri of pain syndromes that were poorlyor inadequately treated at the time. Janssen, astructure-activity pharmacologist and medicaldoctor as well, began looking at the structureof meperidine, an opioid which he consideredsimple enough to experiment with from a struc-ture perspective, but inadequate as an analge-sic molecule because of its lack of potency.Janssen reasoned that by changing the basicmeperidine structure to increase its lipid solu-bility, he might increase potency and, perhaps,

Address reprint requests to: Theodore H. Stanley, MD,University of Utah Health Sciences Center, 30 North1900 East, Salt Lake City, UT 84132, USA.Accepted for publication: January 5, 2005.

� 2005 U.S. Cancer Pain Relief CommitteePublished by Elsevier Inc. All rights reserved.

specificity. Over the course of 3–4 years, anumber of new molecular entities with signifi-cant opioid analgesic activity were synthesizedand tested in numerous animal models. Thebest of the molecules was a drug that was latercalled fentanyl. In those days, Janssen, after ex-perimenting with a new molecule in the labora-tory, often gave the compounds to clinicianfriends of his who would study the drugs in aclinical setting. George De Castro, an anesthesi-ologist in the Brussels area, was probably thefirst clinician to evaluate fentanyl.

De Castro began experimenting with fentanylas a component of narcotic/hypnotic/nitrousoxide/oxygen anesthesia. He also used thedrug in combination with inhaled drugs, andsome years later as a pure narcotic anestheticin very large doses. De Castro was impressedwith the potency, speed of onset, and relativelyshort duration of fentanyl. He reported backto Janssen that this would be a useful com-pound. The Janssen Company, on the basis ofDe Castro’s positive reports, began studiesthroughout Europe, which led to fentanyl’s ap-proval in most of the Western European coun-tries in the early to mid-1960s. At that time

0885-3924/05/$–see front matterdoi:10.1016/j.jpainsymman.2005.01.009

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fentanyl was usually used in small incrementsin combination with one of a number ofintravenous hypnotics. The technique, calledneurolept anesthesia, involved the combination offentanyl and rather large doses of droperidol,with or without nitrous oxide and oxygen. Thistechnique became reasonably popular, first inmany Western and then later in most EasternEuropean countries. Janssen realized thatfentanyl, as well as any of his drugs’ ultimatesuccess, depended upon acceptance and use inthe United States, and as a result, he soughtthe advice of an influential Americananesthesiologist.

In 1963 Janssen Pharmaceutica was pur-chased by Johnson & Johnson. At the time ofthe purchase, and for many years later, Dr. PaulJanssen was the single largest shareholder ofthe Johnson & Johnson Company. Through hiscontacts with many of the divisions of Johnson &Johnson, Dr. Janssen was introduced to RobertDripps, Professor and Chairman of Anesthesiol-ogy at the University of Pennsylvania in Phila-delphia. Janssen tried to convince Dripps tohelp him get fentanyl exposed to anesthesiol-ogists in the United States so that eventuallythe drug could be studied and approved by theU.S. Food and Drug Administration (FDA). Atfirst, Dripps was very much opposed to thethought of introducing this incredibly potentopioid into U.S. anesthetic practice. Dripps rea-soned that a drug that was 100 times morepotent than morphine was unnecessary andprobably would create more problems thanadvantages for the average clinician. Dripps wasalso particularly concerned that fentanyl mightbe used as a drug of abuse due to its relativelyrapid onset of action. After years of negotia-tions, Janssen finally convinced Dripps that fen-tanyl was useful, but the compromise was thatthe drug would only be introduced as a compo-nent of a mixture that also contained droperi-dol. The mixture was called Innovar and wasfinally approved in 1968 for use in clinical an-esthesiology. The rationale of combining drop-eridol with fentanyl was based on the fact thatdroperidol produced such negative psychic ef-fects that potential abusers would likely not takethe combination in an attempt to elicit a highfrom fentanyl.

Innovar was introduced with hopes that theneurolept anesthetic technique, as was becom-ing popular in Western Europe, would also

become popular in the United States. For avariety of reasons that are too complex to gointo at this time, fentanyl in combination withdroperidol never became widely accepted, butthe drug was not often abused. Perhaps forthat reason, approximately 4 years later, theJanssen Company was successful in getting fen-tanyl approved by the FDA as a sole agent. Itis important to recognize that after fentanylbecame available, it was rarely used in doses ofmore than 12.5–15 µg. Indeed, its most popularapplication was as a component of nitrousoxide/opioid/oxygen anesthesia in which lessthan 50 µg would be a dose that might be usedfor a 2- or 3-hour surgical procedure.

Given that fentanyl was only available in avery small 50 µg (1 ml) ampoule, was usedin very modest doses of 10–35 µg for any singlepatient, generated sales less than US$ 50 mil-lion per year during the first 3–5 years of itsavailability in the United States, and was virtu-ally unknown outside of the operating room inthe United States, it is remarkable that 30 yearslater the drug has achieved such widespreadpopularity.

The most important event that increased thepopularity of fentanyl in the operating roomwas the concept of high-dose opioid anesthesia,which was first introduced into the UnitedStates by Lowenstein and colleagues in a reportpublished in the New England Journal of Medicinein December 1969. This study led to manyothers in the next 3–4 years, evaluating high-dose morphine/oxygen anesthesia as atechnique for very sick patients undergoingopen heart surgery and then later, major vascu-lar surgery. The popularity of the techniquestemmed from remarkable cardiovascular sta-bility that occurred in this group of patients.Within a few years, virtually every anesthesiolo-gist was using a variant of the high-dose mor-phine/oxygen technique to anesthetizepatientsfor open-heart surgery. Morphine’s popularitylasted for only a short period of time. Withina few years, problems with incomplete amnesia,severe hypertension, hypotension, bradycar-dia, marked increase in volume requirements,and problems with prolonged postoperativerespiratory depression resulted in much lessenthusiasm with high-dose morphine/oxygenanesthesia. It was in this environment thatStanley and his co-workers began evaluatingother potent opioids as alternatives to high dose

Vol. 29 No. 5S May 2005 S69Fentanyl for Anesthesia and Pain

morphine. For the first 3–4 years, studieswere confined to animals. After these initialstudies, tentative exploration with a high-dosefentanyl/oxygen technique was begun in pa-tients with severe valvular disease and then laterin patients with coronary artery disease. High-dose fentanyl/oxygen anesthesia proved supe-rior to high-dose morphine, and within a fewyears, replaced morphine as the technique ofchoice for virtually every patient undergoingcardiac surgery. This stimulated the JanssenLaboratories in Beerse, Belgium, to evaluatepotential alternatives to fentanyl as a pureopioid “anesthetic” or as supplements for use incombination with intravenous hypnotics orinhaled agents. As a result of these studies, al-fentanil and sufentanil were developed andlater studied and approved both in the UnitesStates and most of Western Europe.

In the mid 1980s, the thought of putting fen-tanyl, a very lipid-soluble opioid, in a skin patchevolved at the Alza Corporation. After devel-oping a prototype, studies were initiated withthe fentanyl patch (later called Duragesic) forpatients after surgery to help treat postoper-ative pain. The fentanyl patch delivered appro-priate amounts of fentanyl through the skinand into the body, and many studies dem-onstrated that use of the patch reduced theneed for other opioids in the postoperativeperiod. However, approximately 10–12% of pa-tients experienced rather significant respiratorydepression. As a result of these problems, theFDA indicated to Alza that the drug would notlikely be approved in opioid-naı̈ve patients aftersurgery; therefore, the company sought an ap-proval in opioid-tolerant patients. The studiessupporting this indication were performed inslightly more than 350 patients, most of whomhad cancer. The fentanyl patch (Duragesic) wasapproved for use as a treatment for chronicpain in this type of patient. Since its approvalin 1990, Duragesic has experienced remarkablegrowth that has resulted in sales of $1.2 billionin 2002 and $1.7 billion in 2003.

In addition to the fentanyl patch, other noveldelivery systems incorporating fentanyl havebeen developed and used by numerous clini-cians both in the United States and throughoutWestern Europe. Actiq, commonly known asthe fentanyl lollipop, was also approved in the1990s for opioid-tolerant patients. Actiq’s prin-cipal indication is for patients experiencing

breakthrough pain. Actiq is also often used off-label for all types of acute pain. An earlier formof Actiq, called Oralet, was approved for pre-medication before surgery and before painfulprocedures.

Oralet did not prove to be a popular drugfor premedication but had numerous advocatesaround the United States. Other companieshave studied fentanyl incorporated into a loz-enge, nasal spray, buccal patches, dissolvableoral tablets, and numerous transmucosal deliv-ery systems. Aerosolized fentanyl has been stud-ied for pulmonary tracheal and pharyngealabsorption. An injectable solid that slowly re-leases sufentanil is currently under clinical in-vestigation. In addition, fentanyl is beingevaluated in a number of iontophoretic deliverysystems. Fentanyl is still one of the most populardrugs for use in the operating room, as a shortintravenous infusion, as a premedicant beforesurgery, and as a postoperative analgesic deliv-ered parenterally. It is amazing that fentanyl,which was developed over 40 years ago, is still themost popular opioid analgesic in the periopera-tive period and possibly in all of pain therapyas well.

Suggested Readings1. Janssen PAJ. A review of the chemical features

associated with strong morphine-like activity. Br JAnaesth 1962;34:260–268.

2. Bennett GM, Stanley TH. Cardiovascular effectsof fentanyl during enflurane anesthesia in man.Anesth Analg 1979;58:179–182.

3. Stanley TH. Anesthesia with high doses of anal-gesics. Proceedings of the 1979 Boerhaave Course“Analgesia in Anesthesia and Obstetrics.” MartinusNijnoff: Leiden, Holland, 1979:53–62.

4. Grell FL, Koons DA, Danson JS. Fentanyl in anes-thesia: a report of 500 cases. Anesth Analg 1970;49:523–532.

5. Goroszeniuk JC, Whitwam JC, Morgan M. Usesof methohexitone, fentanyl and nitrous oxide forshort operative procedures. Anaesthesia 1977;32:209–211.

6. Holmes CM. Supplementation of general anaes-thesia with narcotic analgesics. Br J Anaesth 1976;48:907–913.

7. De Castro J, Mundeleer R. Anesthesie sans barbi-turatiques: la neuroleptanalgesie. Anaesth Analg(Paris) 1959;16:1022–1056.

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8. Hecker BR, Lake CL, DeFasio CA, et al. Thedecrease of the minimum alveolar anesthetic concen-tration produced by sufentanil in rats. Anesth Analg1983;62:987–990.

9. Stanley TH, Berman L, Green O, Robertson DH.Plasma catecholamine and cortisol responses tofentanyl-oxygen anesthesia for coronary-artery oper-ations. Anesthesiology 1980;53:250–253.

10. Stanley TH. Hemodynamic effects of narcotics.Cleveland Clinic Quarterly 1981;48:22–29.

11. de Lange S, Stanley TH, Boscow MJ. Alfentanil-oxygen anesthesia for coronary artery surgery. Br JAnaesth 1981;53:11291–11296.

12. Bailey PL, Andriano KP, Pace NL, et al. Smalldoses of fentanyl potentiate and prolong diazepaminduced respiratory depression. Anesth Analg 1984;63:183.

13. Corssen G, Domino EF, Sweet RB. Neuroleptan-algesia and anesthesia. Anesth Analg 1964;43:748–762.

14. Corssen G, Chodoff P, Domino EF, Khan DR.Neuroleptanalgesia and anesthesia for open heartsurgery. J Thoracic Cardiovasc Surg 1965;49:901–920.

15. Fitch W, Barker J, Jennett WB, McDowall DG.The influence of neurolept-analgesic drugs on cere-brospinal fluid pressure. Br J Anaesth 1969;41:800–806.

16. Lowenstein E, Hallowell P, Levine FH, et al. Car-diovascular response to large doses of intravenousmorphine in man. N Engl J Med 1969;281:1389–1393.

17. De Castro J. Analgesic anesthesia based on theuse of fentanyl in high doses. Anesthesia vigile etsubvigile 1977;1:87–166.

18. Lowenstein E. Morphine “anesthesia”—a per-spective. Anesthesiology 1971;35:563–565.

19. Stoelting RK, Gibbs PS. Hemodynamic effects ofmorphine and morphine-nitrous oxide in valvularheart disease and coronary artery disease. Anesthesi-ology 1973;38:45–52.

20. Stanley TH, Gray NH, Stanford W, Armstrong R.The effects of high-dose morphine on fluid andblood requirements in open-heart procedures. Anes-thesiology 1973;38:536–541.

21. Hasbrouk JD. Morphine anesthesia for open-heart surgery. Ann Thorac Surg 1970;10:364–369.

22. McDermott RW, Stanley TH. The cardiovasculareffects of low concentrations of nitrous oxide duringmorphine anesthesia. Anesthesiology 1974;41:89–91.

23. Arens JF, Benbow BP, Ochsner JL, Theard R.Morphine anesthesia for aorto-coronary bypass pro-cedures. Anesth Analg 1972;51:901–909.

24. Frey E. Cardiovascular effects of high dosages offentanyl, meperidine and naloxone in dogs. AnesthAnalg 1974;53:40–47.

25. de Lange S, Boscoe M, Stanley TH, Pace NL.Comparison of sufentanil-O2 and fentanyl-O2 for cor-onary artery surgery. Anesthesiology 1982;56:112–118.

26. Stanley TH. Narcotic anesthesia: advantages anddisadvantages. Res Staff Phys 1981;July:67–72.

27. Nauta J, de Lange S, Koopman D, et al. Anesthe-tic induction with alfentanil: comparison with thio-pental, midazolam and etomidate. Can Anaesth SocJ 1983;30:53–60.

28. Nauta J, de Lange S, Koopman D, et al. Anesthe-tic induction with alfentanil: a new short-acting nar-cotic analgesic. Anesth Analg 1982;61:267–272.

29. de Lange S, Boscoe MJ, Stanley TH, et al. Antidi-uretic and growth hormone responses during coro-nary artery surgery with sufentanil-oxygen andalfentanil-oxygen anesthesia in man. Anesth Analg1982;61:434–438.

30. De Castro J, Van de Water A, Wouters , et al. com-parative study of cardiovascular neurological andmetabolic side effects of eight narcotics in dogs. ActaAnaesthesiol Belg 1979;30:5–99.

31. Strauer B. Contractile responses to morphine,piritramide, meperidine and fentanyl: a compara-tive study of effects on the isolated ventricular myo-cardium. Anesthesiology 1957;18:623–633.

32. Eisele JH, Reitan JA, Torten M, Miller CH. Myo-cardial sparing effect of fentanyl during halothaneanesthesia in dogs. Br J Anaesth 1975;47:937–940.

33. Stanley TH, Webster LR. Anesthetic require-ments and cardiovascular effects on fentanyl-oxygenand fentanyl-diazepam-oxygen anesthesia in man.Anesth Analg 1978;57:411–416.

34. Lunn JK, Webster LR, Stanley TH, Woodward A.High dose fentanyl anesthesia for coronary arterysurgery: plasma fentanyl concentration and influ-ence of nitrous oxide on cardiovascular responses.Anesth Analg 1979;58:390–395.

35. Lappas DG, Fahmy NR, Moss J, Slater EE. Effectsof fentanyl-diazepam anesthesia on hemodynamics,plasma catecholamines and rennin activity in criti-cally ill patients. Anesthesiology 1981;55:A250.

36. de Lange S, Stanley TH, Boscoe M, et al. Cat-echolamine and cortisol responses to sufentanil-O2and alfentanil-O2 anaesthesia during coronary arterysurgery. Can Anaesth Soc J 1983;30:248–254.

37. Stanley TH. High-dose fentanyl. Mt Sinai JMed 1983;50:308–311.

38. Stanley TH, Leysen JE, Niemegeers CJ, Pace NL.Narcotic dosage and central nervous system opiatereceptor binding. Anesth Analg 1983;62:705–709.

39. Stanley TH, de Lange S. The effect of populationhabits on side effects and narcotic requirementsduring high dose fentanyl anesthesia. Can AnaesthSoc J 1984;31(4):368–376.

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 1884–1984 (Proceed-ings of the Centennial Meeting of European Societyof Regional Anaesthesia). Sodertalje, Sweden: ICMAB, 1984:154–158.

41. Strauer B. Contractile responses to morphine,piritramide, meperidine and fentanyl: a compara-tive study of effects on the isolated ventricular myo-cardium. Anesthesiology 1972;37:304–310.

42. Eisele JH, Reitan JA, Torten , Miller CH. Myocar-dial sparing effect of fentanyl during halothane anes-thesia in dogs. Br J Anaesth 1975;47:937–940.

43. Stanley TH, Webster LR. Anesthetic require-ments and cardiovascular effects of fentanyl-oxygenand fentanyl-diazepam-oxygen anesthesia in man.Anesth Analg 1978;57:411–416.

44. Lunn JK, Webster LR, Stanley TH, Woodward A.High dose fentanyl anesthesia for coronary arterysurgery: Plasma fentanyl concentrations and influ-ence of nitrous oxide on cardiovascular responses.Anesth Analg 1979;58:390–395.

45. Lappas DG, Fahmy NR, Moss J, Slater EE. Effectsof fentanyl-diazepam anesthesia on hemodynamics,plasma catecholamines and rennin activity in criti-cally ill patients. Anesthesiology 1981;55:A250.

46. Stanley TH. The pharmacology of intravenousnarcotic anesthetics. In: Miller RD, ed. Anesthesia.New York: Churchill Livingstone, 1981:425–449.

47. Bailey PL, Wilbrink J, Zwanikken P, et al. Anes-thetic induction with fentanyl. Anesth Analg 1985;64:48–53.

48. Liu WS, Bidwai AV, Hodges MR, Stanley TH.Comparison of the cardiovascular effects of nitroglyc-erin before and during morphine-nitrous oxide anes-thesia in the dog. Anaesthesiologica Sinica 1984;22:185–191.

49. Bailey PL, Port JD, Pace NL, Stanley TH. TheED50 of carfentanil for elk immobilization with andwithout the tranquilizer R51703. J Wild Management1985;49:931–934.

50. Stanley TH, Port JD. Fentanyl “anesthesia” indogs [letter]. Anesthesiology 1985;62:837–838.

51. Benthuysen JL, Stanley TH. Concerning the pos-sible nature of reported fentanyl seizures [letter].Anesthesiology 1985;62:205.

52. Stanley TH. The physiological background ofstress-free anesthesia. Anesth Sinica 1984;22:321–323.

53. Stanley TH. Anesthetic management: Injectableagents of the future (and other techniques). In: Pro-ceedings of the 2nd International Congress of Veteri-nary Anesthesia in Sacramento, CA October 7–10,1985. Santa Barbara, CA: Veterinary Practice Pub.Co. for the American College of Veterinary Anesthe-siologists, pp. 18–20.

54. Stanley TH. Anesthesiology in the 21st Century:analgesia, sedative and anesthetic focusing. Int J ClinMonit and Comput 1986;3:21–25.

55. Stanley TH. Future possibilities in pharmaco-logic pain control. Postgrad Med (Special Report—Patient Controlled Analgesia) August 28, 1986, pp.51–55.

56. Clark NJ, Meuleman T, Liu WS, et al. Compari-son of sufentanil-N2O and fentanyl-N2O in patientswithout cardiac disease undergoing general surgery.Anesthesiology 1987;66:130–135.

57. Bailey PL, Port JD, McJames S, et al. Is fentanylan anesthetic in the dog? Anesth Analg 1987;66:542–548.

58. Stanley TH. Species differences. Br J Anaesth1988;60:116S–118S.

59. Stanley TH, de Lange S. Comparison of sufen-tanil-oxygen and fentanyl-oxygen anesthesia formitral and aortic valvular surgery. J CardiothoracAnes 1988;2:6–11.

60. Stanley TH. New routes of administration andnew delivery systems of anesthetics [editorial]. Anes-thesiology 1988;68:665–668.

61. Nelson PS, Streisand JB, Mulder SM, et al. Com-parison of oral transmucosal fentanyl citrate and anoral solution of meperidine, diazepam and atropinefor premedication in children. Anesthesiology1989;70:616–621.

62. Streisand JB, Stanley TH. Opioids: New tech-niques in routes of administration. Curr Opin Anesth1989;2(4):456–462.

63. Stanley TH, Hague B, Mock DL, et al. Oral trans-mucosal fentanyl citrate (lollipop) premedication inhuman volunteers. Anesth Analg 1989;69:21–27.

64. Streisand JB, Stanley TH, Hague B, et al. Oraltransmucosal fentanyl citrate premedication inchildren. Anesth Analg 1989;69:28–34.

65. Stanley TH, Leiman BC, Rawal N, et al. The ef-fects of oral transmucosal fentanyl citrate premedica-tion on preoperative behavioral responses andgastric volume and acidity in children. Anesth Analg1989;69:328–335.

66. Ashburn MA, Fine PG, Stanley TH. Oral trans-mucosal fentanyl citrate for the treatment of break-through cancer pain: a case report. Anesthesiology1989;71:615–617.

67. Tarver SD, Stanley TH. Alternative routes of drugadministration and new drug delivery systems. AdvAnesthesia 1989;7:337–368.

68. Ashburn MA, Streisand JB, Tarver SD, et al. Oraltransmucosal fentanyl citrate for premedication inpaediatric outpatients. Can J Anaesth 1990;37:856–866.

69. Stanley TH, Bailey PL. Fentanyl and sufentanilanesthesia revisited: Establish an effective plasmaconcentration and achieve it at the right time. Anes-thesiology 1991;74:388–389.

70. Stanley TH. The history and development of thefentanyl series. J Pain Symptom Manage 1992;7:S3–S7.