Vol.7No. 3 (Su@i.)Aa/1 1992

S8 Journal of Painand $mptom Manogemmt

Tramdermal Fentanyl: Clinical Pharmacology Klaus A. Lehmann, MD, and Detlev Zech, MD Dt$anment ofAnesthesiologyand OperativeIntensiveCare, Unkrsi&~of Cologne,li’ln, Germany

Abstract lh transdermaltherapeuticsystem (li?‘S) fmtanyl has been de$pdfor rate-controlleddq ~%~SJLIt pro&&s a convenientregimenfor the use of a drugprevious&limited by a short duration of action and a nonmva.sh,eparent-era1routefor a drug that is unsuitablefor oral administration. TiTfmtanyl has been developed to provide conlinuouscontrolledsystemicdelrky offmkznyl basefor 72 hr. it is a rectangular, transparentunit composedof a p*.ttective peel strtipandfourfictional &errs. i’he amount offmtanyl re.teasedjFomeach system(25 rc9/hrper IO cm-2,isproportionalto the surfacearea. Sofar, four patch s&es are available (10-40 cm2). when the ~stem 0 applied a fmtanyl depot concentratesin the upper shin layers. Fenta~ylplasma concentrationsare not measurable until 2 hr a&r application, and it takes 8-16 hr latency until&l1clinicalfmtanyl effectsare observed.Steady-stateserumconcentrationsare obtained a& several sequential 72-hr applications, and thereare maintainedfor as long as a systemis applied. Following removal, senunf~tanyl concentrationsdeclinegradual~ andfall about 50% in approximate& 16hr. This prolonged apparent eliminationhaFl$ occurs becausefen&r@ continuesto be absorbedjom the shin. Transdermalf~tanyl transportis essentkzl~the same between the chest, abdomen, and th&h. i’he shin-permeabilityconstantis about 0.0125 mL/hr/cm2, much lower than the regional blood supp& to a chest-shinarea. Because of potential permeabili~ var&ions among individuals,a special rate-controlling membrane in the stem provides additional controlof drug release. lhe rate-controlleddeliveryreducesthe variations in skin transportby 50%. Small amountsof alcohol are used as an absorption enhancer. TXS f&y1 appears to be a valuable toolfor chronicpain patients requiringcontinuousopiate treatmentbut is, due to its long dehzyand detay times,probably unsuitablefor the routinemanagementof short-lastingacute pain stat&J Pain Symptom Manage 1992;7:S8-SI6. KPy words Opiate ana&ssics,fmtany& noninvasiveapplication, transakrmal,phannacohtnetics

Prior to the introduction of transdermal therapeutic systems, topical delivery was achieved by application of ointments or creams to intact skin. When the goal was systemic therapy, reproducible dosing was extremely diflicult because of the difliculty of applying uniform amounts of ointment over a fixed skin area, the differences in rate and extent of drug absorption, and the variabiity in skin metabolism.

AaVressre#nt requests to: Klaus A. Iehmann, MD, Department of Anesthesiologyand Operative Intensive Care, University of Cologne,Joseph-Stelzmann-Stre 9, W-5000 Kiiln 41, Germany. Q U.S. Cancer Pain Relief Committee, 1992 Published by Elsevier, New York, New York

The transdermal therapeutic system (TTS) fentanyl has been designed for rate-controlled drug delivery. It provides a convenient re,imen far the use of a drug previously limited by a short duration of action and a noninvasive parenteral route for a drug that is unsuitable for oral administration. This article will discuss transdermal permeation, physicochemical aspects of fentanyl, and some pharmacokinetic experience with TTS fentanyl.

Tra The use of the skin as a reproducible route to deliver drugs into the bloodstream requires knowledge of its barrier properties (Figure 1). The skin is

Vol. 7 Jkh 3 (Sup~l.) April 1992

Transdemal Fen!any.bClinical Pharmacology

s9

Stratum Spinosum Stratum

Germinativum

Connective

tissue

Fig. 1. Schematic diagram of a crosssection of the skin. (Reprinted with permission from reference no. 8.)

composed

of three layers. The stratum comeum

forms the outermost layer and consists of lO-2U layers of flattened, closely packed, kerabized cells without nuclei. The epidermis, 50-100 pm thick,

has rapidly dividing basal cells that flatten as they move into the stratum corneum to replace cells lost Corn the surface. The innermost layer, the 2- to 3-mm-thick dermis, is a matrix of various cells including those that produce collagen and other fiber proteins. Hair follicles, sebaceous glands, and eccrine and apocrine sweat glands are also part of the dermis. Sweat glands and lipids secreted by the sebaceous glands into the hair follicles help maintain the skin pH at about 5 and can affect adhesion of transdermal systems. Skin permeability was first investigated systematically by Scheuplein and Blank using excised specimens of skin in di&sion chambers.’ They verified that permeation of foreign substances was mediated primarily by cliff&ion and that the primary reason for differences in permeation was the variation in thickness of the stratum corneurn. More recent studies with human skin were performed by Neubert and Wohlrab,2 and cutaneous permeation was described mathematically by Michaels and colleagues? Excellent reviews on transdermal delivery have been prepared by Kligman4 and Wester and Maibach.5 Percutaneous absorption of some drug (e.g., scopolamine) is dependent on the anatomical site.6 The transdermal absorption of fentanyl, however, is essentially the same from the chest, abdomen,

and thigh,’ as was shown with TTS fentanyl applied over samples of cadaver skin of the same individual. After a drug passes through the skin, it is absorbed into the general circulation by local blood vessels. Thus, from a physiological perspective, the appearance of the drug in the systemic circulation is governed not only by skin permeability but also by local blood flow. The skin permeability constant of fentanyl is a.bout 0.002 1 mLJmin/cm2,3 a figure that is 60- to 120-fold lower than the regional blood supply to a chest-skin area (0.0122-0.0224 mL/ min/cm2).s Therefore, the permeation of feutanyl through the skin is a much slower process than is permitted by the local blood supply under normal physiological conditions. Only extreme conditions, such as the cutaneous blood supply being completely cut off, would inlluence fentanyl absorption. For drugs delivered transdermally, the percutaneous metabolism could also be a significant factor. The skin is well known for its metabolizing potential, including phase I and phase II reactions (oxydation, reduction, hydrolysis, glucuronidation, etc.). Studies in which fentanyl was incubated with skin homogenates found no sign&ant metabolism, however? Similarly, when fentanyl was incubated with keratinocytes in vitro, no metabolism was detected.s In bioavailabiity studies, 92% of the dose delivered by ‘ITS fentanyl reached the systemic circulation as unchanged fentanyl.‘OThus, fentanyl metabolism during transdermal penetration can be neglected.

Lehmannand the delay ranged Corn 1.2 to 3 1.3 hr, with a mean value of 12.7 hr. A sbih vtibiity WAS found in a double-blind study, with a mean delay time of 16.7 f 10 hr for a 75-pg/hr system and 18.9 f 10.9 hr for a 50-pg/hr system.1s~21~22 Thus, if effective fentanyl blood concentrations are required in the immediate postoperative period, the TTS fentanyl should be applied 12-18 hr prior to surgery. 0therwise, alternative pain-relieving procedures will inevitably be required.

w

Mmann and.&h

S12

730.3

(SuppL) Apd 1992

2.5

Fig.3.Mean36-to4Mrbloodfentanyl concentration (ng/ml) as a function of system therapeutic tmnsdermal (TB) fentanyl dose bg/hr). Each point wpresents an individual patient. The dashed line at 0.63 ng/mL represents the mean minimum effective concentration (MEC) for fentanyl to control postopemtive pain in a similar group of patients using intravenous patient-controlled analgesia (P(X). The shaded area around the dashed line represents the extremes in MEC values obtained in the PCA study. (Rep&ted with permission from reference no. 18.)

2.0

1.5

1.0 0.63 nghll 0.5

0

Patients reach steady-state serum concentrations he 1Z-24 hr after the last of several sequential 724~ applications. These concentrations are main-

tained for as long as a system is applied.10J5*1a*23 The serum fentanyl kinetics do not change signicandy with repeated applications.24 Data tirn Gourlay and Mathe@ indicate that a dose rate of at least 75 pg/hr would be required to provide acceptable analgesii in the majority of postoperative patients (Figure 3). In chronic pain patients, who receive reapplication every 72 hr, it is possible to obtain the sustained and relatively constant serum fentanyl concentrations that are comparable with continuous intravenous or subcutaneous opioid delivery without the need for invasive procedures or special equipment (Figure 4).24*25Although this de!ivery pcofre ensures, in principle, an&d-the-clock analgesia, reduced frequency of remedication, and good compliance, rescue medication should be -:x-tiable for breakthrough pain. Following TTS removal, serum fentanyl concentrations decline gradually and fall about 50% in approximately 16 hr. lo Gourlay and MatheP defined the decay time in an analogous manner to the initial delay time, i.e., as the time between removal and the time for fentsanyl plasma concentrations to fall below the MJX of 0.63 ng/mL (Figure 5). In postoperative patients, the mean f SD decay time was 16.1 f 7.1 hr with a range of 2.3-22.3 hr. Terminal ha&life for ‘ITS fentanyI was also calculated as approximately 1617 hr by

50 TtS

75

100

DOSE (I.LQ/h)

ot&er investigators.“JJ3J4 In the studies by Gourlay

and Mather,18 the apparent mean total body clearance during the 36- to 4%hr period was 721 mL/min, which is consistent with literature reports for intravenous fentanyl.*‘j This suggests that the slow decay after ‘ITS removal is not a consequence of low clearance. Rather, ?t :s like!y that the previously mentioned cutaneous reservoir ocfentanyl washes out slowly, thereby maintainiig relatively high blood concentrations. The clinical significance of thii prolonged decay phase is twofold. First, the beneficial effect of pain control continues for 12-24 hr after the TTS fentanyl has been removed. If the pain stimulus decreases during this period, however, which is very likely in the postoperative patient, there may be an increased risk of respiratory depression. Second, adverse effects also continue for a longer time than expected based on normal fentanyl pharmacokinetics. Hence, removing ITS fentanyl will not result immediately in the elimination of adverse effects, and patients witb serious opioid toxicity may require more than one naloxone dose.

Since the problem of respiratory depression, which already has been demonstrated in some case might restrict the widespread repot% 13~*4*21~27~28 acceptance of TT.S fentanyl, some guidelines shall

4.0

3.5

2 E

23 5

3.0

5 'Z b g

2.5

0

1.5

3 2 5 IL

1.0

2.0

0.5 0.0

Fig. 4. Mean ( + SD) observed serum fentanyl concentrations during five consecutive 3-day transdermal therapeutic system (‘ITS) fentanyl 100~%/lx applications in 10 patients. (Reprinted with permission from reference no. 24.)

discussed in more detail. Anesthesiologists became particularly interested in the correlation between pharmacokinetic data and respiratory depression when Becker and colleagueP reported on a biphasic depression of CO, response curves follotig fentanyl-supplemented neuroleptanalgesia and, shortly later, Staeckel and colleagues30 be

0

12

24

found a reasonable-at first sight-explanation in “secondary fentanyl plasma peaks.” The mechanism proposed for small “bumps” in plasma concentration during the terminal haKli& period was that fentanyl was sequestered into the acid stomach juice and, after duodenal reabsorption, concentration transiently increased. Wbat was

36

46

66

92

Fig. 5. Blood fentanyi concentrations (ng/mL) as a function of time (hr) following the application of transdermal therapeutic system (‘ITS) fentanyl in three surgical patients. The systems were changed 24 hr and removed 48 hr after the first application. The dashed line represents fentanyi minimum effectiveconcentration. (Reprinted with permission fromreferenceno. 18.)

SI1

.!chmann

wong with this theory from the very beginning was &at virtually all fentanyl absorbed from the intestine has to pass through the liver and is nearly completely metabolized to pharmacologically inactive metabolites. Later, other mechanisms were posited to be a more likely reason for the unsteady decline of fentanyl plasma concentrations, including release of drug from the lungs or the muscle compartments’ Some physicians still mistakenly believe that respiratory depression is connected with well-definedthreshold plasma opioid concentration. Increasing experience in the management of acute and chronic pain has negated this view and led to a better understanding of opioid-induced respiratory depression. Automaticity and rhythm+ of ventilation are generated by the so-called respiratory center& the brainstem. The respiratory centers are triggered by several mechanisms, of which the central chemoreceptors (with high density in the wall of the fourth ventricle) are best known. Any increase in cerebrospinal fluid $0, or decrease of brainstem pH causes these chemoreceptors to activate the respiratory centers. Opioid analgesics are well known to depress this reflex in a dosedependent manner. As the respiratory centers are part of the reticular formation, however, they are also triggered by the reticular formation in an “activity-dependent” manner. Brainstem stimulation by whatever mecha&m (e.g., awakening from anesthesia, conversation, and any input from the exterior or interior milieu, including the most important factor: pain) compensates to a certain degree for the depression of the chemoreceptor reflex activity. Opioid-iuduced respiratory depression has long been known to be usually overcome by commands to breathe. The new hypothesis states that a clinically relevant respiratory depression is connected to relative overdosage. Thii, in turn, reduces the problem to adequate dose-finding strategies. If one admits that 1040% of surgical patients need no postoperative analgesic at all, then even 5 mg morphine intramuscularly may mean overdosage in this group. On the other hand, it can be shown with PCA that patients demanding relatively high opioid dosage because of severe pain are never in danger of respiratory depression.‘2 Thus, the general de to prevent opioid-induced respiratory depression must be to administer only that dosage that is individuallynecessary. This means in&r& d titration, which can be performed best by intravenous injections. As soon as the individual need has been defined, other application modes

and .&h

Vol.7No. 3 (&j#) ApTir1992

can be used for maintenance of analgesia. Adequate surveillance must be guaranteed, of course, and naloxone should always be available. Moreover any pharmacologically induced reduction of vigilance should be avoided once patients have been titrated to their individual opioid dosage; there are several reports of patients who ceased to breathe when opioids were supplanted with benzodiazepines or barbiturates. Some particularIy interesting case reports also stress that surgical complications, e.g., slowly developing hemodynamic shock states, can also lead to decompensation in such a way that earlier, well-tolerated opioid dosages become deleteriOUS~**~~; in these cases, respiratory depression was treated successfully by normalizing the blood volume, not by naloxone! Although opioid blood concentrations were not determined, it is conceivable these cases illustrate a situation in which respiratory depression was not caused by increases in plasma concentration but by an imbalance of central chemoreceptor occupancy and the reticular formation compensatory potential. Finally, the literature contains many examples of opioidinduced respiratory depression where well-tolerated (and needed) opioid dosages turned out to be dangerous after additional pain management techniques (e.g., regional blockade or spasmolytic agents in spastic pain states) were used. It is obvious that T’I’S fentanyl, with its variability in drug delivery, also has to be carefully titrated to the patient’s needs. Since postoperative pain intensity cannot be predicted preoperatively, prophylactic ITS applications might be hazardous (or insufficient in individual patients) and require qualifiedmonitoring in the recovery room. On the other hand, pain levels and opioid requirements in cancer patients are often relatively constant over long periods of time. in these cases, ITS fentanyl is not more dangerous than other centrally acting analgesics of whatever application mode, provided that dosages are tailored to individual needs.

ITS fentanyl recently has been approved by the United States Food and Drug Administration for the management of chronic pain in patients requiring opioid .analgesics. The clinical efficacy was demonstrated in several studies.1’~24~34 In the authors’ opinion, TTS fentanyl appears a valuable tool for chronic pain patients requiring continuous opioid treatment, but is, due to its long delay and

Vol.7No. 3 (Suppl.)April 1992

Transdmal FentanykChical Phmacologv

decay times, probably unsuitable for the routine management of relatively short-lasting acute pain states. Due to the long latency of the first TTS fentanyl, however, there remains the clinical problem

of fxt

and adequate

dose&ding

strate-

gies, even in cancer patients. This problem can be solveci easily by intravenous PCA, which has been under investigation for some years by the authors’ team and is highly appreciated by patients and their relatives.24

1. Schcnplein RJ, Blank IH. Pcrmeabiity of the skin. Physiol Rev 1971;51:702-747. 2. Neubert R, Wohhab W. A multilayer membrane system for modehing drug penetration and permeation into and through human skin. In: Rietbrock N, ed. Die Haut als Transportorgan fiir Anmeistoffe. Darmstadt: Steinkopf, 199O;I!?5-130. 3. Michacls AS, Chandrasekaran SK, Shaw JE. Drug permeation through human skin: theory and in vitro cxperimcntal measurement. Am Inst Chem Eng 1975;2 1:935-996. 4. Kligman AM. Skin permeability: dcrmatologic aspectsof transdcrnal drug dclivcry. Am Heart J 1984; 188:200- 206. 5. Westcr RC, Maibach HI. Cutaneous pharmacokinetits: 10 steps to percutaneous absorption. Drug Mctab Rev 1983;14:169-205. 6. Shaw JE, Chandrasekaran SK. Transdermal therapentic systems. In: Prescott LF, Nimmo WS, eds. Drug absorption. Balgowlah: ADLS Press, I981:186-193. 7. Roy SD, analgesics: cutaneous Pharm Res

Flynn GL. Transdermal delivery of narcotic pH, anatomical, and subject influences of permcabiity of fentanyl and sufentanil. 1990;7:842-847.

8. Hwang SS, Nichols KC, Southam MA. Transdermal permeation: physiological and physicochemical aspects. In: I&nnann KA, Zech D, eds. Transdermal fentanyl. Berlin: Springer, 1991:1-7. 9. Witham SL, Roy SD, Humg AC, Flynn GL. Concepts in tmnsdermal delivery of narcotics. I. Enzymatic activity in the hairless mouse skin and human epidermal homogenates. Pharm Res 1986;3:54S. 10. Varvelfi Shafer SL, Hwang SS, Coen PA, Stanski DR. Absorption characteristics of transdermally administered fentanyl. Anesthesiology 1989;70:928-934. 11. Caplan RA, Southam MA. Transdermal drug delivery and its application to pain control. Adv Pam Res Ther 1990;14:233-249. 12. Lehmann KA. Patient-controlled intravenous analgesia for postoperative pain relief. Adv Pam Res Ther 1991;18:481-506. 13. Duthie DJR, Rowbotham DJ, Wyld R, Henderson PD, Nhnrrro WS. Plasma fentanyl concentrations &ring transdermal delive_ry of fentanyl to sxr&d

si5

patients. BrJ Anaesth 1988;603614-618. 14. Holley FO, van Stcennis C. Postoperative analgesia with fentanyl: pharmacokinctics and pharmacodynamjm of constant-rate iv and transdermal delivery. Br J Anaesth 1988;60:608-6 13. 15. Pleaia PM, Kramer TH, Linford J, Hameroff SR. Transdermal fentanyk pharmacokinetics and preliminary clinical evaluation. Pharmacotherapy 1989;9:2-9. 16. Rowbotham DJ, Wyld R, PeacockJE, Duthic DJR, Niimo WS. Transdermal fentanyl for the relief of pain after upper abdominal surgery. Br J Anaesth 1989;63:56-59. 27. Lehmann KA, Eirmolf C, Eberiein HJ, Nagel R. Transdermal fentanyl for the treatment of pain after major urological operations: a randomized double-blind cornparison with placebo using intravenous patient-eontroked analgesia. Eur J Clin Pharmaeol 199 1;48: 17-2 1. 18. Gourlay GK, Mather LE. Postoperative pain management with T’S fentanyk pharmacokinetics and pharmacodynamics. In: I&nxmn KA, Zech D, eds. Transdermal fentanyl. Berlin: Springer, 1991:119-140. 19. Gourlay GK, Kowalski SR, Plummer PL, Cousins MJ, Armstrong PJ. Fentanyl blood concentrationanalgesic response relationship in the treatment of postoperative pain. Anesth Analg 1988;67:329-337. 20. Lehmann KA, Heimich C, van Heiss R Balanced anesthesia and patient-controlled postoperative anaIgesia with fentanyk minimum effective concentrations, accumulation and acute tolerance. Acta Anaesthesiol Belg 1988;39: 1 l-23. 21. Gourlay GK, Kowabki SR, Phnnmer JL, Cherry DA, Gaukroger P, Cousins MJ. The tranadermal administration of fentanyl in the treatment of postoperative pain: pharmacokinetics and pharrnacodynamic effects. Pain 198337: 193-202. 22. Gourlay GK Kowalski SR, PhnnmerJL, et al. The efficacy of transdermal fentanyl in the treatment of postoperative pain: a double-blind comparison of fentanyl and placebo systems. Pain 1990;40:21-28. 23. Larijani GE, Bell SD, Go&erg ME, Lessin JB. Pharmacokinetics of fentanyl following transdermal application. Anesthesiology 1988;69:A363. 24. Southa.m ht, Gnpta B, Knowles N, Hwang SS. Transdermal fentanyk an overview of pharmacokinetics, efficacy and safety. Im I&mann KA, Zech D, eds. Tmnsdcrmalfentanyl. Berlin: Springer, 1991:107-l 16. 25. Zech D, Grond S, Lynch J. Cancer pain managefentanyk clinical experience. In: Iehmann KA, Zech D, eds. Transdermal fentanyl. Berlin: Springer, 1991:171-187.

ment with mS

26. Mather LE. Clinical pharmacokinetics of fentanyl and its newer denvatives. Chn Pharmacokinet 1983;8:422-446. 27. Von Bormann B, Ratthey K, Schwetlick 6, Schneider C, Mueller H, Hempehnann G. Postoperative Schmentherapie durch transdermales Fentanyl. Anaesth Intensivther Notfalhned 1988;23:3-8.

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28. Latasch L, Liiders S. Transdermal fentanyl against postoperative pain. Acta Anaesthesiol Belg 1989;40: 113119.

31. Iehmann KA, Freier J, Daub D. Fentanyl-Pharrnakokinctik und postoperative Atemdepression. Anaesthesist 1982;31:11 l-l 18.

29. Becker ID, Paulson BA, Miller RD, Severinghaus JW, Eger EI. Biphasic respiratory depression after fentanyl-droperidol or fentanyl alone used to supplement nitrOllS ozide anesthesia. Anesthesiology 1976;44:291-296.

32. Dahlsttim B, Tamsen A, Paalzow L, Hartvig P. Patient-controlled analgesic therapy. IV Pharmacokinetics and analgesic plasma concentrations of morphine. Clin Pharmacokinet 1982;7:266-279.

30. Stoeckel H, HengstmannJH, Schiittler J. Pharmacokinetics of fentanyl as a possible explanation for recurrence of respiratory depression. Br J Anaesth 1979;51:741-745.

33. Owen H, Szekely SM, Phunmer JL, Cushnie JM, Mather LE. Variables of patient-controlled analgesia. 2. Concurrent infusion. Anaesthesia 1989;*11-13. 34. Hill HF. Clinical pharmacology fentanyl. Eur J Pain 1990;11:81-91.

of transdermal