--_
S4O j’ournal of Pain and S&nptomManagement
._
RI. 7 No. 3 (Suppl.)April 1992
Transdermal Fentanyl: Suggested Recommendations for Clinical Use Richard
Payne,
MD
Departmentof Jveuroogv, Uniuersi~of CincinnatiMedicaI Center,Cincinnati, Ohio
Abstract ~~~&maf&myl
of
off.2~theadvantage of providing continuousadministration a potent opt%d in the absence of needles and expensivedrug-in&ion pumps for the treatment of cancer pain. when transdermal
fm&znyl is initiated, it may be necessq to change the dose wq 24-48 hr until an appropriati dose is titrated to the needs of thepatient. Tl~isshould be done byprouidiq short-acting opioids as rescue anakesics for breakthroqh pain, Well-acceptedprinciples e-stablishedfor chronic opioid use in cancer pain management should appb to the administration of tramdennalfentanyl as well. These include dose titration, the coadministration of adjuvant drugs to counteractopioid side eJects and enhance anakesia, and the need to reassess the patient continuous&for recurrenttumor and other new sources of pain. Further clinical& relevant studies are needed and include I) the debznninationof the relatiuepotency of transdermal fmtanyl, especiaUyin compmison with oral andparenteral morphine; 2) a prospective St&y of the side-@ect pro@ of trazrdennalf~tunyl in relationship to oral morphine; and 3) the role of oral transrnucosal admin&tration offentanyl in selection of starting doses of transdermalfentanyl and as a means to provide wcue dosesfor breakthroughpain. J Pain Symptom
Manage
1992;7:S40+44.
ray words Transdennalfentany~ breakthroqh pain, anakesza
Oral administration phine,
of opioids,
is now accepted
moderate-to-severe
especially
as standard
therapy
cancer pain.‘e2 Recently,
ever, Coyle and colleagues3 reported of 90 patients
followed
service required tion
attractive
that 60 (67’10)
supportive
route of administration because
is particularly
it is simple, is inherently
of a potent
with persistent
care
in the last 4 wk of life. The
vasive, and offers a means to provide infusion
for how-
continuous-infusion methods of opioid administration provide the means to minimize “bolus” effects associated with peak and trough variations in blood concentrations, which typically occur with intermittent oral or parenteral dosing regimens.
at least two routes of administra-
of opioids
transdermal
in their
mor-
opioid,
nonin-
a continuous
fentanyl,
daily pain.4 Furthermore,
in patients in theory,
Addressre@ht requeststo: Richard Payne, MD, Department of Neurology, University of Cincinnati Medical Center, 231 Bethesda Avenue, Cincinnati, OH 45267-0525. 0 U.S. Cancer Pain Relief Committee, 1992 Published by Elsevier, New York, New York
Summary of C&Gal Studies Evaluating Transdermal Fentaozyl The efficacy of transdermal fentanyl as an analgesic in humans was established definitively by two randomized, placebo-controlled, prospective studies in postoperative pain.5a6 These studies demonstrated a reduction in pain intensity and a decrease in supplemental analgesics required to maintain satisfactory pain relief in the treated
Voi. 7 No. 3 (SupP) April 1992
Transdmal Fentanylfor Clinical Use
groups versus those groups wearing skin patches with no active drug. Pharmacokinetic studies performed in postoperative patients7+ demonstrated that the rate of absorption of fentanyl from the transdermal delivery system into blood was constant beginning 4-8 hr after placement of the patches, and that plasma concentrations pIateaued at 14-24 hr after placement. Although the bioavailabiity of fentanyl by the transdermal route was shown to be greater than 90%, studies in the postoperative setting demonstrated that there is substantial inter-individual variation in blood concentrations achieved with this route of administration. This variability, the need to place the system prior to surgery, and the 4% incidence of hypoventilation (delined as respiratory rate of C 8 breaths/n&i and arterial p@Q, tensions of > 55 mm Hg) observed in opioid-naive patients,‘0 justifies a relative contraindication for the use of transdermal fentanyl in postoperative pain. The risk of hypoventilation appears to increase with blood concentrations of fentanyl at greater than 2 ng/nL, and these values often are obtained with the placement of 1OO-ng/hr dosages or greater.g~t’ Uncontrolled clinical studies in cancer pain patients support the safe and effective use of transdermal fentanyl for this condition,“J2 although current clinical experience is still limited. For example, Miser and colleagues’ I reported pain relief ranging from “fair” to “excellent” in 5 patients treated with doses of transdermal fentanyl ranging from 75 to 305 ug/hr (median effective dose, 225 ug/hr). These patients were selected because oral opioid dosing was no longer possible for a variety of reasons. The determination of plasma fentanyl blood concentrations in 1 patient confirmed the observations noted in postoperative patients. The terminal half-life of elimination was longer than that measured after intravenous (IV) administration of fentanyl (14-34 hr for transdermal administration, as opposed to 3-l 2 hr after IV do&g), and dose increments of transdennal fentanyl produced linear increases in blood concentrations. The relatively long half-life of transdermal fentanyl may be problematic for the management of cancer pain, because patients experiencing significant adverse effects (e.g., sedation with concomitant respiratory depression) would require the repetitive administration or continuous IV infusion of naloxone, as the effect of fentanyl is not simply terminated by removing the patch from the skin.
541
Simmons and colleagues13 evaluated transdcrma1 fentanyl in 39 cancer patients with significant pain who responded to titration with oral opioids. Morphine doses necessary to control pain prior to the start of transdermal fentanyl ranged from 60 to 790 mg/day (mean dose, 120 mg/day). Using relative potency estimates of 1:20 to 1:30 for fentanyl relative to morphine, starting doses of transdermal fentanyl ranged from 25 to 250 pg/hr (median, 50 pg/hr). Patients were allowed to self-administer oral morphine on an as-needed basis for breakthrough pain; these “rescue” doses were taken by almost all patients and ranged from 0 to 720 mg/day (median dose, 105 mg/day). Patient compliance and acceptance of the transdermal therapeutic system (TTS) fentanyl was excellent. Patients could continue wearing the fentanyl patches during chemotherapy infusion, surgery, and herpes zoster eruptions. Both of the cancer pain studies cited above concluded that transdermal fentanyl could be used safely on a long-term basis (patches were worn up to 365 days in some cases). Furthermore, when used alone or in combmation with other opioids, transdermal fentanyl could be effective in cancer pain management. The side effects associated with transdermal fentanyl were diEcult to interpret in these studies because the majority of patients used oral morphine as well, but the incidence of nausea, constipation, sedation, mental clouding, urinary retention, and pruritus appeared no greater than that associated with the use of oral morphine alone, and constipation may have been less prominent.5
In comparison with oral administration of opioids, transderrnal fentanyl administration may be more convenient, offering the advantage of continuous administration and a long duration of action. Its disadvantages relative to oral opioid administration are related to its slower onset of action and relatively high cost (especially when compared with oral methadone or immediaterelease morphine). In addition, the dililculties inherent in rapid dose titration and in the reversal of side effects are also disadvantages of this mode of drug delivery. The unique problem of poor adhesion to skin in some patients (especially on sweaty or hairy skin) is also a relative disadvantage (Table 1).
Sessment of the patient; dose titration to pain relief with the minimal possible side effects; the use of adjuvant analgesics to enhance the analgesic effects of opioids and/or to counteract side effects; and the proactive management of predictable side effects of chronic opioid use such as nausea, constipation, and sedation. There are several other factors, however, that should be considered in the longterm use of transdermal ientanyl.
TableI T~sdemnal Fentanyk C~~&SOII with Oral Administration
Advantages
Disadvantages
Convenience Continuous administration hngcr duration of action
cost Slower onset of action More ditlicult to reverse side cffccts Slow titration Adhesive problem
Given the relatively long time required to achieve a constant rate of absorption with initial patch application and the relatively long time needed to attain steady-state concentrations, transdermal fentanyl administration is not attractive for management of acute severe pain, in which rapid dose titration to pain relief is desired. Because rapid dose adjustments with transdermal fentanyl are relatively diicult to achieve, it follows that patients are best suited for this route of administration if they have relatively stable baseline pain with minimal fluctuations in hourly pain intensities. It is usually necessary to titrate the patients to stable baseline pain relief with conventional opioid dosing regimens (oral or IV) prior to initiating transdennal fentanyl administration. As is the case for treatment of cancer pain with slow-release morphine preparations, patients should be provided with supplemental analgesics for breakthrough pain. The majority of patients on transdermal fentanyl will require “rescue” dosing, and rapidly acting, short-duration oral analgesics such as immediate-release morphine, oxycodone, codeine, and hydromorphone have been employed. Because of the increased risks of side effects associated with the accumulation in the blood of long half-lie opioids when used alone or in combination, it is not advisable to use transdermal fentanyl in combination with slowrelease morphine, methadone, or levorphanol on a routine basis.
In comparison with other continuous parenteral opioid delivery systems (e.g., continuous subcutaneous [SC], Iv, or spinal), transdermal fentanyl administration offers the advantage of being noninvasive. It is also less expensive as a result (Table 2). The cost advantage is even greater when one considers that skilled “hands-on” nursing and pharmacy expertise are not required to maintain these systems at home or in the hospital. Clearly, transdermal fentanyl administration is much easier on the caregiver than are the more complicated pump-driven systems. Currently, however, clinicians have much more experience with SC, IV, or spinal routes of administration and, therefore, can more effectively titrate the opioids delivered by these routes to the clinical needs of the patient, particularly if the situation is changing rapidly.
Based on the still-limited clinical experience with transdermal fentanyl, the following guidelines are proposed for its clinical use in cancer pain (Table 3). Pain complicating chronic medical conditions other than cancer may be managed with transdermal fentanyl, but to date there is very little clinical experience with which to establish guidelines for use in these circumstances. In general, published guidelines concerning the use of chronic opioid administration for the management of cancer pain should be followed when transdermal fentanyl is used.14 These guidelines emphasiie the principles of continuous reas-
The concept of transdermal opioid delivery is unfamiliar to all patients, and they must be educated with regard to the time/action characterTable 2
Transdermal
Fentanyl:
Comparison
Advantages
Disadvantages
No needles (less invasive) No infusion pumps
Slower onset of action
Iess cxpcnsive Easier for carcgiver Lx ‘%ands-on” nursing experience
with Continuous
More difficult to reverse adverse effects Marc expericncc with pump-driven system
IV/SC
FM.7No. 3 (Su/.$d)A/nil 1992
T~ansdmd Fmtanylfor Clinical Use
TibL 3 TranddF
i&lines for clinical use
Apply standard guidelines for chronic opioid use Stable pain baseline Minimal incident pain Provide mscuc analgesic Liberal use of rescue analgesicsin first 48 hr Use average daily dose ofrcscuc analgesics to caiculate dose increment Rotate skin sites Clarify patient and family expectations Allow several weeksfor therapeutic trial
isticsof
this drug. The concept of PRN or as-needed “rescue” dosing must be understood. This concept is no different from that employed with the use of slow-release morphine and is particularly important in the first several days after initiating therapy with transdermal fentanyl. During this time, patients should be instructed to take “rescue” analgesics liberally. Indeed, continuation of the previous around-the-clock opioid regimen in the first 4-g-72 hr may be necessary for some patients. In contrast, once appropriate dose titration with transdermal fentanyl is achieved, aroundthe-clock dosing with the previous regimen, if maintained, will lead to unacceptable side effects, especially sedation. The experience and expectations of many patients are that UpiUsflare always necessary for pain relief, however, and many will continue to take “rescue” analgesics almost by habit unless clearly instructed otherwise. In summary, transdermal fentanyl appears to be most suited for patients with persistent daily pain and a minimal incident component to the pain. Given the unique pharmacokineties of fentanyl when delivered by this route, the liberal use of short-acting analgesics for “rescue” dosing is usuaily necessary, especiahy as therapy is being initiated and/or the dose is being changed. The average 724~ consumption of “rescue” analgesics should be used to calculate dose increments of transdermal fentanyl at the time of the next patch change. Skin sites should be rotated to min-Lnixe variations in blood levels resulting from the buildup of subcutaneous skin depots, and patients should be warned about poor skin adhesion resulting from sweating and hair growdq such patients usually benefit from applying extra (transparent) tape over the patch and shaving the areas of skin to which the patch is to be applied. There are s~::ral areas of future clinical investi-
SC?3
gation that would influence clinical use oftransdermal fentanyl directly by providing more definitive experience and extending the guidelines for its use in cancer pain management. These studies include an investigation of the efficacy and side-effect profiles of this agent in cancer pain management in comparison with standard therapies, such as slowrelease morphine. In addition, direct study of the potency of transdermal fentanyl relative to oral morphine and oral transmucosal fentanyP5 would be of substantial interest, as these would provide guidelines for the more accurate selection of starting doses and incremental changes in transderma1 fentanyl dosing. The early experience with this drug is promising in selected populations of patients with cancer pain.
1. Twycros~ RG. Choice of strong analgesic in terminal cancer: diamotphine or morphine? Pain 1977;3:93-104.
2. Walsh TD. Oral momhine in chronic cancer pain. Pam 1984;18:1-11. 3. Coyle N, Adelhart J, Foley KM, Portenoy RK. Character of terminal ilhress in the advanced cancer patient: pain and other symptoms during the last four weeks of life.J Pam Symptom Manage 1990;5:83-93. 4. Niio WS. The promise of transdermal drug delivery. BrJ Anaesth 1990;64:7-10. 5. Gourlay GK, Kowalski SR, Plummer JL, et al. The efficacy of transdermal fentanyl in the treatment of postoperative pain: a double-blind comparison of fentanyl and placebo systems. Pam 1990;40:21-28. 6. Caplan RA, Ready LB, Oden RV, Matsen FA, Nessley ML Olsson GL Transdermal fentanyl for postoperative pain management. A double-blind placebo study.JAMA 1989;261:1036-1039. 7. Pleaia PM, Dramer TH, I&ford J, Hameroff SR. Transdermal fentanyk phannacokinetics and preliminary clinical evalnation. Pharmacotherapy 1989;9:2-9. 8. Gourlay GK, Kowalski SR, PiummerJL, Cherry DA, Gaukroger P, Cousins IQ. The transdermal administration of fentanyl in the treatment of postoperative paim pharmacokinetics and pharmacodynamic effects. Pain 1989;37: 193-202. 9. VarvelJR, Shafer SL Hwang SS, Coen PA, Stanski DR. The absorption characteristics ci transdermally administered fentanyl. Anesthesiologv 1989;70:928-934. IO. Dumgesic product insert. 11. Miser AW, Namng PK, Dothage JA, Young RC, Sindelar W, Misser JS. Transdermal fentanyl for pain control in patients with cancer. Pain 198337: 15-2 1.
12. Payne R, Moran K, Southam M The role of transdermal fentanyl in the management of cancer pahr.
s44
In: Estafaous FG, ed. Opioids in anesthesia II. Stoncham: Butterworth, 1990:215-222. 13. Simmons MA, Payne R, Richcnbacher J, Moran K, Southam MA. TTS (fentanyl) in the management of pain in patients with cancer. Proc Am Sot Clin Oncology 1989383234. 14. Foley KM, Arbit E. The management of cancer pain.
Pyte
Vol. 7X0. 3 (Suppl.)Apri 1992
In: Dcvita VT, Hcllman S, Rosenberg SA, cds. Cancer: principles and practice of oncology, 3rd ed. Philadelphia: JB Lippincott, 1989:2064-208 7. 15. Ashbum MA, Fine PG, Stanley TH. Oral transmucosal fcntanyl citrate for the treatment of breakthrough cancer pain: a case report. Anesthesiology 1989;7 1:615617.
S4O j’ournal of Pain and S&nptomManagement
._
RI. 7 No. 3 (Suppl.)April 1992
Transdermal Fentanyl: Suggested Recommendations for Clinical Use Richard
Payne,
MD
Departmentof Jveuroogv, Uniuersi~of CincinnatiMedicaI Center,Cincinnati, Ohio
Abstract ~~~&maf&myl
of
off.2~theadvantage of providing continuousadministration a potent opt%d in the absence of needles and expensivedrug-in&ion pumps for the treatment of cancer pain. when transdermal
fm&znyl is initiated, it may be necessq to change the dose wq 24-48 hr until an appropriati dose is titrated to the needs of thepatient. Tl~isshould be done byprouidiq short-acting opioids as rescue anakesics for breakthroqh pain, Well-acceptedprinciples e-stablishedfor chronic opioid use in cancer pain management should appb to the administration of tramdennalfentanyl as well. These include dose titration, the coadministration of adjuvant drugs to counteractopioid side eJects and enhance anakesia, and the need to reassess the patient continuous&for recurrenttumor and other new sources of pain. Further clinical& relevant studies are needed and include I) the debznninationof the relatiuepotency of transdermal fmtanyl, especiaUyin compmison with oral andparenteral morphine; 2) a prospective St&y of the side-@ect pro@ of trazrdennalf~tunyl in relationship to oral morphine; and 3) the role of oral transrnucosal admin&tration offentanyl in selection of starting doses of transdermalfentanyl and as a means to provide wcue dosesfor breakthroughpain. J Pain Symptom
Manage
1992;7:S40+44.
ray words Transdennalfentany~ breakthroqh pain, anakesza
Oral administration phine,
of opioids,
is now accepted
moderate-to-severe
especially
as standard
therapy
cancer pain.‘e2 Recently,
ever, Coyle and colleagues3 reported of 90 patients
followed
service required tion
attractive
that 60 (67’10)
supportive
route of administration because
is particularly
it is simple, is inherently
of a potent
with persistent
care
in the last 4 wk of life. The
vasive, and offers a means to provide infusion
for how-
continuous-infusion methods of opioid administration provide the means to minimize “bolus” effects associated with peak and trough variations in blood concentrations, which typically occur with intermittent oral or parenteral dosing regimens.
at least two routes of administra-
of opioids
transdermal
in their
mor-
opioid,
nonin-
a continuous
fentanyl,
daily pain.4 Furthermore,
in patients in theory,
Addressre@ht requeststo: Richard Payne, MD, Department of Neurology, University of Cincinnati Medical Center, 231 Bethesda Avenue, Cincinnati, OH 45267-0525. 0 U.S. Cancer Pain Relief Committee, 1992 Published by Elsevier, New York, New York
Summary of C&Gal Studies Evaluating Transdermal Fentaozyl The efficacy of transdermal fentanyl as an analgesic in humans was established definitively by two randomized, placebo-controlled, prospective studies in postoperative pain.5a6 These studies demonstrated a reduction in pain intensity and a decrease in supplemental analgesics required to maintain satisfactory pain relief in the treated
Voi. 7 No. 3 (SupP) April 1992
Transdmal Fentanylfor Clinical Use
groups versus those groups wearing skin patches with no active drug. Pharmacokinetic studies performed in postoperative patients7+ demonstrated that the rate of absorption of fentanyl from the transdermal delivery system into blood was constant beginning 4-8 hr after placement of the patches, and that plasma concentrations pIateaued at 14-24 hr after placement. Although the bioavailabiity of fentanyl by the transdermal route was shown to be greater than 90%, studies in the postoperative setting demonstrated that there is substantial inter-individual variation in blood concentrations achieved with this route of administration. This variability, the need to place the system prior to surgery, and the 4% incidence of hypoventilation (delined as respiratory rate of C 8 breaths/n&i and arterial p@Q, tensions of > 55 mm Hg) observed in opioid-naive patients,‘0 justifies a relative contraindication for the use of transdermal fentanyl in postoperative pain. The risk of hypoventilation appears to increase with blood concentrations of fentanyl at greater than 2 ng/nL, and these values often are obtained with the placement of 1OO-ng/hr dosages or greater.g~t’ Uncontrolled clinical studies in cancer pain patients support the safe and effective use of transdermal fentanyl for this condition,“J2 although current clinical experience is still limited. For example, Miser and colleagues’ I reported pain relief ranging from “fair” to “excellent” in 5 patients treated with doses of transdermal fentanyl ranging from 75 to 305 ug/hr (median effective dose, 225 ug/hr). These patients were selected because oral opioid dosing was no longer possible for a variety of reasons. The determination of plasma fentanyl blood concentrations in 1 patient confirmed the observations noted in postoperative patients. The terminal half-life of elimination was longer than that measured after intravenous (IV) administration of fentanyl (14-34 hr for transdermal administration, as opposed to 3-l 2 hr after IV do&g), and dose increments of transdennal fentanyl produced linear increases in blood concentrations. The relatively long half-life of transdermal fentanyl may be problematic for the management of cancer pain, because patients experiencing significant adverse effects (e.g., sedation with concomitant respiratory depression) would require the repetitive administration or continuous IV infusion of naloxone, as the effect of fentanyl is not simply terminated by removing the patch from the skin.
541
Simmons and colleagues13 evaluated transdcrma1 fentanyl in 39 cancer patients with significant pain who responded to titration with oral opioids. Morphine doses necessary to control pain prior to the start of transdermal fentanyl ranged from 60 to 790 mg/day (mean dose, 120 mg/day). Using relative potency estimates of 1:20 to 1:30 for fentanyl relative to morphine, starting doses of transdermal fentanyl ranged from 25 to 250 pg/hr (median, 50 pg/hr). Patients were allowed to self-administer oral morphine on an as-needed basis for breakthrough pain; these “rescue” doses were taken by almost all patients and ranged from 0 to 720 mg/day (median dose, 105 mg/day). Patient compliance and acceptance of the transdermal therapeutic system (TTS) fentanyl was excellent. Patients could continue wearing the fentanyl patches during chemotherapy infusion, surgery, and herpes zoster eruptions. Both of the cancer pain studies cited above concluded that transdermal fentanyl could be used safely on a long-term basis (patches were worn up to 365 days in some cases). Furthermore, when used alone or in combmation with other opioids, transdermal fentanyl could be effective in cancer pain management. The side effects associated with transdermal fentanyl were diEcult to interpret in these studies because the majority of patients used oral morphine as well, but the incidence of nausea, constipation, sedation, mental clouding, urinary retention, and pruritus appeared no greater than that associated with the use of oral morphine alone, and constipation may have been less prominent.5
In comparison with oral administration of opioids, transderrnal fentanyl administration may be more convenient, offering the advantage of continuous administration and a long duration of action. Its disadvantages relative to oral opioid administration are related to its slower onset of action and relatively high cost (especially when compared with oral methadone or immediaterelease morphine). In addition, the dililculties inherent in rapid dose titration and in the reversal of side effects are also disadvantages of this mode of drug delivery. The unique problem of poor adhesion to skin in some patients (especially on sweaty or hairy skin) is also a relative disadvantage (Table 1).
Sessment of the patient; dose titration to pain relief with the minimal possible side effects; the use of adjuvant analgesics to enhance the analgesic effects of opioids and/or to counteract side effects; and the proactive management of predictable side effects of chronic opioid use such as nausea, constipation, and sedation. There are several other factors, however, that should be considered in the longterm use of transdermal ientanyl.
TableI T~sdemnal Fentanyk C~~&SOII with Oral Administration
Advantages
Disadvantages
Convenience Continuous administration hngcr duration of action
cost Slower onset of action More ditlicult to reverse side cffccts Slow titration Adhesive problem
Given the relatively long time required to achieve a constant rate of absorption with initial patch application and the relatively long time needed to attain steady-state concentrations, transdermal fentanyl administration is not attractive for management of acute severe pain, in which rapid dose titration to pain relief is desired. Because rapid dose adjustments with transdermal fentanyl are relatively diicult to achieve, it follows that patients are best suited for this route of administration if they have relatively stable baseline pain with minimal fluctuations in hourly pain intensities. It is usually necessary to titrate the patients to stable baseline pain relief with conventional opioid dosing regimens (oral or IV) prior to initiating transdennal fentanyl administration. As is the case for treatment of cancer pain with slow-release morphine preparations, patients should be provided with supplemental analgesics for breakthrough pain. The majority of patients on transdermal fentanyl will require “rescue” dosing, and rapidly acting, short-duration oral analgesics such as immediate-release morphine, oxycodone, codeine, and hydromorphone have been employed. Because of the increased risks of side effects associated with the accumulation in the blood of long half-lie opioids when used alone or in combination, it is not advisable to use transdermal fentanyl in combination with slowrelease morphine, methadone, or levorphanol on a routine basis.
In comparison with other continuous parenteral opioid delivery systems (e.g., continuous subcutaneous [SC], Iv, or spinal), transdermal fentanyl administration offers the advantage of being noninvasive. It is also less expensive as a result (Table 2). The cost advantage is even greater when one considers that skilled “hands-on” nursing and pharmacy expertise are not required to maintain these systems at home or in the hospital. Clearly, transdermal fentanyl administration is much easier on the caregiver than are the more complicated pump-driven systems. Currently, however, clinicians have much more experience with SC, IV, or spinal routes of administration and, therefore, can more effectively titrate the opioids delivered by these routes to the clinical needs of the patient, particularly if the situation is changing rapidly.
Based on the still-limited clinical experience with transdermal fentanyl, the following guidelines are proposed for its clinical use in cancer pain (Table 3). Pain complicating chronic medical conditions other than cancer may be managed with transdermal fentanyl, but to date there is very little clinical experience with which to establish guidelines for use in these circumstances. In general, published guidelines concerning the use of chronic opioid administration for the management of cancer pain should be followed when transdermal fentanyl is used.14 These guidelines emphasiie the principles of continuous reas-
The concept of transdermal opioid delivery is unfamiliar to all patients, and they must be educated with regard to the time/action characterTable 2
Transdermal
Fentanyl:
Comparison
Advantages
Disadvantages
No needles (less invasive) No infusion pumps
Slower onset of action
Iess cxpcnsive Easier for carcgiver Lx ‘%ands-on” nursing experience
with Continuous
More difficult to reverse adverse effects Marc expericncc with pump-driven system
IV/SC
FM.7No. 3 (Su/.$d)A/nil 1992
T~ansdmd Fmtanylfor Clinical Use
TibL 3 TranddF
i&lines for clinical use
Apply standard guidelines for chronic opioid use Stable pain baseline Minimal incident pain Provide mscuc analgesic Liberal use of rescue analgesicsin first 48 hr Use average daily dose ofrcscuc analgesics to caiculate dose increment Rotate skin sites Clarify patient and family expectations Allow several weeksfor therapeutic trial
isticsof
this drug. The concept of PRN or as-needed “rescue” dosing must be understood. This concept is no different from that employed with the use of slow-release morphine and is particularly important in the first several days after initiating therapy with transdermal fentanyl. During this time, patients should be instructed to take “rescue” analgesics liberally. Indeed, continuation of the previous around-the-clock opioid regimen in the first 4-g-72 hr may be necessary for some patients. In contrast, once appropriate dose titration with transdermal fentanyl is achieved, aroundthe-clock dosing with the previous regimen, if maintained, will lead to unacceptable side effects, especially sedation. The experience and expectations of many patients are that UpiUsflare always necessary for pain relief, however, and many will continue to take “rescue” analgesics almost by habit unless clearly instructed otherwise. In summary, transdermal fentanyl appears to be most suited for patients with persistent daily pain and a minimal incident component to the pain. Given the unique pharmacokineties of fentanyl when delivered by this route, the liberal use of short-acting analgesics for “rescue” dosing is usuaily necessary, especiahy as therapy is being initiated and/or the dose is being changed. The average 724~ consumption of “rescue” analgesics should be used to calculate dose increments of transdermal fentanyl at the time of the next patch change. Skin sites should be rotated to min-Lnixe variations in blood levels resulting from the buildup of subcutaneous skin depots, and patients should be warned about poor skin adhesion resulting from sweating and hair growdq such patients usually benefit from applying extra (transparent) tape over the patch and shaving the areas of skin to which the patch is to be applied. There are s~::ral areas of future clinical investi-
SC?3
gation that would influence clinical use oftransdermal fentanyl directly by providing more definitive experience and extending the guidelines for its use in cancer pain management. These studies include an investigation of the efficacy and side-effect profiles of this agent in cancer pain management in comparison with standard therapies, such as slowrelease morphine. In addition, direct study of the potency of transdermal fentanyl relative to oral morphine and oral transmucosal fentanyP5 would be of substantial interest, as these would provide guidelines for the more accurate selection of starting doses and incremental changes in transderma1 fentanyl dosing. The early experience with this drug is promising in selected populations of patients with cancer pain.
1. Twycros~ RG. Choice of strong analgesic in terminal cancer: diamotphine or morphine? Pain 1977;3:93-104.
2. Walsh TD. Oral momhine in chronic cancer pain. Pam 1984;18:1-11. 3. Coyle N, Adelhart J, Foley KM, Portenoy RK. Character of terminal ilhress in the advanced cancer patient: pain and other symptoms during the last four weeks of life.J Pam Symptom Manage 1990;5:83-93. 4. Niio WS. The promise of transdermal drug delivery. BrJ Anaesth 1990;64:7-10. 5. Gourlay GK, Kowalski SR, Plummer JL, et al. The efficacy of transdermal fentanyl in the treatment of postoperative pain: a double-blind comparison of fentanyl and placebo systems. Pam 1990;40:21-28. 6. Caplan RA, Ready LB, Oden RV, Matsen FA, Nessley ML Olsson GL Transdermal fentanyl for postoperative pain management. A double-blind placebo study.JAMA 1989;261:1036-1039. 7. Pleaia PM, Dramer TH, I&ford J, Hameroff SR. Transdermal fentanyk phannacokinetics and preliminary clinical evalnation. Pharmacotherapy 1989;9:2-9. 8. Gourlay GK, Kowalski SR, PiummerJL, Cherry DA, Gaukroger P, Cousins IQ. The transdermal administration of fentanyl in the treatment of postoperative paim pharmacokinetics and pharmacodynamic effects. Pain 1989;37: 193-202. 9. VarvelJR, Shafer SL Hwang SS, Coen PA, Stanski DR. The absorption characteristics ci transdermally administered fentanyl. Anesthesiologv 1989;70:928-934. IO. Dumgesic product insert. 11. Miser AW, Namng PK, Dothage JA, Young RC, Sindelar W, Misser JS. Transdermal fentanyl for pain control in patients with cancer. Pain 198337: 15-2 1.
12. Payne R, Moran K, Southam M The role of transdermal fentanyl in the management of cancer pahr.
s44
In: Estafaous FG, ed. Opioids in anesthesia II. Stoncham: Butterworth, 1990:215-222. 13. Simmons MA, Payne R, Richcnbacher J, Moran K, Southam MA. TTS (fentanyl) in the management of pain in patients with cancer. Proc Am Sot Clin Oncology 1989383234. 14. Foley KM, Arbit E. The management of cancer pain.
Pyte
Vol. 7X0. 3 (Suppl.)Apri 1992
In: Dcvita VT, Hcllman S, Rosenberg SA, cds. Cancer: principles and practice of oncology, 3rd ed. Philadelphia: JB Lippincott, 1989:2064-208 7. 15. Ashbum MA, Fine PG, Stanley TH. Oral transmucosal fcntanyl citrate for the treatment of breakthrough cancer pain: a case report. Anesthesiology 1989;7 1:615617.
