S4O j’ournal of Pain and S&nptom Management RI. 7 No. 3 (Suppl.) April 1992 --_ ._

Transdermal Fentanyl: Suggested

Recommendations for Clinical Use

Richard Payne, MD

Department of Jveuroogv, Uniuersi~ of Cincinnati MedicaI Center, Cincinnati, Ohio

Abstract ~~~&maf&myl off.2~ the advantage of providing continuous administration of a potent opt%d in the

absence of needles and expensive drug-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 the patient. Tl~is should be done by prouidiq short-acting opioids as rescue anakesics

for breakthroqh pain, Well-accepted principles e-stablished for 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 counteract opioid side eJects and enhance anakesia, and

the need to reassess the patient continuous&for recurrent tumor and other new sources of pain. Further

clinical& relevant studies are needed and include I) the debznnination of the relatiue potency of transdermal

fmtanyl, especiaUy in 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 doses for breakthrough pain. J Pain Symptom Manage 1992;7:S40+44.

ray words Transdennalfentany~ breakthroqh pain, anakesza

Oral administration of opioids, especially mor-

phine, is now accepted as standard therapy for

moderate-to-severe cancer pain.‘e2 Recently, how-

ever, Coyle and colleagues3 reported that 60 (67’10)

of 90 patients followed in their supportive care

service required at least two routes of administra-

tion of opioids in the last 4 wk of life. The

transdermal route of administration is particularly

attractive because it is simple, is inherently nonin-

vasive, and offers a means to provide a continuous

infusion of a potent opioid, fentanyl, in patients

with persistent daily pain.4 Furthermore, in theory,

Address re@ht requests to: Richard Payne, MD, Department of Neurology, University of Cincinnati Medical Center, 231 Bethesda Avenue, Cincinnati, OH 45267-0525.

continuous-infusion methods of opioid administra-

tion provide the means to minimize “bolus” effects

associated with peak and trough variations in blood

concentrations, which typically occur with inter-

mittent oral or parenteral dosing regimens.

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

0 U.S. Cancer Pain Relief Committee, 1992 Published by Elsevier, New York, New York

Voi. 7 No. 3 (SupP) April 1992 Transdmal Fentanylfor Clinical Use 541

groups versus those groups wearing skin patches with no active drug. Pharmacokinetic studies performed in postoperative patients7+ demon- strated 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 demon- strated 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 respi- ratory 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 1 OO-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 al- though 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 transder- mal administration, as opposed to 3-l 2 hr after IV do&g), and dose increments of transdennal fenta- nyl produced linear increases in blood concentra- tions. 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.

Simmons and colleagues13 evaluated transdcr- ma1 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 transder- mal therapeutic system (TTS) fentanyl was excel- lent. 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 immediate- release 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).

Table I T~sdemnal Fentanyk

C~~&SOII with Oral Administration

Advantages Disadvantages

Convenience cost Continuous administration Slower onset of action hngcr duration of action More ditlicult to reverse

side cffccts Slow titration Adhesive problem

In comparison with other continuous parenteral

opioid delivery systems (e.g., continuous subcuta-

neous [SC], Iv, or spinal), transdermal fentanyl

administration offers the advantage of being nonin-

vasive. 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, clini-

cians 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 transder-

mal 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 guide-

lines emphasiie the principles of continuous reas-

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 long-

term use of transdermal ientanyl.

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 attrac-

tive 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 administra-

tion 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 prepara-

tions, patients should be provided with supplemen-

tal 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 mor- phine, 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 slow-

release morphine, methadone, or levorphanol on a

routine basis.

The concept of transdermal opioid delivery is unfamiliar to all patients, and they must be educated with regard to the time/action character-

Table 2 Transdermal Fentanyl: Comparison with Continuous IV/SC

Advantages Disadvantages

No needles (less invasive) Slower onset of action No infusion pumps More difficult to reverse adverse effects Iess cxpcnsive Easier for carcgiver

Marc expericncc with pump-driven system

Lx ‘%ands-on” nursing experience

FM. 7No. 3 (Su/.$d) A/nil 1992 T~ansdmd Fmtanylfor Clinical Use SC?3

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 analgesics in first 48 hr Use average daily dose ofrcscuc analgesics to caiculate dose

increment Rotate skin sites Clarify patient and family expectations Allow several weeks for therapeutic trial

istics of 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. Dur- ing 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 titra- tion with transdermal fentanyl is achieved, around- the-clock dosing with the previous regimen, if maintained, will lead to unacceptable side effects, especially sedation. The experience and expecta- tions of many patients are that UpiUsfl are 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-

gation that would influence clinical use oftransder- mal 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 slow- release 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 transder- ma1 fentanyl dosing. The early experience with this drug is promising in selected populations of patients with cancer pain.

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