SF?6 Journal of Pain and S&mptom Management VOL 7No. 3 (Suppl.) April 1992

Transdermal Fentanyl: Long-Term Analgesic Studies Mary A. Simmonds, MD, and Jeanine Richenbacher, RN Division of Medical Oncology, Milton S. Hers& Medical Center, Hershgr, Pennqlvania

Abstract A/ma.& routes of dng delivery have particular relevancefor use in chronic pain. when the pain experience

k constant or warb constm~ a continuous in@-ivn of drug is an ideal wq to achieve effective pain relkf Earb experience with the transdmal application offmtaql in chronic cancerpain suggests that it is a safe, noninvasive, @ective method of managing pain. i’hejrst experience with the use of transdennalfentanyl in

cancer pain wlls reported by Miser and colleagues in Spat&m& Thy demonstrated that steady-state blood concentrations offmtanyl were linear& related fo the transdermalfentanyl dose. lhe terminal elimination hay-lye was approximatetj 34 hr. <ech and colleagues studied 13 patients with chronic cancer pain. Pain relief was obtained and was correlated with plasma fmtanyl levelr. lhe largest experience so far was reported in 39 patients in a multicenter trial conducted by Simmonds and colkgues. lhe median fentanyl dose was IO0 &hr (range, 25-525 ugihr). The initial dose offmtauyljom morphine conversion (61) was adequate in 50% ofpatients and titrated upward by 72 hrfor the remaining 50%. Patients wore the syst.em$r a median of 84 dqs (range, 5-365 chgs). Median supplementary dai& dose of morphine was 105 mg/dq (range, O-720 mgldq). The system was able to be maintained through a varie& of concomitant events. lhis experience demonstrated the safeety and clinical e$ectiveness of transdermal

fmtanyl. lhe transdermal therapeutic system @ntany~ is apromising advance in achieving noninvasive, contkous drug administration for the management of chronic cancer pain. J Pain Symptom Manage 1992;7:S36339.

K&y words Cancer pain, alternate routes of adminirtration, transdennaifentaql

Introduction Pain is a common consequence of cancer. It is a

major symptom in 70% of patients with advanced malignancies.’ Pain is caused directly by the cancer

in the majority of instances (70%). It also can be

associated with cancer therapy (15%/o), or it may be

coincidental and unrelated to the cancer (15”,@.*

Most cancer pain is chronic in nature. The painful

experience is constant, or nearly constant, and it

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Address reprint requests to: Mary Simmonds, MD, Cowley Associates, Plaza 21,425 North 21 Street, Camp Hi, PA 17011.

goes on for extended lengths of time. The patient must cope with this symptom on a daily basis.

Analgesic medications are the main modality in managing cancer pain. Opiates are used for moderate-to-severe pain. The most effective thera- peutic regimens aim at maintaining consistent serum levels of drug. The oral route is used initially, especially for titrating dose levels with short-acting narcotic analgesics.

Intermittent opioid dosing, however, may pro- duce peak-and-trough fluctuations in drug levels in the blood and, therefore, at the opioid receptors. This may result in variable levels of pain control. Ditliculty achieving a fairly consistent blood level by the oral route for any reason, such as poor

0 U.S. Cancer Pain Relief Committee, 1992 Published by Elscvicr, New York, New York 08853924/92/65.00

W. 7 No 3 (Sup~l.) April 1992 Transhal Fentunyk Long-T&m Studies s37 -

compliance or bowel obstruction, gives a rationale for considering a route of adminiitration that facilitates a constant infusion of drug.

The tools available to date to achieve more consistent drug delivery have had some limitations. Sustained-release morphine products are available, but use of these formulations only decreases the number of doses per day by 2-3 times. That is, when used properly, doses of opiate are needed at least every 8-12 hr. Additional doses of short- acting drugs may be needed for incident pains

Continuous intravenous (TV) or even subcutane- ous (SC) infusions of opiates are used comm~nly.~~ They can be used very effectively and for pro- longed periods of time, but they require needle placement, a pump to supply the drug, and experienced health-care workers to supervise ad- ministration.

The development of the transdermal therapeutic system (ITS) for the transdermal adminiitration of fentanyl allows the continuous administration of an opioid analgesic in a convenient, noninvasive formulation. This paper will summarize data related to the clinical use of TTS (femanyl) in the management of chronic cancer pain.

The first clinical study involving cancer patients using TTS (fentanyl) was conducted at the National Institutes of Health under the direction of Dr. Angela Miser.6 In this study, 5 patients were examined in whom oral administration of opioids was either ineffective or not possible. The transder- mal fentanyl dose was selected after an IV fentanyl inlirsion was titrated to achieve satisfactory pain relief The transdermal dose was then selected to deliver the same pg/hr dose, and the IV infusion was tapered and discontinued over 6 hr. The patients changed the transderrnal system every 24 hr. The patients in this study wore the systems for a range of 3-156 days. The dose range of transder- mal fentanyl requked to achieve good-to-excellent pain relief in the 5 patients was 75-305 ug/hr. The median effective dose was 225 pg/hr. Steady-state fentanyl plasma levels were analyzed and found to be linearly related to the transdermal fentanyl dose in the dose range studied. Serial plasma fentanyl levels in one patient demonstrated that the drug level plateaued. In this patient, the transdermal fentanyl dose was tapered over 12 days with relatively little decrement in plama concentra- tions. After the system was removed, plasma

concentrations declined relatively slowly. The estimated terminal halflife of elimination was 34 hr. ‘Ilk value is about twice as long as the k&life elimination calculated for postoperative single

applications of ITS (fentanyl). Zech and colleagues7 have reported their experi-

ence with these systems in 13 cancer patients_ As in the previous study, patients were treated with IV fentanyl and then converted to the comparable ‘ITS (fentanyl) dose. lV fentanyl was used on demand for another 48 hr. After that, SC morphine was used for breakthrough pain. ‘ITS (fentanyl) was applied for 72 hr per dose. They concluded that patients achieved analgesia. Compliance and acceptance were excellent.

The largest experience in the use of TTS (fentanyl) in the management of chronic cancer pain was conducted as a multi-institutional study by Simmonds and c0lleagues.s The purpose of this study was to use the transde,mal system in cancer outpatients on a long-term basis to determine the safety and efficacy of this approach. This was an open-label study, so that all patients used the ‘ITS (fentanyl).

Patients were converted to or continued on an immediate-release or sustained-release form of morphine. The dose was titrated to satisfactory pain relief. At the baseline visit, the dose of morphine that the patient determined adequately controlled the pain was used to convert to the starting dose of TTS (fentanyl) (see Table 1). The baseline dose of morphine was maintained for the first 18 hr. Patients were then given immediate- release morphine to be used on an as-needed basis for incident or breakthrough pain. The patients wore the systems for 72 hr per dose.

The conversion from oral to parenteral narcotic was based on the 6: 1 ratio, as determined by Houde and colleagues9 The conversion for fentanyl was based on the equivalence between 10 mg of

Tiie 1 Dosage of Morphine and TTS Fentanyl)

Required

Dosage Median Range

TTS (fentanyl) starting dose (&hr) 50 25-225 ‘ITS (fentauyl) final dose (pg/hr) 150 25+00 Duration of ?TS (fentanyl) use 84 5-365

(days) Supplemental morphine sulfate 105 O-720

(mg) -- -~._--. ~__^_______.c_ - - TTS, transdcrmai lhcrapeutic syslcm.

S38 Simmonds and Rithbah ?fd. 7No. 3 (Su#$L) April 1992

parenteral morphine and 100 ug of fentanyl. The vtem were supplied in four dosage forms (Z5,50, 75, and 100 pgg/ht$. The patients wore the number

of systems to equal the appropriate dose required. This clinical trial involved a total of 39 patients.

They s&red from a wide variety of cancers in advanced stages. The median age was 61 yr with a

range of 33-78 yr. The median Eastern Coopera- tive Oncology Group performance SWIGS at the

rtart of the study was 3 (bedridden 50% of the day). The media;, morphine stabilization dose was 120

mg/day, with a range of SO-790 mg/day.

The median ‘ITS (fentanyl) dose at the start of the study was 50 &hr, with a range of 25-255 &hc. Tire median final dose of fentanyl was 100 ug/hr, with a range of 25-525 pg/hr. This rate of increase in dose over time is consistent with that seen by patients using both IV and SC administra- tion of opiates.

The patients wore the systems for a median of 84 days with a range of 5-365 days. The median “rescue” dose of morphine was 105 mg/day with a range of O-720 mg/day.

Of the 39 patients, 19 required an increase in the ITS (fentanyl) dose at 1 wk. No one required a decrease in the dose. The remaining 20 patients judged their pain to be adequately controlled after using the systems for 1 wk.

The majority of patients wore the systems until their deaths from cancer; 2 patients were removed from the study because they developed severe increases in pain, which necessitated large doses of parenteral narcotics, and the caretaker of another patient decided to remove him fmm the study because it was becoming impractical to comply with the study visits during the terminal phase of his illness.

Side effects were sii to those in patients managed with conventional opioids. No specific side effects were attributed to ‘ITS (fentanyl). A few patients noted mild skin irritation after wearing the system for 3 days, but no allergic reactions were seen. One patient had local exacerbation of a generalized dermatophytic infection under the system. This “occlusive-dressing” effect ceased after the patient was treated with the appropriate

systemic antiftmgal agent.

During this lengthy experience with the use of

T’B (fentanyl), a number of typical events OC-

amd as complications of the cancer diagnosis (see Table 2). The ‘ITS (fentanyl) was maintained through these concomitant events, such as an acute

infection of herpes zoster, surgical stabilization of

T&e 2 Cmmmitant Events while Using TTS (Fentanyl)

Events (no.)

Surgery for pathologic fracture Herpes-zoster eruption Chemotherapy infusion Bowel obstruction Thrombotic event Gastric bleed

?TS, transdermal therapeutic system.

3 3

15 4 2 2

pathologic fractures of bone, bowel obstruction, gastrointestinal bleeding, thrombotic events, and chemotherapy infusions.

codasiolz From our experience and that of other investiga-

tors, we conclude that TTS (fentanyl) is a safe and effective tool in the management of chronic cancer pain. Patient compliance and acceptance of this modality have been uniformly excellent. There have been no unexpected untoward reactions attributed to ‘ITS (fentanyl) in these trials. The only unwelcome effects were those associated with using any opioid analgesic. No skin allergic reactions were observed.

Patients were easily converted to ‘ITS (fentanyl) and achieved an eqnianalgesic effect. The conver- sion tables recommended are conservative; that is, 50% of patients need an increase in the ITS (fentanyl) dose in the titration period. Using this titration, however, is safe, as no patient had an untoward effect of the opiate.

In thii preliminary experience, TTS (fentanyl) seen6 to provide a consistent level of analgesia. The work of Miser and colleagues6 showed that consis- tent serum levels can be obtained with repeated dosing of systems. As with other routes and modalities providing sustained administration of opiates, it was fairly common to need additional doses of short-acting analgesics for incident pain.

There was no difIiculty in using the TTS (fentanyl) during a variety of concomitant events. Experience thus far has demonstrated the use of

these systems through events including the acute infection of herpes zoster, surgery for pathologic fractures of bone, bowel obstructions, thrombotic events, gastrointestinal bleeding, and chemother- apy infusions.

Therefore, it may be concluded that ITS (fentanyl) is useful and safe for some patients in managing chronic cancer pain. It remains for

Rb. 7 No. 3 (Sup~l.) April 1992 Transahal Fmtanyk long-T&m S&lies s39

further experience and research to find its true

place within the armamentarium of cancer pain

management modalities.

es

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