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Transdermal Fentanyl

A Review of its Pharmacological Properties and Therapeutic Efficacy in Pain Control

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Summary

Synopsis

Fentanyl is a synthetic opioid with short-acting analgesic activity after intravenous or subcutaneous administration. The low molecular weight, high potency and lipid solubility of fentanyl make it suitable for delivery via the transdermal therapeutic system (TTS). These systems are designed to release the drug into the skin at a constant rate ranging from 25 to 100 µg/h, multiple systems can be applied to achieve higher delivery rates. Initially, much of the clinical experience with fentanyl TTS was obtained in patients with acute postoperative pain. However, because of the increased risk of respiratory complications, fentanyl TTS is contraindicated in this setting. Fentanyl TTS is recommended for use in chronic cancer pain. Moreover, in 11 countries worldwide including the US, its use is not restricted to chronic cancer pain; the drug is also available for treatment of general chronic pain, including that of nonmalignant origin.

At the start of fentanyl TTS treatment, depot accumulation of the drug within skin tissue results in a significant delay (17 to 48 hours) before maximum plasma concentration is achieved. Approximately half of the cancer patients converted to transdermal fentanyl from other opioid agents required increased dosages after initial application of the patch. However, concomitant use of short-acting morphine maintained pain relief during the titration period, and the use of such supplementary medication decreased with the duration of fentanyl TTS treatment.

In patients with chronic cancer pain, changes in visual analogue scale (VAS) pain scores ranged from a 10% increase (worse pain) to >50% decrease (less pain) during transdermal fentanyl therapy compared with previous opioid treatment. In addition, patient preference for fentanyl TTS was indicated by the number of patient requests (up to 95%) for continued use of the drug at the end of the study.

Although fentanyl TTS is contraindicated in patients postoperatively, the efficacy of fentanyl via the transdermal route was investigated in this patient group. Supplementary patient controlled analgesia was significantly reduced in patients who received fentanyl TTS 75 µg/h compared with placebo, although this was not apparent until ≥12 hours after application. Data evaluating pain relief, which was assessed by VAS pain scores, were inconclusive.

Preliminary data, although from relatively small numbers of patients, indicate that transdermal fentanyl may be useful in the management of chronic non-malignant pain. Indeed, some patients whose pain was previously uncontrolled became completely pain free.

The most frequently occurring adverse events during fentanyl TTS therapy (as with other opioid agents) included vomiting, nausea and constipation, although vomiting and nausea were not clearly associated with the drug. The most serious adverse event was hypoventilation, which occurred more frequently in postoperative (4%) than in cancer patients (2%). In surgical patients, fentanyl-associated respiratory events (reduced respiratory rate and apnoea) generally occurred within 24 hours of patch application; however, there were isolated reports of late onset (≥36 hours postsurgery) fentanyl-associated respiratory depression. In cancer patients, the incidence of constipation was reduced by up to two-thirds after switching from oral morphine to transdermal fentanyl. Transient skin irritation associated with the plastic patch or the adhesive, rather than the drug, was reported in a maximum 3% of patients.

In summary, transdermal fentanyl is a useful alternative to other opioid agents, which are also recommended on the third step of the WHO analgesic ladder, in the management of chronic malignant pain. Preliminary data indicate that it may be useful in the management of chronic nonmalignant pain. The advantages offered by fentanyl TTS over traditional methods of chronic pain control include its ease of administration, less constipation and the 3-day interval between patch renewal. These factors should improve quality of life and be attractive to both patients and caregivers.

Pharmacodynamic Properties

Fentanyl, a 4-anilidopiperidine compound, is a pure opioid agonist and has a selective high affinity for the µ receptor. Unlike morphine, it has high lipid solubility which facilitates its transfer across the blood-brain barrier. The analgesic properties of fentanyl are well known.

Fentanyl caused bronchial hyperreactivity in guinea-pigs by reducing sympathetic activity. In cats, fentanyl inhibited the activity of the ventral group of respiratory neurons and caused irregular bursts of activity in the dorsal group.

Intravenous fentanyl (1 to 4 µg/kg) caused significantly (p = 0.001) greater dose-independent respiratory depression than sufentanil (0.1 to 0.4 µg/kg) in human volunteers. In surgical patients, reductions in minute volume were recorded during and after intravenous infusion of fentanyl (3 µg/kg/h; p < 0.05 compared with baseline) and alfentanil (20 µg/kg/h; not significant).

In rats the dose of subcutaneous or oral fentanyl required to achieve anaesthesia is only marginally greater (approximately 1 to 2 times) than that required for short term (2 hour) protection against castor oil-induced diarrhoea. In contrast, there was a marked difference between the 2 concentrations for morphine (36 and 6 times greater for subcutaneous and oral routes).

During coronary artery surgery, in contrast with morphine recipients (100 µg/kg/min; total dose 1 mg/kg), fentanyl recipients (5 µg/kg/min; total dose 50 µg/kg) did not experience increased cardiac output, peripheral vasodilation and hypotension associated with increased histamine release.

Intravenous administration of fentanyl (0.1 mg) significantly decreased intraoperative plasma levels of immunoreactive µ-endorphin in patients undergoing oral surgery (24.9 ng/L preoperatively to 19.6 ng/L intraoperatively; p < 0.05).

Pharmacokinetic Properties

In in vitro diffusion cell studies using human cadaver skin, fentanyl penetrated the skin at similar rates in a variety of locations on the body. However, interindividual differences were observed.

The transdermal therapeutic system (TTS) was designed to release fentanyl at a constant rate for up to 72 hours. The amount of drug released is proportional to the surface area of the patch and 4 different sizes are currently available with release rates of 25, 50, 75 and 100 µg/h. Under normal physiological conditions, skin temperature and peripheral blood flow have no significant influence on the absorption rate of fentanyl from the patch. However, a rise in body temperature up to 40°C may increase the absorption rate by one-third.

A mean bioavailability of 92% (range 57 to 146%) has been reported for fentanyl TTS, although marked interindividual variation is apparent. The high bioavailability suggests that the drug is not significantly degraded by skin flora or cutaneous metabolism; however, the variation may indicate that absorption varies between patients.

Mean maximum plasma concentration (Cmax) values ranged from 0.69 to 2.6 µg/L (25 to 100 µg/h fentanyl TTS). Although fentanyl has been detected in the blood 1 to 2 hours after initial application of a transdermal system (100 or 75 µg/h), considerable delays (17 to 48 hours) between patch application (25 to 75 µg/h) and occurrence of Cmax were also apparent. The delay has been attributed to depot accumulation of the drug within the skin under the TTS before diffusion into the systemic circulation.

Once attained, steady-state blood fentanyl concentrations persisted for the duration of the patch application. In several trials steady-state concentrations were not achieved until after application of the second patch (24 or 72 hours). However, data from 1 study in 10 patients who wore 2 consecutive 72-hour patches (25 µg/h) suggests that plasma fentanyl concentration may plateau in the second 12-hour period after initial application.

In vitro studies in rats suggest that the drug is primarily metabolised in the liver and produces phenylacetic acid, norfentanyl and small amounts of the pharmacologically active p-hydroxy(phenethyl)fentanyl.

Elimination of fentanyl was prolonged after transdermal application compared with intravenous administration. Elimination half-life (t½) values of 13 to 25 hours were reported after transdermal administration; these are up to 3 times greater than after intravenous administration.

Age did not significantly affect the absorption pharmacokinetics of transdermal fentanyl. However, the elimination half-life of fentanyl after removal of the TTS was significantly greater in elderly compared with younger patients (43.1 vs 20.0 hours; p < 0.05).

Therapeutic Efficacy

In nonblind clinical trials, cancer patients with chronic pain were switched from stabilised opioid therapy, such as morphine (mean dosage 160 or 257 mg/day or median 120 mg/day) to transdermal fentanyl (median initial dosage 25 to 50 µg/h or mean 63 to 66 µg/h) generally without loss of pain relief. Although the majority of patients studied were initially stabilised on short-acting opioids, 2 studies showed that opioid-naive cancer patients could be started on transdermal fentanyl therapy without prior opioid stabilisation. This reduces the delay before achieving satisfactory pain relief.

In a number of trials, dosage increases from the initial calculated dosage were required by approximately half the cancer patients converted to transdermal fentanyl. Pain relief during the titration period was maintained with use of short-acting opioids such as morphine. The use of supplementary analgesia (available throughout all clinical studies) declined with duration of patch application. A37% decrease in patient use of supplementary analgesia was reported after 1 week of fentanyl TTS therapy. Statistically nonsignificant changes in visual analogue scale (VAS) pain scores ranged from 10% increase (worse pain) to >50% decrease (less pain) during transdermal fentanyl treatment.

Several studies in patients with cancer described improvements in quality of life during fentanyl TTS therapy, including increased patient function and patients reporting that they felt less disruptive to family members. In a crossover study, 73 of 136 patients (54%) preferred fentanyl patches compared with 49 of 136 patients (36%) who preferred morphine tablets (p = 0.037). Preference for transdermal fentanyl was confirmed by several small trials in which the majority (61 to 95%) of patients completing the studies requested continued use of the patches.

Use of fentanyl TTS in the acute postoperative setting is contraindicated because the risk of adverse respiratory effects outweighs the therapeutic benefits in this patient population. Clinical trials in patients with postoperative pain were used to investigate the efficacy of fentanyl via the transdermal route. In some double-blind placebo-controlled studies, postoperative use of supplementary patient-controlled analgesia was significantly reduced in fentanyl TTS versus placebo recipients (p < 0.05) although this was not generally apparent until 12 to 24 hours after surgery. Supplementary opioid consumption was not clearly dependent on the rate of fentanyl TTS delivery and was still required by patients wearing 75 µg/h patches. However, with respect to effects on pain perception, data for fentanyl TTS in acute non-stable pain (i.e. postoperative) as measured by decreases in VAS scores were inconclusive.

Limited data revealed that transdermal fentanyl (25 to 125 µg/h) controlled chronic pain of nonmalignant origin; patches were worn for extended periods (up to 1 year or more). In 1 study, 11 of 19 patients (58%) with previously uncontrolled pain became totally pain free after wearing fentanyl patches for 10 to 319 days. The largest study (n = 68) demonstrated improvement (p < 0.0001) from baseline in pain assessed by VAS and numerical pain scales (NPS) in patients with chronic intractable low back pain who wore fentanyl TTS (25 to 100 µg/h) for 1 month.

The direct daily cost per patient to the National Health Service in the UK for the use of transdermal fentanyl was estimated to be approximately two-thirds that of sustained release oral morphine and less than half the cost of subcutaneous morphine. Also, reductions of 97% in nursing costs were estimated on the basis of differences in drug administration time alone. Full pharmacoeconomic analysis is required to accurately determine the relative value of fentanyl TTS.

Tolerability

The most serious adverse event associated with fentanyl TTS was hypoventilation, which occurred in 4% of postoperative patients and 2% of cancer patients. As with other opioid agents, the most frequently occurring events during treatment included vomiting, nausea and constipation, although vomiting and nausea were not clearly associated with the therapy.

Fentanyl-associated respiratory adverse events generally occurred within 24 hours of patch application (50 to 100 µg/h) to patients undergoing surgery, although 2 studies reported isolated cases of late onset (≥36 hours) respiratory adverse events. Reduced respiratory rates were reported in a number of postoperative trials, and in 2 double-blind comparative trials, the incidence of apnoea was dose-dependently greater in fentanyl than in placebo recipients. In postoperative opioid-naive patients, hypoventilation and apnoea were associated with plasma fentanyl concentrations as low as 1.25 and ≤3 µg/L, respectively.

The incidence of constipation in cancer patients was almost halved in transdermal fentanyl recipients (28.6%) compared with oral morphine recipients (50.8%; p < 0.001) in 1 trial. This was supported by another study in which a 66% decrease in the incidence of constipation was reported by patients after switching from oral morphine to transdermal fentanyl therapy.

With respect to drowsiness, data from several studies were inconclusive. Reports included all patients feeling drowsy (1 study), no difference between fentanyl and previous opioid therapy (2 studies) and an approximate 22% decrease in day-time drowsiness in fentanyl compared with oral morphine (a 15-day non-blind crossover study).

Mild to moderate itching and transient erythema associated with the plastic patch or the adhesive rather than the drug were reported in up to 3% of patients.

A rare opioid withdrawal syndrome was observed in cancer patients shortly after termination of sustained release morphine and conversion to transdermal fentanyl; it was attributed to physical and not psychological dependence. Symptoms were relieved by short-acting oral morphine.

Of 50 deaths reported to the US FDA in 1994 in patients wearing fentanyl patches, 34 were in cancer patients who died of their underlying disease. The FDA associated 4 of the 16 remaining non-cancer-related deaths (no further details given) with off-label use of the system, such as in patients with postoperative pain.

Dosage and Administration

Transdermal fentanyl is contraindicated in patients with acute postoperative pain. It should not be administered to children under 12 years, or adults under 18 years who weigh less than 50kg (1101b). The initial dosage should not exceed 25 µg/h in opioid-naive patients or elderly and severely debilitated patients taking <135 mg/day oral morphine (or equivalent). Doses should be personalised according to the manufacturer’s recommended conversion ratio. The first titration should be reserved until 3 days (manufacturer’s recommendation) after initial application and then at 3- to 6-day intervals thereafter if necessary. Adequate rescue medication such as immediate release short-acting oral morphine should be available during this period. The patch should be applied to an area of intact, hair-free (clipped not shaved) skin above the waist.

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    Wendy Jeal & Paul Benfield

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Various sections of the manuscript reviewed by: S. Ahmedzai, Department of Surgical and Anaesthetic Sciences, Royal Hallamshire Hospital, Sheffield, England; L. Anderson, Department of Anaesthesia, Falkirk and District Royal Infirmary, Falkirk, Scotland; I.J. Broome, Department of Anaesthesia, Falkirk and District Royal Infirmary, Falkirk, Scotland; H.H. Bülow, The PUK Department, Roskilde Hospital, Køgevej, Denmark; J. Collins, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; M. Estéve, Department of Anaesthesiology, Hôpital Ambroise-Paré, Boulogne, France; K.M. Foley, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; G.K. Gourlay, Pain Management Unit, Flinders Medical Centre, Adelaide, South Australia, Australia; H. Hays, Palliative Care Service, Misericordia Hospital, Edmonton, Alberta, Canada; J.C. Pétrie, Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, Scotland; M.A. Simmonds, Hematology and Oncology, Cowley Medical Associates PC, Camp Hill, Pennsylvania, USA; M. Van Bastelaere, Department of Anaesthesiology, University Hospital, Ghent, Belgium; M. Zenz, Bergmannsheil, Universitätsklinik, Klinik für Anaesthesiologie, Intensiv- und Schmerztherapie, Bochum, Germany.

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Jeal, W., Benfield, P. Transdermal Fentanyl. Drugs 53, 109–138 (1997). https://doi.org/10.2165/00003495-199753010-00011

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