Transdermal Fentanyl

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Abstract
Fentanyl is a synthetic opioid agonist which interacts primarily with the μ-opioid receptor. The low molecular weight, high potency and lipid solubility of fentanyl make it suitable for delivery by the transdermal therapeutic system. These patches are designed to deliver fentanyl at a constant rate (25, 50, 75 and 100 μg/h), and require replacement every 3 days. Data from randomised, nonblind trials suggest that transdermal fentanyl is as effective as sustained-release oral morphine in the treatment of chronic cancer pain, as reported by patients using visual and numerical analogue scales as well as verbal description scales. No obvious differences in health-related quality of life were found in patients with chronic cancer pain when comparing transdermal fentanyl with sustained-release oral morphine. Nevertheless, significantly more patients expressed a preference for transdermal fentanyl than for sustained-release oral morphine after a randomised, nonblind, crossover trial. Because of the formation of a fentanyl depot in the skin tissue, serum fentanyl concentrations increase gradually following initial application, generally levelling off between 12 and 24 hours. Thereafter, they remain relatively constant, with some fluctuation, for the remainder of the 72-hour application period. Once achieved, steady-state plasma fentanyl concentrations can be maintained for as long as the patches are renewed. The most frequently observed adverse events during transdermal fentanyl administration (as with other opioid agonists) included vomiting, nausea and constipation. Data from a nonblind, randomised trials suggest that constipation occurs less frequently in patients receiving transdermal fentanyl than in those given sustained-release oral morphine. The most serious adverse event reported in US premarketing trials was hypoventilation, which occurred with an incidence of approximately 2%. Adverse reactions related to skin and appendages (i.e. rash and application site reactions —erythema, papules, itching and oedema) were reported in 153 patients with cancer at a frequency between 1 and 3%. Conclusion: Transdermal fentanyl is a useful opioid-agonist for the treatment of moderate to severe chronic cancer pain. The advantages of transdermal fentanyl include ease of administration and the 3-day application interval. These factors coupled with a lower incidence of constipation are likely to contribute to the reported patient preference of transdermal fentanyl over sustained-release oral morphine. Fentanyl interacts with the μ-opioid receptor as a pure agonist. The analgesic potency of fentanyl is 75 to 100 times higher than that of morphine, probably because fentanyl is lipophilic, allowing rapid penetration of the blood-brain barrier. The mechanisms of opioid-induced analgesia are only partly understood. Like other opioid agonists, fentanyl can induce potentially life-threatening respiratory depression. Experiments in cats suggest that fentanyl-induced sustained inspiration (thoracic rigidity) results from increased amplified efferent activity to the spinal cord inspiratory motor neurons. Moreover, studies in rats suggest that fentanyl, unlike morphine, induces respiratory depression via the μ1-receptor. Constipation is a common adverse event after opioid administration. Subcutaneous administration of fentanyl and morphine to rats resulted in an analgesic peak effect at doses of 0.032 mg/kg and 8.0 mg/kg, respectively. This analgesic dose was only 1.1 times higher than the dose required for a 50% inhibition of castor oil-induced diarrhoea for fentanyl, but 36 times higher than that for morphine. These results suggest that fentanyl induces analgesia without incurring the same degree of constipation as morphine. Indeed, transdermal fentanyl administration appears to result in constipation in fewer patients when compared with oral morphine therapy as shown by clinical trials. Peripheral vasodilation and hypotension have been observed after intravenous morphine administration in surgical patients. In this study, however, such haemodynamic effects were not seen following fentanyl administration. There are two possible explanations for this difference. Firstly, morphine-induced vasodilation has been associated with histamine release. Unlike morphine, however, fentanyl administration did not lead to increased plasma levels of histamine. A second explanation could be that morphine, but not fentanyl, stimulates the release of the potent vasodilator nitric oxide by human endothelial cells in vitro by stimulation of the μ3-receptor. Fentanyl can be administered transdermally because of its high solubility in both fat and water and its low molecular weight. The application systems are designed to deliver fentanyl at a constant rate for periods of 72 hours. Currently, patches with a delivery rate of 25, 50, 75 and 100 μg/h are available. Neither local blood flow nor anatomical site of application seem to affect fentanyl delivery. Nonetheless, a rise in body temperature to 40°C may increase the absorption rate by about one-third. In general, the pharmacokinetics of transdermal fentanyl show interindividual variability. After intravenous administration, fentanyl has a high extravascular volume of distribution (3 to 8 L/kg) in surgical patients. In animals, the drug shows wide physiological distribution to the lungs, kidneys, heart, spleen, brain, muscles and body fat. After transdermal application, an average bioavailability of 92% has been estimated in surgical patients. Mean maximum plasma concentration (Cmax) values were 0.6, 1.4, 1.7 and 2.5 μg/L at delivery rates of 25, 50, 75 and 100 μg/h, respectively. Plasma concentrations were proportional to delivery rate. Delays of 34 to 38 hours have been reported between patch application (25 to 100 μg/h) and occurrence of Cmax. This delay is likely to be due to the formation of a fentanyl depot within the skin before the drug diffuses into the circulation. After several sequential 3-day (72-hour) application intervals, steady-state plasma fentanyl concentrations are achieved, which can be maintained for as long as the fentanyl patches are renewed. Fentanyl is mainly metabolised by cytochrome P450 (CYP) 3A4. The major metabolite is norfentanyl and minor metabolites include despropionylfentanyl, hydroxyfentanyl and hydroxynorfentanyl, none of which show clinically relevant pharmacological activity. Elimination of fentanyl after patch removal is slow; elimination half-life values of 13 to 22 hours have been reported. The slow elimination is likely to be due to the slow release of the drug from the skin depot. The total body clearance for fentanyl is 34.2 to 52.8 L/h. Since metabolisation of fentanyl is dependent on CYP3A4, coadministration of drugs that inhibit this isoenzyme may impair fentanyl clearance. Moreover, known CYP inducers may enhance fentanyl clearance. Randomised comparative trials in 40 to 127 patients with chronic pain associated with cancer have indicated that transdermal fentanyl 25 to 300 μg/h provides adequate pain control in 66 to 77% of patients. The only double-blind comparative trial of transdermal fentanyl, however, failed to show any statistically significant benefit over placebo. However, this study has not resulted in any significant doubt regarding the analgesic efficacy of transdermal fentanyl; indeed, treatment with transdermal fentanyl is well established and accepted in this indication, as indicated by recent review articles and treatment guidelines. There are a number of possible confounding factors that need to be considered when evaluating this study [including the absence of an active comparator and the possible masking of effects by rescue medication (oral morphine, 51 and 48 mg/day, respectively)]. Data from the two nonblind, randomised trials suggest that transdermal fentanyl is as effective as sustained-release oral morphine in the treatment of chronic cancer pain. No significant differences between transdermal fentanyl and sustained-release oral morphine were found for any of the efficacy parameters in the 2-week trials. In all trials, patients received oral morphine as rescue medication for breakthrough pain. In the randomised studies, patients were stabilised with morphine before being switched to fentanyl patches. The initial dose of transdermal fentanyl was based on the previous morphine dose as calculated by the conversion table supplied by the manufacturer. In general, the transdermal fentanyl patches were replaced every 72 hours. Pain control was assessed by the use of visual or numerical analogue scales and verbal descriptions by which patients could express pain intensity. Moreover, in three studies, quality-of-life parameters were assessed by elements from validated survey scales. Patients enrolled were adults experiencing chronic cancer pain and requiring strong opioid analgesia. Although possible advantages of transdermal fentanyl on health-related quality of life are difficult to appraise methodologically, they embody important elements of palliative care and are an important clinical outcome. A randomised nonblind trial revealed no significant differences in effect on social, physical, role, cognitive or emotional functioning or global quality of life between transdermal fentanyl and sustained-release oral morphine. Nonetheless, significantly more patients preferred transdermal fentanyl than sustained-release oral morphine and there were significant differences in favour of fentanyl in other quality-of-life parameters (e.g. interruption of daily activities of both patients and caregivers, convenience and satisfaction). The most serious adverse event associated with transdermal fentanyl administration was hypoventilation, which occurred in approximately 2% of patients with cancer pain during a premarketing trial. As with other opioid agents, the most frequently observed adverse events during fentanyl treatment are nausea, vomiting and constipation. Nonblind clinical data, however, suggest that fentanyl is associated with less constipation than sustained-release oral morphine as assessed by patient questionnaires. Clinical data in patients with cancer reveal no obvious differences in the occurrence of nausea and vomiting when comparing transdermal fentanyl with sustained-release oral morphine. Adverse reactions related to skin and appendages (i.e. rash and application site reactions —erythema, papules, itching and oedema) were reported in 153 patients with cancer at a frequency between 1 and 2%. Opioid withdrawal symptoms may occur after discontinuation of transdermal fentanyl administration and after conversion from other opioid analgesics to transdermal fentanyl. Transdermal fentanyl is contraindicated in patients with acute postoperative pain and should not be administered to children under 12 years of age or to patients under 18 years of age who weigh less than 50kg (1101b). Moreover, the initial dosage should not exceed 25 μg/h in opioid-naive patients and elderly or severely debilitated patients taking less than 135 mg/day oral morphine or equivalent. Doses should be personalised according to the manufacturer’s recommended conversion ratio. According to the manufacturer’s recommendations, adjustment of the dosage should be withheld until 3 days after initial application and should then occur at 6-day intervals if necessary. It is important to stress that rescue medication such as immediate-release oral morphine should be readily available to the patient, especially during the titration period. The transdermal fentanyl patches should be applied to an intact, hair-free (clipped not shaved) area of the skin.