Transdermal Fentanyl

Abstract

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. 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). In in...