Effects of application site and subject demographics on the pharmacokinetics of fentanyl HCl patient-controlled transdermal system (PCTS).

INTRODUCTION: The fentanyl HCl patient-controlled transdermal system (PCTS) is a self-contained, preprogrammed, needle-free system currently in development for acute pain management in a medically supervised setting. The objectives of these studies were to evaluate skin application sites for the fentanyl HCl PCTS and to evaluate the effect of patient demographics on its pharmacokinetics. METHODS: The first study was a randomised, open-label, single-centre, 3-treatment, crossover study in which the fentanyl HCl PCTS was applied to the upper outer arm, lower inner arm or chest of healthy volunteers. Fentanyl 25 microg was then delivered via this system twice during the first 20 minutes of every hour for 24 hours. The pharmacokinetics of fentanyl were determined and analysed for each application site using ANOVA. The second study was a nonrandomised, nonblind, multicentre, sequential treatment study. Healthy volunteers received fentanyl HCl 40 microg via the PCTS three times during the first 30 minutes of each hour for 3 hours. After a 5- to 10-day washout period, fentanyl HCl 120 microg was administered intravenously during the first 30 minutes of each hour for 3 hours as a reference treatment. Pharmacokinetic parameters were determined for the fentanyl HCl PCTS, and results were analysed using ANOVA. Safety and tolerability were evaluated in both studies. RESULTS: Application of the system to the upper outer arm or chest resulted in similar maximum serum concentrations (Cmax; 1.193 and 1.176 microg/L, respectively) and areas under the serum concentration-time curve (AUC24-25; 1.033 and 1.015 microg h/L). However, both Cmax and AUC24-25 were less when the system was applied to the lower inner arm (0.859 microg/L and 0.757 microg x h/L). Subject age, bodyweight, sex and ethnicity had no significant effect on pharmacokinetic parameters. No serious adverse events were reported in either study during or after administration of the fentanyl HCl PCTS. CONCLUSION: Fentanyl HCl is comparably absorbed from the PCTS when it is applied to the upper outer arm or chest. The pharmacokinetics of fentanyl HCl delivered by the PCTS are unaffected by sex, age, race or weight.

Evaluation of the efficacy of a bioerodible bupivacaine polymer system on antinociception and inflammatory mediator release.

Pain due to tissue injury is often characterized by the presence of hyperalgesia and allodynia. It is hypothesized that these perceptual states are mediated by sensitization of peripheral terminals of primary afferent neurons together with several changes in the central nervous system. This provides a rationale for preemptive analgesia, whereby the blockade of primary afferent input prior to injury may result in a reduction of post-injury pain. One approach for prolonged blockade of primary afferent input is the use of bioerodible polymer systems providing regulated release of local anesthetics. Bioerodible polymer systems offer the theoretical advantage of controlled drug delivery maintained over prolonged periods. Local application of this system to the inflamed tissue compartment permits the use of smaller total drug doses. This may minimize systemic side effects, while maintaining prolonged peripherally-mediated antinociception. In the present study, we evaluated the effects of a bioerodible polymer/bupivacaine system (PLGA/bupivacaine) on several indices of inflammation and on hindpaw levels of the inflammatory mediators, substance P and bradykinin in the complete Freund's adjuvant model. We observed that PLGA/bupivacaine reduces inflammatory hyperalgesia, edema and hyperthermia in a temporal and dose-related fashion in awake animals. Moreover, we demonstrated that PLGA/bupivacaine has a prolonged inhibitory effect on the tissue levels of substance P and bradykinin in the inflamed hindpaws. The results of these studies clearly indicate the potential therapeutic utility of the PLGA bupivacaine system, with the single dose administration producing a prolonged suppression of hyperalgesia, edema and biochemical indices of inflammation.