Codeine-induced histamine release in intact human skin monitored by skin microdialysis technique: comparison of intradermal injections with an atraumatic intraprobe drug delivery system

BACKGROUND: The skin microdialysis technique makes it possible to measure histamine release in intact human skin in vivo directly. In this study we have used the microdialysis technique to characterize histamine release by codeine after intracutaneous injections and following skin challenge by a novel atraumatic delivery technique.

OBJECTIVE: The purpose of the study was to compare histamine release in human skin by codeine, delivered by an intraprobe drug delivery system (IPD) and intracutaneous injections (ICT), with respect to dose-response relations, kinetics of histamine appearance and decay, correlations between histamine release and skin responses, and reproducibility.

METHODS: Hollow dialysis fibres were inserted intradermally in 12 healthy subjects. Twelve fibres were inserted in each subject, six fibres in each arm. Each fibre was perfused at a rate of 3 microM/min, and samples were collected in 2 min fractions. By the IPD technique, codeine was administered to the skin by adding codeine to the perfusion medium. Sequential IPD challenges were performed in one arm, and ICTs were done on the other arm.

RESULTS: Sixfold serial dilutions of codeine (0.01-3 mg/mL) caused a significant dose-related histamine release by ICT and IPD. Peak histamine release was found within the first 4 min after skin challenge by ICT and IPD, followed by a fast decline with a dialysate histamine half life of approximately 2-3 min. Peak histamine release was linearly correlated with cumulative release of the 20 min sampling period, and histamine release correlated with weal size. The coefficient of variation on peak histamine release was 18.9% and 4.8% for codeine ICT and IPD, respectively.

CONCLUSION: We have described in detail codeine-induced histamine release in intact human skin in vivo by the microdialysis technique. It was possible to administer codeine atraumatically to the skin by intraprobe delivery. The skin microdialysis technique opens up possibilities for measurement of inflammatory mediators release in normal and diseased skin, and it will be possible to deliver immunopharmacologically active drugs to the skin by intraprobe delivery.