Toxicological implications of the delivery of fentanyl from gel extracted from a commercial transdermal reservoir patch

Fentanyl in a rate controlling membrane (RCM) transdermal patch form has been available since the early 1990s for outpatient management of chronic pain. Fatalities associated with misuse or overuse of fentanyl patches have been reported. Concerns have also been raised about the possibility that defects in such patches may result in leaking of the reservoir of the patch onto patients' skin and consequent overdose. In order to investigate the possibility of fentanyl toxicity arising from leaking of patches, the permeation of fentanyl from the reservoir gel of a commercially available fentanyl transdermal patch was examined in vitro. Finite doses of the formulation were applied to human skin and permeation was monitored, at 32 °C under non-occluded conditions, for 48 h. Similar levels of skin permeation of fentanyl from the 1% gel formulation were obtained for the two skin donor samples tested. After 48 h, the dose of fentanyl that had permeated was 7.4 (±3.6)% and 7.7 (±1.9)% of the respective total amounts applied. At the end of the experiment, most of the drug was found in the residual formulation at the skin surface (i.e. 63-66%). For both the skin samples, a relatively small amount of the fentanyl applied (2-3%) was present in the skin at 48 h after application. The maximum flux from the data generated was between 6 and 24 h over which time frame it was 0.3 μg/cm2/h. Assuming spreading of leaked gel over an area of 100 cm2, this would result in a plasma level of 0.6 ng/mL. The anticipated plasma levels from a 100 μg/h patch are known to be approximately 2.5 ng/ml. Thus, the maximum increase in the plasma levels from a patch which leaks gel is calculated to be, at most, about 25%.