Dermal Exposure Risk for Fentanyl and Fentanyl Analogs

"Fentanyl is amenable to transdermal absorption because of its low molecular weight and lipophilicity [19, 20]. Depending on the specific product, transdermal delivery systems (“patches”) take 3–13 h to produce a therapeutic serum fentanyl concentration and 35 h to reach peak concentration [21–24]. Absorption of liquid or aqueous fentanyl increases with larger surface area of application, duration of application, broken skin, and heat. The physical properties of fentanyl analogs are similar to fentanyl, suggesting potential for dermal absorption. In a small volunteer study, sufentanil citrate applied to the forearm and covered in an occlusive dressing was absorbed comparably to fentanyl, although exact bioavailability was not determined [25].

"However, incidental dermal absorption is unlikely to cause opioid toxicity. If bilateral palmar surfaces were covered with fentanyl patches, it would take approximately 14 min to receive 100 mcg of fentanyl [using a body surface area of 17,000 cm2, palm surface area of 0.5% [26], and fentanyl absorption of 2.5 mcg/cm2/h [24]. This extreme example illustrates that even a high dose of fentanyl prepared for transdermal administration cannot rapidly deliver a high dose.

"The above calculation is based on fentanyl patch data, which overestimates the potential exposure from drug in tablet or powder form in several ways. Drug must have sufficient surface area and moisture to be efficiently absorbed. Medicinal transdermal fentanyl utilizes a matrix designed to optimize delivery, whereas tablets and powder require dissolution for absorption. Relatedly, powdered drug sits on the skin, whereas patches have adhesive to hold drug in close proximity to the skin allowing both to remain moist. Finally, in the above quoted figure, 2.5 mcg/cm2/h represents delivery at steady state after drug has penetrated the dermis, which overestimates the amount of absorption in the first few minutes of dermal exposure. This initial period is of most relevance in unintentional exposure, because fentanyl that is observed on skin can be rapidly removed by mechanical (brushing) means or cleansing with water. Therefore, based on our current understanding of the absorption of fentanyl and its analogs, it is very unlikely that small, unintentional skin exposures to tablets or powder would cause significant opioid toxicity, and if toxicity were to occur it would not develop rapidly, allowing time for removal."