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Background: In the dose titration of transdermal fentanyl to prevent unrelieved pain, it is important to consider not only dose adjustment, but also the titration period, which is influenced by the time required to reach the steady state. Many patients with cancer pain experience comorbidities that might affect the skin properties and influence transdermal absorption. We hypothesized that skin changes due to diabetes mellitus (DM) would affect the titration period of transdermal fentanyl. We conducted a retrospective study and diabetic animal model study to test this hypothesis. Methods: In the retrospective study, the titration period was defined in terms of "dose change" and "number of rescue opioids" in patients initiated on transdermal fentanyl. Multiple logistic regression analysis was performed to analyze the relation between the titration period and comorbidities, including DM. In the diabetic animal model study, intercellular lipids of stratum corneum (SC) were analyzed in Goto-Kakizaki (GK) rats, a model of DM, and the pharmacokinetics of intravenously or transdermally administered fentanyl was examined. Results: In the retrospective study, the titration period ranged from 5 to 39 days (n = 387), and the patients taking a longer period (6 days or more) was significantly related to in patients with unspecified DM: AOR (95% confidence interval), 0.438 (0.217–0.884). In the diabetic animal model study, the ceramides (CERs) content in the SC was decreased by approximately 30% in GK rats compared to Wistar rats. The absorption rate constant (ka) of fentanyl administered transdermally was increased approximately 1.4-fold in GK rats, though there was no difference in transdermal bioavailability (F) or systemic clearance (CLtot). Conclusion: Our results suggest that the steady state of transdermally administered fentanyl is reached sooner in cancer patients with DM as a comorbidity. Earlier pain assessment and dose adjustment may be possible in these patients. [ABSTRACT FROM AUTHOR]

Our understanding of the formation, structure, composition, and maturation of the stratum corneum (SC) has progressed enormously over the past 30 years. Today, there is a growing realization that this structure, while faithfully providing a truly magnificent barrier to water loss, is a unique, intricate biosensor that responds to environmental challenges and surface trauma by initiating a series of biologic processes which rapidly seek to repair the damage and restore barrier homeostasis. The detailed ultrastructural, biochemical, and molecular dissection of the classic “bricks and mortar” model of the SC has provided insights into the basis of dry, scaly skin disorders that range from the cosmetic problems of winter xerosis to severe conditions such as psoriasis. With this knowledge comes the promise of increasingly functional topical therapies. [ABSTRACT FROM AUTHOR]