糖尿病导致的皮肤特性变化对透皮芬太尼滴定期的影响：单中心回顾性研究及糖尿病动物模型研究

Effect of changes in skin properties due to diabetes mellitus on the titration period of transdermal fentanyl: single-center retrospective study and diabetic animal model study.

作者信息

Mizuno Satoshi, Takabayashi Makiko, Makihara Hiroko, Ogai Kazuhiro, Tsukui Kei, Ito Yuriko, Kawakami Takahiro, Hara Yusuke, Fujita Arimi, Tokudome Yoshihiro, Akase Tomoko, Kato Yukio, Shimada Tsutomu, Sai Yoshimichi

机构信息

Department of Clinical Pharmacokinetics, Graduate School of Medical Sciences, Kanazawa University, 13-1 Takara-Machi, Kanazawa, 920-8641, Japan.

Department of Hospital Pharmacy, University Hospital, Kanazawa University, 13-1 Takara-Machi, Kanazawa, 920-8641, Japan.

出版信息

J Pharm Health Care Sci. 2024 Dec 18;10(1):80. doi: 10.1186/s40780-024-00402-5.

DOI:10.1186/s40780-024-00402-5

PMID:39696707

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11653581/

Abstract

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 (k) 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 (CL).

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.

摘要

背景

在透皮芬太尼剂量滴定以预防疼痛未缓解时，不仅要考虑剂量调整，还需考虑滴定期，而滴定期受达到稳态所需时间的影响。许多癌症疼痛患者存在可能影响皮肤特性并影响透皮吸收的合并症。我们假设糖尿病（DM）导致的皮肤变化会影响透皮芬太尼的滴定期。我们进行了一项回顾性研究和糖尿病动物模型研究来验证这一假设。

方法

在回顾性研究中，根据开始使用透皮芬太尼患者的“剂量变化”和“挽救性阿片类药物使用次数”来定义滴定期。进行多因素逻辑回归分析以分析滴定期与包括DM在内的合并症之间的关系。在糖尿病动物模型研究中，分析了糖尿病模型Goto-Kakizaki（GK）大鼠角质层（SC）的细胞间脂质，并检测了静脉注射或透皮给药芬太尼的药代动力学。

结果

在回顾性研究中，滴定期为5至39天（n = 387），滴定期较长（6天或更长）的患者与未明确诊断的DM患者显著相关：调整后比值比（95%置信区间），0.438（0.217 - 0.884）。在糖尿病动物模型研究中，与Wistar大鼠相比，GK大鼠SC中的神经酰胺（CERs）含量降低了约30%。透皮给药的芬太尼在GK大鼠中的吸收速率常数（k）增加了约1.4倍，尽管透皮生物利用度（F）或全身清除率（CL）没有差异。