2018 - The opioid oxycodone use‐dependently inhibits the cardiac sodium channel Nav1.5
CardioExcyte 96 publication in British Journal of Pharmacology (2018)
Meents J.E., Juhasz K., Stölzle-Feix S., Peuckmann-Post V., Rolke R. Lampert A.
British Journal of Pharmacology (2018) doi: 10.1111/bph.14348
BACKGROUND AND PURPOSE:
Oxycodone is a potent semi-synthetic opioid that is commonly used for the treatment of severe acute and chronic pain. However, treatment with oxycodone can lead to cardiac electrical changes, such as long-QT syndrome, potentially inducing sudden cardiac arrest. Here, we investigate whether the cardiac side effects of oxycodone can be explained by modulation of the cardiac sodium channel Nav1.5.
Heterologously expressed Nav1.5, Nav1.7 or Nav1.8 were used for whole-cell patch-clamp electrophysiology. A variety of voltage-clamp protocols was used to test the effect of oxycodone on different channel gating modalities. Human stem cell-derived cardiomyocytes were used to measure the effect of oxycodone on cardiomyocyte beating.
Oxycodone concentration-dependently and use-dependently inhibits Nav1.5 with an IC50 of 483.2 μM. In addition, oxycodone slows recovery of Nav1.5 from fast inactivation and increases slow inactivation. At high concentrations, these effects lead to a reduced beat rate in cardiomyocytes and to arrhythmia. In contrast, no effects could be observed on Nav1.7 or Nav1.8.
CONCLUSION AND IMPLICATIONS:
Oxycodone leads to an accumulation of Nav1.5 in inactivated states with a slow time course. While the concentrations needed to elicit cardiac arrhythmia in vitro are comparably high, some patients under long-term treatment with oxycodone as well as drug abusers and addicts might suffer from severe cardiac side effects induced by the slow effects of oxycodone on Nav1.5.