2018 – The opioid oxycodone use‐dependently inhibits the cardiac sodium channel NaV1.5

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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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.