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 Nav 1.5 sodium channel.
Experimental approach: Heterologously expressed human Nav 1.5, Nav 1.7 (HEK293 cells) or Nav 1.8 channels (mouse N1E-115 cells) were used for whole-cell patch-clamp electrophysiology. A variety of voltage-clamp protocols were 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 inhibited Nav 1.5 channels, concentration and use-dependently, with an IC50 of 483 μM. In addition, oxycodone slows recovery of Nav 1.5 channels 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 such effects could be observed on Nav 1.7 or Nav 1.8 channels.
Conclusions and implications: Oxycodone leads to an accumulation of Nav 1.5 channels in inactivated states, with a slow time course. Although the concentrations needed to elicit cardiac arrhythmias in vitro are relatively 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 slowly developing effects of oxycodone on Nav 1.5 channels.
© 2018 The British Pharmacological Society.