Abstract

Buprenorphine is a μ-opioid receptor (MOR) partial agonist used to manage pain and addiction. QT_C prolongation that crosses the 10 msec threshold of regulatory concern was observed at a supratherapeutic dose in two thorough QT studies for the transdermal buprenorphine product BUTRANS^®. Because QT_C prolongation can be associated with Torsades de Pointes (TdP), a rare but potentially fatal ventricular arrhythmia, these results have led to further investigation of the electrophysiological effects of buprenorphine. Drug-induced QT_C prolongation and TdP are most commonly caused by acute inhibition of hERG current (I_hERG) that contribute to the repolarizing phase of the ventricular action potentials (APs). Concomitant inhibition of inward late Na⁺ (I_NaL) and/or L-type Ca²⁺ (I_CaL) current can offer some protection against proarrhythmia. Therefore, we characterized the effects of buprenorphine and its major metabolite norbuprenorphine on cardiac hERG, Ca²⁺, and Na⁺ ion channels, as well as cardiac APs. For comparison, methadone, a MOR agonist associated with QT_C prolongation and high TdP risk, and naltrexone and naloxone, two opioid receptor antagonists, were also studied. Whole cell recordings were performed at 37°C on cells stably expressing hERG, Ca_V1.2, and Na_V1.5 proteins. Microelectrode array (MEA) recordings were made on human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). The results showed that buprenorphine, norbuprenorphine, naltrexone, and naloxone had no effect on I_hERG, I_CaL, I_NaL, and peak Na⁺ current (I_NaP) at clinically relevant concentrations. In contrast, methadone inhibited I_hERG, I_CaL, and I_NaL. Experiments on iPSC-CMs showed a lack of effect for buprenorphine, norbuprenorphine, naltrexone, and naloxone, and delayed repolarization for methadone at clinically relevant concentrations. The mechanism of QT_C prolongation is opioid moiety-specific. This remains undefined for buprenorphine, while for methadone it involves direct hERG channel block. There is no evidence that buprenorphine use is associated with TdP. Whether this lack of TdP risk can be generalized to other drugs with QT_C prolongation not mediated by acute hERG channel block warrants further study.

By Phu N. Tran, Jiansong Sheng, Aaron L. Randolph, Claudia Alvarez Baron, Nicolas Thiebaud, Ming Ren, Min Wu, Lars Johannesen, Donna A. Volpe, Dakshesh Patel, Ksenia Blinova, David G. Strauss, Wendy W. Wu