Mechanisms of QT prolongation by buprenorphine cannot be explained by direct hERG channel block

Abstract

Buprenorphine is a μ-opioid receptor (MOR) partial agonist used to manage pain and addiction. QTC 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 QTC 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 QTC prolongation and TdP are most commonly caused by acute inhibition of hERG current (IhERG) that contribute to the repolarizing phase of the ventricular action potentials (APs). Concomitant inhibition of inward late Na+ (INaL) and/or L-type Ca2+ (ICaL) 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 QTC 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, CaV1.2, and NaV1.5 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 IhERG, ICaL, INaL, and peak Na+ current (INaP) at clinically relevant concentrations. In contrast, methadone inhibited IhERG, ICaL, and INaL. 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 QTC 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 QTC prolongation not mediated by acute hERG channel block warrants further study.

Translational Models and Tools to Reduce Clinical Trials and Improve Regulatory Decision Making for QTc and Proarrhythmia Risk (ICH E14/S7B Updates)

“…Characterizing the exposure‐response relationship is important to determine the potential amount of QTc prolongation in certain patient subgroups that may be subjected to higher drug exposures and evaluate whether the QTc prolongation plateaus, suggesting an indirect mechanism that may be of lower risk. There are multiple potential indirect mechanisms that can lead to QTc prolongation (i.e., not acting through direct ion channel effects), such as from autonomic nervous system effects, 33,34 changes in body temperature, 35 electrolyte abnormalities, 36 and others still being defined ( Figure 6 ) 37 . Further investigation should differentiate which mechanisms can be associated with TdP vs. those that are not.…”

“…There are multiple potential indirect mechanisms that can lead to QTc prolongation (i.e., not acting through direct ion channel effects), such as from autonomic nervous system effects, 33,34 changes in body temperature, 35 electrolyte abnormalities, 36 and others still being defined (Figure 6c). 37 Further investigation should differentiate which mechanisms can be associated with TdP vs. those that are not. Furthermore, an integrated risk assessment could consider a combination of clinical/ pharmacodynamic factors with nonclinical assays to rule in or out certain mechanisms if needed.…”

Transdermal Buprenorphine for Acute Pain in the Clinical Setting: A Narrative Review

“… 34 Despite these findings, those authors and others have not found any association between transdermal buprenorphine and pro-arrhythmic effects. 34 , 35 …”

“…34 Despite these findings, those authors and others have not found any association between transdermal buprenorphine and pro-arrhythmic effects. 34,35 Long-term use of buprenorphine will result in dependency on the drug; that is the normal and expected result of chronic use of any opioid. A once-only use of a sevenday patch treatment of buprenorphine should not result in dependence or tolerance.…”

Antipsychotic Polypharmacy-Related Cardiovascular Morbidity and Mortality: A Comprehensive Review

“…It has been suggested that buprenorphine is the safer option for treating opioid use disorder in heroin users and those with, or that have experienced, methadone-induced torsade de pointes [ 32 ]. However, due to unknown mechanisms, high-dose transdermal buprenorphine can significantly increase QTc interval [ 34 ]. Additionally, buprenorphine can substantially prolong the QTc interval when combined with antiretroviral agents [ 35 ].…”