The opioid tramadol blocks the cardiac sodium channel Nav1.5 in HEK293 cells

Abstract Aims Opioids are associated with increased risk of sudden cardiac death. This may be due to their effects on the cardiac sodium channel (Nav1.5) current. In the present study, we aim to establish whether tramadol, fentanyl, or codeine affects Nav1.5 current. Methods and results Using whole-cell patch-clamp methodology, we studied the effects of tramadol, fentanyl, and codeine on currents of human Nav1.5 channels stably expressed in HEK293 cells and on action potential (AP) properties of freshly isolated rabbit ventricular cardiomyocytes. In fully available Nav1.5 channels (holding potential −120 mV), tramadol exhibited inhibitory effects on Nav1.5 current in a concentration-dependent manner with an IC50 of 378.5 ± 33.2 µm. In addition, tramadol caused a hyperpolarizing shift of voltage-gated (in)activation and a delay in recovery from inactivation. These blocking effects occurred at lower concentrations in partially inactivated Nav1.5 channels: during partial fast inactivation (close-to-physiological holding potential −90 mV), IC50 of Nav1.5 block was 4.5 ± 1.1 μm, while it was 16 ± 4.8 μm during partial slow inactivation. The tramadol-induced changes on Nav1.5 properties were reflected by a reduction in AP upstroke velocity in a frequency-dependent manner. Fentanyl and codeine had no effect on Nav1.5 current, even when tested at lethal concentrations. Conclusion Tramadol reduces Nav1.5 currents, in particular, at close-to-physiological membrane potentials. Fentanyl and codeine have no effects on Nav1.5 current.

[1]  Yong-Yeon Cho,et al.  Tramadol as a Voltage-Gated Sodium Channel Blocker of Peripheral Sodium Channels Nav1.7 and Nav1.5 , 2023, Biomolecules & therapeutics.

[2]  R. Wilders,et al.  The Antidepressant Paroxetine Reduces the Cardiac Sodium Current , 2023, International journal of molecular sciences.

[3]  L. Fabritz,et al.  Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide , 2022, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[4]  Jacqueline A. Treat,et al.  The G213D variant in Nav1.5 alters sodium current and causes an arrhythmogenic phenotype resulting in a multifocal ectopic Purkinje-related premature contraction phenotype in human-induced pluripotent stem cell-derived cardiomyocytes. , 2022, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[5]  H. Tan,et al.  Carbamazepine Increases the Risk of Sudden Cardiac Arrest by a Reduction of the Cardiac Sodium Current , 2022, Frontiers in Cell and Developmental Biology.

[6]  E. Karimi,et al.  Potential Impact of 3% Hypertonic Saline Infusion on Tramadol Poisoning-Induced Electrocardiogram Changes; a Randomized Clinical Trial , 2022, Archives of academic emergency medicine.

[7]  C. Torp‐Pedersen,et al.  Risk of out‐of‐hospital cardiac arrest in antidepressant drug users , 2022, British journal of clinical pharmacology.

[8]  H. Tan,et al.  Opioid use is associated with increased out‐of‐hospital cardiac arrest risk among 40 000‐cases across two countries , 2021, British journal of clinical pharmacology.

[9]  H. Tan,et al.  Non-cardiac depolarization-blocking drugs are associated with increased risk of out-of-hospital cardiac arrest in the community , 2021, Pharmacoepidemiology.

[10]  E. Abner,et al.  Association of Nonacute Opioid Use and Cardiovascular Diseases: A Scoping Review of the Literature , 2021, Journal of the American Heart Association.

[11]  J. Tomek,et al.  Cardiac Transmembrane Ion Channels and Action Potentials: Cellular Physiology and Arrhythmogenic Behavior. , 2020, Physiological reviews.

[12]  I. van der Made,et al.  Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/+ mice , 2020, Europace.

[13]  D. Tester,et al.  Prevalence and electrophysiological phenotype of rare SCN5A genetic variants identified in unexplained sudden cardiac arrest survivors. , 2020, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[14]  J. Singh,et al.  National U.S. time-trends in opioid use disorder hospitalizations and associated healthcare utilization and mortality , 2020, PloS one.

[15]  Jun Guo,et al.  Blockade of the Human Ether A-Go-Go–Related Gene (hERG) Potassium Channel by Fentanyl , 2019, Molecular Pharmacology.

[16]  P. Ruben,et al.  Inhibitory effects of cannabidiol on voltage-dependent sodium currents , 2018, The Journal of Biological Chemistry.

[17]  Yolan J. Reckman,et al.  SCN5A mutation type and topology are associated with the risk of ventricular arrhythmia by sodium channel blockers. , 2018, International journal of cardiology.

[18]  S. Joukar,et al.  Opioids and Cardiac Arrhythmia: A Literature Review , 2018, Medical Principles and Practice.

[19]  A. Lampert,et al.  The opioid oxycodone use‐dependently inhibits the cardiac sodium channel NaV1.5 , 2018, British journal of pharmacology.

[20]  F. Charpentier,et al.  KV4.3 Expression Modulates NaV1.5 Sodium Current , 2018, Front. Physiol..

[21]  Roy J. Vaz,et al.  Proarrhythmic mechanisms of the common anti-diarrheal medication loperamide: revelations from the opioid abuse epidemic , 2016, Naunyn-Schmiedeberg's Archives of Pharmacology.

[22]  B. Dadpour,et al.  Frequency of Electrocardiographic Abnormalities in Tramadol Poisoned Patients; a Brief Report , 2016, Emergency.

[23]  A. Lampert,et al.  The opioid methadone induces a local anaesthetic‐like inhibition of the cardiac Na+ channel, Nav1.5 , 2014, British journal of pharmacology.

[24]  R. Dart,et al.  Electrocardiographic manifestations of tramadol toxicity with special reference to their ability for prediction of seizures. , 2012, The American journal of emergency medicine.

[25]  R. Asinger,et al.  Isolated Tramadol Overdose Associated with Brugada ECG Pattern , 2012, Pacing and clinical electrophysiology : PACE.

[26]  P. Reeh,et al.  Local Anesthetic-like Inhibition of Voltage-gated Na+ Channels by the Partial &mgr;-opioid Receptor Agonist Buprenorphine , 2012, Anesthesiology.

[27]  M. M. Trachez,et al.  Inhibition of L-type calcium current by tramadol and enantiomers in cardiac myocytes from rats. , 2011, Arquivos brasileiros de cardiologia.

[28]  J. Valentin,et al.  On the relationship between block of the cardiac Na+ channel and drug‐induced prolongation of the QRS complex , 2011, British journal of pharmacology.

[29]  Ronald Wilders,et al.  Re-Evaluation of the Action Potential Upstroke Velocity as a Measure of the Na+ Current in Cardiac Myocytes at Physiological Conditions , 2010, PloS one.

[30]  Susan Okie,et al.  A flood of opioids, a rising tide of deaths. , 2010, The New England journal of medicine.

[31]  R. Coronel,et al.  Incorporated Fish Oil Fatty Acids Prevent Action Potential Shortening Induced by Circulating Fish Oil Fatty Acids , 2010, Front. Physio..

[32]  I. Sora,et al.  μ-Opioid receptor-independent fashion of the suppression of sodium currents by μ-opioid analgesics in thalamic neurons , 2009, Neuroscience Letters.

[33]  G. Jensen,et al.  Oxycodone is associated with dose-dependent QTc prolongation in patients and low-affinity inhibiting of hERG activity in vitro. , 2009, British journal of clinical pharmacology.

[34]  P. Jorens,et al.  Fatal intoxication due to tramadol alone: case report and review of the literature. , 2008, Forensic science international.

[35]  R. Dengler,et al.  Tramadol, fentanyl and sufentanil but not morphine block voltage-operated sodium channels , 2006, Pain.

[36]  Sheng-Nan Wu,et al.  Tramadol‐induced blockade of delayed rectifier potassium current in NG108‐15 neuronal cells , 2006, European journal of pain.

[37]  T. L. Martin,et al.  Fentanyl-related deaths in Ontario, Canada: toxicological findings and circumstances of death in 112 cases (2002-2004). , 2006, Journal of analytical toxicology.

[38]  William A. Catterall,et al.  International Union of Pharmacology. XLVII. Nomenclature and Structure-Function Relationships of Voltage-Gated Sodium Channels , 2005, Pharmacological Reviews.

[39]  A. Wilde,et al.  Pathophysiological mechanisms of Brugada syndrome: depolarization disorder, repolarization disorder, or more? , 2005, Cardiovascular research.

[40]  M. Guven,et al.  Differential Effects of Lidocaine and Tramadol on Modified Nerve Impulse by 4-Aminopyridine in Rats , 2003, Pharmacology.

[41]  F. Clarot,et al.  Fatal overdoses of tramadol: is benzodiazepine a risk factor of lethality? , 2003, Forensic science international.

[42]  A. Katchman,et al.  Influence of Opioid Agonists on Cardiac HumanEther-a-go-go-related Gene K+ Currents , 2002, Journal of Pharmacology and Experimental Therapeutics.

[43]  P. C. Viswanathan,et al.  A sodium-channel mutation causes isolated cardiac conduction disease , 2001, Nature.

[44]  F. Musshoff,et al.  Fatality due to ingestion of tramadol alone. , 2001, Forensic science international.

[45]  M. Su,et al.  Opioid receptor independent effects of morphine on membrane currents in single cardiac myocytes. , 1998, British journal of anaesthesia.

[46]  C Antzelevitch,et al.  Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes. , 1996, Journal of the American College of Cardiology.

[47]  H. Fozzard,et al.  Structure and function of voltage-dependent sodium channels: comparison of brain II and cardiac isoforms. , 1996, Physiological reviews.

[48]  R. Peters,et al.  Interaction of ischaemia and encainide/flecainide treatment: a proposed mechanism for the increased mortality in CAST I. , 1995, British heart journal.

[49]  M. Laorden,et al.  Cardiac electrophysiological effects of U-50,488H on guinea-pig papillary muscle , 1993, Neuropeptides.

[50]  J. Lynch,et al.  Liquid junction potentials and small cell effects in patch-clamp analysis , 1991, The Journal of Membrane Biology.

[51]  H L Greene,et al.  Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. , 1991, The New England journal of medicine.

[52]  K. Murray,et al.  Voltage clamp of the cardiac sodium current at 37 degrees C in physiologic solutions. , 1990, Biophysical journal.

[53]  Leonard J. Paulozzi,et al.  Vital signs: overdoses of prescription opioid pain relievers---United States, 1999--2008. , 2011, MMWR. Morbidity and mortality weekly report.

[54]  H. Tan,et al.  Cardiac sodium channelopathies , 2009, Pflügers Archiv - European Journal of Physiology.

[55]  M. Pugsley.  The diverse molecular mechanisms responsible for the actions of opioids on the cardiovascular system. , 2002, Pharmacology & therapeutics.

[56]  M. Weir,et al.  The Cardiac Arrhythmia Suppression Trial Investigators: Preliminary Report: Effect of Encainide and Flecainide on Mortality in a Randomized Trial of Arrhythmia Suppression After Myocardial Infarction. , 1990 .

[57]  W. Rogers,et al.  Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. , 1989, The New England journal of medicine.

[58]  M. FSheets,et al.  Nonlinear relation between Vmax and INa in canine cardiac Purkinje cells. , 1988 .

[59]  R. F. Shaw,et al.  Blood concentrations and clinical findings in nonfatal and fatal intoxications involving glutethimide and codeine. , 1985, Journal of toxicology. Clinical toxicology.