Methadone-Associated Q-T Interval Prolongation and Torsades de Pointes
Methadone-Associated Q-T Interval Prolongation and Torsades de Pointes
Purpose: The association of methadone with Q-T interval prolongation and torsades de pointes (TdP) is reviewed, and recommendations for preventing Q-T interval prolongation in methadone users are provided.
Summary: Abnormalities in voltage-gated potassium channels have been shown to lead to prolonged action potentials that are expressed as long Q-T intervals, and methadone has been found to interact with the voltage-gated potassium channels of the myocardium. While cardiac arrhythmias in methadone users have been reported for several decades, specific reports of methadone-associated Q-T interval prolongation and TdP did not appear in the literature until the early part of the 21st century. Because not every patient experiences Q-T interval prolongation with methadone, recent research has elucidated risk factors that predispose patients to this adverse effect, including female sex, hypokalemia, high-dose methadone, drug interactions, underlying cardiac conditions, unrecognized congenital long Q-T interval syndrome, and predisposing DNA polymorphisms. Given the high mortality rates seen in untreated illicit opioid users and the clear efficacy of methadone in treating opioid addiction, the risk of using methadone, even in a patient with other risk factors for Q-T interval prolongation, may outweigh the alternative of no pharmacologic treatment. A baseline electrocardiogram (ECG), personal and family history of syncope, and a complete medication history should be obtained before a patient begins treatment with methadone. Given the apparent synergistic effects of parenteral methadone and chlorobutanol, oral methadone should be used whenever possible.
Conclusion: Q-T interval prolongation and TdP associated with the use of methadone are potentially fatal adverse effects. A thorough patient history and ECG monitoring are essential for patients treated with this agent, and alterations in treatment options may be necessary.
Q-T interval prolongation occurs when there is an interruption in the normal balance and flow of ions in the myocardium, increasing the time it takes for repolarization to occur. The Q-T interval is measured using an electrocardiograph and averaged over several heartbeats. Heart rate can affect the accuracy of the measurement of the interval, and formulas exist (Bazett's formula, Fridericia's formula) to determine a corrected Q-T interval (Q-Tc) that accounts for variations in heart rate. A Q-Tc interval of 390-420 msec in men or 400-440 msec in women is generally considered normal.
The main cause of Q-T interval prolongation involves the human ether-a-go-go-related gene (hERG) and the subunit of the voltage-gated potassium channels (found predominantly in the myocardium) for which it encodes. These channels are the predominant facilitators of the delayed-rectifier potassium ion currents (IK), which cause repolarization. Abnormalities in these channels have been shown to lead to prolonged action potentials that are expressed as long Q-T intervals on the electrocardiogram (ECG).
The health risks associated with a prolonged Q-T interval are unclear. Although individuals with a prolonged Q-T interval are often asymptomatic, some may develop palpitations, syncope, seizures, or cardiac arrest. Q-T interval prolongation can also lead to the potentially fatal reentrant arrhythmia known as torsades de pointes (TdP). However, the mere presence of Q-T interval prolongation may not lead to TdP. Some medications, such as amiodarone, are commonly associated with a prolonged Q-T interval but rarely with TdP. Conversely, TdP can occur in the individuals with a Q-T interval within the normal range.
The most common (and studied) causes of TdP are congenital abnormalities and drug-induced Q-T interval prolongation. Methadone is a synthetic opioid associated with prolonged Q-T intervals and TdP. This article reviews the available literature on methadone-associated Q-T interval prolongation and TdP and provides recommendations on the prevention of these adverse effects.
Abstract and Introduction
Abstract
Purpose: The association of methadone with Q-T interval prolongation and torsades de pointes (TdP) is reviewed, and recommendations for preventing Q-T interval prolongation in methadone users are provided.
Summary: Abnormalities in voltage-gated potassium channels have been shown to lead to prolonged action potentials that are expressed as long Q-T intervals, and methadone has been found to interact with the voltage-gated potassium channels of the myocardium. While cardiac arrhythmias in methadone users have been reported for several decades, specific reports of methadone-associated Q-T interval prolongation and TdP did not appear in the literature until the early part of the 21st century. Because not every patient experiences Q-T interval prolongation with methadone, recent research has elucidated risk factors that predispose patients to this adverse effect, including female sex, hypokalemia, high-dose methadone, drug interactions, underlying cardiac conditions, unrecognized congenital long Q-T interval syndrome, and predisposing DNA polymorphisms. Given the high mortality rates seen in untreated illicit opioid users and the clear efficacy of methadone in treating opioid addiction, the risk of using methadone, even in a patient with other risk factors for Q-T interval prolongation, may outweigh the alternative of no pharmacologic treatment. A baseline electrocardiogram (ECG), personal and family history of syncope, and a complete medication history should be obtained before a patient begins treatment with methadone. Given the apparent synergistic effects of parenteral methadone and chlorobutanol, oral methadone should be used whenever possible.
Conclusion: Q-T interval prolongation and TdP associated with the use of methadone are potentially fatal adverse effects. A thorough patient history and ECG monitoring are essential for patients treated with this agent, and alterations in treatment options may be necessary.
Introduction
Q-T interval prolongation occurs when there is an interruption in the normal balance and flow of ions in the myocardium, increasing the time it takes for repolarization to occur. The Q-T interval is measured using an electrocardiograph and averaged over several heartbeats. Heart rate can affect the accuracy of the measurement of the interval, and formulas exist (Bazett's formula, Fridericia's formula) to determine a corrected Q-T interval (Q-Tc) that accounts for variations in heart rate. A Q-Tc interval of 390-420 msec in men or 400-440 msec in women is generally considered normal.
The main cause of Q-T interval prolongation involves the human ether-a-go-go-related gene (hERG) and the subunit of the voltage-gated potassium channels (found predominantly in the myocardium) for which it encodes. These channels are the predominant facilitators of the delayed-rectifier potassium ion currents (IK), which cause repolarization. Abnormalities in these channels have been shown to lead to prolonged action potentials that are expressed as long Q-T intervals on the electrocardiogram (ECG).
The health risks associated with a prolonged Q-T interval are unclear. Although individuals with a prolonged Q-T interval are often asymptomatic, some may develop palpitations, syncope, seizures, or cardiac arrest. Q-T interval prolongation can also lead to the potentially fatal reentrant arrhythmia known as torsades de pointes (TdP). However, the mere presence of Q-T interval prolongation may not lead to TdP. Some medications, such as amiodarone, are commonly associated with a prolonged Q-T interval but rarely with TdP. Conversely, TdP can occur in the individuals with a Q-T interval within the normal range.
The most common (and studied) causes of TdP are congenital abnormalities and drug-induced Q-T interval prolongation. Methadone is a synthetic opioid associated with prolonged Q-T intervals and TdP. This article reviews the available literature on methadone-associated Q-T interval prolongation and TdP and provides recommendations on the prevention of these adverse effects.
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