Data
Brief Report: [Gourlay GK et al. Br Med J (Clin Res Ed) 284: 630, 1982; FREE Full-text at PubMed Central]
Pharmacodynamics of methadone in human post-surgical patients: [Gourlay GK et al. Anesthesiology 57: 458, 1982; FREE Full-text at Anesthesiology]
Effect of supplemental doses of methadone: [Gourlay GK et al. Anesthesiology 61: 19, 1984; FREE Full-text at Anesthesiology]
Methadone vs. Morphine [Gourlay GK et al. Anesthesiology 64: 322, 1986; FREE Full-text at Anesthesiology]
QT Prolongation and FDA Warning
There is an FDA Black Box Warning on methadone which states, “In addition, cases of QT interval prolongation and serious arrhythmia (torsades de points) have been observed during treatment with methadone. Most cases involve patents being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction”
Methadone is a known inhibitor of human cardiac ether-a-go-go-related gene (hERG), which encodes Ikr (delayed rectifier inward potassium channel), a common mechanism among known drug-induced QT prolongations. While the effect is dose dependent, sudden cardiac death has been seen in doses as low as 20 mg/day. Risk factors include history of long QT syndrome or sudden cardiac death in the patient or family, other rhythm disturbances, structural heart disease, CPY inhibitors, other QT prolonging drugs (including those of abuse, such as cocaine), and electrolyte abnormalities
An independent advisory panel to the FDA recommended pretreatment ECG, followed by a follow up at 30 days and then annually, although the panel recommended more frequent ECG monitoring for doses in excess of 100 mg/day or if QTc > 450 ms
Methadone and QT Interval (FDA BLACK BOX)
- Background: has caused QT prolongation and torsades. Sudden death reported in doses as low as 20 mg/day
- Etiology: inhibitor of human cardiac ether-a-go-go-related gene (hERG), which encodes Ikr (delayed rectifier inward potassium channel)
- Confounding Factors: history of long QT syndrome or sudden cardiac death in the patient or family, other rhythm disturbances, structural heart disease, CPY inhibitors, other QT prolonging drugs
- Monitoring: pretreatment ECG, follow up at 30 days and then annually (more frequent for doses in excess of 100 mg/day or if QTc > 450 ms)
