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QTc interval prolongation associated with intravenous methadone.
Craig A Kornick1, Michael J Kilborn, Juan Santiago-Palma
1Pain and Palliative Care Service, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Department of Pharmacology, Georgetown University Medical Center, Washington, DC, USA Department of Pharmacy, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Department of Cardiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Department of Medicine, University of Arizona Health Sciences Center, Tucson, AZ, USA.
Intravenous methadone, especially with chlorobutanol, significantly prolongs the QTc interval in patients. This study confirms methadone
Area of Science:
- Pharmacology
- Cardiology
- Molecular Biology
Background:
- Numerous medications prolong the QTc interval by blocking cardiac potassium channels (HERG).
- Methadone is used clinically, and concerns exist regarding its potential to cause arrhythmias like torsades de pointes.
- The preservative chlorobutanol in parenteral methadone formulations may contribute to cardiotoxicity.
Purpose of the Study:
- To determine if intravenous methadone administration prolongs the QTc interval in human patients.
- To investigate whether methadone and/or chlorobutanol block cardiac HERG potassium currents in vitro.
- To assess the potential role of chlorobutanol in methadone-induced QTc prolongation.
Main Methods:
- Retrospective analysis of QTc intervals from ECGs of inpatients receiving intravenous methadone or morphine.
- Measurement of QTc intervals on and off medication, with concurrent dose recording.
- In vitro electrophysiology studies using human embryonic kidney cells to assess HERG channel block by methadone and chlorobutanol.
Main Results:
- Intravenous methadone administration was associated with a significant mean QTc interval prolongation of 41.7 ms (p<0.0001).
- No significant QTc prolongation was observed with intravenous morphine (mean difference 9.0 ms, p=0.15).
- Methadone and chlorobutanol independently and concentration-dependently blocked HERG currents, with chlorobutanol potentiating methadone's effect.
Conclusions:
- Intravenous methadone, particularly in combination with chlorobutanol, is associated with significant QTc interval prolongation.
- The findings suggest that methadone-induced QTc prolongation is mediated, at least in part, by HERG channel blockade.
- This study highlights the potential cardiotoxic risk of parenteral methadone formulations containing chlorobutanol.