Evaluation of Dose-Dependent Association of Methadone to QTc Prolongation in Pediatric Patients

Introduction: Methadone is utilized in pediatric acute care setting in the peri-extubation period when weaning off opioid infusions in order prevent iatrogenic withdrawal syndrome. Methadone is associated with prolongation of the QTc interval. The specific relationship between the degree of QTc prolongation and various weight-based doses of methadone has not been characterized. The primary aim of this study was to determine and characterize the dose dependent relationship between methadone and QTc prolongation in pediatric patients.


Methods: A retrospective chart review of patients less than 18 years old initiated on methadone between January 1, 2023 and April 30, 2024, in the intensive care setting. Patients were excluded if they received methadone for < 24 hours, did not have EKG results while on methadone, had a history of long QT syndrome, had renal dysfunction, or if they were on methadone for the following indications: chronic pain, palliative care, and/or addiction. The primary study endpoint was the dose-dependent relationship between methadone and QTc prolongation. Secondary endpoints included the prevalence of varying severities of QTc prolongation (QTc >450 ms and >500 ms), diagnosis of torsades de pointes, and percentage of QTc prolongation with concomitant QTc prolonging and CYP3A4 drugs compared to methadone monotherapy.


Results: A total of 140 pediatric patients were included. The average age was 1 year old (IQR 0.24-0.55), the majority were male (58.6%). A total of 1010 QTc values were assessed. QTc prolongation, defined as a QTc ≥ 450 ms, was observed in 34.1% of QTcs reviewed. There was no correlation between weight-based methadone dose and QTc interval (r=-0.02). There was a statistically significant change between baseline QTc and QTc while on methadone (417 versus 435, p=0.0018); however, this was not clinically significant. No events of torsade de pointes were observed.


Conclusions: While receipt of methadone demonstrated a prolongation of QTc above baseline, we could not identify that increasing doses of methadone provided further prolongation to the QTc interval.