The opioid most commonly associated with a significant risk of QT interval prolongation is Methadone.

- Methadone is a synthetic opioid frequently used in pain management and opioid substitution therapy.
- One of its notable side effects is its potential to prolong the QT interval on the electrocardiogram (ECG), which can predispose patients to a serious and potentially fatal arrhythmia called Torsades de Pointes.
- This risk is dose-dependent and more pronounced in patients with underlying cardiac conditions or those taking other QT-prolonging drugs.

In contrast, other opioids such as Morphine, Fentanyl, and Codeine have little to no significant effect on the QT interval and are generally not associated with this risk.

Key points:
- Methadone is well-known for QT interval prolongation.
- This effect increases the risk for Torsades de Pointes.
- Monitoring with ECG is recommended for patients receiving high doses or those at risk.
- Other opioids like Morphine, Fentanyl, and Codeine have minimal or no impact on QT interval.

Understanding these differences is critical to ensure safe opioid prescribing, particularly in patients with cardiac risk factors.

Reference: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 13th Edition, Volume 2, Chapter 26, Page 592-593