Which medication is most likely to produce a prolongation of the QTc (QT corrected) interval: hydromorphone, methadone, morphine, or buprenorphine?

Methadone is Most Likely to Cause QTc Prolongation

Among the four opioids listed, methadone is definitively the medication most likely to produce QTc interval prolongation, with well-documented cases of torsades de pointes and potential sudden cardiac death, particularly at higher doses. 1, 2

Evidence Hierarchy for QTc Risk

Methadone: High Risk

• The FDA label explicitly warns that methadone inhibits cardiac potassium channels and prolongs the QT interval, with cases of serious arrhythmia (torsades de pointes) observed during treatment. 2
• High doses of methadone (≥120 mg/day) are associated with QTc prolongation and torsades de pointes that may lead to sudden cardiac death. 1
• Even at typical maintenance doses, QTc prolongation can occur, especially with concomitant medications or clinical conditions like hypokalemia. 2
• In prospective studies, 76% of methadone-treated patients experienced QTc increases, with 19% exceeding 450 msec at 6 months. 3
• The European Heart Journal recommends baseline and follow-up ECGs for patients taking methadone, with additional evaluation if daily dosage exceeds 100 mg. 4

Buprenorphine: Minimal to No Risk

• Treatment with buprenorphine in commonly used doses is a suitable alternative to methadone with regard to the risk of QTc prolongation. 5
• No patients on buprenorphine developed QTc prolongation (defined as >450 ms) at baseline or after 1 or 6 months of treatment. 5
• QTc was not associated with serum concentrations of buprenorphine in linear mixed effects models. 5

Morphine and Hydromorphone: Low Risk

• The mean difference in QTc intervals on and off morphine was 9.0 msec (not statistically significant, p=0.15), compared to 41.7 msec for methadone (p<0.0001). 6
• Neither morphine nor hydromorphone are mentioned in major cardiology guidelines as QT-prolonging medications. 7

Critical Risk Factors for Methadone-Induced QTc Prolongation

When prescribing methadone, assess for these high-risk factors:

• Congestive heart failure (OR: 11.9) - strongest predictor of QTc prolongation 8
• Peptic ulcer disease (OR: 8.3) 8
• Hypokalemia (OR: 6.5) - electrolyte abnormalities significantly increase QTc 8, 5
• Rheumatologic diseases (OR: 4.7) 8
• Concurrent medications with known torsades de pointes risk (OR: 4.4) - including tricyclic antidepressants, class I/III antiarrhythmics, some neuroleptics 2, 8
• Malignancy (OR: 3.3) 8
• Methadone doses >45 mg/day (OR: 1.9) - dose-response relationship exists 8, 9
• Hypocalcemia and hypomagnesemia 1

Monitoring Protocol for Methadone

The NCCN guidelines recommend the following structured approach:

1. Obtain baseline ECG before initiating methadone 1

2. Perform follow-up ECG monitoring for patients with cardiac disease or those taking other QTc-prolonging medications 1

3. Correct modifiable risk factors:

   • Correct hypokalemia, hypomagnesemia, or hypocalcemia 1
   • Avoid other drugs that prolong QTc 1
   • Avoid CYP3A4 inhibitors that increase methadone levels 1, 2

4. Action thresholds:

   • QTc >500 msec: Switch to alternate opioid (absolute contraindication) 1
   • QTc 450-500 msec: Strongly consider alternate opioid while correcting reversible causes 1

Clinical Pitfalls to Avoid

• Do not assume low doses are safe - QTc prolongation can occur at typical maintenance doses, though risk increases significantly above 100-120 mg/day. 2, 9
• Monitor for drug interactions - CYP3A4 inhibitors (azole antifungals, some SSRIs like sertraline/fluvoxamine) increase methadone levels and QTc prolongation risk. 2
• The preservative chlorobutanol in IV methadone potentiates QTc prolongation - it independently blocks cardiac potassium channels and enhances methadone's effect. 6
• Male patients may be at higher risk - 40% of males vs. 20% of females developed QTc prolongation in one study. 9
• Significant dose-response relationship exists in males on methadone <12 months (rho=0.60, p=0.02). 9