Does duloxetine (Cymbalta) prolong the QTc interval in a patient with chronic pain due to a brachial plexus injury and potential underlying cardiac conditions?

Does Duloxetine Prolong QTc?

Duloxetine does not cause clinically significant QTc prolongation at therapeutic or even supratherapeutic doses when used alone, but it can contribute to severe QT prolongation and life-threatening arrhythmias when combined with other QT-prolonging medications, particularly in patients with multiple cardiac risk factors. 1, 2

Evidence from Controlled Studies

The FDA label for duloxetine explicitly states that no QT interval prolongation was detected in controlled studies. 2 A rigorous thorough QT study evaluated duloxetine at 160 mg and 200 mg twice daily (2.7 to 3.3 times the maximum recommended dose) in 117 healthy female subjects and found that duloxetine actually caused concentration-dependent QT shortening rather than prolongation, with no clinically meaningful effects on cardiac repolarization. 2, 3

• In this study, no subject had absolute QTc values >445 ms with duloxetine, and the change in QTc from baseline did not exceed 36 ms. 3
• No relationship was detected between QTc change and plasma concentrations of duloxetine or its metabolites, even at concentrations more than 5 times those achieved at therapeutic doses. 3
• A systematic review of newer non-SSRI antidepressants found that existing studies fail to demonstrate QT prolongation with duloxetine at therapeutic doses. 4

Critical Risk: Drug Combinations and Multiple Risk Factors

The European Heart Journal published a case report demonstrating that duloxetine can cause extreme QT prolongation (QTc 694 ms) and ventricular fibrillation arrest when combined with other QT-prolonging drugs in the presence of multiple risk factors. 1 This case involved a 76-year-old woman taking amiodarone, duloxetine, and pregabalin who developed:

• QT interval of 760 ms (QTc 694 ms) 1
• Ventricular fibrillation requiring resuscitation 1
• Contributing factors included age >65 years, female sex, bradycardia, hypokalemia (2.8 mmol/L, likely pregabalin-induced), pre-existing cardiovascular disease, and drug-drug interactions through CYP2D6 inhibition leading to toxic serum concentrations 1

Risk Stratification Algorithm

Before prescribing duloxetine, assess for cumulative QT prolongation risk factors: 1, 5

• Age >65 years 1
• Female sex 1
• Pre-existing cardiovascular disease 1
• Bradycardia (heart rate <60 bpm) 1
• Electrolyte abnormalities (especially hypokalemia <3.5 mmol/L) 1
• Concurrent use of other QT-prolonging medications (amiodarone, methadone, antipsychotics, certain SSRIs) 1
• Congenital long QT syndrome 1

If ≥2 risk factors are present, obtain a baseline ECG before starting duloxetine. 5 If combining duloxetine with other QT-prolonging agents, ECG monitoring is mandatory. 5

Overdose Data

Real-world overdose data supports the safety profile of duloxetine regarding cardiac effects. A retrospective review of 64 patients who ingested duloxetine alone (median dose 840 mg, range 180-4200 mg) found: 6

• No arrhythmias occurred 6
• Only 2 of 63 patients with ECG recordings had abnormal QT intervals, both transient and without clinical sequelae 6
• No ICU admissions or intubations were required 6
• Predominant effects were sympathomimetic (tachycardia in 48%, mild hypertension in 45%) and serotonin toxicity, consistent with duloxetine's pharmacology 6

Clinical Recommendations for Cardiac Patients

For patients with stable cardiac disease without heart failure, duloxetine can be used with standard monitoring. 5 However:

• Avoid duloxetine in patients with recent myocardial infarction or unstable coronary disease 5
• Start at 30 mg daily for one week before increasing to 60 mg daily in patients with significant cardiac disease 5
• Maximum dose should not exceed 60 mg twice daily 5
• Monitor for orthostatic hypotension, particularly in elderly patients 5

Key Pitfalls to Avoid

Never combine multiple QT-prolonging medications without ECG monitoring and electrolyte assessment. 5, 7 The case report demonstrates that the combination of duloxetine with amiodarone and pregabalin, in the setting of hypokalemia and other risk factors, can be lethal. 1

Do not overlook pregabalin-induced hypokalemia as a contributor to cardiac arrhythmias when these medications are used together. 5 The European Heart Society specifically warns about this interaction. 5

Duloxetine is a CYP2D6 inhibitor, which can increase serum concentrations of other medications metabolized by this pathway, potentially leading to toxic levels and increased QT prolongation risk. 1