Are pregabalin and duloxetine (anticonvulsant and serotonin-norepinephrine reuptake inhibitor) contraindicated in patients with heart disease?

Pregabalin and Duloxetine in Heart Disease

Neither pregabalin nor duloxetine are absolutely contraindicated in heart disease, but both require careful consideration and monitoring based on specific cardiac conditions and risk factors. 1, 2, 3

Duloxetine in Heart Disease

Safety Profile

• Duloxetine does not produce clinically important electrocardiographic changes or blood pressure alterations in most patients and can be used in cardiac disease with appropriate precautions. 1
• The FDA label notes that duloxetine has not been systematically evaluated in patients with recent myocardial infarction or unstable coronary artery disease, as these patients were excluded from premarketing trials. 3
• A 2020 meta-analysis found duloxetine increases heart rate by 2.22 beats/min and diastolic blood pressure by 0.82 mmHg, representing modest cardiovascular effects. 4

Critical Warning: QT Prolongation Risk

• A 2018 European Heart Journal case report documented ventricular fibrillation arrest in a patient taking duloxetine combined with other QT-prolonging medications (amiodarone and pregabalin), with QTc reaching 694 ms. 1
• The risk is substantially elevated when multiple risk factors coexist: age >65 years, pre-existing cardiovascular disease, bradycardia, female sex, electrolyte abnormalities (particularly hypokalemia), and concurrent QT-prolonging drugs. 1
• Before prescribing duloxetine in cardiac patients, assess for these cumulative risk factors and consider baseline ECG if multiple risks are present. 1

Specific Cardiac Considerations

• Duloxetine can cause orthostatic hypotension, falls, and syncope, with risk proportional to underlying fall risk and increasing with age. 3
• The risk of blood pressure decreases is greater in patients taking concomitant antihypertensives or at duloxetine doses above 60 mg daily. 3
• In patients with heart failure or significant cardiac disease, start at 30 mg daily for one week before increasing to 60 mg daily to minimize adverse effects. 1, 5

Practical Recommendation for Cardiac Patients

Duloxetine can be used in stable heart disease but requires ECG screening when combined with other QT-prolonging agents, monitoring for orthostatic hypotension, and avoidance in patients with recent MI or unstable coronary disease. 1, 3

Pregabalin in Heart Disease

Safety Profile and Edema Risk

• The FDA label explicitly warns to exercise caution when using pregabalin in patients with NYHA Class III or IV heart failure due to limited data in this population. 2
• Pregabalin causes peripheral edema in 6% of patients (vs. 2% placebo), with 0.5% discontinuing due to edema. 2
• When pregabalin is combined with thiazolidinedione antidiabetic agents, peripheral edema occurs in 19% of patients (vs. 8% with pregabalin alone and 3% with thiazolidinediones alone). 2
• Weight gain of 7% or more over baseline occurs in 9% of pregabalin-treated patients, and the long-term cardiovascular effects of this weight gain are unknown. 2

Heart Failure Exacerbation Concerns

• Multiple case reports have documented heart failure exacerbation in patients receiving pregabalin, including patients without prior cardiac history. 6, 7
• A 2020 nationwide Danish cohort study found no increased risk of worsening heart failure with pregabalin compared to gabapentin (HR 0.79,95% CI 0.50-1.23) or duloxetine (HR 1.08,95% CI 0.60-1.94). 8
• Despite reassuring population-level data, individual case reports suggest pregabalin can precipitate heart failure in susceptible patients, particularly those with advanced cardiac disease. 6, 7, 9

QT Prolongation Risk

• The 2018 European Heart Journal case documented that pregabalin contributed to severe QT prolongation (QTc 694 ms) and ventricular fibrillation when combined with amiodarone and duloxetine. 1
• Pregabalin likely caused hypokalemia (potassium 2.8 mmol/L) in this case, which exacerbated QT prolongation. 1

Practical Recommendation for Cardiac Patients

Pregabalin is preferred over duloxetine for neuropathic pain in dilated cardiomyopathy and most cardiac conditions due to minimal direct cardiac effects, but avoid in NYHA Class III-IV heart failure and monitor closely for edema, weight gain, and electrolyte disturbances. 10, 2, 8

Clinical Algorithm for Use in Heart Disease

Step 1: Assess Cardiac Status

• Stable cardiac disease without heart failure: Both medications can be used with standard monitoring. 1, 10
• NYHA Class I-II heart failure: Pregabalin preferred; use duloxetine with caution and close monitoring. 10, 2
• NYHA Class III-IV heart failure: Avoid pregabalin per FDA guidance; duloxetine may be used if benefits outweigh risks. 2, 3
• Recent MI or unstable coronary disease: Avoid duloxetine; pregabalin is safer alternative. 3

Step 2: Evaluate QT Prolongation Risk Factors

If ≥2 risk factors present (age >65, female, bradycardia, electrolyte abnormalities, concurrent QT-prolonging drugs), obtain baseline ECG before starting either medication. 1

Step 3: Monitoring Protocol

• Pregabalin: Monitor for peripheral edema weekly for first month, check weight at each visit, assess for worsening heart failure symptoms, and monitor electrolytes (especially potassium) if using with other medications that affect electrolytes. 10, 2
• Duloxetine: Monitor blood pressure and heart rate at baseline and after dose increases, assess for orthostatic hypotension (particularly in elderly or those on antihypertensives), and repeat ECG if new cardiac symptoms develop or when adding other QT-prolonging medications. 3

Step 4: Dosing Strategy

• Pregabalin: Start 50 mg three times daily or 75 mg twice daily, increase to 300 mg/day after 3-7 days, maximum 600 mg/day with renal adjustment. 1
• Duloxetine: Start 30 mg once daily for one week, then increase to 60 mg once daily, maximum 60 mg twice daily. 1, 5

Key Pitfalls to Avoid

• Never combine multiple QT-prolonging medications without ECG monitoring and electrolyte assessment. 1
• Do not overlook pregabalin-induced hypokalemia as a contributor to cardiac arrhythmias. 1
• Avoid assuming pregabalin is completely safe in heart failure—case reports demonstrate real risk despite negative population studies. 6, 7, 8
• Do not prescribe duloxetine to patients with substantial alcohol use due to hepatotoxicity risk, which can indirectly affect cardiac function. 3
• Remember that peripheral edema from pregabalin can mimic heart failure decompensation—distinguish by checking for other signs of volume overload. 2