Which medications interact with trazodone?

Trazodone Drug Interactions

Trazodone interacts with MAOIs (contraindicated), serotonergic drugs, anticoagulants/antiplatelets, strong CYP3A4 inhibitors and inducers, and warfarin, requiring careful monitoring and dose adjustments. 1

Contraindicated Medications

MAOIs are absolutely contraindicated with trazodone due to severe serotonin syndrome risk. 1 This includes:

• Isocarboxazid, phenelzine, selegiline, tranylcypromine, moclobemide 1
• Linezolid and intravenous methylene blue (which have MAOI properties) 1

Serotonergic Drugs (Increased Serotonin Syndrome Risk)

Monitor closely when combining trazodone with other serotonergic medications, as this significantly increases serotonin syndrome risk. 2, 1 These include:

• SSRIs and SNRIs: Fluoxetine, sertraline, paroxetine, citalopram, escitalopram, venlafaxine, desvenlafaxine, duloxetine 2, 1
• Tricyclic antidepressants: Amitriptyline, imipramine, doxepin, nortriptyline 2, 1
• Opioids with serotonergic activity: Tramadol, fentanyl, meperidine, methadone, tapentadol 2, 1, 3
• Triptans (migraine medications) 1
• Other agents: Lithium, buspirone, St. John's Wort, tryptophan, dextromethorphan 2, 1

The combination with SNRIs like desvenlafaxine (Pristiq) requires monitoring for additive sedation but has no absolute contraindication. 4 Start with lower doses of each medication when combining. 4

Anticoagulants and Antiplatelet Agents (Bleeding Risk)

Trazodone potentiates bleeding risk when combined with anticoagulants or antiplatelet drugs due to serotonin's role in platelet function. 1 Monitor closely with:

• Warfarin: Requires close INR monitoring, as trazodone may induce CYP450 enzymes requiring higher warfarin doses 2, 1
• Direct oral anticoagulants: Rivaroxaban, dabigatran 1
• Antiplatelet agents: Clopidogrel, aspirin, NSAIDs 1

For warfarin specifically, check INR within a few days of starting or stopping trazodone, as case reports show trazodone may require 20-70% warfarin dose increases. 2

CYP3A4 Inhibitors (Increased Trazodone Levels)

Strong CYP3A4 inhibitors significantly increase trazodone exposure and cardiac arrhythmia risk—use lower trazodone doses. 1 These include:

• Antifungals: Itraconazole, ketoconazole 2, 1
• Antibiotics: Clarithromycin, erythromycin 2, 1
• Antivirals: Indinavir, ritonavir 2
• Cardiac drugs: Diltiazem, verapamil 2

CYP3A4 Inducers (Decreased Trazodone Efficacy)

Strong CYP3A4 inducers decrease trazodone levels, potentially causing treatment failure—monitor for loss of efficacy and increase trazodone dose if needed. 1 These include:

• Rifampin, carbamazepine, phenytoin, phenobarbital 2, 1
• St. John's Wort 2, 1

Cardiac Medications (Additive Heart Rate Effects)

Combining trazodone with drugs that slow heart rate increases bradycardia and arrhythmia risk. 2 Use caution with:

• Beta blockers: Propranolol, metoprolol, carvedilol, atenolol 2
• Calcium channel blockers: Verapamil, diltiazem (especially when combined with beta blockers) 2
• Antiarrhythmics: Amiodarone, sotalol, quinidine 2

CNS Depressants (Additive Sedation)

Trazodone has additive sedative effects with other CNS depressants—start with lower doses and avoid alcohol. 4, 5 This includes:

• Antihistamines: Hydroxyzine (can be safely combined but requires monitoring for excessive sedation) 5
• Benzodiazepines: May increase seizure threshold during ECT 2
• Barbiturates: Butalbital combinations 2
• Alcohol: Contraindicated due to dangerous sedation potentiation 4, 5

Special Perioperative Considerations

Hold trazodone at least 2 days before surgery when possible to avoid serotonin syndrome with anesthetic agents and opioids. 2 If continuing perioperatively, avoid combining with serotonergic opioids (fentanyl, meperidine, methadone, tramadol). 2

Electroconvulsive Therapy (ECT)

Trazodone may cause prolonged seizures during ECT—discontinue if clinically possible before ECT treatment. 2 If continuation is necessary, provide appropriate monitoring for seizure duration. 2

Clinical Monitoring Recommendations

• Initiate combination therapy: Start with lower doses of both agents, particularly in elderly patients 4, 5
• Warfarin combinations: Check INR within 3-7 days of trazodone initiation or dose change 2
• Serotonergic combinations: Monitor for serotonin syndrome symptoms (neuromuscular excitation, autonomic dysfunction, altered mental status) 2, 1
• Cardiac monitoring: Obtain baseline ECG when combining with QT-prolonging drugs or in patients with pre-existing heart disease 6
• Elderly patients: Use lower doses due to increased sensitivity to sedative and cardiac effects 4, 5