Amitriptyline × Duloxetine

The combination works along two lines. Kinetics: duloxetine is a moderate inhibitor of CYP2D6, an enzyme that clears amitriptyline (labels of both drugs). With another tricyclic, desipramine, duloxetine tripled AUC (duloxetine SmPC). Serotonin: both drugs block the reuptake of serotonin and noradrenaline, and the combination raises the risk of serotonin syndrome (labels of both drugs).

Serotonin syndrome: agitation, hallucinations, coma, tachycardia, labile blood pressure, fever, hyperreflexia, incoordination, nausea, vomiting, diarrhoea. In its most severe form it resembles neuroleptic malignant syndrome, with fever and muscle rigidity (duloxetine SmPC). Signs of amitriptyline excess: drowsiness, dry mouth, constipation, urinary retention, fast heartbeat, dizziness on standing, and at high levels arrhythmias and QT prolongation (amitriptyline SmPC).

Use the combination with caution (labels of both drugs). Watch for serotonin syndrome at the start of treatment and after each dose increase. The FDA labels of both drugs require stopping both drugs at once and starting supportive treatment if it appears. The amitriptyline plasma level may need monitoring and its dose may need reducing (FDA duloxetine label). Measure blood pressure before starting duloxetine and periodically during treatment, and do not start duloxetine in uncontrolled hypertension (duloxetine labels). Use amitriptyline with caution in marked bradycardia, decompensated heart failure and with QT-prolonging drugs; potassium or magnesium disturbances raise the risk of arrhythmia (amitriptyline SmPC).