Nortriptyline Tapering Guide
nortriptyline
Boxed Warning
Suicidality risk in children, adolescents, and young adults under 25 during initial treatment.
Overview
Nortriptyline is a secondary amine tricyclic antidepressant and the active metabolite of amitriptyline. It is used for major depressive disorder and off-label for neuropathic pain, migraine prophylaxis, and smoking cessation. It is better tolerated than amitriptyline with fewer anticholinergic and sedative effects.
10mg, 25mg, 50mg, 75mg
Capsules: 10mg, 25mg, 50mg, 75mg; Oral solution: 10mg/5mL
Category D (positive evidence of risk)
Mechanism of Action
Primarily inhibits norepinephrine reuptake, with lesser serotonin reuptake inhibition. Has less anticholinergic, antihistaminic, and alpha-adrenergic blocking activity compared to tertiary amine TCAs like amitriptyline.
Taper Notes
Secondary amine TCA with less anticholinergic and antihistaminic activity than amitriptyline. Oral solution (10 mg/5 mL) available for fine titration. Therapeutic drug monitoring (target 50–150 ng/mL) is useful when balancing taper pace against persistent indication.
Maudsley Deprescribing Guidance
Oral solution (10 mg/5 mL) supports proportional reductions below 10 mg. Reduced anticholinergic burden compared to amitriptyline typically yields milder cholinergic rebound on discontinuation.
Common Withdrawal Symptoms
Interactions & Safety
Drug Interactions
- MAOIs — contraindicated (hypertensive crisis and serotonin syndrome)
- CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion) significantly increase nortriptyline levels
- QT-prolonging drugs increase arrhythmia risk
Food Interactions
- Food does not significantly affect absorption
- Avoid alcohol (additive CNS depression)
- Grapefruit juice may modestly increase levels
Contraindications
- MAOIs within 14 days
- Acute recovery period post-myocardial infarction
- Known hypersensitivity to nortriptyline
Toxicity
Cardiotoxic in overdose (QRS widening, arrhythmias), though less toxic than amitriptyline. Therapeutic drug monitoring recommended (therapeutic window 50–150 ng/mL).
Pharmacokinetics
ADME Profile
Well absorbed after oral administration. Bioavailability ~46–70%. Tmax 3–12 hours. Food does not significantly affect absorption.
~21 L/kg
Hepatic via CYP2D6 (primary) to 10-hydroxynortriptyline and other hydroxylated metabolites. Also metabolized by CYP2C19 and CYP3A4.
Renal (~40% as metabolites) with ~2% unchanged in urine. Fecal excretion minor.
~93–95%
~500 mL/min (apparent oral clearance, highly variable depending on CYP2D6 status)
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