What is the difference between amitriptyline (tricyclic antidepressant) and nortriptyline (tricyclic antidepressant)?

Key Differences Between Amitriptyline and Nortriptyline

Nortriptyline is the active metabolite of amitriptyline, making them pharmacologically related but distinct in their side effect profiles—nortriptyline causes fewer anticholinergic effects and less sedation while maintaining equivalent efficacy for depression and neuropathic pain. 1, 2

Pharmacological Relationship

• Nortriptyline is formed from amitriptyline metabolism, meaning patients taking amitriptyline automatically produce nortriptyline in their system 1
• Therapeutic drug monitoring shows amitriptyline-treated patients achieve mean amitriptyline levels of 100±41 ng/mL plus nortriptyline levels of 71±38 ng/mL from metabolism alone 1
• Combining both drugs is pharmacologically redundant and increases toxicity risk without additional therapeutic benefit 1

Mechanism of Action Differences

• Amitriptyline inhibits serotonin and noradrenaline reuptake equally 3, 4
• Nortriptyline is a more potent inhibitor of noradrenaline than serotonin uptake 5, 4
• Both interfere with the membrane pump mechanism for neurotransmitter reuptake, but with different selectivity profiles 3, 5

Side Effect Profile Comparison

Anticholinergic Effects

• Amitriptyline causes significantly more anticholinergic side effects including dry mouth, constipation, urinary retention, blurred vision, and confusion 6, 4
• Nortriptyline has fewer anticholinergic effects than amitriptyline, making it better tolerated, especially in elderly patients 1, 4

Sedation

• Amitriptyline is specifically listed among sedating antidepressants and causes more sedation 1, 7
• Nortriptyline is less sedating than amitriptyline, though still more sedating than desipramine 1

Weight Gain

• Weight gain is more common with amitriptyline than nortriptyline 2
• Dry mouth is more prevalent with nortriptyline use 2

Cardiac Effects

• Both drugs prolong QTc interval and can cause arrhythmias 1
• Both are contraindicated in patients with recent MI, arrhythmias, or heart block 1

Efficacy Comparison

Depression Treatment

• Both drugs are equally effective for treating depression 8, 9
• Amitriptyline has been a reference compound for depression treatment for many years 6, 9
• Therapeutic plasma level monitoring shows negative correlation with Hamilton scores for amitriptyline (r = -0.54, P < .025) and positive correlation for nortriptyline (r = 0.49, P < .05) 8

Neuropathic Pain Management

• Both drugs provide equivalent pain relief with approximately 23-26% visual analog scale pain reduction when tolerated 2
• Nortriptyline is preferred over amitriptyline for neuropathic pain due to superior side effect profile while maintaining similar efficacy 6, 1
• Real-world data shows amitriptyline provided pain improvement in 43.3% of patients versus 18.9% for nortriptyline by day 14, though harms were similar (27.9% vs 27.0%) 10
• Benefits without harms occurred in 25.0% with amitriptyline versus 10.8% with nortriptyline 10

Migraine Prevention

• Amitriptyline has consistent evidence for migraine prevention at doses of 30-150 mg/day 6, 7
• No evidence exists for nortriptyline use in migraine prevention 6
• Amitriptyline is superior for patients with mixed migraine and tension-type headache 6

Dosing Considerations

Starting Doses

• Both drugs typically start at 10-25 mg at bedtime 1, 7
• Gradual titration every 3-7 days minimizes side effects 1

Therapeutic Doses

• Amitriptyline: 75-150 mg/day maximum for neuropathic pain and depression 1
• Nortriptyline: 25-100 mg/day as tolerated 1
• Pain management often requires lower doses than depression treatment 1

Special Population Considerations

Elderly Patients

• Nortriptyline is preferentially recommended in elderly patients due to fewer anticholinergic effects 1
• Both tricyclic antidepressants are potentially inappropriate for adults ≥65 years due to anticholinergic effects 7
• Elderly patients are more sensitive to sedative effects and should start at lower doses 1

Cardiovascular Disease

• Both drugs are contraindicated in patients with cardiovascular disease, recent MI, arrhythmias, or heart block 1
• Avoid in patients with prolonged QTc syndrome 1

Clinical Decision Algorithm

When to Choose Nortriptyline Over Amitriptyline

• Elderly patients (fewer anticholinergic effects) 1
• Patients at risk for anticholinergic toxicity (urinary retention, constipation, confusion) 1, 4
• Patients requiring less sedation 1
• Neuropathic pain management (equivalent efficacy with better tolerability) 6, 1

When to Choose Amitriptyline Over Nortriptyline

• Migraine prevention (established evidence) 6, 7
• Mixed migraine and tension-type headache 6
• When sedation is desired (insomnia with pain) 1
• Real-world effectiveness data favors amitriptyline for neuropathic pain in palliative care (43.3% vs 18.9% improvement) 10

Common Pitfalls to Avoid

• Never combine amitriptyline and nortriptyline—this increases toxicity without additional benefit since nortriptyline is already the active metabolite of amitriptyline 1
• Do not use either drug in patients with prolonged QTc or recent cardiac events 1
• Discontinue at least 10 days before MIBG radionuclide imaging (amitriptyline interferes with this procedure) 7
• Monitor for therapeutic response using plasma levels of both parent compound and metabolite when using amitriptyline 1
• Expect discontinuation rates of 26-37% due to inefficacy or adverse effects with either TCA for neuropathic pain 2