What are the interactions between nortriptyline (Tricyclic Antidepressant) and amitriptyline (Tricyclic Antidepressant)?

Drug Interactions Between Nortriptyline and Amitriptyline

Nortriptyline and amitriptyline should not be combined as they are both tricyclic antidepressants (TCAs) with overlapping mechanisms of action, leading to additive anticholinergic effects, cardiac toxicity risks, and no additional therapeutic benefit. 1, 2

Why These Drugs Should Not Be Combined

Pharmacological Redundancy

• Nortriptyline is the active metabolite of amitriptyline, making their combination pharmacologically redundant 1, 3
• When amitriptyline is administered, it is metabolized to nortriptyline in the body, so combining them provides no additional therapeutic mechanism 1, 4
• Therapeutic drug monitoring data shows that patients on amitriptyline 150mg/day achieve mean amitriptyline levels of 100±41 ng/mL plus nortriptyline levels of 71±38 ng/mL from metabolism alone 1

Additive Toxicity Risks

• Both drugs cause identical anticholinergic side effects including dry mouth, orthostatic hypotension, constipation, urinary retention, blurred vision, and confusion 1, 2
• Cardiac toxicity is a major concern as both TCAs prolong QTc interval and can cause arrhythmias, with additive effects when combined 1
• Severe TCA overdose cases demonstrate that even single-agent toxicity can reach plasma concentrations of 2290-2900 μg/L with life-threatening outcomes 5

Serotonin Syndrome Risk

• Combining two TCAs increases the risk of serotonin syndrome, particularly when both have serotonergic activity 1
• Guidelines explicitly warn against combining multiple serotonergic drugs, including TCAs, due to risks of autonomic hyperactivity, hyperthermia, seizures, and potentially fatal outcomes 1

Clinical Decision Algorithm

If Patient Is Currently on Amitriptyline:

• Continue amitriptyline alone at doses of 75-150 mg/day for neuropathic pain or depression 1, 2
• Monitor for therapeutic response using both parent compound (amitriptyline) and metabolite (nortriptyline) plasma levels 1
• Target combined tricyclic levels (amitriptyline + nortriptyline) within therapeutic range for optimal response 4

If Switching from Amitriptyline to Nortriptyline:

• Nortriptyline is preferred over amitriptyline due to superior side effect profile while maintaining equivalent efficacy 1, 2
• Nortriptyline has fewer anticholinergic and antihistaminergic effects compared to amitriptyline 1, 2
• Start nortriptyline at 10-25 mg at bedtime after discontinuing amitriptyline, titrating by 10-25 mg every 2 weeks to goal dose of 75-150 mg 1, 2

If Inadequate Pain Control on Single TCA:

• Do not add a second TCA; instead combine with a different mechanistic class 1
• Add gabapentin or pregabalin (calcium channel α2-δ ligands), which have proven synergistic efficacy when combined with TCAs 1
• Consider adding duloxetine (SNRI) or topical agents rather than another TCA 1

Special Populations and Contraindications

Cardiac Considerations:

• Both drugs are contraindicated in patients with cardiovascular disease including recent MI, arrhythmias, or heart block 1
• TCAs should be avoided in patients with prolonged QTc syndrome 1

Elderly Patients:

• Use nortriptyline preferentially as it has fewer anticholinergic effects than amitriptyline 1, 2
• Start at lower doses (10 mg at bedtime) due to increased sensitivity to sedative and cardiovascular effects 2

Other Contraindications:

• Glaucoma (both drugs contraindicated) 1
• Orthostatic hypotension (both drugs contraindicated) 1
• Hepatic disease (use with extreme caution) 1

Drug Interaction Monitoring

When TCAs Are Combined with Other Medications:

• Fluvoxamine significantly increases amitriptyline/nortriptyline levels through CYP450 inhibition, though this combination may enhance efficacy without increasing adverse effects at lower TCA doses 3
• Divalproex sodium increases amitriptyline AUC by 31% and combined amitriptyline/nortriptyline levels by 42%, requiring dose reduction of the TCA 6
• Terbinafine causes prolonged CYP2D6 inhibition with TCA levels remaining elevated for months after terbinafine discontinuation 7

Critical Pitfall to Avoid:

• Never combine two TCAs thinking one will "augment" the other—this only increases toxicity without therapeutic benefit 1, 2
• The only scenario where both compounds are present should be during the natural metabolism of amitriptyline to nortriptyline, not from intentional co-prescription 1, 4