What is the dosage and usage of Nortriptyline (tricyclic antidepressant)?

Nortriptyline Dosage and Usage

Nortriptyline should be initiated at 10-25 mg at bedtime and titrated gradually every 3-7 days to a target dose of 25-100 mg daily, with a maximum of 150 mg/day, while maintaining plasma levels in the therapeutic window of 50-150 ng/mL (or 70-170 ng/mL per consensus guidelines). 1, 2, 3

Primary Indications and Evidence Base

Depression Treatment

• Nortriptyline is a first-line tricyclic antidepressant for major depression, particularly valuable after failed antidepressant trials with approximately 40% response rate 3
• The therapeutic window is narrower than other antidepressants: plasma levels of 70-170 ng/mL are strongly recommended for optimal efficacy 2
• Levels below 50 ng/mL or above 170 ng/mL are associated with reduced efficacy, creating a true "therapeutic window" rather than just a minimum effective concentration 4
• Full therapeutic response requires 4-8 weeks, though some improvement may be seen within 1-2 weeks 3

Neuropathic Pain Management

• Nortriptyline is a first-line medication for neuropathic pain, recommended alongside duloxetine, venlafaxine, gabapentin, and pregabalin 2
• Nortriptyline is preferred over amitriptyline for pain management due to equivalent efficacy with superior tolerability and fewer anticholinergic effects 5, 3
• Pain relief often occurs at lower doses (10-50 mg) than required for depression, though the same titration principles apply 2, 6
• Evidence is strongest for diabetic neuropathy and postherpetic neuralgia; limited evidence exists for chemotherapy-induced peripheral neuropathy 5, 7

Dosing Algorithm

Initial Dosing

• Start at 10-25 mg at bedtime for all patients, with elderly patients starting at the lower end (10 mg) 1, 3
• The bedtime dosing minimizes daytime sedation and anticholinergic effects 2

Titration Schedule

• Increase by 10-25 mg every 3-7 days based on tolerability and clinical response 3, 1
• For pain management, slower titration (every 7 days) may improve tolerability 2
• Monitor for orthostatic hypotension especially during the first 1-2 weeks of treatment and after each dose increase 3

Target Dosing

• Target dose range: 25-100 mg daily for most patients 1, 3
• Maximum dose: 150 mg/day - doses above this are not recommended 1, 2
• Elderly patients typically require 30-50 mg/day in divided doses 1

Therapeutic Drug Monitoring

• Obtain plasma levels when approaching 100 mg/day or if inadequate response 1, 2
• Target therapeutic range: 50-150 ng/mL (FDA) or 70-170 ng/mL (consensus guidelines) 1, 2
• If levels are below therapeutic range and patient tolerates current dose, continue titration cautiously 3
• Higher concentrations (>170 ng/mL) are associated with increased adverse effects without additional benefit 2, 4

Critical Monitoring Parameters

Pre-Treatment Assessment

• Obtain baseline ECG before initiating therapy, particularly in patients with any cardiac history 3
• Screen for contraindications: recent MI, arrhythmias, heart block, prolonged QTc syndrome 5, 3
• Assess for risk factors: cardiovascular disease, glaucoma, urinary retention, hepatic/renal impairment 2

Ongoing Monitoring

• Monitor orthostatic blood pressure at each visit during titration, especially weeks 1-2 3
• Assess for anticholinergic effects: dry mouth, constipation, urinary retention, blurred vision, confusion 2, 5
• Therapeutic response assessment at 1-2 weeks, with full trial requiring 4-8 weeks 3
• Plasma level monitoring when doses exceed 100 mg/day 1

Common Pitfalls and How to Avoid Them

Underdosing

• 73% of chronic pain patients receive inadequate doses (<50 mg amitriptyline equivalent), limiting efficacy 6
• Many patients respond to low doses for pain, but if inadequate response after 4 weeks at 50 mg, continue titration rather than abandoning treatment 6

Premature Discontinuation

• Side effects are often dose-dependent and transient; reduce dose rather than discontinue if minor side effects occur 1
• Dry mouth (most common) often improves with continued use and can be managed with sugar-free gum or artificial saliva 2

Ignoring the Therapeutic Window

• Unlike most antidepressants, higher doses of nortriptyline may be less effective due to the therapeutic window phenomenon 4
• Patients with levels >170 ng/mL should have dose reduced, not increased, if response is inadequate 2

Cardiovascular Monitoring Gaps

• Both nortriptyline and its parent compound amitriptyline prolong QTc interval - never combine these medications 5
• Elderly patients may develop cardiotoxicity even with therapeutic plasma levels due to active metabolite accumulation 1

Special Populations

Elderly Patients

• Start at 10 mg at bedtime and titrate more slowly (every 7-10 days) 1
• Target dose typically 30-50 mg/day in divided doses 1
• Nortriptyline is preferred over amitriptyline in elderly due to fewer anticholinergic effects 2, 5
• Higher risk of orthostatic hypotension, falls, and confusion 2

Cardiac Patients

• Contraindicated in recent MI, arrhythmias, heart block, or prolonged QTc 5, 3
• Can be used cautiously in stable cardiac transplant recipients with appropriate monitoring 3
• Baseline and follow-up ECGs are essential 3

Outpatients vs. Inpatients

• Lower doses are more important for outpatients who lack close supervision 1
• Hospitalized patients may tolerate more aggressive titration under direct observation 1

Duration of Treatment

Depression

• Continue for 4-9 months after satisfactory response for first-episode major depression 3
• Patients with 2 or more depressive episodes may benefit from longer duration therapy (potentially indefinite) 3
• Maintain at the lowest dose that sustains remission 1

Chronic Pain

• Duration is condition-dependent; many patients require long-term maintenance 2
• Attempt dose reduction after 6-12 months of good control to determine minimum effective dose 2

Alternative Dosing Regimens

Once-Daily Dosing

• The total daily dose may be given once daily at bedtime as an alternative to divided dosing 1
• This approach maximizes convenience and minimizes daytime sedation 1

High Initial Dosing (Not Routinely Recommended)

• One study showed 75-125 mg initial doses based on weight were tolerated in young, healthy inpatients with 45% symptom reduction within 1 week 8
• However, this approach is not recommended for routine practice due to increased risk of orthostatic hypotension and lack of controlled trial data 8
• Standard gradual titration remains the evidence-based approach 1, 3

Drug Interactions and Combination Therapy

Contraindicated Combinations

• Never combine nortriptyline with amitriptyline - nortriptyline is the active metabolite of amitriptyline, making combination redundant and toxic 5
• This combination increases risk of serotonin syndrome, cardiac toxicity, and additive anticholinergic effects 5

Medications Requiring Monitoring

• Fluvoxamine, divalproex sodium, and terbinafine may increase nortriptyline levels through CYP450 interactions 5
• Other serotonergic medications increase serotonin syndrome risk 5