What is the recommended dosage and usage of Nortriptyline (tricyclic antidepressant) for treating major depressive disorder and chronic pain in adults, particularly in older adults or those with a history of heart conditions?

Nortriptyline Dosing and Usage

For neuropathic pain in adults, start nortriptyline at 25 mg at bedtime and increase by 25 mg every 3-7 days as tolerated to a maximum of 150 mg/day, with optimal plasma levels maintained between 50-150 ng/mL. 1, 2

Dosing for Neuropathic Pain (First-Line Indication)

Starting dose: 25 mg at bedtime 1

Titration schedule: Increase by 25 mg every 3-7 days as tolerated 1

Maximum dose: 150 mg/day 1, 2

Duration for adequate trial: 6-8 weeks total, including at least 2 weeks at the maximum tolerated dose 1

Therapeutic plasma levels: 50-150 ng/mL (combined nortriptyline and metabolite) 2

• Plasma level monitoring is recommended when doses exceed 100 mg/day 2
• If plasma levels are below 100 ng/mL, cautious continued titration may be considered 1

Dosing for Major Depressive Disorder

Starting dose: 25 mg 3-4 times daily (or total daily dose given once daily) 2

Usual adult dose range: 75-100 mg/day 2

Maximum dose: 150 mg/day 2

• Doses above 150 mg/day are not recommended by the FDA 2
• In clinical trials for geriatric depression, mean effective dose was 54 mg/day with mean plasma level of 97 ng/mL 3
• Maintenance therapy in elderly patients showed efficacy at 80-120 ng/mL steady-state levels 4

Special Populations: Older Adults (≥60 years)

Critical dosing modifications required:

Starting dose: 30-50 mg/day in divided doses 2

• This represents approximately 50% of the standard adult starting dose 5
• Elderly patients are at significantly greater risk for adverse drug reactions 5

Rationale for dose reduction: Higher plasma concentrations of the active metabolite 10-hydroxynortriptyline occur in elderly patients, which has been associated with cardiotoxicity even when nortriptyline levels are within "therapeutic range" 2

Monitoring requirements: Clinical findings should predominate over plasma concentrations as primary determinants of dosage changes in elderly patients 2

Practical consideration: In geriatric depression resistant to SSRIs, mean effective dose was only 54 mg/day, demonstrating that lower doses are often sufficient 3

Patients with Cardiac History

Mandatory pre-treatment screening: Obtain ECG before initiating nortriptyline in patients with cardiac history 1

Contraindications: Do not use if PR or QTc interval is prolonged 5

Dose limitation: Keep doses below 100 mg/day when possible in patients with ischemic cardiac disease or ventricular conduction abnormalities 1

Age-based screening: Obtain screening ECG for all patients older than 40 years before starting treatment 1

Cardiac toxicity concerns: Both nortriptyline and its parent compound amitriptyline prolong QTc interval and can cause arrhythmias 6

Why Nortriptyline Over Amitriptyline

Nortriptyline is the preferred secondary-amine TCA over tertiary-amine TCAs like amitriptyline 1

Advantages:

• Significantly fewer anticholinergic side effects (dry mouth, constipation, urinary retention, blurred vision, confusion) 6
• Better tolerated, especially in elderly patients 5, 6
• Equivalent efficacy for neuropathic pain and depression 6

Common pitfall: Never combine nortriptyline with amitriptyline, as nortriptyline is the active metabolite of amitriptyline, making combination pharmacologically redundant and increasing toxicity risk 6

Administration and Monitoring

Timing: Once-daily dosing at bedtime is preferred to minimize daytime sedation 1, 2

Monitoring frequency: Reassess pain and quality of life frequently during titration 1

Response criteria:

• Substantial pain relief = average pain reduced to ≤3/10 1
• Partial relief = average pain remains ≥4/10 after adequate trial 1
• If <30% pain reduction at target dose after adequate trial, switch to alternative first-line medication 1

Common Adverse Effects and Management

Anticholinergic effects: Dry mouth, orthostatic hypotension, constipation, urinary retention 1

Management strategy: Start with low doses at bedtime and titrate slowly 1

Serious adverse effects requiring discontinuation: Cardiac conduction abnormalities, severe orthostatic hypotension, confusional states (especially in elderly) 2

Drug interactions of concern:

• Cimetidine significantly increases TCA levels 2
• Fluoxetine can cause >2-fold increases in nortriptyline levels 2
• Caution with other drugs metabolized by CYP2D6 2

Clinical Algorithm for Treatment Failure

Step 1: If inadequate response after 6-8 weeks at maximum tolerated dose, add another first-line medication (gabapentin, pregabalin, or duloxetine) 1

Step 2: If combination therapy fails, switch to alternative first-line medication 1

Step 3: If multiple first-line trials fail, consider referral to pain specialist or multidisciplinary pain center 1