What are the recommended starting dose, titration schedule, contraindications, and major adverse effects of nortriptyline for treating depression or neuropathic pain in adults?

Nortriptyline for Depression and Neuropathic Pain

Starting Dose and Titration

Start nortriptyline at 10–25 mg at bedtime and increase by 10–25 mg every 3–7 days to a target dose of 75–100 mg nightly, with a maximum of 150 mg/day (or 100 mg/day in patients with cardiac concerns or those over 40 years). 1, 2

Detailed Dosing Protocol

• Initial dose: Begin with 10–25 mg at bedtime; use the lower end (10 mg) in elderly patients or those with cardiac risk factors. 1, 2

• Titration schedule: Increase by 10–25 mg every 3–7 days as tolerated to minimize adverse effects while achieving therapeutic benefit. 3, 1, 2

• Target dose: Aim for 75–100 mg at bedtime for most adults; elderly patients should target 30–75 mg/day maximum. 1, 2

• Maximum dose: 150 mg/day is the absolute maximum, but limit to <100 mg/day when possible, especially in patients with cardiac disease or those over 40 years. 3, 1, 4

• Trial duration: Allow 6–8 weeks for an adequate therapeutic trial, including at least 2 weeks at the highest tolerated dose before declaring treatment failure. 3, 1

Special Population Considerations

• Elderly patients: Start at 10 mg/day and titrate more slowly over 2–4 weeks to a maximum of 75 mg/day due to higher plasma concentrations of active metabolites. 1, 4

• Neuropathic pain: Effective doses for pain (25–100 mg) are often lower than those required for depression treatment. 1, 4

Contraindications and Precautions

Nortriptyline is contraindicated in patients with recent myocardial infarction, arrhythmias, heart block, or prolonged QTc syndrome. 4

Cardiac Screening Requirements

• Mandatory ECG: Obtain a screening electrocardiogram in all patients older than 40 years before initiating nortriptyline. 3, 1, 2

• Cardiac disease: Use with extreme caution in patients with ischemic heart disease or ventricular conduction abnormalities; consider alternative treatments when possible. 3, 4

• Dose-related cardiac risk: Doses exceeding 100 mg/day carry increased risk of sudden cardiac death, particularly in patients with cardiovascular disease or elderly patients. 4

Additional Contraindications

• Avoid combination with other TCAs: Do not combine nortriptyline with amitriptyline (nortriptyline is amitriptyline's active metabolite), as this creates pharmacological redundancy and increases risk of serotonin syndrome and cardiac toxicity. 4

Major Adverse Effects

The most common adverse effects are anticholinergic symptoms—dry mouth, constipation, urinary retention, blurred vision, and sedation—though nortriptyline produces fewer anticholinergic effects than tertiary amine TCAs like amitriptyline. 1, 4, 2

Common Side Effects (Well-Tolerated)

• Anticholinergic effects: Dry mouth, constipation, urinary retention, blurred vision, and confusion occur commonly but are less severe than with amitriptyline. 1, 4, 2

• Sedation: Nortriptyline is sedating but less so than amitriptyline; administer at bedtime to leverage this effect for sleep. 1, 4

• Weight gain: Can occur with chronic use. 4

• Orthostatic hypotension: Monitor blood pressure, especially during titration; only 2 of 26 patients in one study required intervention with fludrocortisone. 5

Serious Adverse Effects

• Cardiac toxicity: QTc prolongation and arrhythmias are the most serious concerns; risk increases with doses >100 mg/day. 3, 4

• Withdrawal rates: Expect 26–37% of patients to discontinue due to inefficacy or adverse effects when used for neuropathic pain. 6

• Number needed to harm (NNH): For major adverse effects leading to withdrawal, NNH is approximately 28; for minor adverse effects, NNH is 6. 7

Clinical Efficacy and Treatment Algorithm

Nortriptyline is a first-line agent for neuropathic pain (postherpetic neuralgia, diabetic peripheral neuropathy) with a number needed to treat (NNT) of approximately 3, meaning one in three patients achieves at least moderate pain relief. 1, 7, 8

Evidence for Specific Conditions

• Neuropathic pain: Effective for postherpetic neuralgia and diabetic peripheral neuropathy with similar efficacy to amitriptyline but superior tolerability. 1, 6, 8

• Depression: Effective for major depressive disorder; analgesic effects occur independently of antidepressant action. 1, 8

• Ineffective conditions: Not effective for HIV-related neuropathies, fibromyalgia, knee osteoarthritis, or chemotherapy-induced peripheral neuropathy. 4, 7, 8

Treatment Response Algorithm

• Week 6–8 assessment: If pain is reduced to ≤3/10, continue current regimen. 3, 1

• Partial response (pain ≥4/10): Add gabapentin (start 100–300 mg at night, titrate to 900–3600 mg/day in divided doses) rather than increasing nortriptyline beyond tolerance; combination therapy is superior to either agent alone. 1

• Inadequate response (<30% pain reduction): Switch to an alternative first-line medication (duloxetine, pregabalin) or refer to a pain specialist. 3, 1, 2

Important Clinical Pearls

• Early initiation improves outcomes: Starting nortriptyline soon after neuropathic pain onset significantly impacts efficacy, particularly in postherpetic neuralgia. 1

• Therapeutic drug monitoring: If blood concentration of nortriptyline plus its metabolite is <100 ng/mL at 150 mg/day, cautious further titration may be considered. 3

• Rapid onset possible: Some patients achieve significant benefit within the first week, with 81% reaching therapeutic drug levels on initial dosing by week 1. 5