What is nortriptyline (tricyclic antidepressant) used for and what are its side effects?

Nortriptyline: Clinical Overview

Primary Indication and Mechanism

Nortriptyline is FDA-approved for treating depression, but its most evidence-based use in modern practice is as a first-line agent for neuropathic pain, where it functions by inhibiting norepinephrine and serotonin reuptake in descending pain pathways. 1, 2

• The FDA label indicates nortriptyline is approved for relief of depressive symptoms, particularly endogenous depression 1
• The mechanism involves interference with catecholamine transport, release, and storage, while also blocking histamine, serotonin, and acetylcholine activity 1
• Nortriptyline is the active metabolite of amitriptyline, making it a secondary amine tricyclic antidepressant with reduced anticholinergic effects compared to tertiary amines 2, 3

Evidence-Based Clinical Uses

Neuropathic Pain (First-Line Treatment)

Nortriptyline is recommended as first-line therapy for multiple neuropathic pain conditions based on consensus guidelines, though it should be preferred over amitriptyline due to superior tolerability with equivalent efficacy. 2

• The Mayo Clinic guidelines designate secondary amine TCAs (nortriptyline, desipramine) as first-line options alongside SNRIs and gabapentinoids for neuropathic pain 2
• Nortriptyline has fewer anticholinergic properties than amitriptyline, causing less dry mouth, constipation, urinary retention, and orthostatic hypotension 2, 3
• The number needed to treat (NNT) for neuropathic pain is 1.5-3.5, though this may be influenced by small crossover trial designs 2
• Critical limitation: A 2015 Cochrane review found only third-tier evidence supporting nortriptyline, with no high-quality studies demonstrating superiority over placebo 4

Diabetic Peripheral Neuropathy

For diabetic neuropathy specifically, nortriptyline is effective but requires careful cardiac screening, with doses limited to <100 mg/day in patients with cardiovascular risk factors. 2

• The American Academy of Neurology recommends TCAs as one of several equivalent first-line options (alongside SNRIs, gabapentinoids, and sodium channel blockers) for diabetic peripheral neuropathy pain 2
• A head-to-head trial demonstrated therapeutic equivalency between TCAs, SNRIs, and gabapentinoids, with combination therapy superior to monotherapy 2
• Anticholinergic side effects may be dose-limiting and restrict use in individuals ≥65 years of age 2

Depression (FDA-Approved but Second-Line)

For treatment-resistant depression, nortriptyline achieves approximately 40% response rates after failed antidepressant trials, with therapeutic doses of 25-100 mg daily. 5

• Treatment should continue for 4-9 months after satisfactory response for first-episode major depression 5
• Patients with 2 or more depressive episodes may benefit from longer duration therapy 5

Other Off-Label Uses

• Chronic orofacial pain of non-inflammatory origin (neurogenic or myofascial etiologies) 6
• Migraine prevention, though amitriptyline has more consistent evidence 3
• Irritable bowel syndrome as a gut-brain neuromodulator (second-line) 5
• Insomnia, though nortriptyline is less sedating than amitriptyline 3, 7

Dosing Strategy

Neuropathic Pain Dosing

Start nortriptyline at 10-25 mg at bedtime, increase by 10-25 mg every 3-7 days as tolerated, targeting 50-100 mg daily with a maximum of 150 mg/day. 5, 3

• Lower starting doses (10 mg) are recommended for elderly patients to minimize anticholinergic effects 2, 5
• Analgesic effects typically occur at lower doses than required for depression and onset is usually within 1-2 weeks, though full therapeutic trial requires 4-8 weeks 5
• Therapeutic drug monitoring is recommended when approaching maximum doses to ensure plasma levels remain within the therapeutic window 5

Depression Dosing

For depression, start at 10-25 mg at bedtime and titrate gradually every 3-7 days to a target range of 25-100 mg daily, with maximum dose of 150 mg/day. 5

Absolute Contraindications

Nortriptyline is absolutely contraindicated in patients during acute recovery from myocardial infarction, those with arrhythmias or heart block, prolonged QTc syndrome, and concurrent MAO inhibitor use. 1, 3, 5

• Concurrent use with MAO inhibitors can cause hyperpyretic crises, severe convulsions, and fatalities; discontinue MAO inhibitor at least 2 weeks before starting nortriptyline 1
• Cross-sensitivity with other dibenzazepines is possible 1
• Hypersensitivity to nortriptyline is an absolute contraindication 1

Critical Monitoring Parameters

Cardiac Monitoring

Obtain baseline ECG before initiating therapy, particularly in patients with cardiac history, and limit doses to <100 mg/day in patients with cardiovascular risk factors due to QTc prolongation risk. 5, 2

• A large retrospective study showed increased risk of sudden cardiac death with TCA doses >100 mg/day 2
• If baseline ECG shows PR or QTc interval prolongation, nortriptyline should not be used 2

Other Monitoring

• Monitor for orthostatic hypotension, especially during the first 1-2 weeks 5
• Assess therapeutic response within 1-2 weeks for pain, though full trial requires 4-8 weeks 5
• Blood concentration monitoring when approaching maximum doses 5

Common Adverse Effects

Anticholinergic side effects are common but less severe than with amitriptyline, including dry mouth, constipation, orthostatic hypotension, urinary retention, and sedation. 2

• In real-world palliative care data, 27% of patients on nortriptyline experienced new harms by day 14, most commonly dizziness (23 patients), dry mouth (20 patients), constipation (14 patients), and urinary retention (10 patients) 8
• Weight gain is less common with nortriptyline compared to amitriptyline, though dry mouth may be more prevalent 9
• Adverse effects can be reduced by starting with low dosages at bedtime and slow titration 2

Clinical Decision Algorithm for Neuropathic Pain

Step 1: Screen for Contraindications

• Assess for recent MI, arrhythmias, heart block, prolonged QTc, age >65 years, anticholinergic sensitivity 5, 2
• If cardiac contraindications present, choose duloxetine, pregabalin, or gabapentin instead 2, 10

Step 2: Choose Between Nortriptyline and Amitriptyline

• Prefer nortriptyline over amitriptyline due to equivalent efficacy with superior tolerability profile 3, 2
• Nortriptyline is particularly preferred in elderly patients due to fewer anticholinergic effects 2, 3
• Combining nortriptyline with amitriptyline is pharmacologically redundant and increases toxicity risk without additional benefit 3

Step 3: Initiate and Titrate

• Start 10-25 mg at bedtime 5
• Increase by 10-25 mg every 3-7 days as tolerated 5
• Target 50-100 mg daily for most patients 5
• Maximum 150 mg/day with therapeutic drug monitoring 5

Step 4: Assess Response and Consider Combination

• If partial response after adequate trial, add gabapentin, pregabalin, or duloxetine rather than switching 2
• Combination therapy is superior to monotherapy for diabetic peripheral neuropathy 2
• If no response after 4-8 weeks at target dose, switch to alternative first-line agent 2

Special Populations

Elderly Patients

Start at 10 mg nightly in patients ≥65 years and titrate more gradually due to increased sensitivity to anticholinergic and sedative effects. 2, 5

Cardiac Transplant Recipients

• Nortriptyline can be used safely with appropriate monitoring 5

Palliative Care

• Real-world data shows 18.9% of palliative care patients achieved pain improvement by day 14 on nortriptyline, with benefits without harms occurring in 10.8% 8
• Amitriptyline showed superior benefit rates (43.3% improvement) compared to nortriptyline in this population, though harms were similar 8

Common Pitfalls to Avoid

• Do not combine nortriptyline with amitriptyline: This is pharmacologically redundant since nortriptyline is amitriptyline's active metabolite, and increases cardiac and anticholinergic toxicity without additional benefit 3
• Do not use doses >100 mg/day without cardiac evaluation: Risk of sudden cardiac death increases significantly above this threshold 2
• Do not expect immediate pain relief: Onset typically requires 1-2 weeks, with full therapeutic trial needing 4-8 weeks 5
• Do not use in HIV-related neuropathy: Two RCTs with 270 participants demonstrated no benefit over placebo 10
• Do not start at full doses in elderly patients: Begin at 10 mg and titrate slowly to minimize falls risk from orthostatic hypotension 2, 5