What is nortriptyline (tricyclic antidepressant) used for and how is it prescribed?

Nortriptyline: Clinical Uses and Prescribing

Primary Indications

Nortriptyline is FDA-approved for depression and serves as a first-line agent for neuropathic pain, though secondary-amine tricyclics like nortriptyline are preferred over tertiary amines (amitriptyline) due to superior tolerability. 1, 2

FDA-Approved Use

• Depression treatment: Nortriptyline is indicated for relief of depressive symptoms, with endogenous depressions more likely to respond than other depressive states 1

Off-Label but Guideline-Supported Use

• Neuropathic pain (first-line): Mayo Clinic guidelines recommend secondary-amine tricyclics (nortriptyline, desipramine) as first-line therapy for neuropathic pain, alongside SNRIs (duloxetine, venlafaxine) and calcium channel α2-δ ligands (gabapentin, pregabalin) 2
• Nortriptyline is preferred over amitriptyline because it causes significantly fewer anticholinergic side effects (dry mouth, constipation, urinary retention, confusion) while maintaining equivalent efficacy, particularly important in elderly patients 3

Prescribing Guidelines

Starting and Titration Protocol

For neuropathic pain:

• Start: 10-25 mg at bedtime 2, 3
• Titration: Increase by 25 mg every 3-7 days as tolerated 3
• Target dose: 25-100 mg/day for pain management 3
• Maximum dose: 150 mg/day 3
• Time to adequate trial: 6-8 weeks, including 2 weeks at highest tolerated dose 2

For depression:

• Higher doses typically required than for pain management 3
• Therapeutic drug monitoring recommended when approaching maximum doses 3

Important Prescribing Considerations

Cardiac screening is mandatory:

• Obtain baseline ECG for patients over 40 years old 2
• Use with extreme caution in ischemic cardiac disease or ventricular conduction abnormalities 2
• Limit doses to <100 mg/day when possible in cardiac patients 2
• Contraindicated in recent MI, arrhythmias, or heart block 3

Other contraindications and cautions:

• Glaucoma or urinary retention history: Use with great caution due to anticholinergic activity 1
• Seizure history: Lowers convulsive threshold, requires close monitoring 1
• Hyperthyroid patients or those on thyroid medication: Risk of cardiac arrhythmias 1
• Bipolar disorder screening: Screen all depressed patients before initiating, as antidepressant monotherapy may precipitate manic episodes 1

Mechanism of Action

Nortriptyline's exact mood-elevating mechanism remains unknown, but it:

• Interferes with transport, release, and storage of catecholamines 1
• Inhibits histamine, serotonin, and acetylcholine activity 1
• Increases pressor effect of norepinephrine 1
• Is NOT a monoamine oxidase inhibitor 1

Common Adverse Effects

Anticholinergic effects (less than amitriptyline but still present):

• Dry mouth 2, 3
• Orthostatic hypotension 2, 3
• Constipation 2, 3
• Urinary retention 2, 3
• Blurred vision 3
• Confusion (especially in elderly) 3

Cardiovascular effects:

• Sinus tachycardia 1
• Prolonged conduction time 1
• QTc prolongation 3

Other effects:

• Sedation (less than amitriptyline but more than desipramine) 3
• Weight gain 3
• Impaired mental/physical abilities for operating machinery 1

Critical Safety Warnings

Black Box Warning: Suicidality Risk

All patients on antidepressants require close monitoring for suicidality, especially:

• During initial months of therapy 1
• At times of dose changes (increases or decreases) 1
• Highest risk in patients <24 years old (14 additional cases per 1000 patients vs placebo in age <18) 1
• Protective effect in elderly (6 fewer cases per 1000 patients in age ≥65) 1

Monitor for emergence of:

• Anxiety, agitation, panic attacks 1
• Insomnia, irritability, hostility 1
• Aggressiveness, impulsivity 1
• Akathisia (psychomotor restlessness) 1
• Hypomania or mania 1

Prescribe smallest quantity consistent with good management to reduce overdose risk 1

Drug Interactions

• Alcohol: Potentiating effect increases suicide/overdose risk 1
• Guanethidine: Antihypertensive action may be blocked 1
• Fluvoxamine, divalproex, terbinafine: Require careful monitoring 3

Clinical Efficacy Evidence

For Neuropathic Pain

• Cochrane review (2015): Only third-tier evidence available; small studies with methodological flaws showed similar efficacy to gabapentin, morphine, and other tricyclics, but evidence quality was very low 4
• Real-world utilization: In multidisciplinary pain clinics, nortriptyline is commonly used at low-to-intermediate doses (73% at ≤50 mg amitriptyline-equivalent) 5
• Guideline support remains strong despite limited high-quality trials, based on clinical experience and better tolerability than amitriptyline 2

For Treatment-Resistant Depression

• Approximately 40% response rate in patients who failed 1-5 adequate antidepressant trials 6
• Should be considered after SSRI/SNRI failures 6

Stepwise Treatment Algorithm for Neuropathic Pain

Step 1: Assessment

• Confirm neuropathic pain diagnosis 2
• Screen for cardiac disease, glaucoma, urinary retention, seizures 2, 1
• Obtain ECG if age >40 years 2
• Screen for bipolar disorder if treating depression 1

Step 2: Initiate First-Line Therapy

• Choose nortriptyline (preferred over amitriptyline) OR duloxetine/venlafaxine OR gabapentin/pregabalin 2
• Start nortriptyline 10-25 mg at bedtime 3
• Increase by 25 mg every 3-7 days to target 25-100 mg/day 3

Step 3: Reassess at 6-8 Weeks

• Substantial relief (pain ≤3/10): Continue current therapy 2
• Partial relief (pain ≥4/10): Add second first-line agent from different class 2
• Inadequate relief (<30% reduction): Switch to alternative first-line medication 2

Step 4: Refractory Cases

• Consider second/third-line medications or refer to pain specialist 2

Special Populations

Pregnancy and lactation:

• Safety not established; weigh benefits against risks 1
• Animal studies yielded inconclusive results 1

Elderly patients:

• More sensitive to anticholinergic and sedative effects 3
• Start at lower doses (10 mg) 3
• Nortriptyline preferred over amitriptyline in this population 3