nortriptyline

General Information

Nortriptyline (Pamelor) is a secondary amine TCA used for treatment-resistant depression and neuropathic pain with lower anticholinergic burden than tertiary amines.

Therapeutic drug monitoring (TDM) helps maintain concentrations within a narrow therapeutic window.

Compared with tertiary-amine TCAs, nortriptyline is often better tolerated in older adults, but it still carries meaningful anticholinergic, orthostatic, and arrhythmia risk where structured counseling and monitoring are common.

The compare tool to contrast anticholinergic load, QTc impact, and monitoring requirements, and printable counselling sheets can support taper discussions.

The nortriptyline evidence feed can support review before dosage adjustments or augmentation, especially when aligning neuropathic pain versus mood goals.

Often preferred TCA in older adults due to lower anticholinergic load but still requires cardiac monitoring and a safety plan (overdose risk, fall risk). TDM is often used to avoid under-dosing (nonresponse) and overexposure (toxicity), and goals (mood vs pain vs sleep) are typically aligned before dose escalation.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Inhibits norepinephrine reuptake more than serotonin and antagonizes histamine, muscarinic, and adrenergic receptors to a lesser extent than amitriptyline.

Like other TCAs, it also has sodium-channel blocking properties that contribute to QRS widening and arrhythmias in overdose and in susceptible cardiac patients.

• NET inhibition with moderate H1, M1, and α1 antagonism.
• Sodium-channel blockade (cardiac conduction risk, especially in overdose).

Metabolism and Pharmacokinetics

• Peak 6–8 h; half-life 18–44 h (extended in CYP2D6 poor metabolizers).
• Metabolized via CYP2D6 to inactive metabolites; eliminated renally as metabolites.
• Highly protein bound with a large volume of distribution; plasma levels can rise quickly when CYP2D6 inhibitors are added or when hepatic function worsens.
• Steady state typically takes 5–7 days; TDM is often checked after dose changes once steady state is reached (and sooner if toxicity is suspected).

Dosing and Administration

• Typical start is 25 mg HS with titration every 3–7 days as tolerated to 75–100 mg/day (single HS or divided).
• Target plasma level 50–150 ng/mL; TDM is commonly obtained after steady state (7–10 days).
• For neuropathic pain or insomnia goals, many patients respond at 10–50 mg nightly; escalation above the therapeutic window is generally avoided if pain/sleep improves without full antidepressant targets.
• Older adults, frailty, and cardiac disease: 10 mg nightly is often used as a starting point with slower titration and earlier ECG/TDM checks.
• Tapering is typically gradual to avoid withdrawal symptoms.

Monitoring & Labs

• Baseline ECG for patients >40 years, cardiac disease, electrolyte abnormalities, or higher target doses; repeat after major dose changes or when adding QT-active medications.
• TDM after steady state (about 7–10 days) and after dose adjustments; track both symptom response and adverse effects when interpreting levels.
• Orthostatic vitals, falls risk, and anticholinergic burden (bowel and bladder symptoms), especially in older adults or when adding anticholinergic co-medications.
• Mood activation and suicidality during initiation and titration, particularly in adolescents/young adults and in bipolar-spectrum illness.
• Medication reconciliation for CYP2D6 inhibitors/inducers, QT-active agents, and serotonergic combinations; include OTC antihistamines and decongestants.

Nortriptyline monitoring is centered on safety and dose optimization: ECG + TDM prevent avoidable toxicity while supporting adequate exposure for mood or pain targets.

Adverse Effects

Interactions

• CYP2D6 inhibitors markedly increase levels—adjust dose and monitor plasma concentrations.
• MAOIs contraindicated; observe washout periods.
• Additive anticholinergic effects with other agents (antipsychotics, antihistamines).
• Additive QT/QRS risk with other QT-active agents or sodium-channel blockers (certain antipsychotics, antiarrhythmics); obtain ECG monitoring and correct electrolytes.
• Additive sedation with alcohol, opioids, or benzodiazepines—counsel about impaired alertness and falls risk.

Other Useful Information

• Therapeutic drug monitoring aids in optimizing efficacy and minimizing toxicity.
• Secure storage essential due to overdose lethality.
• When treating bipolar depression, pair nortriptyline with a mood stabiliser, monitor for mania/hypomania, and coordinate care through the bipolar disorder hub.
• For neuropathic pain targets, reassess benefit at lower dose ranges and avoid titrating above the therapeutic window when the goal is pain or sleep rather than full antidepressant response.
• Consider pharmacogenomic context (CYP2D6 status) when patients have prior TCA intolerance, unusual sensitivity, or complex polypharmacy.
• Shared decision-making improves adherence: review what side effects to expect early (dry mouth, constipation, sleepiness) and what symptoms should trigger urgent evaluation (syncope, palpitations).

References

1. Nortriptyline prescribing information — DailyMed (2025)
2. Preskorn1991 TDM Antidepressants