Nortriptyline

Indications

• FDA-approved for the relief of symptoms of depression in adults; endogenous depressions respond better than reactive presentations.
• Off-label but widely used for painful diabetic neuropathy, postherpetic neuralgia, and other chronic neuropathic pain conditions.
• Off-label for migraine and chronic tension-type headache prophylaxis, usually at 10-50 mg at bedtime rather than antidepressant doses.
• Off-label adjunct for smoking cessation, with efficacy comparable to bupropion in older trials but a less favorable side effect profile.
• Preferred tricyclic in older adults and in patients who could not tolerate amitriptyline, imipramine, or doxepin because of orthostasis.
• Not approved for pediatric patients; adolescent use is off-label and carries the antidepressant class suicidality warning.

Mechanism of action

• Predominantly blocks the norepinephrine transporter, with far weaker serotonin reuptake inhibition than tertiary amines such as amitriptyline.
• Muscarinic, histaminergic, and alpha-1 adrenergic blockade are all present but substantially weaker than with the tertiary-amine tricyclics.
• Reduced alpha-1 blockade translates into much less orthostatic hypotension, which is why it is the preferred tricyclic in geriatric practice.
• Sodium channel blockade underlies analgesia in neuropathic pain and also the cardiac conduction delay seen with toxic concentrations.
• Noradrenergic action in descending inhibitory pain pathways explains analgesic benefit at doses well below those needed for antidepressant effect.

Pharmacokinetics

• Well absorbed after oral dosing with peak concentrations at roughly 7 to 8.5 hours; the active metabolite of amitriptyline is this same molecule.
• Elimination half-life averages about 36 hours with a range of 18 to 44 hours, so once-daily bedtime dosing is adequate for most patients.
• Hydroxylated primarily by CYP2D6 to 10-hydroxynortriptyline, a metabolite with modest activity that accumulates in renal impairment.
• CYP2D6 poor metabolizers reach much higher concentrations; CPIC recommends a 50 percent dose reduction with level-guided titration in this group.
• Highly protein bound with a large volume of distribution, so extracorporeal removal is ineffective and overdose management is supportive.

Dosing

• Start 25 mg PO at bedtime in adults, or 10 mg in older patients, and increase by 25 mg every 3 to 7 days as tolerated.
• Usual antidepressant target is 75-150 mg/day; the label states that total daily doses above 150 mg/day are not recommended.
• For neuropathic pain and headache prophylaxis, 10-75 mg at bedtime is usually sufficient and better tolerated than higher doses.
• Supplied as 10, 25, 50, and 75 mg capsules and a 10 mg per 5 mL oral solution; the full dose is customarily given at bedtime.
• No renal dose adjustment is specified, but reduce the dose in hepatic impairment and in patients with confirmed CYP2D6 poor metabolizer status.
• Taper gradually over 2 to 4 weeks when discontinuing to avoid cholinergic rebound with nausea, headache, insomnia, and malaise.

Adverse effects

• Dry mouth, constipation, blurred vision, and urinary hesitancy are common but milder than with tertiary-amine tricyclics.
• Sedation and weight gain occur but are less pronounced than with amitriptyline or doxepin, aiding tolerability in long-term use.
• Orthostatic hypotension is the least of any tricyclic, yet it still occurs and remains a fall risk in frail older patients.
• Cardiac conduction delay with PR, QRS, and QTc prolongation is dose dependent and becomes dangerous above the therapeutic window.
• Overdose is potentially lethal with seizures, wide-complex arrhythmia, hypotension, and coma; dispense limited quantities in high-risk patients.
• Lowers the seizure threshold, can induce mania in bipolar illness, and rarely causes agranulocytosis or cholestatic liver injury.

Monitoring

• Nortriptyline has a true therapeutic window of 50-150 ng/mL; levels above 150 ng/mL are associated with reduced response and greater toxicity.
• Draw the level as a trough 10 to 14 hours after the bedtime dose and at least 5 days after any dose change or steady state is not reached.
• Obtain a baseline ECG in patients over 50 years, in known cardiac disease, and repeat after reaching target dose or after any level above range.
• Check blood pressure with orthostatics, weight, and bowel and bladder function at each visit during titration and periodically thereafter.
• Monitor for emergent suicidality, agitation, and mood switch during the first weeks of therapy and after every dose increase.

Interactions

• Contraindicated with monoamine oxidase inhibitors and within 14 days of stopping one because of hypertensive crisis and serotonin syndrome.
• Strong CYP2D6 inhibitors such as fluoxetine, paroxetine, bupropion, and quinidine can double or triple levels and demand a dose reduction.
• Inducers including carbamazepine, rifampin, and chronic smoking lower concentrations and may cause apparent treatment failure at usual doses.
• Additive QT prolongation occurs with methadone, ondansetron, and class IA or III antiarrhythmics; additive anticholinergic load with oxybutynin.
• Blunts the antihypertensive action of clonidine and guanfacine, and alcohol or sedatives potentiate central nervous system depression.

Special populations

• Human pregnancy data are limited but do not show a clear teratogenic signal; late exposure can cause transient neonatal irritability.
• Relative infant dose in breast milk is low and levels in infants are usually undetectable, making this a preferred tricyclic during lactation.
• Pediatric safety and efficacy have not been established, and enuresis or pain indications in children are entirely off-label.
• Preferred tricyclic in adults 65 and older, though the Beers Criteria still flag the whole class; start at 10 mg and use levels to guide dosing.
• The 10-hydroxy metabolite accumulates in renal impairment, so check levels sooner and titrate slowly in advanced kidney disease.

Clinical pearls

• The only antidepressant with a real therapeutic window: 50-150 ng/mL, with worse response above it.
• Draw the level as a trough 10-14 h post dose, at least 5 days after any change.
• Best tolerated tricyclic in older adults because alpha-1 blockade is comparatively weak.