What are the side effects of nortriptyline, a tricyclic antidepressant (TCA), in adults with a history of chronic pain or neurological conditions, such as restless legs syndrome or nocturnal leg cramps?

Side Effects of Nortriptyline

Nortriptyline causes anticholinergic side effects including dry mouth, constipation, urinary retention, orthostatic hypotension, and sedation, but these effects are significantly less severe than with tertiary amine tricyclics like amitriptyline, making it the preferred tricyclic antidepressant for chronic pain management in adults. 1

Common Anticholinergic Side Effects

The most frequently encountered adverse effects of nortriptyline are related to its anticholinergic properties, though these occur less commonly than with amitriptyline:

• Dry mouth is the most common side effect, reported more frequently with nortriptyline than with other tricyclics in comparative studies 2
• Constipation occurs regularly and may require management with stool softeners or increased fluid intake 1, 3
• Urinary retention can develop, particularly in older adults or those with pre-existing prostatic hypertrophy 1, 3
• Blurred vision results from anticholinergic effects on pupillary accommodation 3
• Confusion may occur, especially in elderly patients who are more sensitive to anticholinergic effects 1, 3

Cardiovascular Side Effects

Cardiac effects represent the most serious potential adverse events with nortriptyline:

• Orthostatic hypotension is common and can lead to falls, particularly in older adults 1
• QTc prolongation and cardiac conduction abnormalities can occur, with increased risk of sudden cardiac death at doses exceeding 100 mg/day 4
• Arrhythmias may develop, especially in patients with pre-existing cardiac disease 4
• ECG screening is mandatory before initiating therapy in patients over 40 years of age 3, 5

The American Heart Association recommends obtaining a baseline electrocardiogram before starting treatment, particularly if doses will exceed 100 mg/day, and the American College of Cardiology advises limiting doses to less than 100 mg/day in patients with any cardiac risk factors 4, 3.

Neurological and Psychiatric Side Effects

• Sedation occurs frequently, though nortriptyline is less sedating than amitriptyline 1
• Weight gain is less common with nortriptyline compared to amitriptyline 2
• Restless legs syndrome can be induced or exacerbated by nortriptyline, though this is uncommon 6
• Periodic limb movements may increase with tricyclic antidepressants, though the clinical significance is unclear 7

Comparative Tolerability Profile

Nortriptyline, as a secondary amine tricyclic, demonstrates a superior side effect profile compared to tertiary amine tricyclics:

• Fewer anticholinergic effects than amitriptyline while maintaining equivalent analgesic efficacy 1
• Better tolerability in elderly patients due to reduced anticholinergic burden 1, 4
• Similar overall discontinuation rates to amitriptyline (26-37% discontinue due to adverse effects or inefficacy) 2
• Equivalent adverse effect profiles when compared head-to-head with amitriptyline in neuropathic pain studies 2

Dose-Related Considerations for Minimizing Side Effects

Starting with low doses and slow titration significantly reduces the risk and severity of adverse effects:

• Initial dosing should begin at 10-25 mg at bedtime 1, 3
• Gradual titration by 10-25 mg every 3-7 days allows tolerance to develop and minimizes side effects 1, 3
• Elderly patients require substantially lower starting doses (10 mg/day) and slower titration due to higher plasma concentrations of active metabolites 4, 3
• Maximum safe dose is 100 mg/day for most patients, with doses above this threshold associated with increased cardiac risk 4

Withdrawal Considerations

• Discontinuation syndrome can occur if nortriptyline is stopped abruptly, manifesting primarily as adrenergic hyperactivity 1
• Dose tapering is advisable when stopping treatment to reduce withdrawal symptoms 1

Critical Safety Monitoring

The American Academy of Neurology recommends monitoring for cardiac side effects, particularly in elderly patients or those with pre-existing cardiac conditions, with high-level evidence supporting the importance of ongoing cardiac surveillance 3.