What is the recommended treatment for neuropathic pain in a patient who did not tolerate gabapentin, Lyrica (pregabalin), or Cymbalta (duloxetine)?

Nortriptyline for Neuropathic Pain After Gabapentin, Pregabalin, and Duloxetine Intolerance

Nortriptyline is an appropriate and evidence-based choice for neuropathic pain in patients who have not tolerated gabapentin, pregabalin, or duloxetine, as tricyclic antidepressants (TCAs) are recommended as first-line therapy alongside these agents. 1

Why Nortriptyline is a Reasonable Option

• Nortriptyline is specifically recommended as a first-line treatment for neuropathic pain by the American College of Physicians, with established efficacy comparable to gabapentinoids and SNRIs 1

• Secondary amine TCAs like nortriptyline are preferred over tertiary amines (such as amitriptyline) because they produce fewer anticholinergic side effects while maintaining similar efficacy 1

• Nortriptyline has a strong evidence base with a number needed to treat (NNT) of 1.5-3.5 for achieving at least moderate pain relief in neuropathic pain conditions 1

• The combination of nortriptyline with gabapentin has demonstrated synergistic effects in preclinical models, suggesting that if the patient develops tolerance to nortriptyline alone, combination therapy could be reconsidered 2

Dosing Protocol

• Start nortriptyline at 10-25 mg at bedtime and titrate slowly over 2-4 weeks to a target dose of 75-150 mg/day 1

• In older adults, the American Academy of Neurology recommends starting at 10 mg/day and titrating more slowly to a maximum of 75 mg/day due to increased sensitivity to anticholinergic effects and cardiac risks 1

• Allow at least 2-4 weeks at the therapeutic dose before assessing efficacy, as adequate trial duration is essential 1

Mandatory Pre-Treatment Screening

• Obtain a screening ECG for patients over 40 years of age before initiating nortriptyline, as recommended by the American Heart Association 1

• Nortriptyline is contraindicated in patients with recent myocardial infarction, arrhythmias, or heart block 1

• Use with caution in patients with cardiac disease, limiting doses to less than 100 mg/day when possible 1

Common Side Effects to Anticipate

• Anticholinergic effects are the most common adverse events, including dry mouth, orthostatic hypotension, constipation, and urinary retention 1

• Cardiac toxicity is a concern, requiring vigilance in patients with underlying cardiac disease 1

• The number needed to harm (NNH) for major adverse effects leading to withdrawal is 16, while the NNH for minor adverse effects is 4.6 3

Alternative and Adjunctive Options if Nortriptyline Fails

• Topical lidocaine 5% patches are recommended for localized peripheral neuropathic pain, particularly when allodynia is present, with minimal systemic absorption making them excellent for elderly patients 1

• Capsaicin 8% patches can provide pain relief for at least 12 weeks with a single 30-minute application, though erythema and pain are common side effects 4

• Tramadol should be considered as a second-line option after documented failure of first-line agents, starting at 50 mg once or twice daily with a maximum of 400 mg/day 1

• Combination therapy with a topical agent plus nortriptyline may provide superior pain relief by targeting different pain mechanisms 1

Critical Pitfalls to Avoid

• Do not dismiss nortriptyline prematurely—many patients discontinue TCAs before reaching therapeutic doses or adequate trial duration 1

• Avoid rapid titration, which significantly increases the risk of adverse effects, particularly in elderly patients 5

• Do not use strong opioids as first-line therapy due to risks of dependence, cognitive impairment, respiratory depression, and pronociception 1

• Be aware that lumbosacral radiculopathy may be relatively refractory to standard neuropathic pain medications, including nortriptyline, compared to other neuropathic pain conditions 1

When to Refer

• Consider referral to a pain specialist or multidisciplinary pain center if trials of first-line medications alone and in combination fail to provide adequate relief 1

• Physical therapy and exercise should be incorporated alongside pharmacotherapy, as cardio-exercise for at least 30 minutes twice weekly can provide anti-inflammatory effects and improve pain perception 1