What are the recommended first‑line pharmacologic treatments and dosing for neuropathic (nerve) pain?

First-Line Pharmacologic Treatments for Neuropathic Pain

Start with either gabapentin (titrated to 1800-3600 mg/day in divided doses) or duloxetine (60 mg once daily), choosing based on patient age, cardiac history, and pain distribution. 1

Treatment Selection Algorithm

For Most Adult Patients (Age <65, No Cardiac Disease)

Begin with duloxetine 30 mg once daily for 1 week, then increase to 60 mg once daily. 1 This approach minimizes nausea while achieving therapeutic effect. Maximum dose is 120 mg/day if needed after 2-4 weeks at 60 mg. 1

• Duloxetine has fewer side effects than tricyclic antidepressants, requires no ECG monitoring, and works across multiple neuropathic pain conditions with a number needed to treat (NNT) of 5.2 for diabetic neuropathy. 1
• Common side effects include nausea (minimized by starting at 30 mg), somnolence, dizziness, constipation, and dry mouth—all typically mild and transient. 1
• Allow at least 2-4 weeks at therapeutic dose (60 mg) before declaring treatment failure. 1

For Older Adults (Age ≥65) or Patients with Cardiac Disease

Begin with gabapentin 100-300 mg at bedtime on day 1, increase to 600 mg/day on day 2, then 900 mg/day on day 3. 1, 2 Titrate over 3-8 weeks to a target of 1800-3600 mg/day in three divided doses. 1, 2

• Gabapentin and pregabalin are first-line recommendations from the American Geriatrics Society due to minimal cardiac risk and no anticholinergic effects. 1
• Doses of 1800-3600 mg/day are required for efficacy; lower doses are ineffective. 2 The NNT is 5.9-8.0 at therapeutic doses. 1
• Common side effects include dizziness, somnolence, and peripheral edema. 3
• Adjust dose in renal impairment per creatinine clearance. 1

Alternative First-Line: Pregabalin (When Faster Titration Needed)

Start pregabalin 75 mg twice daily (or 50 mg three times daily), increase to 150 mg/day after 1 week, then to 300 mg/day in divided doses. 4 Maximum effective dose is 600 mg/day, though most patients achieve control at 150-300 mg/day. 1, 4

• Pregabalin offers faster pain relief than gabapentin due to linear pharmacokinetics and requires shorter titration. 1
• Taper gradually over minimum 1 week when discontinuing to avoid withdrawal. 4
• Monitor for peripheral edema, especially in patients with heart failure. 1

For Localized Peripheral Neuropathic Pain with Allodynia

Apply 5% lidocaine patches daily to the painful area. 1 This is particularly effective in postherpetic neuralgia with an NNT of 2, minimal systemic absorption, and excellent tolerability in elderly patients. 1

• Alternative: 8% capsaicin patch provides 12 weeks of relief after a single 30-minute application. 1

Second-Line: Tricyclic Antidepressants (When First-Line Agents Fail or Are Contraindicated)

Use nortriptyline or desipramine (secondary amines) rather than amitriptyline. 5, 1 Start at 10-25 mg at bedtime and titrate slowly by 10 mg weekly to 75-150 mg/day over 2-4 weeks. 1

• TCAs have the strongest efficacy data with NNT of 1.4-2.5 in optimal doses, superior to gabapentinoids. 5, 6
• Obtain screening ECG in patients over age 40 before starting. 1 Contraindicated in recent MI, arrhythmias, and heart block. 1
• Anticholinergic effects (dry mouth, constipation, urinary retention, orthostatic hypotension) are common but reduced with secondary amines and slow titration. 5, 1
• Allow 6-8 weeks for adequate trial, including 2 weeks at highest tolerated dose. 3

Combination Therapy for Partial Response

If a single first-line agent provides partial relief (pain reduction <50%), add a medication from a different class rather than switching. 5, 1

• Combining a gabapentinoid with an antidepressant (duloxetine or nortriptyline) targets different pain pathways and provides superior analgesia compared to either alone. 1
• This allows lower doses of each medication, potentially reducing side effects. 1
• Maintain therapeutic doses of both agents for 2-4 weeks before assessing combined efficacy. 1

Third-Line: Tramadol (After Documented Failure of First-Line Agents)

Start tramadol 50 mg once or twice daily, maximum 400 mg/day. 1 It combines weak μ-opioid agonism with serotonin-norepinephrine reuptake inhibition. 1

• Caution: Risk of serotonin syndrome when combined with SNRIs/SSRIs. 1
• Use lower doses in older adults and those with renal/hepatic dysfunction. 1

Critical Treatment Principles

• Define treatment success as pain reduction to ≤3/10 with tolerable side effects. 5
• Never use strong opioids as first-line therapy for chronic neuropathic pain due to risks of pronociception, cognitive impairment, respiratory depression, and addiction. 1 Reserve for acute neuropathic pain, cancer-related pain, or severe episodic exacerbations only. 5, 1
• Certain neuropathic pain conditions are relatively refractory to standard treatments: HIV-associated neuropathy, chemotherapy-induced neuropathy, and lumbosacral radiculopathy show limited response to first-line agents. 1
• Incorporate physical exercise and functional training as adjunctive therapy—cardio exercise ≥30 minutes twice weekly provides anti-inflammatory effects and improves pain perception. 1

Common Pitfalls to Avoid

• Stopping gabapentinoids before reaching therapeutic doses (1800-3600 mg/day) or adequate trial duration (2-4 weeks). 1, 2 Subtherapeutic dosing is a primary cause of treatment failure.
• Using tertiary amine TCAs (amitriptyline) instead of secondary amines (nortriptyline, desipramine), which significantly increases anticholinergic burden. 5, 1
• Starting TCAs without cardiac screening in patients over 40, risking undetected arrhythmias or conduction abnormalities. 1
• Combining tramadol with SNRIs/SSRIs without monitoring for serotonin syndrome. 1
• Prescribing opioids before exhausting first-line and combination therapy options. 1