What are the first-line medications for treating neuropathy?

First-Line Medications for Neuropathy

For neuropathic pain, start with either pregabalin (150 mg/day initially, titrating to 300-600 mg/day) or gabapentin (300 mg on day 1,600 mg on day 2, then 900 mg/day, titrating up to 1800-3600 mg/day), as these gabapentinoids are recommended as first-line treatments by multiple major guidelines. 1, 2

Primary First-Line Options

Gabapentinoids (Preferred Initial Choice)

• Pregabalin is FDA-approved for diabetic peripheral neuropathy, postherpetic neuralgia, and spinal cord injury-associated neuropathic pain 3

• Start pregabalin at 150 mg/day in divided doses (75 mg twice daily), increase to 300 mg/day within 1 week, then titrate to 300-600 mg/day based on response 1, 4

• Use "asymmetric dosing" with the larger dose in the evening to optimize tolerability during titration 5

• Pregabalin has predictable absorption, no protein binding, and minimal drug interactions 6

• Higher doses (up to 600 mg/day) produce significantly better pain outcomes—patients who don't respond to 150-300 mg/day often respond when escalated 7

• Gabapentin is equally effective as an alternative gabapentinoid 1, 2

• Start gabapentin at 300 mg on day 1,600 mg on day 2,900 mg on day 3, then titrate to 1800 mg/day minimum for efficacy 4

• Doses up to 3600 mg/day may be needed and should be divided into 2-3 doses daily 1, 4

• Gabapentin requires dose adjustment in renal impairment 1

Antidepressants (Equally Effective First-Line)

• Duloxetine (SNRI) is FDA-approved for diabetic peripheral neuropathy with strong evidence 8

• Start duloxetine at 30 mg once daily for 1 week to minimize nausea, then increase to 60 mg once daily 1, 8

• Maximum dose is 120 mg/day if needed after adequate trial at 60 mg 1, 8

• Duloxetine has fewer anticholinergic effects than TCAs and requires no ECG monitoring 1

• Number needed to treat (NNT) is 5.2 for 60 mg/day in diabetic neuropathy 1

• Tricyclic antidepressants (TCAs) remain highly effective first-line options 1, 2

• Use secondary amines (nortriptyline or desipramine) preferentially over tertiary amines due to fewer anticholinergic effects 1

• Start TCAs at 10 mg/day in older adults, 25 mg/day in younger patients, titrating slowly to 75 mg/day maximum 1, 2

• Obtain screening ECG in patients over 40 years before starting TCAs 1

• Use with extreme caution in cardiac disease, limiting doses to <100 mg/day 1, 2

• TCAs have NNT of 1.5-3.5, among the most effective agents available 2

Topical Agents for Localized Pain

• 5% lidocaine patches are first-line for localized peripheral neuropathic pain, especially with allodynia 1, 2

• Apply daily to painful area with minimal systemic absorption 1

• Particularly useful in older adults due to lack of systemic side effects 1, 2

• 8% capsaicin patches can be considered for localized neuropathic pain, particularly postherpetic neuralgia 1

• Single 30-minute application provides pain relief for at least 12 weeks 1

Treatment Algorithm

1. Assess pain distribution: If localized, consider topical lidocaine or capsaicin first; if diffuse, start with systemic agents 1

2. Choose initial systemic agent based on patient factors:

   • Diabetic peripheral neuropathy: Pregabalin, duloxetine, or gabapentin (all have specific evidence) 2
   • Older adults or cardiac disease: Start with gabapentinoids or duloxetine to avoid TCA risks 1, 2
   • Renal impairment: Reduce gabapentinoid doses; consider TCAs or duloxetine as alternatives 1, 2
   • Younger patients without comorbidities: Any first-line agent is appropriate 1

3. Titrate adequately: Allow at least 2-4 weeks at therapeutic doses before declaring treatment failure 1

   • For pregabalin: Must reach at least 300 mg/day, preferably 450-600 mg/day 7
   • For gabapentin: Must reach at least 1800 mg/day, up to 3600 mg/day 4
   • For duloxetine: Must reach 60 mg/day minimum 1, 8

4. If partial response: Add a second first-line agent from a different class (e.g., combine gabapentinoid with antidepressant) 1, 2

   • Combination of gabapentin and antidepressant may provide better relief than either alone 1

5. If inadequate response to first-line monotherapy and combination: Consider second-line treatments (tramadol) before escalating to third-line opioids 1

Critical Dosing Pitfalls to Avoid

• Do not undertitrate gabapentinoids—many patients are left on subtherapeutic doses of 150-300 mg/day pregabalin or 900 mg/day gabapentin when they would respond to higher doses 7, 4, 5
• Do not abandon pregabalin or gabapentin prematurely—patients who don't respond at lower doses often achieve notable pain relief when escalated to maximum doses 7
• Do not use opioids as first-line therapy—they carry significant morbidity and mortality risks and should be reserved for refractory cases 1, 9
• Do not continue ineffective therapy—if no substantial benefit after adequate trial (≥50% pain reduction), switch to alternative first-line agent rather than continuing 1

Special Population Considerations

• Older adults: Start at lower doses, titrate more slowly, prioritize topical agents, avoid TCAs if possible due to falls risk and anticholinergic effects 1, 2
• Renal impairment: Reduce gabapentin and pregabalin doses proportionally to creatinine clearance 1, 2
• Cardiac disease: Avoid TCAs or use with extreme caution with ECG monitoring; prefer gabapentinoids or duloxetine 1, 2

Refractory Conditions

• Certain neuropathic pain conditions are relatively resistant to first-line treatments: HIV-associated neuropathy, chemotherapy-induced peripheral neuropathy, and lumbosacral radiculopathy 1
• For these conditions, early combination therapy or referral to pain specialist may be warranted 1