What medications are recommended for treating neuropathic pain?

Medications for Neuropathic Pain

First-Line Treatment Options

For neuropathic pain, start with either gabapentinoids (pregabalin or gabapentin) or SNRIs (duloxetine or venlafaxine), with pregabalin and gabapentin being the most strongly recommended first-line agents. 1, 2

Gabapentinoids (Preferred First-Line)

• Pregabalin is FDA-approved for neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, and spinal cord injury 2

  • Start at 75 mg twice daily (150 mg/day), increase to 150 mg twice daily (300 mg/day) within 1 week 3, 2
  • Maximum dose: 300 mg twice daily (600 mg/day) for patients not responding to 300 mg/day after 2-4 weeks 3, 2
  • Doses above 300 mg/day should be reserved only for patients with ongoing pain who tolerate the lower dose, due to dose-dependent adverse effects 2
  • Adjust dose in renal impairment based on creatinine clearance 1, 2

• Gabapentin is an effective alternative to pregabalin 1, 2

  • Start at 100-300 mg at bedtime or three times daily 3
  • Titrate to 900 mg/day over 3 days (300 mg on day 1,600 mg on day 2,900 mg on day 3), then increase by 100-300 mg every 1-7 days as tolerated 3, 4
  • Target dose: 1800 mg/day in divided doses for optimal efficacy 4, 5
  • Maximum dose: 3600 mg/day if needed 3, 4
  • Requires dose reduction in renal insufficiency 3

SNRIs (Alternative First-Line)

• Duloxetine has consistent efficacy in diabetic peripheral neuropathy with NNT of 5.2 1

  • Start at 30 mg once daily for 1 week to minimize nausea, then increase to 60 mg once daily 3, 1
  • Maximum dose: 60 mg twice daily (120 mg/day) if needed 3, 1
  • Allow at least 4 weeks at therapeutic dose to assess efficacy 3, 1
  • No ECG monitoring required, unlike tricyclic antidepressants 1

• Venlafaxine is effective for diabetic peripheral neuropathy and mixed polyneuropathies but not postherpetic neuralgia 3

  • Start at 37.5 mg once or twice daily, increase by 75 mg weekly 3
  • Target dose: 150-225 mg/day 3, 1
  • Requires 2-4 weeks to titrate to efficacious dose 3
  • Use with caution in cardiac disease due to potential blood pressure increases and conduction abnormalities 3
  • Must taper when discontinuing to avoid withdrawal syndrome 3

Tricyclic Antidepressants (First-Line with Cautions)

• Secondary-amine TCAs (nortriptyline or desipramine) are preferred over tertiary amines due to fewer anticholinergic effects 3, 1
  • Start at 25 mg at bedtime (10 mg/day in older adults), increase by 25 mg every 3-7 days as tolerated 3, 1
  • Maximum dose: 150 mg/day (75 mg/day in older adults) 3, 1
  • NNT: 1.5-3.5 for pain relief 6
  • Requires 6-8 weeks for adequate trial, including 2 weeks at maximum tolerated dose 3

Critical safety considerations for TCAs:

• Obtain screening ECG for patients over 40 years before starting 3, 1
• Use with extreme caution in patients with ischemic cardiac disease or ventricular conduction abnormalities 3, 1
• Limit doses to less than 100 mg/day when possible in patients with cardiac disease 3, 1
• Common adverse effects include dry mouth, orthostatic hypotension, constipation, and urinary retention 3, 1

Topical Agents for Localized Peripheral Neuropathic Pain

• 5% lidocaine patches are recommended for localized peripheral neuropathic pain, particularly with allodynia 1, 6

  • Apply daily to painful area with minimal systemic absorption 1
  • Preferred in older adults due to minimal systemic effects 1

• 8% capsaicin patches have moderate-quality evidence for postherpetic neuralgia 1

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

Treatment Algorithm

Step 1: Start with a first-line medication (pregabalin, gabapentin, duloxetine, or TCA) 3, 1

• For localized peripheral neuropathic pain, consider topical lidocaine or capsaicin first 1, 6
• For diffuse neuropathic pain, start with gabapentinoids or antidepressants 1

Step 2: If partial response after adequate trial (2-4 weeks at target dose), add another first-line medication from a different class 3, 1

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

Step 3: If inadequate response (less than 50% pain relief) with tolerable side effects, switch to an alternative first-line medication 3, 1

Step 4: If first-line medications fail alone and in combination, consider second-line treatments 3, 1

Second-Line Treatment Options

• Tramadol has dual mechanism (weak μ-opioid agonist and inhibits serotonin/norepinephrine reuptake) with lower abuse potential than strong opioids 1

  • Start at 50 mg once or twice daily, maximum 400 mg/day 1
  • Use lower doses in older adults and those with renal/hepatic dysfunction 1

• Strong opioids should be reserved for refractory cases only 3, 1

  • Use smallest effective dose 1
  • Not recommended as first-line for long-term management due to risks of pronociception, cognitive impairment, respiratory depression, and addiction 1
  • May consider time-limited trial for moderate to severe pain unresponsive to first-line therapies 1

Special Populations and Considerations

Older adults:

• Start with lower doses and titrate more slowly 1, 6
• Prioritize topical agents due to minimal systemic effects 1, 6
• Start TCAs at 10 mg/day, maximum 75 mg/day 1, 6

Renal impairment:

• Reduce doses of gabapentin and pregabalin based on creatinine clearance 3, 1, 2
• Consider topical lidocaine as first choice 6

Cardiovascular disease:

• Use TCAs with extreme caution, obtain ECG monitoring 1, 6
• Duloxetine preferred over TCAs (no ECG changes) 3, 1
• Venlafaxine requires caution due to blood pressure effects 3

Condition-Specific Considerations

Diabetic peripheral neuropathy: Pregabalin, duloxetine, and gabapentin are specifically recommended 1, 6

Postherpetic neuralgia: All first-line agents effective; topical lidocaine particularly useful 1, 6

Chemotherapy-induced peripheral neuropathy: May be refractory to first-line treatments; nortriptyline, amitriptyline, and gabapentin showed no efficacy in RCTs 1

Lumbosacral radiculopathy: May be relatively refractory to existing first- and second-line medications 1

HIV-associated neuropathy: May be relatively refractory to first-line treatments 1

Common Pitfalls to Avoid

• Inadequate dosing: Ensure adequate trial at target dose for sufficient duration (2-4 weeks for gabapentinoids and SNRIs, 6-8 weeks for TCAs) before declaring treatment failure 3, 1
• Too rapid titration: Start low and go slow, especially with gabapentin and TCAs, to minimize adverse effects 3, 4
• Premature opioid use: Avoid opioids as first-line due to limited efficacy in neuropathic pain and significant risks 1
• Ignoring renal function: Always adjust gabapentinoid doses in renal impairment 3, 1, 2
• Missing cardiac screening: Obtain ECG before starting TCAs in patients over 40 years 3, 1