What are the recommended first-line and second-line treatments for neuropathic pain?

First-Line and Second-Line Treatments for Neuropathic Pain

Start with either pregabalin (150 mg/day, titrating to 300-600 mg/day) or gabapentin (900-3600 mg/day in divided doses) as first-line therapy, with duloxetine (60-120 mg/day) as an equally effective alternative, particularly for diabetic peripheral neuropathy. 1, 2

First-Line Pharmacological Options

Gabapentinoids (Preferred Initial Choice)

Pregabalin:

• Begin at 75 mg twice daily (150 mg/day total) 2, 3
• Increase to 150 mg twice daily (300 mg/day) within 1 week based on response 2, 3
• For inadequate response after 2-4 weeks at 300 mg/day, escalate to 300 mg twice daily (600 mg/day maximum) 1, 3
• Higher doses demonstrate significantly greater pain reduction—many patients who fail at lower doses will respond when escalated 4
• Number needed to treat (NNT) of 5.2 for diabetic peripheral neuropathy 1

Gabapentin:

• Start at 100-300 mg at bedtime on day 1, increase to 300 mg twice daily on day 2, then 300 mg three times daily (900 mg/day) on day 3 1, 5
• Target dose is 1800 mg/day in divided doses for optimal efficacy 2, 5
• May titrate up to 3600 mg/day if needed and tolerated 1, 5
• Adjust dose in renal impairment based on creatinine clearance 1, 2

SNRIs (Equally Effective Alternative)

Duloxetine:

• Start at 30 mg once daily for 1 week to minimize nausea 1, 2
• Increase to 60 mg once daily (target dose) 1, 2, 6
• May escalate to 120 mg/day if needed 1
• Particularly effective for diabetic peripheral neuropathy with NNT of 5.2 1
• Major advantage: no ECG monitoring required, unlike TCAs 1
• Fewer anticholinergic side effects compared to tricyclic antidepressants 1

Venlafaxine:

• Start at 37.5 mg once or twice daily 2
• Target dose 150-225 mg/day 1, 2
• Effective for diabetic peripheral neuropathy but NOT postherpetic neuralgia 2

Tricyclic Antidepressants (TCAs)

Nortriptyline or Desipramine (secondary amines preferred):

• Start at 10-25 mg at bedtime 1
• Titrate slowly over 2-4 weeks to 75-150 mg/day 1
• Critical caveat: obtain screening ECG in patients over 40 years before initiating 1, 2
• Use with extreme caution in cardiac disease; limit to <100 mg/day 1, 2
• Allow 6-8 weeks at therapeutic dose before declaring treatment failure 2
• Secondary amines have fewer anticholinergic effects than tertiary amines (amitriptyline) 1

Topical Agents (First-Line for Localized Pain)

5% Lidocaine Patches:

• Apply daily to painful area 1, 2
• Particularly useful for localized peripheral neuropathic pain with allodynia 1, 2
• Minimal systemic absorption—ideal for older adults and those with renal impairment 1, 2

8% Capsaicin Patches:

• Single 30-minute application provides relief for at least 12 weeks 1, 2
• Moderate-quality evidence for postherpetic neuralgia 1, 2

Second-Line Treatments

Tramadol:

• Start at 50 mg once or twice daily 1
• Maximum 400 mg/day 1
• Dual mechanism: weak μ-opioid agonist plus serotonin/norepinephrine reuptake inhibition 1
• Lower abuse potential than strong opioids 1
• Use lower doses in older adults and those with renal/hepatic dysfunction 1

Combination Therapy:

• If partial response to first-line monotherapy, add another first-line agent from a different class 1
• Gabapentin/pregabalin plus duloxetine or TCA provides superior pain relief compared to either alone 1
• Combination allows lower doses of each medication, potentially reducing adverse effects 1

Treatment Algorithm

1. Assess pain distribution:

   • Localized peripheral neuropathic pain → Start with topical lidocaine or capsaicin 1
   • Diffuse neuropathic pain → Start with gabapentinoid or SNRI 1

2. Initiate first-line therapy:

   • Use "low and slow" titration to minimize side effects 7
   • Allow adequate trial: 2-4 weeks at therapeutic dose for gabapentinoids/SNRIs, 6-8 weeks for TCAs 2

3. If partial response (≥30% but <50% pain reduction):

   • Add second first-line agent from different class 1
   • Consider combination gabapentinoid + antidepressant 1

4. If inadequate response to first-line monotherapy and combination:

   • Switch to tramadol 1
   • Consider referral to pain specialist before escalating to strong opioids 8

Condition-Specific Considerations

Diabetic Peripheral Neuropathy:

• Pregabalin, duloxetine, and gabapentin are all specifically recommended 1, 2

Postherpetic Neuralgia:

• All first-line agents effective; topical lidocaine particularly useful 2

Chemotherapy-Induced Peripheral Neuropathy:

• Often refractory to standard treatments 1, 2
• Nortriptyline, amitriptyline, and gabapentin showed no efficacy in RCTs 1, 2

Lumbosacral Radiculopathy:

• Notably more refractory to first and second-line medications 1, 8
• May require earlier referral to pain specialist 8

Critical Pitfalls to Avoid

Inadequate dosing:

• Most common error—ensure titration to target therapeutic doses before declaring failure 2
• Many patients who don't respond to pregabalin 150-300 mg/day will respond at 450-600 mg/day 4

Too rapid titration:

• Causes unnecessary side effects and premature discontinuation 7
• Use "asymmetric dosing" with larger evening dose when titrating to higher doses 7

Premature opioid use:

• Never use opioids as first-line due to risks of pronociception, cognitive impairment, respiratory depression, and addiction 1, 8
• Reserve for refractory cases after documented failure of first-line combinations 8

Missing renal function assessment:

• Always adjust gabapentinoid doses in renal impairment 1, 2
• Topical lidocaine is first choice in severe renal impairment 2

Ignoring cardiac screening for TCAs:

• Mandatory ECG in patients >40 years before starting TCAs 1, 2
• Avoid in patients with cardiac conduction abnormalities 1

Special Populations

Older Adults:

• Start with lower doses and titrate more slowly 1, 2
• Prioritize topical agents due to minimal systemic effects 1, 2
• Limit TCA doses to <100 mg/day 1

Renal Impairment:

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

Cardiovascular Disease:

• Duloxetine preferred over TCAs 2
• If TCA necessary, obtain ECG monitoring and use extreme caution 1, 2