What is the best treatment for a patient with neuropathy who has not responded to gabapentin (an anticonvulsant)?

Treatment for Neuropathy When Gabapentin Fails

Pregabalin is the best next treatment option when gabapentin does not work, starting at 75 mg at bedtime for one week to minimize side effects, then increasing to 150 mg twice daily (300 mg/day), with potential escalation to 300 mg twice daily (600 mg/day) if needed. 1, 2

Why Pregabalin is the Optimal Choice

• Pregabalin and gabapentin are structurally similar but allergic cross-reactivity is uncommon, meaning failure of gabapentin due to inefficacy does not predict pregabalin failure 1
• Pregabalin offers faster pain relief than gabapentin due to linear pharmacokinetics, allowing more predictable dose titration 3
• FDA-approved specifically for neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, and spinal cord injury 2
• Clinical trials demonstrate significant pain reduction in 66-78% of patients with various neuropathic pain conditions 1

Dosing Strategy to Maximize Success

• Start at 75 mg at bedtime for the first week to minimize nausea and dizziness, which are the most common side effects 1, 2
• Increase to 150 mg twice daily (300 mg/day) after one week as the target therapeutic dose 1, 3
• If inadequate response after 2-4 weeks at 300 mg/day, escalate to 300 mg twice daily (600 mg/day) 1, 3
• Allow at least 2-4 weeks at therapeutic dose before declaring treatment failure 3

Alternative Options If Pregabalin Fails or Is Contraindicated

First-Line Alternatives

• Duloxetine (SNRI): Start at 30 mg once daily for one week, then increase to 60 mg once daily, with maximum dose of 120 mg/day if needed 4, 3

  • Fewer anticholinergic side effects than tricyclic antidepressants and no ECG monitoring required 3
  • Particularly effective for diabetic peripheral neuropathy with number needed to treat (NNT) of 5.2 3
  • Most common side effect is nausea, which is typically mild to moderate and transient 3

• Tricyclic antidepressants (nortriptyline or desipramine): Start at 10-25 mg at bedtime, titrate slowly over 2-4 weeks to 75-150 mg/day 4, 1, 3

  • Secondary amines (nortriptyline, desipramine) preferred over tertiary amines (amitriptyline) due to fewer anticholinergic effects 4, 1, 3
  • NNT of 1.5-3.5, making them highly effective 1
  • Requires screening ECG in patients over 40 years before starting due to cardiac risks 1, 3
  • Contraindicated in recent MI, arrhythmias, heart block, glaucoma, and orthostatic hypotension 4, 1

Topical Treatments for Localized Pain

• 5% lidocaine patches: Apply daily to painful area, with minimal systemic absorption making it excellent for elderly patients 4, 3

  • Particularly effective for well-localized pain with allodynia 1, 3

• 8% capsaicin patch: Single 30-minute application provides pain relief for at least 12 weeks 4

  • Apply 4% lidocaine for 60 minutes before capsaicin to minimize burning sensation 4

Combination Therapy for Partial Response

If pregabalin provides partial but inadequate relief, add duloxetine or a tricyclic antidepressant rather than switching 4, 3

• Combination of gabapentinoid plus antidepressant provides superior pain relief compared to either medication alone by targeting different neurotransmitter systems 3
• This approach allows lower doses of each medication, potentially reducing adverse effects 3
• Continue combination therapy for at least 2-4 weeks before assessing combined efficacy 3

Second-Line Options for Refractory Cases

• Tramadol: Start at 50 mg once or twice daily, maximum 400 mg/day 4, 1, 3

  • Dual mechanism as weak μ-opioid agonist and inhibits serotonin/norepinephrine reuptake 4, 3
  • Avoid combination with SNRIs/SSRIs due to risk of serotonin syndrome 1, 3
  • Lower abuse potential than strong opioids 3

• Strong opioids should be avoided for long-term management due to risks of dependence, cognitive impairment, pronociception, and respiratory depression 4, 1, 3

Critical Pitfalls to Avoid

• Do not assume cross-reactivity between gabapentin and pregabalin without trial - allergic cross-reactivity is uncommon despite structural similarity 1
• Do not start tricyclic antidepressants without cardiac screening in patients over 40 years - undiagnosed conduction abnormalities can lead to fatal arrhythmias 1, 3
• Do not declare treatment failure before allowing at least 2-4 weeks at therapeutic dose for gabapentinoids and antidepressants 3
• Do not combine tramadol with SNRIs or SSRIs due to serious risk of serotonin syndrome 1, 3
• Adjust pregabalin dose in renal impairment (creatinine clearance below 60 ml/min) as it is eliminated unchanged in urine 5

Special Considerations

• Lumbosacral radiculopathy may be relatively refractory to standard neuropathic pain medications compared to other neuropathic pain conditions 3
• Chemotherapy-induced peripheral neuropathy shows limited response to nortriptyline, amitriptyline, or gabapentin in randomized controlled trials 3
• In elderly patients, start with lower doses and titrate more slowly, and prioritize topical agents due to minimal systemic effects 3
• Monitor for peripheral edema and weight gain with pregabalin, particularly in elderly patients 2, 5