How should I treat a patient with neuropathic pain?

Treatment of Neuropathic Pain

Start with either duloxetine 60 mg daily or pregabalin 150-300 mg daily as first-line therapy, choosing duloxetine if the patient has comorbid depression or anxiety, and pregabalin if rapid pain relief is the priority. 1

First-Line Pharmacological Options

Gabapentinoids

• Pregabalin is FDA-approved for neuropathic pain management and offers faster pain relief than gabapentin due to linear pharmacokinetics 1, 2
• Start at 75 mg twice daily (150 mg/day total), increase to 150 mg twice daily after 1-2 weeks, with maximum dose of 300 mg twice daily (600 mg/day) 1
• Pregabalin and gabapentin work by binding to the α-2-δ subunit of voltage-gated calcium channels 1
• Gabapentin is an alternative to pregabalin, starting at 100-300 mg at bedtime and titrating to 1800-3600 mg/day in three divided doses over 3-8 weeks 1
• The number needed to treat (NNT) for gabapentinoids is 5.9-8.0 in neuropathic pain conditions 1

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

• Duloxetine is FDA-approved for diabetic peripheral neuropathy and provides moderate clinical benefit with 59% pain reduction versus 38% with placebo in trials of 231 patients 3, 1, 4
• Start at 30 mg once daily for the first week to minimize nausea, then increase to target dose of 60 mg once daily 3, 1, 4
• Maximum dose can be increased to 120 mg/day if needed after 4 weeks at therapeutic dose 1, 4
• Duloxetine has fewer anticholinergic side effects compared to tricyclic antidepressants and requires no ECG monitoring 1
• Venlafaxine (150-225 mg/day) is an alternative SNRI with proven efficacy in small randomized trials 3, 1

Tricyclic Antidepressants (TCAs)

• Nortriptyline or desipramine are preferred over tertiary amines (amitriptyline) due to fewer anticholinergic effects 3, 1
• Start at 10-25 mg at bedtime and titrate slowly to 75-150 mg/day over 2-4 weeks 3, 1
• The NNT for TCAs is 1.5-3.5, making them highly effective 1
• Obtain screening ECG in patients over 40 years before starting TCAs and use with caution in patients with cardiac disease 3, 1
• Common side effects include dry mouth, constipation, sedation, orthostatic hypotension, and urinary retention 3, 1
• Contraindications include recent MI, arrhythmias, and heart block 1

Topical Agents for Localized Pain

• 5% lidocaine patches are recommended for well-localized peripheral neuropathic pain with allodynia, applied daily to painful areas with minimal systemic absorption 3, 1
• 8% capsaicin patches provide pain relief lasting up to 90 days with a single 30-minute application 3, 1
• 1% menthol cream applied twice daily to the affected area and corresponding dermatomal region shows improvement in pain scores after 4-6 weeks 3, 1
• Topical agents are particularly valuable in elderly patients and those on multiple medications due to minimal systemic effects 1

Combination Therapy for Partial Response

If first-line monotherapy provides less than 50% pain reduction after 2-4 weeks at therapeutic dose, add a medication from a different class rather than switching. 1

• Combination of gabapentinoid plus antidepressant (duloxetine or nortriptyline) provides superior pain relief compared to either alone by targeting different neurotransmitter systems 1
• This approach allows for lower doses of each medication, potentially reducing adverse effects 1
• Continue combination therapy for at least 2-4 weeks before assessing combined efficacy 1

Second-Line Options

Tramadol

• Use tramadol only after documented failure of first-line agents 1
• Start at 50 mg once or twice daily, with maximum dose of 400 mg/day 3, 1
• Tramadol has dual mechanism as weak μ-opioid agonist plus serotonin/norepinephrine reuptake inhibition 3, 1
• Exercise extreme caution when combining tramadol with SNRIs/SSRIs due to risk of serotonin syndrome 1
• Use lower doses in older adults and those with renal/hepatic dysfunction 1

Strong Opioids (Reserve Option Only)

• Neuropathic pain is generally less responsive to opioids than other pain pathophysiologies 3, 1, 5
• Reserve strong opioids for acute neuropathic pain, cancer-related pain, or severe episodic exacerbations only 3, 1
• Use at the smallest effective dose due to risks of dependence, cognitive impairment, respiratory depression, and pronociception 3, 1, 5

Condition-Specific Considerations

Chemotherapy-Induced Peripheral Neuropathy (CIPN)

• Duloxetine is the only agent with large randomized trial evidence for CIPN, showing more pronounced effect with platinum-based therapies than taxanes 3, 1
• Nortriptyline, amitriptyline, and gabapentin have shown no evidence of efficacy in randomized controlled trials for CIPN 1
• Physical exercise and functional training reduce CIPN symptoms when combined with medication 3, 1

Lumbosacral Radiculopathy

• This condition is notably more refractory to standard neuropathic pain medications compared to other neuropathic pain conditions 1
• Recent trials of nortriptyline, morphine, pregabalin, and their combinations have shown limited efficacy 1
• Consider early referral to pain specialist for interventional approaches such as spinal cord stimulation 1

Diabetic Peripheral Neuropathy

• Pregabalin, duloxetine, and gabapentin are specifically recommended by the American Diabetes Association 1
• Duloxetine has NNT of 5.2 for 60 mg/day in diabetic peripheral neuropathy 1

Critical Treatment Timeline

• Allow at least 2-4 weeks at therapeutic dose before declaring treatment failure for gabapentinoids, SNRIs, and TCAs 3, 1
• Ensure target doses are reached before switching medications 1
• Begin treatment as soon as possible after onset of neuropathic pain, as early intervention improves outcomes 3, 1

Non-Pharmacological Interventions

• Cardio-exercise for at least 30 minutes twice weekly provides anti-inflammatory effects and improves pain perception through inhibition of pain pathways 1
• Physical therapy and functional training should begin at the latest with onset of manifest neuropathic pain, but can start earlier when potentially neurotoxic treatment is initiated 3, 1
• Coordination, sensorimotor, and fine motor function training reduce symptoms 3

When to Refer to Pain Specialist

• Inadequate response to combination therapy of first-line agents (duloxetine plus pregabalin) after 8 weeks at therapeutic doses 1
• Severe functional impairment despite optimal medical management 1
• Consideration needed for interventional approaches such as spinal cord stimulation, nerve blocks, or neuroablative procedures 3, 1

Common Pitfalls to Avoid

• Never declare treatment failure before allowing adequate trial duration (2-4 weeks) at therapeutic doses 3, 1
• Avoid using gabapentin or pregabalin "as needed" - these medications require scheduled daily dosing at therapeutic levels to achieve efficacy 1
• Do not combine tramadol with SNRIs/SSRIs without careful monitoring for serotonin syndrome 1
• Avoid strong opioids for long-term management due to risks of dependence and limited efficacy in neuropathic pain 3, 1, 5
• Do not use NSAIDs or acetaminophen as monotherapy - neuropathic pain requires specific neuropathic pain medications 3