What are the first-line medications for neuropathic pain?

First-Line Medications for Neuropathic Pain

Start with either gabapentinoids (gabapentin or pregabalin) or antidepressants (duloxetine or tricyclic antidepressants) as first-line therapy, with the choice depending on patient-specific factors including age, comorbidities, and pain location. 1

Gabapentinoids (Preferred for Most Patients)

Pregabalin is FDA-approved for neuropathic pain and offers the most straightforward dosing 2:

• Start at 150 mg/day in 2-3 divided doses 3
• Increase to 300 mg/day after 1-2 weeks 3
• Maximum dose 600 mg/day, though 300 mg/day is often as effective with fewer side effects 3
• Provides faster pain relief than gabapentin due to linear pharmacokinetics 3
• Dose reduction required in renal impairment 1

Gabapentin is an equally effective alternative 1:

• Start at 300 mg on day 1,600 mg on day 2, then 900 mg/day on day 3 4
• Titrate to 1800 mg/day in divided doses for optimal efficacy 4, 5
• May require up to 3600 mg/day in some patients 4
• Takes 2 months or more for adequate trial 3
• More complex titration but less expensive than pregabalin 3

Expected outcomes with gabapentinoids: In postherpetic neuralgia and diabetic neuropathy, 32-38% of patients achieve at least 50% pain reduction versus 17-21% with placebo (NNT 5.9-6.7) 5, 1

Antidepressants

Duloxetine (SNRI) offers fewer side effects than tricyclics 1:

• Start at 30 mg once daily for one week, then increase to 60 mg daily 1
• Maximum dose 120 mg/day if needed 1
• FDA-approved for diabetic peripheral neuropathy with NNT of 5.2 1
• No ECG monitoring required 1
• Most common side effect is transient nausea; take with food to minimize 6

Tricyclic Antidepressants (TCAs) remain highly effective (NNT 1.5-3.5) 6:

• Use secondary amines (nortriptyline or desipramine) over tertiary amines due to fewer anticholinergic effects 1, 3
• Start at 10-25 mg at bedtime 1
• Titrate slowly to 75-150 mg/day over 2-4 weeks 1
• Obtain screening ECG in patients over 40 years before starting 1
• Limit to <100 mg/day in patients with cardiac disease 1
• Contraindications: recent MI, arrhythmias, heart block 3

Topical Agents (For Localized Peripheral Neuropathic Pain)

5% Lidocaine patches are ideal for well-localized pain with allodynia 3, 1:

• Apply daily to painful area 1
• Minimal systemic absorption makes this excellent for elderly patients 3
• Particularly effective in postherpetic neuralgia 3
• Unlikely to benefit central neuropathic pain 3

8% Capsaicin patches provide prolonged relief 1:

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

Treatment Algorithm

For diffuse neuropathic pain 1:

1. Start with pregabalin (easier titration) or gabapentin (less expensive)
2. If partial response after 2-4 weeks at therapeutic dose, add duloxetine or nortriptyline from different class 1
3. Combination therapy (gabapentinoid + antidepressant) provides superior pain relief by targeting different neurotransmitter systems 1

For localized peripheral neuropathic pain 1:

1. Start with topical lidocaine patches
2. Add or switch to gabapentinoid or antidepressant if inadequate response

For older adults 1, 6:

• Prioritize topical agents first due to minimal systemic effects
• If systemic therapy needed, start with lower doses and titrate slowly
• Gabapentinoids preferred over TCAs due to anticholinergic risks

For diabetic peripheral neuropathy specifically: Pregabalin, duloxetine, and gabapentin are all specifically recommended 1

Second-Line Options (Reserve for First-Line Failures)

Tramadol 3, 1:

• Start at 50 mg once or twice daily
• Maximum 400 mg/day
• Dual mechanism: weak μ-opioid agonist plus serotonin/norepinephrine reuptake inhibition
• Lower abuse potential than strong opioids
• Caution: Can cause serotonin syndrome when combined with SNRIs/SSRIs 3
• Reduce dose in elderly and those with renal/hepatic dysfunction 3

Strong opioids should be avoided for long-term management due to risks of dependence, cognitive impairment, and pronociception 1. Consider only for acute neuropathic pain, cancer-related pain, or severe episodic exacerbations 3.

Critical Pitfalls to Avoid

• Allow adequate treatment duration: All agents require at least 2-4 weeks at therapeutic dose before assessing efficacy 1
• Certain conditions are more refractory: HIV-associated neuropathy, chemotherapy-induced neuropathy, and lumbosacral radiculopathy respond poorly to standard first-line treatments 1
• Avoid premature opioid use: This increases risk of dependence without superior efficacy compared to first-line agents 1
• Don't forget non-pharmacological measures: Physical therapy and exercise provide anti-inflammatory effects and should be added to medication 1