What are the first line treatments for neuropathic pain?

First-Line Treatments for Neuropathic Pain

The first-line pharmacological treatments for neuropathic pain are gabapentinoids (pregabalin or gabapentin), serotonin-norepinephrine reuptake inhibitors (SNRIs) like duloxetine, and tricyclic antidepressants (TCAs), with the choice guided by patient age, comorbidities, and pain characteristics. 1

Primary Treatment Options

Gabapentinoids

• Pregabalin is FDA-approved for neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, and spinal cord injury 2
• Start pregabalin at 150 mg/day in 2-3 divided doses, increase to 300 mg/day after 1-2 weeks, with a maximum dose of 600 mg/day 1
• Pregabalin offers faster pain relief than gabapentin due to linear pharmacokinetics 1
• Gabapentin should be started at 100-300 mg at bedtime, gradually increasing to 900-3600 mg/day in 2-3 divided doses 1
• Gabapentin is particularly effective for HIV-associated neuropathic pain, with dosing titrated to 2400 mg/day 3, 1
• Both agents require dose reduction in renal impairment 1, 4
• Common side effects include somnolence, dizziness, peripheral edema, and weight gain 3, 1

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

• Duloxetine is FDA-approved for diabetic peripheral neuropathic pain at 60-120 mg/day 5
• Start duloxetine at 30 mg once daily for the first week, then increase to 60 mg once daily 1
• Maximum dose can be increased to 60 mg twice daily (120 mg/day) if needed 1
• Duloxetine has a number needed to treat (NNT) of 5.2 for diabetic peripheral neuropathy 1
• The efficacy of duloxetine for neuropathic pain is independent of its antidepressant effects 1
• Common side effects include nausea (minimized by starting at 30 mg), somnolence, dizziness, constipation, and dry mouth 1, 4
• Contraindicated in hepatic disease 3

Tricyclic Antidepressants (TCAs)

• Secondary amine TCAs (nortriptyline, desipramine) are preferred over tertiary amines due to fewer anticholinergic side effects 1, 4
• Start at 10-25 mg at bedtime in older adults, titrating slowly to 75-150 mg/day over 2-4 weeks 1, 4
• TCAs have an NNT of 1.5-3.5, making them highly effective 1, 4
• Obtain a screening ECG for patients over 40 years before starting TCAs 1, 4
• Contraindications include recent myocardial infarction, arrhythmias, heart block, glaucoma, orthostatic hypotension, and cardiovascular disease 3, 1
• Limit doses to less than 100 mg/day in patients with cardiac disease 1, 4
• Side effects include dry mouth, orthostatic hypotension, constipation, urinary retention, and cardiac toxicity 3, 1, 4

Topical Agents for Localized Pain

• 5% lidocaine patches are recommended for well-localized peripheral neuropathic pain with allodynia, particularly in elderly patients due to minimal systemic absorption 1, 4
• Apply daily to the painful area 1
• 8% capsaicin patches provide pain relief for at least 12 weeks after a single 30-minute application 1
• High-concentration capsaicin has moderate-quality evidence for postherpetic neuralgia 1

Treatment Algorithm

Initial Selection Strategy

• For diffuse neuropathic pain, start with either a gabapentinoid or an antidepressant (SNRI or TCA) 1
• For localized peripheral neuropathic pain with allodynia, consider topical lidocaine or capsaicin first 1, 4
• In older adults (>65 years), prioritize gabapentinoids or topical agents due to better tolerability 1, 4
• In patients with cardiovascular disease, avoid TCAs and use gabapentinoids or duloxetine 3, 1, 4
• In patients with peripheral edema or unsteadiness/falls, avoid gabapentinoids and TCAs respectively 3
• For diabetic peripheral neuropathy specifically, pregabalin, duloxetine, and gabapentin are all equally recommended 1, 4

Dose Titration and Assessment

• Allow at least 2-4 weeks at therapeutic doses before assessing efficacy 1
• If substantial pain relief (≥50% reduction) is achieved with tolerable side effects, continue treatment 1
• If partial pain relief is achieved, add another first-line agent from a different class rather than switching 1, 4
• The combination of gabapentin/pregabalin with an antidepressant (duloxetine or TCA) provides superior pain relief compared to either medication alone 1

Special Populations and Refractory Cases

• Start with lower doses and titrate more slowly in older adults 1, 4
• Lumbosacral radiculopathy, HIV-associated neuropathy, and chemotherapy-induced peripheral neuropathy may be relatively refractory to first-line treatments 1, 6
• Chemotherapy-induced peripheral neuropathy has shown no evidence of efficacy with nortriptyline, amitriptyline, or gabapentin in randomized controlled trials 1

Common Pitfalls to Avoid

• Do not use opioids as first-line agents for chronic neuropathic pain due to risks of pronociception, cognitive impairment, respiratory depression, and addiction 1, 6
• Do not continue ineffective therapy—if no response after adequate trial, switch to alternative first-line agent 1
• Do not underdose medications; ensure therapeutic doses are reached before declaring treatment failure 1
• Do not overlook contraindications: screen for cardiac disease before TCAs, check renal function before gabapentinoids, and assess for hepatic disease before duloxetine 3, 1, 4
• Avoid combining SNRIs with tramadol due to risk of serotonin syndrome 1