What medications are used to treat neuropathic pain?

Medications for Neuropathic Pain

First-line medications for neuropathic pain include gabapentinoids (pregabalin, gabapentin), antidepressants (TCAs, SNRIs), and topical agents (lidocaine, capsaicin), with selection based on pain type, comorbidities, and patient characteristics. 1

First-Line Medications

Gabapentinoids

• Pregabalin and gabapentin are considered first-line treatments for neuropathic pain, acting by binding to the α-2-δ subunit of voltage-gated calcium channels 1
• Pregabalin is FDA-approved for diabetic peripheral neuropathy, postherpetic neuralgia, and neuropathic pain associated with spinal cord injury 2
• Effective pregabalin dosing typically ranges from 150-600 mg/day in two divided doses, while gabapentin dosing ranges from 900-3600 mg/day in 2-3 divided doses 1
• Start with low doses in older adults (pregabalin 25-50 mg/day or gabapentin 100-200 mg/day) to minimize side effects like somnolence, dizziness, and mental clouding 1, 3
• A "low and slow" titration approach is recommended to optimize tolerability, with asymmetric dosing (larger dose in evening) when titrating to higher doses 3

Antidepressants

• Tricyclic antidepressants (TCAs) like nortriptyline and desipramine are effective first-line options 1
• Start TCAs at low doses (10 mg/day) in older adults and titrate slowly to a maximum of 75 mg/day due to anticholinergic side effects and potential cardiac risks 1
• Obtain a screening ECG for patients over 40 years before starting TCAs, and use with caution in patients with cardiac disease 1
• Selective serotonin-norepinephrine reuptake inhibitors (SNRIs) like duloxetine (60-120 mg/day) and venlafaxine (150-225 mg/day) are effective alternatives with fewer anticholinergic effects 1
• Duloxetine has shown consistent efficacy in diabetic peripheral neuropathy, with NNT of 5.2 for 60 mg/day 1

Topical Agents

• Topical treatments should be considered whenever feasible in older adults due to their high safety profile and low systemic absorption 1
• 5% lidocaine patches are effective for localized peripheral neuropathic pain, particularly with allodynia 1
• High-concentration capsaicin has moderate-quality evidence for postherpetic neuralgia 1

Second-Line Medications

Opioids and Tramadol

• Tramadol and opioid analgesics are generally reserved for second-line use but may be appropriate first-line treatments for acute neuropathic pain, cancer-related neuropathic pain, or during titration of first-line medications when prompt pain relief is needed 1
• Tramadol has a dual mechanism (weak μ-opioid agonist and inhibits serotonin/norepinephrine reuptake) with lower abuse potential than strong opioids 1
• Start tramadol at 50 mg once or twice daily, with maximum dose of 400 mg/day; use lower doses in older adults and those with renal/hepatic dysfunction 1
• Monitor for constipation, nausea, and sedation with opioids; implement bowel regimen for chronic use 1

Other Anticonvulsants

• Older anticonvulsants (carbamazepine, phenytoin, valproate) may be effective but have less favorable side effect profiles than newer agents 1
• Oxcarbazepine has shown efficacy in peripheral neuropathic pain 1
• Lamotrigine and lacosamide have shown some efficacy but results are equivocal 1

Special Considerations

Combination Therapy

• When monotherapy provides inadequate relief, combination therapy may be more effective 1
• Combinations of gabapentin/pregabalin with antidepressants or opioids may provide better pain relief at lower doses of each medication 1
• The combination of nortriptyline and gabapentin has shown superior efficacy compared to either medication alone 1

Elderly Patients

• Start with lower doses and titrate more slowly in older adults 1
• Topical agents should be prioritized when feasible due to minimal systemic effects 1
• TCAs should be used cautiously in older adults; limit doses to less than 100 mg/day and obtain ECG screening 1
• Gabapentinoids may require dose adjustment in patients with renal impairment 1

Treatment Algorithm

1. Assess pain type and location (peripheral vs. central, localized vs. diffuse) 1
2. For localized peripheral neuropathic pain: Consider topical lidocaine or capsaicin first 1
3. For diffuse neuropathic pain: Start with either:
   • Gabapentinoid (pregabalin or gabapentin) OR
   • Antidepressant (SNRI like duloxetine or secondary amine TCA) 1
4. If partial response after adequate trial (6-8 weeks), add another first-line agent from a different class 1
5. If inadequate response to first-line agents, switch to or add second-line treatments 1
6. For refractory pain, consider referral to pain specialist 1

Common Pitfalls and Caveats

• Suboptimal dosing is common with gabapentinoids; ensure adequate titration before declaring treatment failure 3
• TCAs can increase risk of sudden cardiac death at doses >100 mg/day; use with caution in patients with cardiovascular disease 1
• Expect and manage side effects proactively; most side effects of gabapentinoids diminish within approximately 10 days 4
• Regular reassessment of pain relief, functional improvement, and side effects is essential 1
• Selective serotonin reuptake inhibitors (SSRIs) have inconsistent evidence for neuropathic pain and are not recommended as first-line therapy 1