What are the treatment options for neuropathic pain?

Treatment Options for Neuropathic Pain

Start with gabapentinoids (gabapentin or pregabalin) or SNRIs (duloxetine) as first-line therapy, with the choice guided by pain distribution (topical agents for localized pain), patient age, and comorbidities. 1, 2

First-Line Pharmacological Treatments

Gabapentinoids

• Gabapentin should be initiated at 300 mg on day 1, increased to 600 mg on day 2, then 900 mg/day on day 3, with further titration to 1800-3600 mg/day in divided doses based on response and tolerability. 1
• Pregabalin offers faster pain relief due to linear pharmacokinetics, starting at 150 mg/day in 2-3 divided doses, increasing to 300 mg/day after 1 week, with a maximum of 600 mg/day. 1, 3
• Both gabapentinoids bind to the α-2-δ subunit of voltage-gated calcium channels, inhibiting calcium currents and decreasing excitatory transmitter release. 2, 4

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

• Duloxetine should be started at 30 mg once daily for 1 week to minimize nausea, then increased to the target dose of 60 mg once daily, with a maximum of 120 mg/day if needed. 1, 2
• Duloxetine has a number needed to treat (NNT) of 5.2 for neuropathic pain and demonstrates sustained efficacy for up to one year. 1, 2
• Venlafaxine is an alternative SNRI at 150-225 mg/day, though duloxetine has more robust evidence. 2

Tricyclic Antidepressants (TCAs)

• Secondary amine TCAs (nortriptyline, desipramine) are preferred over tertiary amines due to fewer anticholinergic effects, starting at 10-25 mg at bedtime and titrating slowly to 75-150 mg/day over 2-4 weeks. 2, 5
• TCAs have an NNT of 1.5-3.5, making them highly effective, but require screening ECG in patients over 40 years before initiation due to cardiac risks. 2
• Contraindications include recent myocardial infarction, arrhythmias, and heart block; doses should be limited to less than 100 mg/day when possible in older adults. 2

Topical Agents for Localized Pain

• 5% lidocaine patches should be applied daily to well-localized painful areas with allodynia, offering minimal systemic absorption and excellent tolerability in elderly patients. 1, 2
• High-concentration 8% capsaicin patches can provide pain relief for at least 12 weeks after a single 30-minute application for localized peripheral neuropathic pain. 2, 6
• 1% menthol cream applied twice daily to the affected area and corresponding dermatomal region provides additional symptomatic relief. 1

Second-Line Treatments

Combination Therapy

• If first-line monotherapy provides only partial relief after 2-4 weeks at therapeutic doses, add another first-line agent from a different class (e.g., gabapentinoid plus SNRI or TCA) rather than switching. 1, 2
• Combination therapy of gabapentin/pregabalin with an antidepressant provides superior pain relief compared to either medication alone by targeting different neurotransmitter systems. 5, 2
• The combination of gabapentin and extended-release morphine required lower dosages of both medications and resulted in better pain relief than either alone in patients with postherpetic neuralgia or painful diabetic neuropathy. 5

Tramadol

• Tramadol should only be considered after documented failure of first-line agents, starting at 50 mg once or twice daily, with a maximum of 400 mg/day in 2-3 divided doses. 1, 2
• Tramadol has dual mechanisms as a weak μ-opioid agonist and inhibits serotonin/norepinephrine reuptake, with lower abuse potential than strong opioids. 2
• Exercise caution when combining tramadol with SNRIs/SSRIs due to risk of serotonin syndrome. 2

Psychotherapy as Adjunct

• Cognitive behavioral therapy and mindfulness should be added as second-line therapy to augment pharmacological treatments. 6

Third-Line Treatments for Refractory Cases

Strong Opioids (Reserve Option)

• Strong opioids should be avoided for long-term management due to risks of dependence, cognitive impairment, respiratory depression, and pronociception, and may only be considered for acute severe pain, cancer-related pain, or episodic exacerbations using the smallest effective dose. 1, 2
• Neuropathic pain is generally less responsive to opioids than other pain types. 2

Intravenous Lidocaine for Severe Refractory Pain

• For severe, refractory neuropathic pain, intravenous lidocaine can be administered as an initial bolus of 1-3 mg/kg over 20-30 minutes, followed by continuous infusion of 0.5-2 mg/kg/hr (maximum 100 mg/hour), which is particularly effective for opioid-refractory neuropathic pain. 1, 7
• IV lidocaine reduces opioid requirements and provides significant pain relief, especially for cancer-related neuropathic pain. 7
• Side effects are generally self-limiting and include tinnitus, perioral numbness, sedation, lightheadedness, and headache. 7

Neurostimulation

• High-frequency repetitive transcranial magnetic stimulation (rTMS) targeting the motor cortex is recommended as third-line treatment. 6, 8
• Spinal cord stimulation should be considered for failed back surgery syndrome and painful diabetic polyneuropathy when medications are ineffective. 2, 6

Non-Pharmacological Interventions

• Initiate physical exercise and functional training as early as possible, including vibration training, coordination exercises, and sensorimotor training, which provide anti-inflammatory effects and improve pain perception through inhibition of pain pathways. 1
• Transcutaneous electrical nerve stimulation (TENS) is recommended specifically for peripheral neuropathic pain. 6, 8

Critical Treatment Principles

• All proposed agents for neuropathic pain should be used for at least 2-4 weeks at adequate therapeutic doses before evaluating efficacy and declaring treatment failure. 1, 2
• Avoid NSAIDs and glucocorticoids as there is no data supporting their benefit in neuropathic pain. 1
• Address concurrent sleep disturbance, anxiety, depression, and central sensitization, as these factors can aggravate neuropathic pain. 1

Condition-Specific Considerations

Diabetic Peripheral Neuropathy

• Pregabalin, duloxetine, and gabapentin are specifically recommended by the American Diabetes Association for diabetic peripheral neuropathy. 2

Postherpetic Neuralgia

• 5% lidocaine patches are particularly effective in postherpetic neuralgia. 2

Chemotherapy-Induced Peripheral Neuropathy

• Duloxetine has moderate clinical benefit with effect more pronounced with platinum-based therapies than taxanes; nortriptyline, amitriptyline, and gabapentin have shown no evidence of efficacy in randomized controlled trials. 2

Lumbosacral Radiculopathy

• This condition is notably more refractory to standard neuropathic pain medications compared to other neuropathic pain conditions, with limited efficacy shown for nortriptyline, morphine, pregabalin, and their combinations. 2

Common Pitfalls to Avoid

• Do not prescribe opioids as first-line agents for long-term management of chronic neuropathic pain due to risks of pronociception, cognitive impairment, respiratory depression, and addiction. 2
• Do not underdose or discontinue medications prematurely—ensure target therapeutic doses are reached and maintained for 2-4 weeks before declaring treatment failure. 1, 2
• Do not overlook topical agents for localized pain, as they offer excellent efficacy with minimal systemic side effects. 1, 2
• Avoid combining tramadol with SNRIs/SSRIs without careful monitoring for serotonin syndrome. 2