Treatment Options for Neuropathic Headaches

For neuropathic headaches, first-line treatment should include pregabalin or gabapentin, with duloxetine as an effective alternative. 1

First-Line Medications

Gabapentinoids (pregabalin and gabapentin) are FDA-approved for neuropathic pain and should be considered first-line treatments, acting by binding to the α-2-δ subunit of voltage-gated calcium channels 1, 2
Pregabalin is FDA-approved for multiple neuropathic pain conditions including diabetic peripheral neuropathy, postherpetic neuralgia, and neuropathic pain associated with spinal cord injury 2
Gabapentin should be started at 300 mg/day and titrated to an effective dose of 1800-3600 mg/day divided into three doses 3
Pregabalin can be started at 150 mg/day and titrated to 300-600 mg/day in divided doses, with efficacy demonstrated across various neuropathic pain conditions 2
Duloxetine (60-120 mg/day) is an effective alternative first-line option with fewer anticholinergic effects than tricyclic antidepressants 1

Tricyclic antidepressants (TCAs) like nortriptyline and desipramine are effective second-line options for neuropathic pain 1
Start TCAs at low doses (10 mg/day) and titrate slowly to a maximum of 75 mg/day, particularly in older adults, 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
For patients who don't respond to first-line treatments, consider adding a medication from a different class rather than continuing ineffective therapy 4

For localized neuropathic pain, consider topical treatments such as 5% lidocaine patches or 8% capsaicin patches 1, 4
Topical treatments have minimal systemic effects and should be prioritized especially in older adults or those with multiple comorbidities 1

Start with pregabalin (150 mg/day) or gabapentin (300 mg/day) and titrate to effective dose 1, 3
If partial response after 2-4 weeks of adequate dosing, add duloxetine (starting at 30 mg/day, target 60 mg/day) 1, 4
If inadequate response to first-line agents, switch to or add a TCA (starting at 10 mg/day) 1
For localized pain, add topical lidocaine or capsaicin 1
Allow at least 2-4 weeks at therapeutic doses to properly assess efficacy 1

Adjust gabapentinoid doses in patients with renal impairment 1
Be vigilant for side effects, particularly in older adults, and start with lower doses and titrate more slowly 4
Common side effects of gabapentinoids include dizziness, somnolence, peripheral edema, and weight gain 5
Duloxetine can cause nausea (take with food to reduce this), dizziness, somnolence, and constipation 4
TCAs can cause dry mouth, orthostatic hypotension, constipation, and urinary retention 1

For diabetic peripheral neuropathy, pregabalin, duloxetine, and gabapentin are specifically recommended 6, 1
For HIV-associated neuropathy, gabapentin has shown efficacy 1
For chemotherapy-induced peripheral neuropathy, standard first-line treatments may be less effective 1
For post-dural puncture headaches, gabapentin has shown benefit in case series 7

If single-agent therapy provides only partial relief, consider adding a medication from a different class 1
The combination of gabapentin and an antidepressant may provide better pain relief than either medication alone 6
Begin treatment of neuropathic pain as soon as possible after onset, using combination therapy when appropriate 6

Avoid opioids or butalbital for the treatment of neuropathic pain due to risks of dependence and medication overuse headache 6, 1
Be aware of medication overuse headache, which can occur with frequent use of acute medications (≥15 days per month with NSAIDs; ≥10 days per month with triptans) 6
Some neuropathic pain conditions like lumbosacral radiculopathy may be relatively refractory to first-line treatments 1