What are the considerations for using mexiletine in a patient with neuropathy?

Mexiletine Should Probably Not Be Used for Neuropathic Pain

Based on the highest quality evidence from the American Academy of Neurology, mexiletine should probably not be considered for the treatment of painful diabetic neuropathy (Level B recommendation), as the only Class I study demonstrates it is probably ineffective. 1

Evidence Against Mexiletine for Neuropathy

Guideline Recommendations

• The American Academy of Neurology explicitly recommends against mexiletine for painful diabetic neuropathy, stating that while evidence is contradictory, the single Class I study indicates probable ineffectiveness 1

• The European Society of Cardiology and American College of Cardiology note that mexiletine's use is limited by its problematic side-effect profile, even when considered for refractory ventricular arrhythmias 2

• For HIV-associated neuropathy, the HIVMA of IDSA guideline found no superiority over placebo in randomized controlled trials examining mexiletine 600 mg/day 1

Clinical Trial Evidence

• A double-blind, placebo-controlled crossover study of 20 patients with neuropathic pain and allodynia found mexiletine (up to 900 mg/day) had minimal effects on pain, with only a significant effect on stroking-induced pain but no other pain measures 3

• In HIV-related painful peripheral neuropathy, a crossover trial of 22 patients showed no statistically significant difference between mexiletine (600 mg/day) and placebo, with dose-limiting adverse events in 39% of mexiletine recipients 4

• The evidence showing benefit is limited to specific pain subtypes: patients describing stabbing, burning pain or formication showed statistically significant VAS reductions in retrospective subgroup analysis 5, 6

Preferred Alternatives for Neuropathic Pain

First-Line Agents

• Gabapentin should be the first-line oral pharmacological treatment for chronic neuropathic pain, titrated to 1800-3600 mg/day divided in three doses 1

• Pregabalin is an alternative calcium channel α2-δ ligand, started at 75 mg at bedtime with gradual weekly increase to maximum 600 mg daily 1

• Duloxetine (an SNRI) is FDA-approved for painful diabetic polyneuropathy with strong recommendations for use at doses of 20-120 mg/day 1

Second-Line Considerations

• Tricyclic antidepressants remain effective for neuropathic pain despite being ineffective in approximately 50% of patients 5

• Topical capsaicin 8% is probably effective for painful diabetic neuropathy (Level B), though many patients are intolerant of burning side effects 1

• Lidoderm patch may be considered (Level C) with moderate to large effect sizes (20-30% pain reduction) 1

When Mexiletine Might Be Considered

Limited Clinical Scenarios

• Only as a second- or third-line treatment in refractory neuropathic pain after failure of gabapentin, pregabalin, duloxetine, and tricyclic antidepressants 1

• For cancer-related neuropathic pain when standard treatments have failed, mexiletine may be considered as it is more effective than placebo in selected patients 1

• Optimal dosing appears to be 450 mg/day rather than higher doses, as efficacy does not rise proportionally with increased dosage 6

Important Caveats

• Heat intolerance is a unique and problematic side effect due to mexiletine's effects on sodium channels involved in thermoregulation 7, 2

• Gastrointestinal complaints (especially nausea) are the most common adverse events, occurring in 13.5-50% of patients 5

• Dose-limiting side effects frequently prevent achieving therapeutic levels, with discontinuation rates of 39% in some trials 4

• Drug interactions are significant: mexiletine metabolism varies between CYP2D6 extensive and poor metabolizers, and it inhibits metabolism of metoprolol and theophylline 5

Clinical Algorithm for Neuropathic Pain Management

1. Start with gabapentin (titrate to 1800-3600 mg/day) or pregabalin (75-600 mg/day) 1

2. If inadequate response, add or switch to duloxetine (20-120 mg/day) or tricyclic antidepressant 1

3. Consider topical agents (capsaicin 8% or lidoderm patch) for localized pain 1

4. Reserve mexiletine only for refractory cases after exhausting preferred options, using 450 mg/day dosing 1, 6

5. Monitor closely for heat intolerance and gastrointestinal side effects if mexiletine is prescribed 7, 5