What is the role of Mexilitine in treating muscle spasms in patients with Amyotrophic Lateral Sclerosis (ALS)?

Mexiletine for Muscle Cramps in ALS

Mexiletine is highly effective for treating muscle cramps in ALS patients, with significant dose-dependent reductions in both frequency and severity of muscle cramps, though it should be used at 300 mg/day rather than 900 mg/day due to better tolerability. 1

Efficacy for Muscle Cramps in ALS

Mexiletine has demonstrated substantial benefits for muscle cramps in ALS patients:

• A randomized, double-blind crossover trial showed mexiletine 150 mg twice daily reduced cramp frequency in 18 of 20 patients, with an average reduction of 1.8 cramps per day (from 5.3 with placebo to 3.5 with mexiletine) 2
• Cramp severity was reduced by approximately 15 units on a 100-unit scale (p=0.01) 2
• A larger randomized controlled trial demonstrated dose-dependent reductions in muscle cramp frequency:
  • 300 mg/day: reduced to 31% of placebo frequency (p=0.047)
  • 900 mg/day: reduced to 16% of placebo frequency (p=0.002) 1
• Cramp intensity was also significantly reduced:
  • 300 mg/day: reduced to 45% of placebo intensity (p=0.08)
  • 900 mg/day: reduced to 25% of placebo intensity (p=0.005) 1

Dosing and Safety Considerations

• Recommended dose: 300 mg/day (divided doses) is the optimal balance between efficacy and tolerability 1
• Higher doses (900 mg/day) provide greater reduction in cramp frequency and severity but lead to significantly higher discontinuation rates (32% vs 5% for placebo, p=0.026) 1
• Mexiletine has no effect on ALS disease progression, functional disability, or survival 3, 1
• Pharmacokinetic studies show peak plasma concentration at 2 hours post-dose with strong correlation between plasma and CSF levels 1

Side Effects and Monitoring

Common adverse effects include:

• Nausea (7.8% of patients) 3
• Tremors (3.6% of patients) 3
• Dizziness (can lead to discontinuation in some patients) 2
• Gastrointestinal and central nervous system side effects 4

Alternative Approaches for Muscle Symptoms in ALS

For patients who cannot tolerate mexiletine or have inadequate response:

• Exercise: Moderate intensity, endurance-type exercises may help reduce spasticity, though evidence is limited 5
• Gabapentin or pregabalin: While primarily recommended for restless legs syndrome, these alpha-2-delta ligands may be considered for muscle symptoms in ALS patients, particularly those with chronic kidney disease (with appropriate dose adjustment) 6

Clinical Algorithm for Mexiletine Use in ALS

1. Confirm muscle cramps are significantly affecting quality of life
2. Start with mexiletine 150 mg twice daily
3. Evaluate after 2-4 weeks for:
   • Reduction in cramp frequency and severity
   • Tolerability and side effects
4. If inadequate response but well tolerated, consider dose increase up to 300 mg/day maximum
5. If intolerable side effects occur:
   • Reduce dose
   • Consider alternative approaches like moderate exercise regimens
   • Consider gabapentin (with dose adjustment for renal impairment)

Monitoring

• Regular assessment of symptom improvement
• Monitoring for adverse effects, particularly gastrointestinal and neurological symptoms
• No specific monitoring of disease progression is required as mexiletine does not affect ALS disease course

Mexiletine represents a valuable symptomatic treatment specifically for muscle cramps in ALS patients, providing significant quality of life improvement without affecting disease progression.