What muscle relaxer is safe to use with Keppra (Levetiracetam) and Zonisamide?

Safe Muscle Relaxant Options with Keppra (Levetiracetam) and Zonisamide

Non-benzodiazepine skeletal muscle relaxants like cyclobenzaprine (Flexeril) at a low dose of 5 mg three times daily are the safest option to use with Keppra (levetiracetam) and zonisamide.

Medication Interactions and Safety Considerations

Avoid Benzodiazepines

• Benzodiazepines (such as diazepam) should be avoided when used with antiepileptic drugs like Keppra and zonisamide due to:
  • Increased risk of central nervous system depression 1
  • FDA black box warning against co-prescribing benzodiazepines with other centrally acting drugs 1
  • 3-10 fold higher risk of death when benzodiazepines are combined with other centrally acting medications 1

Preferred Options

1. Cyclobenzaprine (Flexeril)

   • Recommended at lower doses (5 mg TID rather than 10 mg TID) to minimize sedation 2
   • Research shows 5 mg TID is as effective as 10 mg TID with fewer side effects 2
   • While cyclobenzaprine has some sedative properties due to H1 receptor antagonism 3, it doesn't have the same dangerous potentiation of respiratory depression as benzodiazepines when combined with antiepileptic drugs

2. Other Non-Benzodiazepine Options

   • Metaxalone (Skelaxin)
   • Methocarbamol (Robaxin)
   • Tizanidine (Zanaflex) - use with caution due to sedative properties

Monitoring and Precautions

• Start with lower doses and titrate slowly to minimize sedation
• Monitor for excessive sedation, dizziness, and cognitive impairment
• Be aware that all muscle relaxants can cause some degree of CNS depression that may be additive with antiepileptic drugs
• Advise patients about potential driving impairment and fall risk, especially in elderly patients

Evidence Summary

Levetiracetam (Keppra) and zonisamide are commonly used antiepileptic medications for focal epilepsy 4, 5. When considering muscle relaxants with these medications:

1. Clinical guidelines strongly recommend against combining benzodiazepines with other centrally acting medications due to significant safety concerns 1

2. Skeletal muscle relaxants have been shown to be effective for acute low back pain in multiple high-quality trials 1

3. Low-dose cyclobenzaprine (5 mg TID) has demonstrated efficacy similar to higher doses with fewer side effects 2

4. While levetiracetam has fewer drug interactions than many other antiepileptic drugs 6, all centrally acting medications should be used cautiously in combination

Common Pitfalls to Avoid

• Pitfall #1: Using benzodiazepines like diazepam as muscle relaxants with antiepileptic drugs

  • Avoid this combination due to significantly increased risk of excessive sedation and respiratory depression

• Pitfall #2: Starting with high doses of muscle relaxants

  • Always start with lower doses (e.g., cyclobenzaprine 5 mg instead of 10 mg) to minimize side effects

• Pitfall #3: Not monitoring for cumulative sedative effects

  • Regularly assess for excessive sedation, especially when initiating therapy

• Pitfall #4: Prolonged use of muscle relaxants

  • Limit use to short-term therapy (2-3 weeks) as evidence for long-term efficacy is limited 1

By following these guidelines and selecting non-benzodiazepine muscle relaxants at appropriate doses, patients taking Keppra and zonisamide can safely receive treatment for muscle spasms while minimizing adverse effects.