Does valproic acid cause rhabdomyolysis or elevated creatinine kinase levels?

Valproic Acid and Its Association with Rhabdomyolysis and Elevated Creatine Kinase

Valproic acid can cause rhabdomyolysis and elevated creatine kinase levels in rare cases, particularly in patients with underlying metabolic disorders such as carnitine palmitoyltransferase type II deficiency. While not a common adverse effect, case reports document this serious complication that can lead to acute kidney injury.

Evidence for Valproic Acid-Induced Rhabdomyolysis

The evidence linking valproic acid to rhabdomyolysis comes primarily from case reports rather than large clinical studies:

• Case reports document patients on chronic valproic acid therapy developing rhabdomyolysis with elevated creatine kinase levels and subsequent acute kidney injury 1
• A specific case describes a 47-year-old man with bipolar disorder who developed acute rhabdomyolysis with renal failure after starting valproic acid therapy 2
• The patient was later found to have carnitine palmitoyltransferase (CPT) type II deficiency, suggesting that valproic acid may trigger rhabdomyolysis in patients with underlying metabolic disorders 2

Mechanism and Risk Factors

The mechanism by which valproic acid may cause rhabdomyolysis is not fully elucidated, but several factors appear relevant:

• Valproic acid may interfere with mitochondrial fatty acid metabolism, particularly in patients with underlying metabolic disorders
• Patients with carnitine palmitoyltransferase type II deficiency appear to be at higher risk 2
• Chronic valproic acid therapy may lead to cumulative toxicity in susceptible individuals

Clinical Presentation and Diagnosis

When rhabdomyolysis occurs due to valproic acid, patients typically present with:

• Muscle pain or weakness
• Elevated serum creatine kinase levels (may be significantly elevated)
• Dark urine (due to myoglobinuria)
• Signs of acute kidney injury (elevated creatinine, reduced urine output)

Laboratory evaluation should include:

• Serum creatine kinase (CK) measurement
• Renal function tests (BUN, creatinine)
• Urinalysis for myoglobin
• Liver function tests (as valproic acid can also cause hepatotoxicity)

Management

If rhabdomyolysis is suspected in a patient taking valproic acid:

1. Discontinue valproic acid immediately
2. Initiate aggressive intravenous fluid administration to prevent acute kidney injury
3. Monitor renal function and creatine kinase levels
4. Consider alternative anticonvulsant or mood stabilizer therapy
5. Evaluate for underlying metabolic disorders, particularly in severe or recurrent cases

Contrasting Evidence

Interestingly, one animal study suggests that valproic acid might actually have protective effects against experimentally induced rhabdomyolysis in rats 3. This study demonstrated that valproic acid administration attenuated both muscle injury and acute kidney injury induced by hypertonic glycerol. However, this protective effect observed in experimental models contrasts with the clinical case reports of valproic acid-induced rhabdomyolysis in humans.

Monitoring Recommendations

For patients on valproic acid therapy:

• Consider baseline creatine kinase measurement before initiating therapy
• Educate patients to report muscle pain, weakness, or dark urine immediately
• Monitor for symptoms of muscle injury during therapy
• Consider periodic creatine kinase monitoring in high-risk patients (those with history of muscle disorders or metabolic conditions)
• Measure creatine kinase if symptoms suggestive of muscle injury develop

Conclusion

While rhabdomyolysis is not among the common adverse effects of valproic acid, clinicians should be aware of this potential complication, particularly in patients with underlying metabolic disorders. Prompt recognition and management are essential to prevent progression to acute kidney injury and other complications.