Can allopurinol cause elevated creatine kinase (CK) levels?

Allopurinol and Elevated Creatine Kinase

Allopurinol can cause elevated creatine kinase (CK) levels, particularly in patients with renal impairment, though this is a rare adverse effect that is not commonly highlighted in major guidelines. 1

Mechanism and Evidence

The relationship between allopurinol and elevated CK appears to be related to:

• Muscular damage that can occur as part of allopurinol-induced hypersensitivity reactions
• Direct muscular toxicity, particularly in patients with impaired renal function
• Accumulation of oxypurinol (allopurinol's active metabolite) in patients with decreased renal clearance

A case report documented a 73-year-old woman with chronic renal failure who developed generalized muscular weakness and pain 6 days after starting allopurinol 200 mg/day. Laboratory tests revealed elevated serum creatine kinase levels, and she was diagnosed with rhabdomyolysis likely due to severe myositis. High serum oxypurinol levels were detected, suggesting a correlation between allopurinol metabolite accumulation and muscle damage 1.

Risk Factors

Several factors may increase the risk of allopurinol-induced muscle damage:

• Renal impairment (particularly CKD stage 3 or worse)
• Higher allopurinol doses relative to renal function
• Concomitant use of medications that may affect muscle metabolism
• Genetic factors (HLA-B*58:01 allele carriers are at higher risk for allopurinol hypersensitivity)

Clinical Implications

When prescribing allopurinol:

1. Dosing should be adjusted based on creatinine clearance, not just serum creatinine levels 2
2. Start with low doses (≤100 mg/day) in patients with renal impairment 3
3. Gradually titrate doses every 2-5 weeks with monitoring 3
4. Consider HLA-B*58:01 screening in high-risk populations 4, 3

Monitoring Recommendations

• Monitor renal function (BUN, creatinine) every 2-5 weeks during dose titration 3
• Consider baseline and follow-up CK measurements in patients with risk factors
• Be vigilant for symptoms of muscle damage (weakness, pain, dark urine)
• Watch for signs of allopurinol hypersensitivity syndrome, which can include muscle involvement

Alternative Treatments

In patients who develop CK elevation or have high risk for muscle complications:

• Febuxostat is preferred over allopurinol in patients with renal impairment 4, 3
• Benzbromarone can be used in patients with mild to moderate renal impairment 4
• Pegloticase may be considered for severe refractory cases 4

Clinical Pitfalls

1. Failure to recognize muscle symptoms as allopurinol-related: Muscle pain or weakness may be misattributed to other causes rather than recognized as a potential allopurinol adverse effect.

2. Inappropriate dosing: Using fixed doses of allopurinol (e.g., 300 mg) regardless of renal function can lead to toxicity, including muscle damage 2.

3. Delayed recognition of allopurinol hypersensitivity syndrome: This potentially life-threatening reaction can include muscle involvement with elevated CK, and has a 25% mortality rate 4.

4. Inadequate monitoring: Failing to monitor renal function during allopurinol titration may miss early signs of toxicity 3.

While elevated CK is not among the most commonly reported adverse effects of allopurinol in major guidelines, case reports and clinical experience suggest it can occur, particularly in the context of renal impairment or hypersensitivity reactions.