NSAIDs in G6PD Deficiency: Safety Considerations
Most NSAIDs can be safely used in patients with G6PD deficiency as there is minimal evidence of clinically significant hemolysis risk with these medications.
Understanding G6PD Deficiency and Medication Risk
G6PD deficiency is the most common human enzyme defect worldwide, affecting approximately 400 million people. This X-linked genetic disorder reduces the body's ability to protect red blood cells from oxidative stress, potentially leading to hemolytic anemia when exposed to certain triggers.
Risk Stratification for NSAIDs
NSAIDs as a class are generally considered safe in G6PD deficiency, with important exceptions:
Safe NSAIDs (Low Risk):
- Ibuprofen
- Ketoprofen
- Naproxen
- Most other common NSAIDs
NSAIDs to Avoid (Higher Risk):
- Phenazopyridine (technically not an NSAID but sometimes used for pain relief)
Evidence Supporting NSAID Safety
The American Family Physician guidelines list aspirin as a medication that can be used in G6PD-deficient patients, with specific contraindications only for aspirin/NSAID-induced asthma, not G6PD deficiency 1. This suggests that standard NSAIDs are generally acceptable in these patients.
A comprehensive systematic review found solid evidence to prohibit only seven medications in G6PD deficiency (dapsone, methylthioninium chloride, nitrofurantoin, phenazopyridine, primaquine, rasburicase, and tolonium chloride) - notably, common NSAIDs were not included in this prohibited list 2.
Specific Evidence for Individual NSAIDs
Ibuprofen: A 2022 systematic review specifically examining ibuprofen in children with G6PD deficiency found only "scant, low-quality evidence of hemolytic anemia" with an extremely rare occurrence rate of approximately 1/100,000 affected children per year 3.
Ketoprofen: A study of 34 G6PD-deficient patients (including both hemizygous males and heterozygous females) treated with ketoprofen lysine salt showed no evidence of hemolysis or adverse events 4.
Practical Recommendations for Clinical Practice
Assess G6PD status and variant:
- Mediterranean variants (B-) have higher risk of severe hemolysis than African variants (A-) 1
- Consider quantitative G6PD testing when available
NSAID selection approach:
- Choose standard NSAIDs (ibuprofen, naproxen) as first-line when indicated
- Use the lowest effective dose for the shortest duration
- Avoid phenazopyridine for urinary pain in these patients
Monitoring recommendations:
- Educate patients about signs of hemolysis (fatigue, jaundice, dark urine)
- Consider baseline CBC before starting therapy in high-risk patients
- Monitor more closely during initial therapy in patients with severe G6PD deficiency variants
Special Considerations
Risk Factors for Increased Hemolysis
Be more cautious with NSAIDs in G6PD-deficient patients who have:
- Concurrent infections (which can trigger hemolysis independently)
- Concomitant use of other oxidative medications
- Recent fava bean consumption
- History of previous hemolytic episodes
Real-World Safety Data
A large real-world study of 31,962 G6PD-deficient patients found only 71 cases (0.2%) of major hemolysis requiring hospitalization, with only 3 cases (4.2%) potentially associated with medications. The vast majority of hemolysis cases (71.8%) were caused by fava bean ingestion, not medications 5.
Conclusion
While caution is always warranted when prescribing medications to patients with G6PD deficiency, the available evidence indicates that most common NSAIDs can be safely used in these patients. The risk of clinically significant hemolysis with standard NSAIDs appears to be extremely low, especially compared to other known triggers like fava beans or high-risk medications.