Safest Antitussive for G6PD Deficiency
Codeine and codeine derivatives are the safest first-line antitussive agents for patients with G6PD deficiency, as they have not been shown to cause hemolytic crises and can be used without restriction. 1
Evidence-Based Medication Safety
Safe Antitussive Options
Codeine and codeine-containing preparations are explicitly safe in G6PD-deficient patients based on comprehensive literature review and have no documented cases of hemolysis. 1
Benzodiazepines can be used safely if sedation or anxiolysis is needed alongside cough suppression, with no evidence of oxidative stress or hemolytic risk. 1
Opioid analgesics including fentanyl have been studied in the perioperative setting and show no hemolytic potential in G6PD deficiency. 1
Medications to Absolutely Avoid
The following seven medications have solid evidence for causing hemolysis and must be avoided in all G6PD-deficient patients: 2
- Dapsone – potent oxidant causing methemoglobinemia and hemolysis 3
- Methylene blue (methylthioninium chloride) – contraindicated, causes severe hemolytic anemia 3, 2
- Nitrofurantoin – documented hemolytic trigger 2, 4
- Primaquine – antimalarial with high hemolytic risk 5, 3
- Rasburicase – absolutely contraindicated 6, 7
- Phenazopyridine – urinary analgesic with oxidative properties 2
- Tolonium chloride (toluidine blue) – surgical dye causing hemolysis 2
Clinical Management Algorithm
Before Prescribing Any Medication
Screen patients of Mediterranean, African, Indian, or Southeast Asian descent for G6PD deficiency before starting any oxidant drug therapy. 5, 3
Use qualitative screening for initial assessment in males and homozygous females with suspected severe deficiency. 5, 6
Obtain quantitative G6PD testing when results are borderline or in heterozygous females where enzymatic testing may be inconclusive. 6, 3
Timing Considerations for Testing
Avoid testing during acute hemolytic episodes because reticulocytes contain near-normal enzyme levels and will mask true deficiency. 6
Wait at least 50 days post-transfusion before performing G6PD assays, as donor red cells can cause false-negative results. 6
Warning Signs Requiring Immediate Action
Educate patients to recognize hemolysis symptoms and discontinue any suspect medication immediately if they develop: 7, 4
- Pallor (present in 100% of hemolytic crises) 4
- Dark red or cola-colored urine (hemoglobinuria in 89.6% of cases) 4
- Jaundice (occurs in 87.8% of hemolytic episodes) 4
- Back or abdominal pain 7
- Fatigue and weakness 7
These symptoms typically appear 24-72 hours after exposure to oxidative triggers. 4
Common Pitfalls to Avoid
Do not assume all NSAIDs are safe – while ibuprofen and diclofenac have been implicated in some hemolytic cases, the evidence is mixed and they were likely administered during concurrent infections. 4
Do not withhold codeine-based cough suppressants based on outdated or overly cautious medication lists; extensive evidence supports their safety. 1, 2
Do not rely on historical G6PD results when timing of testing, transfusion history, or reticulocyte count are unknown; repeat testing under optimal conditions. 6
Recognize that infections themselves (pneumonia, tonsillitis, typhoid, hepatitis A, UTI) are the second most common trigger of hemolysis after dietary factors, accounting for 12.4% of hemolytic crises. 4
Variant-Specific Considerations
Mediterranean variant (Gdmed) causes life-threatening hemolysis and requires stricter avoidance of all oxidant medications. 5, 3
African variant (GdA-) produces milder, self-limited hemolysis and is found in 10-15% of Black individuals. 5, 3
Genetic testing helps identify specific variants when enzymatic results are borderline or when determining whether modified dosing of certain medications might be feasible. 6