Aspirin intolerance: role of your DNA

Aspirin (acetylsalicylic acid) is one of the most widely used over-the-counter medications for pain, fever and inflammation. In low doses, it is also prescribed to prevent heart attacks and strokes in people who have already had one, or who have had a stent. But aspirin does not suit everyone. Some people develop hives, facial swelling, a stuffy nose or a sudden asthma attack after taking it, and in rare cases a severe reaction called anaphylaxis.

Many people call this an "aspirin allergy", but most of these reactions are not true allergies. Knowing the difference matters, because it affects which other pain relievers you can safely take. Here is what causes aspirin intolerance, what your genes can and cannot tell you, and how a pharmacogenetic test can still make pain relief safer.

What is aspirin intolerance?

Aspirin belongs to a class of medications called nonsteroidal anti-inflammatory drugs (NSAIDs), which also includes ibuprofen and naproxen. Reactions to aspirin and other NSAIDs fall into two main groups:

• Cross-reactive reactions (intolerance). These are the most common. They are not caused by the immune system recognizing the drug. Instead, they happen because aspirin blocks an enzyme called COX‑1, which shifts the body's inflammation chemistry toward substances that trigger swelling and airway narrowing. Because ibuprofen, naproxen and most other NSAIDs also block COX‑1, people with this type of reaction usually react to several NSAIDs, not just aspirin.
• Selective reactions (true allergy). Less often, the immune system reacts to one specific drug. These people may react to aspirin but tolerate other NSAIDs. True allergic reactions can include hives, swelling and anaphylaxis.

Learn more about the difference between a drug allergy and a drug intolerance.

What are the signs of aspirin intolerance?

Reactions usually start within minutes to a few hours of taking the medication. Common signs include:

• hives, itching or skin redness
• swelling of the lips, eyes or face
• a stuffy or runny nose, sneezing or watery eyes
• wheezing, chest tightness or an asthma attack
• rarely, anaphylaxis: throat swelling, trouble breathing or a drop in blood pressure, which needs emergency care

Some people have a condition called NSAID-exacerbated respiratory disease (N-ERD, also known as aspirin-exacerbated respiratory disease). It combines asthma, chronic sinus inflammation and nasal polyps, and symptoms flare after aspirin or other NSAIDs. According to a European Academy of Allergy and Clinical Immunology (EAACI) position paper, it affects about 1 in 10 people with asthma and chronic rhinosinusitis. Nasal polyps are part of this underlying condition, not a reaction to a single dose. People with chronic hives can also find that aspirin and other NSAIDs make their hives worse.

Stomach upset, heartburn and bleeding are common side effects of aspirin, but they are not intolerance. They happen because aspirin reduces the stomach's protective lining and affects blood clotting.

Is aspirin intolerance genetic?

Genes may play a role, but no genetic test can predict it today. Researchers have studied genes involved in inflammation and the immune system in people with aspirin intolerance, but results have been small and inconsistent, and none is used in clinical care.

A 2011 study from Korea looked at genes for three enzymes involved in aspirin metabolism (CYP2C9, NAT2 and UGT1A6) in 148 people with aspirin-intolerant hives and 260 healthy people. One CYP2C9 variant was more common in people with hives, while NAT2 and UGT1A6 showed no link. This was a single small study that has not been confirmed, so it does not mean that CYP2C9 testing can predict who will react to aspirin.

In fact, aspirin is mostly broken down by esterase enzymes in the gut, blood and liver, which quickly convert it to salicylic acid. CYP2C9 plays only a small role. Neither the Clinical Pharmacogenetics Implementation Consortium (CPIC) nor the Dutch Pharmacogenetics Working Group (DPWG) has a gene-based recommendation for aspirin.

How does CYP2C9 guide other NSAIDs?

While CYP2C9 does not predict aspirin reactions, it matters a great deal for several other NSAIDs. The CYP2C9 enzyme breaks down celecoxib, ibuprofen, flurbiprofen, lornoxicam, meloxicam, piroxicam and tenoxicam. People with reduced CYP2C9 function (intermediate or poor metabolizers) clear these medications more slowly, so the drugs build up in the blood. For example, poor metabolizers had about four times more celecoxib in their blood than normal metabolizers. Higher levels can increase the risk of stomach bleeding, high blood pressure, kidney problems and heart side effects.

The CPIC guideline for CYP2C9 and NSAIDs recommends:

• Celecoxib, ibuprofen, flurbiprofen, lornoxicam: some intermediate metabolizers should start at the lowest dose; poor metabolizers should start at 25 to 50% of the lowest dose, or use another medication.
• Meloxicam: some intermediate metabolizers should start at half the lowest dose or use another medication; poor metabolizers should use another medication.
• Piroxicam and tenoxicam: these stay in the body for a very long time, so some intermediate metabolizers and all poor metabolizers should use another medication.

CYP2C9 also affects warfarin. CPIC advises that people with reduced CYP2C9 function avoid taking warfarin together with NSAIDs because of a higher risk of bleeding. Read more about how genetics affects pain relievers.

Which other genes matter for people taking aspirin?

• CYP2C19 and clopidogrel. After a heart attack or a stent, aspirin is often combined with clopidogrel. Clopidogrel must be activated by the CYP2C19 enzyme. According to CPIC, intermediate and poor metabolizers activate less clopidogrel and have a higher risk of heart attack and stroke, so another antiplatelet medication is recommended in many cases.
• G6PD. People with G6PD deficiency are often told to avoid aspirin. In its 2022 review, CPIC found that the lack of reported reactions with widely used low-dose aspirin strongly suggests it does not cause red blood cell breakdown (hemolysis) in G6PD deficiency. Other medications, such as rasburicase and standard-dose primaquine, do carry a high risk. Knowing your G6PD status helps your care team choose safely.

What should I do if I react to aspirin?

• Stop taking aspirin and other NSAIDs, and tell your doctor and pharmacist. Ask them to record the reaction in your health file.
• Seek emergency care for throat swelling, trouble breathing or fainting.
• Ask about a referral to an allergist. An allergist can tell whether you have a cross-reactive intolerance or a true allergy, usually from your history and, if needed, a supervised test dose (oral challenge). This shows which pain relievers you can take safely.
• If you need aspirin for your heart, or you have N-ERD, an allergist may offer aspirin desensitization, a supervised process that gradually builds tolerance.
• Do not test other NSAIDs on your own. Some people who react to aspirin can tolerate a COX‑2 selective drug such as celecoxib, or acetaminophen, but this should be confirmed by an allergist.

How can a pharmacogenetic test help?

A Pillcheck test cannot tell you whether you will react to aspirin. It can tell you how your body handles many other pain and heart medications. Pillcheck reports CYP2C9 for NSAIDs and warfarin, CYP2C19 for clopidogrel, and G6PD, and a pharmacist medication review puts these results together with all the medications you take.

Pillcheck testing is performed in CAP- and COLA-accredited clinical genetic laboratories located in Canada. Pillcheck reports on 24 genes, increasing coverage with new guidelines and drug labels (see the genes tab), and covers 355 medications, which account for over 70% of dispensed prescriptions. The Pillcheck test panel ensures high accuracy for people of non-European and admixed ancestries. Your results last a lifetime, and report updates are free of charge.

Summary

• Most reactions to aspirin are not true allergies. They are caused by COX‑1 blocking, so people often react to other NSAIDs as well.
• Signs include hives, swelling, nasal symptoms and asthma attacks. N-ERD combines asthma, sinus inflammation and nasal polyps.
• No genetic test can predict aspirin intolerance. A single small study linked a CYP2C9 variant to aspirin-induced hives, but it has not been confirmed.
• CYP2C9 results do guide the dose or choice of celecoxib, ibuprofen, meloxicam, piroxicam and other NSAIDs. CYP2C19 guides clopidogrel, which is often taken with aspirin.
• If you react to aspirin, an allergist can confirm which pain relievers are safe for you.

Frequently asked questions

Is aspirin intolerance the same as an aspirin allergy?

Usually not. Most reactions are caused by the way aspirin blocks the COX‑1 enzyme, not by an immune response to the drug. This is why people who react to aspirin often react to ibuprofen and naproxen as well. A true allergy to aspirin alone is less common.

Can a genetic test tell me if I will react to aspirin?

No. No genetic test can currently predict aspirin intolerance, and Pillcheck does not claim to. Pillcheck does report CYP2C9, which guides the dose and choice of several other NSAIDs, such as celecoxib, ibuprofen and meloxicam.

If I react to aspirin, can I take ibuprofen?

Often not. If your reaction is a cross-reactive intolerance, ibuprofen and naproxen can cause the same symptoms. Talk to your doctor or an allergist before trying any other NSAID.

Is low-dose aspirin safe if I have G6PD deficiency?

According to CPIC's 2022 review, low-dose aspirin does not appear to cause hemolysis in people with G6PD deficiency. Always tell your doctor and pharmacist about your G6PD status so they can check your other medications.

References

Palikhe NS, Kim SH, Nam YH, Ye YM, Park HS. Polymorphisms of Aspirin-Metabolizing Enzymes CYP2C9, NAT2 and UGT1A6 in Aspirin-Intolerant Urticaria. Allergy Asthma Immunol Res. 2011;3(4):273-276.

Kowalski ML, Agache I, Bavbek S, et al. Diagnosis and management of NSAID-Exacerbated Respiratory Disease (N-ERD): a EAACI position paper. Allergy. 2019;74(1):28-39.

Theken KN, Lee CR, Gong L, et al. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs. Clin Pharmacol Ther. 2020;108(2):191-200.

Lee CR, Luzum JA, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update. Clin Pharmacol Ther. 2022;112(5):959-967.

Gammal RS, Pirmohamed M, Somogyi AA, et al. Expanded Clinical Pharmacogenetics Implementation Consortium Guideline for Medication Use in the Context of G6PD Genotype. Clin Pharmacol Ther. 2023;113(5):973-985.