Allergic and "pseudoallergic" reactions to NSAIDs

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D, Allergist/Immunologist and Assistant Professor at NSU

NSAIDs are the drugs most commonly involved in hypersensitivity drug reactions.

NSAIDs can cause several allergic and "pseudoallergic" reactions. Allergic reactions are immunologic reactions to NSAIDs that are presumed IgE-mediated. Pseudoallergic reactions are non-immunologic.

Pseudoallergic reactions are non-immunologic abd are related to the COX-1 inhibition. They can be elicited by any NSAID that inhibits COX-1, including aspirin. Precise mechanism has not been established.

Allergic NSAID reactions are presumed to be IgE-mediated. They are elicited by a single NSAID in a susceptible individual.

Allergic and "pseudoallergic" reactions to NSAIDs (click to enlarge the image).

Pseudoallergic NSAID reactions

Pseudoallergic reactions can be caused by any COX-1 inhibiting NSAID, and the likelihood of these reactions is related to the degree of COX-1 inhibition. Pseudoallergic reactions are usually seen in patients with one of the following comorbidities: the combination of asthma and chronic rhinosinusitis with nasal polyposis; or chronic urticaria.

Pseudoallergic reactions are divided into 4 types:

- Type 1: NSAID-induced asthma and rhinosinusitis
- Type 2: NSAID-induced urticaria/angioedema in patients with chronic urticaria
- Type 3: NSAID-induced urticaria/angioedema in otherwise asymptomatic individuals
- Type 4: Blended reactions in otherwise asymptomatic individuals

Type 3: NSAID-induced urticaria/angioedema in otherwise asymptomatic individuals

There is a small subsets of patients without chronic urticaria who develop acute urticaria and/or angioedema with COX-1 inhibiting NSAIDs/ASA. Isolated angioedema following NSAID ingestion typically involves the face, particularly the periorbital skin, lips, and mouth. This condition is uncommon. These patients may develop urticaria and/or angioedema only after NSAID ingestion or may have intermittent episodes of unexplained urticaria unrelated to NSAID ingestion, but they do not have chronic urticaria.

The probable mechanism is related to COX-1 inhibition, as patients with type 3 pseudoallergy can react to their very first dose of a COX-1 inhibitor and to structurally different COX-1 inhibiting NSAIDs. They are able to tolerate highly selective COX-2 inhibiting NSAIDs (eg, celecoxib).

Allergic NSAID reactions (presumed IgE-mediated)

Allergic reactions to NSAIDs range from urticaria/angioedema to life-threatening anaphylaxis. In contrast to pseudoallergic reactions, these reactions are elicited by a single NSAID, or rarely by more than one agent with similar molecular structures.

These reactions are believed to be IgE-mediated via a drug hapten/carrier protein phenomena. While most of these reactions have been associated with ibuprofen, the first NSAID to become available over the counter in the United States, they can happen with any COX-1 inhibitor. There are no practical available tests to detect IgE to NSAIDs (such as skin testing or drug-specific serum IgE tests).

Allergic reactions may be divided into two types, based on the severity of the symptoms:

- Type 5: Urticaria/angioedema to a single NSAID - urticaria and/or angioedema within minutes to one hour of taking a particular NSAID or ASA. These patients generally do not have underlying chronic urticaria.

- Type 6: Anaphylaxis to a single NSAID (not ASA) - Type 6 reactions are distinguished from type 5 reactions based only upon severity. Typical symptoms of anaphylaxis include shortness of breath/wheezing due to bronchospasm or laryngeal edema and hypotension due to vascular collapse.

It is notable that there are no confirmed cases of anaphylaxis to aspirin itself.


There are no in vitro or skin testing methods available. Definitive diagnosis requires a challenge procedure, although this is only indicated if the patient has a specific need for regular NSAID therapy (ie, usually NSAIDs for rheumatologic disease or aspirin for cardiovascular disease).

Management of pseudoallergic reactions

Challenge procedures

If a definitive diagnosis is required, then a provocative challenge procedure must be performed.

Without additional information, the clinician must advise the patient to avoid all NSAIDs. However, a challenge procedure with aspirin would clarify whether the patient reacts to all COX-1 inhibitors (pseudoallergic), or only to ibuprofen (allergic).

Alternative to the challenge

An alternative to the challenge is to administer a highly selective COX-2 inhibitor. Highly selective COX-2 inhibitors (eg, celecoxib) are tolerated by patients with pseudoallergic reactions. These agents demonstrate at least a 200 to 300-fold selectivity for inhibition of COX-2 over COX-1 at the defined therapeutic doses.

It is generally safe for patient with a pseudoallergic NSAID reaction to take a highly selective COX-2 inhibitor, such as celecoxib. Some allergists prefer to give an initial dose in a medically supervised setting (eg, a clinic), although there are no reported cases of pseudoallergic reactions who subsequently reacted to celecoxib.

Management of allergic reactions

Type 5 and 6 reactions are presumed IgE-mediated reactions to single NSAIDs. Patients with these types of reactions should avoid the causative agent.

Patients with types 5 and 6 reactions may require diagnostic challenge with aspirin to confirm that they are not sensitive to all COX-1 inhibitors (ie, exclude pseudoallergy), if the history is not sufficient to determine this. Confirmed cases of anaphylaxis to aspirin have not been reported.

Patients with types 5 or 6 reactions may safely take NSAIDS that are structurally dissimilar to the drug that caused the initial reaction.

However, selective COX-2 inhibitors may be unsafe in subjects with urticaria and/or angioedema caused by hypersensitivity reactions to NSAIDs with cross-intolerance if they are intolerant to paracetamol. Allergy, 2011.


Practical approach to management of hypersensitivity to NSAIDs - 2013 EAACI position paper
Patient with Arthritis and Hypersensitivity to Nonsteroidal Antiinflammatory Drugs (NSAIDs)
UpToDate, 2010.
The Kounis-Zavras syndrome with the Samter-Beer triad
NSAIDs are responsible for 21-25% of reported adverse drug events
Selective COX-2 inhibitors may be unsafe in subjects with urticaria and/or angioedema caused by hypersensitivity reactions to NSAIDs with cross-intolerance if they are intolerant to paracetamol. Allergy, 2011.
How Can We Better Classify NSAID Hypersensitivity Reactions – Validation from a Large Database

Published: 07/27/2010
Updated: 07/27/2012


Angela said...

Thank you for your article. This week I experienced what appears to be a type 3 reaction. I would be very interested in participating in providing information regarding my experience to assist with research in this matter. First reaction ten years ago to Motrin 800 prescription. have been able to take OTC Motrin since up to 800mg with no problems. One week ago--I took Alka seltzer and had the same reaction as with the Motrin 800--urticaria/angioedema(periorbital) stomach pain and hoarseness. I am still experiencing GI and urticaria.


Anonymous said...

It is notable that there are no confirmed cases of anaphylaxis to aspirin itself.

Anonymous said...


My doctor has been giving me various nsaids trying to find one that works to ease my post thoracotomy pain syndrome.

Since I've been taking the nsaids (for about a month now) I've developed a sneeze that won't stop. I seriously sneeze at least 2 or 3 hundred times within the hour following taking my meds. I know 2 or 3 hundred times sounds like an exaggeration but I promise you it's not.

Also I have developed a tightness and severe pain in my chest (almost constantly), I'm always irritable, I've had diarrehea for a month (since the first day I took the nsaids), and I can't sleep. All that on top of the fact that my pain is not any better and may even be getting worse. It's for sure worse at night.

Does anybody know if all the above is a reaction to the nsaids or is it something else?

Believe it or not I haven't been to the doctor or even taken an aspirin since 1978. Then on September 13th 2010 I went to the emergency room with what I thought was a kidney infection, since it was my right kidney that was hurting. A week later they done a surgical pleurodesis (has nothing to do with kidneys) and I've been a train wreck ever since.

When I told my doctor about the above symptoms she told me to INCREASE my medication from once a day to 3 times a day. I'm no doctor but that just doesn't sound right to me.

My doctor graduated from a college that was rated 1 star with a special note that the reason it was rated 1 star was that there was no such rating as a zero star.

I'm a veteran and I've been told I'm stuck with that doctor or no doctor (my choice). I just doesn't seem fair that just beause I'm a veteran I'm stuck with a veterinarian. Does anybody have any suggestions or can any of you doctors out there help me out?


Anonymous said...

Comments don't work if you choose to post as name/url and probably others too. I could only get it to work as anonymous.

Anonymous said...

How odd. I used ibuprofen for years as pain relief from arthritis. 10 years ago, doctor gave me Vioxx and I had anaphylaxis reaction. Went for serum allergy testing and results showed extreme allergy to aspirin Doctor said I could safely use NSAIDS, just not aspirin, and no explanation for Vioxx reaction. Used ibuprofen and anaphylaxis again. Nearly killed me. While the article says no confirmed cases of anaphylaxis to aspirin, I could probably be a confirmed case for that -- but not going to try it since I'd likely end up dead.

Anonymous said...

Having suffered anaphylaxis twice due to aspirin intake, I am shocked!

Anonymous said...

Forgot to mention my first anaphylaxis was due to Excedrin, second due to Alka-Seltzer. Both contain aspirin.

Noel said...

Wow this article is dangerously misleading someone could die after reading this Asprin most assuredly can cuase Anaphallaxis