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Allergy to NSAIDs and adverse reactions: what are and how they occur


Aspirin, ibuprofen or other non-steroidal anti-inflammatory drugs or drugs (NSAIDs or NSAIDs) are among the best helpers for fever and various types of pain today. And at the same time, NSAIDs are one of the most common groups of medicines that cause skin and gastrointestinal side effects. Most of these reactions are not allergies, but that doesn’t make them any less unpleasant.


Although mankind has been using various plants for antipyretic or analgesic purposes since prehistoric times, in fact, the history of aspirin begins relatively recently. In the 18th century, the Englishman Edward Stone brought to the attention of the medical world the certain effectiveness of willow bark in treating malaria . He expressed the opinion that its medicinal properties are not worse than those of cinchona bark . But the truth was that it was quinine that fought the infection, but salicin, obtained from willow bark , only alleviated the symptoms of the disease. But attention to salicylic acid was again drawn in 1897. Then the chemist Felix Hoffmann invented a way to synthesize salicylic acid in a pure and stable form suitable for further use in the pharmaceutical industry. Subsequently, the name “aspirin” appeared.

Today it is known that aspirin can not only have an analgesic and antipyretic effect, but also prevent thrombosis and angina pectoris.

In addition to aspirin, there are still a number of synthetic NSAIDs.

They are most often used systemically, usually as oral preparations. But they can also be applied topically as suppositories or injected intramuscularly. There are also NSAID creams and gels that can be used for joint pain, sports injuries, and keratosis.


NSAIDs such as aspirin, ibuprofen and others are inhibitors of the cyclooxygenase enzymes (COX-1 and COX-2). These enzymes play a key role in the synthesis of substances such as thromboxane , prostaglandins, and prostacyclin from arachidonic acid . COX1-produced prostanoids are important in regulating kidney function, platelet aggregation, and the integrity of the gastric mucosa. COX-2 can be synthesized in the cell background , as well as in response to inflammatory stimuli. It is responsible for the formation of prostaglandins, which are important in the response to inflammation.

NSAIDs bind reversibly to COX-1 and COX-2 receptors and inhibit the binding of arachidonic acid to these receptor sites. This mechanism prevents the conversion of arachidonic acid to various inflammatory prostaglandins. One of their properties is the ability to irritate pain nerves. Its prevention explains the analgesic effect of NSAIDs.

Different NSAIDs differ markedly in their ability to inhibit COX-1 and COX-2, which not only affects their clinical efficacy, but explains the different ability to generate side effects and cause hypersensitivity reactions.

For example, aspirin and most “classic” NSAIDs (eg, indomethacin, naproxen , and diclofenac) predominantly inhibit COX-1 and, to a lesser extent, COX-2, which inhibit the synthesis of protective prostaglandins. This leads to common adverse side effects of their action on the gastrointestinal tract.

At the same time, for example, nimesulide and meloxicam predominantly inhibit COX-2. And selective COX-2 inhibitors (for example, celecoxib , rofecoxib ) are strong inhibitors of inflammatory prostaglandins, but only slightly affect the production of protective prostaglandins.


Allergic reactions to NSAIDs include immunologically mediated reactions in which immunoglobulin E ( IgE ) is released or a T cell response occurs. These reactions are independent of COX-1 inhibition and may be caused by a single NSAID or by a class of NSAIDs with a similar chemical structure. It is believed that hypersensitivity reactions to NSAIDs approximately account for 20-30% of all drug-related reactions. But if the reactions are not immunologically mediated, they are called non-allergic.

True allergy to NSAIDs is relatively rare. But if you have a tendency to hives, nasal polyps, or asthma, the risk of an aspirin allergy rises from 1% (in people without these conditions) to about 10-30%. In turn, the presence of an allergy to aspirin increases the likelihood of allergies to other drugs, in particular, ibuprofen.

Allergic reactions to NSAIDs can be divided into two types, which differ in form and timing of manifestation (immediate – SNIUAA or delayed – SNIDR).

SNIUAA reactions account for over 20% of all NSAID reactions. These conditions are characterized by urticaria, angioedema, or a particularly dangerous form of allergic reaction – anaphylaxis after taking one or more drugs with similar chemical structures.


Symptoms of an immediate allergic reaction usually occur suddenly and appear quickly enough: from seconds to minutes. The timing and range of symptoms associated with SNIUAA reactions are indicative of a type 1 immunological reaction. In this case, specific IgE antibodies can be detected in patients’ molecular tests .

The most common causes (data from the USA) of such allergies are diclofenac and aspirin.

In contrast to SNIUAA reactions, delayed reactions (SNIDR) occur 24-48 hours after exposure to ingestion or topical application of NSAIDs. The exact prevalence of SNIDR reactions is unknown, but it is believed that their proportion is small and is less than 5%.

The most common symptoms associated with this reaction are maculopapular rashes, contact dermatitis, and photosensitivity reactions.

Severe skin reactions – Stevens -Johnson syndrome / toxic epidermal necrolysis and drug reaction with eosinophilia , are less common. But in general, clinical symptoms depend on the specific NSAID. For example, ibuprofen and naproxen are most commonly associated with maculopapular rashes, while diclofenac and ketoprofen are most commonly associated with contact dermatitis.

In general, NSAID allergy symptoms may include:


swelling of the face


exacerbation of asthma (wheezing)

·      labored breathing


redness of the skin.

As already noted, severe and life-threatening anaphylaxis can also develop. This condition is characterized by low blood pressure, fainting, hives, breathing problems, and so on. With the development of anaphylaxis, a person must immediately enter epinephrine.


Side effects of taking NSAIDs are much more common than allergic reactions and are usually manifested by stomach pain, an ulcer, or an increase in blood pressure.

Some NSAIDs, such as aspirin, should not be given to children and teenagers to treat chickenpox or the flu, as they can lead to Reye’s syndrome ( a condition with inflammation of the liver and swelling of the brain).

Side effects of NSAIDs can be classified as a hypersensitivity reaction. According to some reports, such a reaction is observed in approximately 0.3% – 6% of the population. It is believed that these reactions occur mainly due to the inhibition of COX-1. It may result in the induction or exacerbation of respiratory and/or skin reactions.

There are three types of non-allergic reactions to NSAIDs.

The first type , the so-called NECD reactions , occur in patients with underlying chronic spontaneous urticaria, which may be present in a person at the time of taking NSAIDs or aggravated due to their use. These reactions account for approximately 8% of all cases of hypersensitivity to NSAIDs.

Symptoms usually appear within 30 minutes to 4 hours after ingestion of the drugs and are usually limited to the skin and subcutaneous layer of the skin, not affecting the respiratory tract. However, sometimes symptoms may not appear immediately, but with a delay of up to 24 hours after ingestion. The severity of symptoms depends on the dose. However, they usually go away within a few hours, although they can last up to several days.

The second type is NIUA reactions , which occur in healthy people (without a history of urticaria) after the administration of at least two NSAIDs that are not chemically related to each other, and are manifested by the development of urticaria and / or angioedema . About 60% of non -immunologic reactions are thought to be NIUA reactions.

In most cases, with this type of reaction, symptoms appear within 30 to 90 minutes after taking the medication.

The third type of reactions – NERD is characterized by the development of predominantly respiratory symptoms, such as:

tightness in the chest



Nasal polyposis and/or nasal congestion.

Usually, in this case, symptoms occur 30 minutes to 3 hours after taking NSAIDs.

This condition occurs in patients with underlying chronic respiratory diseases of the lower or upper respiratory system. Because NERD is also considered a chronic eosinophilic inflammatory disorder, these patients have elevated blood eosinophils after a NERD exacerbation. The prevalence of NERD varies from 4% to 20% depending on the country. Patients with severe asthma and middle-aged women have a high prevalence of such reactions.

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