NSAIDs (including aspirin): Allergic and pseudoallergic reactions

INTRODUCTION — Nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin (acetylsalicylic acid; ASA), are associated with an array of adverse effects, ranging from mild gastritis to life-threatening allergic reactions. (See "Nonselective NSAIDs: Overview of adverse effects".)

The ingestion of NSAIDs can give rise to several allergic and "pseudoallergic" reactions, which develop within minutes to hours of administration. Allergic reactions are abnormal immunologic reactions to NSAIDs, while pseudoallergic reactions are nonimmunologic reactions that are believed to result from acquired alterations in the biochemical pathways upon which NSAIDs act.

The prevalence of allergic and pseudoallergic reactions to NSAIDs in the general population is not known. These reactions occur sporadically in both children and adults. Symptoms include rhinoconjunctivitis, bronchospasm, urticaria/angioedema, and anaphylaxis.

In addition to allergic reactions, there are various types of idiosyncratic adverse reactions to NSAIDs that are presumed or known to involve other types of immune mechanisms. These include, but are not limited to, aseptic meningitis, hypersensitivity pneumonitis, thrombocytopenia, interstitial nephritis, erythema multiforme, fixed drug eruptions, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema nodosum, maculopapular eruptions, and bullous leukocytoclastic vasculitis [1]. These types of reactions are discussed in various topic reviews. (See "Nonselective NSAIDs: Overview of adverse effects" and "Drug eruptions" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

The clinical manifestations of allergic and pseudoallergic reactions caused by NSAIDs will be reviewed here. The challenge protocols used by allergy specialists to evaluate and manage affected patients are presented separately. (See "Diagnostic challenge and desensitization protocols for NSAID reactions".)

CLASSIFICATION OF NSAIDs — NSAIDs inhibit the cyclooxygenase (COX) enzymes (also known as prostaglandin H synthases). There are two known COX isoforms: COX-1 and COX-2.

●COX-1 is expressed constitutively in all human cell types and is involved in protective physiologic functions, such as gastric mucosal protection. Inhibition of COX-1 impairs these protective functions and is generally undesirable. As an example, COX-1 inhibition by NSAIDs results in diminished production of the protective compound prostaglandin E₂ in the gastric mucosa, leading to gastritis in susceptible patients.

●COX-2 is an inducible enzyme expressed in many inflammatory cells in the presence of appropriate stimuli. COX-2 mediates the generation of the same range of prostaglandins as COX-1 but only at sites of inflammation. Thus, COX-2 inhibition is largely responsible for the desired antiinflammatory effects of NSAIDs.

The various NSAIDs inhibit COX-1 and COX-2 to different degrees. Aspirin is a strong inhibitor of COX-1. In this topic, NSAIDs that inhibit COX-1 are said to be "cross-reactive" with aspirin (table 1). NSAIDs that inhibit both COX-1 and COX-2 are called "nonselective," while those that predominantly inhibit COX-2 are called "COX-2 selective." Within the group of selective NSAIDs are those that are weakly selective for COX-2 but also inhibit COX-1, such as nabumetone, meloxicam, and nimesulide (not available in the United States). Other agents are considered highly selective for COX-2, such as celecoxib.

The mechanism of action of NSAIDs and the different types of agents available are reviewed in more detail separately. (See "NSAIDs (including aspirin): Pharmacology and mechanism of action" and "Overview of COX-2 selective NSAIDs".)

CLASSIFICATION OF REACTIONS — NSAID reactions can be categorized as either pseudoallergic or allergic. Pseudoallergic reactions are induced by multiple different NSAIDs, while allergic reactions are usually induced by a single NSAID or a small number of structurally similar agents:

●Pseudoallergic NSAID reactions – Pseudoallergic reactions are nonimmunologic reactions that are related to the cyclooxygenase (COX) 1-inhibiting properties of the drug. In susceptible individuals, these reactions may be elicited by any NSAID that inhibits COX-1, including aspirin (table 1). Affected patients are believed to have acquired alterations in the biochemical pathways affected by COX-1-inhibitors, although the precise mechanism underlying pseudoallergic reactions has not been established.

●Allergic NSAID reactions – Allergic NSAID reactions are presumed to be immunoglobulin E (IgE) mediated immunologic reactions based upon their clinical characteristics. These are elicited by a single NSAID in a susceptible individual.

PSEUDOALLERGIC REACTIONS — Pseudoallergic reactions are elicited by any cyclooxygenase (COX) 1-inhibiting NSAID, and the likelihood that an NSAID will cause these in a susceptible patient is related to the strength with which that drug inhibits COX-1. 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 can be divided into four types (table 2) [1]:

●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 (mixed respiratory and/or cutaneous) reactions in otherwise asymptomatic individuals

Type 1: NSAID-induced asthma and rhinosinusitis — NSAID ingestion precipitates a constellation of nasoocular and/or lower respiratory symptoms in some patients with concomitant asthma and chronic rhinosinusitis (often with nasal polyposis). These include one or more of the following: rhinorrhea, nasal congestion, periorbital edema and/or injection of the conjunctiva, bronchospasm, and/or laryngospasm. Some patients can experience hives and/or angioedema in addition to the respiratory tract symptoms. A few patients with severe respiratory reactions have accompanying extra respiratory tract symptoms, such as flushing, abdominal pain, diarrhea, and hypotension. These reactions are termed "type 1 pseudoallergic reactions." Type 1 reactions typically begin one to three hours after administration.

Patients with the combination of NSAID pseudoallergy, asthma, and chronic rhinosinusitis with nasal polyposis are said to have aspirin-exacerbated respiratory disease (AERD). Another term for this disorder is NSAID-exacerbated respiratory disease (NERD). AERD and the diagnosis of aspirin pseudoallergy are discussed in detail separately. (See "Aspirin-exacerbated respiratory disease" and "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization".)

Type 2: NSAID-induced urticaria/angioedema in patients with chronic urticaria — Patients with a history of chronic urticaria can develop an exacerbation of their hives, sometimes with angioedema, beginning 30 to 90 minutes after ingestion of aspirin or NSAIDs that inhibit COX-1 [2-4]. The exacerbating effects of NSAIDs may be noticeable in up to 30 percent of patients with stable chronic urticaria, and higher rates of NSAID sensitivity are typical in patients with active urticaria [5]. These reactions are usually dose dependent.

Avoidance of COX-1-inhibiting NSAIDs can be helpful in minimizing acute flares in chronic urticaria, although it does not appear to alter the long-term course of the condition [6,7]. Pharmacotherapy of patients with chronic urticaria is reviewed separately. (See "Chronic spontaneous urticaria: Standard management and patient education".)

Type 3: NSAID-induced urticaria/angioedema in otherwise asymptomatic individuals — In this form of pseudoallergy, children and adults without underlying chronic urticaria develop acute urticaria and/or angioedema 30 to 90 minutes after ingestion of COX-1-inhibiting NSAIDs. Isolated angioedema following NSAID ingestion typically involves the facial areas, particularly the periorbital skin, lips, and mouth. 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 underlying chronic urticaria (ie, recurrent episodes of urticaria/angioedema persisting for six weeks or longer). It is not known whether these patients subsequently develop chronic urticaria more frequently than the general population.

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. In addition, such patients usually tolerate highly selective COX-2-inhibiting NSAIDs (eg, celecoxib) [8,9].

Type 4: Blended reactions in otherwise asymptomatic individuals — Occasionally, reactions to NSAIDs/aspirin do not fit into the above three reaction types. Some patients with underlying AERD develop cutaneous symptoms as well as respiratory symptoms in response to NSAIDs and are included in this group. Patients without apparent underlying conditions may develop combinations of symptoms affecting both the respiratory tract and skin, including bronchospasm, rhinitis, urticaria, and/or angioedema after ingestion of different COX-1-inhibiting NSAIDs. These reactions are usually triggered by multiple COX-1-inhibiting NSAIDs and may represent a combination of mechanisms. Until they are better characterized, these reactions have been classified as a separate type.

The time course of type 4 reactions is variable. The author has observed the following patterns: Reactions that are purely cutaneous usually appear within 30 minutes, while patients with AERD with cutaneous symptoms as part of respiratory reactions show a delay identical to patients with type 1 reactions (with an average delay after administration of approximately 90 minutes). Patients with both cutaneous and respiratory reactions, but without underlying AERD, typically react at approximately 60 minutes.

ALLERGIC 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. Patients with allergic reactions to an NSAID have had at least one prior exposure to the culprit drug, which presumedly sensitizes them and results in symptoms upon repeat exposure to the same drug [10,11].

These reactions are believed to be immunoglobulin E (IgE) mediated, and the allergen is thought to be a drug metabolite bound to a carrier protein. In the United States, most of these reactions have been associated with ibuprofen, the first NSAID to become available over the counter, although they can happen with any NSAID. There has been one case report of aspirin-induced angioedema with measurable specific IgE to aspirin/human serum albumin complex [12]. However, the generalizability of this finding is unknown, and there are no practical or commercially 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 solely upon the severity of the symptoms (table 2). The underlying mechanism is believed to be the same. It is possible that most patients with type 5 reactions would progress to anaphylaxis (type 6) if they took the same NSAID repeatedly. Thus, some experts consider types 5 and 6 to be different severities of the same type of reaction.

Type 5: Urticaria/angioedema to a single NSAID — Patients with type 5 reactions typically develop urticaria and/or angioedema within minutes to one hour of taking a particular NSAID [9,13]. Affected individuals generally do not have underlying chronic urticaria.

Type 6: Anaphylaxis to a single NSAID (not aspirin) — Type 6 reactions are distinguished from type 5 reactions based only upon severity. Patients with anaphylaxis have usually experienced urticarial reactions to the culprit NSAID in the past but did not realize the association and continued to reexpose themselves to the drug. Typical symptoms of anaphylaxis include shortness of breath/wheezing due to bronchospasm or laryngeal edema and hypotension due to vascular collapse. (See "Anaphylaxis: Emergency treatment".)

Anaphylaxis has been reported with various NSAIDs, including most of the cyclooxygenase (COX) 1-inhibiting agents [14-17], as well as from celecoxib (a highly selective COX-2 inhibitor) [18,19]. Ibuprofen is the NSAID most commonly implicated in severe anaphylaxis in the United States, whereas diclofenac is more common in France, and the pyrazole NSAIDs (phenylbutazone, oxyphenbutazone, azapropazone) are commonly implicated in Spain [10,20]. It is notable that there are no confirmed cases of anaphylaxis to aspirin itself. This is one reason that aspirin is used in challenge procedures. (See 'Diagnostic strategy' below.)

There are also reports of anaphylaxis due to acetaminophen (paracetamol) [21,22]. This agent is an antipyretic and pain reliever, rather than an antiinflammatory.

DIAGNOSIS — NSAID reactions range from mild to life threatening and are challenging to diagnose because some of the signs and symptoms of minor and severe reactions are similar. The presumptive diagnosis of an allergic or pseudoallergic reaction to an NSAID is based upon the historical details of the reaction. In some situations, an aspirin challenge procedure can be performed to assess specificity. However, challenges should be done by clinicians trained in performing them. There are no validated in vitro or skin testing methods available.

History — Certain critical pieces of information should be obtained from the history, if possible:

●Is the reaction elicited by one NSAID or multiple NSAIDs? It is important to discern if the patient took any other cyclooxygenase (COX) 1-inhibiting NSAIDs subsequent to the first recognized reaction. If so, did this drug also cause a reaction? If other NSAIDs also caused symptoms, then the patient has pseudoallergic reaction. In contrast, NSAIDs that were ingested without problems before the first reaction are not relevant, because reactions to NSAIDs are nearly always acquired (rather than present from birth).

●Is there underlying asthma/rhinosinusitis/nasal polyposis (ie, aspirin-exacerbated respiratory disease [AERD]) or chronic idiopathic urticaria? Any recurrent symptoms of asthma or sinus problems or previous episodes of urticaria should be explored to discern if one of these conditions may be present but undiagnosed. These chronic conditions usually develop before the NSAID reaction, with rare exceptions.

Testing — For types 1 to 4 NSAID reactions, there are no validated in vitro or skin testing methods available. However, there may be exceptions for some type 5 and 6 reactions. As an example, in a series of six cases of severe anaphylaxis to diclofenac, intradermal skin testing was positive in four patients, at concentrations ranging from 0.25 to 25 mg/mL [20]. In this series, a parenteral preparation of diclofenac was available for skin testing, though testing results with control patients was not reported. Intravenous preparations of ketorolac are available as well, and skin testing can be performed with concentrations ranging from 0.001 to 0.01 mg/mL [23]. Intravenous ibuprofen is available but extremely expensive.

Challenge procedures — If a definitive diagnosis is required, then a challenge procedure must be performed. In most situations, this is only indicated if the patient has a medical need for future NSAID therapy. If so, a challenge procedure can determine if the patient tolerates NSAIDs other than the one that caused the reaction or could be desensitized to NSAIDs. Challenges with the culprit drug are only rarely done to confirm a type 5 or 6 reaction to a specific NSAID since this can elicit severe anaphylaxis [20].

Diagnostic strategy — It is sometimes difficult to determine what type of reaction has occurred if a patient has had only one event and has avoided all NSAIDs since. As an example, if a patient with asthma developed flushing and bronchospasm after taking diclofenac, then the reaction may have been type 1, type 4, or type 5. Without additional information, the clinician must initially advise the patient to avoid all NSAIDs.

A diagnostic strategy used successfully at the author's center for decades is to challenge patients with past reactions to NSAIDs using an aspirin challenge protocol. Aspirin is a potent COX-1 inhibitor, and it has not been implicated in type 5 or 6 reactions. Thus, if the patient reacts to aspirin, the patient has a pseudoallergic reaction. If there is no reaction to aspirin, the patient likely has an isolated type 5 or 6 reaction to the NSAID that caused the past reaction.

The protocols used for aspirin challenge and desensitization are reviewed separately. (See "Diagnostic challenge and desensitization protocols for NSAID reactions" and "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization".)

MANAGEMENT — The type of NSAID reaction (ie, pseudoallergic or allergic) determines the possible management options. If the symptoms of the reaction were severe and the type of reaction is uncertain, then the patient should avoid all NSAIDs until further evaluation can be performed.

Referral — NSAID reactions can be challenging to diagnose because the various types of reactions can have overlapping signs and symptoms. Referral to an allergist/immunologist with expertise in drug allergy is recommended if the reaction was severe or life threatening or if avoidance of all NSAIDs is not a feasible option for the patient.

Advice on avoidance — Patients with allergic or pseudoallergic reactions to NSAIDs should be advised to read over-the-counter medications labels carefully:

●Combination medications, such a multisymptom cold preparations, often contain NSAIDs.

●Dietary salicylates do not cause symptoms in NSAID-sensitive patients as they are not significant cyclooxygenase (COX) 1 inhibitors.

Reactions of uncertain type — If the type of NSAID reaction cannot be determined based upon the available historical information and the patient's underlying conditions, then the simplest approach is avoidance of all NSAIDs.

●For treatment of minor pain, most patients can safely receive doses of acetaminophen (paracetamol), up to 650 mg per dose. This includes patients with aspirin-exacerbated respiratory disease (AERD) and extreme sensitivity to COX-1 inhibitors. However, approximately 20 percent of patients with AERD react to acetaminophen at a dose of 1000 mg [24] since acetaminophen weakly inhibits COX-1 at higher doses. Patients with AERD are usually identifiable clinically by the presence of concomitant asthma and chronic rhinosinusitis.

●Opioid pain medications are an option for more severe pain.

Types 1 to 4: Treatment options — Patients with pseudoallergic NSAID reactions who require subsequent antiinflammatory therapy have several options. The best option for an individual patient depends upon that patient's antiinflammatory and pain relief needs.

Acetaminophen only — Acetaminophen (paracetamol) is usually tolerated at doses up to 650 mg (per dose) [24]. This is the simplest option for patients with types 1 to 4 pseudoallergic reactions, provided acetaminophen provides adequate pain relief and antiinflammatory therapy is not needed. Patients with AERD sometimes react to higher doses of acetaminophen (ie, 1000 mg) since it weakly inhibits COX-1 at these doses. (See 'Reactions of uncertain type' above.)

Weak COX-1 inhibitors — The NSAIDs listed below are non-acetyl salicylates and weak inhibitors of COX-1. One of these agents is a reasonable choice for patients who require some antiinflammatory effect and can obtain adequate pain relief with a relatively weak NSAID. At higher doses, these agents may inhibit COX-1 enough to cause symptoms, so we suggest limiting the dose to that specified for each drug. Even with these lower doses, highly sensitive patients may develop symptoms.

●Salsalate (up to 2000 mg daily, divided into two or three doses)

●Diflunisal (up to 1000 mg daily, divided into two or three doses)

Because not all patients will tolerate these agents, we suggest that any patient whose reaction to standard NSAIDs was severe should be in a medically supervised setting when these agents are administered for the first time. We administer the highest dose that we expect the patient to tolerate (ie, the doses specified above) and observe for three hours.

NSAIDS that are weakly selective for COX-2, but also inhibit COX-1 to some degree, include nabumetone, meloxicam, and nimesulide (not available in the United States) (table 1). A meta-analysis of controlled trials found that 1 in 13 patients with AERD reacted to these weakly selective COX-2 inhibitors [25]. Data are limited for patients with other types of pseudoallergic reactions. Thus, these agents should either be avoided or given for the first time in a medically supervised setting if the patient's past reaction to NSAIDs was severe.

Highly selective COX-2 inhibitors — Highly selective COX-2 inhibitors demonstrate at least a 200- to 300-fold selectivity for inhibition of COX-2 over COX-1 at the defined therapeutic doses. Highly selective COX-2 inhibitors are tolerated by most patients with pseudoallergic reactions to NSAIDs, with the exceptions discussed below. This option is appropriate for patients who need an antiinflammatory agent or have had gastrointestinal toxicity with NSAIDs and are not seeking to take aspirin for its cardioprotective effects. Selective COX-2 inhibitors include celecoxib (available worldwide), etoricoxib, parecoxib, and lumiracoxib (the last three are not available in the United States). The dosing and side effects of COX-2 inhibitors are reviewed separately. (See "Overview of COX-2 selective NSAIDs".)

●Patients with aspirin-intolerant asthma and AERD, with type 1 pseudoallergy to nonselective NSAIDs, can safely take COX-2 inhibitors, as shown in a meta-analysis of 14 placebo-controlled, blinded clinical trials [25]. This meta-analysis included 426 adults with AERD and challenge-proven reactions to aspirin or other NSAIDs who underwent blinded challenges with standard doses of COX-2 inhibitors. No reactions were observed. However, the authors noted that moderate doses of COX-2 inhibitors were used in all studies, so these data do not exclude the possibility that some very sensitive patients might still react to very high doses of these agents. Until that is known, it is prudent to recommend that patients begin with a low dose of COX-2 inhibitor and increase the dose gradually, as tolerated, if high-dose therapy is needed. However, as AERD patients can generate normal amounts of this inducible enzyme, it is the author's approach simply to tell patients with AERD that it is safe to take COX-2 inhibitors and to recommend a specific initial dose. However, if the patient is anxious about this or the clinician is not confident about some aspect of the patient's history, it is advisable to be cautious and either refer the patient to a drug allergy expert or to administer the first dose in a supervised setting.

●Patients with type 3 pseudoallergy (urticaria/angioedema in otherwise asymptomatic individuals) usually tolerate highly selective COX-2 inhibitors, although one study did not find this. In this report of 252 subjects with type 3 pseudoallergy, 25 percent developed symptoms after taking a highly selective COX-2 inhibitor, etoricoxib. The reactions were quite mild and resolved rapidly after administration of diphenhydramine. Some of these patients had reacted to 1000 mg acetaminophen (paracetamol) in placebo-controlled challenges, indicating sensitivity to even weak COX-1 inhibition (note that this dose is higher than the 650 mg recommended in this review) [26]. Based on this one report, some clinicians may prefer to give an initial dose of COX-2 inhibitor to highly sensitive patients with type 3 pseudoallergy in a medically supervised setting (eg, a clinic), at least until these data have been reproduced. Additional case reports of possible reactions to COX-2 inhibitors exist, although these are likely flawed [27,28].

●Among patients with types 2 and 4 pseudoallergy, all except rare individuals will tolerate highly selective COX-2 inhibitors.

Desensitization — Desensitization is a technique in which the patient is given incrementally increasing doses of a medication under medical supervision to induce a state of temporary tolerance. After a patient has been successfully desensitized to an NSAID, that agent or another equivalent NSAID must be ingested daily in order to maintain tolerance. Therefore, desensitization is appropriate in patients who require daily NSAIDs for an inflammatory disorder or aspirin for antiplatelet therapy.

NSAID desensitizations are usually performed by allergy specialists. Some pulmonary specialists are also experienced in this procedure. The supervising specialist should have experience in recognizing and treating the symptoms that may arise during these procedures. Desensitizations are performed in medical settings with appropriate medications, equipment, and support staff. NSAID desensitizations are discussed separately. (See "Diagnostic challenge and desensitization protocols for NSAID reactions".)

The different types of pseudoallergic reactions are variably amenable to desensitization:

●Type 1: Aspirin/NSAID-induced rhinosinusitis and asthma – Patients with AERD can nearly always be desensitized to aspirin. Once they have been successfully desensitized to aspirin, they are able to ingest other NSAIDs safely and can take different NSAIDs interchangeably. Desensitization enables AERD patients with cardiovascular disease to take prophylactic daily aspirin or those with rheumatologic conditions to take daily NSAIDs. Furthermore, daily aspirin therapy ameliorates the inflammation underlying sinus and pulmonary disease in AERD and can be used to treat both asthma and chronic rhinosinusitis with nasal polyposis. Aspirin desensitization and the management of AERD are reviewed separately. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization".)

●Type 2: Aspirin/NSAID-induced urticaria/angioedema with underlying chronic urticaria – Patients who need antiinflammatory or pain medications may tolerate a highly selective COX-2 inhibitor or an NSAID that weakly inhibits COX-1, as outlined above. This is the preferred management approach.

Desensitization is not generally a useful modality in these patients [5,29]. Although they can sometimes be successfully desensitized at first, almost all patients have recurrent reactions over time, presumably because the ongoing presence of NSAIDs aggravates the underlying chronic urticaria [5,29,30].

Despite this, patients with type 2 reactions who need aspirin for cardioprotection can sometimes tolerate 81 mg (or 100 mg) dose of aspirin daily without significant worsening of their symptoms. An approach for rapidly introducing low-dose aspirin is detailed elsewhere. (See "Introduction of aspirin to patients with aspirin hypersensitivity requiring cardiovascular interventions", section on 'Indications for urgent aspirin therapy'.)

●Type 3: Aspirin/NSAID-induced urticaria/angioedema without underlying chronic urticaria – Patients with type 3 pseudoallergic reactions can be successfully desensitized, although it may be difficult because they tend to react multiple times during the desensitization procedure. Suggestions for approaching desensitization in these patients are found separately. (See "Diagnostic challenge and desensitization protocols for NSAID reactions".)

●Type 4: Blended reactions in otherwise asymptomatic individuals – Desensitization can be attempted in patients with type 4 pseudoallergic reactions, but it is not uniformly successful. (See "Diagnostic challenge and desensitization protocols for NSAID reactions".)

Types 5 and 6: Treatment options — Types 5 and 6 reactions are presumed to be IgE-mediated reactions to specific 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 make this determination. This can be safely undertaken by an allergy specialist even in patients with life-threatening anaphylaxis to an NSAID since 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 [31]. Chemical groupings of NSAIDs are shown in the table (table 3). Desensitization to the individual NSAID to which the patient is allergic is not indicated, since there is an array of alternative COX-1 inhibitors available.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Drug allergy and hypersensitivity".)

SUMMARY AND RECOMMENDATIONS

●Classification of reactions to NSAIDs – Adverse and idiosyncratic reactions to nonsteroidal antiinflammatory drugs (NSAIDs) (including aspirin [ASA]) may be classified as pseudoallergic or allergic (table 2). (See 'Classification of reactions' above.)

●Pseudoallergic reactions – Pseudoallergic reactions are related to the inhibition of cyclooxygenase (COX) 1 and may be triggered by aspirin and all ("cross-reacting") COX-1-inhibiting NSAIDs (table 1). Pseudoallergic reactions are usually seen in patients with certain preexisting conditions, specifically either the combination of asthma, nasal polyps, and chronic rhinosinusitis (ie, aspirin- or NSAID-exacerbated respiratory disease [AERD or NERD]) or chronic urticaria. (See 'Pseudoallergic reactions' above.)

●Allergic reactions – Allergic reactions to NSAIDs are characterized by urticaria, angioedema, or anaphylaxis in response to a single drug or a small number of structurally related drugs. These reactions are presumed to be immunoglobulin E (IgE) mediated, although there are limited data about mechanism(s). (See 'Allergic reactions (presumed IgE-mediated)' above.)

●Diagnosis – The presumptive diagnosis of an allergic or pseudoallergic reaction to an NSAID is based upon the historical details of the reaction(s) and the presence of certain underlying conditions. It is critical to determine if the patient has taken other NSAIDs since the initial reaction and whether the other drugs also caused symptoms. There are no in vitro tests, and skin testing methods are only reported for very few NSAIDs. Definitive diagnosis requires a challenge procedure, although this is only indicated if the patient has a specific need for subsequent NSAID therapy. (See 'Diagnosis' above.)

●Challenge procedures – Challenge procedures have been established for the evaluation of both allergic and pseudoallergic NSAID reactions. These should be performed by allergy specialists with experience in the techniques involved. (See "Diagnostic challenge and desensitization protocols for NSAID reactions".)

●Management options – Management depends upon the type of NSAID reaction present:

•Patients with reactions to NSAIDs that cannot be characterized as pseudoallergic or allergic based on the available information should avoid all NSAIDs, if possible. If treatment of minor pain is required, we suggest acetaminophen (paracetamol; ie, up to 650 mg per dose). Patients should be advised to use the lowest dose that effectively manages their pain. If subsequent antiinflammatory therapy is required, the patient should be referred to an allergy specialist with expertise in drug reactions for further evaluation. (See 'Reactions of uncertain type' above.)

•Patients with pseudoallergic reactions to NSAIDs (types 1 to 4) do not need to avoid dietary salicylates and have several options for future therapy:

-Administration of acetaminophen (paracetamol) at doses no higher than 650 mg per dose. This is the simplest option for patients in whom acetaminophen (paracetamol) provides adequate pain relief and antiinflammatory therapy is not necessary. (See 'Acetaminophen only' above.)

-Administration of moderate doses of an NSAID that weakly inhibits COX-1, such as salsalate or diflunisal. This is an option for patients who can obtain adequate relief with one of these relatively weak NSAIDs. (See 'Weak COX-1 inhibitors' above.)

-Administration of a highly selective COX-2-inhibiting NSAID, such as celecoxib. This option is appropriate for patients who need a stronger NSAID or have gastrointestinal intolerance to standard NSAIDs and are not specifically seeking the antiplatelet actions of aspirin. (See 'Highly selective COX-2 inhibitors' above.)

-Referral to an allergy specialist for possible NSAID desensitization. Desensitization is appropriate in patients who require daily NSAIDs for an inflammatory disorder or aspirin for antiplatelet therapy. Desensitization is nearly always successful in patients with type 1 (AERD) pseudoallergic reactions. It is variably successful in patients with types 2, 3, and 4 reactions. (See 'Desensitization' above.)

•Patients with allergic reactions to a specific NSAID (types 5 and 6) should avoid the causative agent and other NSAIDs in the same chemical grouping (table 3). However, in many cases, the history is not sufficient to make a definite diagnosis of a type 5 or 6 reaction, and patients should be referred to an allergy specialist with experience in NSAID challenges for a diagnostic challenge with aspirin to exclude pseudoallergy. Once a definitive diagnosis has been made, patients may safely take NSAIDS that are structurally dissimilar to the drug that caused the initial reaction. (See 'Types 5 and 6: Treatment options' above.)