• aspirin;
  • drug hypersensitivity;
  • nonsteroidal anti-inflammatory drugs;
  • oral drug challenges;
  • tolerance

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used analgetic therapeutics worldwide and are known to cause about 21–25% of all the adverse drug reactions (1, 2). The common mechanism of action, inhibition of cyclo-oxygenases (COX), seems to explain the observed cross-reactivity between nonselective COX-1/2 inhibitors and tolerability of selective COX-2 inhibitors. Assuming that cross-reactivity exists mainly between COX-1 inhibitors, oral challenges with COX-2 inhibitors are often primarily carried out in case of a drug reaction to a COX-1 inhibitor, to identify a safe alternative NSAID (3). This practice may however result in unnecessary avoidance of potentially useful nonselective NSAIDs, while treatment options in the management of pain, inflammation, and anticoagulation are already limited. The aim of this study was to determine the tolerance of aspirin (a nonselective COX inhibitor) in 14 patients with proven hypersensitivity to nonselective COX inhibitors.

To all patients, diagnosed with NSAID-hypersensitivity in our clinic between 2003 and 2009, whom passed a challenge with a selective COX-2 inhibitor (n = 50), we offered an additional challenge with aspirin. Of these 50 patients, 18 were willing to undergo this challenge. Patients with hypersensitivity to three or more NSAIDs, known hypersensitivity to aspirin, or current use of aspirin without symptoms, were excluded (n = 4). Fourteen patients could participate in this study (Table 1). Mean age of the study group was 49 years, 78.6% were women. All patients experienced at least one episode of hypersensitivity symptoms (consisting of urticaria (n = 10), angioedema (n = 7), dyspnea, (n = 2) and/or anaphylactic shock (n = 8)), subsequent to ingestion of one (n = 13) or more (n = 1) NSAID(s). The diagnosis was based on a detailed and reliable history (n = 11), or an oral challenge with the culprit drug in cases with a doubtful history (n = 3).

Table 1.   Clinical features and results of oral aspirin challenges
Patient numberSex/ageCo-morbid disordersCulprit drugType of reactionManner of diagnosisOral challenges
  1. NS, none specific; CU, chronic urticaria; As, asthma; ibu, ibuprofen; dic, diclofenac; prop, propyfenazon; nap, naproxen; An, anaphylaxis; U, urticaria; D, dyspnea; A, angioedema; PH, patient history; C, challenge test; Neg, negative reaction.

 4M/21NSprop, ibuU/APH/CNeg

Single blind placebo-controlled aspirin challenges were performed. The oral challenge protocol, adapted from EAACI guidelines (4), consisted of oral administration of placebo on the first and aspirin on the second day. Aspirin was given in five increasing doses: 10 mg with a time interval of 30 min, 44 mg, 117 mg, and 312 mg with an interval of 60 min, and 500 mg after an interval of 120 min. Patients were observed for at least 3 h after the last dose. A challenge test was considered to be positive at the presence of pruritis and erythema, urticaria, angioedema, dyspnea or 30 mmHg drop in systolic blood pressure (SBP).

No reactions to placebo were observed. Eleven (78.6%) of the 14 patients tolerated aspirin. Three (21.4%) patients experienced mild angioedema, after which the challenge was discontinued. Two of them had symptoms after ingestion of 44 mg (cumulative dose: 54 mg), one after intake of 117 mg (cumulative dose: 171 mg).

We observed that more than three-quarters (78.6%) of the patients tolerated aspirin. This correlates with the study of Asero (5), showing aspirin tolerance in 76% of 117 patients with NSAID-hypersensitivity. In this study, only cutaneous symptoms were observed. This might be attributed to the fact that only patients with a history of a cutaneous reaction were included, in contrast to our study. We included eight (57.1%) patients with a history of anaphylactic shock. Seven of these patients also tolerated aspirin.

Aspirin is tolerated in most (78.6%) of the patients with NSAID-hypersensitivity; limiting of the NSAID-repertoire as a result of hypersensitivity to a single NSAID is unnecessary. Oral challenges should be performed to confirm tolerance.


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