**4.3 The single-blind, placebo controlled oral challenge with NSAID: how do we do it?**

The SBPCOC with NSAID is the gold standard for the diagnosis of skin NH. SBPCOC is indicated in 3 main scenarios: 1) to confirm/discard if the NSAID involved in the reaction is responsible (especially in those cases where the history is not very suggestive of a reaction to NSAID); 2) To confirm/exclude multiple reactivity among potent COX-1 inhibitors with another NSAID, usually aspirin; and 3) to identify potential alternative NSAIDs that are well tolerated by the patients.

However, there are several clinical situations in which it is contraindicated: If there is severe or uncontrolled bronchial asthma, active spontaneous urticaria/ angioedema, pregnancy, active infection, and a recent vaccination (≤ 1 week) and uncontrolled psychiatric disorders. Relative contraindications are also the use of beta-blockers or ACE-inhibitors.

We propose an order of administration of NSAIDs trying to stratify them according to the in vitro potency of COX-1 and COX-2 inhibition (**Table 2**) [3, 14]. This risk stratification management makes us start with, some of the selective COX-2 inhibitors (etoricoxib and celecoxib). Later, if there is no clinical response, the preferential COX-2 NSAIDs are continued (with a dose-dependent inhibitory effect on COX-1, as was the case with meloxicam). Thirdly, if there is no clinical response, a weak NSAID inhibiting both isoforms (e.g. paracetamol) will be administered; to continue, finally, with the potent COX-1 and COX-2 inhibitors.

Stratification of NSAIDs according to their COX-1 inhibition potency allows, to generate effective alternatives that these patients can take if the response during SBPCOC is negative; and to confirm the pattern of reactivity between NSAIDs that allows us to classify clinical phenotypes appropriately.

In the case of NECD the ideal is to carry out the study in a period of remission of chronic spontaneous urticaria. If this is not possible, we will titrate the treatment with antihistamines until the minimum effective control dose is achieved and then perform the SBPCOC. A complete withdrawal of all anti-histamines may determine a high rate of false positives in this subset of patients with NH [8].

The existence of NSAID anaphylaxis contraindicates the use of that specific NSAID or other structurally related one during SBPCOC [3, 8]. However, this type of reaction presents a selective pattern of sensitivity to NSAID, and even those with high COX-1 inhibition potency can be taken with impunity.
