Q: Should patients with a history of NSAID sensitivity avoid all NSAIDs?
A: To answer the question, we need to review the different types of non-steroidal anti-inflammatory drugs (NSAIDs) and sensitivity reactions.
NSAIDs are used commonly to relieve pain and inflammation. They are available as over-the-counter and prescription products. However, approximately 2% of the population will develop a sensitivity to NSAIDs.1 This sensitivity is manifested by allergic reactions, such as bronchospasm, urticaria/angioedema, and anaphylaxis, which may or may not be immunoglobulin E (IgE) dependent.2-4 NSAID sensitivity is more common in patients with asthma. About 20% of patients with asthma will have sensitivity to aspirin or NSAIDs, with women being 2.5 times more likely to be affected.4
Pathophysiology of Reactions
NSAIDs exert their mechanism of action by inhibiting cyclo-oxygenase (COX), a key enzyme responsible for the biosynthesis of prostanoids, including prostaglandins.5,6 Nonselective NSAIDs inhibit both COX-1 and COX-2. The COX-1 isoform is constantly expressed in tissue and regulates protection of the gastric mucosa, platelet activation, and renal function.7 Inhibition of COX-1 is thought to be largely responsible for some of the adverse events (AEs) associated with NSAIDs, including most sensitivity reactions. In contrast, inhibition of the COX-2 isoform primarily is responsible for the anti-inflammatory effects of NSAIDs.
As noted, the majority of sensitivity reactions are thought to be due to COX-1 inhibition, which leads to diminished levels of prostaglandin E2 and increased levels of leukotrienes.2,4 Less prostaglandin E2 inhibits normal histamine release from mast cells. Increases in leukotrienes may cause bronchoconstriction and increased mucus production, leading to respiratory symptoms of NSAID sensitivity. Leukotrienes also may be responsible for other common reactions to aspirin and NSAIDs, specifically urticaria and angioedema.4
Drug Considerations (COX -1 vs COX- 2 Selective)
To best determine the safest NSAID, the clinician must first differentiate between possible AEs of NSAIDs, such as upset stomach, and sensitivity reactions (eg, respiratory, dermatologic).2 This can be done by taking a careful medical history. Once a reaction has been determined to be a sensitivity reaction, then the clinician must determine whether the patient is allergic to all NSAIDs or just one type of NSAID.
Table 1lists NSAIDs by their COX-1 and COX-2 sensitivity.8,9 To determine NSAID cross-reactivity, clinicians can conduct an oral drug challenge by exposing the patient to a different NSAID than the one linked to the sensitivity reaction. The patient is given a fraction of the full dose, titrating up every hour and evaluating for a reaction until a full dose is administered.
Respiratory reactions to aspirin begin within 2 to 3 hours; urticaria generally occurs within 4 hours (up to 24 h), but it can occur as quickly as 15 minutes after administration.3 If no reaction occurs within 3 to 4 hours, that NSAID likely is safe to use. If there is reactivity, a selective COX-2 inhibitor, such as celecoxib (Celebrex), may be tested. If the patient reacts to the COX-2 inhibitor, then all NSAIDs should be avoided.10 Patients with a history of asthma or chronic urticaria should have their primary condition under control before undergoing a NSAID challenge because patients with these diseases are more prone to cross-reactivity.3
A retrospective analysis carefully exposed patients with a history of NSAID hypersensitivity (presenting as urticaria, angioedema, and respiratory symptoms) to celecoxib and meloxicam (Mobic, others). Asthma was present in 27% of the population. Of the patients challenged with celecoxib 200 mg, 4 out of 78 patients had a positive reaction (5.1%); of those challenged with 7.5 mg of meloxicam, 11 out of 112 patients (9.8%) reacted.11 The study found that allergic reactions to celecoxib and meloxicam were relatively uncommon—94.9% and 90.2% of the patients, respectively, tolerated these drugs. In another study, investigators tested patients who had prior NSAID sensitivity with meloxicam 15 mg; 49 of the 51 patients (96%) were found to be able to tolerate meloxicam.12
Acetaminophen (Tylenol, others) generally is a safe alternative in NSAID-sensitive patients; however, each dose should be less than 1,000 mg to prevent COX-1 inhibition. The drug has both analgesic and antipyretic activity, and its effects have been noted to be similar to those of aspirin.5 Acetaminophen exerts its mechanism of action via one or more central nervous system pathways.13 These proposed mechanisms include a serotonergic pathway, a central COX-3 pathway, and a cannabinoid-mediated pathway. It has poor inhibition of the COX-1 and COX-2 isoforms, which distinguishes it from NSAIDs. Acetaminophen’s antipyretic effects are attributed to inhibition of the activity of the hypothalamic heat-regulation center.7
Patients with a sensitivity to aspirin, especially patients with aspirin-exacerbated respiratory disease (AERD), should avoid greater than 1,000 mg doses of acetaminophen.1,3 Patients with AERD may be treated with COX-2 inhibitors after administering a test dose in a physician’s office. One other option for patients severely sensitive to aspirin and NSAIDs is aspirin desensitization. This is recommended only when clinicians are planning long-term use of aspirin, such as for cardiac event prophylaxis, because daily doses must be administered to preserve desensitization.1,2
As noted, celecoxib is tolerated by most patients who experience urticaria, angioedema, and/or respiratory symptoms from aspirin or NSAIDs, with only a few experiencing cutaneous reactions.3,11 Although celecoxib is a potentially safe treatment for pain in sensitive patients, long-term use is discouraged due to increased risks of thrombotic events (eg, stroke, pulmonary embolism, heart attack), and caution must be used in patients with a history of cardiovascular disease.1,14 Celecoxib should not be used in patients with the aspirin triad (asthma, nasal polyps, and aspirin sensitivity); however, if a patient wants, the drug may be trialed with the first full dose administered in a medical setting where treatment can be given if a reaction occurs.1,2,11
If a patient has a true IgE-mediated allergy to a particular NSAID, other NSAIDs are not likely to have the same reaction, but confirming a true immunologic response is challenging.2 NSAIDs with the same chemical structural classification should be avoided because there is high cross-reactivity between similar groups.1,4 For example, diclofenac and ketorolac (Sprix, others) are heteroaryl acetic acids; indomethacin (Indocin, others), sulindac, and etodolac (Lodine, others) are indole acetic acids; and ibuprofen (Advil, Motrin, others), naproxen (Naprosyn, Aleve others), and ketoprofen are arylpropionic acids.