Skip to main content
SpringerLink
Log in

NSAID-Induced Urticaria and Angioedema

A Reappraisal of its Clinical Management

  • Leading Article
  • Published:
American Journal of Clinical Dermatology Aims and scope Submit manuscript

Abstract

Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs), resulting in urticaria and angioedema, is being observed with increasing frequency. Prevalence rates range from 0.1–0.3%, which is partly due to the large size of the exposed (at risk) population. Some predisposing factors for these cutaneous reactions have been identified, among them atopic diathesis, female sex, young adulthood, a history of chronic urticaria and the use of the NSAID for the relief of acute pain.

The description of two different arachidonic acid cyclo-oxygenases (COX) about a decade ago, designated COX-1 and COX-2, and the incorporation into the therapeutic armamentarium of more selective enzyme inhibitors for the control of inflammation and pain, has led to an improved understanding of the pathogenesis of adverse reactions to NSAIDs. This has allowed investigators to study ‘sensitive’ individuals to see if they can safely receive these new pharmaceutical compounds.

The reasons why some people react to NSAIDs are not completely clarified. The prevalent theory about the pathogenesis of urticaria and angioedema due to NSAIDs in cross-reactive patients assumes that the inhibition of COX-1 leads to a shunting of arachidonic acid metabolism towards the 5-lipoxygenase pathway, which results in an increased synthesis and release of cysteinyl leukotrienes.

Although COX-2 inhibitors are well tolerated by the majority of classic NSAID-sensitive patients, cutaneous reactions to highly selective inhibitors of COX-2 have been described in some of these individuals, casting some doubts about the relevance of such hypotheses.

On the other hand, in patients who react to a single NSAID and chemically similar products (single-reactors), specific immunoglobulin E antibodies to haptenated NSAID metabolites have been suspected, although these metabolites are not easily demonstrated by means of routine in vivo or in vitro techniques.

Facial (periorbital) angioedema constitutes the most common form of clinical presentation, and one-third of the patients show a mixed clinical pattern of cutaneous (urticaria and/or angioedema) and respiratory symptoms which include upper respiratory tract edema, rhinorrhea, cough, breathlessness and tearing.

When necessary, diagnosis is confirmed by means of controlled peroral drug challenges done by experienced physicians in the hospital setting and test results are helpful for clinical management, which will be based on strict avoidance, and the use of alternative tolerated medications. This approach is specially indicated in hypersensitive patients with chronic medical conditions who require continuous NSAID therapy, such as those with arthritis and coronary heart disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Table I
Table II
Table III
Table IV
Table V
Table VI
Table VII
Fig. 3

Similar content being viewed by others

References

  1. Settipane G.A. Aspirin and allergic diseases. Am J Med 1983; 74: 102–10

    Article  PubMed  CAS  Google Scholar 

  2. Strom B.L., Carson J.L., Lee Morse M., et al. The effect of indication on hypersensitivity reactions associated with zomepirac sodium and other nonsteroidal antiinflammatory drugs. Arthritis Rheum 1987; 30: 1142–8

    Article  PubMed  CAS  Google Scholar 

  3. Sánchez-Borges M., Capriles-Hulett A. Atopy is a risk factor for non-steroidal anti-inflammatory drug sensitivity. Ann Allergy Asthma Immunol 2000; 84: 101–6

    Article  PubMed  Google Scholar 

  4. Capriles-Behrens E., Caplin J., Sánchez-Borges M. Facial angioedema in a selected pediatric atopic population. J Inv Allergol Clin Immunol 2000; 10: 277–9

    CAS  Google Scholar 

  5. Vervloet D., Pradal M., Castelain M. Drug allergy. Uppsala: Pharmacia & Upjohn, 1999

    Google Scholar 

  6. Fu J.Y., Masferrer J.L., Seibert M., et al. The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J Biol Chem 1990; 262: 16737–40

    Google Scholar 

  7. Feldman M., McMahon A.T. Do Cyclooxygenase-2 inhibitors provide benefits similar to those of traditional nonsteroidal anti-inflammatory drugs, with less gastrointestinal toxicity? Ann Intern Med 2000; 132: 134–43

    PubMed  CAS  Google Scholar 

  8. Bombardier C., Laine L., Reicin A., et al. Comparison of upper gastrointestinal toxicity of Rofecoxib and Naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343: 1520–8

    Article  PubMed  CAS  Google Scholar 

  9. Silverstein F.E., Faich G., Goldstein J.L., et al. Gastrointestinal toxicity of Celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis, the CLASS Study: a randomized controlled trial. JAMA 2000; 284: 1247–55

    Article  PubMed  CAS  Google Scholar 

  10. Patrono C., Ciabattoni G., Pinca E., et al. Low dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Thromb Res 1980; 17: 317–27

    Article  PubMed  CAS  Google Scholar 

  11. Patrignani P., Panara M.R., Greco A., et al. Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. J Pharmacol Exp Ther 1994; 271: 1705–12

    PubMed  CAS  Google Scholar 

  12. Sánchez-Borges M., Capriles-Hulett A., Caballero-Fonseca F. NSAID hypersensitivity in the COX-2 inhibitor era. Allergy Clin Immunol Int 2001; 13: 211–8

    Article  Google Scholar 

  13. Szczeklik A., Gryglewski R.S., Czerniawska-Mysik G. Clinical patterns of hypersensitivity to nonsteroidal anti-inflammatory drugs and their pathogenesis. J Allergy Clin Immunol 1977; 60: 276–84

    Article  PubMed  CAS  Google Scholar 

  14. Okazaki T., Ilea V.S., Rosario N.A. Regulatory role of prostaglandin E in allergic histamine release with observation on the responsiveness of basophil leukocytes and the effect of acetylsalicylic acid. J Allergy Clin Immunol 1977; 60: 360–6

    Article  PubMed  CAS  Google Scholar 

  15. Wedi B., Kapp A. Aspirin induced adverse skin reactions: new pathophysiological aspects. Thorax 2000; 55: 570–1

    Article  Google Scholar 

  16. Pérez C., Sánchez-Borges M., Capriles-Hulett A. Pretreatment with Montelukast blocks NSAID-induced urticaria and angioedema. J Allergy Clin Immunol 2001; 108: 1060–1

    Article  PubMed  Google Scholar 

  17. Asero R. Leukotriene receptor antagonists may prevent NSAID-induced exacerbations in patients with chronic urticaria. Ann Allergy Asthma Immunol 2000; 85: 156–7

    Article  PubMed  CAS  Google Scholar 

  18. Kowalski M.L., Bienkiewicz B., Woszczek G., et al. Diagnosis of pyrazolone drug sensitivity: clinical history versus skin testing and in vitro testing. Allergy Asthma Proc 1999; 20: 347–52

    Article  PubMed  CAS  Google Scholar 

  19. Stevenson D.D., Simon R.A. Sensitivity to aspirin and nonsteroidal anti-inflammatory drugs. In: Middleton E.R., Reed C.E., editors. Allergy. St Louis (MO): CV Mosby, 1992: 1747–65

    Google Scholar 

  20. Quiralte J., Blanco C., Castillo R., et al. Intolerance to nonsteroidal anti-inflammatory drugs: results of controlled drug challenges in 98 patients. J Allergy Clin Immunol 1996; 98: 678–85

    Article  PubMed  CAS  Google Scholar 

  21. Stevenson D.D. Diagnosis, prevention and treatment of adverse reactions to aspirin and nonsteroidal anti-inflammatory drugs. J Allergy Clin Immunol 1984; 74: 617–22

    Article  PubMed  CAS  Google Scholar 

  22. Stevenson D.D., Sánchez-Borges M., Szczeklik A. Classification of allergic and pseudoallergic reactions to drugs that inhibit cyclo-oxygenase enzymes [editorial]. Ann Allergy Asthma Immunol 2001; 87: 1–4

    Article  Google Scholar 

  23. Meyer E. Atopy and NSAID sensitivity [abstract]. J Allergy Clin Immunol 2002; 109: S142

    Article  Google Scholar 

  24. Pastorello E.A., Zara C., Sforza G.G., et al. Atopy and intolerance of antimicrobial drugs increase the risk of reactions to acetaminophen and nimesulide in patients allergic to nonsteroidal anti-inflammatory drugs. Allergy 1998; 53: 880–4

    Article  PubMed  CAS  Google Scholar 

  25. Asero R. Risk factors for acetaminophen and nimesulide intolerance in patients with NSAID-induced skin disorders. Ann Allergy Asthma Immunol 1999; 82: 554–8

    Article  PubMed  CAS  Google Scholar 

  26. May A., Weber A., Gall H. Means of increasing sensitivity of an in vitro diagnostic test for aspirin intolerance. Clin Exp Allergy 1999; 29: 1402–11

    Article  PubMed  CAS  Google Scholar 

  27. Ispano M., Fontana A., Scibilia J., et al. Oral challenge with alternative nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol in patients intolerant to these agents. Drugs 1993; 46 Suppl. 1: 253–6

    Article  PubMed  Google Scholar 

  28. Nettis E., Marcandrea M., Ferrannini A., et al. Tolerability of nimesulide and paracetamol in patients with NSAID-induced urticaria/angioedema. Immunopharmacol Immunotoxicol 2001; 23: 343–54

    Article  PubMed  CAS  Google Scholar 

  29. Ruxrungtham K., Chantaphakul H., Tiyasatapon S., et al. Acetaminophen crosssensitivity is common in Thai patients with aspirin/NSAIDs sensitivity and may be life-threatening [abstract]. J Allergy Clin Immunol 2002; 109: S141

    Article  Google Scholar 

  30. Andri L., Senna G., Betteli C., et al. Tolerability of nimesulide in aspirin-sensitive patients. Ann Allergy 1994; 72: 29–32

    PubMed  CAS  Google Scholar 

  31. Bernstein M., Rodriguez C. Challenge with nimesulide, a new NSAID, in patients with reactions to aspirin and other NSAIDs [abstract]. J Allergy Clin Immunol 1996; 97: 345

    Article  Google Scholar 

  32. Bavbek S., Celik G., Ediger D., et al. The use of nimesulide in patients with acetylsalicylic acid and nonsteroidal anti-inflammatory drug intolerance. J Asthma 1999; 36: 657–63

    Article  PubMed  CAS  Google Scholar 

  33. Mori J.E., Guerra F.T. Nimesulide as an alternative in patients with allergic reactions to NSAID [abstract]. J Allergy Clin Immunol 2000; 104: S343

    Article  Google Scholar 

  34. Barranco P., Muñoz-Robles M.L., Caballero M.T., et al. Tolerance to nimesulide in nonsteroidal anti-inflammatory drug intolerant patients [abstract]. J Allergy Clin Immunol 2000; 105: S273

    Article  Google Scholar 

  35. Sánchez-Borges M., Capriles-Hulett A., Caballero-Fonseca E., et al. Tolerability to new COX-2 inhibitors in NSAID-sensitive patients with cutaneous reactions. Ann Allergy Asthma Immunol 2001; 87: 201–4

    Article  PubMed  Google Scholar 

  36. Quarantino D., Romano A., Di Fonso M., et al. Tolerability of Meloxicam in patients with history of adverse reactions to non steroidal anti-inflammatory drugs. Ann Allergy Asthma Immunol 2000; 84: 613–7

    Article  Google Scholar 

  37. Kosnik M., Music E., Mattaz F., et al. Relative safety of Meloxicam in NSAIDintolerant patients. Allergy 1998; 53: 1231–3

    Article  PubMed  CAS  Google Scholar 

  38. Nettis E., Di Paola R., Ferrannini A., et al. Meloxicam in hypersensitivity to NSAIDs. Allergy 2001; 56: 803–4

    Article  PubMed  CAS  Google Scholar 

  39. Health Canada. Canadian adverse drug reactions newsletter [online]. Available from URL: http://www.hc-sc.gc.ca/hpb-dgps/therapeut/htmleng/cadrnwsletter.html [Accessed 2002 Oct 14]

  40. Adverse Drug Reactions Advisory Committee (ADRAC). Aust Adv Drug React Bull 2000; 19: 6-7

    Google Scholar 

  41. Garcia-Rodriguez R.M., Camacho-Garrido E., Berges M.P., et al. Celecoxib should be tried in NSAID intolerance [abstract]. Allergy 2001; 56: 221

    Google Scholar 

  42. Carretero P., Pérez R, Garcés M.M., et al. Tolerance to Celecovix in patients with NSAID intolerance [abstract]. Allergy 2001; 56: 222

    Google Scholar 

  43. Andri L. Safety of Celecoxib in patients with ASA/NSAID sensitivity [abstract]. Allergy 2001; 56: 223

    Google Scholar 

  44. Levy M.B., Fink J.N. Anaphylaxis to celecoxib. Ann Allergy Asthma Immunol 2001; 87: 72–3

    Article  PubMed  CAS  Google Scholar 

  45. Berges-Gimeno M.P., Camacho-Garrido E., Garcia-Rodriguez R.M., et al. Rofecoxib, a selective high affinity COX-2 inhibitor has proved to be safe in urticaria/angioedema associated with NSAID intolerance [abstract]. Allergy 2001; 56: 49

    Article  Google Scholar 

  46. Pacor M.L., Di Lorenzo G., Brasi D., et al. COX-2 inhibitors in patients with adverse reaction to nonsteroidal anti-inflammatory drugs [abstract]. Allergy 2001; 56: 49

    Google Scholar 

  47. Valero A.L., Baltasar M.A., Pau E.L., et al. Rofecoxib a COX-1 sparing in NSAID sensitive patients [abstract]. Allergy 2001; 56: 221

    Google Scholar 

  48. Boechncke W.H., Kaufmann R., Zollner T.M. Tolerance to the selective cyclooxygenase-2 inhibitor Rofecoxib in patients intolerant to non-steroidal antiphlogistics [abstract]. Allergy 2001; 56: 222

    Google Scholar 

  49. Matucci A., Rossi D., Cecchi L., et al. Rofecoxib a new alternative in patients with intolerance to NSAIDs [abstract]. Allergy 2001; 56: 222

    Google Scholar 

  50. Asero R. Tolerability of Rofecoxib. Allergy 2001; 56: 916–7

    Article  PubMed  CAS  Google Scholar 

  51. Szczeklik A., Nizankowska E., Bochenek G., et al. Safety of a specific COX-2 inhibitor in aspirin-induced asthma. Clin Exp Allergy 2000; 31: 219–25

    Article  Google Scholar 

  52. Dahlen B., Szczeklik A., Murray J.J. Celecoxib in patients with asthma and aspirin intolerance [letter]. N Engl J Med 2001; 344: 142

    Article  PubMed  CAS  Google Scholar 

  53. Yoshida S., Ishizaki K., Onuma K., et al. Selective Cyclooxygenase 2 inhibitor in patients with aspirin-induced asthma. J Allergy Clin Immunol 2000; 106: 1201–2

    Article  PubMed  CAS  Google Scholar 

  54. Stevenson D.D., Simon R.A. Lack of cross-reactivity between Rofecoxib and aspirin in aspirin-sensitive asthmatic patients with asthma. J Allergy Clin Immunol 2001; 108: 47–51

    Article  PubMed  CAS  Google Scholar 

  55. Giuseppe P., Antonino R., Alessandro D.B., et al. Floctafenine: a valid alternative in patients with adverse reactions to nonsteroidal anti-inflammatory drugs. Ann Allergy Asthma Immunol 1997; 78: 74–78

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors have provided no information on sources of funding or on conflicts of interest directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Allergy-Immunology Service, Centro Médico-Docente La Trinidad, Caracas, Venezuela

    Mario Sánchez-Borges, Arnaldo Capriles-Hulett & Fernan Caballero-Fonseca

Authors
  1. Mario Sánchez-Borges
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arnaldo Capriles-Hulett
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fernan Caballero-Fonseca
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mario Sánchez-Borges.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sánchez-Borges, M., Capriles-Hulett, A. & Caballero-Fonseca, F. NSAID-Induced Urticaria and Angioedema. Am J Clin Dermatol 3, 599–607 (2002). https://doi.org/10.2165/00128071-200203090-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00128071-200203090-00002

Keywords

Search

Navigation