Aspirin is not only one of the best-documented medicines in the world, but also one of the most frequently used drugs of all times. In addition to its role as an analgesic and anti-inflammatory agent, aspirin is being increasingly used in the prophylaxis of ischaemic heart disease and strokes.

Prevalence

The prevalence of aspirin intolerance is about 5 to 6%. To October 1998, the Centre for Adverse Reaction Monitoring (CARM) in New Zealand had 81 reports of bronchospasm following the ingestion of aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) and 6 reports of exacerbation of asthma symptoms. This includes 1 fatality following aspirin ingestion.

Who is susceptible?

Anyone with moderate to severe asthma and chronic sinusitis is at risk to be aspirin sensitive. The people at highest risk of bronchospasm from aspirin include those with non-allergic rhinitis, nasal polyps, pansinusitis, and asthma. Up to 15% of adults with asthma may have aspirin-induced asthma. The risk increases to 40% in patients with both asthma and nasal polyps. Advancing age and asthma severity increase the prevalence of aspirin sensitivity.
Asthmatics with nasal polyps should avoid using NSAIDs.

History of Aspirin

In early Egyptian, Assyrian, and Greek manuscripts a white yellow bark was mentioned as being used to combat pain and fever. It was used for headache, fever, sore muscles, rheumatism, and chills by many Native American tribes. In the early 1700's it was even used to treat malaria.

The active ingredient, salicin, was isolated from the willow bark in 1828. In 1838, through the oxidation and hydrolysis of salicin, salicylic acid was produced. Later, in 1853 acetylsalicylic acid was produced from salicylic acid. In 1893 acetylsalicylic acid became known as aspirin. The official trade name aspirin was granted on March 6, 1899 to Bayer.

Aspirin Sensitivity

Aspirin (acetyl-salicylic acid or ASA) sensitivity is not a true (IgE-mediated) allergy. This idiosyncratic type reaction can be very serious – sometimes even life threatening (Anaphylaxis).

Most NSAIDs (Non-steroidal anti-inflammatory drugs), even when they are structurally dissimilar, cross-react markedly with aspirin, meaning that they cause the same type of reaction in aspirin sensitive people.

Even the use of NSAID ophthalmic drops has been reported to exacerbate asthma, necessitating hospital admission.

See below for common NSAIDs in New Zealand.

What are the main types of adverse reactions to aspirin and NSAID?

• SKIN REACTIONS – itching, urticaria (hives), angioedema (swelling of extremities of mouth)
• RESPIRATORY / OCULAR – Acute or immediate: nasal congestion, runny nose (rhinorrhea), itchy/watery eyes, swollen eyes, cough, difficulty breathing or wheezing.
Chronic: nasal polyps, sinusitis (leading to loss of smell, cough, post nasal drip), and worsening of chronic asthma.
• CARDIOVASCULAR – in very severe cases cardiovascular collapse (anaphylactic-type shock) can occur.

The Gastrointestinal symptoms related to aspirin (heartburn, epigastric pain, vomiting and gastrointestinal bleeding) are not allergic or idiosyncratic types of reactions, but are usually due to irritation of the stomach lining (toxicity).

What causes aspirin hypersensitivity?

The pathogenesis of aspirin-induced asthma has implicated both the cyclooxygenase (COX) and lipooxygenase (LO) pathways. By inhibiting the COX pathway, aspirin diverts arachidonic acid metabolites to the LO pathway. This also leads to decrease in the levels of Prostaglandin (PG) E (2), the anti-inflammatory PG, along with an increase in the synthesis of cysteinyl leukotrienes (LTs). Evidence suggests that patients with Aspirin-induced Asthma (AIA) have increased activity of Leukotriene C4 (LTC4) synthase, the rate-limiting enzyme in the cysteinyl LT synthesis, in their bronchial biopsy specimen, thereby tilting the balance in favour of inflammation.

Aspirin-induced asthma (AIA) has been found to be associated with decreased prostaglandin levels and increased leukotriene levels. On challenge, elevations have been found in urine histamine and leukotriene levels as well as serum tryptase levels, the latter presumably from mast cells. Although antihistamines are not effective for preventing aspirin-induced asthma, leukotriene antagonists have been shown to be inhibitory. It is believed that Leukotriene C4 mediates the bronchospasm associated with aspirin sensitivity.

Treatment of aspirin sensitivity

1. Complete avoidance of aspirin and all NSAIDs

NSAID available in New Zealand:
• Aspirin
• Diclofenac – Cataflam, Diclax, Voltaren
• Ibuprofen – Anafen, Brufen, Motrin, Nurofen, Panafen
• Indomethacin – Indocid, Arthrexin, Rheumacin
• Ketoprofen – Orudis, Oruvail
• Mefanamic acid – Ponstan
• Naproxen – Naprosyn, Noflam, Naxen
• Piroxicam – Piram
• Sulindac – Saldac
• Tiaprofenic acid – Surgam
• Tenoxicam – Tilcotil

Controversy exists whether or not true cross-reactivity occurs between aspirin and acetaminophen. Acetaminophen is a weaker inhibitor of cyclooxygenase in certain tissues. In one study (7) cross-reactivity was found when large doses (1000mg) of acetaminophen were used.

2. Aspirin Desensitisation – is effective for patients with aspirin-induced asthma who require aspirin therapy for cardiovascular or rheumatic diseases.

This procedure is time-consuming, sometimes requires hospitalisation, and is potentially dangerous, but in most cases is performed with little morbidity or mortality (1).

One study (1)(2) found that desensitisation significantly reduces urinary leukotriene E4 levels, nasal symptoms, and nasal polyps as well as the need for corticosteroid therapy, emergency room visits and hospitalisations, and sinus operations.

There are several different protocols for desensitisation. In general, the procedure consists of small, incremental increases of the aspirin dose at intervals ranging between half-an-hour to 3 hours, followed by continued daily use of aspirin to maintain the desensitised state.

Long-term use of aspirin and NSAIDs after desensitisation is limited mainly by gastrointestinal side effects. Discontinuation of therapy because of adverse reactions can be expected in 40% to 45% of successfully desensitised patients. This rate is expected to be less if enteric-coated aspirin is used. A recent study (3), following a desensitisation protocol of only 100mg/day (most previous protocols use average of 600mg aspirin/day), showed a very high success rate for aspirin-induced asthma, rhinitis and sinusitis. More importantly, a lower side effect profile should be expected.

Rapid oral challenge-desensitisation to ASA (4) can also be performed safely and successfully for aspirin related urticaria-angioedema.

3. COX-2 inhibitors

Cox-2 inhibitors available in New Zealand:

• Celecoxib- Celebrex
• Rofecoxib- Vioxx

Cox is an abbreviation for "cyclooxygenase". There are two primary cyclooxygenase enzymes: Cox-1 and Cox-2.
Cox-1 is involved in normal physiological functions including the production of protective prostaglandins in the stomach and kidney, while Cox-2 is induced in inflammation and repair.

Selective Cox-2 inhibitors, like Celebrex (celecoxib) and Refecoxib (vioxx) are now available, which specifically inhibits Cox-2 to provide relief of pain and inflammation, but retains the protective effects of prostaglandins on the stomach, and therefore have lower incidence of gastrointestinal adverse effects.

Two trials: the CLASS (4) and VIGOR (5), which looked at all the new Cox-2 inhibitors and older NSAIDs, showed that only rofecoxib (Vioxx) significantly reduced complicated peptic ulcers. It was felt that patients on Vioxx might even have more myocardial infarctions than patients on naproxen. Total adverse events were not lower in the newer drugs and withdrawals due to renal adverse events were similar for the new drugs and their comparators.

In a double blind, placebo-controlled trial, Dr. Stevenson and colleagues at the Scripps Institute in La Jolla, California (6), challenged 15 asthmatics with known aspirin sensitivity to escalating doses of celecoxib. Eighteen similar patients received rofecoxib. There were no reactions in any subjects to either COX-2 inhibitor, but all patients reacted to an aspirin challenge, confirming their sensitivity to COX-1 inhibitors.

4. Leukotriene receptor Antagonists
In a study (8) at the Scripps Research Institute, La Jolla, California, Montelukast (Singulair) was found to be only partially effective in inhibiting aspirin response in aspirin-sensitive asthmatics.

References

1. Stevenson D. D. Hankammer M.A., Mathison D.A., et al, Long term ASA desensitisation-treatment of aspirin sensitive asthmatic patients: clinical outcome studies. J. Allergy Clin. Immunol., 1996; 98: 751-758
2. Stevenson DD., Pleskow W.W., Simon R.A., et al., Aspirin-sensitive rhinosinusitis asthma: a double blind crossover study of treatment with aspirin. J. Allergy Clin. Immunol., 1984; 73: 500-507
3. Gosepath J, Schaefer D, Amadee R.G., Mann W.J., Individual monitoring of aspirin desensitisation. Arch Otolaryngol Head Neck Surg 2001 Mar; 127
4. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib versus nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS study: a randomized controlled trial. JAMA. 2000; 284:1247-1255
5. Bombardier C, Laine L, Reicin A, et al, for the VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000; 343:1520-8.
6. Stevenson D.D, Simon R.A., Lack of cross-reactivity between rofecoxib and aspirin in aspirin-sensitive patients with asthma. J Allergy Clin Immunol 2001; 108:47-51
7. Settipane R A, Stevenson D.D., Cross sensitivity with acetaminophen in aspirin sensitive subjects with asthma. J Allergy Clin Immunl 1989 Jul; 84(1): 26-33
8. Stevenson DD, Simon RA et al, Montelukast is only partially effective in inhibiting aspirin responses in aspirin-sensitive asthmatics. Ann Allergy Asthma Immunol 2000 Dec; 85(6 Pt 1): 477-82

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