Q&A 85.2

Can nonsteroidal anti-inflammatory drugs be used in adult patients with asthma?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals

Date prepared: October 2012

Background
Nonsteroidal anti-inflammatory drugs (NSAIDs) include aspirin, and several other classes of compounds, for example, propionic acid derivatives (e.g. ibuprofen, naproxen, ketoprofen), acetic acid derivatives (e.g. indometacin), heteroaryl acetic acids (e.g. diclofenac), substituted pyrazoles (e.g. celecoxib) etc. (1). They act as inhibitors of the enzyme cyclo-oxygenase (COX) which results in the direct inhibition of the synthesis of prostaglandins from arachidonic acid (2).

Aspirin sensitivity that occurs in some asthmatic patients principally manifests as the onset of asthma within one to three hours of ingesting aspirin (3,4). This has been described by a number of terms including ‘aspirin induced asthma (AIA)’, ‘aspirin intolerance’ or ‘aspirin-exacerbated respiratory tract disease’ (5). Although the terms refer to aspirin only, “patients who are sensitive to aspirin are often cross-sensitive to other NSAIDs as they share a common mechanism of action (2)”.

The main clinical features of patients who have aspirin sensitivity in general include middle-age, female sex, diagnoses of asthma or rhinitis, a personal or family history of atopy, and a history of nasal polyps.The occurrence of aspirin sensitivity in patients with asthma and nasal polyps has been referred to as the ‘aspirin triad' (2). In these patients, nasal symptoms (nasal congestion and rhinorrhoea accompanied by nasal polyps) usually start first in the third or fourth decade of life, followed by the development of asthma and aspirin sensitivity (4,6). Specific clinical features that have been identified to suggest an increased risk of aspirin sensitivity in asthmatics include: a) severe asthma accompanied by chronic nasal congestion and profuse rhinorrhoea; b) frequent development of nasal polyps; c) sudden severe attacks of asthma requiring admission to intensive care unit and d) adult onset, non-allergic asthma (6,7).

In asthmatic patients exhibiting aspirin sensitivity, additional symptoms that accompany the onset of asthma include profuse rhinorrhoea, peri-orbital oedema, conjunctival infection, flushing of head and neck, and on occasions vomiting and diarrhoea (4,7). Patients may have any or all of these symptoms, and the reactions can vary in individuals (7). In some cases, it is likely that aspirin- or NSAID-induced rhinitis and asthma reactions occur in patients who have underlying rhinosinusitis, nasal polyps and asthma but in whom the drug-induced reactions are too mild to be recognised clinically and may go unnoticed (8). Alternatively, bronchoconstriction may be severe and life threatening, requiring hospital admission (8,9).

The reactions are possibly dose dependent: small doses may not induce a significant reaction, whereas larger and possibly therapeutic doses may provoke severe reactions (8,10). However, some individuals are highly sensitive and develop worsening of their asthma even with low dose aspirin (11).

The prevalence of AIA in adult asthmatics is controversial. It has been stated to occur in approximately 10% of adult asthmatics (4,5,11). However, prevalence has also been quoted to be in the range 2 – 20% (9,11,12) and up to 44% has also been stated (12). These variations may be explained by the differences in populations studied, methods used for data collection, definitions of outcomes and criteria for defining sensitivity reactions (3).

The symptoms precipitated by aspirin or other NSAIDs in patients with AIA resemble immediate hypersensitivity reactions, however, specific antibodies to aspirin/NSAIDs are rarely shown in these individuals. Additionally, there is cross-reactivity between NSAIDs that do not have similar chemical structures, and the onset of asthma frequently occurs on first exposure to the new NSAID (7,13).

The mechanism of hypersensitivity to aspirin and other NSAIDs in asthmatic patients is therefore not considered to be immunological, but has been attributed to the pharmacological properties of the drugs – inhibition of COX, The two major enzymes in the COX pathway are cyclo-oxygenase 1 and 2 (COX-1 and COX-2 respectively). Most of the evidence suggests that inhibition of COX-1 is related to the pathogenesis of AIA in patients sensitive to aspirin. It is thought that this inhibition causes a deficiency in the protective bronchodilator/anti-inflammatory prostaglandins, and an excess of pro-inflammatory/bronchoconstrictive leukotrienes, specifically cysteinyl-leukotrienes (12,13). Patients with AIA are particularly susceptible to the effects of leukotrienes that manifest as excessive nasoocular and asthmatic reactions (5).

AnswerAsthmatic patients with known Aspirin Induced Asthma (AIA)

Use of aspirin and NSAIDs

Aspirin and other NSAIDs are contra-indicated in patients in whom attacks of asthma have been precipitated by aspirin or any other NSAID (14).

Use of COX-2 specific inhibitors as an alternative to non-selective NSAIDs

There has been interest in the use of COX-2 specific inhibitors as an alternative to non-selective NSAIDs in patients with AIA considering that the pathogenesis of AIA involves mainly inhibition of COX-1. Studies evaluating COX-2 specific inhibitors are presented below. (Products which have been withdrawn from the UK market are not considered in this review).

Importantly, the authors of a review conducted in 2006 advised a word of caution for the use of such agents: despite the safety data and lack of cross-reactivity for use of COX-2 specific inhibitors in large numbers of patients with AIA, rare case reports of respiratory reactions to COX-2 specific inhibitors have appeared in the literature. They conclude that such reports make it impossible to take the position that COX-2 specific inhibitors never induce respiratory reactions in patients with AIA (15).

Currently, the manufacturers state in their summary of product characteristics (SPCs), that celecoxib, etoricoxib, and parecoxib are contra-indicated in patients who have experienced asthma/bronchospasm, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic-type reactions after taking acetylsalicylic acid (aspirin) or NSAIDs including COX-2 (cyclooxygenase-2) inhibitors(16,17,18). Therefore, use of these agents in patients with AIA would be outside the product licence.

Studies of celecoxib

Woessner et al conducted a 2 day, double-blind, placebo-controlled study with celecoxib in 69 patients with stable asthma and AIA. Antihistamines, sodium cromoglicate, nedocromil sodium, salmeterol, salbutamol and ipratropium bromide were discontinued upon admission, and leukotriene receptor antagonists (40 patients) and corticosteroids were continued. Patients were challenged with celecoxib (100mg, 200mg) and 2 placebos over 48 hours, and then the next day to aspirin to confirm positive aspirin sensitivity.

Sixty patients had a positive reaction to aspirin, but none of them reacted to celecoxib. Mean changes in forced expiratory volume in 1 second (FEV1) and nasoocular symptoms were not statistically significantly different between placebo and celecoxib doses. The authors calculated a 95% confidence interval (CI) of 0 to 5% for the probability of celecoxib inducing a cross reaction in a patient with AIA. The authors concluded that the study supports the theory that COX-1 inhibition plays a role in precipitating AIA, and demonstrates safety of celecoxib in patients with asthma (19).

Gyllfors et al conducted a small study of 33 patients with stable asthma and proven AIA. The study consisted of 3 phases in which participants were initially given either placebo or increasing doses of celecoxib (10, 30 and 100mg) in a double-blinded fashion, followed by the crossover phase (second phase). The third phase was an open-label challenge with 400mg celecoxib. Leukotriene receptor antagonists, cromones (sodium cromoglicate, nedocromil sodium)and bronchodilators had been withheld. FEV1 and nasal symptoms scores were measured at specified intervals. No significant bronchoconstrictor responses from either placebo or celecoxib during double-blind phase or open-phase were observed, and no changes were noted in the nasal symptom scores either. The authors conclude that patients with AIA might use selective COX-2 inhibitors only after having been exposed to the drug under supervision by a specialist in a setting with access to rescue measures (20).

A recent single-blinded study conducted by Celik et al looked at the effect of celecoxib in 75 patients with a reliable history of aspirin and/or NSAID sensitivity (urticaria/angioedema, naso-ocular symptoms, bronchospasm, and/or anaphylactoid reaction). This sensitivity was not confirmed with oral challenge. Twenty one patients were stable asthmatics, and were allowed to continue inhaled corticosteroids (systemic users were not included). On 2 separate days, the total daily dose of placebo and celecoxib (200mg) was divided into ¼ and ¾ doses and given at 2 hour intervals. FEV1, naso-ocular and bronchial reactions were monitored following administration. No reactions were observed with placebo and celecoxib. The authors concluded that considering the serious adverse events reported in the literature with celecoxib, it should only be administered in aspirin sensitive patients by experienced allergists with oral challenge in equipped settings, and that further large studies are warranted (21).

Yoshida et al (n=17 patients, limited details in the published report) and Martin-Garcia et al report similar findings suggesting that celecoxib might be a suitable alternative in patients with AIA (22, 23 (abstract only seen)).

Overall, the results of these studies seem to suggest that celecoxib may be a safe alternative to non-selective NSAIDs in patients with AIA (19-23). However, there are a number of limitations/points that need to be considered in interpreting these results: small sample size employed in the trials (ranging from 17-69 patients with AIA), short duration of exposure to celecoxib (ranging from 1-3 days), patients were stable asthmatics, differences between the trials in continuing or discontinuing maintenance medicines for asthma, and aspirin sensitivity not always confirmed in the trials. The authors of two of the studies state that large long term studies are required to further establish safety and tolerability of COX-2 inhibitors in patients with AIA (20,21).

Studies of etoricoxib and parecoxib

The use of parecoxib has been investigated in 10 patients with aspirin-exacerbated respiratory disease (AERD) (24). Patients with a history of asthma exacerbations precipitated by two or more different NSAIDs were challenged with parecoxib - The parecoxib challenge consisted of the administration of intramuscular placebo, followed by the administration of 10mg of parecoxib intramuscularly, then 40mg intramuscularly – each step was separated by intervals of 1 hour in order to assess possible reactions due to any of the doses. During the parecoxib challenge, no symptoms were reported with the administration of any parecoxib doses, and there were no signs of immediate or delayed hypersensitivity. Additionally, there were no alterations in the FEV1 measurements.

Insufficient data were found in the literature to allow assessment of the safety of etoricoxib as an alternative to non-selective NSAIDs in patients with AIA.

Use of COX-2 selective inhibitors as an alternative to non-selective NSAIDs

Meloxicam is a preferential inhibitor of COX-2 (i.e. it has a higher selectivity for COX-2 than COX-1 but is not an exclusive/specific COX-2 inhibitor); etodolac and nabumetone are also claimed to have preference for COX-2 although there is less evidence for this (2).

There are several studies which have assessed the safety of meloxicam in patients who cannot tolerate NSAIDs in general i.e. patients who have had adverse cutaneous or respiratory reactions (25-28). Limited data seem to suggest that meloxicam may be a “safe” alternative in some asthmatic patients who are sensitive to NSAIDs but not all. Furthermore, several limitations within the trials limit the conclusions that can be drawn e.g. maximum dose meloxicam not used in all cases and sensitivity not confirmed in all participants by means of oral challenge tests. Therefore due to the limited data available, no definitive conclusions can be drawn regarding the safety of meloxicam as an alternative to non-selective NSAIDs in asthmatic patients who are sensitive to NSAIDs. Currently, meloxicam is contra-indicated in patients who have developed signs of asthma, nasal polyps, angioneurotic oedema or urticaria following the administration of aspirin or other NSAIDs (29).

A statement from the European Network on Hypersensitivity to Aspirin and NonSteroidal Anti-Inflammatory Drugs states that meloxicam is quite well tolerated by most (86-96%) of patients with AIA (30). However, the use of meloxicam should be preceded by tolerance testing.

Of the others i.e. nabumetone and etodolac, due to lack of or limited published information regarding their tolerability in patients with AIA, no conclusions can be drawn regarding their use in this setting. The SPCs for both drugs contraindicate their use in patients in whom aspirin or other NSAIDs precipitate asthmatic attacks, urticaria or rhinitis (31, 32).

Desensitisation as a management option

Desensitisation to aspirin and NSAIDs can be induced in patients with AIA by the gradual introduction of increasing doses of oral aspirin until a dose of about 450 to 600mg daily is tolerated (9,11). Daily administration of high dose aspirin is required to maintain tolerance (and allow administration of aspirin or other NSAIDs), as tolerance is only maintained for 2-5 days after stopping aspirin in which case patients would need to be desensitised again (7).

Aspirin desensitisation has obvious risks, and should only be carried out by experienced clinicians in a hospital setting with full facilities for cardiopulmonary resuscitation. Further, aspirin may not be tolerated by individuals due to gastrointestinal adverse effects(7,11).

Due to the associated risks, desensitisation would need to be considered in line with the clinical need of aspirin or other NSAIDs in patients with AIA, and advice sought from a specialist. It is also important to note that desensitisation would not necessarily be a viable/realistic option for those individuals who only need NSAIDs on an occasional when–required basis, as they would need to administer high dose aspirin on a regular basis to allow them to do so.

Leukotriene receptor antagonists in preventing aspirin or other NSAID provoked respiratory symptoms

There has also been interest in the use of leukotriene receptor antagonists in preventing aspirin-provoked respiratory symptoms in patients with AIA, owing to the pathogenesis highlighted above. However, data are limited, and the efficacy variable (33, 34). Thus, the role of these agents is yet to be fully established. The currently marketed leukotriene receptor antagonists, montelukast and zafirlukast, are not licensed for preventing asthmatic or other symptoms following administration of aspirin or other NSAIDs in patients with AIA (35, 36). Furthermore the manufacturer of montelukast states that “treatment with montelukast does not alter the need for patients with aspirin-sensitive asthma to avoid taking aspirin and other non-steroidal anti-inflammatory drugs (35)”.

Asthmatic patients who have not been exposed to aspirin or other NSAIDs

Aspirin and other NSAIDs should be used with caution in patients with a history of asthma (2). However, based on prevalence data, a large proportion of adult asthmatic patients will be able to tolerate aspirin and NSAIDs. The clinical features that suggest an increased risk of AIA in these individuals are outlined in the background and summary sections.

Asthmatic patients who are tolerant of aspirin and other NSAIDs (i.e. known exposure)

Based on prevalence data, a large proportion of adult asthmatic patients will be able to tolerate aspirin and other NSAIDs. It has been suggested however, that these individuals should be warned about the potential development of AIA late in life (11).

Summary

NSAIDs are contra-indicated in patients in whom attacks of asthma have been precipitated by aspirin or any other NSAID. Further studies are required to confirm the safety and tolerability of both COX-2 specific inhibitors and COX-2 selective inhibitors as “safe” alternatives to non-selective NSAIDs in patients with AIA. At present, their use in patients with AIA would be outside the product licence.

For adult asthmatic patients who have not been exposed to aspirin or other NSAIDs, it is not possible to provide a definitive answer. However, in making the clinical decision as to whether aspirin/NSAIDs should be used in this patient group, the following should be considered:

Prevalence of aspirin induced asthma (AIA) in adult asthmatics is approximately 10%, and patients who are sensitive to aspirin will often exhibit cross-sensitivity to other NSAIDs.

Clinical features that suggest an increased risk of sensitivity to aspirin/NSAIDs in asthmatics include female sex, middle age, severe asthma accompanied by chronic nasal congestion and profuse rhinorrhoea, and a history of nasal polyps. Aspirin/NSAIDs can induce asthma/bronchoconstriction and a range of other symptoms in susceptible patients. These can range from mild reactions which may not be recognised clinically to severe and life threatening asthma.

Based on prevalence data, approximately 80-90% of adult asthmatics will be able to tolerate aspirin and other NSAIDs, but may need to be warned of the potential for development of AIA, particularly late in life.

Limitations

This review has NOT included the following:

A detailed and comprehensive review of the literature available regarding aspirin desensitisation and its regimes; it is recommended that specialist advice be sought.

Aspirin provocation tests (i.e. challenge tests) that may need to be employed to confirm the diagnosis of aspirin sensitivity. These may need to be considered particularly when the history of the reaction is unclear to allow an accurate diagnosis, and would be performed preferably in hospitals with facilities for resuscitation under the supervision of experienced clinicians (6,9,11).

Any Information that may be available for asthmatic children who are sensitive to NSAIDs. (This review has considered the use of aspirin and other NSAIDs in adult asthmatic patients only.)

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References