Portuguese Version

Year:  2003  Vol. 69   Ed. 3 - (4º)

Artigo Original

Pages: 312 to 316

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Use of analgesics and anti-inflammatory drugs in patients with eosinophilic nasal polyposis tolerant and intolerant to aspirin

Author(s): Helena M. G. Becker[1],
Evaldo Nascimento[2],
Roberto E. S. Guimarães[3],
Celso G. Becker[1],
Paulo F. T. B. Crosara[3],
Wanessa D. de Oliveira[4]

Keywords: nasal polyposis, analgesic, anti-inflammatory.

Abstract:
Following aspirin introduction as medicine, several reports were described concerning adverse reactions after its ingestion. Widal et al. (1922)1 were the first investigators to associate Aspirin intolerance (AI) with asthma and nasal polyps (NP) followed by Samter & Beers (1967)2. Such intolerance was manifested mainly by nasal obstruction and/or bronchospasm related to the cyclooxygenase-1 (COX-1) inhibition and consequent overproduction of leukotrienes. This might also be triggered by the administration of other non-steroid anti-inflammatory drugs, acetaminophen, food dyes and additives and alcohol. Objective: To analyze the risks of the analgesics and anti-inflammatory drugs use in patients with eosinophilic nasal polyposis tolerant and intolerant to aspirin. Study Design: Transversal study. Material and Method: 45 patients were selected # 15 suffering from eosinophilic nasosinusal polyposis, tolerant to aspirin (group TA); other 15 with eosinophilic nasosinusal polyposis associated with aspirin intolerance (group AI), and 15 patients without nasosinusal polyposis with septal deviation (control group). The presence of reaction to aspirin, dipyrone, acetaminophen, other non-steroids anti-inflammatory drugs, food dyes and additives, other drugs or chemical substances was detected by inquiry. To exclude aspirin intolerance in TA and control groups, oral provocation test with aspirin was carried out. Results: Bronchospasm was the main aspirin reaction in patients suffering from eosinophilic nasosinusal polyposis and which also showed with ingestion of acetaminophen (20%), alcohol (27%), non-steroids anti-inflammatory drugs (60%) and dipyrone (47%). Conclusion: In patients with eosinophilic nasosinusal polyposis associated with aspirin intolerance it is important to do the diagnosis of intolerance to other drugs. The use of dipyrone and alcohol is worth attention, once its intolerance was observed in half and one third of the patients, respectively.

INTRODUCTION

Since acetyl-salicylic acid (ASA) was introduced in 1897, several reports have described adverse reactions after the ingestion of aspirin. These reactions manifested by urticaria and/or angioederma or bronchospasm and could lead to death. In 1922, Widal et al.1 were the first researchers to associate ASA intolerance, asthma and naso-sinusal polyposis (NP), while Samter & Beers2 observed that aspirin could cause fatal attacks in patients with non-atopic nasal polyps. Since then, the clinical triad consisting of asthma, nasal polyps and ASA intolerance has been described in the literature as the Fernand Widal's Syndrome, Aspirin triad or Samter's syndrome.

ASA intolerance can also be found after the ingestion of other nonsteroidal anti-inflammatory drugs, COX-1 inhibitors, dyes and food additives, and alcohol. Intolerance to aspirin and other nonsteroidal anti-inflammatory drugs (NSAID) associated with NP is not an IgE-mediated reaction (that is, it is not a true allergic reaction, once it is related to cyclooxygenase inhibition) and it manifests three to four times more often as bronchospasm than as urticaria/angioedema, differently from what is found in the general population2,3.

The pathophysiology of ASA intolerance3,4 suggests that the hypersensitivity to aspirin is related to the inhibition of prostaglandin biosynthesis. During the biosynthesis of prostaglandins, the arachidonic acid of the lipid cell membrane is usually converted by cyclooxygenase (COX) to form prostacyclins, prostaglandins (PG) and thromboxane (TX), or by lipooxygenase (LOX) to form hydroxyeicosatetranoic acids (HETE) and, finally to form leukotrienes (LT) C4 and D4, which are the two components of the slow-reacting substance of anaphylaxis (SRS-A). Corticosteroids inhibit arachidonic acid released from the phospholipid membrane, reducing LOX and COX products. In sensitive subjects, aspirin and NSAID would present an inhibitory pharmacological effect on the prostaglandin synthetase activity, inhibiting COX-1 and cyclooxygenase-2 (COX-2) in every cell, leading to the interruption of PGE2 synthesis and its modulatory effects on inflammatory cells and on the overproduction of cysteinil leukotrienes (Cis-LT) sent to the LOX pathway (Figure 1). Leukotrienes are bronchoconstriction and chemotactic substances, therefore, inflammatory substances. Patients with nasal polyps show great infiltration of eosinophils, the major LT-producing cell. Increasing evidence indicates that highly selective COX-2 inhibitor NSAIDs are well tolerated by these patients, showing that COX-1 inhibition triggers bronchospasm in susceptible patients.

Adverse reactions to analgesics can be divided in two groups: true allergic reaction and pseudo-allergic reaction5. In a true allergic reaction, the anaphylactic reaction is the most common manifestation. Other manifestations include angioedema, urticaria and maculopapular rash. Only 8% of patients in this group experience asthma attacks. True allergic reaction takes place probably due to an immune mechanism. Conversely, patients with pseudo-allergic reactions usually experience asthma attacks probably through COX inhibition. Therefore, two clinical forms of ASA intolerance are recognized: the respiratory form that manifests as bronchospasm and/or nasal obstruction and the cutaneous form, with urticaria or Quincke's edema.

ASA and NSAID intolerance can be detected by medical history or through oral provocation test6.
More than half of the patients (58%) with aspirin triad shows intolerance to another drug, especially NSAID7. With the introduction of more COX-2 selective anti-inflammatory drugs, the analysis of the inhibitory spectrum of anti-inflammatory drugs suggested that COX-1 inhibition was responsible for bronchoconstriction in sensitive patients. Thus, even low doses of aspirin, indomethacin and piroxicam would lead to an asthma attack in ASA-intolerant patients since they are more potent as COX-1 inhibitors than they are as COX-2 inhibitors. Inhibitory drugs, preferably COX-2 inhibitors, nimesulid and meloxicam would be more tolerated. COX-2 selective inhibitors, celecoxib and rofecoxib, would not cross-react and could be used in patients with nasal polyps and ASA intolerance8,9. (Table 1)
Acetaminophen intolerance is rare, since it causes no significant COX-1 or COX-2 inhibition. Dyes and food additives, as well as alcohol, can also cause bronchospasm in these patients 3,8,10,11.

Dipyrone was reported to trigger asthma attacks in ASA- and NSAID-intolerant patients, probably due to COX inhibition, although the incidence and risk estimates are unknown5,12.

Intolerance to xylocaine, codeine, antibiotics containing metabilsufide as preservative that manifests as respiratory symptoms has been observed in 42% of patients that suffered from ASA intolerance and nasal polyps 3,13.

The purpose of this study is to analyze the risk of using aspirin and other analgesics and anti-inflammatory drugs in nasal polyposis patients that are tolerant or intolerant to aspirin.

MATERIAL AND METHODS

A transversal study was conducted from November 1997 to March 2000 at the Service of Otorhinolaryngology, UFMG Hospital, selecting non-allergic adults divided into groups of 15 patients:

- Group 1-IA (aspirin intolerant), comprising patients with eosinophilic nasal polyposis and clinical history of ASA intolerance manifested as bronchospasm; 6 were male, with ages ranging from 19 to 58.
- Group 2-TA (aspirin tolerant), comprising patients with eosinophilic nasal polyposis and no aspirin intolerance; 7 were male, with ages ranging from 27 to 69.
- Control group, comprising patients without nasal polyps, no nasal eosinophilia and no aspirin intolerance; 13 were male, with ages ranging from 17 to 69.

The presence of nasal allergy was excluded by clinical history and skin testing. The presence of nasal polyps was confirmed by nasal endoscopy. Nasal eosinophilia (>30%) was observed after hematoxylin-eosin staining.

Every patient enrolled in this study was asked about reactions to analgesics (aspirin, dipyrone and acetaminophen), to NSAID, alcohol, food dyes, as well as any other drug or chemical. ASA intolerance, manifested by bronchospasm, was diagnosed by clinical history in group 1-IA patients, as well as intolerance to other analgesics and anti-inflammatory drugs in groups 1-IA and 2-TA. The oral provocation test with aspirin was conducted in patients with negative history of ASA intolerance (groups 2-TA and control) to confirm the absence of ASA intolerance. Basal spirometry was conducted using a KOKO-TREK® spirometer manufactured by Pulmonary Data Service Instrumentation, Inc., USA. After the ingestion of 100 mg of aspirin, serial spirometry with ½ was conducted in the 1st, 2nd and 3rd hour. The reduction in forced expiratory volume in one second was considered positive if equal or higher than 20%.

Before submitting patients to cutaneous testing and to nasal biopsies for pathology analysis, the use of topic or systemic corticosteroids and anti-histaminic drugs were ruled out for at least 30 days prior to the test.

RESULTS

After ingesting aspirin, all 15 patients in group 1-IA (100%) developed bronchospasm, and two of them (13%) had simultaneous nasal obstruction, while other two (13%) had coryza, and none of the patients reported angioedema or urticaria.

ASA intolerance associated with eosinophilic nasal polyposis was manifested mainly as bronchospasm and, in decreasing order of occurrence, with the administration of NSAID in nine patients (60%), dipyrone in seven patients (47%), alcohol in seven patients (47%), and acetaminophen in three patients (20%). One patient had bronchospasm with an IV infusion of hydrocortisone. None of the patients reported reactions after ingestion of food.

In group 2-TA, one patient reported urticaria reaction to dipyrone, another with cephalosporin, and a third patient had bronchospastic reaction due to alcohol and latex allergy. In the control group, only one patient reported urticaria reaction with dipyrone.

Table 1. Inhibition spectrum of anti-inflammatory drugs

Figure 1.

Figure 1. Biosynthesis of prostaglandins, thromboxanes and leukotrienes from arachidonic acid (Moneret-Vautrin, 2000).

DISCUSSION

Nasal polyposis has a positive association with the bronchospastic reaction and/or nasal obstruction and a negative association with urticaria manifestation with ASA14. In this study, similar results were observed to those found in the literature, according to which patients with nasal polyposis and asthma manifested ASA intolerance as bronchospasm and, in 26% of cases, it was associated with nasal obstruction and coryza. None of the patients had cutaneous manifestation due to ASA intolerance, that is, urticaria and angioedema. One could challenge that bronchospasm after ASA ingestion was an inclusion criteria and could not be evaluated. However, no patient with ASA intolerance and nasal polyposis who came to our hospital while this study was being conducted was excluded for reporting reactions other than bronchospasm.

The level of intolerance to nonsteroidal anti-inflammatory drugs (NSAID) was shown by Szczeklik et al.(1975)4. In that study, nine patients (60%) with ASA intolerance had bronchospasm after ingesting NSAID; among these patients, one simultaneously developed urticaria and another one developed angioedema. It is interesting to note that angioedema and urticaria were not observed after the ingestion of aspirin. Eight cases involved diclofenac, while one case involved tenoxicam. One of the patients who reacted to diclofenac also reacted to mefenemic acid. Although there is evidence that inhibitory drugs, preferably COX-2 inhibitors, nimesulid and meloxicam, would be better tolerated and that selective COX-2 inhibitors, celecoxib and rofecoxib, would not cross-react, and consequently could be used in patients with nasal polyposis and ASA intolerance8,9; in our study, no patient reported having used those drugs.

Acetaminophen was considered a good substitute for aspirin in ASA intolerant patients, since acetaminophen intolerance was observed in only 4 to 18% of ASA-intolerant patients9. In our study, we also noted that 20% of the patients of the group IA suffered from acetaminophen intolerance that always manifested as bronchospasm.

Dipyrone intolerance, manifested as urticaria and/or angioedema and even as anaphylactic reaction is due to an IgE-mediated reaction. Dipyrone intolerance in ASA-intolerant patients is mentioned only by Szczeklik (1986)5 and Levy (2000)11, who reported that it could provoke bronchospasm in these patients, probably also by COX inhibitors, although they were unaware of its incidence. Surprisingly, our study detected that 47% of group IA patients also suffered from dipyrone intolerance, which was always manifested as bronchospasm. In groups TA and Control, dipyrone intolerance was observed in one patient (7%) of each group, and manifested as urticaria.

Alcohol intolerance was observed in 14% to 20% of ASA-intolerant patients3,13. In our study, 40% of ASA-intolerant patients also had alcohol intolerance, manifested as bronchospasm in 27%, urticaria in 6.5% and angioedema in 6.5% of the cases. This increased incidence of alcohol intolerance detected in our study could be questioned when compared to the incidence described in the literature, whether it is detected from the systematic inquiry about such intolerance or when the patient spontaneously reported it. In group TA, only one patient reported bronchospasm after ingesting alcohol.

During hospital stay, a patient in group IA had bronchospasm immediately after an injection of hydrocortisone succinate. It is believed that this intolerance is an IgE-mediated reaction to the succinate molecule and not a reaction to hydrocortisone5.

Tartrazine intolerance is usually found in ASA-intolerant patients and is detected in 4% to 50% of the cases3. However, other authors9,13 observed that tartrazine intolerance was extremely rare among aspirin-induced asthma patients and probably took place by an IgE-mediated reaction. Intolerance to additives (sodium benzoate and metabisulfide) was detected in 18.5 to 23% of ASA-intolerant patients by oral provocation test13. In our study, we observed intolerance to neither tartrazine nor other food additives.

CONCLUSIONS

These results show the importance of diagnosing intolerance to other drugs in ASA intolerant patients with nasal polyposis, since bronchospasm related to ASA intolerance was also related, in decreasing order of occurrence, to the intake of nonsteroidal anti-inflammatory drugs, dipyrone, alcohol and acetaminophen.

Patients with nasal polyposis and/or severe bronchial asthma should be advised not to use aspirin or other nonsteroidal anti-inflammatory drugs that are COX-1 inhibitors.

The use of dipyrone and alcohol requires attention, since intolerance to these drugs was observed in almost half and one third of the patients, respectively. It should be stressed that such cases of intolerance are not highlighted in the literature and further research should be carried out on this subject.

REFERENCES

1. Widal F, Abrami P, Lermoyez J. Anaphylaxie et idiosyncrasie. Presses Med 1922; 18: 189-93.
2. Samter M, Beers RF. Concerning the nature of intolerance to aspirin. J Allergy 1967 Nov; 40(5): 281-93.
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12. Levy M. Hypersensitivity to pyrazolones. Thorax 2000 Oct(suppl2); 55: 72-4.
13. Moneret-Vautrin DA, Wayoff M, Bonne C. Mechanisms of aspirin intolerance. Ann Otolaryngol Chir Cervicofac 1985; 102(2):357-63.
14. Probst L, Stoney P, Jeney E, Hawke M. Nasal polyps, bronchial asthma and aspirin sensitivity. J Otolaryngol 1992; 21(1) Feb: 60-5.

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1 - Joint Professor, Department of Otorhinolaryngology, Ophthalmology and Speech and Hearing Therapy, Medical School, Federal University of Minas Gerais.
2 - Joint Professor, Department of Parasitology, Institute of Biological Sciences, Federal University of Minas Gerais.
3 - Otorhinolaryngologist, Ph.D. studies under course, Medical School, Federal University of Minas Gerais.
4 - Undergraduate, Medical School, Federal University of Minas Gerais. Resident in Otorhinolaryngology, Minas Gerais, Brazil.

Affiliation: Medical School - UFMG

Address correspondence to: Helena M. Gonçalves Becker, Av. Pasteur 88, 4º andar Belo Horizonte MG 30170-2900. - Tel. (55 31) 3222-2891 E-mail: hbecker@medicina.ufmg.br

Study presented at the 36o Congresso Brasileiro de Otorrinolaringologia (SBORL), in Florianópolis/SC, between November 19 - 23, 2002.

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