Hypersensitivity to Pyrazolones

Home , Propyphenazone, Pyrazolidine, Pyrazolone

S72 Thorax 2000;55 (Suppl 2):S72–S74 Thorax: first published as 10.1136/thorax.55.suppl_2.S72 on 1 October 2000. Downloaded from Hypersensitivity to pyrazolones

Micha Levy

To the allergologist, hypersensitivity to drugs Virtually all adverse reactions to pyrazolones means immunological drug reactions as classi- are non-dose related.11 The following syn- fied in the Gell and Coombs system. To others, dromes of pyrazolone hypersensitivity have it may also include non-dose related adverse been reported. drug reactions including the non-immune mediated idiosyncratic drug reactions (type B). Anaphylaxis In the following discussion the broad definition Immediate hypersensitivity reactions are pre- of idiosyncrasy including all type B reactions sumably IgE mediated and clinically character- and a clinical approach rather than a mechanis- ised by laryngeal and angioneurotic oedema, tic one will be used. generalised urticaria, bronchospasm, vaso- Pyrazolones are veteran drugs. Antipyrine motor collapse, and death. Patients with such was synthesised for clinical use in 1883. The reactions to pyrazolones display tolerance to methylated nitrogen derivative aminopyrine NSAIDs. They often have a family history of was introduced in 1897 and taken oV the mar- allergic diseases. ket in the 1970s because of its propensity to Szczeklik12 described 22 patients who devel- form nitrosamines. Dipyrone has been in clini- oped anaphylactic shock after taking a single cal use since 1922. In some countries it was dose of aminopyrine or dipyrone and another banned because of the risk of agranulocytosis. six patients in whom urticaria/angio-oedema In others it is the leading analgesic/antipyretic occurred. All had positive skin tests to these drug. Annual sales figures of pyrazolones drugs but oral challenge with NSAIDs was amount to kilotons, mainly dipyrone and negative in all cases. There are no reliable in propyphenazone. vitro tests for the diagnostic use of pyrazolone Unlike the acidic non-steroidal anti- specific IgE. A history of pyrazolone hypersen- inflammatory drugs (NSAIDs) which are sitivity is the most important way to make the known to act on inflamed tissue by the inhibi- diagnosis. It has recently been suggested that a tion of prostaglandin synthesis, pyrazolones genetic predisposition to immediate hypersen- produce analgesic/antipyretic eVects associated sitivity to pyrazolones is linked to the HLA DQ with a much less potent anti-inflammatory locus.13 eVect on peripheral tissues. As shown in several Cases of anaphylaxis have been described

animal species and also in humans, dipyrone following the use of dipyrone and http://thorax.bmj.com/ acts on the central nervous system by the inhi- amidopyrine14 15 and occur following parenteral bition of prostanoids.12 Dipyrone has more as well as oral administration. The estimation than 20 known metabolites.3 A central hypo- of risk of pyrazolone induced anaphylaxis, par- thesis of immune mediated (hypersensitivity) ticularly following parenteral administration, drug reactions has been that drugs are metabo- by case-control studies is diYcult because of lised to a reactive metabolite which can act as the low exposure of control subjects and the an hapten.4 There are limited reports concern- unclear deﬁnition of the appropriate time of ing the immunogenic potential of pyrazolone aetiologically signiﬁcant exposure. In a study of

and pyrazolidine metabolites.56 Genetic a population of 14.5 million in Holland for two on September 26, 2021 by guest. Protected copyright. heterogeneity could also predispose patients to years an incidence of drug induced anaphylaxis 16 adverse drug reactions by the formation or of 3.7 per million annually was found. The inability to detoxify a reactive metabolite. excess mortality estimate associated with dipy- In 1977 Szczeklik 7 put forward the rone use was 0.22 per 100 million. et al 17 hypothesis that, in sensitive patients, induction Hoigne has described cases of severe hypo- of asthmatic attacks by aspirin-like drugs is due tensive reaction following the intravenous to inhibition of tissue prostaglandin biosynthe- administration of pyrazolones. The mechanism sis. In about 10% of adult asthmatics NSAIDS of these reactions is unclear. Kewitz et al precipitate such attacks.8 Inhibition of cyclo- reported that the risk of severe reactions induced by pyrazolone derivatives is no higher oxygenase leading to changes in the metabo- 18 lism of arachidonic acid can also be the cause than that with opioids. of urticaria/angio-oedema. As for pyrazolones, hypersensitivity can be of Cutaneous reactions two distinct forms. There are patients, usually Skin eruptions following aminopyrine and Department of with chronic asthma, whose idiosyncratic reac- dipyrone include urticarial, morbilliform, scar- Medicine, Hadassah University Hospital, P tions resemble aspirin induced asthma and latiniform, erythematous, bullous, purpuric, 19 O Box 12000, probably involve prostaglandin inhibition and exudative, and ﬁxed lesions. The occurrence Jerusalem, Israel overproduction of cysteinyl leukotrienes. The of IgE mediated hypersensitivity reactions to M Levy second group comprises patients who develop pyrazolones has been suggested by skin prick anaphylaxis, urticaria, and other forms of rash tests and intradermal testing. In other cases Correspondence to: Dr M Levy where the hypersensitivity seems to have an positive delayed responses to patch tests have [email protected] immunological background.910 been described. A case displaying both IgE

www.thoraxjnl.com Hypersensitivity to pyrazolones S73 Thorax: first published as 10.1136/thorax.55.suppl_2.S72 on 1 October 2000. Downloaded from mediated (type I) and a cell mediated (type IV) locytosis was provided by Moeschlin and hypersensitivity reaction has recently been Wagner.32 Since that time, however, conflicting reported.20 In 1973 the Boston Collaborative data, judgements and regulations have pre- Drug Surveillance Program noticed that drug vailed as to the incidence of agranulocytosis rash occurred more frequently in Israel than in and the use of pyrazolones in general, and US patients. At that time 41.6% of Israeli dipyrone in particular. This has led to the con- patients received dipyrone, whereas in the USA duct of one of the largest pharmacoepidemio- dipyrone was not in use. The risk of dipyrone logical studies ever performed—The Inter- rash was estimated to be 2.4% of the exposed. national Study of Agranulocytosis and Aplastic However, it was recognised as being caused by Anemia (IAAAS).33 Its report on analgesics was the drug in only one third of the aVected published in 198634 and a full description of the cases.21 study experience appears as a monograph.35 In most cases dipyrone rash is mild. Rarely, it Analgesic antipyretic drug use in the week may also be part of a generalised drug reaction. before the clinical onset of illness—that is, the Pyrazolone induced urticaria/angio-oedema period of aetiological significance—was com- can also be a manifestation of a pseudoallergic pared between 275 confirmed cases of agranu- reaction, probably occurring via cyclo- locytosis and 1636 hospital controls identified oxygenase inhibition.810 by the study centres in Jerusalem, Berlin, Ulm, Asero22 has recently shown that three out of Milan, Barcelona, Sofia, Budapest, and Stock- 34 patients (9%) with a history of pyrazolone holm. The study base comprised the total induced urticaria/angio-oedema had such reac- experience in these areas during the years tions after aspirin administration. He recom- 1980–6, which amounted to nearly 107 million mended performing a simple single blind, pla- person-years. There was significant regional cebo controlled drug challenge with aspirin in variability in the rate ratio estimate for the use all patients with pyrazolone induced urticaria of dipyrone. In Ulm, Berlin, and Barcelona to prevent severe reactions in susceptible (grouped together) it was 23.7 (lower 95% patients and to allow the safe use of NSAIDs in confidence interval (CI) 8.7), and for Israel it the others. was 2.0 (lower CI 0.9). In Budapest and Sofia The more serious life threatening cutaneous the estimates were close to unity, in Milan data complication is that of Stevens-Johnson’s were too sparse, while in Stockholm dipyrone syndrome and toxic epidermal necrolysis was not in use. The excess risk estimate in (Lyell’s syndrome). Cases have been reported Ulm, Berlin, and Barcelona connected with following the use of pyrazolones and in combi- hospital admission for agranulocytosis from nation with barbiturates.23 A large population- any dipyrone use in a seven day period based case-control study covering about 120 amounted to 1.1 cases per million users. million inhabitants of France, Germany, Italy, The reason for the geographical variation in and Portugal was conducted between the years the risk of dipyrone induced agranulocytosis is 1989 and 1992 to quantify the risks associated intriguing.36 EVorts made by the investigators

with the use of specific drugs within the week to detect the extent to which the variation is a http://thorax.bmj.com/ preceding the first manifestation of the disease. reflection of methodological problems or hid- Seven of the 245 cases (3%) and 1% of the den bias have not provided an answer. If real, controls used pyrazolones. The association regional diVerences could provide an impor- between both pyrazolones as a group and dipy- tant scientific lead in understanding the rone and these conditions, according to the aetiology of the disease. multivariate relative risk, is statistically not One hypothesis to explain causality in the significant.24 order of magnitude of one case per million exposures is that several environmental and Respiratory reactions host factors act in concert. Viral infection on September 26, 2021 by guest. Protected copyright. Aspirin induced asthma has long been recog- could be such a factor. The rate ratio of nised and the diagnosis, symptomatology, and patients with agranulocytosis having had a treatment of the syndrome have been described recent viral infection was estimated as 2.4 in detail.25 It is more common in patients with (95% CI 1.5 to 3.9).37 asthma, nasal polyps, rhinitis, and chronic urti- The Swedish Medical Products Agency has caria. Current evidence indicates that cyclo- recently reported that, since the re- oxygenase inhibition and increased production introduction of dipyrone in August 1995, up to of cysteinyl leukotriene plays an important part March 1999 seven cases of agranulocytosis in these obstructive reactions.26–28 It has been were seen in patients who were reported to shown that aspirin may cross react not only have used the drug. At the moment this can with certain NSAIDs, but also with pyrazolone only be evaluated according to sales figures, derivatives including dipyrone929in the precipi- which would translate to a much higher risk tation of asthmatic attacks. The incidence and than that found by the IAAAS. Could this be risk estimates of the asthma syndrome induced an even more pronounced example of geo- by pyrazolones are unknown. graphical variation in risk? Further assessment is required. Agranulocytosis Agranulocytosis was first described by Schultz in 1922.30 In 1934 it was shown by rechallenge Fever that amidopyrine was a cause of the disease.31 As for all drugs, the pyrazolone antipyretics can In the 1950s evidence for the immunological also cause drug fever. I have personally seen pathogenesis of amidopyrine induced agranu- cases in which fever has resolved after dechal-

www.thoraxjnl.com S74 Levy Thorax: first published as 10.1136/thorax.55.suppl_2.S72 on 1 October 2000. Downloaded from lenge and appeared following the re- 17 Hoigne R, Stocker F, Barbier A, et al. Dual purpose of inpa- tient drug monitoring by physicians in two teaching hospi- introduction of dipyrone. Similar cases have tals in Berne. A. Patient adverse reaction surveillance in the been reported by others.38 hospital. Demonstration of the system by the detection of arterial hypotension due to novamine sulfone (Novalgin). In: Ducrot M, et al,eds.Computer aid to drug therapy and Conclusions drug monitoring. Amsterdam: North Holland, 1978: 9–12. Mild forms of skin rash are relatively common. 18 Kewitz H, Harter G, Feldman U, et al. Observational cohort study in general practice: diVerences and equivalence The incidence of pyrazolone induced asthma is among analgesics for treatment of colic pain In: Kewitz H, unknown. Life threatening reactions, including Roots I, Voight K, eds. Epidemiologic concepts in clinical pharmacology. Berlin: Springer Verlag, 1987: 73–86. Stevens-Johnson’s syndrome, toxic epidermal 19 Voigtlander V. Adverse dermatological reactions to pyra- necrolysis, anaphylaxis, and agranulocytosis zolones. Agents Actions Suppl 1986;19:303–11. 20 Bellegrandi S, Rosso R, Mattiacci G, et al. Combined are extremely rare. However, study and identi- immediate and delayed type hypersensitivity to Metamizol. fication of subpopulations carrying higher risks Allergy 1999;54:88–90. (and, in particular, questions relating to the 21 Levy M for the Boston Collaborative Drug Surveillance Program. Dipyrone as a cause of drug rashes. Int J geographical variation of risk) and the acquisi- Epidemiol 1973;2:167–70. tion of comparable quantitative data for all 22 Asero R. Detection of aspirin reactivity in patients with pyrazolone-induced disorders. Allergy 1998;53:214–5. major adverse events to analgesic antipyretic 23 Schulz KH, Glowania HJ. Lyell syndrome. Allergologie drugs should be goals for the future. 1983;6:450–3. 24 Roujeau JC, Kelly JP, Naldi L, et al. Medication use and the risk of Steven-Johnson syndrome or toxic epidermal 1 Shimada SG, Otterness IG, Stitt JT. A study of the necrolysis. N Engl J Med 1995;33:1600–7. mechanism of action of the mild analgesic dipyrone. Agents 25 Virchow C, Schmitz-Schumann M, Juhl-Schaub E. Pyra- Actions 1994;41:188–92. zolones and analgesic asthma syndrome. Agens Action Suppl 2 Levy M, Brune K, Zylber-Katz E, et al. Cerebrospinal fluid 1986;19:291–301. prostaglandins after systemic dipyrone intake. Clin Phar- 26 Israel E, Fischer AR, Rosenberg MA, et al. The pivotal role macol Ther 1998;64:107–12. of 5-lipoxygenase products in the reaction of aspirin- 3 Levy M, Zylber-Katz E, Rosenkranz B. Kinetics of dipyrone sensitive asthmatics to aspirin. Am Rev Respir Dis and its metabolites. Clin Pharmacokinet 1995;28:216–34. 1993; :1447–51. 4 Uetrecht JP. 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