Tuesday, 2nd September 2014

Research Articles

Ibuprofen & Asthma

 

The British National Formulary describes Ibuprofen as follows:

General: "Ibuprofen is a propionic acid derivative with anti-inflammatory, analgesic and antipyretic properties. It has fewer side-effects than other NSAIDs (non-steroidal anti-inflammatory drugs) but its anti-inflammatory properties are weaker. Doses of 1.6-2.4g daily are needed for rheumatoid arthritis, and it is unsuitable for conditions where inflammation is prominents such as acute gout."
Indications: "Pain and inflammation in rheumatic disease (including juvenile arthritis) and other musculoskeletal disorders; mild to moderate pain including dysmenorrhoea, postoperative analgesia, fever and pain in children."

Contraindications: "NSAIDs are contraindicated in patients with a history of hypersensitivity to aspirin or any other NSAID - which includes those in whom attacks of asthma, angioedema, urticaria or rhinitis have been precipitated..."

CSM warning (asthma): "Any degree of worsening of asthma may be related to ingestion of NSAIDs, either prescribed or (in the case of ibuprofen and others) purchased over the counter."

Side-Effects: "The side effects of NSAIDs vary in severity and frequency. Gastrointestinal discomfort, nausea, diarrhoea, and occasionally bleeding or ulceration occur; dyspepsia may be minimised by taking these drugs with food or milk. Other side effects include hypersensitivity reactions (particularly rashes, angioedema and bronchospasm), headache, dizziness, vertigo, hearing disturbances such as tinnitus, photosensitivity and haematuria. Blood disorders have also occurred. Fluid retention may occur (rarely precipitating congestive heart failure in elderly patients). Renal failure may be provoked by NSAIDs especially in patients with pre-existing renal impairment. Rarely, papillary necrosis or interstitial fibrosis associated with NSAIDs may lead to renal failure. Hepatic damage, alveolitis, pulmonary eosinophilia, pancreatitis, eye changes, Stevens-Johnson syndroms and toxic epidermal necrolysis are other rare side effects. Induction or exacerbation of colitis has been reported. Aseptic meningitis has been reported rarely with NSAIDs, patients with connective tissue disorders such as systemic lupus erythromatosus may be particularly susceptible."

Ibuprofen and Asthma (Literature Review)

A computer search of the Medline database has found the following reports using key-words ibuprofen and asthma.

The earliest clinical study was in 1976 by Szczeklik et al, who investigated increasing doses of a range of NSAIDs on bronchial response in a group of 18 aspirin-sensitive patients, reporting "Low doses of the (ibuprofen) induced bronchoconstriction in all the patients as evidenced by fall in peak expiratory flow and appearance of clinical symptoms." and "The results obtained suggest that precipitation of asthmatic attacks by nonsteroidal anti-inflammatory drugs is mediated through inhibition of prostaglandin biosynthesis. The degree of enzymic inhibition, which is sufficient to precipitate bronchoconstriction, is an individual hallmark. "

Case Studies: Kawai et al reported "A 25-year-old woman was admitted to our hospital because of wheeze, dyspnea, nasal obstruction, epiphora, and ear fullness. These symptoms occurred 30 minutes after the intake of 200 mg of ibuprofen and 100 mg of norfloxacin, which had been prescribed by a local clinic for an upper respiratory tract infection." Symptoms disappeared when 20 hamsters were removed from her home. Antonicello et al described "the case of a 40 year old woman, who had suffered from asthma since infancy, with a negative case history of asthma induced by aspirin or nonsteroidal anti-inflammatory (NSAID) agents, who died after ingesting 400 mg of ibuprofen. The autopsy specimens collected 3 months after death had all the characteristic pathological features of fatal asthma."

Merritt & Selle described "an adverse reaction occurring in a 53-year-old, aspirin-sensitive asthmatic male with nasal polyps following administration of a 400-mg ibuprofen tablet is reported. Symptoms of the adverse reaction included an urticarial rash, labored breathing, laryngeal edema and tightness of the chest." Mertens et al reported a long-distance runner suffering exercise-induced asthma attacks and using ibuprofen for mild pain relief. Ibuprofen-triggered asthma attacks have also been described by Andersen &Guldager, Mathur, Ayres et al (fatal), Watts, Sharma, Canto-Diez et al, the Munich Medical association , & Simonetti et al.

Clinical Studies: Capriles-Behrens conducted "A 10-year retrospective random review of 1,007 charts of atopic children (60.9% male) attending an allergy clinic for management of asthma and/or rhinitis " but investigated facial angioedema rather than asthmatic reactions to NSAIDs (including ibuprofen). Studying paediatric patients, Menendez et al reported "a patient with moderately severe asthma who experienced an episode of anaphylaxis following ingestion of 400 mg of ibuprofen while under therapy with 20 mg of zafirlukast given twice a day.", however Lesko & Mitchell found "The risk of hospitalization with asthma, bronchiolitis, or vomiting/gastritis did not differ by antipyretic assignment. CONCLUSIONS: The risk of serious adverse clinical events among children <2 years old receiving short-term treatment with either acetaminophen or ibuprofen suspension was small and did not vary by choice of medication. "

Biochemical Studies: Pang & Knox found ibuprofen interfered with cyclo-oxygenase and prostaglandin activity in human smooth muscle airway cells which "play an important role in the regulation of the inflammatory process in asthma." Kroegel & Matthys noted a role for Ibuprofen in modulating the response in blood platelets during asthma "The fatty acid cyclo-oxygenase inhibitor, ibuprofen, abolished both the spontaneous and PAF-stimulated generation of prostanoids by eosinophils." Lundgren et al, studying human and feline platelet activating factor noted "It has been suggested that platelet activating factor (PAF) may participate in many aspects of bronchial asthma, including stimulation of mucus secretion. ...The cyclooxygenase inhibitor ibuprofen (65 and 420 microM) either failed to effect or slightly enhanced PAF induced RGC release in both species."

Advice to Clinical Practitioners: Silverstone advised child-care workers to advise mothers to seek medical advice before using over the counter cold remedies containing ibuprofen to children with pre-existing medical conditions such as asthma. Clinch & Waller stated "The role of various NSAIDs in causing asthma is now well recognised." Furst advise of the need for "careful use of (ibuprofen in) individuals with ... aspirin-induced asthma." Szczeklik warned "Drugs that precipitate possibly life-threatening bronchoconstriction and are absolutely contraindicated in patients with aspirin-induced asthma include... ibuprofen". Settipane reported "Aspirin intolerance manifests itself as an acute urticaria-angioedema, bronchospasm, severe rhinitis, or shock occurring within three hours of aspirin ingestion. Aspirin intolerance occurs most commonly in patients with chronic urticaria (23 percent), in whom it is mostly manifested by the urticarial type of aspirin intolerance, and in asthmatic persons (4 to 19 percent), in whom it is mostly manifested by the bronchospastic type. ... In the bronchospastic type, an association between prostaglandins and the slow-reacting substance of anaphylaxis seems likely. ... Various drugs, most of which are prostaglandin inhibitors, cross-react with aspirin in intolerant persons. They are, in decreasing order of frequency, as follows: indomethacin (100 percent), ibuprofen, mefenamic acid, phenylbutazone, sodium benzoate, tartrazine and acetaminophen (5 percent)." Friedlander et al cautioned "Aspirin, other nonsteroidal antiinflammatory agents (e.g., ibuprofen) and local anesthetic agents containing vasoconstrictor and preservative (antioxidants, i.e., sulfite) agents should be avoided in children with concurrent asthma because of their propensity to trigger an asthmatic attack."

Conflicting Report: One case study by Kordansky et al described a single patient who reported NSAIDs to improve her reaction to bronchospasm. They found "ibuprofen administration resulted in marked (45% to 80%) improvement in forced expiratory volume in 1 second (FEV1) compared to lactose placebo." .and concluded "This case suggests that aspirin and other nonsteroidal anti-inflammatory drugs may be beneficial rather than harmful in some asthmatic patients."

Summary

There are numerous reports within the clinical literature of ibuprofen-induced bronchospasms (asthma attacks), most particularly in patients who have sensitivity to aspirin or other non-steroidal anti inflammatory drugs. In extreme cases, such attacks can be fatal.

Several studies have provided evidence for a direct effect of ibuprofen in modulating the biochemical processes underlying airway regulation and the onset of asthma attacks.

In relation to the wide availability of ibuprofen both on prescription and in over-the-counter preparations, the number of adverse reactions reported is small, however for patients with aspirin-sensitivity, the risk of asthma attacks rises significantly.