Urticaria, the second most common drug eruption after exanthematous drug eruptions,1 is characterized by episodic short-lived swellings of the skin, oropharnyx, or genitalia. Transient leakage of plasma from small blood vessels into the surrounding connective tissue of the dermis results in itchy, pink plaques or papules with edematous pale centers, known as wheals. Deeper swellings of the subcutaneous or mucosal tissues are called angioedema (Figure 1).
Spontaneous wheals fluctuate from day to day, appearing in one area and disappearing within 24 hours. This is an important distinction from an urticarial rash, which may appear like urticaria but tends to run a different time course, and has different etiologies and longer-lasting lesions.
Drug-induced urticaria (DIU) may be allergic (immunologically mediated) or pseudoallergic (nonimmunologically mediated), but a specific mechanism may be difficult to ascertain.
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The course of time over which a cutaneous reaction is observed is crucial in determining whether a drug is likely to be causative. This will vary depending on whether immunologic or nonimmunologic mechanisms are involved.
Type 1 reactions (immunologically mediated) require a period of sensitization of the patient to the drug. Usually the initial therapeutic course with the drug is uneventful, although reactions can occur later during a prolonged course.
Reaction on re-exposure results in the elicitation phase, with urticaria usually occurring in minutes, although it may take up to one hour. This immediate hypersensitivity can produce more severe manifestations, such as angioedema and anaphylaxis.
The term pseudoallergy implies a clinical reaction resembling immediate hypersensitivity but occurring by nonimmunologic mechanisms. There is no sensitization phase. Therefore, pseudoallergic reactions may occur after first contact with chemically and structurally unrelated compounds. They are suggested by the slow onset of symptoms, up to 24 hours after ingestion, with half of reactions occurring in the first six hours.2 The rash tends to disappear within several days following discontinuation of the drug.
DIU can be caused or aggravated by medications. Nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, antibiotics, and vaccines are the most frequently reported causes (Table 1).3 Acute DIU, lasting less than six weeks, is often easy to identify from the history of exposure. In chronic urticaria, defined by continuous disease lasting at least six weeks, adverse effects of drugs that aggravate the existing urticaria may be more difficult to identify.
Implications of penicillin allergy
The most common drugs causing DIU are penicillins.1 Patients with a history of penicillin allergy are four to eight times more likely to have an allergic reaction to cephalosporins than those without.4 Cross-reaction with first-generation cephalosporins is higher than with second- or third-generation cephalosporins.5,6 Aztreonam was found to be well tolerated in penicillin-allergic patients without causing an immunoglobulin (Ig) E-mediated reaction.7
In the setting of acute urticaria, in which an upper respiratory tract infection is treated with antibiotics or symptomatically with analgesics, it may be difficult to identify the cause of urticaria from the history. In such a situation, diagnostic testing may be appropriate to confirm or refute the suspected history of an adverse drug reaction. Specific IgE antibodies and skin prick tests to penicillin are only useful for detecting type I reactions to penicillin. Looking for alternative antibiotics is better than challenging patients to antibiotics to which they may be intolerant, unless there is no alternative.3
Antihypertensives and analgesics
Angioedema after ACE inhibitor treatment is well described, with an incidence of approximately 0.1%-1.0%.8 Onset of ACE inhibitor-induced angioedema may be within days, months, or even years of the treatment. It is a class effect, so cross-reactions are to be expected between all drugs in this group.
Angiotensin II receptor blockers (ARBs) have many properties similar to those of ACE inhibitors but act further downstream in the renin-angiotensin-aldosterone pathway. The risk of persistent angioedema developing after patients with previous ACE inhibitor-associated angioedema are switched to an ARB has been found to be less than 10%.9 It was concluded that an ARB can be administered to such patients if they are suitably advised as to the risk of recurrent angioedema.
The risk of angioedema from antihypertensive agents is not limited to ACE inhibitors and ARBs. One study found 0.12% of 42,418 patients who were receiving antihypertensives had angioedema.10 Although 70% of cases were due to ACE inhibitors, the rest were attributed to diuretics, alpha blockers, and calcium channel blockers. Beta blockers have also been reported to cause urticaria.3
Aspirin, NSAIDs, and codeine are often cited as drugs to be avoided in patients with chronic urticaria. Although aspirin will trigger or aggravate chronic ordinary urticaria in 20%-40% of patients, it is not possible to predict who will be affected.11 Oral aspirin challenge to predict future reactions is not indicated because a negative challenge may be followed months or years later by a severe reaction to aspirin or an NSAID.12 Patients with aspirin sensitivity often display cross-reactions to nonselective NSAIDS that inhibit the COX-1 enzyme. It is therefore generally recommended that aspirin and NSAIDs should be avoided in patients with chronic urticaria.
Avoidance of aspirin and NSAIDs can cause therapeutic challenges in patients requiring alternative analgesics and anti-inflammatory drugs. The inclusion of codeine in the list of drugs to be avoided further limits this choice. However, in a series of 220 patients, codeine was reported as a cause of ordinary chronic urticaria in 0.4%.13
Only small studies evaluating tolerability of codeine and tramadol in patients with chronic urticaria who reported exacerbations with multiple NSAIDs have so far been reported.14,15 A study of 28 patients found that tramadol aggravated urticaria in 18% of such patients,14 with one developing laryngeal edema. A further study involving 25 controlled challenges with paracetamol in addition to 30 mg codeine resulted in one patient developing urticaria (4%). Based on these findings, the recommendations are to consider codeine and its derivatives as a possible analgesic but first to assess tolerability by oral challenge in a clinical setting.
Acetaminophen is widely used in patients with aspirin-sensitive urticaria or anaphylaxis,16 but anaphylaxis has been described.17
In patients with chronic urticaria as well as a history of NSAID hypersensitivity, drug reactivity is associated with inhibition of the constitutive COX-1 pathway resulting in overproduction of leukotrienes. Selective COX-2 inhibitors are generally much better tolerated, although some can aggravate chronic urticaria. Research continues into quantifying the risk of using these drugs in multiple NSAID-intolerant patients.
Research in Italy showed etoricoxib to be tolerated in 100% of the 17 patients in one study,16 but to induce urticaria in 7.1% of patients in another.18 By contrast, celecoxib was not tolerated by one third of challenged patients.19 It is estimated that overall, 4% of patients with a history of NSAID-induced skin reaction have a cutaneous reaction after challenge to a COX-2 selective NSAID.20 In patients who develop cross-reaction to a COX-2 selective NSAID, a challenge with a different agent from that class can be cautiously tried.18
Although theoretically, aspirin-sensitive patients are at risk of urticaria or anaphylaxis from low-dose aspirin prescribed for cardiovascular prophylaxis, in practice, it is rare for patients with established urticaria to improve on discontinuation.
Other implicated drugs
Acute or chronic urticaria can commence within days or weeks of vaccination. Vaccines have been cited as the third most common cause of DIU.3 H1 antihistamines are the first-line treatment for all patterns of urticaria. Not all patients respond well and very occasionally, antihistamines appear to make urticaria worse. DIU has been reported for H1 and H2 antihistamines,3 which are sometimes combined for urticaria that has responded poorly to treatment.
Dr. Chetty is a specialist registrar in dermatology and Dr. Grattan is a consultant in dermatology at Norfolk & Norwich University Hospital in Norwich, England.
References
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