Can Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) cause angioedema like Angiotensin-Converting Enzyme (ACE) inhibitors?

NSAIDs and Angioedema: Mechanism and Risk

Yes, NSAIDs can cause angioedema similar to ACE inhibitors, though through different mechanisms, with NSAIDs causing several distinct patterns of angioedema reactions. 1

Types of NSAID-Induced Angioedema

• NSAIDs can cause a spectrum of allergic reactions including urticaria, angioedema, anaphylaxis, and rarely pneumonitis and meningitis 1
• There are four primary categories of NSAID reactions that can be diagnosed via history, presence of comorbid diseases, and drug challenges 1:
  1. NSAID-induced urticaria and angioedema - occurs in patients without underlying chronic urticaria 1
  2. NSAID-exacerbated cutaneous disease - worsening of urticaria or angioedema in patients with chronic spontaneous urticaria 1
  3. Single NSAID-induced reactions - drug-specific reactions not cross-reactive with other structurally unrelated NSAIDs 1
  4. Aspirin-exacerbated respiratory disease (AERD) - characterized by respiratory reactions rather than angioedema as the primary manifestation 1

Mechanism of NSAID-Induced Angioedema

• Unlike ACE inhibitor-induced angioedema (which occurs through inhibition of bradykinin degradation), most NSAID-induced angioedema occurs through COX-1 inhibition 1
• The prevalent theory is that inhibition of COX-1 leads to a shunting of arachidonic acid metabolism towards the 5-lipoxygenase pathway, resulting in increased synthesis and release of cysteinyl leukotrienes 2
• This mechanism explains why patients who react to one COX-1 inhibiting NSAID often cross-react with other structurally unrelated NSAIDs 1
• In single-reactors, specific IgE antibodies to haptenated NSAID metabolites have been suspected, although these are not easily demonstrated by routine testing 2

Clinical Presentation

• Facial (periorbital) angioedema is the most common form of clinical presentation 2
• One-third of patients show a mixed clinical pattern of cutaneous symptoms (urticaria and/or angioedema) and respiratory symptoms 2
• Unlike ACE inhibitor-induced angioedema which can be life-threatening due to laryngeal edema, NSAID reactions are typically mild but can occasionally be severe 3, 2

Risk Factors

• Atopic diathesis, female sex, young adulthood, and a history of chronic urticaria are predisposing factors 2
• Prevalence rates range from 0.1-0.3%, partly due to the large size of the exposed population 2

Management Options

• For patients with any NSAID hypersensitivity phenotype who require an NSAID, selective COX-2 inhibitors may be used as an alternative analgesic 1
• However, there is still a low rate of reactions (8%-11%) that occur with COX-2 inhibitors, so the first dose should be given under observation 1
• Concomitant high-dose H1-antihistamines (2-4 times the standard daily dose) might allow occasional safe use of NSAIDs in some patients 1
• For patients with NSAID-exacerbated cutaneous disease, desensitization has been attempted but is not typically successful 1

Important Distinctions from ACE Inhibitor-Induced Angioedema

• ACE inhibitor-induced angioedema is mediated through inhibition of bradykinin degradation, not through COX pathways 4
• ACE inhibitor angioedema can be life-threatening and accounts for one-third of all emergency department visits for angioedema 4
• Unlike NSAID reactions, ACE inhibitor-induced angioedema can occur after long-term use without previous reactions 4

Precautions and Recommendations

• NSAIDs should be avoided in patients with chronic urticaria as they may exacerbate the condition 1
• ACE inhibitors should be avoided in patients with angioedema without weals and used with caution in urticaria if angioedema is also present 1
• For patients who have experienced NSAID-induced angioedema, challenge testing with NSAIDs in a different structural class may provide options for pain control 1

Remember that while both NSAIDs and ACE inhibitors can cause angioedema, they do so through different mechanisms, and management strategies differ accordingly.