Work

Cross-Reactivity and Cross-Intolerance Among Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Clinical Patterns, COX-1-Mediated Mechanisms, and Implications for COX-2 Inhibitors and Paracetamol

Year: 2026

Type: article

Abstract: Cross-reactivity among nonsteroidal anti-inflammatory drugs (NSAIDs) creates a significant clinical difficulty, especially in patients with NSAID hypersensitivity. These reactions are based on cyclooxygenase-1 (COX-1) inhibition and non-immunoglobulin E (IgE)-mediated reactions. COX-1 inhibition leads to dysregulation of arachidonic acid metabolism, with decreased prostaglandin synthesis and increased leukotriene production. Clinically, cross-intolerant reactions manifest in different phenotypes, including NSAID-exacerbated respiratory disease (NERD), NSAID-induced urticaria/angioedema (NIUA), and NSAID-exacerbated cutaneous disease (NECD). In contrast, true allergic reactions-such as single-NSAID-induced urticaria/angioedema and anaphylaxis (SNIUAA) and single-NSAID-induced delayed hypersensitivity reactions (SNIDHR)-are immunologically mediated and drug-specific. These phenotypes differ in underlying conditions, clinical manifestations, and patterns of NSAID tolerance. Paracetamol is generally considered a safer alternative due to its weak COX-1 inhibition; however, reactions may still occur, particularly at higher doses. Selective COX-2 inhibitors are usually better tolerated, however their safety should be confirmed, preferably through controlled drug provocation testing due to sporadic reactions in cross-intolerant patients. Understanding the distinction between pharmacologically mediated cross-intolerance and true allergic reactions is essential for accurate diagnosis, risk stratification, and therapeutic decision-making. This review summarizes current evidence on the mechanisms underlying NSAID hypersensitivity, analyzes the tolerability of paracetamol and alternative analgesics, and discusses practical management strategies to reduce the risk of adverse reactions.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms27093727

Authors: Wiktoria Andryszkiewicz, Martyna Lippik, Małgorzata Makieła, Bartosz Modrzyk, Krzysztof Gomułka

Institution: Wroclaw Medical University

Language: English

Topic: Drug-Induced Adverse Reactions

Subfield: Pharmacology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,499