Exploring the link between pholcodine exposure and neuromuscular blocking agent anaphylaxis

Abstract

Neuromuscular blocking agents (NMBAs) are the most commonly implicated drugs in IgE‐mediated anaphylaxis during anaesthesia that can lead to perioperative morbidity and mortality. The rate of NMBA anaphylaxis shows marked geographical variation in patients who have had no known prior exposure to NMBAs, suggesting that there may be external or environmental factors that contribute to the underlying aetiology and pathophysiology of reactions. Substituted ammonium ions are shared among NMBAs and are therefore thought to be the main allergenic determinant of this class of drugs. Substituted ammonium ions are found in a wide variety of chemical structures, including prescription medications, over‐the‐counter medications and common household chemicals, such as the quaternary ammonium disinfectants. Epidemiological studies have shown parallels in the consumption of pholcodine, a nonprescription antitussive drug which contains a tertiary ammonium ion, and the incidence of NMBA anaphylaxis. This link has prompted the withdrawal of pholcodine in some countries, with an ensuing fall in the observed rate of NMBA anaphylaxis. While such observations are compelling in their suggestion of a relationship between pholcodine exposure and NMBA hypersensitivity, important questions remain regarding the mechanisms by which pholcodine is able to sensitize against NMBAs and whether there are other, as yet unidentified, agents that can elicit similar hypersensitivity reactions. This review aims to explore the evidence linking pholcodine exposure to NMBA hypersensitivity and discuss the implications for our understanding of the pathophysiology of these reactions.

Reclassifying Anaphylaxis to Neuromuscular Blocking Agents Based on the Presumed Patho-Mechanism: IgE-Mediated, Pharmacological Adverse Reaction or “Innate Hypersensitivity”?

“…The incidence varies according to geographical factors [8], indicating that environmental factors might have an effect on the risk of anaphylaxis during anesthesia. Isolated cutaneous symptoms seem to be more frequent in non-IgE-mediated anaphylaxis, whereas bronchospasm and cardiovascular symptoms are more often seen in IgE-mediated anaphylaxis [2].…”

Acute generalised exanthematous pustulosis and other severe drug eruptions from over the counter medications: A case report and review of the literature

“…10 In addition, there is also well-documented evidence that the ingestion of pholcodine causes the production of antibodies, which can result in anaphylactic reactions when neuromuscular blocking agents are used during general anaesthesia. 11 This has led to the withdrawal of pholcodine in a number of countries and has prompted calls for its removal from the Australian market. 12 Other severe drug eruptions, including TEN or SJS, DRESS or DHS, erythroderma and anaphylaxis have been caused by OTC medications.…”

An update on allergy and anaphylaxis in pediatric anesthesia

“…The drug was withdrawn in Norway in 2007, with a subsequent fall in perioperative anaphylaxis and IgE sensitization to pholcodine and suxamethonium . The immunological mechanisms behind these observations are still to be clarified …”