Response to letter regarding article 'Exploring the link between pholcodine exposure and neuromuscular blocking agent anaphylaxis'.

Uyttebroek et al. [1] raise some pertinent questions regarding the utility of various testing modalities in the assessment of neuromuscular blocking agent (NMBA) hypersensitivity. In our cases, clinical history was the major assessment tool for identifying pholcodine as the inciting agent of anaphylaxis [2]. In both patients, the temporal association between pholcodine exposure and clinical reaction was in keeping with drug-induced anaphylaxis and no alternative causes were identified. The positive allergen-specific IgE levels to pholcodine (ImmunoCAP Phadia, Uppsala, Sweden) were used to substantiate the high index of clinical suspicion. As mentioned in the article, skin testing to pholcodine has limited utility because it causes wheal and flare reactions in normal control subjects. While drug provocation challenges are sometimes used to confirm allergy in situations where history and skin/allergen-specific IgE testing are ambiguous, in this circumstance this was not felt appropriate, owing to the severity of systemic reaction in both patients' index events. In one of our cases, a tramadol challenge was performed to give additional options if opiate analgesics were required, and the avoidance of codeine and its active metabolite morphine was recommended. Subsequent evaluation in both our patients was targeted toward the potential for NMBA hypersensitivity given previous studies [3–6], presented in the review, suggesting an association between pholcodine exposure and NMBA anaphylaxis. The recommendations regarding NMBA use in both patients were based on the outcome of skin testing and allergen-specific IgE testing. As Uyttebroek et al. [1] allude to, sensitization to a drug does not always equate with clinically meaningful allergy. However, provocation challenges with various NMBAs, as a means of demonstrating patient tolerance or allergy, are not feasible. Thus, the recommendations were made on the available testing at the time of assessment. The development of basophil activation tests as an adjunct to skin testing and specific IgE testing will no doubt help in the assessment of cases of suspected drug allergy. However, these tests are currently not validated or routinely available in most centres, and sensitivity may be lacking even when cases are carefully phenotyped and selected. The cases presented demonstrate the potential for sensitization to NMBA to occur in the context of pholcodine hypersensitivity. These case studies are reflective, at an individual patient level, of the population-based evidence cited previously [3,5,6]. We agree that consideration of whether the patients are able to tolerate opiates following true pholcodine immediate (IgE) hypersensitivity reactions is an important practical concern, and the specific haptenated products mediating such reactions are unknown. Indeed, codeine is metabolized by the genetically polymorphic isoform CYP2D6 to the active metabolite morphine, adding additional potential variability to potential cross-reactivity and patient tolerance. However, the focus of our article [2] was on the potential association of pholcodine exposure and NMBA allergy, and thus, the presentation of the case studies reflects this. Immunoglobulin E-mediated hypersensitivity reactions to pholcodine and morphine are rare, and this does indeed raise important questions regarding the pathogenesis of pholcodine sensitization and NMBA anaphylaxis. At present, the mechanisms underlying why exposure and sensitization to a substituted ammonium ion in pholcodine can prime NMBA anaphylaxis but not result in allergy to all compounds containing similar substituted ammonium ions remain unresolved.