Letter to the authors concerning the accepted manuscript: exploring the link between pholcodine and neuromuscular anaphylaxis by Brush et al.

We read with interest the manuscript by Brusch et al. [1] about the putative role of pholcodine in the sensitization to curarizing myorelaxants [2,3]. We would like to raise some issues and questions, especially concernig the recommendations put forward for the individual cases. In both cases, due to uncertainties associated with skin tests and the unavailability of basophil activation tests, the diagnosis of pholcodine allergy appears to rest upon history and measurement of pholcodine-specific IgE (sIgE) antibodies. Therefore, the authors presumably applied the technique available from Thermo Fisher Scientific, which is not a radioallergosorbent test as indicated. Because pholcodine is known to boost IgE production, results of total IgE and atracurium ImmunoCAP would be welcome, as this could shed light on the relevance of sIgE findings. In both patients, cross-sensitization was studied with skin testing. In the first patient, according to these results, combined with the sIgE results, future use of atracurium and rocuronium was discouraged. Suxamethonium and vecuronium were proposed as alternatives. Several issues should be considered here, as these recommendations might not be fully correct. First, the recommendation not to use atracurium relies upon a positive skin test with undiluted formulation, which is a 10-fold greater concentration than advocated [4]. Second, the patient is dissuaded further use of rocuronium, solely on the basis of a positive sIgE result. However, we recently demonstrated sIgE to exhibit low predictive value and we recommended additional basophil activation tests to elucidate on the clinical relevance of an solated IgE positivity [5]. Third, the authors did not make any recommendation about further use of the structurally related opiates, viz. morphine and codeine. In other words, why is the sIgE rocuronium considered relevant and the sIgE morphine not? Finally, taking into account the extensive cross-reactivity between rocuronium, vecuronium [6] and suxamethonium [7], it seems odd to propose vecuronium and suxamethonium as safe alternatives, particularly as basophil activation tests and measurement of IgE to suxamethonium were not performed. Would the authors recommend further use of suxamethonium with a positive sIgE result for this compound, or, like rocuronium, would they than alter their proposal?

The same comments apply to the second case. However, in this patient the advice is limited to the suxamethonium that tested positive in the intradermal test. Could this be the reflection of an incomplete diagnostic approach in this patient (e.g. no measurement of sIgE to morphine and rocuronium)?

The authors conclude their case reports to endorse the hypothesis that intake of pholcodine is associated with sensitivity to myorelaxants (without any precision). To us, this conclusion seems premature and controversial. In the absence of any provocation tests or longitudinal follow-up data, we would suggest prudence upon interpretation of a positive sIgE result to curarizing myorelaxants in patients with negative skin tests or basophil activation tests [5]. Pioneering studies have already made clear that the application of tests for curarizing myorelaxants and morphine should not be used to predict clinical outcomes [3]. It seems odd that sIgE results to curarizing myorelaxants in patients allergic to pholcodine should be interpreted differently from sIgE results to structurally almost similar opiates, such as morphine. As a matter of fact, we have recently reported that patients allergic to pholcodine were able to tolerate a graded codeine provocation test [8].

Competing Interests

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.

Didier Ebo is a Senior Clinical Researcher of the Research Foundation Flanders (FWO: 1800614N).