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Pholcodine Consumption Increases the Risk of Perioperative Anaphylaxis to Neuromuscular Blocking Agents: The ALPHO Case-Control Study
26 Pages Posted: 13 Dec 2022
More...Abstract
Background: Neuromuscular blocking agents (NMBAs) are the leading cause of perioperative anaphylaxis (POA), most reactions being IgE mediated. Because many subjects with NMBA-related POA have no previous exposure, allergic sensitization induced by environmental exposure to other quaternary ammonium-containing compounds, such as pholcodine, has been suggested. The aim of this study was to assess the relationship between pholcodine exposure and NMBA-related POA.
Methods: ALPHO is a multicentre case-control study, commissioned by the European Medicines Agency, comparing pholcodine exposure within a year before anaesthesia between patients with NMBA-related POA (cases) and control patients with uneventful anaesthesia. Each case was matched to two controls by age, sex, type of NMBA, geographic area, and season. Pholcodine exposure was assessed by a self-administered questionnaire and pharmaceutical history retrieved from their pharmacy records. The diagnostic values of anti-pholcodine and anti-quaternary ammonium specific IgE (sIgE) were also evaluated.
Findings: Overall, 167 cases were matched with 334 controls. NMBA-related POA was significantly associated with pholcodine consumption (OR =4·2; CI95% 2·3-7·0), occupational exposure to quaternary ammoniums (OR = 6·1; CI95% 2·7-13·6) and hepato-gastro-intestinal history (OR = 2·1; CI95% 1·3-3·3). Anti-pholcodine and anti-quaternary ammonium sIgEs had a high negative predictive value (99·9%) but a very low positive predictive value (< 3%) for identifying NMBA-related POA.
Interpretation: Patients exposed to pholcodine 12 months prior to NMBA exposure have a significantly higher risk of a NMBA-related POA. These results should encourage a careful re-evaluation of the benefit/risk ratio of pholcodine-containing preparations. The low positive predictive values of pholcodine and quaternary ammonium sIgEs precludes their use to identify a population with a high risk of NMBA-related POA. The strong association of NMBA-related POA with occupational exposure suggests that other environmental factors may also lead to sensitization to NMBAs.
Trial Registration Details: The study protocol is available on ClinicalTrials.gov, NCT02250729.
Funding Information: The ALPHO study (NCT02250729) was funded by a consortium of pharmaceutical companies: Zambon, Urgo, Pierre Fabre, Boots, Hepatoum, Biocodex, Sanofi, LBR, GSK, APL, Bells Healthcare, Pinewood, T & R, Ernest Jackson.
Declaration of Interests: We declare no competing interests.
Ethics Approval Statement: The COMITE de PROTECTION des PERSONNES EsT-111
Hopital de Brabois. Rue du Morvan - 54511 VANDCEUVRE-LES-NANCY Cedex has approved this study.
Keywords: Anaphylaxis, Anaesthesia, Neuromuscular Blocking Agents, Pholcodine, Quaternary ammonium compounds
Suggested Citation: Suggested Citation