Pholcodine consumption increases the risk of perioperative anaphylaxis to neuromuscular blocking agents: the ALPHO case-control study

Background Neuromuscular blocking agents (NMBAs) are the leading cause of perioperative anaphylaxis (POA), most reactions being IgE mediated. 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, 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 pharmacy records. The diagnostic values of anti-pholcodine and anti-quaternary ammonium specific IgE (sIgE) were also evaluated. Results 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) and occupational exposure to quaternary ammoniums (OR = 6.1; CI95% 2.7-13.6). 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. Conclusion Patients exposed to pholcodine 12 months prior to NMBA exposure have a significantly higher risk of a NMBA-related POA. 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. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT02250729 ### Funding Statement This study ([NCT02250729][1]) was funded by a consortium of pharmaceutical companies marketing pholcodine (Zambon, Urgo, Les Laboratoires Pierre Fabre, Boots, Hepatoum, Biocodex, Sanofi, Laboratoires Bouchara Recordati, GSK, Alliance Pharmaceuticals Ltd, Bells Healthcare, Pinewood, T & R, Ernest Jackson, Vemedia). The consortium had no role in study design, data collection, data analysis, data interpretation, or writing of the report. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The French Ethical Committee named "Comite de Protection des Personnes (CPP) Est III" gave its favorable advice on March 7th, 2013 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02250729&atom=%2Fmedrxiv%2Fearly%2F2022%2F12%2F14%2F2022.12.12.22283353.atom