Pholcodine, used as an over-the-counter cough suppressant in syrups and lozenges to manage cold symptoms, has now been withdrawn from the market by authorities including the EU, UK, US, Australia, and in Asian countries Malaysia and Singapore [1-3]. The recent market withdrawal was based on the publication of the ALPHO case-control study [4] assessing the relationship between pholcodine exposure and neuromuscular blocking agents (NMBAs) related anaphylaxis in France.
The researchers mentioned that for any anaphylaxis reactions to happen, it requires prior exposure to the antigen to induce sensitisation. But many patients who react to NMBAs have never been exposed to such agents before. In 2005 scientists proposed quaternary ammonium (QA) containing pholcodine as a potential cause, which led to the official request from European Medicines Agency (EMA) to conduct a case-controlled study establishing a potential relationship, thus the birth of ALPHO study. Previously in 2007, Norwegian authorities withdrew the medication citing the risk, with a subsequent reduction in prevalence of anaphylactic reactions [5].
The study screened 937 patients between July 2014 to July 2020. After eligibility screening, 334 were enrolled as control – with normal perioperative course; and 167 positive cases with perioperative anaphylaxis. The multivariable analysis showed that pholcodine consumption over the 12 months period leading to NMBA exposure was associated with NMBA-related anaphylaxis with an OR of 4.2 (95% CI 2.3-7.0). Occupational exposure to QA and hepato-gastrointestinal history were also associated with NMBA-related anaphylaxis with an OR of 6.1 (95% CI 2.7-13.6) and 2.1 (95% CI 1.3-3.3), respectively. The full table showing risk factors and corresponding OR for NMBA-related perioperative anaphylaxis is shown in Table 1 below.
Table 1
ALPHO study confirms a significant association between pholcodine consumption in the year preceding NMBA exposure and NMBA-related perioperative anaphylaxis. Other environ- mental factors, including occupational exposure to quaternary ammonium compounds, should be considered in the risk of NMBA-related anaphylaxis, but they currently remain poorly defined. However, researchers also acknowledged a higher proportion of missing community pharmacy information in the control group. There were also discrepancies between questionnaires and prescription history, which is hard to verify considering some patients might be taking medication prescribed for their family members.
Citing the positive result from ALPHO study, since February 2023, the EMA, UK, US, Australia, Malaysia and Singapore have all removed the licence of Pholcodine containing cough suppressants. Despite no known local cases, Singapore’s Health Sciences Authority (HSA) also advised patients that ‘If you are undergoing surgery involving the use of general anaesthesia and had taken any pholcodine-containing medicines, particularly in the past 12 months, inform your anaesthetist or doctor.’ [3]
Despite Pholcodine withdrawn in Malaysia and Singapore, it is still available in most other Asian countries. Indonesia’s National Food and Drug Supervisory Agency (BPOM) is currently attempting to trace the sales of syrup drugs containing pholcodine following the withdrawal [6]. Meanwhile, dozens of cough suppressant medications are still available, many over the counter and are equally effective in suppressing mild cough [7]. Future research could look into how to desensitize patients exposed to Pholcodine over the past year before surgery, thus further reducing the risk of anaphylactic reaction.
Reference:
- Mei CS. [Updated] Pholcodine: Risk of Anaphylaxis to Neuromuscular Blocking Agents (NMBAs) [Internet]. www.npra.gov.my. 2023 [cited 2023 Jun 24]. Available from: https://www.npra.gov.my/index.php/en/component/content/article/449-english/safety-alerts-main/safety-alerts-2023/1527471-pholcodine-risk-of-anaphylaxis-to-neuromuscular-blocking-agents-nmbas.html?Itemid=1391#:~:text=In%20Malaysia%2C%20pholcodine%20is%20classified
- Goods T. Pholcodine [Internet]. Therapeutic Goods Administration (TGA). 2023. Available from: https://www.tga.gov.au/news/safety-alerts/pholcodine
- Withdrawal of Pholcodine-Containing Medicines in Singapore [Internet]. HSA. 2023 [cited 2023 Jun 24]. Available from: https://www.hsa.gov.sg/announcements/news/withdrawal-pholcodine-containing-medicines
- Mertes PM, Petitpain N, Tacquard C, Delpuech M, Baumann C, Jean Marc MALINOVSKY, et al. Pholcodine exposure increases the risk of perioperative anaphylaxis to neuromuscular blocking agents: the ALPHO case-control study. British Journal of Anaesthesia. 2023 Jul 1;131(1):150–8.
- Dumančić J, Stipić Marković A. CORRELATION BETWEEN PHOLCODINE AND PERIOPERATIVE ANAPHYLAXIS. Acta medica Croatica : Časopis Akademije medicinskih znanosti Hrvatske [Internet]. 2012 [cited 2023 Jun 24];66(2):111–3. Available from: https://hrcak.srce.hr/clanak/143088
- BPOM traces sales of syrup drugs containing pholcodine – ANTARA News. [cited 2023 Jun 24]. Available from: https://en.antaranews.com/news/276912/bpom-traces-sales-of-syrup-drugs-containing-pholcodine
- UpToDate [Internet]. Uptodate.com. 2023 [cited 2023 Jun 24]. Available from: https://www.uptodate.com/contents/image?imageKey=EM%2F94240
