NEWS AND COMMENTARIES
Pholcodine in cough medicines and IgE-sensitization in the EU: an urgent task
Version of Record online: 2 MAR 2012
© 2012 John Wiley & Sons A/S
Volume 67, Issue 5, pages 581–582, May 2012
How to Cite
Florvaag, E. and Johansson, S.G.O. (2012), Pholcodine in cough medicines and IgE-sensitization in the EU: an urgent task. Allergy, 67: 581–582. doi: 10.1111/j.1398-9995.2012.02803.x
- Issue online: 11 APR 2012
- Version of Record online: 2 MAR 2012
According to a recent press release, the European Medicines Agency (EMA) after conducting a review of the safety and effectiveness of pholcodine (PHO) – a morphine (MOR) analogue and possibly one of the strongest IgE-sensitizing agents known – has decided to let patients in the European Union continue to be exposed through the unrestricted use of cough and cold medicines. As suggested by published information, summarized in this commentary, we advise this decision be revised.
Following concerns that use of PHO in cough medicines may put people at risk of developing anaphylactic reactions to neuromuscular blocking agents (NMBA) used during surgery, the EMA has completed a review of the safety and effectiveness of PHO. According to its recent press release (http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/11/news_detail_001389.jsp&mid=WC0b01ac058004d5c1), the Agency's Committee for Medicinal Products for Human Use (CHMP) has concluded that the existing evidence of the risk is weak and that the benefits of PHO continue to outweigh its risks. Therefore, it recommended that all marketing authorizations for medicines containing PHO should be maintained throughout the European Union (EU) and that patients taking PHO-containing medicines can continue to do so and should contact their doctor or pharmacist if they have any questions.
We are deeply concerned about the possible medical consequences of the conclusions drawn by the CHMP because they do not seem to place sufficient focus on the basic adverse affect of PHO, namely its extraordinary effects on IgE-synthesis [1, 2]. PHO is one of the most potent IgE-sensitizing agents known! According to Norwegian estimates, possibly as many as one in 4–5 of exposed individuals may develop IgE antibodies to PHO. Furthermore, once sensitized, one-third of the recommended daily dose of PHO for cough suppression taken during 1 week within 3 weeks leads to up to a 100-fold polyclonal increase in IgE-antibody levels and serum IgE [1, 2] previously seen only in graft versus host disease after bone marrow transplantation and in angioblastic lymphadenopathy . In most cases, after the booster, IgE levels normalize within 1–2 years, but individual patients maintain highly elevated IgE levels for many years.
The possible medical consequences of the IgE responses to PHO are several, but as PHO works in subtle ways, many of them may go clinically undetected for a considerable time. As a MOR analogue, PHO functionally is a monovalent hapten with two independent, non-cross-reacting allergenic epitopes . IgE antibodies to PHO therefore have two specificities, either towards the quaternary, or rather tertiary, ammonium ion (QAI) shared with the NMBA like suxamethonium (SUX) bivalent for the QAI, or to an epitope specific for PHO and MOR not shared with the NMBAs. One consequence of this monovalency is that PHO very rarely gives rise to severe IgE-mediated allergic reactions towards itself. Thus, successions of apparently uneventful re-exposures through cough medicines may take place and high degrees of resulting IgE-sensitization will go virtually unnoticed, if not specifically looked for. However, upon exposure to a NMBA during induction of general anaesthesia, they have the potential to initiate an IgE-mediated anaphylactic reaction, unexpected to the beforehand unaware patient and doctor. Although rare, such adverse reactions represent the most dramatic clinical consequences of a PHO sensitization. Norwegian data suggested a prevalence of anaphylactic reactions to NMBA to be 1/5200 general anaesthesias using NMBA at a time when PHO was still on the market . Prior IgE-sensitization to the QAI epitope (i.e. SUX) was estimated to increase the risk to 1/20 .
Other reported consequences of PHO's effect on IgE-synthesis are increased prevalences of highly elevated IgE levels, often combined with a broad spectrum of elevated IgE antibodies to food and/or airborne allergens. As a consequence, such patients are referred to allergy clinics for evaluation. The quick shift in IgE levels may also interfere with the treatment of patients with severe allergic bronchial asthma with anti-IgE antibodies, for example omalizumab (Xolair©; Novartis, Basel, Switzerland) as optimal dosage depends on a stable IgE body pool. Furthermore, it should be noted that we still do not understand the beneficial roles of IgE. That interference with the IgE-synthesis mechanism could have negative effects on possible beneficial functions like handling of immune complexes , viral infections  and cancer  has been seriously discussed.
Our prospective interventional study  showed that IgE-sensitization to PHO, MOR and SUX had fallen statistically significantly 1 year after withdrawing PHO from the market, and after 2–3 years, reporting of anaphylactic reactions during anaesthesia also dropped significantly during which time, according to the Norwegian Medicines Agency, sales of NMBAs were maintained virtually unchanged. Similar effects were seen in Sweden in the 1980s when a PHO-containing cough syrup after close to 20 years was withdrawn from the market . And in Denmark, where PHO has never been on the market, diagnosed IgE-mediated anaphylactic reactions to NMBAs are indeed rare . So, from these Scandinavian experiences, it would seem excitingly easy and effective to reduce widespread IgE-sensitization to PHO in exposed populations and as a consequence, prevent the quite rare, but potentially debilitating and life-threatening, anaphylactic reactions to NMBAs caused by IgE-mediated mechanisms.
Pholcodine-containing medicines are marketed in the EU Member States of Belgium, France, Ireland, Lithuania, Luxembourg, Malta, Slovenia, Spain and the United Kingdom, either by prescription or as over-the-counter medicines. They may be available as syrups, oral solutions, suppositories, tablets and capsules under various trade names and as generics (http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/11/news_detail_001389.jsp&mid=WC0b01ac058004d5c1). For example, in France, according to VigiBase, there would be close to 100 cases of anaphylaxis to NMBA per year. Previous reports, for example from Australia, indicate death rates above 3% .
The use as cough depressants and cold medicines, to a considerable degree sold OTC, allows their distribution and successive sensitization to become widespread in populations. The former marketing authorization holder in Norway estimated that about 40% of the population was exposed. Given market shares of similar sizes in the major PHO-consuming EU nations and that the EU citizen's IgE-response equals that of the Scandinavian's, we really wonder how a decision of status quo best represents the ‘Interest of the Communities involved’ according to the Article 31 of Directive 2001/83/EC, under which the EMA review on PHO was carried out. Hopefully, the allergy background of the new EMA Executive Director  will improve the understanding of IgE-sensitization within EMA.
In our opinion, the ‘Pholcodine case’ is far from finally closed, and we have long since looked forward to research groups in other European PHO-consuming nations to conduct their own trials. Hopefully, such will follow now, in addition to those asked for in the CHMP/EMA statement. However, we sincerely feel that the Scandinavian data represent sufficient warning signals against deciding to continue exposure of large EU populations for many years to come pending further research data.
Conflict of interest
No conflict of interest stated for any of the authors.