National pholcodine consumption and prevalence of IgE-sensitization: A multicentre study

Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden.
Allergy (Impact Factor: 6.03). 10/2009; 65(4):498-502. DOI: 10.1111/j.1398-9995.2009.02193.x
Source: PubMed


The aim of this study was to test, on a multinational level, the pholcodine (PHO) hypothesis, i.e. that the consumption of PHO-containing cough mixtures could cause higher prevalence of IgE antibodies to PHO, morphine (MOR) and suxamethonium (SUX). As a consequence the risk of anaphylaxis to neuromuscular blocking agents (NMBA) will be increased.
National PHO consumptions were derived from the United Nations International Narcotics Control Board (INCB) database. IgE and IgE antibodies to PHO, MOR, SUX and P-aminophenyl-phosphoryl choline (PAPPC) were measured in sera from atopic individuals, defined by a positive Phadiatop test (>0.35 kU(A)/l), collected in nine countries representing high and low PHO-consuming nations.
There was a significant positive association between PHO consumption and prevalences of IgE-sensitization to PHO and MOR, but not to SUX and PAPPC, as calculated both by exposure group comparisons and linear regression analysis. The Netherlands and the USA, did not have PHO-containing drugs on the markets, although the former had a considerable PHO consumption. Both countries had high figures of IgE-sensitization.
This international prevalence study lends additional support to the PHO hypothesis and, consequently, that continued use of drugs containing this substance should be seriously questioned. The results also indicate that other, yet unknown, substances may lead to IgE-sensitization towards NMBAs.

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Available from: Prof Suranjith L Seneviratne
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    • "The PHO molecule, which shares the major allergenic epitope, the quaternary ammonium ion, quaternary ammonium ion (QAI), with NMBA [2], has been shown to be very immunogenic, possibly sensitizing as many as 20-25% of individuals exposed [3], in addition to having an enormous polyclonal boosting capacity, increasing IgE levels up to 100 folds in sensitized and re-exposed individuals [4, 5]. Thus, an NMBA-related presensitization may be induced by exposure to the widespread and unrestricted use of PHO-containing cough and cold medicines sold over the counter in around a third of the nations in the world [1]. The European Medicines Agency (EMA) in 2011, after a formal review of all available data, however, advised to continue the unrestricted use of PHO-containing cough medicines throughout the European Union [6]. "
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    ABSTRACT: Accumulating data indicates that pholcodine (PHO)-consuming countries have higher sero-prevalences of immunoglobulin E (IgE)-antibodies to PHO and suxamethonium (SUX) and increased frequencies of IgE-mediated anaphylaxis to neuromuscular blocking agents (NMBAs) than nonconsuming. Withdrawing PHO-containing cough syrups resulted in a significant decrease of cases with anaphylaxis in Scandinavia. Nevertheless, the European Medicines Agency in 2011 advised to continue the unrestricted use throughout the European Union. To extend studies on PHO consumption and prevalence of IgE-sensitization to morphine (MOR), PHO, and SUX to countries representing high (Australia), and low (Korea and Japan), consumers, respectively. IgE-antibodies to SUX, MOR, and PHO in atopic subjects were determined by immunoassay and compared with official figures for PHO consumption and reported anaphylaxis to NMBA. The prevalences of IgE-antibodies to PHO, MOR, and SUX were 10%, 8.6%, and 4.3%, respectively, in Australia. The corresponding figures for Japan were 0.8%, 0.8%, and 1.5%, and for Korea 1.0% to PHO and 0.5% to MOR and SUX. Of the SUX-positive sera, 100% were positive to PHO or MOR in Australia and 0% in Japan and Korea. The study supports previous findings; exposure to PHO may induce IgE-antibodies to the substituted ammonium ion epitope of NMBAs, thus increasing risk of NMBA-induced anaphylaxis considerably. However, other, still unknown factors occasionally might induce IgE-antibodies to SUX.
    Full-text · Article · Apr 2014
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    • "Responsibility of pholcodine in these reactions is suspected [8]. This variability in the incidence of anaphylactic reactions between countries could be explained by the variability in consumption of pholcodine them [9]. These agents can induce two types of reactions. "
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    ABSTRACT: Epinephrine is the recommended treatment in anaphylactic shock. Recently cases of anaphylactic shock refractory to epinephrine have been reported. The authors report the efficacy of a bolus of vasopressin in a refractory anaphylactic shock caused by rocuronium after failure the epinephrine. Thought this case report and review of literature, the authors discuss the mechanism of action and the effectiveness of this alternative treatment, vasopressin, in refractory anaphylactic shock to epinephrine.
    Preview · Article · Apr 2013 · Egyptian Journal of Anaesthesia
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    • "An international multicenter study comparing consuming and nonconsuming countries, found a significant association (P < 0.03) between the national consumptions of PHO, according to the INCB, and the percentages of sera with IgE antibodies to PHO using Phadiatop (IDD; Thermo Fisher Scientific) positive allergics as screening populations [8]. For 2 countries in this study, the Netherlands and the United States, the results were interesting because both showed IgE sensitization to PHO but neither had known PHO-containing drugs on their markets. "
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    ABSTRACT: The Scandinavian data on pholcodine (PHO) strongly indicates that there is a biological chain from PHO exposure through IgE-sensitization to IgE-mediated anaphylaxis to neuromuscular blocking agents (NMBA). PHO is probably one of the strongest inducer of an IgE antibody response known. Of individuals taking PHO in cough medicines, over-the-counter accessibility to large populations, as many as 20 to 25% may become IgE sensitized. Once sensitized, PHO re-exposure will booster IgE antibody levels and IgE by around 100-fold. PHO is monovalent for 2 non-cross-reacting epitopes the quaternary ammonium ion (QAI), the main allergenic epitope of NMBA, and a non-QAI epitope. Thus, PHO most unlikely would initiate an allergic inflammatory response. Consequently, IgE sensitization is not revealed by obvious clinical signs, neither through tests based on IgE-sensitized effector cells. Therefore, it will escape detection if not assayed serologically. However, when subjected to general anesthesia, and thus the IgE-sensitized individual is administered a bivalent NMBA intravenously, the unrecognized presence of serum IgE antibodies to QAI may increase the risk of anaphylaxis 200- to 300-fold. Severe damages to patient's health can result, and mortality rates of 3 to 10% are reported. The Scandinavian experience indicates that the chain of events can efficiently be avoided by stopping PHO exposure: Within 1 year, the prevalence of IgE sensitization to PHO and QAI decreases significantly, and after 2 to 3 years, the numbers of reported anaphylactic reactions decreases equally so.
    Full-text · Article · Jul 2012 · World Allergy Organization Journal
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