During the perioperative period, patients are exposed to multiple substances, including anaesthetics, analgesics and antibiotics, which could all potentially induce adverse drug reactions (ADRs), including hypersensitivity reactions. Neuromuscular blocking agents (NMBAs) are most frequently incriminated, being the causal agent in 50 to 70% of the cases of allergic reactions during anaesthesia.1 In a French study, the median incidence of allergic reactions to NMBAs has been reported to be 184 per million procedures.2 Another study in Western Australia reported a rate of anaphylaxis to NMBAs between 2.8 and 8.0 per 100 000 administrations.3 These adverse reactions, as are ADRs in general, are largely underreported. Recently, an increasing number of data have suggested a link between the consumption of pholcodine, an opioid cough suppressant, and immunoglobulin E (IgE)-mediated anaphylactic reactions to NMBAs.4
Pholcodine is an opiate with central antitussive action used in the treatment of cough and cold symptoms in children and adults. Its overall benefit/risk assessment has been recently reviewed by the European Medicines Agency (EMA).5 Most studies established its efficacy in acute nonproductive cough. However, most of them were performed between the 1960s and the 1980s, having therefore a poor methodology according to modern standards.5 The most recent comparative study was published in 2006, and showed that the efficacy of pholcodine was similar to that of dextromethorphan.6 On the basis of available information, the EMA has recommended the maintenance of the marketing authorisations for pholcodine-containing products.5 However, a recent Cochrane review concluded that there is still insufficient evidence for or against the effectiveness of over the-counter (OTC) medications in acute cough, including antitussive drugs. Antihistamines were no more effective than placebo in relieving cough symptoms.7 Meanwhile, codeine, another cough suppressant that is also used for pain relief, is subject to use restrictions under the age of 18.8
From a chemical point of view, pholcodine and NMBAs are believed to share the same IgE-binding epitope, which contains the quaternary ammonium ion (QAI) or its tertiary variety.4 It has been shown that pholcodine induces the production of IgE antibodies to QAI-sensitising properties, therefore being an alternative source of sensitisation to NMBAs. The mechanisms by which pholcodine activates IgE synthesis are not known, but the available data indicate that the morpholino side chain that distinguishes pholcodine from morphine might be involved.4
A relationship between the consumption of pholcodine and the prevalence of IgE-sensitisation to pholcodine and to suxamethonium has been suggested.9 Indeed, pholcodine use differs considerably between countries. In Switzerland, pholcodine consumption is very low (1 g in 2014, 0.125 g per million inhabitants), whereas it is much higher in France (2 050 000 g in 2014, 31000 g per million inhabitants) or in the UK (4 712 000 g in 2014, 73625 g per million inhabitants) [data from the United Nations International Narcotics Control Board (INCB) database].10 In the WHO database, 1510 cases of anaphylactic shock have been reported with suxamethonium thus far (data extracted on 23 April 2015) out of 5859 cases of ADR reported with this compound.11 It is of interest that the majority of the reported cases of anaphylactic shock occurring with suxamethonium were reported by France (1206 cases, 80%), followed by the UK (124 cases, 8%), both of which are countries where pholcodine consumption is very high. This database contains spontaneous reports of ADRs from member countries, describing suspicions that have arisen from observation of an unexpected or unwanted event. Regarding spontaneous pharmacovigilance, it is difficult to prove that a specific pharmaceutical product is the cause of the event. The volume of reports may be influenced by the extent of use of the product, information in Medias and other factors. No information is provided on the number of patients exposed to the product.12 The extracted data for a given drug must be taken in the context of a spontaneous reporting system and cannot be used to calculate an incidence rate. The reports from this database usually contain information about concomitant drugs administered at the time of the ADR, but past drug consumption (e.g. a previous exposure to pholcodine) is not documented. The information from this database does not represent the opinion of the WHO.
Epidemiological results showed that pholcodine cross-sensitisation with suxamethonium might be the key issue. Indeed, a prevalence study conducted in Norway and Sweden showed that the prevalence of IgE-sensitisation to suxamethonium was higher in Norway than in Sweden, as well as the frequency of reported anaphylactic reactions to NMBAs.13 The hypothesis to explain this difference in the prevalence of IgE-sensitisation is the availability of pholcodine in Norway but not in Sweden. A few years later, the same group reported that after the withdrawal of pholcodine from the Norwegian market in 2007, the prevalence of IgE-sensitisation to pholcodine, morphine and suxamethonium in sera from allergic people and blood donors significantly decreased.14 In allergic people, the frequency of IgE antibodies to pholcodine was drastically reduced from 11.0 to 5.0% 1 year and 2.7% 3 years after market withdrawal. The frequency of IgE antibodies to suxamethonium was reduced from 3.7% before withdrawal to 0.7% 1 year and 0.3% 3 years after market withdrawal, suggesting that when exposure to pholcodine is stopped, IgE levels decline within 1 or 2 years.14 Another study assessed the association between the prevalence of serum IgE antibodies to pholcodine, morphine and suxamethonium, and the pholcodine consumption in several countries,9 derived from the INCB database.10 The prevalence of IgE antibodies was measured in sera from atopic individuals collected in several countries with high and low pholcodine consumption. The authors observed a statistically significant association between pholcodine consumption and IgE-sensitisation to pholcodine. When the results were reanalysed after excluding the USA and the Netherlands (two countries showing high prevalences of IgE antibodies to pholcodine, although no pholcodine-based drug is available), there was a statistically significant association between pholcodine consumption and IgE-sensitisation to pholcodine as well as suxamethonium.9
Further research should focus on the mechanisms by which pholcodine may induce sensitivity to other allergens, in particular to NMBAs, and on the epidemiology of anaphylactic shock to NMBAs in relation to past pholcodine exposure. Anaesthetists should be aware of this potential cross-reactivity and the preanaesthetic evaluation should assess exposure to pholcodine during the last 12 to 24 months, as sensitisation seemingly declines within 1 or 2 years in exposed patients. This recommendation is particularly valid in countries where the pholcodine consumption is expected to be high, such as France and the UK. Pholcodine is available in many countries as an OTC drug, and patients may not be aware of the importance to declare its use.
Acknowledgements relating to this article
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Conflicts of interest: none.
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