The Pholcodine Case. Cough Medicines, IgE-Sensitization, and Anaphylaxis: A Devious Connection

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.

Figure 1

Schematic representation of morphine, pholcodine, and, the NMBA, suxamethonium. The IgE-binding epitopes, the quaternary/tertiary ammonium epitopes are encircled.

Figure 2

Relationship between pholcodine exposure, IgE sensitization, and quaternary/tertiary ammonium epitopes (QAI) and estimated risk of IgE-mediated anaphylaxis when receiving suxamethonium during induction of general anesthesia in Norway. IgEab, is the abbreviation of IgE antibodies. The relationships depicted apply for the years before 2007 when pholcodine (PHO) was taken off the Norwegian market. PHO exposure is given as estimated by the former marketing authorization holder in Norway. Percentage IgE-sensitized to PHO and the relative distribution of IgE specificities to the QAI and the non-QAI epitopes of PHO, respectively, is taken from studies by Florvaag et al. [5,6]. The risk estimates for anaphylaxis during general anesthesia with NMBAs for the general population and individuals IgE sensitized to the QAI epitope before anesthesia with suxamethonium are taken from Harper et al. [22]. Risk is given as the ratio of anaphylactic reactions to number of uneventful general anesthesias using a NMBA. Approximate number of populations in millions is given in italics.