Summary

Pholcodine is an antitussive morphine derivative with a structure similar to codeine and to the quaternary ammonium ions found in neuromuscular blocking agents (NMBAs). It has been shown that pholcodine significantly increases levels of IgE antibodies to NMBA in sensitized patients. Cross-inhibition studies indicate that some patients have IgE not only against the ammonium ion, but also against the hydrophobic part of the pholcodine molecule. Cross-reactivity between different NMBA is common since they all share the quaternary ammonium ion allergenic epitope. NMBAs represent a significant cause of anesthesia-related anaphylaxis, which is rare but can be severe. Diagnostic approach of anesthesia-related IgE-mediated immediate hypersensitivity reactions (IHR) generally starts with patient’s history, thorough review of the anesthetic/surgical notes complemented with skin prick testing and/or in vitro quantification of specific IgE antibodies.

Route Of Exposure

Usual route of administration for pholcodine is oral.

NMBA are mainly administered intravenously but may also be given intramuscularly.

Clinical Relevance

Opioids provoke non-specific wheals in the skin by causing direct degranulation of mast cells without the involvement of either opioid receptors or opioid-specific IgE antibodies. Genuine IgE-mediated allergies to opiates (morphine, codeine) remain rare notwithstanding their frequent and universal use. Moreover, correct diagnosis is not straightforward, mainly because of uncertainties associated with measurement of drug-specific IgE antibodies and skin testing.

In recent years, increasing evidence for a connection between the consumption of pholcodine and IgE-mediated anaphylactic reactions to neuromuscular blocking agents (NMBA) have been presented.

Anaphylaxis during general anesthesia is rare but can be severe, as it is often complicated by significant morbidity. Identification of the cause of anaphylaxis may pose a significant dilemma to the allergist and anesthetist. Results from a study in the UK showed that when the drug culprit of anaphylaxis was detected NMBA represented 38.1% of the cases.

In many countries, curarizing NMBAs represent a significant cause of anesthesia-related anaphylaxis. Allergy to neuromuscular blocking agents (NMBA) constitutes a major cause of potentially life-threatening perioperative anaphylaxis. In a study with 344 patients, NMBA accounted for 40% of all patients with an IgE-mediated perioperative allergy. However other studies showed even higher values (up to 60%).

A study in Scandinavian countries indicated that there was a large difference in rates of anaphylaxis to NMBAs in Norway (high) and Sweden (low). The predominant difference identified was in the availability and use of pholcodine (PHO was not available in Sweden but was widely used in Norway). It was postulated that the substituted ammonium ion structure of PHO was resulting in sensitization and an increased reaction rate to NMBAs observed in Norway relative to Sweden (this led to the voluntary withdrawal of the single PHO product on the market in Norway). As a result, six years after PHO withdrawal, the Norwegian population has become significantly less IgE-sensitized and clinically more tolerant to NMBAs.

Another survey showed that the mortality rate from an immediate hypersensitivity reaction to NMBA administration was relatively high (4.1%) in France over the period 2000–2011.

Diagnostics

The major IgE-binding epitope of the NMBA contains the quaternary ammonium ion (QAI) or its tertiary variety. In their well-known studies Florvaag and Johansson have shown that pholcodine (and its parent molecule morphine -MOR-) contains the QAI epitope, which is shared with NMBAs.

The direct effects of pholcodine on IgE synthesis results in a remarkable polyclonal increase in IgE. However, in addition, another epitope of unknown structure on PHO and morphine, not present on NMBAs, was found based on inhibition studies where IgE antibody binding to QAI (suxamethonium), is completely inhibited with PHO and MOR, but, the binding to PHO and MOR is only partially inhibited with QAI. As a consequence, PHO can in principle not initiate an allergic reaction toward itself through cross-binding of IgE antibodies. Therefore, tests dependent on such cross-binding will come out negative with PHO in individuals who are IgE sensitized to PHO. On the other hand, the NMBAs like suxamethonium and rocuronium are structurally bivalent for the QAI epitope. As such, they appear functionally as allergens that through the cross-binding of IgE antibodies on the surfaces of effector cells can induce immediate allergic inflammatory responses and enhanced by way of administration, eventually leading to anaphylaxis.

At present, the mechanisms underlying why exposure and sensitization to a substituted ammonium ion in pholcodine can prime NMBA anaphylaxis, but not result in allergy to all compounds containing similar substituted ammonium ions, remain unresolved.

One of the major uncertainties in evaluating diagnostic test results in suspected cases of anaphylaxis to anesthetic drugs is the possibility that a negative result to the suspected drug(s) may occur in a subject who experienced some or all of the signs associated with an anaphylactic or anaphylactoid reaction due to another, non-allergic, mechanism. In such cases it is difficult to determine whether the result is due to a weakness inherent in the test, such as lack of sensitivity, or whether the negative finding truly reflects the real situation.

The ‘gold standard" to determine correct diagnosis of immediate hypersensitivity reactions (IHR) to drugs is a controlled drug provocation test (DPT) with the thought culprit compound(s). However, DPTs involve a risk of severe, life-threatening complications and can be contraindicated (e.g. patients having suffered from life-threatening reactions) or impossible (e.g., full-dose DPT in hypersensitivity to curarizing neuromuscular blocking agents (NMBA)). Moreover, the predictive value of DPTs is not known and DPTs might yield false negative results. Therefore, the diagnostic approach of anesthesia-related IgE-mediated IHR generally starts with patient’s history, thorough review of the anesthetic/surgical notes complemented with skin testing and/or in vitro quantification of specific IgE (sIgE) antibodies.

Erroneous opiate allergy diagnosis might not only require unnecessary avoidance actions but also, most importantly, put patients at risk by overlooking alternative diagnoses such as an allergy to rocuronium or suxamethonium or, possibly, other compounds as antibiotics or chlorhexidine.

In cases of non-IgE-mediated IHR, diagnosis might benefit from cellular tests such as basophil mediator release tests and basophil activation tests (BAT).

Cross-reactivity

Cross-reactivity between different NMBA is common since they all share the quaternary ammonium ion allergenic epitope. However, the extent of cross-reactivity varies considerably between patients and it is unusual for an individual to be allergic to all NMBA. The explanation for this is that IgE antibody paratopes may not only recognize the quaternary ammonium ion; sometimes the molecular environment around the ammonium ion is also part of the allergenic epitope. The possibility of multiple allergies should therefore be considered.

Cross-inhibition results indicate that some patients have IgE not only against the ammonium ion but also against the hydrophobic part of the morphine molecule.