Summary

Genuine IgE-mediated allergies to opiates (morphine, codeine) remain rare notwithstanding their frequent and universal use. It has been shown that morphine can be used to detect IgE antibodies against various neuromuscular blocking agents (NMBAs) enabling it to be used as a marker allergen for NMBA sensitization. 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 (sIgE) antibodies.

Clinical Relevance

Clinical relevance and Epidemiology

Opioids such as morphine, codeine and pethidine 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. Additionally, correct diagnosis is not straightforward, mainly because of uncertainties associated with measurement of drug-specific IgE antibodies and skin testing.

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, morphine represented 4.8% of the cases (where NMBA represented 38.1%).

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 which considered 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%).

In a well-known study in Scandinavian countries showed that IgE antibodies to morphine are common in healthy individuals and among patients prone to become IgE-sensitized in Norway, where allergic anaphylaxis to NMBA drugs is prevalent, and considerably less so in Sweden, where anaphylactic reactions are rarely reported. 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

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 ascertain correct diagnosis of immediate hypersensitivity reactions (IHR) to drugs is a controlled drug provocation test (DPT) with the culprit compound(s). However, DPTs entail 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.

Some sources report that an isolated positive sIgE result for morphine does not serve as a reliable predictor for genuine NMBA allergy. The exact reason(s) remains elusive but probably relate(s) to the (mostly unknown) origin and extremely heterogeneous specificity of (highly cross-reactive) NMBA sIgE antibodies and non-specific binding to the allergosorbent by high total IgE levels.

Erroneous opiate allergy diagnosis might not only entail unnecessary avoidance measures but also, most importantly, ultimately 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 limitation in cross-reactivity 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.