Dr Caterina Detoraki MD, Ph.D.
Local anesthetics (LAs) are drugs widely used in clinical practice having revolutionized modern medicine from both the diagnostic and therapeutic point of view. In the first case, these drugs are used for patients’ preparation for different procedures (endoscopic, radiologic etc.) whereas in the second case they provide anesthesia for surgical interventions. As such, these agents are commonly administered in dental practice.
LAs were discovered in 1884, by a young Viennese ophthalmologist, Carl Koller that instilled cocaine, a natural agent, in his conjunctiva obtaining an anesthetic effect. A few years later, the first synthetic anesthetic Procaine, was produced (Einhorn, 1904) (1).
As LAs have been widely and increasingly used since last century, different LA agents have been synthesized. LAs can induce adverse reactions following their administration. In particular, allergic (hypersensitivity) reactions to local anesthetics have been reported; although these reactions are rare, in some cases the problem seems over-estimated being responsible for frequent therapeutic abstaining.
Therefore, this communication aims to point up the pathogenic and clinical aspects of hypersensitivity reactions to local anesthetics in order to offer a “model of behavior” for dentists who may face different adverse reactions induced by LAs in the daily clinical practice.
LAs have similar molecular configuration with a lipophilic aromatic ring connected to a hydrophilic amine group (1). The type of linking bond is used to classify these drugs into ester and amide groups (Table 1). Ester are all derivatives of para-aminobenzoic acid (PABA) and include cocaine, procaine, tetracaine, benzocaine e chloroprocaine. The amide group, actually the most frequently used in clinical practice, includes lidocaine, mepivacaine, etidocaine, prilocaine, bupivacaine and dibucaine.
AMIDES(two letters “i” in their name)
Mechanism of action
LAs induce an anesthetic effect by blocking nerve conduction, thus blocking afferent nerve signals to the brain (1). Nerve conduction blockade is obtained by a reversible binding of the anesthetic drug to the voltage gated sodium channels present in the nerve cell membrane, blocking therefore the formation of action potentials. The lipophilic nature of the LA facilitates diffusion across cell membrane and binding inside the cell (2).
Ester LAs are rapidly hydrolyzed by plasma cholinesterases, except cocaine which is metabolized by the liver. PABA is an intermediate metabolite, unable to induce anesthesia but it is a known allergen (1). It must be mentioned that parabens are widely used as additives in several lotions, cosmetics and foods. Thus, patients with hypersensitivity reactions to parabens can cross-react to PABA, if they are injected by LAs of the ester group. These phenomena can be at the basis of the higher prevalence of allergic reactions to ester compared to amid anesthetics. In fact, the incidence of hypersensitivity reactions to LAs has been drastically decreased since 1950, when the amide group has been introduced.
Amides undergo liver metabolism and renal excretion. In patients affected by liver failure it is therefore prudent to pay attention in order to reduce the total dosage of LA administered (3). Similarly to esters, some amides may also contain preservatives, such as sulphites and methyl-parabens, both chemically similar to PABA and therefore can cause allergies in sensitized individuals (2) (4).
In conclusion, the ester group is more frequently implicated in allergic reactions compared to the amid group. In addition, different esters can cross-react within the ester group. The cross-reactivity is not reported between esters and amides.
Adverse reactions to LAs
Drugs used for local anesthesia may provoke adverse reactions caused by different pathogenic mechanisms, that in most cases can be only suspected but rarely demonstrated.
These reactions can be distinguished in two groups: toxic reactions and hypersensitivity reactions.
Toxic reactions may be observed depending on the way of administration of the compound, the site of injection (accidental intravascular injection) and the clinical conditions of the patient (kidney or liver failure). Thus, the risk of toxic reactions could be significantly minimized staying within safe dosage parameters and using safe injection techniques (5). The symptoms of toxicity can be important and include agitation, tremors-convulsion, bradycardia and eventually cardiovascular collapse and respiratory depression.
It should be noted that vasoconstrictors such as adrenaline are frequently associated to the LA injection in order to lengthen anesthesia duration and make the site of surgical intervention ischemic. The administration of adrenaline can induce different signs and symptoms: tachycardia, hypertension, convulsions, loss of consciousness. More often, these events rely on an exaggerated individual response or on a rapid intravascular passage as in case of an accidental intravascular injection. (6).
More frequently, hyperventilation, nausea, vomit, sweating, dizziness or light bradycardia following LA injection may be reported . These reactions -often mimicking allergic reactions- are autonomic reactions (5).
Hypersensitivity reactions to LAs
Mook described the first report of allergic type reaction to LA in 1920 in a dentist who developed eczema on his hand after handling apothesin, a congener of procaine (1).Hypersensitivity reactions to LAs make no more than 1% of LA reactions. However, these reactions may be clinically important as they are unexpected and potentially serious (7). Based on Gell & Coombs classification, hypersensitivity reactions can be distinguished in: immediate (type I) or delayed (type IV).
Type I reactions are mediated by the interaction between specific antibodies of the IgE class, produced following exposure of a sensitized subject to various antigens/allergens (drugs, pollens, foods etc.). The following exposure of the patient to the same allergen induces interaction between two IgE specific molecules and the high affinity receptors for IgE (FcεRI) present on the cell membrane of mast cells and basophils. Mast cells and basophils are namely the primary effector cells of allergic reactions. Activation of these cells is characterized by a series of enzymatic and structural intracellular changes inducing histamine release and production of vaso-active mediators (leukotrienes, prostaglandines, PAF, tryptase, chymase ecc.), cytokines and chemokines responsible for the clinical manifestations of allergic reactions (8).
From the clinical point of view, signs and symptoms may vary and different organs and systems may be involved. Skin manifestations such as urticaria with pruritic rush, often associated to angioedema (lips, tongue, eyelid etc.) may be present. Respiratory symptoms may vary from rhinorrea to bronchospasm whereas cardiovascular symptoms such as severe hypotension may dominate the signs. In this context, systemic anaphylaxis represents without doubts, the most critical and dramatic clinical event within the scenario of hypersensitivity reactions. Anaphylactic reactions may be characterized by clinical symptoms of different grading of severity (Table 2)
Table 2 Grading of severity of anaphylactic reactions
Grade of severity
Blood pressure change
Although principal targets of anaphylaxis are cardiovascular, respiratory and gastrointestinal systems and the skin, these may be involved separately or in combination. Thus, it is important to understand that signs and symptoms considered “minor” may not be always present before the involvement of the respiratory and cardiovascular systems. In some cases, typical signs such as tachycardia, often considered a characteristic sign of systemic anaphylaxis, may not be present.
Allergic reactions mostly elapse like a unique event within minutes or a few hours from drug administration, but in some cases clinical manifestations may be present even after many hours from the initial event or they may have a prolonged duration (> 24 hours).
In some cases, a pseudo-allergic mechanism may be involved, induced by the activation of complement components following exposure to exogenous antigens (drugs, radiographic contrast media) or endogenous antigens (tryptase) with formation of anaphylatoxins. The later can directly induce degranulation of the primary effector cells (mast cells and basophils) of allergic reactions. From the clinical point of view these manifestations can’t be distinguished from anaphylactic reactions.
Type IV hypersensitivity reactions to LAs are basically induced by contact through the skin with subsequent manifestation of eczema lesions often involving the hands. These reactions appear after a prolonged period of exposure to the drug and may be secondary to the release of histamine by non IgE- mediated mechanisms.
Parallel to hypersensitivity reactions to LAs, reactions induced by preservatives -metabisulphites and parabens- contained in commercially available LA preparations have been reported. Metabisulphites are present as anti-oxidants, in different concentrations, in preparations containing adrenaline. These compounds are widely used in food industry, being contained as additives in different foods (wine, beer, etc.) and are marked as E221-E227. Metabisulphites may cause non IgE-mediated hypersensitivity reactions, characterized by rhinitis, rush, headache, dyspnoea, cramping (10).
Parabens, are rarely used as preservatives in different preparations of local anesthetics and can induce hypersensitivity reactions of type I and IV. Methylparabens and propylparabens are metabolized in chemical components structurally similar to PABA (4).
A correct evaluation of patients at risk of hypersensitivity reactions to LAs is necessary for their prevention and/or management.
Subjects at risk of hypersensitivity reactions to LAs are considered those who experience one or more of the previously described clinical manifestations during or following injection of a LA agent. Thus, a detailed history is an essential first step towards an accurate diagnosis. In some cases, in the base of symptoms reported by the patient (agitation, sweating, nausea, bradycardia), it may be possible to suspect an adverse autonomic reaction excluding an allergic sensitization.
It is important to underline that atopy is not a risk factor for the majority of allergic drug reactions (11). This means that patients affected by allergic diseases such as bronchial asthma, allergic rhinitis, food allergy etc., are not at higher risk for hypersensitivity reactions to drugs, compared to non atopic individuals. However, patients affected by chronic diseases (bronchial asthma, cardiovascular diseases etc.), may have a more severe course of allergic reactions due to the diseases’ nature and to the therapy administered (β-blockers or ACE-inhibitors ) for their treatment. Therefore, patients affected by chronic diseases must be adequately controlled and β-blockers or ACE-inhibitors therapy should be suspended before surgery.
In differential diagnosis of hypersensitivity reactions to LAs, allergy to various agents used during anesthesia in dental practice (chlorexidine, latex etc.) should be considered. Similarly, drug allergy induced by antibiotics and/or FANS, administered to patients before or during dental interventions should be examined.
In case of previous hypersensitivity reactions to LAs the patient should be referred to a specialist (allergist) to perform specific challenge tests in order to identify which LA should be used for future surgery.
When evaluating a patient for LA allergy, it is essential to obtain a detailed history including the LA used previously and a description of the reaction. The Joint Council of Allergy, Asthma, and Immunology (JCAAI) recommends that if the LA that caused the reaction in a patient is known, the specialist should consider for skin testing a LA of another class: for example if an ester caused the reaction, than an amide LA should be used for testing. If an amide is involved, then another amid may be tested, as there has not been reported cross-reactivity between amid groups (1). LAs used for testing should not contain preservatives and adrenaline that may alter skin reactivity.
Testing should be performed in the hospital where in case of severe hypersensitivity reactions therapeutic interventions can be immediate (12).
The incremental dose challenge test protocol is the following:
1. Prick test with undiluted LA
2. Intra-dermal injection with diluted LA in increasing concentrations (1:100, 1:10, 1:1)
3. Subcutaneous injection with undiluted LA in increasing concentrations (0,1 ml, 0,3 ml, 0,5 ml).
Injections are repeated every 15 minutes.
After the last injection, patients remain under clinical observation for approximately 2 hours.
The performance of alternative skin tests or in vitro tests without the for mentioned incremental dose challenge test are not safe and efficacious.
It should be mentioned that even in case of a negative challenge test, it is not possible to exclude the possibility of non IgE-mediated reactions. Thus, in case of patients with documented adverse reactions to LAs and negative challenge tests, it is necessary to prescribe a preventive therapy to administer prior to the LA injection .
In the clinical practice, the use of the following pharmacologic protocol, has demonstrated efficacy in reducing the incidence and severity of hypersensitivity reactions to local anesthetics:
48, 24 and 2 hours before dental surgery:
CETIRIZINE 10 mg
RANITIDINE 300 mg
13, 7 and 1 hours before dental surgery :
PREDNISONE 25 mg
1 hour after dental surgery:
CETIRIZINE 10 mg
RANITIDINE 300 mg
LA agents, have revolutionized our ability to provide surgical interventions in a pain-free manner .
The classification of LAs in two groups, esters and amids, is based on their structural and metabolic characteristics. Esters can more frequently induce allergic hypersensitivity reactions. Amids, are less allergenic and not significantly cross-reactive. They are widely used in clinical- surgical practice.
As 1% or less of the reactions to LAs are truly immune system mediated (type I or type IV), the problem of allergic reactions to LA appears often over estimated in dental practice and frequently induces to therapeutic abstaining.
Challenge skin tests with incremental doses of LA, preservative and adrenaline-free, performed by the specialist, are currently considered the gold standard, shown to be efficacious and safe in the evaluation of LA allergy. Challenge tests should be performed in patients with documented previous adverse reactions to LAs.
The best therapy for allergic, hypersensitivity reactions including anaphylaxis is prevention. Thus, patients at risk should be rapidly recognized in order to prevent or possibly attenuate severity of allergic reactions.
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Dr Caterina Detoraki (Aikaterini Detoraki)
Dr Detoraki graduated in 1999 from the School of Medicine of the University of Naples Federico II where she also followed her residency in Allergy and Clinical Immunology. She attended the Asthma and Allergy Center of the Johns Hopkins University, Baltimore (USA) and after her residency, the Division of Allergic and Respiratory Diseases in the Department of Pediatrics -University of Naples Federico II, obtaining additional experience in the diagnosis and management of allergic diseases in children.
She attended various National and International Congresses and is co-author of scientific papers published by Italian and international journals.
In 2008 she received her Ph.D. degree in Clinical Physiology and Experimental Medicine from the University of Naples Federico II.
Since 2006 she works as a specialist in Allergy and Clinical Immunology, in the University Hospital Federico II of Naples.