Allergic reactions to local anesthetics

INTRODUCTION — Local anesthetics (LAs) have been used to provide anesthesia since the initial use of cocaine in 1884 [1]. They may be administered by topical, infiltrative, nerve block, epidural, or spinal routes [1]. Adverse reactions to LAs are not uncommon, and most are nonallergic in etiology. However, allergic reactions to LAs can occur, and the evaluation and management of patients with these reactions will be reviewed here. Anaphylaxis in the setting of anesthesia or surgery is found separately. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management" and "Perioperative anaphylaxis: Evaluation and prevention of recurrent reactions".)

The use of LAs for infiltrative anesthesia and for topical anesthesia and a general approach to the management of pain and sedation in children are discussed separately. (See "Subcutaneous infiltration of local anesthetics" and "Clinical use of topical anesthetics in children" and "Procedural sedation in children: Approach".)

TYPES OF ALLERGIC REACTIONS TO LOCAL ANESTHETICS — Two distinct types of allergic reactions to LAs have been described:

●Allergic contact dermatitis and delayed swelling at the site of administration – These types of reactions are uncommon but well established. They begin hours after injection and usually peak within 72 hours. (See 'Rare: Delayed reactions (contact dermatitis or local swelling)' below.)

●Generalized urticaria and/or anaphylaxis – These types of reaction are rare, and the data implicating LAs are limited to case reports. Signs and symptoms begin quickly (within seconds to one hour) after injection, and this type of reaction is also called immediate hypersensitivity. Some immediate reactions may be immunoglobulin E (IgE) mediated. (See 'Rare: Immediate reactions (urticaria and anaphylaxis)' below.)

MANAGEMENT ALGORITHM FOR NONALLERGY CLINICIANS — Clinicians preparing to perform a procedure who encounter patients reporting past adverse reactions to LAs must determine if the history suggests a nonallergic reaction (common) or some type of allergic reaction, either delayed or immediate, both of which are rare. A decision algorithm for this situation is provided (algorithm 1).

Nonallergic symptoms can arise from absorption or accidental intravenous injection of epinephrine or the LA, vasovagal reactions, or anxiety-related symptoms. The clinical manifestations of nonallergic reactions can resemble aspects of immediate allergic reactions. For example, dyspnea, hypotension, lightheadedness, and syncope are signs and symptoms that can be seen in both allergic and nonallergic reactions. However, certain symptoms can help distinguish between the two types. Immediate-type allergic reactions often include itching, urticaria, angioedema, or wheezing, and the absence of these symptoms suggests a nonallergic reaction.

Delayed-type allergic reactions, which generally present as contact dermatitis or local swelling at the injection site, are caused by a mechanism separate from immediate allergic reactions. Delayed-type allergy does not progress to anaphylaxis and is not dangerous. In contrast, immediate allergic reactions may be life threatening. If an immediate allergic reaction is suspected, the clinician must then decide how to manage the current scenario, depending upon whether the procedure is urgent or elective:

●If the procedure must go forward and the LA associated with the past reaction is known, the clinician can simply choose a different LA. The most useful and appropriate alternative LA for that procedure should be chosen. The clinician does not need to limit choices based on the chemical class of the LAs (amides versus esters) in question. This issue is discussed below. (See 'Cross-reactivity' below.)

●If the procedure must go forward and the culprit LA is not known, lidocaine is a reasonable choice because it is among the most commonly used LAs, and, despite this, there are few reports of proven immediate allergy. Lidocaine can, however, cause delayed local swelling and contact allergy, but these reactions are not dangerous [2]. Alternatively, LAs can be avoided altogether.

●If the procedure is elective, the patient should be referred to an allergist or dermatologist, depending on the type of reaction, for further evaluation.

Referral — Suspected allergic reactions to LAs should be referred for evaluation when possible because most patients can tolerate some LA agents. Simply advising a patient to avoid all LAs is unnecessarily restrictive and subjects that patient either to the pain of procedures performed without local anesthesia or to the increased risks of general anesthesia.

Patients with contact dermatitis or delayed local swelling may be referred to either dermatology or allergy specialists who perform patch testing. Patients with suspected anaphylaxis should be referred to allergy specialists. Even patients whose reactions were more suggestive of sympathetic stimulation can benefit from allergy testing and challenge as the experience of having negative test results and tolerating a dose of an LA under close supervision is often sufficient to reduce the patient's anxiety about future use of LAs.

COMMON: NONALLERGIC REACTIONS — Nonallergic reactions to LAs are far more common than true allergic reactions. These reactions include sympathetic stimulation, psychomotor or anxiety-related reactions, vasovagal syncope, and systemic toxic effects related to the pharmacologic properties of these agents.

Sympathetic stimulation — Tachycardia, hypertension, anxiety, and palpitations may be caused by the release of endogenous catecholamines in response to pain. In addition, the vasoconstrictor epinephrine is sometimes added to LA solutions for the purposes of reducing bleeding, potentiating the degree of local anesthesia achieved, limiting the total dose required, and minimizing systemic absorption of the LA [3,4]. The amount of epinephrine in these preparations is too small to induce significant systemic responses in most normal subjects, as well as in those with heart disease, high blood pressure, hyperthyroidism, or on tricyclic antidepressants [3-5]. However, it is still possible that some patients are very sensitive to epinephrine's actions.

Psychomotor reactions — Psychomotor reactions or anxiety-related symptoms include hyperventilation (manifested by dyspnea and tachypnea), paresthesias in the fingers or perioral area, dizziness, palpitations, tachycardia, nausea, or simply "not feeling good" [6,7]. Note that these symptoms overlap with those of early LA toxicity. (See 'Systemic toxic effects' below.)

Vasovagal syncope — Vasovagal syncope is usually associated with bradycardia (rather than tachycardia) and pallor (rather than flushing). These differences can be helpful in distinguishing it from anaphylaxis. Rapid spontaneous recovery is also a common feature.

Systemic toxic effects — LAs can cause central nervous stimulation, even at therapeutic levels, and patients differ in their sensitivity to these effects. Highly sensitive individuals may experience circumoral numbness/tingling, anxiety, tremulousness, excitement, or even convulsions. At toxic doses, vasomotor collapse with hypotension, apnea, stupor, and myocardial dysfunction may occur. (See "Clinical use of local anesthetics in anesthesia", section on 'Neurotoxicity of local anesthetics'.)

One of the newer agents, articaine, has been implicated in the development of persistent paresthesias due to nerve damage [8]. The toxic effects of specific LAs are discussed elsewhere. (See "Subcutaneous infiltration of local anesthetics" and "Clinical use of topical anesthetics in children".)

RARE: DELAYED REACTIONS (CONTACT DERMATITIS OR LOCAL SWELLING) — LAs can cause delayed swelling, localized dermatitis, or mucosal inflammation at the site of administration due to delayed-type (type IV) hypersensitivity (table 1) [9-15]. (See "Clinical features and diagnosis of allergic contact dermatitis" and "Common allergens in allergic contact dermatitis", section on 'Anesthetics'.)

Clinical manifestations — Acute allergic contact dermatitis typically presents as a localized eczematous and pruritic rash appearing within 72 hours at the site of administration. Vesiculation, blistering, or weeping can occur. The area affected is limited to tissue that was in direct contact with the causal agent. LAs may also cause delayed-onset swelling, with or without overlying dermatitis, at sites of injection. Mucosal reactions may blister and progress to sloughing [9].

Evaluation — Evaluation usually consists of clinical history, patch testing, and possibly, challenge.

History — The clinician should review the medical procedure in detail and events immediately surrounding it for possible exposure to other contact allergens, such as topical antibiotics [16,17], suture materials [14], rubber chemicals, or disinfectants [18].

Patients should be asked about prior reactions to LAs used in medical procedures and in over-the-counter products (preparations for hemorrhoids, vaginal irritation, sunburn, and other uses) [9,19,20].

Other possible culprits — The differential diagnosis of localized swelling and/or dermatitis at the site of an LA injection includes:

●Excessive swelling due to operative trauma.

●Local toxic effects.

●Allergic contact dermatitis from other topical preparations, such as neomycin, disinfectants (eg, chlorhexidine), and other topical agents used in wound dressings [18,21,22].

●Allergic contact dermatitis to additives and preservatives in the LA itself, such as sulfites and parabens, although these are believed to be relatively uncommon culprits [23-29].

LA preparations may contain sulfite (bisulfite or metabisulfite), which are included to stabilize added vasoconstrictors. A small number of case reports have described local reactions attributed to sulfite sensitivity [23-25]. One case described a woman with severe edema of the face and neck after receiving an LA for dental work with a positive patch test to both the LA and metabisulfite [24].

People with asthma that is exacerbated by sulfite in foods are not known to be at increased risk for reactions to sulfites in LAs. One study found that doses of metabisulfite of up to 10 times the amount usually found in LA preparations did not cause symptoms when injected subcutaneously in a group of patients with known sulfite-sensitive asthma [26].

Parabens (either methyl- or propyl-) are added to many commercial preparations of LAs as preservatives [27]. Parabens are an uncommon cause of contact dermatitis [28,29]. (See "Common allergens in allergic contact dermatitis", section on 'Parabens'.)

Patch testing — Patch testing is a means of diagnosing type IV hypersensitivity reactions by exposing a small area of skin (usually the upper back) to the suspected allergen in a controlled manner. Patches are removed at 48 hours, and readings are usually taken at 48 and 72 hours [9,30]. A positive result varies from mild erythema and induration to severe vesiculation. The patient should not have applied a topical corticosteroid to the tested skin for at least one week and should not have taken systemic glucocorticoids for at least one to two weeks prior to testing [31]. Testing can be performed using aluminum or synthetic material chambers mounted on nonocclusive tape strips [9]. Techniques and material for patch testing are reviewed in more detail separately. (See "Patch testing".)

The optimal concentration of LAs for use in patch testing has not been determined. In published studies, concentrations of lidocaine (in a petroleum vehicle) used for testing have ranged from 5 to 15 percent [10,13,14,32,33].

Cross-reactivity — LAs have been divided into two groups based upon their chemical structure (table 2):

●Group I – The benzoic acid ester agents, including benzocaine, procaine, and tetracaine

●Group II – The amide agents, including bupivacaine, lidocaine, and mepivacaine

Information about cross-reactivity among LAs based upon patch testing is limited. There is some evidence for cross-reactivity within each group of agents [34-36] and minimal evidence for cross-reactivity between the two groups [34]. Thus, we suggest choosing one or more drugs from the other LA group as an alternative agent for patch testing if that drug is useful for the patient's anticipated future needs. A case report described a patient with delayed hypersensitivity to several amide LAs (lidocaine, mepivacaine, and bupivacaine), which all contain a meta-xylene entity but not to articaine, which is a thiophene derivative (ie, not an ester or amide). The authors hypothesized that the meta-xylene entity could be the eliciting epitope in amide LA allergy and that, in such cases, articaine could be an alternative [37]. However, a subsequent report described a patient with delayed-type hypersensitivity to articaine with cross-reactivity with bupivacaine and lidocaine but tolerance of mepivacaine [38].

The commercially available standard T.R.U.E. TEST panel includes a "caine mix," which contains tetracaine hydrochloride, dibucaine hydrochloride, and benzocaine, representing both groups I and II LAs [39]. However, the clinician should consider whether the information provided by a positive test to this mix of LAs would be useful to the patient's care. In North America, dibucaine and benzocaine are used in topical and over-the-counter preparations, and tetracaine is used for spinal and ophthalmic anesthesia in some circumstances, but none of these agents are commonly used in dental, regional, or infiltration anesthesia. Thus, patch testing with individual LAs may be more helpful.

Diagnosis — A clinical history consistent with a delayed cutaneous reaction to an LA combined with a positive patch test result is sufficient for diagnosis.

Management — Patients who have demonstrated type IV allergic reactions to one LA may tolerate other LAs. Management consists of identifying other agents that the patient tolerates. When evaluating patients for tolerance to other LAs, we suggest choosing an agent from the other chemical group (table 2). (See 'Cross-reactivity' above.)

RARE: IMMEDIATE REACTIONS (URTICARIA AND ANAPHYLAXIS) — LAs have been implicated in rare, IgE-mediated, type I hypersensitivity reactions (table 1). These are also called immediate hypersensitivity reactions.

Prevalence — Immediate hypersensitivity reactions to LAs are extremely rare. Evidence for their existence consists of a small number of case reports in which patients had reactions that were consistent with immediate hypersensitivity and positive skin tests were demonstrated [40-50].

The rarity of immediate hypersensitivity to LAs was demonstrated by two large series:

●One series included 162 patients who were evaluated over 10 years in the Danish Anaesthesia Allergy Center for suspected allergy associated with anesthesia and surgery [51]. No instances of true immediate hypersensitivity were identified. Skin testing to LAs was performed in all patients, and subcutaneous provocation (challenge) was performed regardless of skin testing results. In total, 162 patients underwent 203 provocations to various LAs, all of which were negative. Other culprit agents that were implicated included chlorhexidine, cefuroxime, and patent blue dye.

●A second series described 402 patients evaluated over 20 years in a German allergy clinic for reactions to LAs occurring within 30 minutes of injection [52]. Most occurred during outpatient dental or surgical procedures. Two patients (0.5 percent) were found to have true immediate allergy and positive intradermal skin tests to LAs. Acute urticaria (with or without angioedema) was the presenting symptom in 29 patients, of whom 14 were determined to have spontaneous urticaria, and 13 had reactions to other agents, including nonsteroidal antiinflammatory drugs (NSAIDs), atracurium, cephalosporins, latex, gelatin, and dipyrone. All of these 27 patients had negative LA skin tests and nonreactive subcutaneous challenges, indicating the very high negative predictive value of skin testing.

Clinical manifestations — Clinical manifestations of immediate allergic reactions to LAs include pruritus, urticaria, bronchospasm, angioedema, rhinitis, laryngeal edema, and/or anaphylaxis, typically occurring within one hour of administration (table 3) [40,41,43-50]. A study of 100 dentists with histories of adverse reactions to lidocaine reported that the 13 individuals with documented immediate allergy based on lidocaine skin tests were significantly more likely to have experienced rhinitis, urticaria, and angioedema than those with negative immediate lidocaine skin tests [53]. Contact urticaria to topical creams containing LAs (eg, lidocaine, prilocaine, and castor oil; EMLA cream [brand name]) has also been reported [42].

Case reports describe patients with reactions to mepivacaine and lidocaine [40], articaine [41], lidocaine [43-46], levobupivacaine and ropivacaine [47], mepivacaine, lidocaine, and bupivacaine [48], and epidural lidocaine and chloroprocaine [49]. Drug-specific IgE has been demonstrated in vitro in just one report (to mepivacaine) [54].

Evaluation — Evaluation of a patient with a possible immediate allergic reaction following administration of an LA involves a detailed history, consideration of other possible allergens, skin testing, and challenge. The most common indication for skin testing and challenge is a history of symptoms that could have been either immediate allergy or nonallergic (such as syncope or hypotension).

History — The clinician should review the entire procedure and events surrounding it. As much information as possible regarding the patient's reaction(s) should be obtained, including the specific drug preparation used, the presence of added vasoconstrictor or preservatives, the time between administration and onset of the reaction, and the specific symptoms experienced. Any documented objective records should be ascertained and reviewed.

Other potential allergens — Other potential allergens often encountered during minor medical procedures include latex, disinfectants, antibiotics, and analgesics [55,56].

●Latex from gloves or other medical equipment used during procedures (especially dental procedures) can be a source of allergic reactions. However, the incidence of latex reactions has declined dramatically with the widespread use of latex-free products. (See "Latex allergy: Epidemiology, clinical manifestations, and diagnosis".)

●Chlorhexidine is a topical antiseptic and surgical scrub that is increasingly implicated in anaphylaxis occurring during surgical and dental procedures [57,58]. Products containing chlorhexidine include antiseptic solutions applied to surgical fields (especially mucosal surfaces) and urethral lubricants. Chlorhexidine hypersensitivity is discussed in more detail elsewhere. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Chlorhexidine'.)

●Antibiotics, both topical and systemic, can act as allergens. Systemic antibiotics are a well-established source of anaphylactic reactions. Topical antibiotic preparations, including bacitracin and the combination of bacitracin-neomycin-polymyxin b, have also been implicated in anaphylaxis, particularly when applied to nonintact skin following minor procedures [59-61]. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Antibiotics'.)

●NSAIDs and opiates are both capable of causing anaphylaxis or reactions resembling it in susceptible patients [62]. Allergic reactions to NSAIDs are reviewed in detail separately. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions".)

●Parabens (either methyl- or propyl-) are added to many preparations of commonly used LAs as a preservative [27]. Parabens are structurally related to the benzoic acid ester LAs and are capable of producing immediate hypersensitivity reactions [63]. In several case reports, the apparent adverse reaction to an LA was actually due to immediate hypersensitivity to paraben [5,64-67].

●Ethylenediaminetetraacetic acid (EDTA) added to an LA as a preservative was implicated in one case of systemic allergic reactions to LAs [68]. The patient had also reacted to intravenous radiocontrast agents containing EDTA. Intradermal skin testing was positive to calcium disodium EDTA at a concentration of 0.3 mg/mL.

●Depot corticosteroids and additives within these preparations are another potential cause of immediate allergy [69,70]. This is discussed in greater detail separately. (See "Hypersensitivity reactions to systemic glucocorticoids".)

Skin testing and challenge — Skin testing and subcutaneous challenge are performed to determine what alternative LAs the patient tolerates. In all of the case reports of immediate reactions, alternative anesthetics that the patients tolerated were identified in this manner [40-49].

Reagents — It is important to communicate with the referring clinician in order to include any LAs that are preferred or required for specific procedures. If the LA associated with the past reaction was not lidocaine or is unknown, lidocaine should be chosen for testing since it is commonly available and because there are cases of tolerance of lidocaine even in patients who reported previous reactions to lidocaine [56,71]. If lidocaine was the LA associated with prior reaction, the type of reaction and indication for the LA would help the clinician and patient decide whether to test with lidocaine or an alternate LA (table 2). In addition to the chosen LA, skin testing should include a positive (histamine) and negative (saline) control.

Preparations without vasoconstrictors (such as epinephrine) should be used for skin testing because the vasoconstrictor may mask a positive test [72].

Although paraben preservatives may occasionally be responsible for LA reactions, the wider availability of LA preparations containing parabens, as well as the infrequency of paraben reactions, suggests that initial skin tests may be performed with paraben-containing preparations. However, if skin testing is positive, paraben sensitivity must be considered. This can be evaluated by repeat testing with preservative-free preparations [67].

Cross-reactivity — Evidence for the relevance of the ester/amide groups (table 2) to immediate allergic reactions is limited to case reports, in which findings about cross-reactivity were inconsistent [40,41,46-48]. Therefore, the author and editors of this topic do not believe the evidence supports basing the choice of alternative LAs on the structural groups and that a better approach is to choose alternative LAs that are likely to be useful to the patient or referring provider in the future.

Testing procedures — There are several approaches to skin testing and challenge with LAs [73,74]. The approach described herein is that of the author and has proven clinically useful (table 4) [75-78]:

●Skin prick testing with undiluted drug is performed initially.

●If prick testing is negative, intracutaneous (intradermal) testing should be performed with a 1:100 dilution of drug [52]. Undiluted group I drugs have been reported to yield positive intradermal tests in up to 20 percent of subjects with no history of an adverse LA reaction [75]. Use of 1:10 dilutions can also yield false-positive results [52], although some guidelines do include this concentration [73,79]. However, we advocate the use of a 1:100 dilution for intradermal testing since false-positive skin tests have not been reported with this concentration [78].

A general discussion of the techniques for allergen skin testing is provided elsewhere. (See "Overview of skin testing for IgE-mediated allergic disease".)

Skin test interpretation

●Positive result – For the purposes of management, a positive result should be interpreted as possible allergy, unless a normal control subject has reacted to the same solution.

If a paraben-containing preparation was used for testing, paraben sensitivity should be considered. Testing should be repeated with a paraben-free solution (ie, from a single-dose vial). If the paraben-free preparation also elicits a positive test, then that specific LA should be avoided. Other LAs could then be evaluated looking for a safe alternative.

●Negative result – In the case of LAs (like almost all other drugs), skin testing with the native drug cannot be considered absolutely conclusive in excluding IgE-mediated allergy, since the allergenic determinant(s) or hapten-carrier complex responsible for IgE-mediated allergic reactions to LAs have not been identified. Despite this, case reports and extensive clinical experience suggest that a negative intradermal test is predictive of tolerance of that LA on challenge [52,76,77].

False-negative skin tests have occurred in less than 1 percent of reported patients. These individuals reacted when challenged with a drug to which they were skin test negative [75,80]. However, these reactions were very mild and often were not suggestive of IgE-mediated reactions [67,75,81].

If the prick and intradermal skin tests are negative, incremental challenge is performed next to confirm that the patient tolerates the drug in question.

Challenge — A negative skin test to an LA should be confirmed with a subsequent incremental challenge before clinical use of that drug is recommended because false-negative skin tests are rare but possible [80].

Challenge should generally not be performed with a drug for which skin testing was positive at a dilution of 1:100 if the history was suggestive of an IgE-mediated reaction. However, one may consider challenge in spite of a positive skin test at this dilution if there are limited alternatives available or if the history was not consistent with an IgE-mediated reaction.

●Recommended protocol – Challenge procedures should be performed under careful observation, with experienced personnel and appropriate facilities immediately available to treat a potential adverse reaction. The patient is usually observed for at least one hour after the final challenge step.

A widely used protocol for subcutaneous incremental challenge involves injections, typically in the upper lateral arm, of gradually increasing volumes of an LA to which the patient is skin test negative (table 5) [75].

•A single-blind saline step may be added (as the first step) in a patient whose prior reaction is strongly suspected of being anxiety related in origin [75,81].

•After a negative skin test and a negative single-blind saline challenge, we sometimes omit the 0.1 mL and 0.5 mL undiluted subcutaneous challenge steps and proceed directly to a subcutaneous injection of 1 mL of undiluted LA [67].

●Outcomes – A challenge is considered positive if the patient develops any of the following within 20 minutes after administration of any challenge step: a wheal-and-flare reaction at the site of injection, any acute-onset rash distant from the site of challenge, a 15 percent decrease in blood pressure, wheezing, or a 15 percent decrease in pulmonary function [67].

If an LA was tolerated on incremental challenge, adverse reactions to the next clinical use of that agent are uncommon and not likely to be IgE mediated [82-84]. If the LA is tolerated on challenge but the past reaction was highly suggestive of true allergy, it is important to reconsider other possible allergens. (See 'Other potential allergens' above.)

Communication of results for future local anesthetic use — After a specific LA has been tolerated in an incremental challenge, a report should be supplied to the referring clinician or dentist that includes the following information:

●The specific LA tolerated in challenge

●Its vasoconstrictor, preservative/stabilizer content (or if a preservative-free preparation should be used)

●The total dose tolerated during challenge (which is useful for patients with toxic reactions)

The patient should not be at increased risk for experiencing an immediate allergic reaction if preparations with the same LA and additives as those given in the challenge are used in future procedures.

Desensitization — A report describes a patient with bilateral central vein occlusion and subsequent retinal edema who required intraocular ranibizumab injections every five weeks with ocular LA pretreatment [85]. She developed immediate reactions to lidocaine, tetracaine, benoxinate, and bupivacaine. Because of the history of reactions to multiple ocular LAs and the morbidity of the disease, an ocular desensitization protocol to bupivacaine was successfully implemented with seven steps over two hours.

Patients with past nonallergic reactions — Several strategies exist for the prevention of subsequent nonallergic reactions to LAs:

●For patients with past psychomotor reactions and sympathetic stimulation, anxiety may be reduced by reassurance of the benign nature of these reactions, empiric use of a different LA, and, if necessary, premedication with an anxiolytic. A placebo-controlled challenge may also be useful under these circumstances.

●For patients with toxic effects, the cumulative dose used in future procedures should be kept as low as possible.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Drug allergy and hypersensitivity".)

SUMMARY AND RECOMMENDATIONS

●Most reactions to local anesthetics are nonallergic – Most idiosyncratic reactions to local anesthetics (LAs) are nonallergic in nature. Common nonallergic reactions include sympathetic stimulation from pain, psychomotor responses related to anxiety, or toxic effects attributable to heightened sensitivity to known properties of the drug or added vasopressor. Several strategies are proposed for minimizing the recurrence of these reactions. (See 'Common: Nonallergic reactions' above and 'Patients with past nonallergic reactions' above.)

●True hypersensitivity reactions are rare but may take several forms – Rarely, LAs cause true hypersensitivity reactions. Both immediate, type I hypersensitivity (eg, urticaria, anaphylaxis) and delayed, type IV hypersensitivity (eg, contact dermatitis, delayed local swelling) have been described. (See 'Types of allergic reactions to local anesthetics' above.)

●Management algorithm for urgent use – A management algorithm is provided for situations in which a procedure is needed urgently and the patient has a history of a past reaction but there is insufficient time for evaluation (algorithm 1). (See 'Management algorithm for nonallergy clinicians' above.)

●Referral for suspected allergic reactions – Patients with suspected allergic reactions to LAs should be referred for evaluation (by an allergist or dermatologist) because most do not truly have allergy to LAs. (See 'Referral' above.)

•Anaphylaxis and immediate allergic reactions, which typically begin within one hour of drug administration, have been convincingly attributed to LAs in only a small number of case reports. Allergists can perform skin testing and subcutaneous challenge to evaluate these reactions and identify safe alternative LAs. If testing with LA is negative in cases with allergic symptoms, other allergens with simultaneous exposure, such as disinfectants, antibiotics, and latex, should be considered. (See 'Rare: Immediate reactions (urticaria and anaphylaxis)' above.)

•Contact dermatitis and delayed-onset localized swelling are examples of type IV, delayed-type hypersensitivity reactions. Symptoms develop at the site of exposure, one to three days after drug administration, and are rarely dangerous. Dermatologists can perform patch testing in some cases. (See 'Rare: Delayed reactions (contact dermatitis or local swelling)' above.)