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Allergic reactions to local anesthetics

Author: Michael Schatz, MD, MS
Section Editor: N Franklin Adkinson, Jr, MD
Deputy Editor: Anna M Feldweg, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2022. | This topic last updated: Jun 20, 2022.

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 outside of the operating room".)

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 (Ig)E-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].

Sulfite-sensitive asthmatics 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 known sulfite-sensitive asthmatic patients [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 commercially prepared panels or using 10 mm
Finn Chambers (brand name) on Scanpor tape (brand name) (or equivalent products) [9]. (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 describes 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 anti-inflammatory 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 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 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.)

● 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.)

● A management algorithm is provided for situations in which a procedure is needed

urgently and there is insufficient time for evaluation ( algorithm 1). (See 'Management
algorithm for nonallergy clinicians' above.)

● 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 a small number of case
reports. Skin testing and subcutaneous challenge can be used 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 one to three days after drug
administration and can be evaluated with patch testing. Reactions are localized and rarely
dangerous. (See 'Rare: Delayed reactions (contact dermatitis or local swelling)' above.)

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Topic 2084 Version 18.0
GRAPHICS

Preprocedural evaluation and management of

suspected history of local anesthetic (LA) allergy if LA
would ordinarily be used

LA: local anesthetic; IgE: immunoglobulin E.

* Anaphylaxis due to LAs is rare, and the literature consists of case

reports. Refer to the UpToDate topic on allergic reactions to local
anesthetics, section on urticaria and anaphylaxis.

¶ Refer to the UpToDate topic on allergic reactions to local anesthetics,

section on contact dermatitis and delayed local swelling.

Δ Decisions to potentially delay the procedure for testing will depend

upon the risks of delaying the procedure and the risks/benefits of the
use of LA versus other forms of anesthesia or analgesia.

◊ Lidocaine is chosen in preference to other LAs because it is among the

most commonly used LAs and yet there are few reported cases of
anaphylaxis and also because there are cases of tolerance to lidocaine
even in patients who reported previous reactions to lidocaine.

Graphic 117594 Version 1.0

Gell and Coombs classification of immunologic drug reactions

Clinical
Type Description Mechanism
features

I IgE-mediated, Antigen exposure causes IgE- Anaphylaxis

immediate-type mediated activation of mast cells and
Immediate Angioedema
hypersensitivity basophils, with release of vasoactive
reaction (within
substances, such as histamine, Bronchospasm
one hour)
prostaglandins, and leukotrienes. Urticaria (hives)

Hypotension

II Antibody- An antigen or hapten that is intimately Hemolytic anemia

dependent associated with a cell binds to
Thrombocytopenia
cytotoxicity antibody, leading to cell or tissue
injury. Neutropenia

III Immune complex Damage is caused by formation or Serum sickness

disease deposition of antigen-antibody
Arthus reaction
complexes in vessels or tissue.
Deposition of immune complexes
causes complement activation and/or
recruitment of neutrophils by
interaction of immune complexes with
Fc IgG receptors.

IV Cell-mediated or Antigen exposure activates T cells, Contact dermatitis

delayed which then mediate tissue injury.
Some morbilliform
hypersensitivity Depending upon the type of T cell
reactions
activation and the other effector cells
recruited, different subtypes can be Severe exfoliative
differentiated (ie, types IVa to IVd). dermatoses (eg,
SJS/TEN)

AGEP

DRESS/DiHS

Interstitial
nephritis

Drug-induced
hepatitis

Other
presentations

IgE: immunoglobulin E; Fc IgG: Fc portion of immunoglobulin G; SJS/TEN: Stevens-Johnson

syndrome/toxic epidermal necrolysis; AGEP: acute generalized exanthematous pustulosis;
DRESS/DiHS: drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity
syndrome.

Adapted from: Weiss ME, Adkinson NF. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clin Allergy
1988; 18:515.

Graphic 80466 Version 18.0

Classification of local anesthetics

Group I. Benzoic acid esters

Benzocaine (Americaine, Lanacane)

Chloroprocaine (Nesacaine)

Cocaine

Procaine (Novocaine)

Proparacaine (Alcaine, Ophthetic, Paracain)

Tetracaine (Pontocaine)

Group II. Amides

Articaine (Septocaine, Zorcaine)

Bupivacaine (Marcaine, Sensorcaine)

Levobupivacaine

Dibucaine (Nupercainal)

Etidocaine (Duranest)

Lidocaine (Xylocaine)

Mepivacaine (Carbocaine)

Prilocaine (Citanest)

Ropivacaine (Naropin)

Graphic 57120 Version 6.0

Immediate allergic reactions to drugs (IgE-mediated or non-IgE-mediated):
Possible signs and symptoms

Skin

Itching*
Urticaria*
Angioedema*
Warmth
Flushing
Other exanthema

Eyes, ears, nose

Periorbital edema*
Rhinorrhea*
Nasal itching*
Nasal congestion*
Ocular itching
Tearing
Conjunctival injection and/or edema
Sneezing

Mouth

Itching or tingling of lips, tongue, oral mucosa*

Angioedema of lips, tongue, or uvula*
Metallic taste

Throat

Itching*
Sense of constriction or swelling in throat*
Change in voice quality*
Difficulty swallowing*
Stridor*
Hoarseness
Drooling

Lungs

Shortness of breath*
Chest tightness*
Repetitive cough*
Wheezing*
 Drop in oxygen saturation, cyanosis

Cardiovascular

Lightheadedness/faintness/dizziness*
Tachycardia or occasionally, bradycardia*
Hypotension*
Syncope/loss of consciousness
Palpitations
Tunnel vision
Difficulty hearing
Urinary or fecal incontinence
Cardiac arrest

Gastrointestinal

Nausea
Vomiting
Abdominal cramping or pain
Diarrhea

Gynecologic

Vaginal itching
Uterine cramping or bleeding

Neurologic

Anxiety
Sense of impending doom
Altered mental status/confusion
Seizures

Immediate reactions to drugs often present with combinations of the signs and symptoms listed in
the table. Those bolded and marked with an asterisk (*) are more consistent and representative than
the others, and one or more of these should be present to consider the reaction immediate.

IgE: immunoglobulin E.

Graphic 100732 Version 5.0

Skin testing protocol for patients with histories of possible IgE-mediated
reactions to local anesthetics

Step Route Volume (mL) Dilution

1 Puncture – Undiluted*

2 Intradermal 0.02 cc 1:100

Prick (epicutaneous) testing is performed initially, with appropriate positive (histamine) and negative
(diluent) controls. Results are assessed at 20 minutes. A positive result consists of a wheal 3 mm
greater than the negative control. If prick tests are negative, then intradermal testing is performed
by injecting 0.02 mL of a 1:100 dilution of the local anesthetic in question.

IgE: immunoglobulin E.

* The concentration of the local anesthetic (usually 1 to 2%) to be used for the procedure.

Graphic 80642 Version 5.0

Protocol for subcutaneous incremental challenge in patients with histories
of prior reactions to local anesthetics

Step* Volume (mL) Dilution

1 0.5 Saline¶Δ

2 0.1 cc Undiluted◊

3 0.5 cc Undiluted

4 1.0 cc Undiluted

* Administered at 20- to 30-minute intervals.

¶ A single-blind, subcutaneous saline step may be inserted before a subcutaneous local anesthetic
injection for patients in whom the reaction is suspected to be due to the injection, rather than the
drug.

Δ After negative skin testing and a negative saline challenge (step 1), consider proceeding directly to
step 4.

◊ The concentration of the local anesthetic (usually 1 to 2%) to be used for the procedure.

Graphic 56788 Version 8.0

Contributor Disclosures
Michael Schatz, MD, MS Grant/Research/Clinical Trial Support: ALK [Mite SLIT]; Merck [Cough].
All of the
relevant financial relationships listed have been mitigated. N Franklin Adkinson, Jr, MD Equity
Ownership/Stock Options: AllerQuest [Penicillin allergy diagnosis].
Consultant/Advisory Boards: Aeglea
[DSMB for drug products under development];AMAG Pharma [Hypersensitivity reactions and anaphylaxis
in drugs under development];BioMarin [Hypersensitivity reactions and anaphylaxis in drugs under
development];Genzyme/Sanofi [DSMB for drug products under development];IQVIA [DSMB for drug
products under development];Merck [Hypersensitivity reactions and anaphylaxis in drugs under
development];ViiV Healthcare [Hypersensitivity reactions and anaphylaxis in drugs under development].
All of the relevant financial relationships listed have been mitigated. Anna M Feldweg, MD No relevant
financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

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