Hypersensitivity to local anesthetics: causes, types, and management

Hypersensitivity to local anesthetics
Natthiya Pholmoo, MD
Natthiya Pholmoo, MD.
October 2020

CONTENTS
• Background
• Introduction
• Types of Local Anesthetics
• Adverse Reactions
• Systemic reaction
• Allergic reactions of LA
• Management

Background
• 1860
• Niemann
• Alkaloid isolated from coca leaves
• Cocaine
• Numbing effects
• 1884
• Koller
• Cataract operation
• 1905
• Einhorn
• Novocain / Procaine
P. Rangappa, 2008
Oettmeier R, Reuter U, Bonilla LBP, 2019https://www.narconon.org/drug-information/cocaine-circa-1500-1800.html

Introduction
• Multiple forms
• Gels
• Ointments
• Sprays
• Solutions
• Local anesthetics are used in
• Dentistry
• Surgery/Plastic surgery
• Dermatology
• Orthopedics
• Ophthalmology
• Minor surgery
• Endoscopies
• Obstetrics
Gerald W. Volcheck, Paul Michel Mertes, 2014

Introduction
• First report of LA allergic-type reaction in 1920 in a dentist
who developed eczematous contact dermatitis on his hands
after handling apothesin, a congener of procaine.
• Skin testing was positive.
• Dermatitis resolved when apothesin exposure ceased.
Eric Boren, Suzanne S. Teuber, Stanley M. Naguwa, and M. Eric Gershwin, 2007

Types of Local Anesthetics
Siyi Yu, Bin Wang, Jiqin Zhang, Kaiyun Fang, 2019
Ester
Amide

El-Boghdadly K, Pawa A, Chin KJ, 2018

Benzoic acid esters
• The amino-ester LA compounds were the
only option available until Lofgren
discovered the amino-amide LA in 1943
• Procaine (Novocain®) was one of the
commonly used benzoic acid esters.
• The benzoic acid esters often cross-react
with each other but generally do not
cross-react with the amino-amide LA .
Joanna Luk a wsk a, M Rosario Caballero, Sophia Tsabouri,Pierre Dugué, 2009

Benzoic acid esters
• Para-aminobenzoic acid (PABA) is a metabolite of
ester-type LA.
• Higher incidence of allergic reactions due to para-
amino benzoic acid (PABA).
• PABA is structurally similar to methylparaben.
• Methylparaben, as a preservative in preparations of
both amides and esters, may show allergic cross-
reactivity with para-aminobenzoic acid
Philipp Lirk, Markus W. Hollmann, Gary Strichartz, 2018
methylparaben

The amides
• The amides are not metabolized into
the para-aminobenzoic acid
(PABA) molecule
• Less sensitizing and do not generally
cross-react with each other.
• Most local anesthesia is performed
using amides.
Joanna Luk a wsk a, M Rosario Caballero, Sophia Tsabouri, Pierre Dugué, 2009

Mechanism of Action
• Blocking nerve conduction
• Blocking afferent signals to the brain
• Reversible binding of LA to the voltage-gated sodium
channels in the nerve-cell membrane
• Preventing action potentials from forming

Philipp Lirk, Markus W. Hollmann, Gary Strichartz, 2018

Metabolism
• Ester LA : rapid hydrolysis by nonspecific plasma cholinesterases
• Para-aminobenzoic acid (PABA) is an intermediate metabolite
that is inactive for anesthesia induction.
• PABA is a known allergen.

Metabolism
• Amide LAs are cleared primarily by hepatic metabolism with
renal excretion.
• Amide LA preparations may also contain preservatives, such as
• methylparaben
• sulphites
• Chemically similar to PABA and may be antigenic in sensitized
individuals

BLOOD CONCENTRATIONS
John Butterworth IV. [2020].Clinical Pharmacology of Local Anesthesia.
https://www.nysora.com/foundations-of-regional-
anesthesia/pharmacology/clinical-pharmacology-local-anesthetics/
• Peak LA concentrations vary by the site of injection.
• With the same LA dose, intercostal blocks consistently produce greater peak LA
concentrations than epidural or plexus blocks.
• In blood, all LAs are partially protein bound, primarily to α1-acid glycoprotein and
secondarily to albumin.
• Amide LA clearance is reduced by factors that decrease hepatic blood flow, such
as β-adrenergic receptor or H2-receptor blockers, and by heart or liver failure.

Esters Amides
(two letter “i”s in their name)
Benzocaine
Butamben picrate (Butesinc)
Cocaine
Procaine (Novocain)
Proparacaine
Tetracaine (Pontocaine)
Chloroprocaine (Nesacainea)
Lidocaine (Xylocaine)
Lidocaine with epinephrine
Mepivacaine (Carbocaine, Polocaine)
Prilocaine (Citanest)
Bupivacaine (Marcaine)
Levobupivacaine (Chirocaine)
Articaine (Septocainea)
Dibucaine (Nupercainal)
Ropivacaine (Naropina)

Local anesthetic drugs in KCMH
Esters Amides
- 0.5% Tetracaine eye drop ED
- Cardioplegia (Magnesium chloride +
Potassium chloride + Procaine HCL)
NED – เลิกจำหน่ำย
- Juvederm Volbella with Lidocaine injection
(Hyaluronic acid, cross-linked, Lignocaine) NED
- 2% Lidocaine ED
- 1% Xylocaine with adrenaline ED
- 2% Xylocaine with adrenaline ED
- 2% Xylocaine ED
- 0.5% Bupivacaine ED
- Chirocaine (Levobupivacaine) NED
- 5% Dermacream (Lidocaine + Prilocaine) ED
- 5% EMLA cream (Lidocaine + Prilocaine) ED
- Lignopad patch NED
- 2% Xylocaine Jelly ED
- 10% Xylocaine Spray ED
- 2% Chulacaine Viscous ED

Siyi Yu, Bin Wang, Jiqin Zhang, Kaiyun Fang, 2019

Epinephrine
• Vasoconstrictors such
• Decrease systemic absorption
• Lowers peak plasma
concentrations
• Slows the time to produce peak
tissue levels and the cumulative
• Reduces the potential for toxicity
• Prolonging the anesthetic effects
JOSHUA F. PHILLIPS, ANNE B. YATES, RICHARD D. DESHAZO, 2007

Epinephrine
• Side effects
• Hypertension
• Tachycardia
• Cardiac arrhythmias
• myocardial ischemia can occur in
some individuals.
• Similar symptoms may be secondary
to the release of endogenous
catecholamines as a response to
pain/anxiety.
• One study showed no significant
hemodynamic response to lidocaine
with epinephrine in dental
procedures, despite significant
elevations in plasma levels of
epinephrine above baseline.

Preservatives Parabens
• Preservatives are more commonly found in multidose vials
• Parabens (typically methylparaben)
• Bacteriostatic agent related in structure to the benzoic acid
ester local anesthetics
• Methylparaben induced an anaphylactoid release of
vasoactive substances and that IgE-mediated effects were
excluded by negative intradermal testing
methylparaben

Preservatives Sulfites
• Antioxidants used to stabilize vasoconstrictors such as epinephrine in
local anesthetic preparations.
• The breakdown product sulfur dioxide is released in the airway leading
to bronchoconstriction, similar to the actions of bradykinin.
• Metabisulfite induces mast cell degranulation via non-IgE dependent
mechanisms.

Latex Allergy
• Another potential cause of reported allergy
to local anesthetics is latex antigen.
• Latex found in gloves or rubber dams used
during dental procedures can cause
contact dermatitis, the most common
manifestation of latex allergy.

Adverse
Reactions
• Any patient who presents with a history of
an allergic reaction to local anesthetics
should be carefully questioned to
determine the nature of the reaction.
• Differentiating between local
hypersensitivity and other causes of
adverse reactions can be difficult because
systemic symptoms such as dyspnea,
swelling, and lightheadedness may occur by
multiple mechanisms.
• There is currently no reliable method to
identify or measure serum IgE specific to
local anesthetics

Classification of Types of Adverse
Reactions to Local Anesthetics
Local reactions
Local toxic effects
Trauma
Contact dermatitis
Systemic reactions
Psychosomatic (anxiety, needle phobia, panic attacks, vasovagal syncope)
Toxic reactions (CNS, cardiovascular)
Idiosyncratic (methemoglobinemia)
Anaphylactoid
Anaphylactic

Psychosomatic Responses
• Most common adverse reaction
• More common in dental procedures ; this may be related to the general anxiety some patients
have in the dentist’s chair.
• Anxiety may lead to
• Dyspnea
• Hyperventilation
• Tachypnea
• Tachycardia
• Diaphoresis
• Hypertension
• Nebulous symptoms : peripheral and/or circumoral paresthesias

Psychosomatic Responses
• Another common event is vasovagal syncope, which is frequently
accompanied by bradycardia.
• In contrast, most patients with systemic allergic reactions have some
combination of tachycardia, pruritus, dermal erythema, or urticaria.

Systemic Toxicity
• Intravascular injection
• Excessive dosage
• Toxicity
• Potency
• Dose
• Rate of plasma uptake
• The amount of protein binding
• Site of injection JOSHUA F. PHILLIPS, ANNE B. YATES, RICHARD D. DESHAZO, 2007

Systemic Toxicity

Systemic Toxicity
Cardiovascular
• Significantly higher serum concentrations of the drug
• Depressed myocardial contractility and conduction abnormalities
• Atrioventricular block
• QRS-widening
• Asystole
• Peripheral vasodilation
• Shock JOSHUA F. PHILLIPS, ANNE B. YATES, RICHARD D. DESHAZO, 2007

Marina Gitman, Michael R. Fettiplace, Guy L. Weinberg,
Joseph M. Neal, Michael J. Barrington, 2019

Ana Carolina Figueiredo Pereira Cherobin, Glaysson Tassara Tavares, 2019

Incidence
• Less than 1% of LA reactions are immune system-mediated.
• LA are too small to be antigenic by themselves, so they must
bind to host proteins as a hapten–carrier complex to be
allergenic.
• The number of deaths attributed to the use of local
anesthetics ranges from 1 in 1.4 million to 1 in 1.5 million
patients.

Allergic reactions
•Type I hypersensitivity
(IgE-mediated hypersensitivity)
•Type IV hypersensitivity
(T cell–mediate hypersensitivity)

Type I hypersensitivity
• Local reactions are more common and include urticaria
and angioedema without respiratory compromise.
• Immediate systemic hypersensitivity reaction
(anaphylaxis) symptoms are observed in the first 30 min
after the exposure to the anesthetic.
• True immediate IgE-mediated allergic reactions to amide-
type local anesthetics are considered a very rare event
• Skin tests were a useful tool for the diagnosis of
sensitization to amide-type local anesthetics.
• Reported patient who reacted to mepivacaine, showed a
positive reaction in skin tests with mepivacaine and
ropivacaine, but tolerated lidocaine and bupivacaine.
• Reported a patient who showed extensive local urticaria
after local lidocaine and for whom positive results were
obtained in skin tests with lidocaine, bupivacaine,
mepivacaine, and ropivacaine.
P González-Delgado, R Antón, V Soriano, P Zapater, E Niveiro, 2006

Type IV
hypersensitivity
• Local anesthetic-induced contact dermatitis
and patch testing commonly reveal
crossreactivity between benzoic acid esters
but an absence of cross-reactivity with amide-
type local anesthetics.
• A few recent case reports cross-reactivity
among amides Type IV hypersensitivity
reactions to local anesthetics have been well
documented in the literature, predominantly
to ester-type anesthetics but also to amide
type.
• Benzocaine is the most common allergen
(45%), which is followed by lidocaine (32%)
and dibucaine (23%).25 It is estimated that its
incidence reaches 3.4% in the United States.
Ana Carolina Figueiredo Pereira Cherobin, Glaysson Tassara Tavares, 2019

Ramin Fathi, Marc Serota, Mariah Brown, 2016

History
• Type of procedure performed at time
of reaction
• Timing of administration of local
anesthetic in relation to symptom
development
• Complete review of systems of the
reaction
• Type, amount, and concentration of
the local anesthetic used
• Whether the local anesthetic
contained epinephrine
• Patients’ medical history, particularly
kidney, liver, cardiac, and psychiatric
history

Management
• For immediate symptoms that may indicate anaphylactic mechanisms, the
recommendation is to perform skin prick and intradermal testing.
• The preparation used should not contain a preservative or vasoconstrictor to
minimize false-positives.
• Epinephrine may inhibit potential wheal-and-flare reactions, contributing to
false-negative skin tests.
• Future use involves skin prick/intradermal testing followed by a subcutaneous
provocative dose challenge.
• If there is suspicion of psychosomatic response, the single-blinded injection of
normal saline should be performed before skin testing.

Management
• With delayed or cutaneous symptoms indicating type IV
hypersensitivity/contact dermatitis, patch testing is indicated.
• The challenge is best performed 24 to 48 hours after skin testing to confirm
that there is no delayed reaction from testing, particularly if history suggests
delayed onset of symptoms.
• If the intradermal skin test is positive, another agent should be chosen and
the procedure started over.
• A negative provocative dose challenge suggests that the drug is safe.

Skin testing procedure
Skin prick test
• Undiluted preserved local
anesthetic solution without
epinephrine
http://www.rcot.org/datafile/_file/_doctor/
991c9f19657de53508b754b3c8dae495.pdf

Skin testing procedure
• Intradermal test
• 1:100 dilution
• 1:10 dilution
http://www.rcot.org/datafile/_file/_doctor/
991c9f19657de53508b754b3c8dae495.pdf

Patch test
• 5% lidocaine gel
• One of the chamber fill with lidocaine was
placed on the upper part of the patient’s back
• The first reading was performed after 48 hours
• When the patch test was removed and the
patient’s skin was examined.
• The formation of erythema, papules, bumps or
blisters in the place where lidocaine had been
present was recognized as a positive result.
ANNA JANAS-NAZE, PIOTR OSICA, 2019

Maximum doses for skin test
Ask D. Kvisselgaard, BMSc, Holger F. Mosbech, DMSc, Sara Fransson, Lene H. Garvey, 2017

Subcutaneous challenge
• Undiluted LA solution
• 0.1 mL
• 0.5 mL
• 1.0 mL
• 2.0 mL
Ask D. Kvisselgaard, BMSc, Holger F. Mosbech, DMSc, Sara Fransson, Lene H. Garvey, 2017
• NaCl placebo injection
• Diluted LA solution
• 1/100
• 1/10
• 1/1
30-45 minute interval

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