Local anesthetic allergy

Local anesthetic allergy

Reviewed by Sirapassorn Sornphiphatphong, MD.

Overview

• Introduction

• Adverse reaction to LA

• Prevalence of LA allergy

• Categories of LA

• Types of allergic reactions of LA

– Contact dermatitis and Delayed type

hypersensitivity

– Immediate type hypersensitivity

Local anesthetics (LA)

• Discovery of cocaine in 1884

• Multiple forms: gels, ointments, sprays,

solutions and injectable forms

• Topical, infiltrative, nerve block, epidural, or

spinal routes

• Dentistry, ophthalmology, minor surgery,

endoscopies and obstetrics

Volcheck GW, et la. Immunol Allergy Clin N Am 34 (2014) 525–546

Adverse reactions to LA

deShazo RD, et al. JACI 1979

Adverse reactions to LA

Bhole MV, et al. British Journal of Anaesthesia, 2012

Categories of LA

Joanna Lukawska, et al. Current Allergy & Clinical Immunology, 2009 Vol 22, No. 3

Benzoic acid esters LA

• Metabolised by pseudocholinesterase in plasma

to para-aminobenzoic acid (PABA)

• Reactions thought to be secondary to PABA

• Procaine (Novocain) most common

• Often cross-react with each other but generally

do not cross-react with the amide groups



The amides

• Less sensitizing and do not generally cross-

react with each other

• Not metabolized into the PABA molecule

• Metabolised in the liver

• Decreased hepatic function are at increased risk

of overdosage and toxic reactions



Lidocaine

• Prototype for amide

local anesthetics

• Rapid onset,

intermediate duration

• Metabolized by the

liver and excreted by

the kidneys with 10%

unchanged and 80%

as metabolites


Mepivacaine

• Rapid onset, medium

duration

• metabolized by the

liver

• Higher-concentration

(4%) causes slight

vasoconstriction,

longer duration


Prilocaine

• Secondary amide

• Metabolized in both liver and kidneys

• Methemoglobinemiawhen using large doses

• Avoided in sickle cell anemia, chronic anemia, and hypoxia and in patients taking high doses of acetaminophen


Articaine

• Unique structures

including a

thiophene ring that

enhances its lipid

solubility

• less systemic

toxicity


Bupivacaine

• 4 times more potent than lidocaine, mepivacaine, and prilocaine

• Long-term pain control; extraction of impacted third molars, epidural block, or surgical wound sites

• Higher cardiotoxicity, caution in patients taking b-blockers or digoxin


Epinephrine

• 1:100,000

• Vasoconstriction

• Increased duration, less systemic absorption

• Adverse effect: cause palpitations, tachycardia,

arrhythmia, hypertension, tremor, headache,

and anxiety


Prevalence of LA allergy

• Frequently reported adverse reactions by

patients

• Extremely rare true immune-mediated reactions

estimated <1% of all adverse reactions to LA

Fisher MM, et al. Anaesth Intensive Care 1997; 25: 611–614.

Gall H, et al. J Allergy Clin Immunol 1996; 97: 933–937.

Baluga JC, et al. Allergol Imunopathol 2002; 30(1): 14–19.

Gonzalez-Delgado P, et al. J Investig Allergol Clin Immunol 2006

Batinac T, et al. Journal of Dermatology 2013; 40: 522-527

Bhole MV, et al. British Journal of Anaesthesia 108 (6): 903–11 (2012)

Types of allergic reactions of LA

• Allergic contact dermatitis and delayed swelling

at the site of administration

• Immediate reaction: urticaria, anaphylaxis

• Other causes that mimic allergic reactions

• Multiple drugs used

• Other topical agents, such as neomycin

• Additives and preservatives; sulfites and parabens

Parabens

• Preservatives

• Reported reactions to methylparaben in LA

• In 1984, FDA mandated its removal from single-

dose LA cartridges

Macy E, et al. JACI 2002

• Immediate hypersensitivity to pure amide LA agents is

extremely rare

• Methylparaben was the only established cause for an

immediate hypersensitivity reaction during LA identified in

a large allergy practice during the past 16 years

Sulfites

• Bisulfite or metabisulfite

• Antioxidants, stabilize epinephrine

• Non–IgE-mediated hypersensitivity reactions,

particularly in patients with asthma

A case report

• 40-year-old woman with severe edema of the

face and neck after 2 hr of Neo-lidocaton injection

for dental procedure and lasted for 2 days

Case report

• Patch testing: positive to Neo-lidocaton at 48,

96 hr and positive patch testing with sodium

metabisulfites at 48 and 72 U

• No reaction when used lidocaine without

metabisulfites

Dooms-Goossens A, et al. Contact Dermatitis 1989; 20:124

Neo-Lidocaton contains lidocaine, vasopressin,

norepinephrine, p-hydroxybenzoates, 0.2% sodium

metabisulfite, sodium chloride, potassium chloride

and calcium chloride

Contact dermatitis,

delayed local swelling

• Within 72 hours

• Limited to area in direct contact with agent,

at the site of administration

• Localized eczematous, pruritic rash, vesicle,

blister

• Clinical history, patch testing, and possibly

challenge

History taking

1. Type of procedure performed

2. Timing of administration of local anesthetic in relation to symptom development

3. Complete review of systems of the reaction

4. Type, amount, and concentration of the local anesthetic used

5. Whether the local anesthetic contained epinephrine

6. Patients’ medical history, particularly kidney, liver, cardiac, and psychiatric history


Patch testing

• Various concentration of LA in patch testing

• Lidocaine (in a petroleum vehicle) ranged

5-15%

• Finn chambers on Scanpor tape

• T.R.U.E. test panel (Allerderm Lab, Phoenix, AZ)

includes a "caine mix” contains

tetracaine hydrochloride, benzocaine

dibucaine hydrochloride,Mackley CL, et al. Arch Dermatol 2003; 139:343

Amado A, et al. Dermatitis 2007; 18:215

Kaufmann JM, et al. J Drugs Dermatol 2002; 1:192

Sanchez-Morillas L, et al. Contact Dermatitis 2005; 53:352

Patch testing

Cross-reactivity

• Limited data

• Evidence for cross-reactivity within each

group of agents

• Minimal evidence for cross-reactivity

between the two groups

Bircher AJ, et al. Contact Dermatitis 1996; 34:387

Sensitisation and cross-reactivity,

resulting in delayed-type IV reactions, between ester-LAs are common

• Benzocaine, frequently used ester-LAs for

topical applications

• sun creams and haemorrhoid creams, as well

as some topical anaesthetics

• PABA, is a common and potent sensitiser


Case report

• 43-yr-old woman

• Localized angioedema 24 hr after local anesthesia for

dental surgery and after applying sunburn

• Contact allergy to ester LA; benzocaine, procaine and

tetracaine

• Sensitization to lidocaine and cross-reactivity to the other

aminoacylamide LA; bupivacaine, mepivacaine,

prilocaine but not to articaine

• Tolerated to subcutaneous challenge to articaine

Amado A., et al. Dermatitis 2007




Case report

• 70-year-old woman with soft-tissue

swelling of the cheek 48 hr after dental

treatment

• Positive patch testing to lidocaine,

prilocaine, mepivacaine, and dibucaine

Curley RK, et al. Arch Dermatol 1986; 122:924

Immediate type

• Pruritus, urticaria, bronchospasm,

angioedema of noncontiguous tissues,

and anaphylaxis

• Within one hour

History taking

1. Type of procedure performed

2. Timing of administration of local anesthetic in relation to symptom development

3. Complete review of systems of the reaction

4. Type, amount, and concentration of the local anesthetic used

5. Whether the local anesthetic contained epinephrine

6. Patients’ medical history, particularly kidney, liver, cardiac, and psychiatric history


Skin prick test, SPT

• In the 23 large series, 2487 out of 2978

patients (83.5%) tested using this method

• Thirty (1.2%) had positive results

• Many authors have used undiluted LA for

skin prick tests, although some have

preferred to use dilutions


Intra-dermal tests, ID test

• 2648 of 2978 patients (89%)

• Positive in 37 (1.4%) when using 1:10 or greater

dilutions of LA

• Neat preparations of LA were not commonly

used for intra-dermal testing


Subcutaneous challenge

• 2560 of the total 2978 patients (86%) had

subcutaneous challenges

• Positive challenge tests in 19 patients (0.74%)

• In most cases, this procedure has been used to

demonstrate tolerance to an alternative agent

rather than confirm allergy


Drug provocative test


Skin testing and challenge

deShazo RD, et al. JACI 1979

SPT, ID

1. SPT and IDT (concentrations not defined),

if negative, a single subcutaneous challenge (as

opposed to incremental); if positive, then skin test and

challenge to an unrelated local anesthetic

2. If negative SPT → IDT with (1:100) 0.04 mL, if

negative → 1 mL subcutaneous challenge. if

positive skin test, retest with pure local

anesthetic solution without methylparaben or

other preservative

Volcheck GW, et la. Immunol Allergy Clin N Am, 2014

Bhole MV, et al. Br J Anaesth 2012

Harboe T, et al. Acta Anaesthesiol Scand 2010;54:536–42

SPT, ID

3. If negative SPT→ IDT with 1:100 dilution,

if negative → subcutaneous challenge with (1:10)

0.1 mL, then undiluted 0.1 mL, then undiluted

1.0 mL

Volcheck GW, et la. Immunol Allergy Clin N Am, 2014

Macy E. Ann Allergy Asthma Immunol 2003;91:319–20

NPV of SPT

• The negative predictive value of the skin

test was 97%

Brad McClimon, et al. Allergy Asthma Proc, 2011

Specjalski K, et al. Int Arch Allergy Immunol 2013;162:86–88

Skin testing and challenge

Chandler MJ, et al. JACI 1987:79:883-6


• No cases of immediate-type hypersensitivity by

skin test or test-dose challenge

• We suggest that intradermal testing be

abandoned in favor of prick testing followed by

incremental subcutaneous provocative dose

testing

• “The patient has received 3 ml of the local

anesthetic without an adverse reaction and

appears to be at no greater risk for a repeat

reaction than the general population”

Chandler MJ, et al. JACI 1987:79:883-6


• Injecting 0.1 mL, 0.5 and 1 ml of undiluted local

anesthetic solution subcutaneously into the

upper arm at a different location at 15 min

interval

• A positive subcutaneous challenge was defined

as a wheal 3 mm greater than negative control

Brad McClimon, et al. Allergy Asthma Proc, 2011


• Poland, 2006 to July 2012

• 154 patients

• SPT

– 1%lidocaine, 0.5%bupivacaine, mepivacaine

and articaine

• The next step, ICT with LA diluted (1: 10), positive in the case of a wheal of ≥ 5 mm in

diameter



• The drug was injected in the lateral side of

an arm every 30 min in increasing doses:

0.1 ml of diluted drug (1: 10), 0.1 ml of

undiluted drug and 1 ml of undiluted drug


Cross-reactivity

• 39-year-old man, in Spain

• Itching, generalized urticaria with facial

angioedema 15 min after mepivacaine

administration

• SPT: strong positive reaction to mepivacaine,

lidocaine, and ropivacaine, but negative

reactions to bupivacaine and levobupivacaine

• Double-blind placebo-controlled subcutaneous

challenge with bupivacaine and levobupivacaine

was well tolerated

González-Delgado P, et al. J Investig Allergol Clin Immunol 2006

1%, 2% lidocaine

• with 1:80,000

epinephrine injection

solution

• No-methylparaben

formulation

2% Mepivacaine

• With adrenaline

• 1.8, 2.2 ml

• Contains sulfites

• 3% is SULFITE FREE

• without vaso-

constrictor


3% Mepivacaine

4% articaine


• With 1:100,000 epinephrine injection solution

• Contains sodium metabisulfite

Citanest (Prilocaine)

• 1%prilocaien

• Contains Paraben

Conclusions: Facts

• Adverse reactions to LAs are often related to

epinephrine, psychogenic factors, other drugs

• Toxic effect of LA may occasionally be

misdiagnosed as LA allergy

• Risk of adverse drug reaction to LA may be

increased in patients with deranged liver

function or pseudocholinesterase dysfunction


Conclusions

• Rare IgE-mediated hypersensitivity to LAs

• Sensitisation and cross-reactivity, resulting in

delayed-type IV reactions, between ester-LAs

are common

• Patch testing is a reliable method of diagnosis

of delayed-type IV hypersensitivity reactions

Health & Medicine

Local anesthetic allergy