This document summarizes local anesthetic allergy. It discusses the prevalence, categories, types of reactions, and testing for local anesthetic allergy. Key points include: - True immune-mediated local anesthetic allergy is rare, estimated at <1% of adverse reactions. - Allergic reactions can be contact dermatitis/delayed swelling at the site or immediate reactions like anaphylaxis. - Patch testing and skin prick/intradermal testing can help diagnose delayed or immediate allergy, followed by subcutaneous drug challenges if needed. - Cross-reactivity is more common within drug classes like esters but minimal between classes like esters and amides. Testing alternative local anesthetics

1. Local anesthetic allergy
Reviewed by Sirapassorn Sornphiphatphong, MD.

2. 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

3. 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

4. Adverse reactions to LA
deShazo RD, et al. JACI 1979

5. Adverse reactions to LA
Bhole MV, et al. British Journal of Anaesthesia, 2012

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

7. 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
Joanna Lukawska, et al. Current Allergy & Clinical Immunology, 2009 Vol 22, No. 3
Volcheck GW, et la. Immunol Allergy Clin N Am 34 (2014) 525–546

8. 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
Joanna Lukawska, et al. Current Allergy & Clinical Immunology, 2009 Vol 22, No. 3
Volcheck GW, et la. Immunol Allergy Clin N Am 34 (2014) 525–546

9. 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
Volcheck GW, et la. Immunol Allergy Clin N Am 34 (2014) 525–546

10. Mepivacaine
• Rapid onset, medium
duration
• metabolized by the
liver
• Higher-concentration
(4%) causes slight
vasoconstriction,
longer duration
Volcheck GW, et la. Immunol Allergy Clin N Am 34 (2014) 525–546

11. Prilocaine
• Secondary amide
• Metabolized in both
liver and kidneys
• Methemoglobinemia
when using large
doses
• Avoided in sickle cell
anemia, chronic anemia,
and hypoxia and in
patients taking high
doses of acetaminophen
Volcheck GW, et la. Immunol Allergy Clin N Am 34 (2014) 525–546

12. Articaine
• Unique structures
including a
thiophene ring that
enhances its lipid
solubility
• less systemic
toxicity
Volcheck GW, et la. Immunol Allergy Clin N Am 34 (2014) 525–546

13. 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
Volcheck GW, et la. Immunol Allergy Clin N Am 34 (2014) 525–546

14. Epinephrine
• 1:100,000
• Vasoconstriction
• Increased duration, less systemic absorption
• Adverse effect: cause palpitations, tachycardia,
arrhythmia, hypertension, tremor, headache,
and anxiety
Volcheck GW, et la. Immunol Allergy Clin N Am 34 (2014) 525–546

15. 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

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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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
Volcheck GW, et la. Immunol Allergy Clin N Am 34 (2014) 525–546

23. 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

24. Patch testing

25. 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

26. 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
Joanna Lukawska, et al. Current Allergy & Clinical Immunology, 2009 Vol 22, No. 3

27. 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

28. Amado A., et al. Dermatitis 2007

29. Amado A., et al. Dermatitis 2007

30. Amado A., et al. Dermatitis 2007

31. Amado A., et al. Dermatitis 2007

32. 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

33. Immediate type
• Pruritus, urticaria, bronchospasm,
angioedema of noncontiguous tissues,
and anaphylaxis
• Within one hour

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

35. 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
Bhole MV, et al. British Journal of Anaesthesia, 2012

36. 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
Bhole MV, et al. British Journal of Anaesthesia, 2012

37. 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
Bhole MV, et al. British Journal of Anaesthesia, 2012

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

39. Skin testing and challenge
deShazo RD, et al. JACI 1979

40. 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

41. 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

42. 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

43. Skin testing and challenge
Chandler MJ, et al. JACI 1987:79:883-6

44. Drug provocative test
• 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

45. Drug provocative test
• 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

46. Drug provocative test
• 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
Specjalski K, et al. Int Arch Allergy Immunol 2013;162:86–88

47. Drug provocative test
• 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
Specjalski K, et al. Int Arch Allergy Immunol 2013;162:86–88

48. 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

49. 1%, 2% lidocaine
• with 1:80,000
epinephrine injection
solution
• No-methylparaben
formulation

50. 2% Mepivacaine
• With adrenaline
• 1.8, 2.2 ml
• Contains sulfites
• 3% is SULFITE FREE
• without vaso-
constrictor
• No-methylparaben
3% Mepivacaine

51. 4% articaine
• No-methylparaben
• With 1:100,000 epinephrine injection solution
• Contains sodium metabisulfite

52. Citanest (Prilocaine)
• 1%prilocaien
• Contains Paraben

53. 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
Joanna Lukawska, et al. Current Allergy & Clinical Immunology, 2009 Vol 22, No. 3

54. 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