Q:

9/5/2013
I have a patient that needs to have a procedure and is unable to get a local anesthetic. Two months ago she received a Kenalog injection in her hand with a local anesthetic which was Lidocaine. Within 30 minutes she developed generalized erythema which appears to have been urticarial. Her symptoms were self-limited. She has since tolerated a steroid injection of a different class. She was tested to 7 different local anesthetics and reacted on intradermal testing to all of them. I am waiting for the records but she told me that 3 were of one class and 4 of the other class of anesthetics. She may have had a subtle reaction to lidocaine at the dentists in the year before. That was very mild and she is not sure if it was a true reaction. And no one will touch her now.

I was wondering if you have ever heard of anyone not being to tolerate any type of local anesthetic. I know it would be exceptionally rare. She has no underlying psychological problems. My inclination would be to take the weakest reacting anesthetic of the other class and challenge her in the hospital. I forgot to mention that she reacted to multiple classes of steroids on intradermal testing as well. She has a history of RA. So we don't know if this was from the steroid or the local anesthetic. She does not remember the last time she had a local anesthetic without any question of a reaction.

I wanted to see what your advice would be. And would San Diego have the most expertise in this area.

A:

Thank you for your inquiry.

Before beginning a specific response, it might be helpful to review some of the underlying principles related to the approach to a patient who presents with an adverse event occurring during the administration of a local anesthetic.

Pertinent to this, I have copied for you below several references dealing with this issue. Of particular note is a reference which is available to you free of charge online by Dr. Daniel Becker. It is entitled “Essentials of local anesthetic pharmacology.” A link to this article is copied below. It contains an excellent discussion of “possible allergic reactions to local anesthetics.” In addition, Dr. Michael Schatz, who I am also going to contact for his help in regards to your inquiry, has published a number of excellent reviews of this topic over the years, and I have copied the abstracts and/or references to two such reviews; one of which appeared in Immunology and Allergy Clinics (reference only coped below), and one of which appeared in The Journal of Allergy and Clinical Immunology (reference and abstract copied below).

These reviews not only discuss the principles involved in approaching the patient, but also describe the protocol for testing and incremental challenge.

There are several concepts that can be extracted from these reviews as follows:
1. It is extremely rare for a reaction to local anesthetic to actually be IgE-mediated and anaphylactic in nature.
2. The concept that IgE-mediated reactions did occur to local anesthetics was based upon early reports of reactions to ester base anesthetics which can react, because of their para-aminobenzoic acid structure, with large molecules thus forming a hapten-carrier complex. This para-aminobenzoic acid structure, connected to a large carrier molecule, is known to be immunogenic based upon studies of contact dermatitis which have documented that delayed hypersensitivity can be induced by this type of local anesthetic. However, amide anesthetics, which consist of those that are most commonly used (lidocaine, mepivacaine, prilocaine, et cetera), are far less chemically reactive in terms of binding with a carrier (see Berkun Y, et al., Phillips JF, et al., and Gal, et al. copied below) and thus less immunogenic. Therefore, in the vast majority of instances, the skin testing portion of the protocol employed for graded challenge to local anesthetics is actually probably unnecessary. However, rarely, IgE-mediated events have been reported (see two abstracts copied below - Stahl, et al. and Yamaguchi, et al.).

It is because of these rare reports that the approach to your patient becomes more complex and unfortunately more guarded.

Based upon the above literature and my personal experience with such patients over the last four decades, I am going to reply to your inquiry, but I am also going to contact, as noted above, Dr. Michael Schatz, who is a well-recognized authority in this area, as well as Dr. Mark Stahl, who is the lead author of an abstract mentioned above which presented, in my opinion, the most authoritative evidence that local anesthetics can produce IgE-mediated events.

I think that your suggested approach of skin testing and graded challenge is valid, and indicated in your patient if further administration of the local anesthetics will be needed. And I presume they will be based upon your inquiry.

First of all, in such procedures, I would employ as pure an anesthetic preparation as possible for testing and challenge. Several amide local anesthetics including lidocaine, mepivacaine, and prilocaine, are available in multidose preparations that do not contain a vasopressor. I would use these both for testing and challenge. Other authors have suggested using these for testing only, and that would certainly be acceptable, but my personal preference would be, should your patient require a local anesthetic, that it be as free as possible of all extraneous excipients.

In the past we have done all testing and graded challenge procedures in an outpatient setting. A hospital setting is certainly appropriate, but I first would suggest testing to a preservative-free preparation of mepivacaine or prilocaine since these two are the drugs of choice in such situations according to Becker, et al., and since her previous reaction occurred with the administration of lidocaine. If the tests were negative to the “vasopressor-free” preparations in-office, I would personally feel comfortable in administering the graded challenge in-office as well. If not - that is, if the tests were positive, you would then perhaps have to consider your procedure a desensitization as well as a graded challenge procedure. In this case, one might consider starting with a concentration a log less than that commonly employed for graded challenges.

I personally have no experience with any patient who has demonstrated a positive skin test during the multiple evaluations we have done over the last four decades. However, perhaps Drs. Stahl or Schatz has had an opportunity to administer a local anesthetic to a patient with a positive skin test, and if so, I am sure they would be willing to share their experience(s) with us.

Thank you again for your inquiry, and please accept this initial response as a prologue, awaiting the thoughts of Drs. Stahl and Schatz.

Anesth Prog. 2006 Fall; 53(3): 98–109.
doi: 10.2344/0003-3006(2006)53[98:EOLAP]2.0.CO;2
PMCID: PMC1693664
Daniel E Becker
Essentials of Local Anesthetic Pharmacology

Schatz M. Adverse reactions to local anesthetics. Immunol Allergy Clin North Am. 1992;12:585–609
J Allergy Clin Immunol. 1984 Oct;74(4 Pt 2):606-16.
Skin testing and incremental challenge in the evaluation of adverse reactions to local anesthetics.
Schatz M.
Abstract
True allergic reactions to local anesthetics (LAs) probably make up no more than 1% of all adverse LA reactions. A diagnosis of true potential allergic reactivity is made difficult because (1) the history of the prior reaction may be vague or equivocal and (2) the lack of identification of the actual specific LA hapten-carrier complex limits the potential usefulness of immunologic tests. Nonetheless, since avoidance of LAs may be associated with substantial increased pain or increased risk and because true allergic reactions are rare, investigators and clinicians have used skin testing, incremental challenge, or both as a means of identifying a safe LA for a patient with a history of a prior adverse reaction. Review of the literature dealing with LA skin testing and incremental challenge suggests the following: (1) Skin testing with LAs may correlate with a history of an adverse reaction but may produce systemic adverse reactions, especially with undiluted drug. (2) Although false positive skin tests have been reported, most skin-tested patients who subsequently tolerate an LA have a negative skin test to that drug, and false negative skin tests have not been clearly documented. (3) Incremental challenge beginning with diluted LA is a safe and effective means of identifying a drug that a patient with a history of a prior adverse reaction can tolerate. (4) Current concepts of non-cross-reacting LA groups may be useful in the choice of a drug for use in skin testing and incremental challenge. (5) Preservatives in LAs may account for some but probably not the majority of adverse reactions to LAs. On the basis of this literature review, a practical protocol including dilutional skin testing and incremental challenge is presented for use in evaluating patients with prior adverse reactions to LAs.

Ann Allergy Asthma Immunol. 2003 Oct;91(4):342-5.
Evaluation of adverse reactions to local anesthetics: experience with 236 patients.
Berkun Y, Ben-Zvi A, Levy Y, Galili D, Shalit M.
Source
Department of Pediatrics, Bikur Cholim Hospital, Jerusalem, Israel.
Abstract
Background: Adverse reactions to local anesthetics (LAs) are frequently reported. Although most of these reactions are not immune mediated, many patients are referred to allergy clinics and undergo extensive evaluation.
Objective: To determine the prevalence of true LA allergy among the patients referred for suspected hypersensitivity and to evaluate the usefulness of the currently used evaluation protocol.
Methods: A total of 236 patients referred to our allergy clinic for investigation of LA hypersensitivity were included in this study. The evaluation protocol was composed of skin prick and intradermal tests, followed by subcutaneous challenge with unrelated LA preparations that contained preservatives.
Results: Skin prick and intradermal test results were negative for all subjects. No objective adverse reactions were observed during the challenge in all but 1 patient, who developed local erythema at the site of injection and later underwent an uneventful challenge with a different LA.
Conclusions: Allergic reactions were not reproduced during testing and challenge with LA preparations that contained preservatives or preservatives with adrenaline in our large group of patients with suspected LA allergy. Since both prick and intradermal skin test results were negative in all the patients and did not provide us with useful information, we propose to modify the standard protocol by omitting intradermal tests and shortening the challenge. We also suggest that the whole procedure be performed with LAs that contain preservatives, which are usually the preferred preparations widely used in daily practice.

Am J Med Sci. 2007 Sep; 334(3):190-6.
Approach to patients with suspected hypersensitivity to local anesthetics.
Phillips JF, Yates AB, Deshazo RD.
Source
Department of Pediatrics, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
Abstract
Adverse reactions to local anesthetics are relatively common, but true IgE-mediated hypersensitivity is extremely rare. Fortunately, the vast majority of adverse reactions occur via nonimmunologic means, but considerable confusion still exists among providers. We conducted a review of the literature to determine if earlier estimates of IgE-mediated allergy are consistent with current reports and whether current management strategies are consistent with these findings. We identified several confounding variables involved in the evaluation, including the roles of preservatives/additives, epinephrine, latex, and inadequate testing procedures. These problems may cause significant diagnostic challenges for clinicians. It is in fact much more likely that there is an alternate diagnosis, and in many cases clinicians can begin the evaluation in the office. When local anesthetic allergy is still suspected, the patient should be referred to an allergist for testing to determine if the suspected culprit drug can be safely used, or, if necessary, identify a suitable alternative.

Gal et al: Adverse reactions to local anesthetics: Analysis of 197 cases. Journal of Allergy and Clinical Immunology Vol. 97, Issue 4, Pages 933-937
Background: Adverse drug reactions to local anesthetics are frequently reported. However, little is known about the underlying mechanisms. Therefore we investigated 177 patients with a history of 197 events after application of these drugs.
Methods: The diagnostic approach included prick and intracutaneous tests, provocative challenge tests with causative and unrelated local anesthetics, and in selected cases, radioimmunoassays to detect specific IgE. In addition, tests were performed with preservatives, including sodium metabisulfite and parahydroxybenzoic acid ester.
Results: Results of prick and intracutaneous tests with local anesthetics were all negative. Only three patients reacted after subcutaneous challenge with the causative drug (local anesthetics of the amide type). Although one patient showed a delayed-type response to mepivacaine, two patients had immediate-type reactions to articaine and lidocaine. However, in both cases no specific IgE could be detected. In five patients with positive skin test reactions to preservatives, challenge test results remained negative.
Conclusions: Two immediate-type reactions were not IgE-mediated. In only one of 197 reported adverse reactions were we able to prove delayed-type allergic response. Therefore true allergic reactions caused by local anesthetics are extremely rare.

Stahl MC et al: IgE-Mediated Reactions to Local Anesthetics: a Case Report.The Journal of Allergy and Clinical Immunology
Volume 127, Issue 2, Supplement , Page AB193, February 2011
Rationale: IgE-mediated reactions to local anesthetics are rare. Here we report a 44 year-old female who demonstrated in vivo and in vitro IgE-mediated reactions to both amide and ester anesthetics.
Methods: Percutaneous and intradermal skin testing followed by a graded injection challenge was performed. ELISA was performed on the patient's serum with local anesthetics from the amide and ester classes, latex, metabisulfite, and methylparabens.
Results: Intradermal skin testing was positive to a 1:10 dilution of 1% tetracaine. A graded injection challenge to both 1% lidocaine and 4% articaine was positive with generalized pruritis and hives. The patient demonstrated positive ELISA results for lidocaine, articaine, mepivacaine, bupivacaine, procaine, and tetracaine; metabisulfite and methylparabens were negative on ELISA. A basophil histamine release assay for lidocaine was negative. Latex skin testing, serum latex IgE, and a latex glove use test were negative.
Conclusions: This is the first case report to demonstrate in vitro IgE binding within a single patient to both amide and ester anesthetics. Although the patient had a positive challenge to local anesthetics, demonstration of IgE varied between different methodologies.

Arerugi. 2009 Jun;58(6):657-64.
[Clinical examination of challenge test to local anesthetics].
[Article in Japanese]
Yamaguchi T, Nakagome K, Udagawa K, Takaku Y, Sato N, Soma T, Hagiwara K, Kanazawa M, Nagata M.
Source
Department of Respiratory Medicine, Saitama Medical University.
Abstract
Background: Although adverse reactions to local anesthetics are often diagnosed as local anesthetic allergy, there is evidence that most of these reactions occur via non-allergic mechanisms.
Methods: To evaluate allergic reactions to local anesthetics, challenge tests were performed in 20 patients who had a history of adverse events to local anesthetics for whom dental treatment was planned. The diagnostic protocol of this challenge test consisted of skin prick and intracutaneous tests, as well as subsequent incremental subcutaneous challenge tests with local anesthetics such as lidocaine.
Results: 17 patients (85%) showed no immediate allergic response to lidocaine, which could then be used for dental treatment. Three patients (15%) reacted positively to lidocaine: one had local erythema at the site of the skin prick, and two reacted to subcutaneous challenge.
Conclusion: The proportion of immediate-type reactions to local anesthetics is small but not rare in patients suspected of having local anesthetic allergy. This result suggests that the diagnostic approach to confirm allergy to local anesthetics is clinically important and requires further study in a larger population.

Sincerely,
Phil Lieberman, M.D.

We have now heard from both of our consultants, and Dr. Schatz has sent an article regarding the possible role of methylparabens in producing false-positive skin tests to local anesthetics. I was unaware of this article, and found it interesting. Therefore I am forwarding it to you by attachment.

In summary, I think that my initial response to you remains my suggested approach to your patient. I do agree with going ahead and performing the challenge.

Once again, thank you for your inquiry and we hope our response has been of help to you.

Dr. Stahl's response is as follows:
I read through your response and it certainly is very thorough. Testing techniques vary widely but it seems like the patient had positive responses on testing, perhaps on SPT/ID but if there is any question regarding some of the excipients in the various mixes, consideration of an IM challenge could be performed.
 
I have included the actual finished case report as it appeared in Annals for your assistance. Our approach to this patient was rather haphazard and in parallel; she initially tested positive to a few various local anesthetics and we attempted to utilize ELISA to determine what she could tolerate, only to discover cross-reactivity amongst all the LAs. In the end, we recommended avoidance and for future procedures consideration of topical Benadryl (some numbing effects) or inhalant anesthesia.
 

Immediate Hypersensitivity to Methylparaben Causing False-Positive Results of Local Anesthetic Skin Testing or Provocative Dose Testing
 

I hope that helps. Thanks for the opportunity,

Mark Stahl

AAAAI - American Academy of Allergy Asthma & Immunology