Risk of Systemic Toxicity With Topical Lidocaine/Prilocaine: A Review
September 2014 | Volume 13 | Issue 9 | Original Article | 1118 | Copyright © September 2014
Anh N. Tran MSa,b and John Y. Koo MDa
aJohn A. Burns School of Medicine, University of Hawaii, Honolulu, HI
bDepartment of Dermatology, Psoriasis and Skin Treatment Center, University of California, San Francisco, San Francisco, CA
The eutectic mixture of lidocaine and prilocaine (EMLA, APP Pharmaceuticals, LLC.) is an anesthetic cream frequently used by dermatologists.
Although side effects of EMLA are usually mild local skin reactions (ie, edema, pallor, erythema), more severe complications
can be encountered including methemoglobinemia, central nervous system toxicity, and cardiotoxicity. This article reviewed
the literature regarding risk of systemic toxicity associated with use of EMLA in the pediatric and adult population. All 12 clinical trials
evaluating the safety of EMLA in either the pediatric or adult population generally followed dosing and administration guidelines set
by the manufacturer and reported clinically insignificant plasma levels of methemoglobin, lidocaine, prilocaine, and their respective
metabolites. To date, nine pediatric cases and three adult cases of systemic toxicity associated with EMLA have been published.
Possible factors that contributed to the development of systemic toxicity include excessive amount of EMLA, large application area,
prolonged application time, diseased and/or inflamed skin (eg, vascular malformations, molluscum contagiosum, eczema, previously
abraded skin), age less than 3 months, prematurity, and concomitant use of a methemoglobin-inducing agent. Recommendations
are provided on how to safely use EMLA to minimize the risk of systemic toxicity. J Drugs Dermatol.
The eutectic mixture of local anesthetics (EMLA, APP
Pharmaceuticals, LLC.) is an anesthetic cream frequently
used by dermatologists. It is a mixture of two crystalline
powders (2.5% lidocaine and 2.5% prilocaine), which has a
melting point below room temperature and therefore exists as
a liquid oil. In this way, it is optimized for cutaneous application,
able to penetrate intact skin and provide topical anesthesia to
a depth of 5mm. After topical application under occlusion for
60-120 minutes, EMLA provides sufficient local anesthesia in
a variety of painful superficial procedures including superficial
surgery, laser surgery, epilation, cautery of condylomata, debridement
of leg ulcers, and venipuncture.1
Although side effects of EMLA are usually mild local skin reactions
(ie, edema, pallor, erythema), more severe complications
can be encountered including methemoglobinemia, central
nervous system (CNS) toxicity, and cardiotoxicity. The cardinal
sign in methemoglobinemia is a “brownish” cyanosis that is
not reversible with the administration of 100% oxygen, which
becomes apparent at methemoglobin (metHb) levels of 10-20%.
Headache, tinnitus, circumoral numbness, lightheadedness,
lethargy, weakness, confusion, and dyspnea can be noted at
higher levels. Levels above 50% can produce respiratory depression,
arrhythmias, convulsions, or coma, and those higher
than 70% are potentially lethal.2
In this article, the authors review the literature regarding risk of
systemic toxicity associated with use of EMLA in the pediatric
and adult population. Recommendations are provided on how
to safely use EMLA to minimize the risk of systemic toxicity.
Studies assessing risk for systemic toxicity following non-mucosal
topical application of EMLA were identified in PubMed’s
MEDLINE databases from August 1985 to March 2013 using
the key search terms: “lidocaine,” “prilocaine,” “EMLA,” “safety,”
“toxicity,” and “methemoglobinemia.” Search terms were
also used in combinations. Reference lists of relevant publications
were manually searched for additional relevant studies.
The search was limited to articles published in the English language.
Animal studies and studies involving multiple forms of
anesthesia were excluded.
12 studies (ie, five randomized controlled trials, one controlled trial
without randomization, five nonrandomized uncontrolled trials, and
one medical record review) evaluating the safety of EMLA and 12
case reports of EMLA-associated systemic toxicity were reviewed.
Safety Reported in Infants and Children
Frayling et al. studied use of EMLA in children ages 1-6 years
old and measured a small but significant increase in metHb
concentration up to 24 hours following a 2-hour application of
5g of EMLA to the arms in the treatment group that received
EMLA compared to the control group that did not receive the
cream.3 The peak metHb concentration observed (0.85% ±