Risk of Systemic Toxicity With Topical Lidocaine/Prilocaine: A Review

September 2014 | Volume 13 | Issue 9 | Original Article | 1118 | Copyright © 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

Abstract

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. 2014;13(9):1118-1122.

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introduction

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.

METHODS

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.

RESULTS

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% ±

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