Serum Lidocaine Levels and Cutaneous Side Effects After Application of 23% Lidocaine 7% Tetracaine Ointment to the Face † PATRICK E. MCCLESKEY, MD, FAAD,* SEEMA M. PATEL,* KATHERINE A. MANSALIS, MD, FAAFP, ‡ AMANDA L. ELAM, MD, AND TINA R. KINSLEY, MD, FAAD* BACKGROUND Few published studies have analyzed serum lidocaine levels and individual patient characteristics affecting metabolism after application of compounded topical anesthetics. OBJECTIVE To measure serum lidocaine levels during and cutaneous side effects after standardized application of 23% lidocaine/7% tetracaine compounded anesthetic to the face of healthy volunteers. METHODS AND MATERIALS Fifty-two volunteers were enrolled, and compounded 23% lidocaine/7% tetracaine ointment was applied to their faces for 2 hours. Lidocaine levels were determined every 30 minutes during application and for 2 hours after removal. Follow-up telephone calls 3 days later assessed cutaneous side effects. RESULTS Median peak lidocaine level was 1.15 lg/mL, and the highest peak lidocaine level in an individual was 3.4 lg/mL. Higher serum lidocaine levels were found in men (p < .01), nonwhite volunteers (p = .02), and those with larger facial surface area (p = .04). Age and body mass index did not affect lidocaine levels. Irritant contact dermatitis was common, resulting in hyperpigmentation in some patients. CONCLUSION Facial surface area, male sex, and nonwhite ethnicity were associated with higher serum lidocaine levels after topical application of lidocaine. Compounded anesthetics containing lidocaine should be used with caution under the direct supervision of a physician. The authors have indicated no significant interest with commercial supporters. ermatologists commonly use topical anesthet- been published about the safety and side effects of D ics to reduce the pain associated with laser this compounded anesthetic. procedures,1,2 but mixtures such as 4% lidocaine cream or 2.5% lidocaine/2.5% prilocaine eutectic This investigator-initiated study analyzed peak mixture (EMLA) that the Food and Drug Adminis- serum lidocaine and its primary metabolite (mono- tration (FDA) has approved provide inadequate ethylglycinexylidide (MEGX)) levels after applica- topical anesthesia for some patients. Some physi- tion of 23% lidocaine 7% tetracaine ointment to the cians obtain compounded formulations with higher face for 2 hours. Maximum anesthetic effects are concentrations of topical anesthetics to reduce pain achieved within 2 hours, so there is little added in these patients. Of the many products used, 23% benefit with longer exposure times.5 The secondary lidocaine/7% tetracaine in an ointment base has objective was to compare maximum serum lidocaine become a common formulation for preprocedure levels based on five demographic factors: sex, age, – anesthesia in laser therapy,2 4 but few data have ethnicity, body mass index (BMI), and facial surface † *Department of Dermatology, David Grant Medical Center, Travis Air Force Base, Fairfield, California; Department of ‡ Family Medicine, David Grant Medical Center, Travis Air Force Base, Fairfield, California; Wilford Hall Medical Center, Lackland Air Force Base, San Antonio, Texas © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2013;39:82–91 DOI: 10.1111/dsu.12064 82 M CCLESKEY ET AL area. A third objective was to evaluate cutaneous (IV) catheter was inserted into the antecubital fossa side effects 3 days after application of the or dorsum of the hand. Baseline hemoglobin, anesthetic mixture. hematocrit, lidocaine levels and vital signs were measured. Materials and Methods The topical anesthetic mixture used was a com- This study was performed under U.S. Air Force pounded 23% lidocaine/7% tetracaine mixture in a Surgeon General–approved Clinical Investigation nonaqueous medium called Lipothene133 (Central FWH20110057H. The voluntary, fully informed Avenue Pharmacy, Pacific Grove, CA); the Lipoth- consent of the subjects used in this research was ene133 delivery vehicle contains mineral oil and a obtained as required by 32 CFR 219 and AFI 40–402, small amount of butylated hydroxytoluene. The com- Protection of Human Subjects in Biomedical and pounding pharmacy provided a copy of an indepen- Behavioral Research, in compliance with the ethical dent analysis confirming the compound’s sterility and guidelines of the 1975 Declaration of Helsinki. potency. Before it was applied, the mixture was stirred for 60 seconds to ensure uniformity, and 12 g was We recruited healthy volunteers aged 20–59 drawn into a syringe. Experienced dermatology med- eligible for care at our military treatment facility. ical assistants then spread 12 g of the compounded Exclusion criteria included history of heart disease, anesthetic in a uniform layer over the face (from peripheral vascular disease, stroke, cirrhosis or preauricular sulcus to preauricular sulcus and from other liver disease, seizure disorder, coagulopathies, jawline to hairline or superior border of frontalis use of CYP1A2 inhibitors6 (including fluoroquinol- movement) except the orbital rim, nares, and mouth. ones [ciprofloxacin, enoxacin], fluvoxamine, antiarrhythmics [mexiletine, verapamil, ticlopidine], Blood was drawn every 30 minutes, and patients cimetidine, and propranolol), conditions that may were assessed for symptoms and signs of lidocaine mimic symptoms of lidocaine toxicity (pregnancy toxicity. A small amount of blood (5 mL) was and anemia), and known allergy to lidocaine or drawn through the line before taking each sample, tetracaine. After informed consent was obtained, to avoid sampling error from dilution. After the age, ethnicity, and sex were recorded. Height and blood was drawn at each interval, the line was weight were measured to determine BMI. Facial flushed with 10 mL of saline. After 2 hours, the surface area was measured using the Fraxel re:store topical anesthetic was removed with soap and water. laser system (Solta Medical, Inc., Hayward, CA), Blood samples continued to be drawn and signs of defining width as the distance from the philtrum to toxicity assessed at 30-minute intervals for another the preauricular sulcus anterior to the tragus and 2 hours. Three days later, participants were length as the distance from the hairline (or superior contacted by telephone to ask about cutaneous border of frontalis movement) to the mandible in a reactions after the study. vertical line intersecting the lateral aspect of the right orbital rim. Three measurements of facial Serum samples were centrifuged, frozen, and surface area were taken for each patient, and the shipped according to the procedures recommended average was used. To maximize precision, one by the processing laboratory (NMS Labs, Willow investigator (TRK) measured height and weight for Grove, PA). Gas chromatography was performed on all study volunteers, and another (PEM) measured each sample. The lower limit of detection for total facial surface area. serum lidocaine and MEGX was 0.1 lg/mL. Volunteers washed their faces with soap and water, A power analysis performed before the initiation and for ease of multiple blood draws, an intravenous of the study determined that a minimum of 17 39:1:JANUARY 2013 83 SERUM LEVELS AND SIDE EFFECTS OF 23% LIDOCAINE 7% TETRACAINE OINTMENT patients was needed to estimate mean serum lido- caine level within 0.1 lg/mL, with an alpha of 0.05 and beta of 0.8. To conduct univariate analysis of each subgroup to detect a difference of 0.3 lg/mL, nine members of each demographic subgroup were needed. To conduct multivariate analysis, at least 10 subjects were needed for each of five demographic characteristics studied, for a total of at least 50 volunteers. Statistical analysis was performed using STATA data analysis and statistical software (STATA Corp., College Station, TX). Serum lidocaine and MEGX Figure 1. Median serum lidocaine and monoethylglycinexyli- levels were tested for conformity to a normal dide (MEGX) concentrations. distribution. If they were not normal, medians rather than means would be presented, and com- parison of medians would be made using nonpara- TABLE 1. Demographic Characteristics and Median metric tests. Categorical comparisons were made Peak Serum Lidocaine Levels using a chi-square test. Median Peak Serum Results Subjects, Lidocaine, Variable n lg/mL p-Value Fifty-two volunteers participated in the study. Age Lidocaine and MEGX levels did not follow a normal 20–29 16 1.0 .81 distribution (Shapiro-Wilk test p = .05). Thus, 30–39 17 1.3 data are presented and analyzed using medians 40–49 9 1.1 50–59 10 1.1 instead of means, and nonparametric tests were Sex employed. The median peak lidocaine level was Male 20 1.6 <.01 1.15 lg/mL for all volunteers; the median peak Female 32 0.8 MEGX level was 0.14 lg/mL. Peak lidocaine con- Ethnicity White 26 0.8 .02 centrations occurred after 120 minutes of exposure African-American 5 1.3 to the topical anesthetic, and lidocaine levels Hispanic 10 1.6 declined after removal of the topical anesthetic. Asian or Pacific 11 1.6 MEGX concentrations were low but rose steadily, Islander Body mass index as expected (Figure 1). Normal 24 1.1 .60 Overweight 20 1.3 Volunteer demographics and median peak serum Obese 8 1.4 Facial surface area, cm2 lidocaine levels are shown in Table 1. There was no <300 29 0.9 .04 difference in median peak serum lidocaine levels 300—349 17 1.3 based on age or BMI using the Mann-Whitney 350 6 1.8 U-test. Male sex (Figure 2), non-white ethnicity (Figure 3), and greater facial surface area (Figure 4) were significantly associated with higher peak serum 0.8 lg/mL p < .01), and Asians had higher levels lidocaine levels. Non-whites had higher median peak than non-Asians (1.6 lg/mL vs 1.1 lg/mL, p = .04). serum lidocaine levels than whites (1.6 lg/mL vs The differences in median peak serum lidocaine 84 DERMATOLOGIC SURGERY M CCLESKEY ET AL Figure 2. Median serum lidocaine concentrations according Figure 4.