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

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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

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patients was needed to estimate mean serum lidocaine 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 comparison 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

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Figure 2. Median serum lidocaine concentrations according Figure 4. Peak serum lidocaine concentrations according to to sex. facial surface area.

was not (p = .37). Similarly, although analysis of variance testing is better used for parametric data, when applied to our data for multivariate analysis, only sex and ethnicity remained signiﬁcantly associated with serum lidocaine levels (p < .001 and p < .01 respectively), whereas facial surface area did not (p = .38). Therefore, despite facial surface area being positively correlated with peak serum lidocaine levels, it is likely that sex accounted for some of this difference in our study because men have larger facial surface area than women. The highest peak lidocaine level in our study (3.4 lg/mL) was seen in a male volunteer with a facial surface area of 388 cm2.

Figure 3. Median serum lidocaine concentrations according to ethnicity. PI, Pacific Islander. Eleven of 52 volunteers (21%) reported a symptom that has been associated with high blood concen- levels between African-Americans versus non- trations of lidocaine. These included dizziness African-Americans (p = .84) and between Hispanics (n = 2); drowsiness (n = 5); lightheadedness (n = 6); and non-Hispanics (p = .09) did not reach statistical numbness or tingling other than face, lips, or tongue significance. The 11 volunteers who reported an (n = 2); and back pain (n = 2). None complained Asian or Pacific Islander background described their of muscle twitching, ringing of the ears, blurred ethnicity as Filipino (n = 5), Pacific Islander n = 3), vision, or chest pain; likewise, none exhibited signs Indian or Pakistani (n = 2), and Korean (n = 1). of lidocaine toxicity (somnolence, respiratory depression, euphoria, nervousness, confusion, Although sex and ethnicity are independent from twitching, seizures, or loss of consciousness). each other, either could have an effect on facial Reported symptoms were transient, and all resolved surface area. Chi-square analysis showed that sex before the end of the study day. At the time of was associated with facial surface area (men, reported symptoms, only two of 11 volunteers had 331 cm2 vs women, 272 cm2, p < .01), but ethnicity serum lidocaine levels greater than 2 lg/mL (2.1

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and 2.3 lg/mL). There were no differences in peak Volunteers with dermatitis or hyperpigmentation lidocaine levels (p = .80) or peak MEGX levels were treated aggressively with topical steroids, (p = .56) between those who reported any hydroquinone, or both, and most dermatitis resolved symptoms and those who did not; this also held within 2–3 days. Hyperpigmentation resolved in true when comparing each symptom separately all affected individuals. Thirty-one percent of (data not shown). Age, sex, BMI, and facial volunteers reported acne in the 3 days after surface area were not associated with reporting the study (Figure 6d). symptoms. White volunteers were less likely to have symptoms than nonwhite volunteers (p = .02). Discussion African-American race was associated with having symptoms (p = .02), but the small numbers (3 Lidocaine toxicity can cause a range of adverse symptomatic of 5 total African-American effects, from localized topical reactions to seizures, volunteers) present a sample bias. There was no hypotension, and cardiovascular collapse. P450 difference in symptoms between Asian and isoenzymes metabolize lidocaine to two active non-Asian volunteers or between Hispanic and metabolites: MEGX and glycine xylidide (GX).7 non-Hispanic volunteers. CYP1A2 is the predominant P450 isoenzyme in N-demethylation of lidocaine at therapeutic and On follow-up, cutaneous side effects of the topical subtherapeutic concentrations (<5 lg/mL).8 anesthetic were frequent (Figure 5); 47 of 52 CYP3A4 is also relevant at much higher levels volunteers reported at least one cutaneous side effect (>8 lg/mL).8 MEGX is 80%–90% as potent as after the study. Redness lasting more than 24 hours lidocaine, and it is approximately as toxic as after removal of the anesthetic occurred most lidocaine.7 MEGX levels rise more slowly and take commonly. Many volunteers experienced flaking, longer to fully metabolize. GX is approximately 10% scaling, peeling, itching, or burning that began as potent as MEGX.7 Oni and colleagues examined within 24 hours of exposure to the anesthetic, serum lidocaine and MEGX levels in 25 subjects after suggesting an irritant contact dermatitis (Figure 6a). application of varying amounts of 4% lidocaine to Two study subjects had an immediate reaction noted the face with and without occlusion for 30–60 min- after removal of the anesthetic, with erythematous utes and found significant interindividual variability or hyperpigmented papules that eroded within a day in serum lidocaine levels that could not be attributed (Figure 6b). Hyperpigmentation (Figure 6c) was to dose or exposure time.9 Lidocaine and MEGX more common in nonwhites than whites (p = .05). levels were significantly greater with the use of occlusion. Similar variability has been previously described in the use of transmucosal and subdermal lidocaine.9

Hepatic metabolism is widely recognized as being the chief pathway for the breakdown of lidocaine, and although cutaneous metabolism has also been shown to play a role, much is still unknown about the metabolizing capacity of human skin.10 Previous studies have demonstrated enzymes including CYP450 that metabolize lidocaine in the skin but at a much slower rate than in the liver.9,11 Rolsted and colleagues examined the dermal metabolism of Figure 5. Cutaneous side effects in study follow-up. lidocaine and found that conversion to MEGX

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(A) (B)

Figure 6. Clinical photographs of cutaneous side effects, including scaling and erythema (A), erosion (B), postinflammatory hyperpigmentation (C), and acne (D). was observed after topical application10, but with statistically significantly higher serum lidocaine lev- the small sample size there was great variability in els was the subgroup of volunteers identifying as the extent of dermal metabolism. Janmohamed Asian or Pacific Islander. Men also had higher serum and colleagues described metabolic enzymes to lidocaine levels than women. Greater facial surface include CYP3A4 in the epidermis, sebaceous area in men than women could not entirely explain glands, and hair follicles, and noted that there is these differences, so there may be other differences interindividual variations in the level of expression between the sexes that affect lidocaine metabolism. of these genes.11 Greater facial surface area was associated with higher serum lidocaine levels in univariate analysis, The variability in lidocaine metabolism between but in multivariate analysis, only male sex and non- individuals is not well understood. A study of white ethnicity remained significant. Regardless, intravenously injected lidocaine showed no differ- serum levels are clearly related to the surface area to ences in pharmacokinetics between blacks, Cauca- which the anesthetic is applied, and greater surface sians, and Asians.12 Feely and colleagues found a area of anesthetic application correlates to higher difference in plasma protein binding and levels of detectable levels of the anesthetic in the blood. For alpha-1 acid glycoprotein between Chinese and Irish this reason, physicians using topical anesthetics are volunteers13 and suggested that lidocaine toxicity cautioned to limit the surface area to which they are may be related to free rather than bound lidocaine. applied.14 In our study, nonwhite volunteers had higher levels of serum lidocaine than white volunteers, suggesting Most reports of lidocaine toxicity result from possible variability in skin or hepatic metabolism mucosal or injected lidocaine, although topical based on race. The only racial subgroup that had lidocaine has been associated with two deaths.1

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These cases were unusual because large surface areas tetracaine in the topical anesthetic may also influence were covered with compounded topical lidocaine serum lidocaine levels. Some suggest that a combi- mixtures (10% lidocaine/10% tetracaine/0.5% nation of ester and amide may have a higher risk of phenylephrine in one and 6% lidocaine/6% tetra- toxicity than the combination of two amides such as caine in the other) and occluded for an unknown lidocaine and prilocaine. A study in rats showed no duration (at least several hours) without physician such synergy between lidocaine and tetracaine with supervision. Marra reported a patient with a history regard to central nervous system toxicity,20 but this of anxiety who complained of agitation, anxiety, does not directly address human metabolism. In palpitations, and nausea after 30 minutes of 30% summary, higher serum lidocaine levels were seen lidocaine gel applied to the face, but no serious with higher concentrations of topical lidocaine, effects were noted.15 Elsaie reported a patient who longer duration of exposure, larger surface area developed an arrhythmia and hypotension after covered, and occlusion.4,21 application of a eutectic mixture of local anesthetics (EMLA) cream16; the patient had methemoglobine- One limitation of our study is that the testing did not mia, which is better attributed to prilocaine (in the differentiate free from bound lidocaine or quantify case of EMLA) and benzocaine, when used in the alpha-1 acid glycoprotein in the sample. It has – anesthetic combinations, than to lidocaine.16 18 been hypothesized that each of these affects whether patients are symptomatic at low serum lidocaine Other studies of serum lidocaine levels after topical levels. Another limitation of our study was our application of lidocaine to intact skin have all shown recruitment of only eight of nine target obese subtherapeutic levels (<2 lg/mL), even when higher volunteers, as a result of recruiting in a military percentages of lidocaine than the FDA has approved facility and excluding patients with certain comor- were used. Oni and colleagues showed that, even after bid conditions. There may be additional effects in occlusion of 4% lidocaine on the face and neck for lidocaine metabolism that obese persons experience 60 minutes, mean serum lidocaine level was 0.28 lg/ that we cannot adequately analyze here. We also mL.9 Nestor applied 5% lidocaine to 600 cm2 on the decided to stop actively recruiting African-American legs under occlusion for 60 minutes and found serum volunteers after noting that the side effects of the lidocaine levels less than 0.5 lg/mL, the lower topical anesthetic included hyperpigmentation that detection limit of the test used.19 Carruthers and was worse in African-American volunteers than colleagues applied 15% lidocaine/5% prilocaine to other groups. Additionally, tetracaine concentra- the face or the face, neck, and chest of patients for 30 tions were not studied. Although tetracaine may to 60 minutes, and found mean serum lidocaine levels have a lower toxicity threshold than lidocaine, we of 0.122 lg/mL (face) and 0.272 lg/mL (face, neck, could find no reports of toxicity to tetracaine after and chest).1 The patient that Marra reported after exposure to intact skin. Therefore, we limited the 30% lidocaine applied to the face for 30 minutes had focus to serum lidocaine levels. Last, efficacy of the a serum lidocaine level of 1.5 lg/mL.15 In our study, compounded anesthetic was not studied. Many prior median peak serum lidocaine level was 1.15 lg/mL studies address efficacy of topical anesthetics,5,14,21 after 120 minutes of exposure to 23% lidocaine/7% and we know that this compound works well for our tetracaine on the face. The highest peak lidocaine level patients undergoing nonablative laser therapy. was 3.4 lg/mL, which is significantly higher than Because most dermatologists apply compounded reported in any other study of topical lidocaine so far. anesthetics for 30–60 minutes before procedures, it It stands to reason that the higher serum lidocaine would be interesting to research the optimal appli- levels in our study are due primarily to the higher cation time required to achieve sufficient anesthesia concentration of lidocaine in the compounded mix- for common painful skin procedures, but that was ture, as well as the 2-hour duration. The presence of not the focus of this study.

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Although patient selection and limited surface area compounding pharmacies. In 2006, the FDA sent and duration may mitigate the risk of toxic serum warning letters to five compounding pharmacies, lidocaine levels, the risk of mild cutaneous side including the two pharmacies that created the effects from topical anesthetics is significant. Bjerr- compounds used in the deaths related to topical ing and colleagues found that all of their volunteers cutaneous lidocaine exposure, warning that they developed erythema after 2 hours of EMLA appli- were in violation of the law because their topical cation.22 Tetracaine and lidocaine are associated anesthetics were “marketed for general distribution with erythema and pruritus,5 and the immediate rather than responding to the unique medical needs reaction to 23% lidocaine/7% tetracaine may be of individual patients.” severe enough to cause erosions.2 In our study, 90% of volunteers reported at least one cutaneous side Additionally, because compounded medications are effect in the 3 days after the study. Another limita- not studied vigorously in large clinical trials, physi- tion of our study is that subjects reported side effects cians may have concerns about compounded med- over the telephone, resulting in possible bias, ications that include guaranteeing the potency of although all of those that one of two principal products as ordered, consistency across various investigators (PEM or TRK) evaluated in person compounding pharmacies, sterility of product, and demonstrated clinical findings that correlated with lack of published data on side effects and safety their symptoms. Irritant contact dermatitis profiles. U.S. Pharmacopeial Convention standards was common after application of the compounded 795 and 797 provide guidelines for pharmaceutical anesthetic used in this study. It is not possible to compounding of nonsterile and sterile compounds, draw any conclusions about whether lidocaine, including the rules that regulate strength, quality, tetracaine, or another component of this compound and purity of compounded pharmaceuticals. They contributed to the contact dermatitis. Tetracaine must include between 90 and 110% of the labeled and other ester anesthetics are suspected to cause quantity of active ingredient, and the pharmacy more allergic reactions than amides,14 and tetracaine should maintain documentation from independent has been shown to cause erythema, itching, and analysis about their compounded products. When edema.5 A future study might compare the side using compounded anesthetics in clinical practice, effects of the isolated components. Furthermore, the dermatologists should take care to educate their duration of application in this study probably patients about possible risks because the FDA does contributed to irritant contact dermatitis. We stud- not approve monographs for patient education on ied 2 hours of application because there is little these compounds. Therefore, physicians providing additional anesthetic benefit after 2 hours,5 so we them to patients take on some liability regarding assumed that that would be the maximum duration their use. that would be used in outpatient dermatology offices. Most dermatologists apply topical anesthesia Conclusions for 30–60 minutes, so incidence of irritant contact dermatitis would probably be lower in practice than Our study’s aim was to evaluate serum lidocaine in our study. Application times should be limited to levels after 2 hours of application of 23% lidocaine/ decrease the risk of contact dermatitis from com- 7% tetracaine to the face. Mean peak serum pounded topical anesthetics. lidocaine level was 1.15 lg/mL. Factors associated with higher serum lidocaine levels included greater Compounded medications share a long history with facial surface area, male sex, and nonwhite race. dermatology. Although compounded medications are exempt from the 1997 Food and Drug Mod- We found higher levels of serum lidocaine in men ernization Act, the FDA keeps a watchful eye on than women and nonwhite volunteers than white

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volunteers. The cause of this variability based on sex position of the U.S. Government, the Department of and race is a subject for further study, but physicians Defense, or the Department of the Air Force. should be aware that men and nonwhite individuals may be at risk of higher serum lidocaine levels after References

application of this compounded anesthetic. Volun- 1. Carruthers JA, Carruthers JD, Poirier J, Oliff HS, et al. Safety of teers with larger facial surfaces area had higher serum lidocaine 15% and prilocaine 5% topical ointment used as local anesthesia for intense pulsed light treatment. Dermatol Surg lidocaine levels, so the surface area to which anes- 2010;36(7):1130–1137. thetics are applied is a risk factor for systemic 2. Vij A, Markus R. Immediate vesicular eruption caused by topical toxicity. Although we did not study it as a variable, 23% lidocaine 7% tetracaine ointment in a patient scheduled occlusion increases serum lidocaine levels; we rec- for laser therapy: a new adverse drug reaction. J Cosmet Dermatol 2011;10(4):307–310. ommend caution when occluding compounds with 3. Glaich AS, Rahman Z, Goldberg LH, Friedman PM. high concentrations of lidocaine. Patients should be Fractional resurfacing for the treatment of hypopigmented screened for medical history that can impair lidocaine scars: a pilot study. Dermatol Surg 2007;33(3):289–94, discussion 293–4. metabolism and potentially increase risk of lidocaine toxicity, including cardiovascular disease, liver 4. Glaich AS, Goldberg LH, Dai T, Friedman PM. Fractional photothermolysis for the treatment of telangiectatic matting: a disease, and concurrent use of CYP1A2 inhibitors. case report. J Cosmet Laser Ther 2007;9(2):101–103.

5. Leopold CS, Maibach HI. Percutaneous penetration of local A high percentage of volunteers experienced irritant anesthetic bases: pharmacodynamic measurements. J Invest Dermatol 1999;113(3):304–307. contact dermatitis. Further study could focus on the 6. US Food and Drug Administration. Drug development and drug individual components contributing to this, as well interactions: table of substrates, inhibitors, and inducers. as duration of application. Additionally, patients Available from: http://www.fda.gov/drugs/ developmentapprovalprocess/developmentresources/ should be warned that compounded anesthetics may druginteractionslabeling/ucm093664.htm Accessibility veriﬁed cause contact dermatitis resulting in postinﬂamma- June 14, 2012. tory hyperpigmentation, an independent risk from 7. Wang JS, Backman JT, Taavitsainen P, Neuvonen PJ, Kivisto KT. the procedure they are undergoing, and physicians Involvement of CYP1A2 and CYP3A4 in lidocaine N-deethylation and 3-hydroxylation in humans. Drug Metab should be prepared to manage this side effect. Dispos 2000;28(8):959–965.

8. Kenkel JM, Lipschitz AH, Shepherd G, Armstrong VM, et al. In summary, we recommend that the use of com- Pharmacokinetics and safety of lidocaine and monoethylglycinexylidide in liposuction: a microdialysis pounded 23% lidocaine/7% tetracaine ointment be study. Plast Reconstr Surg 2004;114(2):516–24, discussion limited to 400 cm2 surface area, less than 2 hours 525–6. duration, and application only under direct super- 9. Oni G, Brown S, Burrus C , Grant L, et al. Effect of 4% topical vision of a physician. lidocaine applied to the face on the serum levels of lidocaine and its metabolite, monoethylglycinexylidide. Aesthet Surg J 2010;30 (6):853–8. Acknowledgments We would like to thank 10. Rolsted K, Benfeldt E, Kissmeyer AM, Rist GM. Cutaneous in Dr. Kevin Grayson for his statistical analysis and vivo metabolism of topical lidocaine formulation in human skin. the staff of the David Grant Medical Center Skin Pharmacol Physiol 2009;22(3):124–7. Clinical Investigation Facility for their support. 11. Janmohamed A, Dolphin CT, Phillips IR, Shephard EA. Quantiﬁcation and cellular localization of expression in human skin of genes encoding ﬂavin-containing Copyright: All authors were full-time federal monooxygenases and cytochromes P450. Biochem Pharmacol employees at the time this work was conducted and 2001;62(6):777–86. prepared for publication. Therefore, it is not pro- 12. Goldberg MJ, Spector R, Johnson GF. Racial background and lidocaine pharmacokinetics. J Clin Pharmacol 1982;22(8–9): tected by the Copyright Act, and copyright owner- 391–4.

ship cannot be transferred. It is in the public domain. 13. Feely J, Grimm T. A comparison of drug protein binding and The views expressed in this material are those of the alpha 1-acid glycoprotein concentration in Chinese and – authors, and do not reﬂect the ofﬁcial policy or Caucasians. Br J Clin Pharmacol 1991;31(5):551 2.

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14. Friedman PM, Mafong EA, Friedman ES, Geronemus RG. 20. Spiegel DA, Dexter F, Warner DS, Baker MT, Todd MM. Central Topical anesthetics update: EMLA and beyond. Dermatol Surg nervous system toxicity of local anesthetic mixtures in the rat. 2011;27:1019–26. Anesth Analg 1992;75:922–8.

15. Marra DE, Yip D, Fincher EF, Moy RL. Systemic toxicity from 21. Sobanko JF, Miller CJ, Alster TS. Topical anesthetics for topically applied lidocaine in conjunction with fractional dermatologic procedures: a review. Dermatol Surg 2012;38 photothermolysis. Arch Dermatol 2006;142(8):1024–26. (5):709–21.

16. Elsaie ML. Cardiovascular collapse developing after topical 22. Bjerring P, Andersen PH, Arendt-Nielsen L. Vascular response of anesthesia. Dermatology 2007;214(2):194. human skin after analgesia with EMLA cream. Br J Anaesth 1989;63(6):655–60. 17. Jakobson B, Nilsson A. Methemoglobinemia associated with a prilocaine-lidocaine cream and trimetoprim-sulphamethoxazole. A case report. Acta Anaesthesiol Scand 1985;29(4):453–5. 18. Martin DG, Watson CE, Gold MB, Woodard CL Jr, Baskin SI. Address correspondence and reprint requests to: Patrick E. Topical anesthetic-induced methemoglobinemia and McCleskey, MD, FAAD, Department of Dermatology, sulfhemoglobinemia in macaques: a comparison of benzocaine David Grant Medical Center, 101 Bodin Circle, and lidocaine. J Appl Toxicol 1995;15(3):153–8. Travis Air Force Base, CA 94535, or e-mail: 19. Nestor MS. Safety of occluded 4% liposomal lidocaine cream. [email protected] J Drugs Dermatol 2006;5(7):618–20.

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