Systemic exposure to lidocaine and tetracaine is low after an application of a lidocaine 7%–tetracaine 7% peel in adults

Authors



Lazarre Ogden, md University of Utah Health Science Center 30 North, 1900 East Department of Anesthesiology, 3c444 Salt Lake City, UT 84132
E-mail: lazarre.ogden@hsc.utah.edu

Abstract

Background  The lidocaine 7%–tetracaine 7% (LT) peel has been demonstrated to be useful for a variety of dermatologic applications, including cosmetic, laser, and vascular access procedures.

Aim  To measure and evaluate the detectable plasma levels and safety of lidocaine and tetracaine in adult volunteers after a single application of an LT peel, a novel method of topical anesthesia that does not require occlusion.

Methods  A randomized, factorial design study was used to evaluate the pharmacokinetic profile of lidocaine and tetracaine after a single application of the LT peel in adult volunteers (n = 36; mean age, 26.6 years). The LT peel was applied to the anterior surface of the left or right thigh of volunteers for 30, 60, or 90 min over a 50-, 100-, or 200-cm2 area. Venous blood samples were collected at 0, 30, 60, 90, 120, 150, 180, 210, 300, and 420 min after the initial application of the LT peel.

Results  At all time points, plasma concentrations of lidocaine and tetracaine were below the limits of quantification for the assay: 100 ng/mL and 5 ng/mL, respectively. Because of the lack of concentrations above the limit of quantification, it was not possible to determine the pharmacokinetic parameters, other than the maximum concentrations of < 100 ng/mL for lidocaine and < 5 ng/mL for tetracaine. A single application of the LT peel was well tolerated, and no study subject reported an adverse event.

Conclusions  A single application of LT peel to up to 200 cm2 of anterior thigh in adults with a duration of up to 90 min produces systemic levels of lidocaine and tetracaine that are of no clinical significance at all time points measured up to 420 min after the initial application.

Introduction

Recent studies have shown the frequent use of topical local anesthetics in current dermatologic practice.1–3 The numbing of cutaneous tissue with topical local anesthetics obviates the need for painful local anesthetic injections. It also simplifies interventions, such as intravenous catheter placement, and decreases the pain associated with cutaneous surgical and laser procedures. Dermatologic conditions amenable to noninvasive drug delivery systems are rapidly expanding, creating a need for more effective topical local anesthetics. These include skin biopsies, shave excisions, deep excisions, electrosurgical procedures, intralesional injections, collagen injections, and laser surgery.

One such new topical local anesthetic preparation, which does not require occlusion, is the lidocaine 7%–tetracaine 7% (LT) peel. The LT peel is composed of a eutectic mixture of lidocaine and tetracaine. The LT peel is applied as a cream and, when exposed to air, dries to form a flexible membrane that can be easily peeled off (Figs 1 and 2).

Figure 1.

Application of lidocaine 7%–tetracaine 7% (LT) peel

Figure 2.

Removal of lidocaine 7%–tetracaine 7% (LT) peel

In a study by Alster and Lupton,4 the LT peel was compared with a eutectic mixture of lidocaine and prilocaine (EMLA cream) on a 16-cm2 section of the cheek before cutaneous laser surgery. After a 30-min application, pain scores were significantly lower with the LT peel than with EMLA cream. The side-effects of LT peel were limited to mild transient erythema and skin blanching, similar to EMLA cream.

The systemic delivery of lidocaine and tetracaine following application of the LT peel remains untested, however. Systemic toxicity has been reported following the topical application of other local anesthetic preparations.5,6 Therefore, it is important to document the extent of systemic absorption following application of any new topical local anesthetic preparation. The objective of this study was to measure and evaluate the detectable levels of lidocaine and tetracaine in the plasma of adult volunteers after a single topical application of the LT peel, and to monitor the nature and frequency of adverse events associated with its administration.

Materials and Methods

The study incorporated an open-label, randomized, parallel-group design to evaluate the pharmacokinetic profile of tetracaine and lidocaine after a single application of LT peel in adult volunteers.

Subjects meeting the following criteria were eligible for inclusion in the study: (i) age between 18 and 70 years, any race, and either gender; (ii) no known allergies or sensitivities to lidocaine, tetracaine, or other local anesthetics; (iii) healthy, as determined by medical history and physical examination; (iv) adequate bilateral antecubital veins; and (v) signed, dated, written informed consent form. Subjects with any of the following criteria were excluded from study participation: (i) known sensitivity to any components of the test materials; (ii) damaged, denuded, or broken skin at the designated LT peel site; and (iii) pregnant or breastfeeding. Subjects were allowed to withdraw or be removed from the study at any time for the following reasons: (i) the occurrence of a serious adverse event related to the treatment; (ii) a desire by the subject to withdraw; (iii) a judgment by the investigator that study withdrawal was in the best interest of the subject; or (iv) failure to comply with the study requirements.

The study drug was the LT peel formulation composed of a 1 : 1 (w/w) eutectic mixture of 7% tetracaine base and 7% lidocaine base. Subjects who met the study entry criteria were randomized equally into one of nine treatment groups. The peel was applied to the skin on either the right or left anterior thigh on areas of 50, 100, or 200 cm2 for 30, 60, or 90 min. Twelve subjects each were randomized to the 30-, 60-, and 90-min application time groups. The peel was applied in a thin layer (approximately 2-mm thick) to the anterior surface of the subject's left or right thigh on the assigned surface area (50, 100, or 200 cm2). After the assigned treatment periods, the clinician removed the LT peel by grasping a free edge of the peel and pulling it away from the skin surface.

Plasma samples were collected from the antecubital vein at baseline (preapplication) at time zero, and at 30, 60, 90, 120, 150, 180, 210, 300, and 420 min after the initial application. The following pharmacokinetic parameters were calculated for each subject: maximum concentration (Cmax), time of maximum concentration (Tmax), and area under the plasma concentration vs. time curve from 0 to 7 h (AUC0–7).

The investigator examined the study drug application site for erythema, edema, and blanching immediately after its removal from the subject's skin. Erythema was graded into one of five categories: no erythema; very slight erythema; well-defined erythema; moderate to severe erythema; and severe erythema (beet redness) to slight eschar formation (injuries in depth). Edema formation was graded into one of five categories: no edema; very slight edema (barely perceptible); slight edema; moderate edema (raised approximately 1 mm); and severe edema (raised more than 1 mm and exceeding the area of exposure). Blanching was graded into one of five categories: no blanching; slight, diffuse blanching with indistinct outline; more intense blanching with half the treated site perimeter outlined; marked blanching with a distinct outline of the treated site; and extreme blanching with a distinct outline of the treated site. Moderate or severe cases of erythema and edema were recorded as adverse events. The frequency and severity of adverse events were documented. In addition, vital signs (heart rate, blood pressure, and respiratory rate) were measured at the blood sampling intervals.

The randomized groups were compared with regard to demographic and background variables using one-way analysis of variance, Kruskal–Wallis nonparametric analysis of variance, or chi-squared analysis. Pharmacokinetic parameters were compared using analysis of variance for a factorial design. Skin reactions were compared using Kruskal–Wallis nonparametric analysis of variance.

Results

All subjects (n = 36) who were enrolled completed the study. One subject received the 200-cm2 LT peel for 90 min instead of the randomly assigned 60-min application. For pharmacokinetic analysis, this subject was included in the 90-min, 200-cm2 group.

The demographic variables were comparable between the randomized groups. All but two subjects were Caucasian. Slightly more than 50% of the subjects were male. The mean age of the subjects was 26.6 years. Most subjects had Fitzpatrick skin type III or IV. There were no statistically significant differences between the treatment groups for any of the demographic variables.

The medical history findings were consistent with the classification of the subjects as healthy volunteers. The most frequently reported medical conditions were ear, nose, and throat conditions (47%), allergies (36%), and musculoskeletal conditions (31%). The physical examinations of the subjects were unremarkable. Of the 36 subjects enrolled, three had findings noted, including arthritis, facial acne, and allergy/sinusitis, and 12 were using concomitant medication on enrollment. The most common medications were for birth control (17%) and general health promotion (11%).

The systemic concentrations for both lidocaine and tetracaine in all the samples collected were below the lower limits of quantification (LLQ) for the assays (lidocaine, 100 ng/mL; tetracaine, 5 ng/mL). Because there were no concentrations above the LLQ for either LT peel component, it was not possible to determine the pharmacokinetic parameters other than Cmax < 100 ng/mL for lidocaine and Cmax < 5 ng/mL for tetracaine. Thus, the systemic exposures to both lidocaine and tetracaine were low after application of the LT peel for up to 90 min on areas of up to 200 cm2.

The LT peel was well tolerated by subjects in all treatment groups, with application times ranging from 30 to 90 min and surface areas ranging from 50 to 200 cm2; none of the subjects experienced an adverse event. There were no statistically significant differences in pretreatment vital signs between the treatment groups and no changes to vital signs that were noted as adverse events during the course of the study.

The incidence and severity of erythema formation (Table 1) at the treatment site immediately after removal of the LT peel increased significantly with a longer administration time (P = 0.042), but did not increase significantly with a larger application area (P = 0.212). There were no significant differences in post-treatment erythema according to administration time or application area at the 60- and 120-min evaluation times. At discharge, 23 subjects presented with very slight or well-defined erythema, but no significant differences were found according to administration time or application area. Post-treatment edema was not observed for any treatment combination.

Table 1.  Severity of erythema immediately after treatment with lidocaine 7%–tetracaine 7% (LT) peel*
Severity of erythema30 min, n (%)
(n = 12)
60 min, n (%)
(n = 11)
90 min, n (%)
(n = 13)
50 cm2, n (%)
(n = 12)
100 cm2, n (%)
(n = 12)
200 cm2, n (%)
(n = 12)
  • *

    P values were 0.042 for time and 0.212 for area using the Kruskal–Wallis nonparametric test.

None3 (25)3 (27)1 (8)2 (17)4 (33)1 (8)
Very slight8 (67)6 (55)5 (38)7 (58)6 (50)6 (50)
Well defined1 (8)2 (18)7 (54)3 (25)2 (17)5 (42)
Moderate to severe0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)
Severe erythema to slight eschar formation0 (0)0 (0)0 (0)0 (0)0 (0)0 (0)

One subject experienced marked blanching of the skin at the treatment site after study drug removal (Table 2). Another subject experienced more intense blanching 2 h after study drug removal. All other cases of blanching were considered to be slight. No significant differences in blanching were noted at the time of LT peel removal; however, at 2 h, the 200-cm2 area still showed blanching whereas the other areas did not (P = 0.013, Kruskal–Wallis nonparametric test).

Table 2.  Severity of blanching immediately after treatment with lidocaine 7%–tetracaine 7% (LT) peel*
Severity of blanching30 min, n (%)
(n = 12)
60 min, n (%)
(n = 11)
90 min, n (%)
(n = 13)
50 cm2, n (%)
(n = 12)
100 cm2, n (%)
(n = 12)
200 cm2, n (%)
(n = 12)
  • *

    P values were 0.113 for time and 0.162 for area using the Kruskal–Wallis nonparametric test.

None11 (92)6 (55)8 (62)10 (83)6 (50)9 (75)
Slight 1 (8)4 (36)5 (38) 2 (17)5 (42)3 (25)
More intense 0 (0)0 (0)0 (0) 0 (0)0 (0)0 (0)
Marked 0 (0)1 (9)0 (0) 0 (0)1 (8)0 (0)
Extreme 0 (0)0 (0)0 (0) 0 (0)0 (0)0 (0)

Discussion

Systemic toxicity has been reported following the topical application of other local anesthetic preparations.5,6 In general, increased systemic levels of topically applied local anesthetic preparations occur when the preparation is applied over very large surface areas, especially in children. Therefore, it is important to document the extent of systemic absorption following the application of any new topical local anesthetic preparation.

For all subjects, the levels of lidocaine and tetracaine in the systemic circulation were < 100 ng/mL and < 5 ng/mL, respectively. Thus, systemic exposure to both lidocaine and tetracaine was low, below the LLQ, after application of the LT peel in adults on areas up to 200 cm2 for up to 90 min.

As the lidocaine and tetracaine levels were all below the LLQ, we were unable to quantify increased systemic delivery with LT peel application over larger surface areas; however, it is important to note that it can reasonably be expected that systemic exposure to lidocaine and tetracaine in the LT peel (or any other topical local anesthetic preparation) will increase with application over larger surface areas, or following application over mucous membranes or broken skin.

In theory, an increased application time above 60–90 min should not be associated with increased systemic absorption of lidocaine or tetracaine following application of LT peel, because peel formation should be complete within 60–90 min after application. The completely dry peel should be very inefficient with regard to the transdermal flux of lidocaine and tetracaine; however, this potential advantage to this drug delivery preparation has not yet been confirmed.

The LT peel has been shown to be effective in previous investigations under conditions similar to those used in this study. Bryan and Alster7 showed that application of the LT peel to facial areas [7 mm, 10 mm, or 2 mm × 7 mm pulsed dye laser (PDL) spot size] before PDL to treat telangiectases or port-wine stains led to significant pain reduction compared with placebo. An application time of 20 or 30 min was as effective as 60 min in achieving anesthesia, as measured by mean patient pain ratings using the visual analog scale. In another study, treatment with the LT peel for 60 min also led to patients experiencing significantly less pain vs. placebo for the PDL treatment of lower extremity telangiectases (0.5–1.5 mm in diameter).8 A third study showed that, after a 30-min application of the LT peel to patients’ cheeks before nonablative laser treatment, the LT peel was found to provide safe and effective dermal anesthesia vs. placebo.9

A single 30-, 60-, or 90-min application of the LT peel to a surface area of 50, 100, or 200 cm2 was well tolerated in this study. None of the study subjects reported an adverse event. As expected with local anesthesia, most of the subjects had erythema at the treatment site, and some subjects experienced blanching. No subject experienced moderate or severe erythema, edema, or severe dermal reaction as a result of the LT peel. The ranges of application time (30–90 min) and surface area (50–200 cm2) are inclusive of treatment scenarios likely to be seen in clinical practice, and the safety results of the study are consistent with those expected with a local anesthetic. The pharmacokinetic and safety data obtained in this study demonstrate that a single application of LT peel to up to 200 cm2 of anterior thigh in adults, with a duration of up to 90 min, leads to low systemic levels, below the LLQ of lidocaine and tetracaine, i.e. of no clinical significance.

Acknowledgments

This work was supported by ZARS, Salt Lake City, UT and OrthoNeutrogena, Los Angeles, CA. Editorial support was provided by Accel Medical Education, New York, NY.

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