Two-Minute Skin Anesthesia Through Ultrasound Pretreatment and Iontophoretic Delivery of a Topical Anesthetic: A Feasibility Study

Blackwell Publishing IncMalden, USAPMEPain Medicine1526-23752007 Blackwell Publishing Ltd? 2007915559Original Article Two-Minute Topical AnesthesiaSpierings et al. PAIN MEDICINE Volume 9 Number 1 2008 Two-Minute Skin Anesthesia Through Ultrasound Pretreatment and Iontophoretic Delivery of a Topical Anesthetic: A Feasibility Study Egilius L. H. Spierings, MD, PhD,* Julie A. Brevard, MPH, and Nathaniel P. Katz, MD, MS *MedVadis Research Corporation, Wellesley Hills, Massachusetts, USA; Inflexxion Incorporated, Newton, Massachusetts, USA ABSTRACT ABSTRACT Background and Objectives. The pain associated with percutaneous procedures is a significant source of distress in clinical practice, especially in children. Topical anesthetics require 30 60 minutes to provide skin anesthesia; with, they minimally require 10 minutes, and with ultrasound pretreatment, 5 minutes. In this study, we assessed the feasibility of providing skin anesthesia to needle prick with the combination of ultrasound pretreatment and 2-minute low-voltage (1 ma). We compared it with sham-ultrasound pretreatment and with standard, 10-minute high-voltage (4 ma). Methods. This is a single-blind, randomized, controlled, crossover study in healthy volunteers, specifically for the purpose of the study subjected to standardized needle prick. They rated the absolute pain associated with the needle prick on a 10-cm visual analog scale, with 0 being no pain and 10 being extremely painful. Results. Of the 31 subjects who consented to the study, 30 were randomized and completed the study. The mean duration of the ultrasound pretreatment was 21.4 seconds (range: 6 85). The absolute pain scores for the ultrasound plus 2-minute low-voltage and the standard, 10-minute high-voltage were not statistically significantly different (0.9 ± 0.31 vs 0.46 ± 0.20; P = 0.49). However, they were statistically significantly different from the sham-ultrasound plus 2-minute low-voltage pain score (2.6 ± 0.55) (P = 0.0001 and 0.0012, respectively). Conclusions. Ultrasound pretreatment plus 2-minute low-voltage provides better skin anesthesia than sham-ultrasound plus 2-minute low-voltage, and similar to standard, 10-minute high-voltage. Key Words. Topical Anesthesia; Needle Pain; Lidocaine; Ultrasound; ; SonoPrep Introduction P ercutaneous procedures, such as intravenous cannulation, lumbar puncture, bone-marrow aspiration, and abscess drainage, are common in clinical practice. The pain associated with them is a significant source of distress, especially in children [1,2], and negatively affects procedural success rate [3]. Topical anesthetics have been developed, such as EMLA (Astra Zeneca Phar- Reprint requests to: Egilius L. H. Spierings, MD, PhD, 25 Walnut Street, Suite 400, Wellesley Hills, MA 02481-2106, USA. Tel: 781-431-1113; Fax: 781-431-1086; E- mail: spierings@medvadis.com. maceuticals, Wilmington, DE) (a eutectic mixture of 2.5% lidocaine and 2.5% prilocaine) and LMX4 (Ferndale Laboratories Incorported, Ferndale, MI) (liposomal 4% lidocaine). However, these topical anesthetics require 30 60 minutes to provide skin anesthesia [4,5], precluding their widespread use in practice. Skin anesthesia by application of a topical anesthetic can be expedited through ; however, this still requires a minimum of 10 minutes at relatively high voltage (4 ma) [6 8]. Ultrasound can also be used to facilitate the transdermal delivery of medications through permeation of the most superficial layers of the skin. American Academy of Pain Medicine 1526-2375/08/$15.00/55 55 59 doi:10.1111/j.1526-4637.2007.00281.x

56 Spierings et al. This is a reversible effect that usually does not cause macroscopically discernable lesions. The technology allows for the relatively rapid transfer of medications and, when used with a topical anesthetic, such as EMLA or LMX4, it has been shown to provide skin anesthesia in 5 minutes [9,10]. In this single-blind, randomized, controlled, crossover study, we assessed the feasibility of providing skin anesthesia to needle prick with the combination of ultrasound pretreatment and 2- minute low-voltage (1 ma). We compared it with sham-ultrasound pretreatment plus 2-minute low-voltage (1 ma), as well as with standard, 10-minute high-voltage (4 ma). Methods The protocol, approved by Asentral Institutional Review Board in Salisbury, Massachusetts, excluded pregnant or nursing women and subjects who had participated in a study in the previous month specifically involving the forearm. It also excluded those who had an implanted pacemaker or defibrillator, out of concern for electrical interference, and those who had a documented history of hypersensitivity to sodium lauryl sulfate, topical anesthetics, or adhesives in order to avoid contact dermatitis. For the ultrasound pretreatment, the Sonoprep device (Sontra Medical Corporation, Franklin, MA) was used, consisting of a microprocessor-controlled ultrasound generator [10,11]. The device creates an electrical signal, converted by a series of piezoelectric crystals in the hand piece into mechanical vibration at a frequency of 55 khz. The mechanical vibration causes cavitation of the coupling fluid, which, in turn, results in poration of the skin [12]. The inclusion in the medium of a surfactant, in this case sodium lauryl sulfate, permits the ultrasound and surfactant to act synergistically. This synergistic action breaks down the lipids in the skin surface, creating transient microscopic channels to allow the diffusion of medication [13]. The closed-loop control of the device stops the ultrasound treatment once optimal skin conductance is obtained, delivering less than 1,000-mW energy to the skin. The increase in skin conductivity, or decrease in its impedance, has been shown to last for 12 24 hours [14]. For the, the Numby PM900 and Phoresor PM700 devices (Iomed Incorporated, Salt Lake City, UT) were used. They are also microprocessor controlled and are used to transport soluble ions across intact skin by electrical current. The Numby PM900 was used for the standard, 10-minute high-voltage (4 ma) for which it is preset. The Phoresor PM900, which delivers current at an adjustable voltage of 0.1 4 ma, was used for the 2-minute low-voltage (1 ma). The topical anesthetic used in the study was Iontocaine (Abbot Laboratories, Chicago, IL), which is a water-based formulation containing 2% lidocaine hydrochloride and 1:100,000 epinephrine. It is the preferred topical anesthetic for, which requires the medication to be in ionized form [15]. Commercial, disposable kits were used, which include the Iontocaine, the drug-delivery electrode, and the return dispersivepad electrode. Prior to each treatment, the adhesive return electrode was applied to the upper arm at a minimum distance of 4 inches from the treatment sites. In total, 1 ml of Iontocaine was used to saturate the 1-inch-diameter drug-delivery electrode, which was placed over the treatment site and secured in place by pressing on its adhesive border. The iontophoretic lead clips were subsequently attached to the electrodes. Upon completion of each treatment, the electrodes were removed and the topical anesthetic wiped off the skin. The three treatments, ultrasound plus 2-minute, sham-ultrasound plus 2-minute, and 10-minute, were randomly applied to nonoverlapping distal, middle, and proximal sites of the volar surface of the nondominant arm. The 10-minute, the lengthiest treatment, was tested first, followed by the ultrasound/ and shamultrasound/ treatments, with the (sham-)ultrasound always applied before the. With the sham-ultrasound, no energy was delivered to the skin, but the device made the same noise as the active device, securing the singleblind nature of the study. Within 15 seconds of initiation of the, the subject was asked to rate the level of discomfort associated with the procedure as mild, moderate, severe, or painful, to assess its tolerability. After completion of each treatment, the skin was assessed for irritation, which was rated as none, minor, moderate, or major redness, piloerection, blanching, erythema, urticaria, burn, or other. The site was subsequently tested for absolute and relative pain sensitivity on 10-cm visual analog scales, with 0 being no pain and 10

Two-Minute Topical Anesthesia 57 4 3.5 3 2.5 2 1.5 1 0.5 0 Figure 1 Absolute pain scores (mean + 95% confidence interval) as measured on a 10-cm visual analog scale: 0 = no pain and 10 = extremely painful (for P values, see text). being extremely painful for the absolute pain score, and 0 being no pain and 10 being same as the reference pain for the relative pain score. The reference pain was elicited from sites immediately adjacent to the treatment sites. The absolute and relative pain scores were determined by averaging the pain scores associated with three consecutive needle pricks, always administered by the same person, using a Standardized Prick Test Needle (Morrow Brown Allergy Diagnostics, Alkaline Corporation, Oakhurst, NJ). The subjects were contacted by telephone 24 48 hours after the testing to determine the (delayed) occurrence of skin irritation and to collect any other adverse events. Information regarding age, gender, height, weight, smoking, skin type, and tanning was collected and analyzed as potential covariates for relation to the absolute pain scores. The pain scores were analyzed using a one-way anova, with treatment as the independent variable and pain score as the dependent variable. Subject treatment preferences were analyzed using the chi-square test; however, the Fisher exact probability test was used when the frequency of observations in any of the cells was below 5. Evaluable subjects were those who were randomized and received all three treatments as described above. A power calculation was not performed because this constituted an initial, feasibility study. Results 10-minute Ultrasound + 2-minute Sham-ultrasound + 2-minute The study included 31 healthy subjects, 18 years or older, who signed the informed consent, of whom one declined after consenting and 30 were treated. All treated subjects completed the study, including the 24- to 48-hour telephone follow-up. The treated subjects included 19 men (63%) and 11 women (37%); their mean age was 50.5 ± 13.1 (SD) years (range: 24 74). Fourteen (47%) were smokers, and they smoked an average of 9.3 cigarettes per day. Of the covariates (age, gender, height, weight, smoking, skin type, and tanning), only gender was found to correlate with absolute pain score, with the mean score in men being 1.58 ± 0.47 (SEM) and in women 0.89 ± 0.29 (P = 0.117). The mean duration of the ultrasound pretreatment to achieve optimal skin conductance was 21.4 seconds (range: 6 85). The absolute and relative pain scores for the three treatments are shown in Figures 1 and 2, respectively. The absolute pain scores for the ultrasound plus 2-minute and the standard, 10-minute were not statistically significantly different (0.9 ± 0.31 vs 0.46 ± 0.20; P = 0.49). However, they were statistically significantly different from the sham-ultrasound plus 2-minute pain score (2.6 ± 0.55) (P = 0.0001 and 0.0012, respectively). Similar observations were made for the relative pain scores, with the scores for the ultrasound plus 2-minute and the 10-minute being identical (1.5 ± 0.49 and 1.5 ± 0.55, respectively; P = 0.86) and statistically significantly different from the sham-ultrasound plus 2- minute (5.08 ± 0.66; P < 0.0001). Upon completion of each treatment, the subjects were asked whether they would like to have this application prior to a needle procedure (yes, no, or don t know). The results are shown in Table 1 and indicate no statistically significant difference in distribution of the responses (P = 0.39). Upon completion of all three treatments, the sub- 7 6 5 4 3 2 1 0 10-minute Ultrasound + 2-minute Sham-ultrasound + 2-minute Figure 2 Relative pain scores (mean + 95% confidence interval) as measured on a 10-cm visual analog scale: 0 = no pain and 10 = same as reference pain (for P values, see text).

58 Spierings et al. Table 1 Preference for each application prior to a needle procedure as expressed by the subjects (Fisher exact test: χ 2 = 4.4, df = 4, P = 0.39) jects were asked which one they would prefer prior to a needle procedure. In response to this question, 14 (47%) selected the 10-minute, 10 (33%) the ultrasound plus 2-minute, and 6 (20%) the sham-ultrasound plus 2-minute (χ 2 = 3.2; df = 2, P = 0.2). The skin assessment after ultrasound pretreatment generated similar results as it did after shamultrasound pretreatment, that is, no observable lesions in 93% and 98% of the subjects, respectively. Two subjects experienced minor redness after ultrasound pretreatment, and one subject experienced erythema after sham-ultrasound pretreatment. However, blanching or erythema was commonly observed after the and needle-prick testing. Interestingly, both occurred much more often after the 2-minute on (sham-)ultrasound pretreated skin than after the 10-minute (Table 2). There were no adverse events reported for up to 24 48 hours after the treatments; however, two subjects reported minor redness of the ultrasound pretreated skin. Discussion 10-Minute (After Ultrasound) (After Sham) Yes 25 (83%) 24 (80%) 21 (70%) No 1 (3%) 3 (10%) 6 (20%) Don t know 4 (13%) 3 (10%) 3 (10%) The time required for currently available, topical anesthetics to provide anesthesia of normal, intact skin is 30 60 minutes; this necessitates proactive placement or delay of the procedure [16], which is not always possible or desirable. Ultrasound and alike have been shown to expedite the time to onset of topical anesthesia, reducing the painfulness of cutaneous procedures [6 10]. Here, we report on the combined use of ultrasound and to accomplish skin anesthesia in 2 rather than 10 minutes. This difference may seem small but is relevant in time-pressure clinical practice, where it may determine whether skin anesthesia is offered or not. Although low-frequency ultrasound treatment has been used to expedite the onset of both EMLA [9] and LMX4 [10], in this study we evaluated ultrasound treatment for 2% lidocaine hydrochloride and epinephrine 1:100,000 in water (Iontocaine ). The addition of the epinephrine potentially prolongs the duration of the anesthetic effect (not determined in the present study) by decreasing local blood flow and counteracting the vasodilation caused by the lidocaine and the electrical current. Ultrasound treatment of the skin followed by 2-minute (2 ma-minutes) was similar to 10-minute (40 ma-minutes) with regard to pain intensity evoked by needle prick. This suggests that ultrasound pretreatment can reduce the duration of required for skin anesthesia, making it more attractive for use in clinical practice. Both treatments were superior to the skin anesthesia provided by the sham-ultrasound plus 2-minute treatment. We purposefully limited the painfulness of the pin prick by the type of needle employed because of humanitarian reasons and the feasibility nature of the study. The limited painfulness of the needle prick is reflected in the relatively low, mean absolute pain score with the sham-ultrasound plus 2-minute treatment. The values obtained with the ultrasound plus 2-minute and the 10-minute treatments have to be considered against this background. Of course, the ultimate usefulness of the combined application of ultrasound and has to be demonstrated in a clinical study, evaluating the painfulness of percutaneous procedures rather than that of needle prick. However, before such a study can be conducted with ethical justification, the present feasibility study was deemed necessary. The nature of the pain stimulus also did not allow us to determine the depth of the skin anesthesia, and we did not study the duration of the effect. The subjects did not express a statistically significant preference regarding the three treatments despite the differences in anesthetic effects, although trends favored the two combined treat- Table 2 Skin assessment immediately after (before testing) Lesion 10-Minute (After Ultrasound) (After Sham) None 24 (80%) 3 (10%) 2 (7%) Blanching 6 (20%) 27 (90%) 28 (93%) Erythema 1 (3%) 10 (33%) 9 (30%) Minor redness 0 1 (3%) 0

Two-Minute Topical Anesthesia 59 ments over the singular, iontophoretic treatment. This is possibly due to the relatively low intensity of the needle-prick pain and it, therefore, not being representative of the pain associated with percutaneous procedures. In terms of safety of the applied treatments, discernable skin lesions attributable to either ultrasound or were minor and resolved quickly. In conclusion, ultrasound pretreatment plus 2- minute low-voltage provides better skin anesthesia than sham-ultrasound plus 2- minute low-intensity, and similar to standard, 10-minute high-voltage. Ultrasound shortens the duration and intensity of the required to anesthetize the skin, providing anesthesia to needle prick in 2 minutes. Ultrasound and are technologies currently available for use in clinical practice, but the development of a single device, combining the two, would probably facilitate and encourage their combined use, pending further studies confirming benefit in practice. Acknowledgments This study was sponsored by Sontra Medical Corporation, Franklin, Massachusetts. We thank the volunteers for their participation in the study, and Ellie Sneirson, R.N., and Grace Trieu for administering the study procedures. References 1 Cummings EA, Reid GJ, Finley GA, et al. Prevalence and source of pain in pediatric inpatients. Pain 1996;68:25 31. 2 Pitetti RD. Do no harm But first, do no hurt. CMAJ 2005;172:1699. 3Taddio A, Kaur Soin H, Schuh S, et al. Liposomal lidocaine to improve procedural success rates and reduce procedural pain among children: A randomized controlled trial. CMAJ 2005;172:1691 5. 4 Kleiber C, Sorenson M, Whiteside K, et al. Topical anesthetics for intravenous insertion in children: A randomized equivalency study. Pediatrics 2002;110:758 61. 5 Eichenfield LF, Funk A, Fallon-Friedlander S, Cunningham BB. A clinical study to evaluate the efficacy of ELA-Max (4% liposomal lidocaine) as compared with eutectic mixture of local anesthetics cream for pain reduction of venipuncture in children. Pediatrics 2002;109:1093 9. 6 Zempsky WT, Anand KJS, Sullivan KM, et al. Lidocaine for topical anesthesia before intravenous line placement in children. J Pediatr 1998;132:1061 3. 7 Kim MK, Kini NM, Trshynski TJ, Hennes HM. A randomized clinical trial of dermal anesthesia by for peripheral intravenous catheter placement in children. Ann Emerg Med 1999;33:359. 8 Zeltzer L, Regaldo M, Nichter L, et al. versus subcutaneous injection: A comparison of two methods of local anesthesia delivery in children. Pain 1991;44:73 8. 9 Katz NP, Shapiro DE, Herrmann TE, et al. Rapid onset of cutaneous anesthesia with EMLA cream after pretreatment with a new ultrasound-emitting device. Anesth Analg 2004;98:371 6. 10 Becker BM, Helfrich S, Baker E, et al. Ultrasound with topical anesthetic rapidly decreases pain of intravenous sticks. Acad Emerg Med 2005;12:289 95. 11 Mitragotri S, Kost J. Low-frequency sonophoresis: A review. Adv Drug Deliv Rev 2004;56:589 601. 12 Mitragotri S, Kost J. Low-frequency sonophoresis: A non-invasive method of drug delivery and diagnosis. Biotechnol Prog 2000;16:488 92. 13 Tezel A, Sens A, Tuchscherer J, Mitragotri S. Synergistic effect of low-frequency ultrasound and surfactants on skin permeability. J Pharm Sci 2002;91:91 100. 14 Farinha A, Kellogg S, Dickinson K, Davidson T. Skin impedance reduction for electrophysiology measurements using ultrasonic skin permeation: Initial report and comparison to current methods. Biomed Instrum Technol 2006;40:72 7. 15 Bezzant JL, Stephen RL, Petelenz TJ, Jacobson SC. Painless cauterization of spider veins with the use of iontophoretic local anesthesia. J Am Acad Dermatol 1988;19:869 75. 16 Zempsky WT, Cravero JP. Relief of pain and anxiety in pediatric patients in emergency medical systems. Pediatrics 2004;114:1348 56.