Anesth Analg 2007;104:847-849
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000257925.36641.9e
ANESTHETIC PHARMACOLOGY
A Comparison of Laser-Assisted Drug Delivery at Two Output Energies for Enhancing the Delivery of Topically Applied LMX-4® Cream Prior to Venipuncture
Jeffrey L. Koh, MD, MBA*
,
Dale Harrison, MPH,
Veronica Swanson, MD*,
Daniel C. Norvell, PhD
, and
Darren C. Coomber, PhD
From the Departments of *Anesthesiology and Peri-Operative Medicine and Pediatrics, Oregon Health and Science University, Doernbecher Children’s Hospital, Portland, Oregon; Olympic Research, Incorporated, Lakewood, Washington; and Norwood Abbey, Limited, Chelsea Heights, Victoria, Australia.
Address correspondence and reprint requests to Jeffrey L. Koh, MD, MBA, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Mail Code UHS2, Portland, OR 97239. Address e-mail to kohj{at}ohsu.edu.
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Abstract
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BACKGROUND: Laser-assisted drug delivery (LAD) has the potential for facilitating topical anesthesia with reduced onset time.
METHODS: In this randomized, double-blind, crossover study we compared the efficacy and adverse event profile of LAD for topical anesthesia before venipuncture using two output energies (2.0 and 3.5 J/cm2).
RESULTS: Mean Visual Analog Scale pain scores were not statistically different (P = 0.57) between the low-energy (mean = 6.7) and high-energy (mean = 8.1) lasers.
CONCLUSIONS: LAD at an energy of 2.0 J/cm2 (570 mJ) is as effective, with similar adverse events, as an energy of 3.5 J/cm2 (1000 mJ) in facilitating topical anesthesia.
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Introduction
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Topical anesthesia is being used with increasing frequency to reduce the pain associated with venipuncture. One option for enhancing the absorption of local anesthetic without the use of a needle is removal of the stratum corneum (1,2). Epiture Easytouch TM (Norwood Abbey, Melbourne, Australia) is a low-powered Er:YAG laser device that removes the stratum corneum by using an output energy of 3.5 J/cm2 to enhance delivery of over-the-counter (OTC) 4% lidocaine. This laser-assisted drug delivery (LAD) using 3.5 J/cm2 is reportedly effective at reducing pain associated with needlesticks (3–5), but it is unclear whether this amount of energy is necessary to remove the stratum corneum. A higher energy output allows for removal of the stratum corneum at sites with thicker skin, but could also increase the incidence of undesirable effects. Thus, this study serves as an initial inquiry into determining if a lower energy (2.0 J/cm2) is as effective as a higher energy (3.5 J/cm2) for stratum corneum ablation at the antecubital fossa prior to a 5-min application of OTC topical 4% lidocaine cream (LMX-4®, Ferndale Laboratories, Ferndale, MI) to reduce pain associated with venipuncture.
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METHODS
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After receiving IRB approval, 30 healthy volunteers (ages >18 yr) were enrolled. Written informed consent was obtained from each subject prior to enrollment in the study.
Procedures
The LAD devices were calibrated prior to the study, looked identical, and were identified only by the letters A (low-energy) and B (high-energy). The order of the laser output energy applications and the arm for the first treatment were randomized. The subject, the clinician selecting the site and administering the laser application, the anesthesiologist performing the venipuncture, and the biostatistician were all blinded to the laser energy.
After selection of an appropriate site on the randomized antecubital fossa, the randomized laser energy was used and LMX-4® was applied. After 5 min the cream was removed, and the site was wiped with alcohol and allowed to dry. The anesthesiologist then inserted an 18-gauge needle through the treated site. The pain associated with the venipuncture was scored by the subject by marking a line on the 100 mm Visual Analog Scale (VAS) (6,7). After a washout period of 5 min, the laser energy not used on the first arm was applied to the antecubital fossa on the other arm and study procedures repeated.
Subjects were contacted and asked to report any adverse events (e.g., pain, swelling, itching, redness) as none, mild, moderate, or severe. Subjects reporting moderate or greater adverse events at 2 days were followed-up 1 wk after initial contact. All subjects with evidence of adverse skin reactions after 16 days were followed-up at 5 wk.
Sample Size and Data Analysis
We hypothesized that there would be no difference in mean pain scores between the low energy and high energy [H0: VASLow (2.0 J/cm2) = VASHigh (3.5 J/cm2)]. Based on a mean pain VAS score of 8.21 mm, a standard deviation of 13.35 mm for both groups and a statistical power of 95%, it was determined that at least 26 subjects per laser energy treatment were needed (3).
Demographic data consisting of descriptive statistics for age and gender were reported. To determine if the treatment sequence influenced the VAS scores (i.e., carryover effect), the average sums between the two treatment sequences were compared using a two-sided, two-sample t-test for mean comparisons and a Wilcoxon rank-sum (Mann–Whitney) test for median comparisons. Statistical significance was defined as P < 0.05.
An unpaired analysis comparing mean and median pain scores between low energy and high energy were performed. Because the data were sufficiently skewed (i.e., standard deviations were more than the means), the nonparametric comparison of median pain scores was more appropriate using the Wilcoxon rank-sum (Mann–Whitney) test. Additional comparisons were made for within-subject differences, means, and medians by dropping a single outlier to determine if this had an appreciable influence on the outcomes.
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RESULTS
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Patient Characteristics
A total of 29 subjects completed the study. One subject was dropped after randomization due to failure to meet study criteria. Subject characteristics are presented in Table 1.
Efficacy
Mean VAS pain scores were not statistically different (P = 0.57) between low energy (mean = 6.7) and high energy (mean = 8.1) (Table 2), when a single outlier (VAS = 91) was removed. When the outlier is included in the analysis the pain scores between laser energies (low energy = 9.6; high energy = 8.1) were also not statistically significant (P = 0.70). Nonparametric methods were used to compare median pain scores, and the difference between laser energies was not statistically significant (P = 0.88). These findings did not differ significantly by gender (P = 0.62). The test for carryover effect using both median and mean comparisons was not significant (P = 0.34 and 0.59, respectively). Thus, there was no adjustment for a carryover effect per the a priori criteria set in the study protocol (P < 0.10).
Adverse Effects
At the second day follow-up there was a higher rate of mild pain, moderate redness, and swelling from high energy; however, these difference between the laser energies were not statistically significant (P = 0.16–0.22). One subject receiving high energy reported severe redness at 2 days, but this was reported as mild at the 1-wk follow-up.
At the 1-wk follow-up, there were two reports of mild pain. Both resolved by the 5-wk follow-up. The trend of higher reports of redness for high energy (28%) compared to low energy (3%) approached significance at 1 wk after application (P = 0.06).
At the 5-wk follow-up, one subject (3.5%) who received low energy and eight subjects (28%) who received high energy reported hyperpigmentation at the respective ablation site. This difference in hyperpigmentation between the laser energies was statistically significant (P = 0.01). This hyperpigmentation was not of concern to any of the subjects. All moderate or severe reactions resolved by the 5-wk follow-up.
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DISCUSSION
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These results indicate that LAD using low energy output followed by OTC 4% is equally effective as high energy output for reducing pain associated with venipuncture. Although not statistically significant, low energy seems to produce fewer adverse events, such as pain, redness, or swelling at the ablation site. A note of consideration when reviewing these results is that the generalizability of the pain scores may be limited when a skilled clinician (i.e., staff anesthesiologist) performs all venipunctures.
The ideal topical anesthetic would be safe and effective, and would have an immediate onset. Although topical anesthetic creams have provided a much needed method for applying safe and painless topical anesthesia, their delayed onset of 30–60 min may limit their usefulness in certain clinical situations. Our results provide support for the use of LAD as a tool for facilitating topical anesthesia. However, these results also highlight the need for more research to determine the optimal output energy that can facilitate anesthesia with the fewest adverse events. Moreover, future studies should examine the safety and effectiveness of LAD technology for facilitating topical anesthesia in specific populations, such as children. Finally, research is needed to better understand the output energies most appropriate for other sites frequently used for needlestick procedures, such as the back of the hand.
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Footnotes
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Accepted for publication December 28, 2006.
Supported by Norwood Abbey, Ltd.
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REFERENCES
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Abstract
Introduction
