A comparative study of pain perception during the microfocused ultrasound procedure between topical anesthesia and combined topical anesthesia with forced air cooling

The experience of pain during microfocused ultrasound with visualization (MFU‐V) treatment is common and crucial for dictating patient satisfaction and retention.


| INTRODUC TI ON
The use of microfocused ultrasound with visualization (MFU-V) for skin tightening and rejuvenation has been in the spotlight for the past 10 years. Owing to its ability to generate focus and well-defined thermal injury zones, collagen denaturation, and new tissue formation occur. This results in neocollagenesis and elastogenesis in predefined layers, leading to tightening and rejuvenating effects. 1,2 The efficacy and safety profile of MFU-V for treating skin laxity, lines, and wrinkles have been demonstrated in several studies. 1,3 Common side effects, including tenderness, redness, and edema are typically mild and transient. However, varying degrees of pain perception were observed, which might be attributed to individual pain tolerance, treated area, treatment settings (i.e., the depth, energy level, and number of treatment lines), and anesthetic options. [2][3][4][5][6][7][8][9][10][11][12][13][14] Aside from delivering a proper procedure, optimizing patients' comfort is another critical concern since it dictates patient satisfaction and retention. 4 To address the discomfort, various pharmacologic and nonpharmacologic modalities have been applied in clinical practice, including topical anesthesia, injectable anesthesia, distraction techniques, oral nonsteroidal anti-inflammatory drugs, oral narcotics, oral anxiolytics, nitrous oxide, and cooling of the treated area. 2,[5][6][7][8][9][10][11][12][13][14] Forced air cooling has been widely used for analgesia during various dermatologic laser procedures to mitigate pain. The advantages of this anesthetic method include ease of use, a good safety profile, and a high level of patient acceptance. In addition, it decreases the post laser-related side effects, including erythema, purpura, and crusting. Although previous studies have shown its analgesic efficacy, either alone or in combination, there have been few reports on its use during the MFU-V procedure. [15][16][17][18][19] This study aimed to compare the pain perception during the MFU-V procedure between pretreatment with topical anesthesia alone or combined topical anesthesia with forced air cooling.

| Study subjects
Healthy participants aged between 18 and 60 years, who were willing to participate in the study were recruited. The exclusion criteria were pregnancy or active breastfeeding, active skin diseases (including cystic acne), history of surgery at the experimental sites within 6 months, metal implantation at the experimental sites, and allergy to local anesthesia.

| Study protocol
A square area of 2.5 × 2.5 cm was drawn at the inner side of both arms 5 cm laterally and 7.5 cm superiorly to the medial epicondyle which was determined as the experimental site. Each arm was randomly assigned to receive one pain reduction method (i.e., topical anesthesia alone or combined topical anesthesia with forced air cooling). After the assigned intervention, the MFU-V procedure was performed in a random sequence to assess the pain perception ( Figure 1). A random sequence was generated using a computer-based generator and was concealed from the evaluators.
Topical anesthetic cream (2.5%/2.5% lidocaine-prilocaine; Galentic Pharma) was applied to the experimental site (both arms) with an occlusive dressing for 30 min before the MFU-V procedure. The anesthetic cream was removed immediately prior to the procedure. Forced air cooling was delivered to the as-

| Pain assessment
A visual analog scale (VAS) was used to assess the pain perception. It is a common and standard method for evaluating the levels of pain. 20 The 10 cm VAS score (0 cm, no pain; 10 cm, worst possible pain) was measured at three time points: immediately after the use of 4.5 mm transducer (T1a), immediately after use of the 3.0 mm transducer (T1b), and overall pain experience (T2). At each time point, the VAS scores were compared between the sites treated with topical anesthesia alone and those treated with forced air cooling.

| Statistical analysis
The categorical data were described as frequencies and percentages.
The mean and standard deviation (SD) or median and interquartile range (IQR) were used to present for continuous data depending on the distribution of the data. The outcomes of interest were the VAS scores at three time points (T1a, T1b, and T2), which were compared between two pain reduction methods using the mixed-effect model.
The statistical significance was set at a p-value <0.05. All analyses were performed using the Stata statistical software version 14.0 (StataCorp).

| VAS pain score
A total of 21 recruited participants, of which 20 participants were women, completed the study. The mean age of the participants was 34.67 ± 6.18 years. Fourteen (66.67%) and seven (33.33%) participants had Fitzpatrick skin type III and IV, respectively. Eight participants (38.10%) were naive to microfocused ultrasound procedures for skin tightening or rejuvenation.
The VAS pain scores at T1a, T1b, and T2 were compared between two pain reduction methods and have been presented as box and whisker plots (Figure 2). The participants experienced more pain at between the two methods ( Table 1).
No side effects related to topical anesthesia or forced air cooling were observed in this study.

| DISCUSS ION
Although usually mild to moderate in severity, the pain experi-  In addition to its efficacy in temperature reduction, its safety benefits include a low risk of frostbite, usage convenience, high application compatibility (i.e., pre-, parallel, and post-cooling application, ability to be combined with other anesthetic therapies, and compatibility with most dermatologic procedures), and environmental and economical friendliness, which encourage the use of forced air cooling to continuously increase. [15][16][17][18][19]23 Previous studies have reported good analgesic efficacy of forced air cooling during dermatologic procedures, including non-ablative Nd-YAG laser, pulsed dye laser, carbon dioxide laser, fractional photothermolysis, fractionated carbon dioxide laser, photodynamic therapy, and hyaluronic acid injections. [15][16][17][18][19]24,25 However, the role of cold-air anesthesia during the MFU-V procedure is still under investigation.
To limit the variability of individual pain tolerance, an intraindividual comparative study was conducted to compare the impact of two pain reduction methods on the pain perception during MFU-V treatment. The participants reported lower pain perception during the MFU-V procedure on the side treated with combined topical anesthesia and cold-air anesthesia compared with topical anesthesia alone. However, this difference was not statistically significant.
To induce collagen denaturation, MFU-V generates heat in the dermis and superficial musculoaponeurotic system by producing small thermal coagulation points at a depth of 1.5-4.5 mm, depending on the transducer that was used. The target temperature was between 60 and 70°C, allowing skin tightening and rejuvenation without heat accumulation in the superficial layer. 1 Regarding the pain associated with the MFU-V treatment, a noxious heat temperature (>43°C) resulting from heat accumulation in the deeper layers of the skin is responsible for the pain and discomfort experienced by patients. Noxious heat stimuli stimulate fast-conducting Aδ and slow conduction of C nociceptive fibers through TRPV1 and TRPV2 receptors. Following the stimulation, a first, spontaneously, sharp, or pricking pain develops mediated by fast-conducting Aδ fibers followed by a second, dull, or burning pain mediated by slow-conducting C fibers. 26 Hence, discomfort, in particular stinging, heat, and pain can occur during the delivery of MFU-V energy. 27 Cutaneous nerve fibers in the skin are primarily sensory, with some components of autonomic nerve fibers. The sensory nerves innervate numerous layers of the skin (e.g., the epidermis, dermis, and subcutaneous fat) as a three-dimensional network. The epidermis, dermis, blood vessels, hair follicles, sebaceous glands, sweat

F I G U R E 2
The box and whisker plot compares the visual analog scale for pain during microfocused ultrasound with visualization (MFU-V) between topical anesthesia (L/P; lidocaine-prilocaine) and combined topical anesthesia with forced air cooling (Cooling + L/P) immediately after the MFU-V procedure with 4.5 mm transducer (T1a), immediately after the MFU-V procedure with a 3.0 mm transducer (T1b), and after the entire procedure (T2). glands, and apocrine glands are innervated by several sensory nerve subtypes. However, most of the nerve fibers are found in the middermis and papillary dermis, and with a 2-h application of a eutectic mixture of local anesthetics (2.5% lidocaine and 2.5% prilocaine), the depth of anesthesia reached 5 mm. 28,29 The anesthetic effect of cooling used in the non-ablative lasers can be explained by the theory of the spatial selectivity of cooling.

F I G U R E 3
A certain temperature should be achieved to target chromophores; consequently, elevated temperatures can damage the epidermal keratinocytes and melanocytes. The use of cooling can reduce the temperature at the epidermal level and maintain it below the noxious heat threshold, whereas the required higher temperature is reached at the target chromophores.
In contrast to lasers, MFU-V energy is delivered precisely to a predefined deep layer of the skin. Based on the results of this study, we hypothesized that the temperature reduction effect of forced air cooling is not delivered to the deep layers of the skin. Therefore, we did not observe a significant difference in the pain perception during the MFU-V procedure between the sites treated with topical anesthesia alone and combined topical anesthesia with forced air cooling. For non-optimal neocollagenesis and neoelastogenesis, we conducted a histologic examination of three volunteer participants. A comparable degree of new collagen and elastic tissue formation following the MFU-V procedure between two methods has been demonstrated. This could imply that the process of heat accumulation generated from the MFU-V does not interfere with forced air cooling.
The strength of our study lies in its prospective design. Compared to the previous studies, this study mainly focused on the real-time pain perception. Therefore, a recall bias was less likely to occur.
However, this study had some limitations. The small sample size may compromise the power and generalizability of the results. The study examined only the effect of forced air cooling at a particular flow level and distance; therefore, the results may not be compatible with other settings of forced air cooling (e.g., the direction of forced air cooling, the distance between cooling nozzle and the skin surface, etc.). In addition, we did not evaluate the effect of forced air cooling on the MFU-V using a 1.5 mm transducer. Further randomized controlled trials with larger sample sizes and using different techniques are required to address these limitations.

| CON CLUS ION
The use of a forced air cooling device in combination with topical anesthesia provided no additional beneficial effects for pain reduction during MFU-V with transducers of 4.5 mm and 3.0 mm. The temperature reduction effect could not be delivered to the deeper layers of the skin, which is the target site of the MFU-V. Writing, reviewing, and revising the manuscript.

ACK N OWLED G M ENTS
We thank Dr. Kunlawat Thadanipon for his help in statistical analysis and Dr. Poonkiat Suchonwanit for the preparation of illustrations.

FU N D I N G I N FO R M ATI O N
The authors received no financial support for the research and authorship.

CO N FLI C T S O F I NTE R E S T
The authors have stated explicitly that there are no conflicts of interest in connection with this article.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.

E TH I C A L A PPROVA L
Authors declare human ethics approval was not needed for this study.