A Pilot Investigation Comparing Low-Energy, Double Pass 1,450 nm Laser Treatment of Acne to Conventional Single-Pass, High-Energy Treatment

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1 Lasers in Surgery and Medicine 39: (2007) A Pilot Investigation Comparing Low-Energy, Double Pass 1,450 nm Laser Treatment of Acne to Conventional Single-Pass, High-Energy Treatment Eric F. Bernstein, MD* Laser Surgery and Cosmetic Dermatology Centers, Bryn Mawr, Pennsylvania Background and Objectives: Laser treatment using a 1,450 nm diode laser has been shown to improve acne and acne scarring. Its widespread adoption in younger populations has been significantly limited by discomfort. Study Design/Materials and Methods: Six subjects with active papular acne were treated in a pilot study to determine parameters for a split-face, double-pass, lowenergy protocol of 1,450 nm laser treatment. Sides of the face were randomized to receive single-pass, high-energy treatment (13 14 J/cm 2 ), or double-pass, low energy treatment (8 11 J/cm 2 ), for a total of four treatments delivered at monthly intervals. Acne counts and standardized, digital photograph were performed 2 months following the final treatment, and compared to pre-treatment counts and photographs. Results: Improvement was evaluated comparing pre- and post-treatment photos and averaged 2.5 for the highenergy, single-pass side and 2.3 for the low-energy, double-pass side, using a 0 (worse) to 4 (max improvement) scale. Acne counts were reduced 78% on the high-energy, single-pass side and 67% on the low-energy, double-pass side. Pain ratings on a 1 (min) to 10 (max) scale averaged 5.6 (range 1 9) for the high-energy, single-pass side and 1.3 (range 1 2) for the low-energy, double-pass side. Conclusions: Low-energy, double-pass 1,450 nm laser treatment effectively reduces acne counts 2 months posttreatment, and dramatically reduces the pain associated with treatment. The treatment parameters used in this study have eliminated the need for anesthetic cream in daily practice. Lasers Surg. Med. 39: , ß 2006 Wiley-Liss, Inc. Key words: laser; acne; diode; non-ablative INTRODUCTION Acne is one of the most common problems seen by dermatologists, and treatment regimens are often used for decades, until acne wanes due to changes in skin physiology [1 3]. Acne can result in permanent scarring, and leave psychological scars that are even more significant [4]. Topical antibiotics, keratoyltics, oral antibiotics, and oral retinoids are the mainstays of treatment [2 6]. Ionizing radiation and ultraviolet C radiation had been used in the past to suppress acne [7,8], but we now know that the risks of such treatment far outweigh the benefits [9,10]. Recently, other longer and thus safer wavelengths of electromagnetic radiation have been shown to exert a beneficial effect on acne. Virtually the full spectrum of visible radiation has been used to treat acne [11 21]. Blue wavelengths of visible light have been used to exploit endogenous porphyrins in proprionibacterium acnes bacteria, targeting these bacteria and reducing their numbers [11,12]. Visible lasers targeting hemoglobin have also been shown to have activity against acne [19 21]. Photodynamic therapy, using a variety of visible wavelengths and a number of photosensitizing dyes, has been used to treat acne [17,18]. In addition to visible wavelengths of light, radiofrequency has also been used to treat acne [22]. Recently, the most commonly used laser modalities for treating acne with electromagnetic radiation are the infrared lasers [23 29]. These devices were originally developed for dermal remodeling and applied to treatment of rhytides and acne scarring. They usually incorporate some technique for cooling the epidermis, while allowing heat to build up in the underlying dermis. One of the most widely used wavelengths for this purpose is the relatively recently developed 1,450 nm diode laser incorporating cryogen spray cooling (Smoothbeam, Candela Corporation, Wayland, MA). Initial studies treating acne scarring with the 1,450 nm diode laser revealed the potential to treat acne, and subsequent studies proved it to be effective at reducing acne [25 29]. While the 1,450 nm, diode laser has been shown to be effective for treating acne, one of its major limitations is the pain associated with treatment. Typically, treatment energies have ranged from 12 to 14 J/cm 2. Even with the associated dynamic cooling device which dramatically reduces pain associated with laser treatment, the treatment is often too painful for many patients to tolerate (especially teenagers), despite application of topical anesthetic cream. In this pilot study, we investigate the Parts of this study were presented at the 25th Annual Meeting of the American Society for Laser Medicine and Surgery in Boston, Massachusetts on April 9, *Correspondence to: Dr. Eric F. Bernstein, Bryn Mawr Center for Laser Surgery, 931 Haverford Road, 2nd Floor, Bryn Mawr, PA dermguy@hotmail.com Accepted 26 July 2006 Published online 18 September 2006 in Wiley InterScience ( DOI /lsm ß 2006 Wiley-Liss, Inc.

2 194 BERNSTEIN efficacy and tolerability of delivering two passes of a relatively low laser fluence, as compared to standard treatment using a single high-energy pass using a split-face comparison. MATERIALS AND METHODS Subjects Seven subjects were enrolled into the study protocol. One discontinued treatment to treat her acne at a tanning salon after the first treatment. The remaining six completed the study treatment protocol and follow-up visit. Patients ranged in age from 23 to 41, with the average age 29. There were six women and one man enrolled in the study. Subjects had Fitzpatrick skin types I III. Laser Treatment Subjects had a 4% lidocaine anesthetic cream (LMX-4; Ferndale Laboratories, Inc., Ferndale, MI) applied to their entire face 40 minutes prior to laser treatment. Immediately prior to treatment, cream was washed off using soap and water, and the face cleaned with a 3% solution of hydrogen peroxide. A 1,450 nm, diode laser (Smoothbeam, Candela Corp., Wayland, MA) was used. Energy was delivered using a 6 mm spot, and a cryogen-cooling device to protect the epidermis and selectively heat the superficial dermis. The Smoothbeam administers laser energy in a pulse comprised of 4 micro-pulses lasting a total of 50 milliseconds; with five cryogen spurts interspersed before, in-between, and after the micro-pulses lasting a total of milliseconds. Thus, each laser pulse is actually a succession of laser micropulses sandwiched in-between cryogen spurts. The cryogen is an environmentally friendly Freon substitute that cools the epidermis by evaporation, thus allowing heat to build up below the epidermis. Subjects were treated to one-half of their face with a single-pass, high-energy treatment and a double-pass, low-energy treatment to the contra-lateral side, and were randomized as to which side of the face received which treatment. Laser energies on the high-fluence side ranged from 13 to 14 J/cm 2, averaging 13.7 J/cm 2,witha cryogen setting of 33 milliseconds. High-energy, single-pass treatments began at 13 J/cm 2, escalating to 14 J/cm 2. Energies on the low-energy, double-pass side began with 11 J/cm 2 with a cryogen setting of 30 milliseconds for the first treatment, and were reduced to 8 J/cm 2 with a cryogen setting of 28 milliseconds for all of the subsequent treatments, because 11 J/cm 2 was considered painful by a majority of subjects. The average treatment energy on the doublepass, low-fluence side was 8.6 J/cm 2. To avoid cryogen injury, the amount of cryogen administered was reduced correspondingly with lower laser fluences. After completing a single-pass to the side of the face receiving two passes, a second pass was immediately begun using the same pattern as was used in the first pass. Subjects received four treatments administered at monthly intervals, and were evaluated for improvement and side-effects 2 months following the final treatment. Evaluation Each subject had his or her acne papules and pustules counted in each cosmetic unit of the face, and an acne severity rating recorded before each laser treatment, and 8 weeks following the fourth and final laser treatment by the treating physician. Acne severity ratings were determined using the Allen-Smith acne severity scale. The Allen- Smith scale is based on a 0 8 scale, with 0 representing no acne and 8 representing involvement virtually the entire face by acne. In addition, the treating physician made a global assessment of the degree of improvement using a 0 4 scale with 0 representing worsening, 1 no improvement, 2 mild improvement, 3 moderate improvement, and 4 marked improvement, using pre-treatment photographs as a baseline at the final follow-up visit. Standardized, digital photographs of the left, right, and central face were taken before any treatments were administered, and 2 months following the fourth laser treatment (Canfield Scientific, Fairfield, NJ). Three physicians blinded as to the treatment parameters compared pre- and post-treatment photographs in a blinded fashion. Photographs were scored using a 0 4 scale with 0 representing no change (0%), 1 representing mild improvement (1% 25%), 2 representing moderate improvement (26% 50%), 3 representing marked improvement (51% 75% improvement), and 4 representing excellent improvement (75% 100%). Subjects scored their improvement subjectively following each treatment. They used a scale of 0 4 scale to grade improvement in their acne and acne scarring, with 0 being worse, 1 being no change, 2 being mild improvement, 3 being moderate improvement, and 4 being marked improvement. Subjects with acne scarring also rated their improvement using the same scale that was used to assess improvement in acne outlined above. Subjective self-assessment of pain was performed by the subjects immediately following each treatment as rated on a 0 10 scale with 0 representing no pain and 10 representing maximum pain. Clinical evaluation of side-effects including erythema and edema as rated by the treating physician were recorded following each treatment on a 0 3 scale, with 0 representing no erythema or edema and 3 representing maximal erythema or edema. Side-effects of hyper-pigmentation, hypo-pigmentation, and scarring were evaluated 4 weeks following each treatment and at the 8 week follow-up period, using the 0 3 scale, with 0 representing no hyper-pigmentation, hypo-pigmentation, or scarring, and 3 representing maximum levels of these side-effects. RESULTS Acne Counts Acne counts 1 month following each treatment and 2 months following the fourth and final treatment are outlined in Table 1. Acne counts were slightly higher at baseline on the single-pass, high-fluence side, than they were on the double-pass, low-fluence side, averaging 19.5 and 16.2 acne papules or pustules per side of the face, respectively. Acne counts dropped after the first treatment

3 A PILOT INVESTIGATION OF ACNE 195 TABLE 1. Individual Subject Lesion Counts at Follow-Up Visits Post Treatments 1 Through 4 Baseline 1 month f/u Tx 1 1 month f/u Tx 2 1 month f/u Tx 3 8 week f/u Tx 4 Subject # 1 Pass 2 Passes 1 Pass 2 Passes 1 Pass 2 Passes 1 Pass 2 Passes 1 Pass 2 Passes Average and stayed at half their original values or less for during the treatment period. Two months following the final treatment, acne counts were at their lowest levels, dropping 78% on the high-energy, single-pass side to 22% of the baseline value. Acne counts on the low-fluence, double-pass side dropped 68% from pre-treatment counts to 32% of the original number of lesions. Acne Severity Scores Baseline acne severity scores were similar on each sides of the face averaging 3.1 for the single-pass, high-fluence side of the face, and 3.2 for the double-pass, low-fluence side, out of a possible high of 8 (Table 2). Following the first treatment, acne severity scores decreased to less than half of their pre-treatment values after subsequent treatments, although that decrease was greater after the first and second treatments for the single-pass, high-fluence treatment sites. After the third treatment, acne severity scores were less than a third of their pre-treatment values and were 32% and 25% of baseline evaluations, for the singlepass, high-fluence side and the double-pass, low-fluence sides, respectively. This represents a 68% reduction in acne severity scores for the single-pass, high-fluence side, and a 75% reduction for the double-pass, low-fluence side, 2 months following the final of four treatments. Blinded Physician Evaluation of Standardized Photographs The average improvement score for the three physician assessors was 1.6þ1.1 (meanþsd) for the high-fluence, single-pass side and 2.4þ0.9 for the low-fluence, doublepass side. This corresponded to mild-moderate improvement for the single-pass, high-fluence side, and moderate to market improvement for the low-fluence, double-pass side (Fig. 1). Subjective Evaluation of Improvement by Subjects Subjects rated their improvement in acne and acne scarring using a 0 4 scale, where a score of 0 meant worsening and 1 represented no change, while 2, 3, and 4 represented, mild, moderate, and market improvement, respectively. On the high-fluence, single-pass side scores for improvement of acne ranged from 1 to 4, averaging 2.3; while on the low-fluence, double-pass side scores ranged from 2 to 4, averaging 2.3. Four of the six subjects had acne scarring. These subjects had improvement scores ranging from 1 to 3 and averaging 2.0, for both the high- and lowfluence sides. When asked to rate which side improved the most relative to the other for improvement of acne, subjects were evenly divided with three choosing the high-fluence, single-pass side, and three choosing the low-fluence, double-pass side. Side-Effects Pain. The mean scores rating the pain of treatment ranged from 2 to 9 on the high-fluence, single-pass side and from 1 to 5 for the low-fluence, double-pass side, averaging 5.5 and 1.6 for the high-fluence and low-fluence sides, respectively (Fig. 2). Because pain was still considered TABLE 2. Individual Subject Acne Severity Grade at Baseline and at Follow-Up Visits Post Treatments 1 Through 4 Baseline 1 month f/u Tx 1 1 month f/u Tx 2 1 month f/u Tx 3 8 week f/u Tx 4 Subject # 1 Pass 2 Passes 1 Pass 2 Passes 1 Pass 2 Passes 1 Pass 2 Passes 1 Pass 2 Passes Average

4 196 BERNSTEIN Fig. 1. A: Subject before (left) and 8 weeks after (right) four single-pass, high-energy laser treatments. B: Same subjects as in A before (left) and 8 weeks after (right) low-energy, doublepass laser treatment. C: Subject before (left) and 8 weeks after (right) four single-pass, high-energy, laser treatment. D: Same subject as in C before (left) and 8 weeks after doublepass, low-energy laser treatments. significant by most subjects and the treating physician after the first treatment on the low-fluence side using 11 J/ cm 2 and a DCD setting of 33 milliseconds, subsequent treatments were administered using 8 J/cm 2 with a DCD setting of 28 milliseconds. Pain ratings for the 2nd 4th treatments averaged 5.6 (range 2 9) on the high-fluence, single-pass side and 1.3 (range 1 2) on the low-fluence, double-pass side. Erythema, Edema, Blistering Averaging all four treatments, erythema immediately post-treatment in the single-pass, high-fluence side was rated as mild in 37.5% treatments, moderate in 58.4%, and severe in only one treatment or 4.2%. Erythema in the double-pass, low-fluence side was mild in 54.2% of the treatments, and moderate in 45.8%. Edema immediately post-treatment in both the single-pass, high-fluence side, and the double-pass low fluence side was rated as absent in 75%, mild in 20.8%, and moderate in 1 or 4.2% of treatments. Edema was consistent within a subject and independent of the treatment condition. There was no blistering seen in any subject. Hyper-Pigmentation, Hypo-Pigmentation, and Scarring No scarring hyper- or hypo-pigmentation was seen following any treatment, reported by any subjects, or identified in any photographs.

5 A PILOT INVESTIGATION OF ACNE 197 Fig. 2. Mean pain scores for all six subjects: Mean ( SD) pain scores for each treatment. Diamonds represent results from 1 pass and squares represent results from 2 passes. DISCUSSION In this pilot study, acne improved significantly as measured by acne severity scores, lesion counts, photographic evaluation, and subjective self-evaluation on both the high-fluence, single-pass side as well as the low-fluence, double-pass side. Rates of improvement were similar with acne counts decreasing 78% for the high-fluence, single-pass side and 68% for the low-fluence, double-pass side. Acne severity scores similarly improved to 68% and 75% for the high-fluence, single-pass side and low-fluence, double-pass side, respectively. Subjective assessment of improvement measured by the subjects themselves paralleled the other measurements, improving 2.3 out of a possible 4.0 for both sides. Thus, subjects could not distinguish an overall difference in improvement from either treatment condition. It is possible that starting with an initially higher fluence (11 J/cm 2 ) for the first treatment on the on the low-fluence, double-pass side, could have influenced the results of this study, but clinical experience subsequent to this study suggests this is not the case. Sideeffects were minimal with no blistering, scarring, hyper-, or hypo-pigmentation noted in any subjects. Hyperpigmentation has been observed infrequently by the author in tanned individuals or those with Fitzpatrick skin types III IV. In one study investigating the efficacy of the laser used in the current study for improving acne scarring in Asians with Fitzpatrick type IV and V skin, hyperpigmentation was seen in 39% of treated subjects [27]. Perhaps no hyperpigmentation was noted in the current study because no subject had darker than type III skin, using the Fitzpatrick scale. Rarely, this author has seen hyperpigmentation resulting from high-fluence, single-pass treatment last up to 7 months. Hyperpigmentation has not been seen by this author since almost exclusively switching to the lowfluence, double-pass treatment protocol; however, patients with Fitzpatrick type V and VI skin have not yet been treated. Using lower energies delivered in two passes may prove to be quite useful in darker skin types and tanned patients. Further research in these groups is needed to determine the effectiveness and side-effect profile in darkly pigmented or tanned patients. Others have demonstrated improvement in acne following treatment with the 1,450 nm, diode laser used in the current study. Paithankar et al. [25] showed improvement in acne located on the back following four treatments administered at 3-week intervals, using fluences higher than were used in the current study. These investigators noted a 98% improvement in acne lesion counts 24 weeks following the 4th treatment. Transient hyperpigmentation was seen in a few patients and was the only significant sideeffect [25]. Paithankar et al. utilized fluences much higher than are currently available with this laser, and the back was treated instead of facial skin. This important study paved the way for further refinements in the treatment protocol for using the 1,450 nm, diode laser for treating acne. Zelickson s group attempted to reduce the pain of treatment by using microdermabrasion prior to the application of a topical anesthetic, to hopefully increase penetration of the topical anesthetic into skin [28]. Although no improvement in anesthesia was seen using microdermabrasion in this study, a 55% reduction in acne severity was noted, and improvement was measured 12 weeks following the final treatment [28]. Friedman et al. [26] combined treatment with the 595 nm pulsed-dye laser, and the 1,450 nm diode laser using fluences similar to the high-fluence, single-pass side used in the current study. They delivered treatment with 595 nm pulsed-dye laser, immediately followed by the 1,450 nm diode laser. They administered three treatments at 4 6 week intervals and assessed improvement 4 6 weeks following the final treatment, demonstrating an 84% improvement in acne lesions counts [26], slightly better than the improvement measured in our current study. Larger studies with longer follow-up may be able to assess the relative benefits of including pulsed-dye laser treatment with 1,450 nm diode laser treatment. Although significant improvement in acne severity was measured in the current study, improvement was followed for 2 months following the final treatment, so no conclusions can be drawn from this study about the duration of improvement and the relative long-term benefits of each treatment condition beyond this time period. However, Paithankar et al. utilized a treatment protocol more similar to the high-fluence, single-pass side and demonstrated persistent improvement for 24 weeks following a series of four treatments to back skin [25]. Thus in at least one setting, long-term improvement has been demonstrated following 1,450 nm laser treatment. Even if the low-fluence, double-pass protocol is found to offer a less durable response, there will be a significant subset of patients who will only tolerate this option, due to the discomfort of the higher-fluence treatments. Thus, the dramatic reduction in pain associated with the low-fluence, double-pass treatment protocol may make acne treatment with this laser viable for a number of patients who would otherwise not be candidates for treatment due to the discomfort

6 198 BERNSTEIN associated with it, especially teenagers. This author currently uses the double-pass, low-fluence treatment protocol almost exclusively to treat acne, often preceded by a single-pass with the pulsed-dye laser, all without the use of topical anesthetic. Larger studies of this treatment protocol with longer-term follow-up should further clarify the role of low-fluence, double-pass 1,450 nm laser treatment for acne, with or without the addition of the pulseddye laser, and its potential to reduce hyperpigmentation in darker skin types. In addition, since the low-fluence, double-pass protocol was well tolerated but requires twice as much time to administer; future advances in this laser system may incorporate a larger spot size which would shorten treatment times and reduce the cost of this procedure. REFERENCES 1. Leyden JJ, Kligman AM. Acne vulgaris: New concepts in pathogenesis and treatment. Drugs 1976;12: Lee DJ, Van Dyke GS, Kim J. 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