Comparative efficacy and safety of the novel Picosecond Alexandrite Laser and the traditional combined Q-switched and long-pulse Nd: YAG lasers in melasma treatment: a randomized evaluator-blinded trial

Abstract

Melasma significantly impacts life quality, and while various laser therapies show promise, rigorous comparative studies, especially between the novel Picosecond Alexandrite Laser (PSAL) and the traditional combined modality of Q-switched and Long-pulse Nd: YAG Lasers (QLNYL), are notably lacking. This study aims to fill this gap by evaluating the efficacy and safety of these modalities, providing insights into their comparative advantages for clinical practice. In a prospective, evaluator-blinded study, 40 participants with Fitzpatrick Skin Types (FST) III and IV underwent three treatment sessions at four-week intervals with either PSAL or QLNYL. Efficacy was primarily assessed by changes in Melasma Area and Severity Index (MASI) scores at baseline, 4, 8, 12, and 24 weeks, along with patient satisfaction evaluations at the 12- and 24-week marks, and safety assessments conducted throughout the study. Both groups experienced significant reductions in MASI scores post-treatment. Overall, the improvement in MASI scores in the QLNYL group significantly surpassed that in the PSAL group (P = 0.010). Patient satisfaction was comparably high between groups, and no significant differences were noted in safety profiles. The PSAL group showed a slightly higher incidence of adverse reactions (not significant) and significantly higher pain scores (P = 0.018). Recurrence rates at the 24-week follow-up were 10.5% for PSAL and 0% for QLNYL, with no significant difference. Both PSAL and QLNYL proved effective in treating melasma, with the traditional combined modality of QLNYL demonstrating superior efficacy in FST III-IV. Safety profiles were similar comparable.

Introduction

Melasma, an acquired pigmentary disorder, presents as asymptomatic yet disfiguring, often inflicting substantial social and psychological distress on patients [1]. This condition primarily affects women with darker skin tones, such as those categorized within Fitzpatrick Skin Types (FST) III and IV. Notably, it manifests a 30% incidence rate among childbearing-age Asian women [2]. Melasma’s pathologic changes extend beyond the epidermis, characterized by hyperactive melanocytes and increased melanin, to include dermal changes like the presence of melanophages, perivascular lymphocytic infiltration, solar elastosis, and vascular proliferation [2].

Large-spot, low-fluence Q-switched Nd: YAG lasers (QSNYL), extensively researched for decades, have proven effective in melasma treatment through subcellular selective photothermolysis [3]. This process involves the targeting and fragmentation of melanin granules for phagocytic removal while maintaining melanocyte integrity. However, the peripheral spread of photothermal effects from these lasers can lead to thermal damage, elevating the risk of post-inflammatory hyperpigmentation (PIH) and hypopigmentation [4].

In response, some experts advocate for the combined use of low-energy QSNYL with long-pulse or dye lasers [5]. Research [6] integrating conventional QSNYL with the 1064 nm long-pulse Nd: YAG laser (LPNYL), in a combined Q-switched and long-pulse Nd: YAG laser (QLNYL) mode, has indicated superior efficacy. This modality also leads to reduced adverse reactions and lower energy output of QSNYL compared to using QSNYL alone.

The advent of picosecond lasers, characterized by their ultra-short pulse durations, has introduced a more potent photomechanical effect over photothermolysis. This advancement allows for more effective pigment fragmentation with reduced energy than traditional nanosecond QSNYL, minimizing thermal damage to adjacent tissues. A study [7] has shown that the non-fractional mode of the 755 nm picosecond alexandrite laser (PSAL) is more effective and quicker at clearing melasma pigmentation than conventional QSNYL. Yet, there are still concerns about the risk of post-inflammatory hyperpigmentation with picosecond lasers [8, 9], and the high cost—almost double that of non-picosecond alternatives—poses accessibility challenges for many patients.

Thus, a critical question remains unanswered: Can traditional non-picosecond lasers in a combined modality rival or surpass the efficacy of novel picosecond lasers? This study aims to compare the efficacy and safety of the non-fractional mode of picosecond laser PSAL (755 nm) and the combined non-picosecond laser modality QLNYL (1064 nm) in treating melasma patients with FST III-IV.

Through this approach, we aimed to evaluate not only whether traditional laser technologies can remain effective under certain conditions but also whether it is necessary to completely replace old devices with new ones, or for patients to incur higher costs for the latest equipment.

Materials and methods

Study design

This prospective, randomized, evaluator-blinded study was registered with a national clinical trial registry (Registry No.: ChiCTR2100050089) and approved by an institutional ethics committee (Approval No.: 2021-P2-118-02). All participants provided written informed consent prior to inclusion in the study.

Study participants

From August to December 2021, 40 participants were recruited through a dermatology outpatient clinic at Beijing Friendship Hospital and online poster advertising.

Inclusion criteria included: (1) Dermatologist-diagnosed melasma; (2) Female; (3) Aged 18–65 years; (4) FST III or IV.

Exclusion criteria included: (1) Active melasma phase: Characterized by spot enlargement, darkening, or redness in the last three months. This phase is less responsive to laser treatments and more likely to lead to adverse effects, such as increased pigmentation or post-inflammatory hyperpigmentation, due to heightened melanocyte activity [10]; (2) Other facial hyperpigmentations or acute inflammatory/infectious facial conditions, psychiatric disorders, or severe systemic disorders that could impact the course of melasma or interfere with treatment efficacy and patient safety, including but not limited to severe cardiovascular and respiratory diseases, skeletal disorders, uremia, autoimmune diseases requiring medications such as corticosteroids, malignancies, and serious infections like sepsis, among others; (3) Facial treatments within the past 6 months, including laser therapy, intense pulsed light (IPL), radiofrequency, chemical peeling, facial injections, fillers, and metal thread implantation, as well as systemic medications that may affect the progression of melasma (such as tranexamic acid, glutathione, vitamin C, vitamin E, corticosteroids, retinoids, and oral contraceptives) within 6 months, and topical skin medications within 4 weeks; (4) Photosensitivity, scar diathesis, pregnancy, lactation, or excessive sun exposure within four weeks.

Intervention and methods

Randomization and blinding

Participants were randomized into two groups: QLNYL (1064 nm) and PSAL (755 nm), in a 1:1 ratio using random numbers generated by Statistical Package for the Social Sciences (SPSS) (Fig. 1). Blinding was not feasible for participants and operators due to distinct laser device appearances, but outcome assessors were blinded.

Fig. 1.

Schematic presentation of the flow of participants through randomization, interventions, and follow-ups. PSAL = picosecond alexandrite laser, QLNYL = Q-switched and long-pulse Nd: YAG laser

Equipment and procedure

QLNYL group utilized 1064 nm Q-switched Nd: YAG laser (Biaxis QS; HLS, Germany). Initial settings were QS 1064 mode with parameters: spot size 7 mm, fluence 1.0-1.3 J/cm², pulse width 6–20 ns, frequency 10.0 Hz; followed by long pulse width 1064 mode (free-running, FR mode) with parameters: spot size 4 mm, fluence 10.0 J/cm², pulse width 0.3ms, frequency 10.0 Hz. In this study, we use the term ‘long-pulsed’ to describe the 0.3-millisecond pulse duration of the Nd: YAG laser’s FR mode, consistent with recent publications [6, 11] that classify sub-millisecond durations as long-pulsed due to their operational characteristics and biological effects.

PSAL group used 755 nm Picosecond Alexandrite laser (Picosure^®; Cynosure, USA) with a flat optic (non-fractional mode). Settings were: spot size 6/8 mm, fluence 0.40–0.71 J/cm², pulse width 750ps, frequency 10.0 Hz.

All patients underwent a full-face scan followed by a focused scan on melasma patches. Average pulse counts per session were 6000 for both modes in QLNYL and 4100 for PSAL. The endpoint of laser treatment was mild erythema. Post-laser, all faces were immediately cooled with distilled water spray for 20 min. Three laser sessions were conducted at 4-week intervals (Fig. 1).

Participants continued using their regular moisturizers but ceased any whitening skincare products, chemical peels, and other phototherapy outside this study. Sun protection education was provided. All participants received the same broad-spectrum sunscreen (SPF 48, PA+++, Winona; Betteni Biotech Group, China) with an application of approximately 2 mg/cm² at least every two hours during daylight (as teaspoon rule [12]). Additional comprehensive photoprotection methods were encouraged, such as avoiding going out during peak UV radiation times, seeking shaded areas, wearing sun-protective masks, wearing sunglasses, and using UV-protective umbrellas.

Clinical efficacy evaluation and follow-up

MASI scoring was the primary outcome measure. Two trained physicians independently performed MASI assessments using utilizing standardized full face, left profile, and right profile photographs taken with VISIA^® (Canfield Scientific, USA) under consistent lighting and angles. Assessments were conducted at baseline, 4, 8, 12, and 24 weeks.

Patient satisfaction, a secondary outcome measure, was assessed at 12 and 24 weeks using a four-point scale: 0 (no improvement or worsening), 1 (< 25% improvement), 2 (25–49% improvement), 3 (50–74% improvement), 4 (75–100% improvement).

Clinical safety assessment and recurrence evaluation

All treatment-related events, including immediate adverse reactions (pain during laser, post-treatment erythema, blistering, itching, infection) and long-term adverse reactions (hypopigmentation, hyperpigmentation, scarring), as well as recurrence, were recorded. Pain was assessed using a Visual Analogue Scale (VAS) ranging from 0 (no pain) to 10 (severe pain).

Rebound hyperpigmentation is defined as the initial lightening of melasma during the treatment period (from week 0 to week 12), followed by a sudden exacerbation within two months post-improvement [11, 13]. Recurrence is characterized as an improvement in melasma at the end of treatment (week 12) compared to pre-treatment status, with a subsequent worsening by the end of the follow-up period (week 24) relative to the condition at the end of treatment (week 12).

Statistical analysis

We applied the intention-to-treat (ITT) principle, analyzing all randomized participants. Baseline characteristics, patient satisfaction, adverse reactions, and recurrence rates at the 24-week follow-up were compared using appropriate tests, including t-tests, rank-sum tests, and chi-square or Fisher’s exact tests for categorical data.

For repeated measures and missing data, we used Generalized Estimating Equations (GEE) for intra-group (week 4, 8, 12, 24 vs. baseline for MASI scores; week 24 vs. week 12 for satisfaction scores) and inter-group comparisons (MASI scores and satisfaction). GEE models included group and time effects, group-time interactions, and baseline MASI scores as covariates. If the group-time interaction effect, which indicates varying treatment effects over time, is not significant, the main group effect, reflecting overall differences between groups regardless of time, was considered the primary measure of the intervention effect.

Missing data were managed by GEE without imputation. Statistical significance was set at p < 0.05 using SPSS 27.0 (IBM Corp, NY, USA).

Results

Participant characteristics

The study included 40 participants, with a completion rate of 95.0% (38/40). Per the ITT analysis, 20 participants were analyzed in both the QLNYL and PSAL groups (Fig. 1). Baseline characteristics (age, disease duration, FST classification, and baseline MASI scores) were compared using t-tests, rank sum tests, and Fisher’s exact test, showing no statistically significant differences (P > 0.05) (Table 1).

Table 1.

Baseline demographic and clinical characteristics of study participants

Characteristics	PSAL group (n = 20)	QLNYL group (n = 20)	Between-group P value
Age, years, mean (SD)	39.5 (6.3)	41.3 (8.3)	0.444
Disease course, years, median (IQR)	7.0 (9.8)	10.5 (8.5)	0.645
Fitzpatric skin type, n (%)
Type III	4 (20.0%)	6 (30.0%)	0.465
Type IV	16 (80.0%)	14 (70.0%)
Baseline MASI Score, mean (SD)	14.9 (5.1)	16.7 (9.2)	0.442

PSAL = picosecond alexandrite laser, QLNYL = Q-switched and long-pulse Nd: YAG laser, SD = standard deviation, IQR = interquartile range, MASI = melasma area and severity index

Clinical efficacy evaluation

MASI scores

Both groups demonstrated a consistent downward trend in MASI scores during and after treatment, with statistically significant differences identified (P < 0.001). From week 4 to week 24, each post-treatment assessment point showed statistically significant differences from pre-treatment MASI scores (Table 2). Figures 2 and 3 depict clinical photographs of patients in the QLNYL and PSAL groups, respectively, before and after treatment.

Table 2.

Melasma area and severity index (MASI) scores

Evaluation Time	PSAL Group (n = 20)	QLNYL Group (n = 20)	P Value between Groups#
	mean (SD)	mean (SD)
Baseline	14.9 (5.1)	16.7 (9.2)	0.442
Week 4	14.3 (5.1)*	15.1 (8.1)†	0.151
Week 8	13.3 (4.6)†	13.6 (6.9)†	0.016
Week 12	12.0 (4.5)†	12.3 (6.7)†	0.021
Week 24	10.9 (4.2)†	11.0 (6.5)†	0.103
PValue within Group	< 0.001	< 0.001	0.010 ^

PSAL = picosecond alexandrite laser, QLNYL = Q-switched and long-pulse Nd: YAG laser, SD = standard deviation.

^*p < 0·05 compared with baseline. ^†p < 0·001 compared with baseline. P values in boldface indicate significance.

^#Between group difference of baseline MASI score were compared by student’s t-test, while others were compared by GEE.

^{^}Group main effect, reflecting overall differences between groups regardless of time, was considered the primary measure of the intervention effect.

Fig. 2.

Clinical photographs of a 34-year-old subject from the QLNYL group. (a1, a2): Photos at Week 0, (b1, b2): Photos at Week 12, (c1, c2): Photos at Week 24. MASI Scores: Week 0–33.9, Week 12–26.7, Week 24–25.9. PSAL = picosecond alexandrite laser, QLNYL = Q-switched and long-pulse Nd: YAG laser

Fig. 3.

Clinical photographs of a 44-year-old subject from the PSAL group. (a1, a2): Photos at Week 0, (b1, b2): Photos at Week 12, (c1, c2): Photos at Week 24. MASI Scores: Week 0–27.4, Week 12–23.2, Week 24–21.5. PSAL = picosecond alexandrite laser, QLNYL = Q-switched and long-pulse Nd: YAG laser

GEE analysis indicated that the group-time interaction effect was not significant (P = 0.795). The estimated marginal means ± standard errors (SE) for post-treatment MASI scores were 12.3 ± 0.3 for the QLNYL group and 13.3 ± 0.3 for the PSAL group, with a significant main effect of group (P = 0.010). Since baseline MASI scores did not differ significantly between groups, the QLNYL group showed significantly lower post-treatment MASI scores compared to the PSAL group, independent of the time effect. This indicates that, overall, the QLNYL group demonstrated superior efficacy compared to the PSAL group.

At various post-treatment assessment points, the rate of improvement in MASI scores for the QLNYL group was higher than that for the PSAL group, with statistical significance noted at weeks 8 and 12 (P < 0.05) (Fig. 4). These individual effects were considered secondary outcome measures.

Fig. 4.

Bar chart of MASI score improvements. The QLNYL group showed greater improvement than the PSAL group, with a significant group main effect (P = 0.010), considered the primary measure of the intervention effect. At various post-treatment assessment points, the QLNYL group demonstrated a higher rate of improvement in MASI scores than the PSAL group, with statistical significance observed at weeks 8 and 12 (P < 0.05). MASI = melasma area and severity index, PSAL = picosecond alexandrite laser, QLNYL = Q-switched and long-pulse Nd: YAG laser. *p < 0·05

Patient satisfaction scores

At week 12, 45% (9/20) of patients in both QLNYL and PSAL groups reported > 50% improvement in melasma; this figure was 47.4% (9/19) at week 24. At week 12, 5.0% (1/20) of patients in both groups reported no effect or worsening post-treatment; at week 24, these figures were 0% (0/19) and 21.1% (4/19), respectively (Fig. 5). Statistical analysis revealed no statistically significant differences in intra-group comparisons of patient satisfaction scores between weeks 12 and 24 (P = 0.176, P = 0.618).

Fig. 5.

Pie charts of patient satisfaction. 0 (no improvement or worsening), 1 (< 25% improvement), 2 (25–49% improvement), 3 (50–74% improvement), 4 (75–100% improvement). PSAL = picosecond alexandrite laser, QLNYL = Q-switched and long-pulse Nd: YAG laser

Patient satisfaction scores showed no significant differences between the QLNYL and PSAL groups at both 12 and 24 weeks (P = 0.829, P = 0.421), with no significant main effect in inter-group comparisons (P = 0.513).

Clinical safety assessment

Adverse reaction rates were 10.0% (2/20) in the QLNYL group and 15.0% (3/20) in the PSAL group, with no statistically significant difference (P > 0.999). No hypopigmentation were noted. In QLNYL, two patients experienced erythema and pruritus, resolving in a week with oral antihistamines, topical anti-infectives, and diligent moisturizing. The PSAL group reported two cases of post-inflammatory hyperpigmentation (PIH); one due to occupational LED light (400–500 nm) exposure without subsequent improvement, and the other resolved within 8 months with topical application of hydroquinone, retinoic acid, and tranexamic acid. No statistical difference in pruritic rash or PIH incidence between groups (P = 0.487).

A single PSAL patient experienced rebound pigmentary changes post-treatment (week 12), unprovoked by external factors, persisting by study’s end, yet no significant difference in rebound pigmentary changes between groups (P > 0.999). Pain scores were significantly higher in the PSAL group (P = 0.018), but post-laser erythema duration was comparable between groups (P = 0.249) (Table 3).

Table 3.

Comparative adverse effects and patient discomfort across laser treatments

Anticipated Effects	QLNYL Group	PSAL Group	P Value
	(n = 20)	(n = 20)
Hypopigmentation, n	0	0	-
PIH, n(%)	0	2(10.0)	0.487
Rebound Hyperpigmentation, n(%)	0	1(5.0)	> 0.999
Erythema and Itching, n(%)	2(10.0)	0	0.487
Total Count, n(%)	2(10.0)	3(15.0)	> 0.999
Duration of Erythematous Appearance after Laser Interventions, h, Median(IQR)	3.0(9.7)	2.0(2.6)	0.249
Pain Scores, Mean(SD)	4.2(1.3)	5.3(1.5)	0.018

PSAL = picosecond alexandrite laser, QLNYL = Q-switched and long-pulse Nd: YAG laser, SD = standard deviation, IQR = interquartile range, PIH = post-inflammatory hyperpigmentation.

P values in boldface indicate significance.

Recurrence rates at the 24-week follow-up

Nineteen participants in each group completed treatment and follow-up (Fig. 1). Recurrence rates at the 24-week follow-up were 10.5% (2/19) in the PSAL group and 0% (0/19) in the QLNYL group. There was no significant differences in recurrence rates at the 24-week follow-up between groups (P = 0.486).

Discussion

Multiple randomized controlled trials [7, 14, 15] have demonstrated the safety and effectiveness of Picosecond Alexandrite Laser (PSAL) in treating melasma. A split-face study [9]indicate that both the fractional and non-fractional modes of PSAL are effective, with the non-fractional mode presenting advantages such as shorter downtime, reduced discomfort, and a lower incidence of post-inflammatory hyperpigmentation (PIH). Therefore, our study employed the non-fractional mode of PSAL. Significant improvements were observed after just one session of non-fractional PSAL treatment (P < 0.05), with these enhancements sustained for four months post three treatments (P < 0.001).

Although previous studies [7, 15] have explored the efficacy of half-face treatments using picosecond and nanosecond lasers, our study employs a combined modality of traditional nanosecond and millisecond lasers, directly comparing them to the newer picosecond lasers. Through this approach, we not only demonstrated that traditional laser technologies remain effective under certain conditions but also highlighted that there is no need to completely replace old devices with new ones, nor is it necessary for patients to incur higher costs for the latest equipment. These findings enhance the robustness of our results and offer solutions to some limitations noted in earlier studies.

Previous studies [7, 15] have consistently demonstrated that the 755 nm non-fractional PSAL is more effective in treating melasma than the traditional 1064 nm QSNYL. The primary factor contributing to this difference is likely the pulse width of the lasers, with picosecond lasers offering more potent photomechanical effects and higher melanin fragmentation efficiency [16]. However, in our study, the traditional nanosecond QSNYL combined with long-pulse LPNYL (QLNYL group) exhibited better outcomes than picosecond PSAL. This might be due to LPNYL’s role in improving the dermal environment of melasma lesions, thereby enhancing the wavelength benefits of QSNYL.

The extended selective photothermolysis of 1064 nm LPNYL leads to the selective absorption of thermal energy by hemoglobin and melanosome in the deep dermis. The millisecond pulse width of LPNYL allows thermal energy to diffuse into surrounding tissues, promoting collagen synthesis and dermal remodeling [17]. Additionally, the photothermal effect on hemoglobin can damage endothelial cells within vessels, potentially blocking the proliferative vessels in melasma lesions [18]. Moreover, studies have shown near-infrared LPNYL’s photomodulatory effects, increasing anti-inflammatory and collagen-synthesis-promoting agents in tissues (TGF-β, PDGF-BB and IL-10) [19, 20] while decreasing pro-inflammatory cytokines (IL-8) [21], aiding in stabilizing melasma.

Aligning with previous research [6, 11], our study confirms the efficacy and safety of the combined low-energy QSNYL and LPNYL modality (QLNYL) for melasma treatment. We observed significant improvement after a single QLNYL treatment (P < 0.001), with improvements in MASI scores increasing over the course of treatments (Fig. 4). Four months post three QLNYL treatments (at 24 weeks), no participants considered the treatment ineffective or worsened post-treatment. The adverse reaction rate of 10.0% (2/20) and a recurrence rate at the 24-week follow-up of 0 demonstrate the treatment’s good safety profile. Contrary to previous studies requiring bi-weekly treatments for a total of ten sessions [6, 11], our study achieved comparable efficacy and safety with fewer treatments– only three sessions every four weeks, suggesting a more practical and feasible approach.

While our findings are promising, there are several limitations to consider. First, the single-center design may limit the generalizability of the findings. Secondly, complete blinding of operators and participants was not feasible due to the visible differences in the laser equipment, which could introduce bias in assessing efficacy, especially in patient satisfaction scores. However, this issue was mitigated by the presence of blinded outcome assessors. Third, the relatively short follow-up period of four months post-treatment may not fully capture long-term outcomes, including recurrence rates and lasting adverse effects.

Conclusion

In conclusion, both QLNYL and PSAL have proven effective in reducing MASI scores in FST III and IV, demonstrating that both new and established laser technologies have their place in the treatment of melasma. However, our study highlights the sustained value of traditional laser technologies, particularly when combined in new ways. The QLNYL, which integrates both Q-switched and long-pulse Nd: YAG modalities, remains a cost-effective and efficient option for treating melasma. While PSAL offers a more efficient procedure with a single-step treatment, the QLNYL’s combination of two laser modes allows for optimized clinical outcomes. These findings emphasize the importance of not only advancing new technologies but also refining and integrating traditional ones to provide optimal patient care.

Author contributions

Xueling Mei and Linfeng Li developed the hypotheses, supervised the research, and critically revised the manuscript. Surong Liang and Shuai Shang conducted the research. Wensi Zhang and Ansheng Tan were responsible for evaluating the primary outcomes based on standardized photographs. Surong Liang managed data analysis, and the creation of tables and figures, and also took the lead in writing the manuscript. Boyang Zhou provided assistance in data analysis and manuscript preparation. All authors made significant contributions to the study and have read and approved the final manuscript for submission.

Funding

This study was funded by the Capital’s Funds for Health Improvement and Research (CFH 2022-2-20212) and the Natural Science Foundation of Beijing Municipal (Grant No.: 7242041).

Data availability

The datasets generated during and analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethical approval

This study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Beijing Friendship Hospital, Capital Medical University (Protocol Number: 2021-P2-118-02).

Competing interests

The authors declare no competing interests.