A randomized comparative study of the efficacy of Q-switched neodymium-doped yttrium aluminium garnet laser versus 4% hydroquinone in the treatment of melasma

INTRODUCTION

Melasma is one of the most common disorders of pigmentation, predominantly affecting females. It is a chronic disorder characteristically involving the sun-exposed sites, presenting as symmetrical light to dark brown macules and patches with irregular borders.¹

Melasma can be categorized based on the distribution pattern as centrofacial, malar, and mandibular. The centrofacial pattern is the most frequently encountered of the three.² It is a multifactorial disease with various trigger factors such as genetic factors, sun exposure, hormonal factors, and drugs. Fitzpatrick skin types III-IV, Asian, and Hispanic women are predisposed to the development of this condition.^3,4

The severity of melasma can be assessed using the melasma area and severity index (MASI), which is an area-weighted numerical evaluation of the pigmentation and homogeneity on the forehead, chin, and right and left malar area. The modified melasma area and severity index (mMASI) was developed after homogeneity was removed from the calculation due to the reduced inter-observer reliability of that measure.⁵

Due to its complicated pathogenesis, unpredictable nature, and frequent relapses, treatment for melasma is challenging.⁶ The treatment approach for melasma involves protection against ultraviolet radiation, suppression of melanocyte activity and melanin production, and facilitation of the breakdown and removal of melanin granules.⁷

The mainstay of melasma treatment continues to be topical therapy. The drug most widely researched for treating melasma is hydroquinone, used at concentrations varying from 2% to 5%.⁷

Recent studies have also demonstrated the efficacy of chemical peels and lasers, either as monotherapy or in combination with topical therapies, for patients who do not respond adequately to topical treatment or for those seeking faster improvement.⁷ The Q-switched neodymium-doped yttrium aluminium garnet (Nd:YAG laser), which relies on the concept of selective photothermolysis, is the preferred laser for treating combined epidermal-dermal and dermal pigmented lesions, especially in people with dark skin.⁸

Despite the availability of numerous topical and procedural treatment options for melasma, the search for an optimal therapeutic modality continues. While low-fluence Q-switched Nd:YAG laser therapy has gained acceptance in the management of melasma, only limited well-designed randomized trials comparing these modalities as monotherapy in Indian skin types are available.⁹ Therefore, the present study was undertaken to compare the efficacy and safety of low-fluence Q-switched Nd:YAG laser and topical 4% hydroquinone cream as monotherapy in patients with melasma.

MATERIAL AND METHODS

After obtaining the ethical clearance from the Institutional Ethics Committee (Certificate No. SU/SMS&R/76–A/2023/48), this open label, prospective, randomized controlled interventional study was conducted over 18 months (May 2023–November 2024) on a total of 80 patients aged 18 years and above of either sex with clinically diagnosed melasma attending the dermatology outpatient department of a tertiary care center in North India. Sample size was calculated using the formula n = Z²pq/d². Taking Z = 1.96 at 95% confidence level, p = 33.3% (maximum reported prevalence of melasma in India), q = 66.7%, and absolute precision (d) = 11%, the calculated minimum sample size was 70.5, approximated to 71.⁴ For the convenience of equal randomization and to improve study feasibility, 80 patients were finally enrolled, with 40 patients in each group [Figure 1].

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Figure 1: Study Protocol. Nd:YAG: Neodymium-doped yttrium aluminium garnet, mMASI: modified melasma area and severity index, IGA: Investigator global assessment, PGA: Patient global assessment

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Patients who had previously received treatment for melasma were included after a washout period of 3 weeks for prior topical therapy and 6 weeks for procedural treatments. Written informed consent was obtained from all patients before they participated in the study. Patients were excluded if they were on oral contraceptives or hormone replacement therapy, were pregnant or lactating, had systemic comorbidities, active facial infections or inflammation, or known hypersensitivity to lasers.

Participants were randomized in a 1:1 ratio using a computer-generated block randomization sequence created using the Sealed Envelope online randomization tool. Participants were assigned to their respective groups according to this sequence at the time of enrollment. The randomization list was concealed from investigators before allocation to ensure allocation concealment.¹⁰

RESULTS

A total of 80 patients with clinically diagnosed melasma were enrolled and randomized equally into two groups: Group A received three sessions of Q-switched Nd:YAG laser at 4-week intervals, while Group B applied topical 4% hydroquinone cream once daily for 12 weeks. All randomized participants completed the study and were included in the final analysis.

The mean age of the study population was 34.48 ± 6.7 years (range, 20–50 years). The majority of patients belonged to the 31–40-year age group (47.50%), followed by 20–30 years (33.75%) and 41–50 years (18.75%). Females constituted 80% of the study population. Fitzpatrick skin type V was observed in 56.25% of patients and type IV in 43.75%. The centrofacial pattern was the most common clinical type, seen in 66.25% of patients, while 33.75% had malar melasma. A positive family history was present in 15% of cases. The two groups were comparable with respect to age, sex, Fitzpatrick skin type, duration of melasma, site of involvement, and family history, with no statistically significant intergroup differences in baseline demographic or clinical variables [Table 1].

mMASI

At baseline, the mean mMASI was higher in Group A than in Group B (6.51 ± 3.84 vs. 5.18 ± 2.86), although this difference was not statistically significant (p = 0.094). Both groups showed significant within-group reduction in mean mMASI over the 12-week study period. In Group A, mean mMASI declined from 6.51 ± 3.84 at baseline to 5.86 ± 3.40 at week 4, 4.92 ± 3.25 at week 8, and 3.97 ± 2.59 at week 12. In Group B, mean mMASI decreased from 5.18 ± 2.86 at baseline to 4.55 ± 2.76 at week 4, 3.62 ± 2.19 at week 8, and 2.98 ± 1.93 at week 12. The within-group reductions were statistically significant at each follow-up in both groups. Inter-group comparison showed lower absolute mMASI values in Group B at week 4 (p = 0.047), week 8 (p = 0.030), and week 12 (p = 0.023) [Figures 2 and 3]. However, these findings should be interpreted in light of the numerically higher baseline mMASI in Group A [Table 2].

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Figure 2: A 38-year-old female with melasma from Group A. (a) Pre-treatment photographs at baseline showing right oblique, frontal, and left oblique facial views (from left to right). (b) Post-treatment photographs after three sessions of Q-switched Nd:YAG (Neodymium-doped yttrium aluminium garnet) laser showing corresponding right oblique, frontal, and left oblique facial views (from left to right).

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Figure 3: A 51-year-old female with melasma from Group B. (a) Pre-treatment photographs at baseline showing right oblique, frontal, and left oblique facial views (from left to right). (b) Post treatment photographs after 12 weeks of using topical 4% Hydroquinone cream showing corresponding right oblique, frontal, and left oblique facial views (from left to right).

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Table 2: Comparison of mean mMASI between group A and B.

Mean mMASI (mean±SD)	Group A	Group B	Total	p-value
At baseline	6.51±3.84	5.18±2.86	5.84±3.43	0.094§
At 4 weeks	5.86±3.4	4.55±2.76	5.2±3.15	0.047§
At 8 weeks	4.92±3.25	3.62±2.19	4.3±2.85	0.03§
At 12 weeks	3.97±2.59	2.98±1.93	3.5±2.34	0.023§

^§Mann–Whitney test, mMASI: Modified melasma area and severity index, SD: Standard deviation. A p-value ≤0.05 was considered statistically significant.

IGA

Mean IGA scores improved over time in both groups. At week 4, the mean IGA score was 1.35 ± 0.53 in Group A and 1.50 ± 0.68 in Group B (p = 0.276). At week 8, the scores were 1.85 ± 0.62 and 2.03 ± 0.69, respectively (p = 0.239). At week 12, the mean IGA score increased further to 2.40 ± 0.74 in Group A and 2.69 ± 0.89 in Group B (p = 0.120). Thus, investigator-assessed improvement was observed in both groups, without a statistically significant intergroup difference at any follow-up visit [Figure 4].

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Figure 4: Line diagram depicting the comparison of investigator global assessment (IGA) score at different time intervals between group A (Laser; Blue line) and group B (4% Hydroquinone; Orange line).

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PGA

Patient-reported improvement also increased progressively over the study period. At week 4, mean PGA scores were 1.32 ± 0.53 in Group A and 1.30 ± 0.65 in Group B (p = 0.850). At week 8, they increased to 1.80 ± 0.79 and 2.03 ± 0.64, respectively (p = 0.174). At week 12, Group B showed a significantly higher mean PGA score than Group A (2.72 ± 0.81 vs. 2.33 ± 0.86; p = 0.043), indicating greater patient-perceived improvement with hydroquinone at the end of the study period [Figure 5].

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Figure 5: Line diagram depicting the comparison of patient global assessment (PGA) score at different time intervals between group A (Laser; Blue line) and group B (4% hydroquinone; Orange line).

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Adverse effects

Treatment-related adverse effects were mild and infrequent in both groups. In Group A, 87.50% of patients reported no side effects. Erythema and itching/burning were observed in 5% each, while post-inflammatory hyperpigmentation was noted in 2.50%. In Group B, 80% of patients reported no side effects. Erythema was the most common adverse effect, occurring in 17.50% of cases, followed by post-inflammatory hyperpigmentation in 5% and itching/burning in 5%. No statistically significant intergroup difference was observed for any adverse effect [Table 4 and Figure 6].

Table 4: Comparison of side effects between group A and B.

Side effects	Group A (n=40) (%)	Group B (n=40) (%)	Total (%)	p-value
No side effects	35 (87.50)	32 (80)	67 (83.75)	0.363†
Erythema	2 (5)	7 (17.50)	9 (11.25)	0.154*
Post-inflammatory hyperpigmentation	1 (2.50)	2 (5)	3 (3.75)	1*
Itching/burning	2 (5)	2 (5)	4 (5)	1*

*Fisher’s exact test, †Chi-square test, A p-value ≤0.05 was considered statistically significant.

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Figure 6: (a) Pretreatment photograph of a patient with malar melasma at baseline, (b) Erythema post-application of 4% hydroquinone cream.

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Both treatment modalities were associated with significant short-term clinical improvement over 12 weeks. Group B demonstrated lower absolute mMASI values at follow-up visits and better patient-reported improvement at week 12. However, percentage reduction in mMASI did not differ significantly between groups, suggesting that both modalities are effective treatment options when compared over a 12-week period.

DISCUSSION

Melasma is a chronic, relapsing pigmentary disorder with a significant psychosocial impact, and its management remains challenging because of multifactorial pathogenesis, treatment resistance, and frequent recurrence.¹² In the present study, both low-fluence Q-switched Nd:YAG laser and topical 4% hydroquinone produced significant short-term improvement over 12 weeks, as reflected by serial changes in mMASI, IGA, and PGA. However, the hydroquinone group demonstrated lower absolute mMASI scores at follow-up visits and significantly better patient-reported improvement at week 12.

The demographic profile of our patients was consistent with the known epidemiology of melasma. The mean age of the study population was 34.48 ± 6.7 years, and most patients belonged to the 31–40 year age group. Females constituted 80% of the total study population, and Fitzpatrick skin types IV and V accounted for all patients. The centrofacial pattern was the most common clinical presentation. These observations are in agreement with previous Indian studies reporting melasma predominantly in women in the third and fourth decades, with greater frequency in darker skin phototypes and centrofacial distribution.^4,13

Both treatment groups showed statistically significant intragroup reduction in mMASI from baseline to week 12. In the laser group, mean mMASI decreased from 6.51 ± 3.84 to 3.97 ± 2.59, while in the hydroquinone group, it decreased from 5.18 ± 2.86 to 2.98 ± 1.93. Although Group B had lower absolute mMASI values at weeks 4, 8, and 12, this finding must be interpreted cautiously because the baseline mean mMASI was numerically higher in Group A. Importantly, when treatment response was assessed using percentage reduction in mMASI, the inter-group differences were not statistically significant at any follow-up visit. This suggests that while hydroquinone showed numerically greater improvement, the present results do not conclusively establish its superiority over laser monotherapy.

One possible explanation for the relatively better performance of hydroquinone in the present study is its established role as a first-line depigmenting agent in melasma, particularly in epidermal-predominant disease. Hydroquinone inhibits tyrosinase and interferes with melanosome formation and transfer, and its benefit typically becomes more evident after several weeks of regular use. In the present study, participants in the hydroquinone arm received continuous daily treatment for 12 weeks, a duration that aligns with previous studies demonstrating significant clinical improvement after 8–12 weeks of therapy.¹⁴

The comparatively modest response in the laser arm may be related to the treatment protocol. Our patients received three sessions of low-fluence Q-switched Nd:YAG laser at 4-week intervals. In contrast, several published studies on laser toning in melasma have used a higher number of sessions with more frequent treatment schedules and have reported better mMASI reduction. Therefore, the number of sessions in our study may have been insufficient to demonstrate the maximal potential benefit of laser therapy. In addition, laser response in melasma is known to depend on multiple factors, including fluence, treatment interval, cumulative number of sessions, patient selection, and background phototype. A cautious low-fluence approach, while safer in darker skin, may also reduce short-term efficacy.^6,15

The depth of melasma also plays a crucial role in determining therapeutic response. Epidermal melasma usually responds better to topical depigmenting agents, whereas dermal and mixed melasma are often more resistant. In the present study, classification into epidermal, dermal, and mixed melasma using Wood’s lamp or dermoscopy was not performed. As a result, subgroup analysis based on melasma depth could not be undertaken. This limits the interpretation of the differential response between the two treatment arms and may have contributed to variability in outcomes.¹⁶

Investigator-assessed improvement increased progressively in both groups, but the intergroup differences in IGA were not statistically significant at any follow-up visit. In contrast, patient-reported improvement at week 12 was significantly better in the hydroquinone arm. This discrepancy may reflect differences between patient perception and investigator scoring, but it may also have been influenced by the open-label design of the study. Because participants and investigators were aware of treatment allocation, expectation bias cannot be excluded, particularly for subjective outcomes such as PGA and IGA.

Both treatments were generally well tolerated. Most patients in both groups reported no adverse effects. Erythema was the most frequent side effect and was more common in the hydroquinone group, while occasional cases of post-inflammatory hyperpigmentation and itching/burning were noted in both groups. No statistically significant intergroup difference in adverse effects was observed. These observations were similar to those of Kaminaka et al.,¹⁷ and Liang et al.¹⁸ These findings suggest that both modalities were relatively safe over the short study period, although longer follow-up would be necessary to evaluate delayed adverse events, relapse, or rebound pigmentation.

Our study has clinical relevance because it directly compares two commonly used monotherapy options for melasma in Indian skin types. While many studies have evaluated hydroquinone or laser therapy in combination regimens, fewer studies have compared these modalities head-to-head as monotherapy. The present findings suggest that both treatments are effective in the short term, but hydroquinone may provide greater apparent benefit over 12 weeks under the treatment conditions used in this study. However, this interpretation should remain guarded because of baseline mMASI imbalance, absence of significant difference in percentage mMASI reduction, lack of blinding, and the limited laser treatment schedule.

CONCLUSION

Both the low-fluence Q-switched Nd:YAG laser and topical 4% hydroquinone were associated with significant short-term improvement in melasma over 12 weeks. The hydroquinone group demonstrated lower absolute mMASI values during follow-up and better patient-reported improvement at week 12. However, definitive superiority of hydroquinone cannot be concluded because the percentage reduction in mMASI did not differ significantly between groups, baseline mean mMASI was higher in the laser arm, and the laser protocol may have been suboptimal in terms of the number of sessions. Larger methodologically robust studies with depth-based classification, blinded outcome assessment, optimized laser schedules, and longer follow-up are needed.