Interventions to Prevent Postinflammatory Hyperpigmentation After Laser and Energy‐Based Device Treatments: A Systematic Review and Network Meta‐Analysis

ABSTRACT

Background

Postinflammatory hyperpigmentation (PIH) is the most common adverse effect following laser treatments, yet the relative efficacy of proposed prophylactic measures remains uncertain.

Objectives

To compare the effectiveness of available interventions for preventing laser‐induced PIH in randomized controlled trials (RCTs).

Methods

PubMed, Embase, Scopus, Cochrane Library, and ClinicalTrials.gov were searched through February 2025. RCTs reporting PIH incidence after laser or other energy‐based treatments were eligible. A random‐effects network meta‐analysis (NMA) combined direct and indirect evidence; treatments were ranked by surface under the cumulative ranking curve (SUCRA).

Results

Fourteen RCTs were included in the systematic review, with 11 included in the NMA. Intradermal tranexamic acid (TXA), topical corticosteroids, topical vasoconstrictors, oral TXA, and epidermal cooling were significantly more effective in reducing PIH incidence compared with sunscreen monotherapy, with intradermal TXA demonstrating the highest efficacy (RR: 0.02, 95% CI: 0.00–0.53). Whitening agents and epidermal growth factor formulations did not show significant benefit over sunscreen, while sunscreen monotherapy was ineffective compared with placebo. Reported adverse events were generally mild, although intradermal TXA was associated with injection site discomfort and bruising.

Conclusion

This systematic review and NMA indicate that topical corticosteroids and intradermal TXA may offer greater protection against laser‐induced PIH than sunscreen monotherapy. Preventive strategies should be incorporated into laser treatment planning, particularly for patients with higher risk of hyperpigmentation. Overall, the findings support an evidence‐based and individualized approach to PIH prevention. Interpretation should remain cautious due to the limited number and modest sample sizes of included trials.

1. Introduction

Postinflammatory hyperpigmentation (PIH) is among the most common and distressing adverse effects following laser and light‐based procedures, particularly in individuals with darker skin phototypes (SP). It presents as hyperpigmented macules or patches, ranging from tan to black, over sites of previous inflammation [1]. Several factors contribute to the development of PIH, including SP, ultraviolet (UV) exposure before and after treatment, the laser modality used, and the extent of postprocedural inflammation [2].

The pathogenesis of PIH is characterized by heightened melanocyte activity along with hyperplasia and hypertrophy, resulting in increased melanin production [1]. Moreover, inflammatory mediators enhance melanin synthesis and contribute to abnormal melanin deposition within the epidermis after laser‐induced skin injury [3, 4].

The severity of laser‐induced skin injury is directly correlated with the intensity of the resulting inflammatory response and, consequently, the risk of developing PIH [5]. Ablative fractional lasers, such as fractional CO₂ and erbium: YAG, are associated with a higher incidence of PIH compared with non‐ablative modalities [6, 7]. Higher treatment densities in fractional laser resurfacing have been shown to increase this risk [7]. Although PIH is typically benign and may gradually resolve, it can significantly affect self‐esteem and overall quality of life (QoL) [8].

Several strategies have been explored for the prevention and management of PIH, including topical agents, oral tranexamic acid (TXA), and intradermal TXA injections [9, 10, 11, 12]. While various studies have examined prophylactic measures [11, 13, 14, 15, 16], one notable trial demonstrated that initiating topical treatment 2 weeks before laser therapy significantly reduced the PIH incidence [12]. Despite growing interest in PIH prevention, there remains no standardized protocols, clear recommendations for optimal timing, or comparative data on the efficacy of available interventions. In this context, prevention remains the most effective strategy.

To address this gap, a systematic review and network meta‐analysis (NMA) of randomized controlled trials (RCTs) was conducted to evaluate and compare interventions for preventing PIH in patients undergoing laser treatment. This analysis also assessed whether factors such as treatment location and laser modality influenced outcomes.

2. Materials and Methods

2.1. Protocol and Registration

The study was registered with the International Prospective Register of Systematic Reviews (PROSPERO; www.crd.york.ac.uk/PROSPERO) under the registration number CRD42024576103. The review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) extension statement for NMA [17].

2.2. Eligibility Criteria

RCTs involving patients who received interventions to prevent PIH following laser or energy‐based device (EBD) treatments were included. Eligible interventions comprised topical agents, oral medications, intradermal injections, and cooling devices, administered before, during, or after the procedures.

The primary outcome was defined as the incidence of PIH at 8 weeks post‐treatment. When 8‐week data were unavailable, outcomes reported at 6, 4, or 12 weeks were used, in that order. The 8‐week time point was selected based on published evidence indicating that PIH incidence typically peaks between Weeks 4 and 8 [13, 18, 19], and was further supported by the clinical experience of the investigator (W.M.), who identified Week 8 as the most consistent time point for maximal PIH expression.

Sensitivity and subgroup analyses were also conducted to compare PIH incidence across different treatment locations and laser modalities. Adverse events associated with each intervention were also assessed.

Only English‐language RCTs reporting sufficient outcome data were included. No restrictions were placed on the duration of follow‐up. Abstracts, conference proceedings, and review articles were excluded from the analysis.

2.3. Databases and Search Strategy

A comprehensive search was conducted across five electronic databases: Scopus, Embase, PubMed, Clinicaltrial.gov, and the Cochrane Central Register for Controlled Trials (Cochrane), covering all records up to February 25th, 2025. Search terms included combinations of the following keywords: “prevention”, “avoidance”, “minimization”, “hyperpigmentation”, “melanogenesis”, “post inflammatory hyperpigmentation”, “postinflammatory hyperpigmentation”, “laser”, “energy‐based device”, “intense pulsed light”, and “low level light”. Reference lists of relevant studies and review articles were also screened to identify additional eligible trials. The complete search strategy is detailed in Supporting Information S1: Appendix 1.

2.4. Study Selection

Two investigators (S.W. and S.Y.) independently screened the titles and abstracts of all retrieved records using Covidence software (www.covidence.org) to identify potentially relevant studies. Full‐text articles were subsequently reviewed by the same investigators to determine final eligibility. Any discrepancies were resolved through discussion and consensus, with input from a third expert reviewer when necessary.

2.5. Data Extraction and Study Appraisal

Data were extracted on study location, participant age, Fitzpatrick skin type (FST), diagnoses and treatment areas, details of treatment and prophylactic interventions (including regimens, initiation, duration, and follow‐up period), sample size, number of patients who developed PIH at each follow‐up visit, concurrent use of sunscreen and cooling devices, and reported adverse events.

When necessary, study authors were contacted to obtain missing outcome data. Studies were excluded if authors did not respond within 1 month.

2.6. Risk of Bias and Certainty of Evidence

Two investigators independently assessed the risk of bias for each included study using the revised Cochrane Risk of Bias Tool for Randomized Trials (RoB 2.0, London, UK) [20]. This tool evaluates several domains, including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome date, and selective outcome reporting. Risk‐of‐bias assessments for each study were summarized in tabular and graphical formats. Judgements for each domain were categorized as low risk, some concerns, or high risk based on predefined signaling questions aligned with RoB 2.0 guidance. Disagreements between investigators were resolved through discussion and, when necessary, consultation with a third reviewer.

2.7. Data Analysis

A random‐effects framework was prespecified for both pairwise and NMAs due to anticipated clinical heterogeneity across studies, including differences in laser and EBD modality, treatment site, participant risk profiles, and preventive intervention protocols. Pairwise meta‐analyses were conducted using the DerSimonian and Laird random‐effects model [21]. Results were reported as relative risks (RRs) with 95% confidence intervals (CIs). Statistical heterogeneity for each pairwise comparison was assessed using the I‐squared (I²) statistic and the chi‐square (χ ²) test, with heterogeneity considered significant at a p‐value of less than 0.1. Observed I² values were interpreted cautiously in the context of the limited number of included studies, recognizing that low I² does not preclude the presence of clinical heterogeneity in sparse networks.

To incorporate both direct and indirect evidence, an NMA was performed using the network command in Stata Statistical Software (version 18, StataCorp LP, College Station, TX, USA), based on random‐effects model described by Lu and Ades [22]. Intervention rankings were generated using rankogram, surface under the cumulative ranking curve (SUCRA) values, mean ranks, and league tables [23]. Network consistency between direct and indirect estimates was evaluated using a global inconsistency test, with p ≥ 0.1 indicating no significant inconsistency. A comparison‐adjusted funnel plot was used to assess potential publication bias and small‐study effects.

2.8. Subgroup and Sensitivity Analyses

Sensitivity analyses were performed to evaluate the robustness of the results by assessing the impact of the study‐level characteristics on the treatment effects. Analyses were stratified by two predefined subgroups: (i) treatment location (face vs. non‐face) and (ii) laser modality (ablative vs. non‐ablative). Statistical significance was determined using two‐sided tests with a p‐value < 0.05 considered statistically significant.

3. Results

A total of 4161 articles were identified through database searches of Scopus, Embase, PubMed, ClinicalTrials.gov, and Cochrane Library. After removing 342 duplicates and excluding 3753 records based on titles and abstracts that did not meet the inclusion criteria, 66 full‐text articles were assessed for eligibility. Of these, 46 studies were excluded for reasons detailed in Figure 1. Among the remaining 20 studies, six were excluded because they did not report PIH incidence as an outcome. Ultimately, 14 RCTs evaluating interventions to prevent PIH following laser treatment, and reporting incidence rates were included in the systematic review [9, 10, 11, 12, 13, 15, 16, 24, 25, 26, 27, 28, 29, 30]. Of these, 11 RCTs were included in the NMA.

Figure 1.

Summary of the study selection via Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) flow diagram.

The characteristics of the 14 included RCTs are summarized in Table 1. Interventions were categorized as follows: topical steroids (three studies) [12, 13, 27], topical antibiotics (one study) [16], topical vasoconstrictors (one study) [27], epidermal growth factor (EGF) agents (three studies) [9, 24, 25], whitening creams (three studies) [25, 28, 30], sunscreen alone (two studies) [28, 29], oral TXA (one study) [10], intradermal TXA (one study) [11], cooling devices (one study) [26], and placebo (nine studies) [9, 10, 11, 13, 15, 22, 24, 27, 30]. Topical steroids with or without occlusion were grouped under the topical steroid category [27]. Moisturizers were classified as placebo treatments [15, 17], while isobutylamido thiazolyl resorcinol (ITR), 10% glycolic acid, 4% hydroquinone, and 0.025% tretinoin were considered whitening creams [12, 30].

Table 1.

Characteristics of randomized clinical trials included in the systematic review.

Authors/year	Country	Age (years), means ± SD	Fitzpatrick skin type	Diagnosis	Location	Laser	Intervention	n	Onset of treatment	Use of sunscreen/cooling	Duration of treatment/follow up
1. Wattanakrai et al./2022	Thailand	N/A	III: 18 (60%) IV: 10 (40%)	ABNOMs	Face	1064‐nm QS Nd:YAG	EGF cream	30	After laser	Yes/No	8 weeks/8 weeks
							Placebo	30
2. Rutnin et al./2019	Thailand	49.4 ± 11.1	III or IV: TXA: 18 (90%) Placebo: 15 (40%)	SLs	Face	532‐nm QS Nd:YAG	Oral TXA	20	On the day of laser	Yes/Ice pack	6 weeks/12 weeks
		52.8 ± 10.7					Placebo	20
3. Techapichetvanich et al./2018	Thailand	31.2 ± 4.6	III: 13 (68.4%) IV: 5 (26.3%) V: 1 (5.3%)	Acne scars or enlarged pore	Face	Fractional CO2 laser	EGF ointment	19	From 24 h after laser	N/A/No	24 h after laser until crusting completely healed/8 weeks
							Placebo	19
4. Lueangarun et al./2019	Thailand	37.6 ± 9.4	III: 6 (30%) IV: 11 (55%) V: 2 (10%)	Atrophic acne scars	Cheeks	Fractional CO2 laser	Moisturizer	20	After laser	Yes/Ice pack	7 days/60 days
							TA 0.02% cream	20
5. Sirithanabadeekul/et al. 2018	Thailand	60.9 ± 6.6	III: 5 (20%) IV: 17 (68%) V: 3 (12%)	SLs	Forearms	532‐nm QS Nd:YAG	ID TXA	25	After laser	Yes/No	1 session/12 weeks
							Placebo	25
6. Vachiramon et al./2024	Thailand	64.8 ± 11.5	III: 12 (50%) IV: 11 (45.8%) V: 1 (4.2%)	SLs	Hands and forearms	532‐nm QS Nd:YAG	ITR‐containing product	48	2 weeks before laser	Yes/N/A	2 weeks/70 days
							Placebo	24
7. Tumsutti 2024	Thailand	58.5	II: 2 (5.56%) III: 10 (25%) IV: 22 (58.33%) V: 4 (11.11%)	SLs	Forearms	532‐nm QS Nd:YAG	Topical clobetasol propionate 0.05% without occlusion	72	After laser	Yes/N/A	2 days/12 weeks
							Topical clobetasol propionate 0.05% with occlusion	72	Immediately after laser	Yes//A	24 h/weeks
							Topical brimonidine tartrate 0.33% gel	72	1 h before laser	Yes/N/A	4 days/12 weeks
							Placebo	72	After laser	Yes/N/A	7 days/12 weeks
8. Kim et al./2021	Korea	56.7 ± 2.6	III: 5 (16.67%) IV: 25 (83.3%)	SLs	Face	532‐nm QS Nd:YAG	EGF ointment	14	After laser	N/A/N/A	4 weeks/8 weeks
		58.6 ± 2.5					Placebo	16
9. Manuskiatti et al./2007	Thailand	43 (27–72)	III: 17 (73.9%) IV: 6 (4.3%)	ABNOMs	Face	1064‐nm QS Nd:YAG	Cooling	21	30 s before laser	Yes/Yes& No	30 s before, during and after laser irradiation/12 weeks
							Placebo	21
10. Bonciani et al./2021	Italy	51 ± 11	I: 4 (20%) II: 10 (50%) III: 5 (25%) IV: 1 (5%)	SLs	Face	532‐nm QS Nd:YAG	Cosmetic treatment	10	After laser	Yes& No/N/A	3 weeks/4 weeks
							Sunscreen	10			3 weeks/4 weeks
11. Cheyasak et al./2015	Thailand	N/A	IV: 40 (100%)	Atrophic acne scars	Face	Fractional CO2 laser	Topical clobetasol propionate 0.05%	40	After laser	Yes/	2 days/12 weeks
							Placebo	40			7 days/12 weeks
12. Wei et al./2021	China	26.2 ± 6.2	III: 18 (30%) IV: 35 (58.3%) V: 7 (11.7%)	Atrophic acne scars	Cheeks	Fractional CO2 laser	Fusidic acid cream	29	After laser	N/A/No	7 days/12 weeks
		25.5 ± 5.8					Erythromycin ointment	28			7 days/12 weeks
13. Puaratanaarunkon et al./2022	Thailand	28.6 ± 6.2	III: 33 (55.9%) IV: 26 (44.1%)	Acne and atrophic acne scars	Face	Picosecond laser, MLA	Sunscreen A	59	Day 4 after laser	Yes/Yes	6 weeks/6 weeks
							Sunscreen B	59			6 weeks/6 weeks
14. West TB et al./1999	USA	N/A	N/A	Patients underwent CO2 laser resurfacing	Face	Full‐field CO2 laser resurfacing	Glycolic acid 10% cream	25	At least 2 weeks prior to laser treatment	Yes/N/A	At least 2 weeks/12 weeks
							Hydroquinone 4% cream and tretinoin 0.025% cream	25			At least 2 weeks/12 weeks
							Placebo	50			N/A/12 weeks

Abbreviations: ABNOMs, acquired bilateral nevus of Ota‐like macules; CO₂, carbon dioxide; EGF, epidermal growth factor; ID, intradermal; MLA, microlens array; QS Nd:YAG, Q‐switched Nd:YAG; SLs, solar lentigines; TA, triamcinolone acetonide; TXA, tranexamic acid; SD, standard deviation.

Details of interventions and laser modalities used in each study are presented in Supporting Information S1: Appendix 2. Three studies were excluded from the NMA due to the inclusion of a single‐arm topical antibiotic trial [16], a comparison of different sunscreen formulations [29], and the absence of overall incidence of PIH incidence reporting [30]. As a result, 11 studies were included in the NMA. Data on PIH incidence used for quantitative synthesis are provided in Supporting Information S1: Appendix 3.

In one study, the exact follow‐up period for assessing PIH incidence was not specified, and the timing of outcome measurement was therefore considered undetermined [13]. Subgroup and sensitivity analyses were conducted to evaluate the potential impact of this uncertainty.

3.1. Risk of Bias

Risk‐of‐bias assessments for the 14 included RCTs are presented in Supporting Information S1: Appendix 4. Of these studies, six were rated as having low risk of bias, two were judged as having some concerns, and six were classified as high risk. Among the high‐risk studies, the most frequently identified issues were deviations from the intended intervention (five studies), missing outcome data (three studies), and selective reporting of results (three studies).

3.2. NMA on PIH Incidence

A total of 11 studies reporting PIH incidence as a percentage outcome were included in the NMA. The majority of participants were treated for solar lentigines (54.5%), followed by acne scars or enlarged pores (27.3%), and acquired bilateral nevus of Ota‐like macules (18.2%). Most studies focused on facial lesions, while three studies (27.3%) included non‐facial sites, such as the forearms and hands [11, 12, 27].

Of these 11 studies, eight (72.7%) employed non‐ablative lasers, specifically 532‐nm QS Nd:YAG laser in six studies and 1064‐nm QS Nd:YAG laser in two studies, while the remaining three studies used fractional carbon dioxide (CO₂) lasers. Nearly all studies were conducted in Asia, with only one study conducted in Italy [28].

Figure 2 and Supporting Information S1: Appendix 5 illustrate the pairwise comparisons and network geometry of the intervention arms. Table 2 presents the NMA results, which combine both direct and indirect evidence. Sunscreen monotherapy, the standard post‐laser care regimen, served as the reference comparator in all analyses.

Figure 2.

Comparison of all intervention strategies to prevent post‐inflammatory hyperpigmentation (PIH) in patients undergoing laser treatments.

Table 2.

Network‐estimated, relative risks with 95% confidence intervals of incidence of post‐inflammatory hyperpigmentation after laser treatment.

Intradermal TXA
0.67 (0.19, 2.45)	Topical steroids
0.63 (0.16, 2.52)	0.93 (0.51, 1.71)	Vasoconstrictor
0.49 (0.11, 2.20)	0.73 (0.30, 1.77)	0.78 (0.28, 2.19)	Oral TXA
0.44 (0.11, 1.76)	0.66 (0.34, 1.28)	0.71 (0.30, 1.64)	0.90 (0.33, 2.49)	Placebo
0.43 (0.12, 1.50)	0.64 (0.47, 0.87)	0.68 (0.37, 1.26)	0.88 (0.38, 2.01)	0.97 (0.54, 1.73)	Cooling
0.14 (0.01, 1.61)	0.21 (0.03, 1.72)	0.23 (0.03, 1.97)	0.29 (0.03, 2.71)	0.32 (0.04, 2.77)	0.33 (0.04, 2.64)	Whitening cream
0.16 (0.04, 0.75)	0.24 (0.10, 0.61)	0.26 (0.09, 0.75)	0.34 (0.10, 1.11)	0.37 (0.13, 1.05)	0.38 (0.16, 0.91)	1.15 (0.12, 10.87)	EGF
0.02 (0.00, 0.53)	0.04 (0.00, 0.61)	0.04 (0.00, 0.69)	0.05 (0.00, 0.93)	0.05 (0.00, 0.97)	0.06 (0.00, 0.95)	0.17 (0.02, 1.16)	0.14 (0.01, 2.80)	Sunscreen

Note: Bold values indicate statistically significant difference p < 0.05.

Abbreviations: TXA, tranexamic acid; EGF, epidermal growth factor.

The NMA demonstrated that sunscreen alone did not offer a significant advantage over placebo in reducing PIH incidence. In contrast, several interventions were associated with significantly lower PIH rates compared with sunscreen. Intradermal TXA showed the greatest effect, with a RR of 0.02 (95% CI, 0.00–0.53) followed by topical corticosteroids (RR, 0.04; 95% CI, 0.00–0.61, topical vasoconstrictors (RR, 0.04; 95% CI, 0.00–0.69), oral TXA (RR, 0.05; 95% CI, 0.00–0.93), and epidermal cooling (EC) (RR, 0.06; 95% CI, 0.00–0.95).

Treatment rankings based on SUCRA probabilities (Supporting Information S1: Appendix 6) identified intradermal TXA (87.4%) as the most effective intervention, followed by topical corticosteroids (80.4%) and topical vasoconstrictors (73.8%).

Detailed results from subgroup analyses (facial vs. non‐facial lesions; ablative vs. non‐ablative treatments) and sensitivity analyses are presented in Supporting Information S1: Appendix 7, Figures S5–S8 and Tables S4–S7.

3.3. Adverse Effects

The application of topical corticosteroids following fractional CO₂ laser resurfacing resulted in acneiform eruptions in 5% of patients [13]. Topical erythromycin ointment was associated with abscesses or papules in 6.9% of cases [16]. Topical brimonidine led to significantly greater pruritus compared with topical corticosteroids (p < 0.01), although both treatments were associated with xerosis in 18%–22% of patients [27]. The use of EGF was frequently accompanied by transient stinging sensation, with no significant differences in adverse events between groups [24].

Sunscreen use was linked only to mild, self‐limiting reactions, including burning (6.0%), erythema (3.4%), dryness (1.3%), and pruritus (0.4%), all of which resolved spontaneously [29].

Oral TXA caused nausea in 20% of participants (p = 1.000) and hypomenorrhea in 15% (p = 0.231), with no thromboembolic events reported [10]. Intradermal TXA was associated with mild, short‐lived burning in 8% of injections [11]. Finally, topical hydroquinone and tretinoin were frequently associated with irritant contact dermatitis [30].

3.4. Network Consistency and Small Study Effect

The NMA of PIH incidence showed no evidence of inconsistency based on the global test (p = 0.711). Additionally, comparison‐adjusted funnel plots revealed no indication of small‐study effects for PIH incidence (Supporting Information S1: Appendix 8).

4. Discussion

PIH is the most commonly reported adverse effect following laser procedures, particularly in patients with higher FST, and may significantly impair QoL [31]. A range of preventive strategies has been investigated, including topical, oral, and intralesional therapies, as well as physical approaches such as EC, although study outcomes have been inconsistent.

This NMA identified five interventions that were significantly more effective than sunscreen monotherapy in preventing PIH. These were intradermal TXA, topical corticosteroids, topical vasoconstrictors, oral TXA, and EC with efficacy decreasing in that sequence. In comparison, whitening creams and EGF did not demonstrate a statistically significant advantage over sunscreen alone. Their limited effect may be attributed to small sample sizes and the paucity of well‐powered RCTs.

4.1. Intradermal TXA Injection

This analysis demonstrated that intradermal TXA was more effective than sunscreen monotherapy in reducing the incidence of post‐laser PIH. In an RCT, intradermal TXA (50 mg/mL) reduced the PIH rate to 16% compared with 28% with 0.9% normal saline on forearm lesions following 532‐nm QS Nd:YAG laser treatment for solar lentigines. The proposed mechanism involves inhibition of inflammatory mediators and suppression of melanogenesis via antiplasmin activity [32]. Unlike oral TXA, the intradermal route avoids systemic exposure and the associated risk of thromboembolic complications [33]. This profile makes it a promising prophylactic option for PIH, particularly on non‐facial sites—such as the extremities—where healing is slower and pigmentation risk is higher [34, 35]. However, its role in facial treatments remains less defined and warrants further evaluation. Despite its potential, the procedure is not without limitations. It requires multiple injection points, which may be painful and less feasible over large treatment areas. Inadvertent intravascular injection can lead to bruising and hemosiderin deposition, causing transient hyperpigmentation that may persist for several weeks [36]. These risks should be weighed when considering intradermal TXA as a preventive measure.

4.2. Topical Corticosteroids

Short‐term use of topical corticosteroids has been shown to significantly reduce the risk of post‐laser PIH compared with the use of sunscreen alone [13, 15]. These agents suppress inflammation by inhibiting phospholipase A2, thereby reducing the release of inflammatory mediators and limiting melanogenesis [13]. Two RCTs demonstrated the effectiveness on facial skin, with triamcinolone 0.02% cream for 7 days [15] and clobetasol propionate 0.05% ointment for 2 days [13], both leading to a lower incidence of PIH following fractional CO₂ laser treatment [13, 15]. In contrast, Tumsutti et al. [27] reported that 0.05% clobetasol propionate ointment, with or without occlusion, applied immediately after 532‐nm QS Nd:YAG laser treatment for solar lentigines on the forearm, did not significantly reduce PIH incidence or severity. The lack of efficacy may reflect differences in treatment site, laser modality, corticosteroids potency, or baseline skin characteristics. Notably, both RCTs demonstrating benefit were conducted on facial skin [13, 15], whereas the study showing no benefit involved non‐facial lesions [27]. Overall, these findings suggest that topical corticosteroids are a practical and effective prophylactic option, particularly for facial procedures where they are safe, easy to apply, and well‐tolerated. Low‐potency corticosteroids are widely considered safe and associated with minimal adverse effects, including a low risk of acneiform eruptions [15], while short‐term use of high‐potency agents may enhanced anti‐inflammatory effects without compromising safety [13]. As topical corticosteroids can be self‐administered, adherence is typically good. Furthermore, several studies have reported that corticosteroid application reduces post‐laser discomfort and improves overall patient satisfaction [15, 27]. Since inflammation can begin immediately after laser exposure and persists for several weeks, early application of corticosteroids during this period is important [5]. While evidence supports their utility, clinical decisions regarding the choice of agent, potency, formulation, and duration should be guided by treatment site and laser type.

4.3. Topical Vasoconstrictors

Brimonidine, a highly selective alpha‐2 adrenergic agonist, produces direct vasoconstriction of superficial dermal vessels [37]. This action is hypothesized to improve laser targeting of melanin by reducing competing absorption from hemoglobin and may also help attenuate post‐laser erythema and edema, potentially contributing to reduced post‐inflammatory pigmentation [38]. In the included RCT by Tumsutti et al. [27], the application of topical brimonidine 1 h before 532‐nm QS Nd:YAG laser treatment for solar lentigines on the forearms did not significantly reduce the incidence of PIH [27]. This limited effect may be attributable to suboptimal timing of application, as vasoconstrictive effects may not have been achieved within the 1‐h interval. Extending the pre‐treatment duration might improve efficacy by allowing more sustained vascular constriction during laser exposure [37]. These findings suggest that the effectiveness of topical vasoconstrictors in PIH prevention may depend on factors such as timing of application, anatomical site, and vascular characteristics of the skin. Additional studies are needed to clarify optimal treatment parameters and to determine whether brimonidine or similar agents have a clinically meaningful role in reducing post‐laser hyperpigmentation.

4.4. Oral TXA

TXA inhibits plasminogen activation, leading to reduced inflammation, suppression of melanogenesis, and antiangiogenic effects [39]. Despite these properties, an RCT evaluating oral TXA at a dose of 1500 mg per day for 6 weeks, initiated on the day of 532‐nm QS Nd:YAG laser treatment, reported no significant reduction in PIH incidence [10]. Additionally, 20% of participants experienced nausea during the treatment period [10]. While oral TXA has a low risk of thromboembolic events, clinicians should be aware of potential adverse effects such as abdominal discomfort, nausea, vomiting, and palpitations [39]. Given its systemic nature and tolerability concerns, oral TXA may be less suited for routine PIH prevention compared with more targeted approaches. Its use may be reserved for select cases where localized options are insufficient or not feasible.

4.5. EC

EC showed greater efficacy than sunscreen monotherapy in reducing the incidence of PIH. However, one RCT reported an increased risk of PIH when cold air was applied 30 s before and after laser treatment [26]. The paradoxical outcome may reflect a hyperreactive response of melanocytes and keratinocytes to laser‐induced injury when combined with cold exposure, potentially promoting melanogenesis. These findings suggest that the effectiveness of EC may depend on timing, duration, and individual skin characteristics. Although it offers non‐pharmacologic approach to PIH prevention, optimizing its application parameters is essential to minimize potential risks.

4.6. Whitening Agents

The efficacy of whitening agents for PIH prevention has shown inconsistent results across the RCTs included. Vachiramon et al. [12] reported that a 2‐week pre‐treatment with ITR significantly reduced PIH following 532‐nm QS Nd:YAG laser therapy. Similarly, the use of topical formulations primarily containing kojic acid and glycolic acid was more effective than sunscreen alone at 4 weeks post‐treatment [28]. In contrast, a study involving patients who underwent full‐field ablative CO₂ laser resurfacing found no benefit with pretreatment using 10% glycolic acid, 4% hydroquinone, and 0.025% tretinoin compared with placebo [30]. These inconsistencies may stem from variations in active ingredients, concentrations, formulation, treatment protocols, and laser modalities. Taken together, these findings suggest that the preventive efficacy of whitening agents is context‐dependent and may not be broadly generalizable.

4.7. Epidermal Growth Factor (EGF)

EGF is a peptide that modulates cellular proliferation, migration, and differentiation by binding to its receptor expressed on melanocytes. It is proposed to reduce inflammation‐induced melanogenesis and help mitigate hyperpigmentation [40].

However, the evidence for its effectiveness in PIH prevention remains inconclusive. Two RCTs found no significant benefit of EGF‐containing formulations following laser treatment [9, 24]. In contrast, Kim et al. [25] reported a lower incidence of PIH at 8 weeks among patients treated with EGF‐containing ointment after 532‐nm QS Nd:YAG laser for solar lentigines. These conflicting findings may reflect differences in formulation, concentration, and application protocols. Currently, no standardized regimen exists for the use of EGF in preventing laser‐induced PIH.

4.8. Sunscreen Alone

The use of sunscreen is typically recommended as a part of routine post‐laser care to reduce the risk of PIH [41]. One RCT comparing sunscreen with and without additional anti‐inflammatory agents reported a decrease in pigmentation scores but found no significant differences following fractional picosecond laser treatment [29]. This finding aligns with the results of the present NMA, which found that post‐procedure sunscreen monotherapy was not effective in reducing the incidence of PIH compared to placebo. This observation should be interpreted cautiously, as real‐world factors such as suboptimal patient adherence, inadequate SPF or formulation, insufficient quantity applied, and inappropriate timing or frequency of application may compromise the protective effect of sunscreen and influence trial outcomes. Although sunscreen was used concurrently with other interventions in the included trials, its lack of independent efficacy suggests that it likely did not confound the observed effects of other preventive interventions. Importantly, photoprotection remains a fundamental and essential component of post‐laser care and should continue to be routinely recommended as part of comprehensive PIH prevention strategies.

4.9. Topical Antibiotics

Topical antibiotics are often prescribed after laser procedures to reduce the risk of secondary infections, yet their role in PIH prevention remains underexplored. One RCT found that 2% fusidic acid (FA) cream applied for 7 days following fractional CO₂ laser treatment for acne scars was associated with a lower incidence and severity of PIH compared with 0.5% erythromycin ointment [16]. The mechanism by which FA may reduce PIH is not fully understood, but its anti‐inflammatory effects and ability to limit subclinical infections may contribute to decreased post‐treatment pigmentation.

4.9.1. Practical Considerations

Among the 14 RCTs included in this review, most interventions (71.4%) were applied after laser treatment, while a minority initiated treatment beforehand, ranging from 30 s to 2 weeks in advance [12, 16, 27, 30]. In clinical settings, combining pre‐ and post‐treatment strategies may yield additive or synergistic effects, particularly for patients at higher risk of PIH, such as those with higher FST or those undergoing treatment on non‐facial areas. Tailoring preventive measures to patient characteristics and procedural variables is essential. For example, short‐term topical corticosteroids are simple, safe, and effective for facial procedures, whereas intradermal TXA may be more suitable for non‐facial areas where PIH risk is higher and systemic exposure is best avoided. Additional options such as topical vasoconstrictors, oral TXA, and EC can be considered based on clinical context, patient preference, and laser modality.

A recent systematic review on PIH prevention in individuals with skin of color reported sunscreen, alone or combined with other ingredients, as an effective preventive strategy [42]. However, most cases in that review followed laser therapy (95%), with fewer resulting from UV‐B exposure (4%) or chemical peels (0.3%). This variation in etiology may explain differences in findings, as sunscreen may offer greater benefit when UV exposure is the primary causative factor. Although PIH is often transient, it can persist for up to a year in darker‐skinned individuals, significantly impacting QoL [31]. Therefore, proactive PIH prevention should be a standard component of care for all patients undergoing laser procedures, particularly those at elevated risk.

This study has several limitations. First, this NMA focused solely on PIH incidence; quantitative measures such as melanin index or L* values could not be pooled due to inconsistent measurement techniques across studies. Second, the relatively small number and limited sample sizes of included trials may have reduced statistical power and the precision of effect estimates, particularly for indirect comparisons within the network. Although no significant heterogeneity, inconsistency, or small‐study effects were detected, assessments have limited sensitivity in sparse networks, and treatment rankings should therefore be interpreted as probabilistic rather than definitive. Efforts were made to minimize bias through comprehensive database searches and clearly defined eligibility criteria. Lastly, as most studies were conducted in Asian populations, findings may not be directly generalizable to other ethnic backgrounds or skin types.

5. Conclusions

This systematic review and NMA suggest that topical corticosteroids and intradermal TXA are among the most effective interventions for preventing PIH following laser treatments, demonstrating greater effectiveness than sunscreen monotherapy on facial and non‐facial sites, respectively. While intradermal TXA ranked highly in comparative analyses, its use requires multiple injections and may be associated with adverse effects such as bruising and hemosiderin‐associated hyperpigmentation. In contrast, topical corticosteroids represent a practical, well‐tolerated, and accessible option, particularly for facial applications. Other interventions, including topical vasoconstrictors, oral TXA, and EC, also demonstrated potential benefits and may be considered as viable alternatives depending on appropriate clinical contexts. Given the significant psychological and QoL impacts of PIH, effective prevention should be an integral part of laser treatment planning, particularly for patients with higher FST or other risk factors for hyperpigmentation. Overall, these findings support a tailored, evidence‐based approach to PIH prevention that balances efficacy, safety, and patient preferences. The clinical implications of this study should be interpreted cautiously, given the limited number of included trials and their relatively small sample sizes, despite analyses suggesting no evidence of small‐study effects.

Funding

The authors received no specific funding for this work.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Supplementary appendix PIH_07SEP2025.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.