Treatments in Periorbital Hyperpigmentation: A Systematic Review and Single-Arm Meta- Analysis of Clinical Trials

doi:10.21203/rs.3.rs-7537721/v1

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Treatments in Periorbital Hyperpigmentation: A Systematic Review and Single-Arm Meta- Analysis of Clinical Trials

https://doi.org/10.21203/rs.3.rs-7537721/v1

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Background:

Periorbital hyperpigmentation (POH) is a common cosmetic concern characterized by bilateral darkening around the eyes, impacting quality of life. Classified as pigmented, vascular, and structural. Treatments include non-invasive treatments encompass topical agents and lasers, while invasive options include fillers or surgery. Despite a standardized guideline, this study synthesizes current evidence to identify the most effective therapies, evidence-based strategies for optimal POH management.

Methods:

Following PRISMA guidelines and registering this review in PROSPERO (CRD420251082683), six databases were searched through June 2025 including randomized controlled trials of periorbital hyperpigmentation therapies. Primary outcomes include dermatologist assessments, pigmentation grading scales, patient-reported satisfaction and studies reporting response categories (e.g., excellent or good). Secondary outcomes will include adverse events as erythema. Random-effects models were used to calculate pooled effect sizes. Risk of bias was assessed using the Cochrane Rob 2.0 tool for randomized controlled trials (RCTs) and the ROBINS-I V2 tool for non-randomized controlled trials.

Results:

Thirty-one studies (n = 1,257) met inclusion criteria. Clinical improvement was assessed by dermatologist evaluation as “good” (>50%) and “excellent” (>75%). Carboxytherapy achieved the highest pooled rate of good improvement 0.50 (95% CI: 0.27 to 0.73; I² = 74.8%), and of excellent improvement 0.26 (95% CI: 0.17 to 0.37; I² = 15.3%). Carboxytherapy also was associated with notable reductions in VAS scores (4.69; 95% CI: 3.97 to 5.40; I² = 67.4%), melanin index reduction (75.23; 95% CI: 23.41 to 127.04; I² = 97.7%) and the lowest pooled value for erythema index (41.09 (95% CI: 28.58 to 53.60). For patient satisfaction carboxytherapy consistently yielded the highest rate of good satisfaction (0.52; 95% CI: 0.38–0.66; I² = 32.8%), whereas carboxytherapy (0.21, 95% CI: 0.07 to 0.47; I² = 56.4%) and PRP consistently achieved an excellent satisfaction (0.18; 95% CI: 0.11–0.28; I² = 0.00%).

Conclusion:

Carboxytherapy and PRP improve clinical efficacy and patient satisfaction in POH by effectively reducing pigmentation and erythema with favorable safety profiles. However, study heterogeneity and lack of standardized subtype classifications limit conclusions. Well-designed, standardized trials are essential to optimize treatment protocols and confirm the long-term safety.

VAS scores

Periorbital hyperpigmentation

Carboxytherapy

Platelet-rich plasma (PRP)

Pigmentation

Erythema

Patient satisfaction

Periorbital hyperpigmentation (POH) is a common dermatological condition, characterized by bilateral darkening around the eyes, sometimes spreading to adjacent facial areas. Although considered a cosmetic concern, POH can negatively affect emotional well-being and quality of life (QOL)[1]. Despite its frequency, data remains limited. An Indian study reported a 30.8% prevalence, predominantly among individuals aged 16 to 25 years[2], [3].

POH is classified into pigmented, vascular, and structural which is associated with post-inflammatory hyperpigmentation (PIH)[4], [5], [6]. Accurate subtype determination is essential for guiding personalized treatment strategies. Multiple therapeutic options can be employed for POH, with topical agents commonly used as first-line therapy. Hydroquinone, a widely used depigmenting agent and kojic acid interfering with melanogenesis [7]. For refractory or severe POH, laser therapy offers a viable treatment option [6]. Structural POH can be addressed with fillers, common filler material options include hyaluronic acid, calcium hydroxyapatite, and autologous fat grafts; the latter is especially beneficial for lower eyelid skin and increased vascular visibility or prominent orbicularis oculi muscle[6]. However, they are not a replacement for surgical correction in cases of significant orbital fat prolapse. In such cases, blepharoplasty remains an effective surgical intervention for hyperpigmentation caused by fat deposits or excess skin[3]. Although some treatments demonstrate benefits in particular cases, no consensus exists on the optimal approach to managing overall POH, reinforcing the importance of additional comparative research. Although POH is a common dermatologic condition with cosmetic and psychosocial implications, the management remains limited, and no standardized treatment guidelines exist. This study provides a comprehensive and up-to-date synthesis of current therapies using meta-analytic methods to assess and compare their effectiveness. By identifying the most effective strategies, we aim to support evidence-based clinical decision-making and address the psychosocial and emotional burden associated with POH.

The present systematic review followed the recommendations and criteria established by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines[8]. We pre-registered the protocol at the International Prospective Register of Systematic Review (PROSPERO) with the identifier code CRD420251082683[9] .

2.1. Eligibility criteria: Type of study, participants, and intervention

We conducted a systematic review and meta-analysis of relevant studies published from the inception of the database to the present, including only randomized clinical trials (RCTs) and cross over studies, in English and Spanish. Studies were excluded if they were duplicates or if the necessary data could not be obtained, or a response from the original author could not be received. This study included participants of all ages undergoing any type of treatment for periorbital hyperpigmentation. Eligible interventions may include, but are not limited to, platelet-rich plasma (PRP), chemical peels, topical depigmenting agents (e.g., hydroquinone, kojic acid), lasers, fillers, autologous fat grafting, baric oxygen, among others. Only studies that evaluated any of these interventions, compared directly with standard care, placebo, or other interventions, were included.

2.1.1. Outcomes

Primary outcomes will include clinical improvement in periorbital hyperpigmentation, measured by blinded photographic assessments, pigmentation grading scales, colorimetric analysis, and patient-reported satisfaction (e.g., VAS or global ratings). Studies reporting response categories (e.g., excellent, good, none) or changes in skin thickness and density will also be included.

Secondary outcomes will include adverse events (e.g., pain, bruising, edema, itching, erythema), and changes in quality of life (e.g., DLQI). Studies must report at least one predefined outcome to be eligible.

2.1.2. Searching methods

We initially conducted a systematic search on June 26th, 2025, on PubMed/MEDLINE, Cochrane, Scopus, Web of Science, EMBASE, CINAHL and Google Scholar using the following terms: of “periorbital hyperpigmentation”, “dark circles”, “infraorbital pigmentation”, and various therapeutic interventions such as “lasers”, “chemical peels”, “fillers”, “platelet-rich plasma”, “topical depigmenting agents”, among others. We have provided all detailed search strategies in the supplementary material (Supplementary Tables 1–7).

2.1.3. Selection of studies

We exported all references to Rayyan (Rayyan Systems Inc., Cambridge, MA, USA) and removed duplicates[10].Two authors independently (A.C.L. and M.V.S.) completed the eligibility assessment, first by title and abstract analysis and, subsequently, by full-text assessment. In disagreements between reviewers, a third reviewer (Y.C.C.) helped reach a consensus.

2.1.4. Data extraction

Two independent reviewers extracted the data (E.M.C. and Y.C.C.), resolving disagreements through consensus.. In cases of multiple overlapping reports from the same study, we included the report with the most relevant information or the earliest publication date. Extracted data included sample sizes, intervention types, and measured outcomes. We employed conventional data extraction methods, complemented by specialized tools such as WebPlotDigitizer (Automeris, Austin, TX, USA) for digitizing data from graphs, Cochrane Calculator for statistical conversions, and StatsToDo for advanced calculations[11], [12], [13]. These outcomes comprised clinical improvement in periorbital hyperpigmentation, measured by blinded photographic assessments, pigmentation grading scales, colorimetric analysis, patient-reported satisfaction (e.g., VAS or global ratings) and response categories (e.g., excellent, good, none) or changes in skin thickness. Additional extracted data included subgroup characteristics, such as country of study, risk of bias levels, and study design.

2.1.5. Assessment of risk of bias in included studies

To assess the quality of the studies included in the systematic review, according to the Cochrane guidelines we applied the Cochrane RoB 2.0 tool for randomized controlled trials (RCTs)[14] and the ROBINS-I V2 tool for non-randomized controlled trials[15]. Two independent reviewers (A.C.L and M.V.S) evaluated the risk of bias in each study, considering the specific criteria and guidelines provided by the respective tools. We resolved discrepancies between reviewers through discussion with a third, blinded reviewer (S.A.B.).

2.1.6. Statistical analysis

A meta-analysis was performed using R version 3.4.3[16], [17]. The pooled effect of the outcomes was examined using a random-effects meta-analysis (DerSimonian-Laird approach)[18]. Whenever the number of studies reporting an outcome of interest was insufficient, only a qualitative analysis of the results was performed. Effect sizes were expressed as Relative Risk (RR), Mean difference (MD), proportions or standardized mean difference (SMD) and 95% CI. The I² statistic assessed heterogeneity, and the following cut-off values used for interpretation: <25, 25–50, and > 50% were considered small, medium, and large heterogeneity respectively[19]. We initially planned to conduct a network meta-analysis (NMA) to compare the relative effectiveness of the included interventions. However, during data extraction, we found that the network was disconnected, with many interventions lacking a shared comparator. This prevented construction of a coherent network. Consequently, we performed single-arm meta-analyses for each intervention separately, without direct or indirect comparisons between treatments. As originally planned, sensitivity analyses according to the leave-one-out method were performed to determine the influence of individual studies on the overall effect, using diagnostic plots proposed by Viechtbauer and Cheung[20]. Egger's regression test examined publication bias when ten or more reports with the same outcome were available[21].

3.1 Study selection

Originally, we identified 1384 potential articles across seven databases. After removing 802 duplicate articles, we conducted a screening based on title and abstract, leading to the exclusion of 500 articles. We sought 82 articles for full-text retrieval and eligibility assessment, of which 52 were excluded. A total of 31 studies were included in this review. Additionally, 1 study identified through previous reviews were included, resulting in a total of 31 studies in this review. We summarized this process in our PRISMA flow diagram (Fig. 1).

3.2 Characteristics of included studies

We analyzed 31 RCTs compromising 1,257 patients across eight countries. Most studies originated from Iran (35%) and Egypt (29%), followed by China (10%), India (10%) and the United States (7%); smaller contributions came from Japan, Pakistan and Thailand (3% each). Melanin Index was assessed in 8 of the 31 studies, 16.13% reported statistically significant improvements with carboxytherapy, placebo, andographins, artemisinin, laser monotherapy, laser combined with placebo and PRP combined with laser; 9.68% showed no effect and 74.19% of studies did not report this outcome. Erythema Index was evaluated in 5 studies with statistically significant improvement observed in 6.45% of studies with artemisinin, carboxytherapy and placebo. Conversely 9.68% showed no statistical difference and 83.87% didn’t report this outcome. Improvement of ≥ 50% by physician assessment was reported in 15 studies where 12.90% demonstrated significant improvement with carboxytherapy, placebo, PRP, TCA combined with lactic acid peeling and plasma gel injection; 35.48% found no significant results and 51.61% of studies did not report this outcome. ≥75% improvement was assessed in 18 studies. From which 16% showed a significant trend favoring carboxytherapy, CO2 laser, placebo, PRP, TCA plus Lactic acid peeling and plasma gel injection, 42% of studies found no significant difference and 42% did not include this outcome. VAS outcomes were reported in 6 studies. Of these 16.12% reported significant benefit from interventions including carboxytherapy, laser (alone or with placebo), PRP alone and combined with laser and plasma gel injections. One study (3.22%) found no significant difference and 80.65% of studies did not include this outcome. A good and excellent patient satisfaction was evaluated in 16 studies, from which 29% reported statistically significant patient satisfaction with PRP alone, carboxytherapy, PRP combined with laser, laser combined with placebo, fat injection alone and with combination therapy, TCA combined with lactic acid peel, Andrographis, placebo, microneedling combined with TCA and CO2 laser; 22.58% found no effet and 48.38% of articles did not report these outcomes. PRP and carboxytherapy were the most frequently reported and consistently demonstrated improvement across multiple outcomes, highlighting their role as therapeutic options. We summarized this information in (Table 1)22–52.

Table 1
General outcome of included studies
Author and Year	Country	Study design	Types of Interventions	Sample size per intervention	Follow up (weeks)	Key points
Afzal N, et al., 2024[22]	USA	RCT	THDA + AZ and THDA alone	44	8	THDA and AZ significantly improved pigmentation, and redness, while THDA alone worsened wrinkles and erythema.
Ahmadraji F, et al., 2015[23]	Iran	RCT-Split face	Emu oil + Vitamin k + Caffeine Pad And Placebo	11	4	The Emu oil + vitamin K + caffeine treatment improved elasticity and decreased in dark circles. In contrast, the placebo showed no elasticity improvement, and worsened pigmentation.
Ahmed N, et al., 2019[24]	Egypt	RCT	Carboxytherapy, TCA + LA Peeling And Vitamin C	45	5	Carboxytherapy, chemical peeling, and vitamin C mesotherapy all effectively reduced periorbital pigmentation, though mesotherapy was less tolerable.
Asilian A, et al., 2021[25]	Iran	RCT-Split face	Carboxytherapy and PRP	21	8	The study concluded that both PRP and carboxytherapy resulted in insignificant changes.
Assaf, et al., 2022[26]	Egypt	RCT - Split face	Carboxytherapy and Microneedling with topical Glutathione	31	13	Carboxytherapy showed significantly greater VAS improvement and higher patient satisfaction than microneedling with glutathione during both treatment and follow-up.
Behrangi E, et al., 2022[27]	Iran	RCT	Fractional CO2 laser therapy and Fractional CO2 laser + PRP treatments	100	26	Adding PRP to CO₂ laser reduced periorbital hyperpigmentation by 25% with erythema resolving faster.
Budania A, et al., 2020[28]	India	RCT - Split face	Novel PRP and Conventional PRP	21	13	Both novel and conventional PRP significantly improved DLQI and reduced VAS scores from baseline.
Dayal S, et al., 2019[29]	India	RCT	20% glycolic acid peeling, 15% lactic acid peeling and 12% ferulic acid peeling	90	13	All three peels significantly reduced under-eye hyperpigmentation, with glycolic acid showing the greatest improvement over lactic and ferulic acid.
Diab H., et al., 2021[30]	Egypt	Split face	PRP and Plasma gel	40	16	PRP and plasma gel were both effective for periorbital rejuvenation, with plasma gel showing better improvement. However, neither significantly reduced melanin concentration. Both treatments were well tolerated.
El-Tahlawi S, et al., 2022[31]	Egypt	Split face	PRP injections and Carboxytherapy	23	16	The study concluded that PRP was more effective and tolerable than carboxytherapy for treating periorbital dark circles; both treatments had high patient and doctor satisfaction, with no significant difference in pain during the procedure.
Ellabban, et al., 2019[32]	Egypt	RCT	Peeling agent: TCA 3.75% + LA 15% and Autologous PRP injections	42	6	Chemical peeling showed significantly better results than PRP, reporting good improvement and most were very pleased to be extremely satisfied.
Fabi S, et al., 2023[33]	USA	RCT	VYC-15L and Placebo	135	52	At 3- and 12-month post-treatment, most VYC-15L patients were satisfied, not bothered by dark circles, and would recommend the treatment.
Ghandehari, et al., 2020[34]	Iran	Clinical trial - Split face	Tranexamic acid + CO2 Laser and Tranexamic acid + Microneedling	30	13	The laser-treated side showed significantly greater improvement in infraorbital hyperpigmentation by day 60. By day 150, both sides showed similar improvement.
Hamdi H, et al., 2022[35]	Iran	RCT	Artemisia extract eye cream and placebo eye cream	60	8.6	The Artemisia absinthium eye cream group showed greater improvements than placebo, with larger reductions in color difference, erythema and melanin, as well as a greater increase in lightness.
Iranmanesh, et al., 2024[36]	Iran	RCT - Split Site	Intradermal injection of PRP and Intradermal injection of tranexamic acid + Vitamin C	18	13	PRP favored for showing higher satisfaction score.
Kadry A, et al., 2023[37]	Egypt	RCT	PRP and Autologous Fat	30	24	Autologous fat treatment was significantly more effective than PRP in improving periorbital hyperpigmentation.
Khan I, et al., 2023[38]	Pakistan	RCT	PRP and carboxytherapy	50	12	PRP had more excellent responders but higher pain scores than carboxytherapy.
Lu Y, et al., 2024[39]	China	RCT	PRP injection after Q-switched ruby laser treatment and Q-switched ruby laser only	30	36	The combined PRP + Q-switched ruby laser treatment showed greater and longer-lasting improvements in hyperpigmentation, and patient satisfaction compared to laser alone.
Nilforoushzadeh M, et al., 2020[40]	Iran	Split face	Fractional Er: YAG laser treatment + PRP and Fractional Er: YAG laser treatment	32	24	Fractional Er:YAG laser with PRP significantly reduced melanin index and VAS scores, while the laser alone only improved VAS scores.
Nilforoushzadeh M, et al., 2021[41]	Iran	RCT	carboxytherapy and Q-switched Nd:YAG laser.	28	13	Both treatments significantly reduced melanin index and improved VAS scores, but carboxytherapy showed greater VAS improvement than Q-switched Nd:YAG laser.
Nofal E. et al., 2018[42]	Egypt	RCT-Split face	PRP and carboxytherapy	30	20	PRP and carboxytherapy have similar efficacy for periorbital hyperpigmentation, but PRP causes more severe, persistent side effects, while carboxytherapy has milder, transient ones and is better tolerated.
Ohshima H, et al., 2009[43]	Japan	Clinical trial - Split face	ANa, Placebo, and AG + placebo	14	26	ANa significantly reduced EI compared to vehicles, while vitamin C and AG showed no significant difference in EI change. MI changes were not significantly different for vitamin C.
Phoo Mon N, et al., 2025[44]	Thailand	RCT-Split face	Andrographis paniculata extract cream And Placebo cream	19	12	Andrographis paniculata cream significantly improves skin elasticity, and reduces hyperpigmentation without harmful side effects, while placebo showed no significant improvement.
Ranjan R, et al., 2016[45]	India	RCT	4% hydroquinone And 30% salicylic acid peel	50	13	Both hydroquinone and salicylic acid significantly improved VAS scores and reduced DLQI.
Roohaninasab M, et al., 2024[46]	Iran	RCT	Nanofat + SVF Nanofat + PRP Nanofat + Nd:YAG laser Nanofat only	30	12	Combined nanofat injections with SVF, PRP, or 1064-nm Q-switched Nd:YAG laser significantly outperformed nanofat alone in reducing under-eye darkness. Specifically, nanofat + PRP improved complete and dermal density, while nanofat + laser enhanced color and dermal thickness.
Roshdy O, et al., 2021[47]	Egypt	RCT	carboxytherapy 30 ml/mn and carboxytherapy 60 ml/mn	80	6	Both standard and high dose carboxytherapy significantly reduced melanin and erythema indices.
Shalash A, et al., 2023[48]	Egypt	RCT	Bilateral injection of PRP gel, Bilateral intradermal injection of CO2 with carboxytherapy machine And Intradermal injection of vitamin C	30	8	PRP and vitamin C significantly improved PODC grading, while carboxytherapy did not; however, no significant differences were found between the three groups.
Wu X, et al., 2022[49]	China	Prospective - Split face	Microneedle Fractional Radiofrequency And no treatment	22	24	Microneedling improved periorbital hyperpigmentation without reducing melanin index, while placebo showed no significant effects.
Yu C, et al., 2020[50]	China	RCT- Split face	Phenylethyl resorcinol gel + nano-microneedle, Phenylethyl resorcinol gel, Placebo gel + nano-microneedle and Placebo gel	20	16	Phenylethyl resorcinol gel, especially when combined with nano-microneedling, significantly reduced melanin index, whereas placebo and microneedling alone did not.
Zaheri, et al., 2022[51]	Iran	RCT - Split face	Sub-cutaneous or intradermal injection of pure carbon dioxide as carboxytherapy and Fractional CO2 laser therapy	30	4	Fractional CO2 laser therapy is a better treatment with fewer side effects than carboxytherapy, but larger studies are needed to confirm this.
Zamanian A, et al., 2017[52]	Iran	RCT	Microneedling + TCA and CO2 Laser	51	27	CO2 Laser showed higher levels of satisfaction on fifth visit and higher response to treatment. However, only in with this intervention was notice side effects such as erythema and irritation.
AG: Ascorbic Acid Glucoside, ANa: Sodium Ascorbate, DLQI: Dermatology Life Quality Index, LA: Lactic Acid, PODC: presumably post-operative pain and dysfunction, SVF: Stromal Vascular Fraction, TCA: Trichloroacetic acid, YAG Laser: Yttrium Aluminum Garnet Laser and VAS: Visual Analog Scale.

3.3 Risk of bias.

We evaluated the risk of bias in 27 RCTs using RoB 2.0 tool[14]. Of these, 6 studies (22%) were deemed high risk of bias, 7 (26%) had some concerns, and 14 (52%) were deemed low risk (Fig. 2). 4 non-randomized studies were assessed with ROBINS-I V2 tool[15], 1 study (25%) showed a moderate risk of bias and 3 studies (75%) were considered low risk (Fig. 2A). Overall, 55% of studies were high quality, 26% moderate quality, and 19% low quality.

3.4 Meta analysis

The planned network meta-analysis was not feasible because the identified studies did not form a connected network, with multiple isolated intervention nodes and no shared comparators. Consequently, single-arm meta-analyses were performed instead.

3.4.1 > 50% improvement

In this meta-analysis, data were synthesized from 30 studies encompassing a total of 718 participants. The pooled proportion of successful outcomes across all interventions was 0.51 (95% CI: 0.38 to 0.65; I² = 77.4%; Fig. 2A). The prediction interval ranged from 0.09 to 0.92. The funnel plot revealed asymmetry suggestive of potential publication bias (Fig. 3A). Egger’s test was not performed due to the inclusion of fewer than ten studies per subgroup. Subgroup analysis by intervention type demonstrated significant differences among treatment modalities (χ²₁₇ = 87.10, p < 0.01). Carboxytherapy alone yielded a pooled proportion of 0.50 (95% CI: 0.27 to 0.73; I² = 74.8%), indicating moderate heterogeneity across included studies. In contrast, CO₂ laser demonstrated a pooled proportion of 0.68 (95% CI: 0.45 to 0.85) with no observed heterogeneity (I² = 0%). Both interventions contributed to the overall model and were associated with favorable response rates.

3.4.2 > 75% improvement

In this meta-analysis, data were synthesized from 31 studies comprising a total of 646 participants. The pooled proportion of successful outcomes across all interventions was 0.24 (95% CI: 0.18 to 0.31; I² = 53.4%; Fig. 2B). The prediction interval ranged from 0.08 to 0.52. The funnel plot demonstrated asymmetry suggestive of potential publication bias (Fig. 3B). Egger’s test was not conducted due to the small number of studies within individual subgroups. Subgroup analysis by intervention type revealed statistically significant differences (χ²₁₁ = 27.48, p < 0.01). Among the interventions with multiple observations, platelet-rich plasma (PRP) demonstrated a pooled proportion of 0.27 (95% CI: 0.11 to 0.52; I² = 71.0%), indicating high variability across studies. In contrast, carboxytherapy showed a more consistent pooled effect of 0.26 (95% CI: 0.17 to 0.37; I² = 15.3%), suggesting homogeneity among included studies. Both interventions contributed substantially to the overall model and showed clinically meaningful effects, with PRP showing wider confidence intervals due to greater heterogeneity.

3.4.3 Visual Analogue scale

In this meta-analysis, we included 12 studies with a combined total of 266 participants. The pooled mean VAS score across all interventions was 4.89 (95% CI: 4.22 to 5.57; I² = 95.7%; Fig. 2C). The prediction interval ranged from 2.23 to 7.56. The funnel plot demonstrated asymmetry suggestive of potential publication bias (Fig. 3C). Egger’s test was not conducted due to the small number of studies within individual subgroups. Subgroup analysis revealed significant differences in treatment efficacy (χ²₇ = 172.28, p < 0.01). PRP demonstrated a pooled VAS of 4.77 (95% CI: 3.12 to 6.43; I² = 95.8%), while carboxytherapy yielded a pooled score of 4.69 (95% CI: 3.97 to 5.40; I² = 67.4%). Both interventions showed clinically significant improvements, although substantial heterogeneity was observed, particularly within the PRP subgroup.

3.4.4 Melanin Index

In this meta-analysis, we included 17 studies with a combined total of 285 participants. The pooled mean melanin index across all interventions was 165.73 (95% CI: 141.76 to 189.69; I² = 97.7%; Fig. 2D). The prediction interval ranged from 62.47 to 268.99. The funnel plot demonstrated asymmetry suggestive of potential publication bias (Fig. 3D). Egger’s test was not conducted due to the small number of studies within individual subgroups. Subgroup analysis revealed significant differences in melanin index outcomes among treatment modalities (χ²₁₃= 251.41, p < 0.01). Placebo-treated groups exhibited the highest pooled melanin index at 207.91 (95% CI: 104.81 to 311.02; I² = 98.1%), while carboxytherapy showed a substantially lower pooled index of 75.23 (95% CI: 23.41 to 127.04; I² = 97.7%). Both subgroups contributed significantly to the overall model. Notably, heterogeneity was high in both groups.

3.4.5 Erythema Index

In this meta-analysis, we included 11 studies with a combined total of 207 participants. The pooled mean erythema index across all interventions was 333.20 (95% CI: 240.64 to 425.76; I² = 99.5%; Fig. 2E). The prediction interval ranged from − 29.09 to 695.49. The funnel plot demonstrated asymmetry suggestive of potential publication bias (Fig. 3E). Egger’s test was not conducted due to the small number of studies within individual subgroups. Subgroup analysis revealed significant differences in erythema scores among treatment modalities (χ²₁₀ = 2014.17, p < 0.01). Platelet-rich plasma combined with laser demonstrated the highest pooled erythema index at 394.40 (95% CI: 380.92 to 407.88), while carboxytherapy high dose showed the lowest pooled value at 41.09 (95% CI: 28.58 to 53.60). Both subgroups contributed substantially to the overall model, high level of heterogeneity was observed.

3.4.6 Patient Satisfaction: Good or > 50%

This meta-analysis included 36 studies with 814 participants. The pooled proportion of successful outcomes across all interventions was 0.59 (95% CI: 0.51 to 0.67; I² = 64.5%; Fig. 2F), with a prediction interval of 0.25 to 0.86. Funnel plot asymmetry suggested potential publication bias (Fig. 3F). Egger’s test was not conducted due to the small number of studies within individual subgroups. Subgroup analysis by intervention type revealed statistically significant differences (χ²₂₂ = 65.75, p < 0.01). Carboxytherapy demonstrated a pooled efficacy of 0.52 (95% CI: 0.38 to 0.66; I² = 32.8%). PRP yielded a pooled proportion of 0.43 (95% CI: 0.24 to 0.64; I² = 63.1%), reflecting moderate heterogeneity. Vitamin C achieved a pooled effect of 0.64 (95% CI: 0.11 to 0.96; I² = 0.00%) with no heterogeneity, TCA combined with lactic acid peeling showed a pooled proportion of 0.72 (95% CI: 0.00 to 1.00; I² = 76.1%), with substantial heterogeneity and imprecise confidence intervals.

3.4.7 Patient Satisfaction: Excellent or > 75%

This meta-analysis included 31 studies with 684 participants. The pooled success rate was 0.24 (95% CI: 0.17 to 0.32; I² = 64.6%; Fig. 2G), with a prediction interval od 0.05 to 0.63. Funnel plot asymmetry suggested potential publication bias (Fig. 3G). Egger’s test was not performed due to few studies per subgroup. Subgroup analysis by intervention type revealed statistically significant differences (χ²₂₁ = 64.6, p < 0.01). Carboxytherapy demonstrated a pooled efficacy of 0.21 (95% CI: 0.07 to 0.47; I² = 56.4%), indicating moderate heterogeneity. PRP yielded a pooled proportion of 0.18 (95% CI: 0.11 to 0.28; I² =0.00) and TCA combined with lactic acid peeling showed a pooled proportion of 0.20 (95% CI: 0.00 to 1.00; I² = 72.5%), though the wide confidence interval and high heterogeneity suggest greater uncertainty in the estimated effect.

This systematic review and meta-analysis evaluate POH treatments using clinical improvement thresholds. Carboxytherapy showed a pooled proportion of 0.50 (95% CI: 0.27 to 0.73; I² = 74.8%), indicating that half of the treated patient achieved > 50% clinical improvement. CO₂ yielded a pooled proportion of 0.68 (95% CI: 0.45 to 0.85), suggesting greater efficacy with consistent results and no observed heterogeneity (I² = 0%). Similarly, trends toward > 75% improvement were observed with carboxytherapy 0.26 (95% CI: 0.17 to 0.37; I² = 15.3%) and PRP (0.27; 95% CI: 0.11 to 0.52; I² = 71.0%). These findings align with a prior meta-analysis conducted by Mohammad A. et al, who reported good (50–75%) responses with PRP and carboxytherapy, and excellent (> 75%) improvement with chemical peel and PRP, though the latter was based on a single study. VAS outcomes, improved with carboxytherapy, laser, PRP both alone and combined with laser. Subgroup analysis showed similar VAS score reductions for PRP (pooled VAS reduction of 4.77) and carboxytherapy (4.69) suggesting a decrease in pain after either treatment. The comparable magnitudes may reflect distinct but similarly effective mechanisms given that PRP promotes collagen synthesis, angiogenesis, and epidermal regeneration, whereas carboxytherapy induces transient hypoxia triggering vasodilation and neovascularization [54]. Heterogeneity, particularly for PRP likely reflects variability in preparation methods, treatment protocols, patient population and subjectivity of VAS scoring, limiting comparability.

In our qualitative synthesis both carboxytherapy and laser reduced melanin index. Subgroup analysis confirmed this with placebo showing the highest pooled melanin index and carboxytherapy the lowest. However high heterogeneity suggests variability in treatment effects. Regarding erythema index, significant reduction was seen with high dose carboxytherapy achieving the lowest value pooled proportion when compared to PRP, which achieved the highest pooled proportion. The substantial heterogeneity observed may reflect differences in treatment depth, inflammatory response and procedural variables. Although Mohammad A. et al, attempted to assess erythema in a previous meta-analysis, inconsistent reporting across the included studies limited the strength of their conclusions [53]. Patient satisfaction was evaluated; for “good” satisfaction (> 50% improvement), carboxytherapy (pooled efficacy of 0.52; low heterogeneity), PRP (pooled proportion of 0.43; moderate heterogeneity), vitamin C (pooled effect of 0.64; no heterogeneity) and TCA + lactic acid peeling (pooled proportion of 0.72; high heterogeneity). These results emphasize the subjective improvement by patients, particularly with carboxytherapy. Compared to analysis by Mohammad A., where laser therapies ranked the highest in-patient satisfaction[53]. For excellent satisfaction (> 75% improvement), carboxytherapy yield a pooled efficacy of 0.21 with moderate heterogeneity, followed by PRP (pooled proportion of 0.18) with no heterogeneity and TCA + lactic acid (pooled proportion of 0.20) which exhibited a wide confidence interval and high heterogeneity. A similar pattern was reported by Mohammad A. et al, where combination therapies, particularly laser, yielded the highest satisfaction, followed by peels, PRP, laser alone, and carboxytherapy[53]. Despite some discrepancies, our findings consistently support PRP, carboxytherapy, and chemical peels as effective options, reinforcing their relevance in clinical practice.

Currently, no standard guidelines exist for POH management. Topical agents remain most common due to availability and ease of use. For stronger effects, chemical peels are employed, though outcomes vary by skin type. Laser therapies show clinical benefit and patient satisfaction, but efficacy and safety depend on patient selection and device parameters[6], [54]. Newer non-invasive options such as PRP and carboxytherapy demonstrate promising efficacy, particularly in vascular subtypes. For structural causes, invasive approaches like fillers or blepharoplasty may be more effective. Dermoscopic subtype identification is essential for individualized care. Beyond aesthetics, POH impacts emotional well-being, underscoring the need for patient-centered treatment.

Strength and limitations

This review synthesizes evidence from 31 studies, including 11 not assessed in prior reviews, and is among the first to quantitatively evaluate outcomes such as melanin and erythema index. It provides new insights into treatment efficacy and adverse effects of POH therapies. However, a network meta-analysis was not feasible, as initially intended, due to insufficient direct and indirect comparisons. Heterogeneity in study design and the absence of a standardized classification for POH subtypes further limit comparability. Treatments target different etiologies (vascular, pigmentary, structural), underscoring the need for a consistent subtype classification to enable subtype-specific outcomes and head-to-head trials. Our definition of “excellent” response was revised from ≥ 90% to ≥ 75% improvement to align with most studies and maintain analytical consistency. Despite these limitations, this review strengthens the evidence base for novel non-invasive therapies, though rigorous trials with standardized subtype definitions and longer follow-up are still needed.

Our meta-analysis synthesizes evidence on clinical improvement. Findings suggest carboxytherapy and PRP, alone or combined, offer favorable efficacy and safety. Despite heterogeneity, results support non-invasive therapies in POH management. Future studies should use standardized subtype classifications and monitor adverse events to strengthen evidence. This review highlights the importance of individualized, patient-centered approaches and the potential of safe treatments to address both the cosmetic and psychological burden of POH.

POH — Periorbital hyperpigmentation

PIH — Post-inflammatory hyperpigmentation

QOL — Quality of life

PRP — Platelet-rich plasma

VAS — Visual analog scale

I. Funding: This research was not funded by any special agency.

II. Conflict of interest: All authors declare no conflict of interest. All authors read and approved the final manuscript.

III. Availability of data and materials: All the data used to perform this analysis is publicly available in the referenced articles. The rest of the material is at the author's disposition upon reasonable request.

Availability of data and materials: All data used in this analysis are publicly available in the cited articles. Additional materials are available from the corresponding author upon reasonable request.

IV. Ethics approval: Given that this meta-analysis utilized previously published data from studies that had already obtained ethics approval and consent to participate, no additional ethics approval or consent was required for this research.

Ethics approval and consent to participate: This study is a systematic review and meta-analysis that synthesized data from publicly available studies which had already received ethics approval and participant consent. No additional ethical approval or consent was required.

V. Consent to participate: Not applicable.

VI. Consent for publication: All authors have provided their consent for publication.

VII. Code availability: At the author's disposition upon reasonable request.

VIII. Author contributions:

o Ernesto Calderon Martinez: Conceptualization, literature search, data extraction, statistical analysis, project supervision and administration, writing, review and editing.

o Camila Sanchez Cruz: Conceptualization, project supervision and administration, writing, review and editing.

o Salma Beltran Covarrubias: Statistical analysis, writing original draft.

o Alejandro Chen Liang: Writing original draft, general project tasks, visualization, data analysis.

o Montserrat Villa Sanchez: Writing original draft, general project tasks, visualization, data analysis.

o Yeison Cruz Castillo: Consensus reviewer in study selection, data extraction, methodology, writing original draft.

o España De la Rosa Valdez: Idea validation, independently selected studies, data analysis.

o Angelo Magallanes Bajana: Independently selected studies , assessment of risk of bias, data analysis.

o Frances Marie Mejia: Reviewing and editing of original manuscript.

o Rovin Picavia: Reviewing and editing of original manuscript.

6. Acknowledgements

Not applicable.

7. Statements of Ethics

Competing interests: The authors declare no competing interests.

Funding: This research was conducted without any external funding.

8. Author’s contributions:

S.B.C.: Statistical analysis, consensus reviewer assessment of risk of bias, writing original draft.

A.M.B.: Methodology, writing original draft, data analysis.

E.D.V: Idea validation, general project tasks, visualization.

A.C.L.: Independently selected studies, assessment of risk of bias, writing original draft, data analysis.

M.V.S.: Independently selected studies, assessment of risk of bias, methodology, writing original draft.

Y.C.C.: Consensus reviewer in study selection, data extraction, methodology, writing original draft.

F.M.M.: Writing & Editing, Supervision

R.P.: Writing, Review and editing.

C.S.C.: Project supervision, assisting with general project tasks.

E.C.M.: Conceptualization, literature search, data extraction, statistical analysis, project supervision and administration, writing, review and editing.

All authors read and approved the final manuscript.

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No competing interests reported.

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Treatments in Periorbital Hyperpigmentation: A Systematic Review and Single-Arm Meta- Analysis of Clinical Trials

Status:

Version 1

Abstract

Figures

1. Introduction

2. Methodology

2.1. Eligibility criteria: Type of study, participants, and intervention

2.1.1. Outcomes

2.1.2. Searching methods

2.1.3. Selection of studies

2.1.4. Data extraction

2.1.5. Assessment of risk of bias in included studies

2.1.6. Statistical analysis

3. Results

3.1 Study selection

3.2 Characteristics of included studies

3.3 Risk of bias.

3.4 Meta analysis

3.4.1 > 50% improvement

3.4.2 > 75% improvement

3.4.3 Visual Analogue scale

3.4.4 Melanin Index

3.4.5 Erythema Index

3.4.6 Patient Satisfaction: Good or > 50%

3.4.7 Patient Satisfaction: Excellent or > 75%

4. Discussion

5. Conclusion

Abbreviations

Statements and declarations

References

Additional Declarations

Supplementary Files

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