Safety and Efficacy of Trichloroacetic Acid Peels in the Treatment of Melasma: A Split-face, Randomized, Prospective Trial in Latin American Women

J Clin Aesthet Dermatol. 2024;17(9):28–32.

by Deyson Lorenzo-Rios, MD; Gabriel Arias Berrios, MD; Grecia I. Cruz Goytía, BS; Sofía Laguna Rocafort, BS; and Cristina N. Brau Javier, MD

Drs. Lorenzo-Rios, Arias Berrios, and Brau Javier are with the Department of Dermatology at the University of Puerto Rico School of Medicine in San Juan, Puerto Rico. Ms. Cruz Goytía is with Florida International University in Miami, Florida. Ms. Laguna Rocafort is with the University of the Sacred Heart in San Juan, Puerto Rico.

ABSTRACT: Background. There is controversy on the efficacy and safety of chemical peels used to treat Hispanic women with melasma. Studies evaluating superficial peels for melasma are limited due to lack of controls, blinding or objective assessment tools, poor inclusion of darker phototypes, and small sample number. Objectives: We sought to evaluate the safety and efficacy of trichloroacetic acid (TCA) peels when added to hydroquinone and tretinoin in the treatment of melasma in Hispanic women.

Methods: A single blinded, prospective, split-face trial of superficial TCA peels was performed on Hispanic women with melasma. Topical hydroquinone and tretinoin were used on both sides. A total of four monthly peels were performed on one side. The relative reduction of melasma severity was evaluated using narrowband reflectance spectrophotometry (NRS), Modified Melasma Area and Severity Index (mMASI), and Global Melasma Severity Assessment (GMSA). Adverse events were monitored.

Results. Thirty-three patients completed the study. Pigment intensity was reduced on both sides based on all measures. A greater improvement of mMASI and GMSA was achieved on the peeled side.

Limitations: Limitations include the single-center study design with one blinded investigator. Conclusion: Based on our results, TCA peels appear to be safe and effective in augmenting treatment response on melasma patients with phototypes III and IV treated with hydroquinone and tretinoin.

Keywords: Melasma, trichloroacetic acid, superficial chemical peels, Latin American women, Hispanic women, post-inflammatory hyperpigmentation

Introduction

Melasma is a multifactorial disorder of hyperpigmentation affecting over five million patients in the United States, with a high prevalence among Latino females in Southern states.¹ Centrofacial melasma is the most common type of melasma and has been shown to cause significant psychological distress and limited quality of life in these patients.¹

Broad spectrum sunscreens are the mainstay of treatment to prevent worsening of melasma.² Topical therapy with hydroquinone (HQ) and retinoid-based products are first line treatments for melasma.³ HQ is a tyrosinase inhibitor used to treat disorders of hyperpigmentation as monotherapy or combined with other topical agents, such as retinoids. Tretinoin can potentially inhibit tyrosinase and accelerate epidermal turnover and disperse pigment granules in keratinocytes.⁴ Despite having demonstrated some benefit in the treatment of melasma, these agents usually take several months to yield visible improvement of hyperpigmentation. Some patients can have melasma that is resistant to treatment and frequently relapses upon discontinuation of therapy.^5,6  

Superficial chemical peels may be a beneficial treatment for patients who do not respond to topical hypopigmenting agents alone.⁷ The addition of chemical peels to a topical regimen provides a more rapid response to treatment in some patients.^7,8 Superficial peeling agents remove the stratum corneum, thereby removing some pigment and enhancing the penetration of topical hypopigmenting agents. Chemical peels are an attractive treatment option for patients, as they are an affordable in-office procedure, quick in achieving results, and the patient can return to daily activities immediately after the procedure.⁹

The role of peeling agents in melasma is controversial. Several studies have reported improvement with superficial peeling agents, especially when combined with daily hypopigmenting therapy, whereas others have shown variable results.^7,10–12 Unfortunately, most studies evaluating superficial peeling agents for melasma lack controls, blinding, objective tools of evaluation, or inclusion of darker skin types. Furthermore, many are limited by the number of subjects.^3,13 Commonly studied superficial peeling agents include salicylic acid, lactic acid, glycolic acid, and TCA. Among these, the latter two agents have the most evidence for effectiveness.³ 

The safety of chemical peels and potential development of post-inflammatory hyperpigmentation (PIH) has been a concern in darker skin types. However, most studies investigating the safety of TCA peels in the treatment of melasma have found the procedure to be safe.^8,14,15  

The aim of the study is to evaluate the safety and efficacy TCA peels as a therapeutic alternative to augment treatment response in Latin American women with skin types III to V with melasma treated with HQ and tretinoin.

Methods

This study was approved by the University of Puerto Rico Institutional Review Board and all patients gave written informed consent. Inclusion criteria included Latin American women of age 21 years and older with bilateral moderate to severe facial melasma. The latter was clinically confirmed at the time of screening by our principal investigator. Only patients with epidermal or mixed (epidermal and dermal) melasma based on Wood’s light examination were enrolled.

Exclusion criteria included pregnancy, breastfeeding, use of HQ within three months prior to study initiation, or prior treatment with isotretioin, surgery, lasers, peels, microdermabrasion or microneedling within six months of study initiation. Patients with a history of immunosuppressive disease, radiotherapy over treatment area, or allergy to TCA were also excluded.

Interventions. Patients applied HQ 4% cream to both sides of the face twice daily and tretinoin 0.025% cream every night throughout the duration of the study. Use of the two topical agents were paused three days prior to and seven days after each peel. The side to be peeled by the non-blinded investigator was randomly chosen by coin flip and was not revealed to the blinded evaluator throughout the study. A superficial TCA peel was performed by the nonblinded investigator to one side of the face on Weeks 0, 4, 8 and 12. TCA 15% was used for the first peel and TCA 20% on all subsequent peels. All patients with history of oral herpes simplex virus (HSV) were treated with valacyclovir on the day of treatment. An additional full-face peel was offered to patients at the end of the study (Week 16).  

Patients were asked to come with their faces washed. The side of the face to be peeled was wiped with isopropyl alcohol. A small fan was directed at the face. TCA was applied to the side of the face to be peeled using a cotton swab until a level I frost (erythema with streaky frost) was achieved. The face was then rinsed with cold water and a moisturizing sunblock was applied (Elta MD UV Physical®). 

Participants were asked to use gentle soap and moisturizers at home. No other topical treatments were allowed other than HQ cream and tretinoin cream. Subjects were instructed to wear and reapply SPF 30 or greater sunscreen daily and to avoid sun exposure, outdoor activities, or intense heat throughout the study period. Hat use when outdoors was encouraged.

Variables. Efficacy was defined as a relative reduction on melasma severity on the peeled side of the face when compared to the unpeeled side at Week 16.  The degree of pigmentation was measured on the peeled and unpeeled sides using a Narrowband Reflectance Spectrophotometer (NRS; Mexameter MX-16, Courage and Khazaka, Cologne, Germany). Three measurements on each side were collected at Weeks 0, 4, 8 12 and 16. The measurements were taken on the darkest area of each cheek and three repeated measures were taken on the same spot at each visit. Photographs were taken at Weeks 0 and 16.

Subjective evaluation of melasma severity was performed by scoring the modified Melasma Area and Severity Index (mMASI) by the blinded investigator at Weeks 0 and 16.¹⁶ Similarly, the blinded investigator rated the severity of melasma on each side using the Global Melasma Severity Assessment (GMSA) scoring a numerical scale from 0 to 3 (0=clear, 1=mild, 2=moderate, 3=severe) at Week 0 and 16. Both the blinded investigator and the patients were asked at Week 16 which side, if any, had more improvement and the degree of improvement (no change, slight improvement, moderate improvement, or marked improvement).  

Adverse events, including redness, burning, irritation, peeling, blistering, crusting, post inflammatory pigmentation were monitored and recorded by history and physical exam at each visit. 

Statistical considerations. A sample size of 35 subjects was estimated using a confidence interval of 95%. The average NRS mexameter reading and the average standard deviation across all the readings (33 patients, 5 timepoints, 2 sides) were calculated. The mMASI and GMSA values are presented as the mean difference between baseline and final scoring +1 standard deviation. The statistical significance of the difference in change of mMASI and GMSA between both sides was determined by a one-sided t-test based on paired data. The statistical significance of the reported data on the side of the face that improved the most according to patient and the blinded investigator was determined by a Chi-squared test.

Results 

Out of 125 screened patients, 44 were enrolled in the study. Patients were recruited from dermatology clinics in our department of dermatology and from patients calling after a media interview of one of the investigators on a local television station. Thirty-three of the 44 enrolled patients completed the study and were included in the data analysis. The remaining subjects were unable to come in for visits due to scheduling difficulties and had no adverse effects at the time of discontinuation. Patient demographic characteristics are presented in Table 1.

Figure 1 shows the NRS readings on the peeled and unpeeled side of the face throughout the duration of the study. Over the course of the study, both sides demonstrated improvement. The average improvements in NRS reading in the unpeeled and peeled sides were 51 mJ/cm² and 27 mJ/cm², respectively. The average standard deviation across all NRS measurements was 20 mJ/cm².  

mMASI scores improved on both sides (Figure 2A). On average, the peeled side displayed an average mMASI decrease of 3.05 (SD 3.45) while the unpeeled side displayed a 2.32 (SD 2.75) decrease. The difference in improvement in mMASI on the peeled side when compared with the unpeeled was 0.7 (p<0.04). 

The average differences in GMSA score at baseline and Week 16 is shown in Figure 2B for both the peeled and unpeeled sides. The GMSA improved by 0.48 (SD: 0.56) and 0.27 (SD: 0.45) on the peeled and unpeeled sides, respectively, with a difference between sides of 0.21 (p<0.003).

When asked at Week 16, which side, if any, had more improvement, the blinded investigator reported that 15 of 33 patients (45%) had better results on the peeled side of their face, 9 (27%) on the unpeeled, and 9 (27%) were identical or could not discern a difference (Figure 3A). At the same time point, 30 patients (91%) perceived greater improvement on the peeled side of their face, 2 (6%) on the unpeeled side, and 1 (3%) perceived both sides as identical or could not discern a difference. The p values for patient and investigator discerned differences were p<0.05 and p=0.22, respectively.

Figure 3B shows investigator-reported and patient-reported data on the perceived degree of improvement of each side of the face. A marked or moderate improvement on the peeled side was reported by 27 (81.8%) patients. Meanwhile, the investigator reported a marked or moderate improvement on the peeled side in 16 (48.4%) patients.  

At Week 16, all subjects were offered a full face peel if desired. All 33 patients who completed the study requested a full face peel at Week 16. Figure 4 shows clinical images of two patients who completed the study at baseline and at Week 16.

No severe adverse effects were observed during the study. Seventeen adverse effects were reported, including flare of acne (n=5), facial redness (n=4), pruritus (n=4), irritation (n=2), minor erosion (n=2), burning (n=1), and reactivation of herpes simplex (n=1). None of these lead to the discontinuation of the treatment. Acne flares resolved with a short course of oral doxycycline. 

Discussion

In this study, 33 patients were treated with TCA peels and topical HQ and tretinoin for melasma, with one side of the face serving as a control (not peeled and treated with HQ and tretinoin only). The efficacy of superficial TCA peels for the treatment of melasma was demonstrated by the relative reduction on melasma severity on the peeled side of the face when compared to the unpeeled side at Week 16. This outcome had both subjective and objective measures. Both subjective measures, mMASI and GMSA, showed improvement on both sides. However, a higher response was seen on the peeled side when compared to the unpeeled side, with a statistically significant difference in decrease in mMASI of 3.0 versus 2.3 (p<0.05), respectively. Similarly, improvement in GMSA score was significantly higher on the peeled side when compared with the control (0.48 vs. 0.27; p<0.003). As for the objective measure, the NRS readings demonstrated improvement on both sides throughout the duration of the study. However, the average improvement in NRS reading was greater on the unpeeled side than the peeled side (51 vs. 27 mJ/cm²). Nonetheless, a significant measure dispersion was observed, which is reflected in the  high standard deviation of 20 mJ/cm² among all values. The spot where the three repeated measurements were taken each visit was in the darkest melasma zone of the middle of the cheek. It is possible that different areas were measured at subsequent visits as these were neither tattooed nor precisely placed, possibly resulting in reading variability between visits. However, other studies comparing the NRS device used in this study (Mexameter MX-16) to other devices have concluded that the narrow-band technology of this device has shown a limited reliability especially in quantifying the darkening of the colors and it was at least two times less reproducible than other devices.^17–18 Future studies examining the reliability of this device would be of importance as there are limited objective tools to evaluate outcomes in the treatment of melasma. 

Ninety-one percent of the patients reported a greater improvement on the peeled side and 100 percent of them requested an optional full-face peel at their last visit. A sunk-cost bias could motivate treated subjects to pursue a more evident improvement on the peeled side. In addition, peels not only treat melasma, but also improve skin luminosity and texture, which could have also motivated the participants to opt for a final full-face peel. 

Topical hydroquinone and retinoid-based products remain the gold standard for melasma treatment. Tranexamic acid has become very popular recently and data has shown promising results in patients who are good treatment candidates.¹⁹ Sun protection and heat avoidance are key to prevent melasma flares. Yet, there are patients who either have more treatment-resistant melasma or who are interested in additional therapy to speed up progress; for those patients, our results suggest that TCA chemical peels are a safe option to consider. 

In this study, we showed that TCA chemical peels not only augment the response to melasma treatment, but are also safe in skin types III and IV. Despite the propensity of the Hispanic population to pigmentation, PIH was not encountered in the study, reassuring the safety of superficial TCA peels as a treatment alternative for melasma. 

Limitations. Our study was limited to a single center and one blinded investigator. The lack of consistency in NRS device measurements and reading location precision also limited the reliability of the objective measures. Variations in treatment adherence and the application of the topical agents by the patient could have also affected the study. Nonetheless, the authors believe these variations reflect the reality of outpatient melasma treatment. 

Conclusion

Our study results support TCA peels as a safe treatment for melasma in Latin American women with skin types III and IV. TCA peels can be effectively used to augment treatment response on melasma patients treated with tropical hydroquinone and tretinoin. 

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